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Purpose: : Several studies have shown that patients with Alzheimer’s Disease (AD) have a significantly increased rate of glaucoma occurrence. The purpose of the study was to evaluate the frequency of glaucoma and changes of the optic... more
Purpose: : Several studies have shown that patients with Alzheimer’s Disease (AD) have a significantly increased rate of glaucoma occurrence. The purpose of the study was to evaluate the frequency of glaucoma and changes of the optic nerve head (ONH) morphology and/or retinal nerve fiber layer (RNFL) thickness in patients with AD. Methods: : 94 eyes of AD subjects and 127 eyes from age-matched controls underwent a complete eye examination including measurements of IOP, central corneal thickness and visual field testing using a Matrix FDT. ONH and RNFL assessment was performed both by slit lamp biomicroscopy and HRT III examination. The diagnosis of glaucoma was based on the presence of at least two of the following criteria: visual field defects characteristic of or compatible with glaucoma, specific ONH alterations and/or changes of HRT parameters. Results: : The Glaucoma Probability Score and Moorfields Regression Analysis (Mann Whitney U test: 0,004 and 0,001, respectively) and HRT3 stereometric parameters Rim Vol, RNFL thickness (ANOVA Tests of Between-Subjects Effects: 0,039 and 0,001, respectively) resulted significantly different along with the Matrix parameters MD (ANOVA: 0,001), PSD and GHT (Mann Whitney U test: 0,001 and 0,001 respectively) in patients with AD compared to the controls. The IOP mean value resulted to be significantly reduced (ANOVA: 0,001) in AD compared to controls. The frequency of glaucoma in AD patients (25,5 %) was significantly higher than in control group (5,5%) (p= 0.001). Conclusions: : The study confirmed that patients with AD have a higher frequency of glaucoma in the absence of elevated IOP levels. HRT III seems to be an useful tool in detecting ONH and RNFL changes in AD patients.
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We have studied Mongolian gerbils using somatosensory evoked potentials (SEP) recordings before, during and after an ischemic event. In six experimental animals, cerebral ischemia was reproduced by clamping both carotid arteries for ten... more
We have studied Mongolian gerbils using somatosensory evoked potentials (SEP) recordings before, during and after an ischemic event. In six experimental animals, cerebral ischemia was reproduced by clamping both carotid arteries for ten minutes. Two recordings were made during this period at 4' and 8'. An additional four recordings were made after removal of the clamp at 4', 8', 12' and 20'. Four animals were utilized as a control group, and were subjected to the identical experimental protocol, with the exclusion of carotid artery clamping. During ischemia we observed an evident alteration of the SEP recordings in the experimental animals, and a more or less rapid recovery during the post-ischemic period. This experimental model may be useful for the monitoring and the evaluation of the evolution of cerebro-vascular damage during the post-ischemic period.
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Dear Sirs, Although the origin of MS remains elusive, several studies have focused on different genetic-environmental factors; in particular, the role of Epstein–Barr Virus (EBV) infection and virus-triggered immunopathology have been... more
Dear Sirs, Although the origin of MS remains elusive, several studies have focused on different genetic-environmental factors; in particular, the role of Epstein–Barr Virus (EBV) infection and virus-triggered immunopathology have been investigated.1–2 We report on a 64-year-old male presenting with fever, lethargy, stiff neck, left-trigeminal and right-facial nerves deficit, astasia, sensory loss in lower limbs, hypotonic and areflexic paraparesis. CSF analysis showed lymphocytic and mononuclear pleocytosis, amplifiable EBVDNA and EBV IgM and IgG. Brain MRI was unremarkable; spinal MRI showed a diffuse T2-weighted high-signal intensity (T2HSI) along the thoracic cord with gadolinium enhancement, and lumbosacral impingement of nerve roots and meninges. The patient achieved a full recovery after intravenous (i.v.) therapy with acyclovir 10 mg/kg t.i.d. and methylprednisolone 1000 mg/day. Combined clinical, CSF and MRI findings led to the diagnosis of encephalomyelomeningoradiculitis related to EBV infection. After a long period of total well-being, the patient presented two acute episodes of lower limbs sensory-motor deficit and severe sphinteric retention. The episodes were separated by a considerable time and each was followed by almost complete recovery. Neurological examination showed in both episodes brisk tendon reflexes in the lower limbs, bilateral Babinski sign and clonus in Achilles tendon reflexes. On both occasions normal cell count and mild increment of protein, lactate and IgG were detected in the CSF, but intrathecal synthesis of oligoclonal bands (OCBs) was unexpectedly evident at the immunoelectrofocusing. Virology from CSF and serum, as vasculitic and rheumatological screens, was negative. Brain and spinal MRI documented the progressive increment in size and number of T2HSI lesions, not evident previously. Somatosensory and visual evoked potentials (SEPs; VEPs) showed bilateral delay of the P40, N20 and P100 waves. In both episodes, a five-day treatment with i.v. methylprednisolone 1000 mg/day produced a full recovery, except for a residual numbness in the feet and sphinteric retention. Therefore, episodes were notably associated to: i) neuraxis-MRI documenting the progressive dissemination in time and space of the white matter lesions; ii) CSF intrathecal synthesis of OCBs; iii) altered evoked potentials; iv) response to i.v. corticosteroids. On this evidence the diagnosis of a demyelinating process occurring after an EBV neuraxis infection was postulated. MS aetiology is still unknown, but one of the most interesting conjectures is that MS may be primed and perpetuated by a neurotropic agent, possibly a virus, in genetically susceptible subjects, suggesting that a virus may initiate or trigger immunopathological demyelinating processes.1 Different neurotropic viruses have been variously invoked as the possible cause of MS and EBV is considered the outstanding candidate.2 In fact, there is ample documentation that a history of symptomatic primary EBV infection increases the risk of developing MS; moreover, it has been recently hypothesized that EBV can promote inflammatory processes by activating innate immune responses, for example IFNα production,3 although these data are still debated.4 The present case documents a clear relationship between an EBV-CNS infection and the subsequent development of a CNS demyelinating process, probably due to an immunological cross-reaction, showing clinical and paraclinical features in agreement with the McDonald criteria for MS diagnosis.5 Hence, we propose that EBV should be considered as playing a possible crucial role as a trigger in the pathogenesis of demyelinating processes.
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Here we investigated the effect of the rivastigmine patch alone on depression in 50 mild... more
Here we investigated the effect of the rivastigmine patch alone on depression in 50 mild Alzheimer's disease (AD) patients with comorbid major depressive episode (MDE). First diagnosis acetyl-cholinesterase inhibitor and psychoactive drug-free outpatients (n=50) were recruited in memory clinics and reassessed after 3 and 6 months. Global cognitive functioning, depressive symptoms and MDE frequency were evaluated with the Mini Mental State Examination, the CERAD Dysphoria scale and the modified DSM-IV criteria for MDE in AD. MDE frequency reduced significantly from the first diagnostic visit (100%) to the 6-month follow-up (62%). We also found a significant reduction in CERAD Dysphoria scores that decreased from 6.2±3.9 mean±standard deviation to 4.9±4.5 at the 6-month follow-up. In AD patients with MDE rivastigmine alone can have a positive impact on depressive phenomena. Thus, future controlled study are justified to definitively verify if rivastigmine alone may improve depression in AD.
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Oxcarbazepine (OCBZ) is the keto-analogue of carbamazepine (CBZ). In humans, OCBZ is rapidly and almost completely metabolized to 10, 11-dihydro-10-hydroxy-CBZ (GP 47779), the main metabolite responsible for the... more
Oxcarbazepine (OCBZ) is the keto-analogue of carbamazepine (CBZ). In humans, OCBZ is rapidly and almost completely metabolized to 10, 11-dihydro-10-hydroxy-CBZ (GP 47779), the main metabolite responsible for the drug's antiepileptic activity. The corticostriatal pathway is involved in the propagation of epileptic discharges. We characterized the electrophysiological effects of GP 47779 on striatal neurons by making intracellular recordings from corticostriatal slices. GP 47779 (3-100 microM) produced a dose-dependent inhibition of glutamatergic excitatory postsynaptic potentials (EPSPs). This effect was not coupled either with changes of the membrane potential of these cells or with alterations of their postsynaptic sensitivity to excitatory amino acids (EAA) suggesting a presynaptic site of action. GP 47779 reduced the current-evoked firing discharge only at concentrations > 100 microM. GP 47779 did not affect the presynaptic inhibitory action of adenosine, showing that presynaptic adenosine receptors were not implicated in the GP 47779-mediated reduction of corticostriatal EPSPs. Our data indicate that GP 47779 apparently acts directly on corticostriatal terminals to reduce the release of EAA, probably by inhibiting high-voltage-activated (HVA) calcium (Ca2+) currents (described in the accompanying article). The inhibitory action of GP 47779 on corticostriatal transmission may contribute to the antiepileptic effects of this drug.
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To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. In a group... more
To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. In a group of 34 HP-infected, motor-fluctuating patients with PD, the short-term (1-week) and long-term (3-month) beneficial effect of HP eradication (n = 17) was investigated in a double-blind fashion in comparison with a generic antioxidant treatment (n = 17), by means of pharmacokinetic, clinical, and gastrointestinal assessments. Results were compared with placebo treatment. Differently from the antioxidant-treated patients, the HP-eradicated patients showed a significant increase of l-dopa absorption, which was coupled with a significant improvement of clinical disability and with a prolonged "on-time" duration, whereas gastritis/duodenitis scores significantly decreased in line with a better l-dopa pharmacokinetics. These data demonstrate a reversible Helicobacter pylori (HP)-induced interference with l-dopa clinical response related to the impaired drug absorption, probably due to active gastroduodenitis. Therefore, the authors suggest that HP eradication may improve the clinical status of infected patients with Parkinson disease and motor fluctuations by modifying l-dopa pharmacokinetics.
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OBJECTIVE: To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations.... more
OBJECTIVE: To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. METHODS: In a group of 34 HP-infected, motor-fluctuating patients with PD, the short-term (1-week) and long-term (3-month) beneficial effect of HP eradication (n = 17) was investigated in a double-blind fashion in comparison with a generic antioxidant treatment (n = 17), by means of pharmacokinetic, clinical, and gastrointestinal assessments. Results were compared with placebo treatment. RESULTS: Differently from the antioxidant-treated patients, the HP-eradicated patients showed a significant increase of l-dopa absorption, which was coupled with a significant improvement of clinical disability and with a prolonged "on-time" duration, whereas gastritis/duodenitis scores significantly decreased in line with a better l-dopa pharmacokinetics. CONCLUSIONS: These data demonstrate a reversible Helicobacter pylori (HP)-induced interference with l-dopa clinical response related to the impaired drug absorption, probably due to active gastroduodenitis. Therefore, the authors suggest that HP eradication may improve the clinical status of infected patients with Parkinson disease and motor fluctuations by modifying l-dopa pharmacokinetics
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CHAPTER 17 Manganese Toxicity: A Critical Reappraisal Patrizia Vernole, Maria Morello, Giuseppe Sancesario, Alessandro Martorana, Giorgio Bernard!, Antonella Canini, Palma Mattioli ABSTRACT Manganese is ... 1991; Jouve et al., 1975; Kimes... more
CHAPTER 17 Manganese Toxicity: A Critical Reappraisal Patrizia Vernole, Maria Morello, Giuseppe Sancesario, Alessandro Martorana, Giorgio Bernard!, Antonella Canini, Palma Mattioli ABSTRACT Manganese is ... 1991; Jouve et al., 1975; Kimes and Morris, 1973; Mullen et al ...
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Twenty-six metals and the oxidative status in 71 patients affected by Parkinson's disease and 44 healthy individuals were compared in order to identify potential biomarkers of the disease. In the patients, the following significant... more
Twenty-six metals and the oxidative status in 71 patients affected by Parkinson's disease and 44 healthy individuals were compared in order to identify potential biomarkers of the disease. In the patients, the following significant imbalances were found (p < or = 0.05): i) in serum, an increment of Ca, Mg, Ni, Si and V, and a decrement of Cd, Co, Fe, Li, Sn, Zn and Zr; ii) in blood, raised levels of Co, Li, Ni and Si and decreased of Al, Be, Ca, Cd, Fe, Mg, Mo, Sn, Zn and Zr; iii) increased formation of oxidant species and lowered anti-oxidant capacity (p < or = 0.001 for both). Barium, Bi, Cr, Cu, Hg, Mn, Pb, Sb, Sr, Tl and W did not change with the disease. The best discriminating variables between patients and controls were Cd, Co, Fe, Ni and Si in serum (91.2% of cases correctly classified), and Al, Cd, Co, Fe, Mo and Si in blood (98.2% of cases properly classified).
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In the overall scenario of precision medicine, we propose a novel paper-based lab-on-a-chip to deliver a cost-effective and easy to use sensing tool for customized administration of drugs in Alzheimer's disease. Among several drugs,... more
In the overall scenario of precision medicine, we propose a novel paper-based lab-on-a-chip to deliver a cost-effective and easy to use sensing tool for customized administration of drugs in Alzheimer's disease. Among several drugs, we designed the device for evaluating the efficacy of compounds (e.g. physostigmine, rivastigmine, donepezil) which are able to inhibit in a reversible way the cholinesterase enzyme. Because cholinesterase activity is peculiar to each patient, the administration of customized amount of the drug can improve the treatment efficacy and the quality of patient life, avoiding side effects due to the overdosage. In detail, we exploited Vivid™ Plasma Separation membrane to threat the whole blood sample, filter paper to load the reagents needed for the measurement, and office paper to print electrodes able to measure the butyrylcholinesterase activity, delivering a reagent free analytical tool. The calibration curve of butyrylcholinesterase obtained in blood sample provided linearity between 2 and 12 U/mL, with sensitivity of 0.050 ± 0.004 μA mL/U. The physostigmine, rivastigmine, and donepezil inhibition activities toward the butyrylcholinesterase enzyme were also measured in blood sample with linearity up to respectively 0.5 μM, 25 μM, 30 μM, and detection limits of 0.009 μM, 0.4 μM, 0.3 μM. These results demonstrate the capability of paper-based origami sensors as point of care devices to customize the drug administration in Alzheimer's disease.
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Involvement of metals in the risk of developing Parkinson&amp;amp;#39;s disease (PD) has been suggested. In the present study, concentration of metals in cerebrospinal fluid (CSF), blood, serum, urine and hair of 91 PD patients and 18... more
Involvement of metals in the risk of developing Parkinson&amp;amp;#39;s disease (PD) has been suggested. In the present study, concentration of metals in cerebrospinal fluid (CSF), blood, serum, urine and hair of 91 PD patients and 18 controls were compared. Blood and hair were microwave digested, while CSF, serum and urine were water-diluted. Elements quantification was achieved by Inductively Coupled Plasma Atomic Emission Spectrometry and Sector Field Inductively Coupled Plasma Mass Spectrometry. Some metal imbalances in PD were observed: i), in CSF, lower Fe and Si; ii), in blood, higher Ca, Cu, Fe, Mg and Zn; iii), in serum, lower Al and Cu; iv), in urine, lower Al and Mn, higher Ca and Fe; and v), in hair, lower Fe. The ROC analysis suggested that blood Ca, Fe, Mg and Zn were the best discriminators between PD and controls. In addition, hair Ca and Mg were at least 1.5 times higher in females than in males of patients and controls. A decrement with age of patients in hair and urine Ca and, with less extent, in urine Si was observed. Magnesium concentration in CSF decreased with the duration and severity of the disease. Elements were not influenced by the type of antiparkinsonian therapy. Variation in elements with the disease do not exclude their involvement in the neurodegeneration of PD.
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Unilateral 6-hydroxydopamine-induced lesions of the substantia nigra have been used as an experimental model for Parkinson&#39;s disease. Although the biochemical and the behavioural effects of striatal denervation have been widely... more
Unilateral 6-hydroxydopamine-induced lesions of the substantia nigra have been used as an experimental model for Parkinson&#39;s disease. Although the biochemical and the behavioural effects of striatal denervation have been widely characterized, the physiological and pharmacological changes caused by dopamine depletion at the cellular level are still unknown. We studied the electrical activity of single rat striatal neurons recorded intracellularly in vitro from a brain slice preparation. Recordings were obtained at different periods after the denervation (4, 6, 8 months). In dopamine-denervated slices, unlike naive slices, most of the neurons showed spontaneous depolarizing postsynaptic potentials. The percentage of cells showing spontaneous depolarizing postsynaptic potentials was maximal 4 months after the denervation. In most of the dopamine-denervated neurons (60%) spontaneous depolarizing postsynaptic potentials were reversibly blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), an antagonist of non-N-methyl-D-aspartate glutamate receptors. In some neurons, however, the amplitude of spontaneous depolarizing postsynaptic potentials was reduced by bicuculline (30 microM) suggesting that they were mediated by the release of endogenous gamma-aminobutyric acid (GABA). Intrinsic membrane properties (membrane potential, input resistance and firing pattern) and postsynaptic responses to different agonists of excitatory amino acid receptors were not altered in neurons recorded from dopamine-depleted slices. In dopamine-depleted slices, unlike in naive slices, LY 171555 (0.1-10 microM), a D2 dopamine receptor agonist, reduced the frequency and the amplitude of CNQX-sensitive spontaneous depolarizing postsynaptic potentials and reduced the amplitude of glutamate-mediated synaptic potentials evoked by cortical stimulation. LY 171555 did not affect the membrane responses to exogenous glutamate. SKF 38393 (3 microM), a D1 dopamine receptor agonist, decreased postsynaptic excitability of striatal neurons recorded from naive animals. On the contrary, this agonist was ineffective in most of the cells obtained from dopamine-depleted slices. These results suggest that dopamine-denervation augments neuronal excitability in the striatum. Abnormal excitability of striatal neurons is not caused by changes of the intrinsic membrane properties of these cells, but is the result of increased glutamatergic cortical inputs to the striatum. Dopamine-denervation also alters the physiological responses to dopamine receptor stimulation. Nigral lesions induce supersensitivity of D2 dopamine receptors controlling the release of glutamate and reduce the inhibitory influence of D1 receptors at postsynaptic level. These functional changes of the striatal neurons may alter the output signals from the striatum to the other structures of the basal ganglia and then produce most of the physiopathological changes observed in Parkinson&#39;s disease.
Research Interests: Chemistry, Electrophysiology, Medicine, Dopamine, Brain, and 14 moreAnimals, Male, Substantia nigra, Quinpirole, Denervation, Rats, Stimulation, Wistar Rats, Tetrodotoxin, Action Potentials, Nerve Conduction Velocity, Corpus striatum, Psychology and Cognitive Sciences, and Medical and Health Sciences
Research Interests: Neuroscience, Cognitive Science, Motor Learning, Long Term Potentiation, Biology, and 15 moreMedicine, Neurodegenerative Diseases, Dopamine, Animals, Neuronal Plasticity, Central Nervous System, Animal Model, Acetylcholine, Neurons, Long Term Depression, Basal ganglia, Membrane Potential, High Sensitivity, cyclic GMP, and Nerve degeneration
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The distribution of 3H-spiroperidol binding sites within rabbit superior mesenteric artery was studied in normal as well as 6-hydroxydopamine (6-OHDA) sympathectomized animals using a histoautoradiographic technique. The labelled drug was... more
The distribution of 3H-spiroperidol binding sites within rabbit superior mesenteric artery was studied in normal as well as 6-hydroxydopamine (6-OHDA) sympathectomized animals using a histoautoradiographic technique. The labelled drug was located in the three layers of the artery (adventitia, media and intima), with the greater density in the media. In the adventitia the radiolabelled drug was located at the level
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Frailty is an evolving concept that is generally defined in biomedical or psychosocial terms. It is not necessarily related to a specific single disease process. Passing by the theories of Selye (1936) on the exhaustion of the General... more
Frailty is an evolving concept that is generally defined in biomedical or psychosocial terms. It is not necessarily related to a specific single disease process. Passing by the theories of Selye (1936) on the exhaustion of the General Adaptation Syndrome,until reaching to the studies of Fried (2001) who, firstly, proposed diagnostic criteria for frailty, in this paper are explored different ways to understand this concept, until endeavour to give a possible modern view. The definition of a frailty syndrome characterized by a multi-system reduction in ?reserve capacity? remains widely accepted.
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Research Interests: Endocrinology, Positron Emission Tomography, Medicine, Cerebrospinal Fluid, Brain, and 13 moreHumans, Internal Medicine, Glucose, Default Mode Network, Clinical Sciences, Aged, Carbohydrate metabolism, Reproducibility of Results, Radiopharmaceuticals, Sensitivity and Specificity, Lactic Acid, Alzheimer Disease, and Tissue distribution
To investigate, in patients with Alzheimer&#39;s Disease (AD), the possible interplay linking alteration of neuronal energy metabolism, as measured via cerebrospinal fluid (CSF) lactate concentration, to severity of AD... more
To investigate, in patients with Alzheimer&#39;s Disease (AD), the possible interplay linking alteration of neuronal energy metabolism, as measured via cerebrospinal fluid (CSF) lactate concentration, to severity of AD neurodegenerative processes and impairment of cognitive abilities. In this study we measured and correlated CSF lactate concentrations, AD biomarker levels (τ-proteins and β-amyloid) and Mini-Mental State Examination (MMSE) score in a population of drug-naïve patients with AD ranging from mild (MMSE≥21/30) to moderate-severe (MMSE&lt;21/30) cognitive decline. They were compared to healthy controls and patients with vascular dementia (VaD). Patients with AD (n=145) showed a significant increase of CSF lactate concentration compared to controls (n=80) and patients with VaD (n=44), which was higher in mild (n=67) than in patients with moderate-severe AD (n=78). Moreover, we found, in either the whole AD population or both subgroups, a CSF profile in which higher CSF levels of t-τ and p-τ proteins corresponded to lower concentrations of lactate. We verified the occurrence of high CSF lactate levels in patients with AD, which may be ascribed to mitochondria impairment. Hypothesising that τ proteins may exert a detrimental effect on the entire cellular energy metabolism, the negative correlation found between lactate and τ-protein levels may allow speculation that τ toxicity, already demonstrated to have affected mitochondria, could also impair glycolytic metabolism with a less evident increase of lactate levels in more severe AD. Thus, we suggest a dynamic relationship between neuronal energy metabolism, τ proteins and cognitive decline in AD and propose the clinical potential of assessing CSF lactate levels in patients with AD to better define the neuronal brain metabolism damage.
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To the Editor: A late-onset myopathic variant of phosphofructokinase (PFK) deficiency has been described in rare patients of Ashkenazic descent1,2 and proposed as a possible unique disorder on the basis of ethnic and genetic... more
To the Editor: A late-onset myopathic variant of phosphofructokinase (PFK) deficiency has been described in rare patients of Ashkenazic descent1,2 and proposed as a possible unique disorder on the basis of ethnic and genetic considerations.3 A recent article published by Sivakumar et al.4 provides elements to question this hypothesis. These authors described three patients from two generations of an Ashkenazi Jewish family with a partial PFK deficiency and late-onset muscle weakness. A surprising feature of these patients was that, despite a partial (33%) muscle PFK activity detected in vitro, they presented with all the clinical features of complete PFK deficiency, including lifelong exercise intolerance, hyperuricemia, and hemolysis. …
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The etiology of Parkinson's disease (PD) is still not fully clear, but several studies have implicated metals as cofactors of risk. To assess a potential]imbalance in the trace elements concentration of hair of subjects affected by... more
The etiology of Parkinson's disease (PD) is still not fully clear, but several studies have implicated metals as cofactors of risk. To assess a potential]imbalance in the trace elements concentration of hair of subjects affected by PD, the content of Al, Ba, Cd, Co, Cr, Hg, Mn, Me, Ph, Sri, Sr and Zr in 81 patients affected by PD and 17 age-matched controls was determined. Quantification of the elements was performed by inductively coupled plasma mass spectrometry. Results indicated significantly lower levels of Ph in the hair of patients (p <= 0.05) compared with controls. Manganese was slightly higher while Ba, Sri and Sr levels were lower in patients, although these differences were not significant, no variations in Al, Cd, Co, Cr, Mo and Zr levels were observed in PD. Barium and Sr in hair were higher in women than in men in both controls and patients. In addition, again Ba and Sr of patients decreased with age with a p < 0.0 1 for both elements. Finally, a decreased value of Ph with the duration and the severity of the disease and Hg with the severity duration of the pathology were observed.
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Research Interests: Immunohistochemistry, Medicine, Corticotropin Releasing Hormone, Pathophysiology, Stroke, and 15 moreInternal Medicine, Caudate Nucleus, Ischemia, Animals, Male, Brain Ischemia, Rats, Time Factors, Cerebral Blood Flow, Blood Vessel, Middle Cerebral Artery, Cerebral Infarction, Axonal transport, Middle cerebral artery occlusion, and Medical and Health Sciences
Research Interests: Endocrinology, Psychology, Chemistry, Mass Spectrometry, Medicine, and 15 moreCerebrospinal Fluid, Humans, Internal Medicine, Copper, Female, Male, Inductively Coupled Plasma Mass Spectrometry, Metals, Aged, Middle Aged, Oxidative Damage, Biological markers, Neural, Neurosciences, and Parkinson Disease
Neuroscience Department, Polyclinic Tor Vergata, V. le Oxford 81, 00133 Rome, ItalyIntroduction: Listeria innocua is widespread in food and the environment and is considered to bea non-pathogenic bacterium in healthy subjects. To date,... more
Neuroscience Department, Polyclinic Tor Vergata, V. le Oxford 81, 00133 Rome, ItalyIntroduction: Listeria innocua is widespread in food and the environment and is considered to bea non-pathogenic bacterium in healthy subjects. To date, this species has only been associatedwith human diseases in a fatal case of bacteraemia in an elderly patient. Here, we describe a caseof acute meningitis infection caused by this bacterium.Case presentation: Our patient had an increased risk of infection because of treatment withetanercept and a corticosteroid given for rheumatoid arthritis. Etanercept use has been describedpreviously as the possible cause of multiple Listeria monocytogenes infections (to date, fourcases have been described, of which two were cases of arthritis and two of meningitis), butetanercept has never been associated with L. innocua meningitis. In our case, despite rapididentification of the pathogen and proper antibiotic treatment, the patient had an unfavourableoutcome.Conclusion: To the best of our knowledge, this report constitutes the first documentation of acase of meningitis due to L. innocua, and our experience serves as a warning to microbiologistsand clinicians that L. monocytogenes is not the only Listeria sp. that can cause human meningitis.Keywords: etanercept; listeriosis; meningitis.
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Research Interests: Neuroscience, Electrophysiology, Biology, Medicine, Cerebral Cortex, and 15 moreAnimals, Metabotropic Glutamate Receptors, Brain Ischemia, Synaptic Transmission, Neurotoxins, Clinical Sciences, Rats, Huntington disease, Annals, Neurosciences, Interneurons, Glutamate Receptor, Excitatory Postsynaptic Potentials, Corpus striatum, and Kainic acid
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Research Interests: Neurology, Neurosurgery, Medicine, Stroke, Humans, and 15 moreNeuroradiology, Male, Two Stroke Engine, Clinical Sciences, Aged, Single Photon Emission Computed Tomography, Guidance and Counseling Intervention Programs, Midbrain, Neurosciences, Parkinsonism, Translation for Neurological Sciences, Functional Laterality, Neurological Sciences, parkinsonian disorders, and Mesencephalon
Without Abstract
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Parkinson’s disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein, encoded by the SNCA gene. The main neuropathological hallmark of PD is the degeneration of dopaminergic neurons leading to... more
Parkinson’s disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein, encoded by the SNCA gene. The main neuropathological hallmark of PD is the degeneration of dopaminergic neurons leading to striatal dopamine depletion. Trophic support by a neurotrophin called glial-derived neurotrophic factor (GDNF) is also lacking in PD. We performed immunohistochemical studies to investigate neuropathological changes in the basal ganglia of a rat transgenic model of PD overexpressing alfa-synuclein. We observed that neuronal loss also occurs in the dorsolateral part of the striatum in the advanced stages of the disease. Moreover, along with the degeneration of the medium spiny projection neurons, we found a dramatic loss of parvalbumin interneurons. A marked decrease in GDNF, which is produced by parvalbumin interneurons, was observed in the striatum and in the substantia nigra of these animals. This confirmed the involvement of the striatum in the pathop...
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Dystonia is a hyperkinetic movement disorder, whose pathogenesis is related to a network disfunction of basal ganglia, specifically to a disrupted equilibrium between direct and indirect pathways. Phosphodiesterase 10A (PDE10A), a key... more
Dystonia is a hyperkinetic movement disorder, whose pathogenesis is related to a network disfunction of basal ganglia, specifically to a disrupted equilibrium between direct and indirect pathways. Phosphodiesterase 10A (PDE10A), a key enzyme in the catabolism of cAMP and cGMP, is localized within Medium Spiny Neurons in the striatum and in their axon terminals in the substantia nigra pars reticulata and external globus pallidus. Therefore PDE10A may represent a map of the balance between the direct and indirect pathways in normal and pathological basal ganglia conditions. Early-onset torsion dystonia (DYT1), the most common form of dystonia, is an autosomal disease caused by a deletion in the gene encoding protein TorsinA. We investigate changes of PDE10A immunoreactivity in basal ganglia of TorsinA DYT1 mice, a transgenic model of DYT1, comparing results between control mice and mice carrying either human wilde-type torsinA(hWT) or mutant torsinA(hMT). In control mice PDE10A immunoreactivity was observed in neuronal bodies and in the neuropil throughout the caudate-putamen, in the neuropil of the globus pallidus and in substantia nigra pars reticulata. Our study revealed that PDE10A expression was increased in the globus pallidus of hWT mice, while in substantia nigra PDE10 immunoreactivity was overexpressed both in hWT mice and in hMT mice. PDE10A up-regulation may lead to a decreased activation in the indirect striatum-external globus pallidus pathway. The increase of PDE10A also in the substantia nigra suggests that dystonia may express a functional up-regulation of basal ganglia circuits both in the direct and indirect pathway
Research Interests: Neuroscience and Biology
We describe how dopamine loss can affect the catabolism of the second messenger cAMP and cGMP in the basal ganglia, pointing out that Phosphodiesterases 10A (PDE10A) may play a key role in such process. 10 weeks after dopaminergic lesion... more
We describe how dopamine loss can affect the catabolism of the second messenger cAMP and cGMP in the basal ganglia, pointing out that Phosphodiesterases 10A (PDE10A) may play a key role in such process. 10 weeks after dopaminergic lesion in the rat midbrain with 6-OHDA, the cGMP levels are decreased in all dopamine deafferented regions. However, in the same regions: a) &cAMP level show significant increase in the striatum and large variability in the globus pallidus and substantia nigra; b) conversely, cAMP levels are markedly decreased in nucleus accumbens. According to cAMP changes, mRNA and PDE10A expression are down-regulated in the striatum, and in striato-pallidal and striato-nigral projections, while PDE10A is up-regulated in the nucleus accumbens. Therefore, altered cGMP and cAMP steady-states occur in experimental parkinsonism, but only modulation of cAMP catabolism likely relies on dopamine-dependent PDE10A changes. PDE10A downregulation in neurons in the striatum, and in striato-pallidal and striatonigral terminals suggest PDE10A can be involved in dysfunctions of postsynaptic and pre-synaptic modulation of cAMP signaling and synaptic plasticity. Moreover, PDE10A up-regulation in nucleus accumbens secondary to dopamine loss suggests an involvement of PDE10A in mood disorders frequently associated with parkinsonism
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In the overall scenario of precision medicine, we propose a novel paper-based lab-on-a-chip to deliver a cost-effective and easy to use sensing tool for customized administration of drugs in Alzheimer's disease. Among several drugs,... more
In the overall scenario of precision medicine, we propose a novel paper-based lab-on-a-chip to deliver a cost-effective and easy to use sensing tool for customized administration of drugs in Alzheimer's disease. Among several drugs, we designed the device for evaluating the efficacy of compounds (e.g. physostigmine, rivastigmine, donepezil) which are able to inhibit in a reversible way the cholinesterase enzyme. Because cholinesterase activity is peculiar to each patient, the administration of customized amount of the drug can improve the treatment efficacy and the quality of patient life, avoiding side effects due to the overdosage. In detail, we exploited Vivid™ Plasma Separation membrane to threat the whole blood sample, filter paper to load the reagents needed for the measurement, and office paper to print electrodes able to measure the butyrylcholinesterase activity, delivering a reagent free analytical tool. The calibration curve of butyrylcholinesterase obtained in blood sample provided linearity between 2 and 12 U/mL, with sensitivity of 0.050 ± 0.004 μA mL/U. The physostigmine, rivastigmine, and donepezil inhibition activities toward the butyrylcholinesterase enzyme were also measured in blood sample with linearity up to respectively 0.5 μM, 25 μM, 30 μM, and detection limits of 0.009 μM, 0.4 μM, 0.3 μM. These results demonstrate the capability of paper-based origami sensors as point of care devices to customize the drug administration in Alzheimer's disease.
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Neuroinflammation is one of the hallmarks of Parkinson’s disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process... more
Neuroinflammation is one of the hallmarks of Parkinson’s disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD – to modulate disease progression – still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early...
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The term orbital pseudotumor refers to a broad category of non-specific idiopathic inflammations of the orbit. This disease, which may affect any orbital structure, is one of the commonest causes of exophtalmus, occurring with a similar... more
The term orbital pseudotumor refers to a broad category of non-specific idiopathic inflammations of the orbit. This disease, which may affect any orbital structure, is one of the commonest causes of exophtalmus, occurring with a similar incidence in both sexes. The diagnosis is based on a combination of clinical, radiological and histopathological findings, after careful exclusion of specific systemic and local diseases. Many classification systems have been proposed and a range of therapeutic modalities, including surgery, steroids, immunosuppressive agents, and radiation therapy, have been employed by various authors in heterogeneous series of patients. This slowly proliferating disease, which usually presents with a long clinical history and high variability in clinical manifestations and prognosis, is difficult to manage with any of the available therapeutic options. The difficulties and controversies regarding the diagnostic and therapeutic management of these patients are addr...
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Obstructive sleep apnea (OSA) is a common sleep disorder. The, literature lacks studies examining sleep, cognition, and Alzheimer's Disease (AD) cerebrospinal fluid (CSF) biomarkers in OSA patients. Therefore, we first studied... more
Obstructive sleep apnea (OSA) is a common sleep disorder. The, literature lacks studies examining sleep, cognition, and Alzheimer's Disease (AD) cerebrospinal fluid (CSF) biomarkers in OSA patients. Therefore, we first studied cognitive performances, polysomnographic sleep, and CSF β-amyloid42, tau proteins, and lactate levels in patients affected by subjective cognitive impairment (SCI) divided in three groups: OSA patients (showing an Apnea-Hypopnea Index [AHI] ≥15/hr), controls (showing an AHI < 15/hr), and patients with OSA treated by continuous positive airway pressure (CPAP). We compared results among 25 OSA, 10 OSA-CPAP, and 15 controls who underwent a protocol counting neuropsychological testing in the morning, 48-hr polysomnography followed by CSF analysis. OSA patients showed lower CSF Aβ42 concentrations, higher CSF lactate levels, and higher t-tau/Aβ42 ratio compared to controls and OSA-CPAP patients. OSA patients also showed reduced sleep quality and continuity a...
Research Interests: Intelligence, Cognition, Biomarkers, Medicine, Memory, and 15 moreBiological Sciences, Humans, Internal Medicine, Obstructive sleep apnea, Female, Male, Aged, Memory Disorders, Lactic Acid, Alzheimer Disease, Early Diagnosis, Continuous Positive Airway Pressure, Neuropsychological Tests, Cognitive dysfunction, and Medical and Health Sciences
Introduction - Phosphodiesterase-10A (PDE10A), a key enzyme in the catabolism of cAMP in the striatum, is increased in some striatal neurons but decreased in others, throughout the dorsolateral striatum in a transgenic mouse model of DYT1... more
Introduction - Phosphodiesterase-10A (PDE10A), a key enzyme in the catabolism of cAMP in the striatum, is increased in some striatal neurons but decreased in others, throughout the dorsolateral striatum in a transgenic mouse model of DYT1 Dystonia (hMT). We hypothesized that PDE10A either increases or decreases selectively in specific populations of striatal neurons of hMT mice. We undertook a double labelling immunohistochemical study of PDE10A and enkephalin (Enk)-containing neurons, which project to the lateral segment of GP giving rise to the “indirect” pathway. Methods - Free floating sections of the striatum were incubated with a PDE10A mouse monoclonal antibody, and with rabbit anti-Leucine-Enk and rabbit anti Met-Enk. Sections were subsequently incubated with goat anti rabbit cyanine Cy™2- and goat anti mouse cyanine Cy™3-conjugated secondary antibody. Results - In control mice, PDE10A immunofluorescence was observed in the vast majority of the striatal neurons with similar intensity in the cell bodies and in the neuropil. Moreover, some cell bodies were expressing a faint ENK immunofluorescence throughout the striatum, colocalizing in PDE10A positive neurons. In hMT mice, some striatal neurons were expressing ENK immunofluorescence; moreover, PDE10A immunofluorescence appeared intense in some neurons, but low in other adjacent neurons throughout the striatum. The subpopulation of striatal neurons expressing up-regulation of PDE10A in hMT mice showed complete overlap with cell bodies expressing ENK immunofluorescences. Conversely, the neurons labelled with low PDE10A immunoreactivity were completely devoid of the ENK immunoreactivity. Conclusions - Our data demonstrate opposite changes of PDE10A expression in ENK positive and ENK negative striatal neurons of hMT mice. We can speculate that such PDE10A changes in the striatum can map widespread functional impairment of striatal projections, differentially affecting the direct and indirect pathway in basal ganglia circuits of hMT mice
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Research Interests: Endocrinology, Positron Emission Tomography, Medicine, Cerebrospinal Fluid, Brain, and 13 moreHumans, Internal Medicine, Glucose, Default Mode Network, Clinical Sciences, Aged, Carbohydrate metabolism, Reproducibility of Results, Radiopharmaceuticals, Sensitivity and Specificity, Lactic Acid, Alzheimer Disease, and Tissue distribution
Research Interests: Psychology, Biomarkers, Medicine, Cerebrospinal Fluid, Humans, and 15 moreInternal Medicine, Sleep Deprivation, Female, Male, Orexins, Clinical Sciences, Polysomnography, Aged, Orexin, Rem Sleep, Neurobiology of Aging, Alzheimer Disease, Neurosciences, Cognitive dysfunction, and Pittsburgh Sleep Quality Index
Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances on amnestic mild cognitive... more
Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances on amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 y. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which was associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI has a positive effect on hippocampus atrop...
Research Interests: Clinical Psychology, Cognitive Science, Magnetic Resonance Imaging, Medicine, Episodic Memory, and 15 moreHippocampus, Humans, Female, Male, Clinical Sciences, Aged, Middle Aged, Longitudinal Studies, Analysis of Variance, Chi Square Distribution, Geriatrics and Gerontology, Neuroprotective Agents, Hippocampal formation, Neuropsychological Tests, and Cognitive dysfunction
SummaryImpaired amyloid beta (Aβ) metabolism is currently considered central to understand the pathophysiology of Alzheimer's disease (AD). Measurements of cerebrospinal fluid Aβ levels remain the most useful marker for diagnostic... more
SummaryImpaired amyloid beta (Aβ) metabolism is currently considered central to understand the pathophysiology of Alzheimer's disease (AD). Measurements of cerebrospinal fluid Aβ levels remain the most useful marker for diagnostic purposes and to individuate people at risk for AD. Despite recent advances criticized the direct role in neurodegeneration of cortical neurons, Aβ is considered responsible for synaptopathy and impairment of neurotransmission and therefore remains the major trigger of AD and future pharmacological treatment remain Aβ oriented. However, experimental and clinical findings showed that Aβ peptides could have a wider range of action responsible for cell dysfunction and for appearance of clinico‐pathological entities different from AD. Such findings may induce misunderstanding of the real role played by Aβ in AD and therefore strengthen criticism on its centrality and need for CSF measurements. Aim of this review is to discuss the role of CSF Aβ levels in li...
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ABSTRACT In most forms of dystonia the brain regions primary affected are thought to have functional rather than structural abnormalities. We report that changes of Phosphodiesterase-10A (PDE10A) immunoreactivity can map the involvement... more
ABSTRACT In most forms of dystonia the brain regions primary affected are thought to have functional rather than structural abnormalities. We report that changes of Phosphodiesterase-10A (PDE10A) immunoreactivity can map the involvement of the basal ganglia pathways in TorsinA DYT1 transgenic model. PDE10A, a key enzyme in the catabolism of cAMP and cGMP, has unique distribution in the basal ganglia, within medium spiny neurons in the striatum, and in their axons/terminals to the direct and indirect pathway, i.e. to the entopeduncular nucleus and external globus pallidus respectively. PDE10A was studied in control mice and in mice carrying either human wild-type torsinA or mutant torsinA. Rabbit anti-PDE10A antibody was used for immunohistochemical identification of PDE10A neurons and nerve fibers. Quantitative analysis of PDE10A expression in the different brain areas was assessed by immunohistochemistry and Western blotting. Moreover, PDE10A dependent cAMP hydrolyzing activity was assessed. Biochemical and morphological studies demonstrate that PDE10A expression and activity were clearly increased in the globus pallidus of mice carrying DYT1TorsinA mutation compared to control mice, while in the entopeduncular nucleus the PDE10A expression and activity were significantly decreased both in mice carrying wild-type human TorsinA and in mice carrying DYT1 TorsinA mutation. However, expression of PDE10A mRNA was comparable in the three groups of animals. Our study demonstrates that PDE10A may act as translational biomarker of the pathophysiology of dystonia, involving the balance between the striato-pallidal and the striato-entopeduncular pathways, which could be investigated in vivo by novel PDE10A PET ligands.
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Amantadine alleviates levodopa dyskinesias both in parkinsonian patients and in rat and monkey models of Parkinson’s disease, but the mechanisms underlying its anti-dyskinetic effects are matter of debate, acting as a NMDA and nicotinic... more
Amantadine alleviates levodopa dyskinesias both in parkinsonian patients and in rat and monkey models of Parkinson’s disease, but the mechanisms underlying its anti-dyskinetic effects are matter of debate, acting as a NMDA and nicotinic receptor antagonist as well as by increasing extracellular dopamine levels. We evaluated whether amantadine may ultimately reestablish the equilibrium of dopamine-dependent cAMP/cGMP levels which are acutely impaired in basal ganglia of levodopa dyskinetic rats. Material and methods: Hemiparkinsonian rats were daily treated with levodopa-carbidopa for 3 weeks to induce dyskinesias. Microdialysis, phosphodiesterase assay, tissues cyclic nucleotides’ evaluation, western blot were performed using standard procedures. Results: We demonstrate that amantadine can significantly increase the cAMP/cGMP levels and inhibit in vivo and in vitro cAMP-PDE activity and, to a lesser extent, cGMP-PDE activity, demonstrating its direct potential as an inhibitor of the...
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In order to sequentially explore central (CNS) and peripheral (PNS) nervous system abnormalities in experimental diabetes mellitus, neuroelectrophysiological and nervous protein biochemical changes were investigated in streptozotocin... more
In order to sequentially explore central (CNS) and peripheral (PNS) nervous system abnormalities in experimental diabetes mellitus, neuroelectrophysiological and nervous protein biochemical changes were investigated in streptozotocin diabetic Sprague-Dawley rats after 1.5, 3, 6 and 12 months from induction of diabetes. Visual (VEP), brainstem-auditory (BAEP) and somatosensory (SEP) evoked potentials were evaluated in control and diabetic rats. Advanced glycation end-product (AGE) levels were measured by spectrofluorimetry in protein extracts from central and peripheral nervous tissue samples. Mean VEP (P1 wave) and BAEP (waves I, II and III) latencies were increased whereas SEP (Tarsus-L6, L6-Cortex and T6-Cortex) conduction/propagation velocities were reduced in diabetic rats at all times (p < 0.05 to p < 0.0001), the alterations being already present after 1.5 months from diabetes induction. Similarly, AGE levels in diabetic rat protein extracts were higher than in control animals, the differences becoming statistically significant with the progression of the disease. When metabolic, neuroelectrophysiological and biochemical alterations were evaluated with time in diabetic rats, a rapid initial change was observed, and followed, in the case of the metabolic control, by steadily abnormal values and as well as, in the case of the electrophysiological and biochemical values, by a continuous slow worsening. Finally, a statistically significant association was found between electrophysiological and biochemical parameters. Thus CNS, but more so PNS, neuroelectrophysiological abnormalities and enhanced nervous protein AGE levels appear relatively early after diabetes induction and, in the presence of an altered metabolic status, are correlated and worsen over time.
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Electrophysiological studies, performed in the past several years, (Bodis-Wollner and Yahr 1978) have demonstrated visual alterations in Parkinson’s disease (PD) patients. Further studies confirmed the delay of the pattern reversal Visual... more
Electrophysiological studies, performed in the past several years, (Bodis-Wollner and Yahr 1978) have demonstrated visual alterations in Parkinson’s disease (PD) patients. Further studies confirmed the delay of the pattern reversal Visual Evoked Potential’s (VEP) (Sollazzo 1984; Tartaglione et al. 1984; Bodis-Wollner et al. 1986) major positive wave (P100). Research has proved that the cause of this delay also dependens on several parameters of the visual stimulus: the type of visual pattern (Tartaglione et al. 1984), the spatial (Onofrj et al. 1986) and temporal frequency (Marx et al. 1987), and the contrast level (Gottlob et al. 1987) (for a review see Bodis-Wollner et al. 1988). Namely, an enhanced P100 delay has been observed in PD patients, when sinusoidal grating stimuli at high spatial frequency (2–4cpd) and at low contrast levels (less then 50%) are utilized (Bodis-Wollner 1988). The physiopathologic relationship with the dopaminergic deficit of PD has been proved by several studies emphasizing the recovery of this delay during L-DOPA therapy (Bodis-Wllner and Yahr 1978; Sollazzo 1984; Bodis-Wollner et al. 1988).
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We describe a case of a patient with Creutzfeldt-Jakob disease (CJD) characterized by a rapid clinical course lasting one and a half months, by: presence of focal dystonic movements at onset, absence of mental deterioration in the period... more
We describe a case of a patient with Creutzfeldt-Jakob disease (CJD) characterized by a rapid clinical course lasting one and a half months, by: presence of focal dystonic movements at onset, absence of mental deterioration in the period preceding the impairment of consciousness, ataxia, myoclonus and periodic EEG abnormalities. The autopsy confirmed subacute spongiform encephalopathy, but no evident neuronal loss was observed. An acute clinical course of CJD may explain this latter histological finding which, in turn, probably provides an explanation for the absence of intellectual impairment.
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A 10-min bilateral carotid occlusion (BCO) in a control group of Mongolian gerbils, induced a transient generalized epileptic activity both in the hippocampal and in the cortical regions, associated with motor manifestations. After... more
A 10-min bilateral carotid occlusion (BCO) in a control group of Mongolian gerbils, induced a transient generalized epileptic activity both in the hippocampal and in the cortical regions, associated with motor manifestations. After recirculation, spiking activity persisted, reaching its maximum peak within 18-36 h and then slowly decreasing till its total disappearance on the 6th-7th day. On the 7th day, histological studies manifested a selective loss of CA1 hippocampal neurons. The treated gerbils (divided in 2 groups according to the dosage used) were administered clonazepam (CZP), a benzodiazepine receptor agonist, immediately after clamping and again every 24 h for the following three days at dosages of 0.05 and 0.1 mg/kg i.p., respectively. The drug inhibited epileptic activity in a dose-dependent manner, while it prevented CA1 neuronal loss at both doses. These results point to a possible derangement of the GABAergic system which probably in turn triggers an exaggerated excit...
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The authors describe a rare case of teratomatous cervical-dorsal-lumbar cyst. Spinal CT was of particular interest in showing lesion extension and its intramedullary and extramedullary location.
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Electrocorticographic (ECoG) activity remains isoelectric for about 15 min after transient (10 min) bilateral carotid arteries occlusion in mongolian gerbils. In this model of global forebrain ischemia N omega-Nitro-L-arginine methyl... more
Electrocorticographic (ECoG) activity remains isoelectric for about 15 min after transient (10 min) bilateral carotid arteries occlusion in mongolian gerbils. In this model of global forebrain ischemia N omega-Nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, significantly delays the recovery of ECoG amplitude. Thus, the present experiments suggest that NO is involved in the cerebrovascular physiological response to brain ischemia.
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Postural changes in 1-G environment induce well documented haemodynamic changes. On going from Earth's 1-G environment to the microgravity of space a marked cephalic blood volume shift occurs in humans with a subsequent loss of 2-3 L... more
Postural changes in 1-G environment induce well documented haemodynamic changes. On going from Earth's 1-G environment to the microgravity of space a marked cephalic blood volume shift occurs in humans with a subsequent loss of 2-3 L of fluid determined by diuresis and decreased fluid intake. Moreover, a number of transient changes in serum concentrations of sodium, potassium and calium have been observed in astronauts during spaceflight. It is conceivable that changes in the fluid status, and reduced muscle activities, which are changed by the microgravity environment, would also result in redistribution of some trace elements, such as zinc, copper and manganese. In particular, zinc metabolism, directly involved in many physiological processes, can be altered by a wide variety of factors including stress, rest, exercise, hormones and diet. Some of the microgravity-induced responses in space can be simulated in humans by using the posture of head-down tilt, and in rat by using t...
Research Interests: Chemistry, Skeletal muscle biology, Biology, Spaceflight, Medicine, and 13 moreBrain, Pubmed, Animals, Male, Zinc, Potassium, Skin, Eye, Rats, Sodium, Wistar Rats, Nose, and Weightlessness
This study evaluated local and systemic leukocyte changes, respectively in the jugular and femoral veins, after an acute reduction of cerebral blood flow (oligoemia) in rats submitted either to permanent bilateral carotid occlusion (BCO)... more
This study evaluated local and systemic leukocyte changes, respectively in the jugular and femoral veins, after an acute reduction of cerebral blood flow (oligoemia) in rats submitted either to permanent bilateral carotid occlusion (BCO) (no. = 36) for 5 hours or to sham operation (no. = 33). In a subgroup of rats (no. = 13) the extent of neural damage was histologically assessed. As a marker of biochemical brain changes the entity of the iron-ascorbate induced lipid peroxidation of synaptosomes was assessed in vitro by measuring malondialdehyde (MDA) reactive products. Five hours after surgery, the percentage of aggregated leukocytes and of activated neutrophils reducing the NBT were significantly higher in BCO rats (p < 0.05). However, leukocyte changes did not differ significantly between the jugular and the femoral districts. The brains of BCO rats showed tiny foci of neuronal necrosis. Synaptosomes obtained from the BCO animals showed a small but highly significant increase ...
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Nitric oxide (NO) has been identified as a putative neurotransmitter in choroidal perivascular nerve fibers originating parasympathetically. Although constitutively produced NO has been implicated in the regulation of the choroidal... more
Nitric oxide (NO) has been identified as a putative neurotransmitter in choroidal perivascular nerve fibers originating parasympathetically. Although constitutively produced NO has been implicated in the regulation of the choroidal circulation, the specific role of neurally derived NO in choroidal vasodilation has not been determined. This study examined the role of neurally derived NO in the control of the choroidal blood flow (ChBF) in vivo. Resting ChBF and a increase in ChBF elicited by electrical stimulation of the nucleus of Edinger-Westphal (EW) were measured transclerally by laser Doppler flowmetry in anesthetized pigeons before and after administration of a selective inhibitor of neural NO synthase, 7-Nitroindazole (7NI; 50 mg/kg given intraperitoneally); a nonselective NO synthase inhibitor, Ng-nitro-L-arginine methyl ester (L-NAME; 30 mg/kg given intravenously); L-arginine (300 mg/kg given intravenously) followed by 7NI (50 mg/kg given intraperitoneally); or vehicle. The ...
Research Interests: Endocrinology, Chemistry, Enzyme Inhibitors, Medicine, Biological Sciences, and 15 moreInternal Medicine, Hemodynamics, Blood Pressure, Nitric oxide, Animals, Neurons, Eye, Blood Flow, Columbidae, Arginine, Methyl Ester, Laser Doppler Flowmetry, Choroid, Medical and Health Sciences, and Electric stimulation
To investigate, in patients with Alzheimer&#39;s Disease (AD), the possible interplay linking alteration of neuronal energy metabolism, as measured via cerebrospinal fluid (CSF) lactate concentration, to severity of AD... more
To investigate, in patients with Alzheimer&#39;s Disease (AD), the possible interplay linking alteration of neuronal energy metabolism, as measured via cerebrospinal fluid (CSF) lactate concentration, to severity of AD neurodegenerative processes and impairment of cognitive abilities. In this study we measured and correlated CSF lactate concentrations, AD biomarker levels (τ-proteins and β-amyloid) and Mini-Mental State Examination (MMSE) score in a population of drug-naïve patients with AD ranging from mild (MMSE≥21/30) to moderate-severe (MMSE&lt;21/30) cognitive decline. They were compared to healthy controls and patients with vascular dementia (VaD). Patients with AD (n=145) showed a significant increase of CSF lactate concentration compared to controls (n=80) and patients with VaD (n=44), which was higher in mild (n=67) than in patients with moderate-severe AD (n=78). Moreover, we found, in either the whole AD population or both subgroups, a CSF profile in which higher CSF levels of t-τ and p-τ proteins corresponded to lower concentrations of lactate. We verified the occurrence of high CSF lactate levels in patients with AD, which may be ascribed to mitochondria impairment. Hypothesising that τ proteins may exert a detrimental effect on the entire cellular energy metabolism, the negative correlation found between lactate and τ-protein levels may allow speculation that τ toxicity, already demonstrated to have affected mitochondria, could also impair glycolytic metabolism with a less evident increase of lactate levels in more severe AD. Thus, we suggest a dynamic relationship between neuronal energy metabolism, τ proteins and cognitive decline in AD and propose the clinical potential of assessing CSF lactate levels in patients with AD to better define the neuronal brain metabolism damage.
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Over a period of time, the authors have studied a case of subacute sclerosing panencephalitis (SSPE), by means of brainstem auditory evoked potentials (BAEPs). The observed abnormalities of the conduction time along the early auditory... more
Over a period of time, the authors have studied a case of subacute sclerosing panencephalitis (SSPE), by means of brainstem auditory evoked potentials (BAEPs). The observed abnormalities of the conduction time along the early auditory pathways appeared to be related to the clinical picture; in fact, during periods of transitory clinical improvement these abnormalities were less evident. In addition, the encountered electrophysiological alterations consisted of a marked pathologic increase in the III-V interpeak latencies. The authors suggest that the BAEPs findings in their case could have been influenced by either unfavourable endogenous conditions (edema, electrolyte changes, etc.) or CNS segmental lesions due to focal viral distribution.
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The prognosis of "benign" intracranial hypertension (Pseudotumor cerebri) is generally favorable. In fact, the resolution of the clinical picture is related to the disappearance of the increased intracranial pressure. However,... more
The prognosis of "benign" intracranial hypertension (Pseudotumor cerebri) is generally favorable. In fact, the resolution of the clinical picture is related to the disappearance of the increased intracranial pressure. However, sometimes an irreversible visual loss can occur. The authors studied, over a period of time, seven subjects suffering from pseudotumor cerebri utilizing pattern visual evoked potentials (VEPs). Five patients showed normal VEPs latencies that remained such in the successive controls. Two patients displayed pathological P100 VEPs latencies. Such findings tended towards a progressive transient improvement following decompressive lumbar puncture. The authors suggest that the VEPs alterations in these patients could be due to the association of general (increased CSF pressure) and local (malformations, scleral canalis constrictions) ocular factors. In these circumstances, the pattern VEPs recordings could be coupled with traditional methods of evaluation ...
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The innervation pattern of parietal pericardium was studied in normal as well as chemically sympathectomized rats using the cholinesterase histochemical method. The existence of important regional variations in the distribution of... more
The innervation pattern of parietal pericardium was studied in normal as well as chemically sympathectomized rats using the cholinesterase histochemical method. The existence of important regional variations in the distribution of cholinergic nerves within various portions of parietal pericardium studied was observed. The atria appear more richly innervated than ventricles, while the innervation of atria is characterized by the existence of thin and thick cholinergic nerve fibers not organized in plexuses and of elbow-shaped acetylcholinesterase cholinergic nerve fibers. Small blood vessels and islands of adipocytes receive a cholinergic innervation as well. The chemical sympathectomy does not alter the pattern of stained cholinergic nerve fibers. A possible afferent significance of the atrial innervation is discussed.
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Research Interests: Medicine, Humans, Female, Male, Middle Aged, and 5 moreAdult, Huntington disease, Hyperkinesis, Choline, and Chorea
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Research Interests: Neurology, Neurosurgery, Medicine, Stroke, Humans, and 15 moreNeuroradiology, Male, Two Stroke Engine, Clinical Sciences, Aged, Single Photon Emission Computed Tomography, Guidance and Counseling Intervention Programs, Midbrain, Neurosciences, Parkinsonism, Translation for Neurological Sciences, Functional Laterality, Neurological Sciences, parkinsonian disorders, and Mesencephalon
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CHAPTER 17 Manganese Toxicity: A Critical Reappraisal Patrizia Vernole, Maria Morello, Giuseppe Sancesario, Alessandro Martorana, Giorgio Bernard!, Antonella Canini, Palma Mattioli ABSTRACT Manganese is ... 1991; Jouve et al., 1975; Kimes... more
CHAPTER 17 Manganese Toxicity: A Critical Reappraisal Patrizia Vernole, Maria Morello, Giuseppe Sancesario, Alessandro Martorana, Giorgio Bernard!, Antonella Canini, Palma Mattioli ABSTRACT Manganese is ... 1991; Jouve et al., 1975; Kimes and Morris, 1973; Mullen et al ...
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Research Interests: Neuroscience, Psychology, Biology, Medicine, Neuronal cell death, and 15 moreHippocampus, Ischemia, Animals, Microglia, Cell Death, Programmed cell death, Mantle Transition Zone, Rats, In Vitro Studies, Laser Scanning Microscopy, Neurosciences, Extracellular, CLSM, Hippocampal formation, and Gerbillinae
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Evaluation of sudomotor innervation to the limbs was performed via electrical stimulation of the median nerve at the wrist and transcranial magnetic stimulation of the brain. Sympathetic skin responses (SSRs) from the palms and the soles... more
Evaluation of sudomotor innervation to the limbs was performed via electrical stimulation of the median nerve at the wrist and transcranial magnetic stimulation of the brain. Sympathetic skin responses (SSRs) from the palms and the soles were recorded in a patient suffering from a form of predominantly sensory neuropathy. Motor responses to nerve stimulation were present, even if with slower than normal conduction velocity. However, median, ulnar and sural nerve sensory potentials were absent. SSRs to median nerve stimulation at the wrist were missing on palms and soles. By contrast, during brain stimulation of the hand motor area with magnetic impulses, SSRs were reliably identifiable at all recording sites. It is hypothesized that SSRs to mixed nerve stimulation need normal functionality of afferent fibers, while those to brain stimulation can be elicited without any sensory information from the limbs.
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Research Interests: Endocrinology, Chemistry, Neurochemistry, Medicine, Dopamine, and 15 moreStriatum, Internal Medicine, Caudate Nucleus, cyclic AMP, Animals, Male, Levodopa, Phosphodiesterase Inhibitors, Rats, Wistar Rats, Putamen, Neurosciences, cyclic GMP, parkinsonian disorders, and Medical biochemistry and metabolomics
1. Intracellular recordings were made from neurones in slice of rat striatum in vitro. 2. The forty-nine neurones studied were immunoreactive for choline acetyltransferase and had the electrophysiological characteristics typical of large... more
1. Intracellular recordings were made from neurones in slice of rat striatum in vitro. 2. The forty-nine neurones studied were immunoreactive for choline acetyltransferase and had the electrophysiological characteristics typical of large aspiny interneurones. 3. Focal stimulation of the slice elicited a hyperpolarizing inhibitory postsynaptic potential in thirty-five neurones. This IPSP lasted 0.5-1 s and reversed polarity at a membrane potential which was dependent on the logarithm of the extracellular potassium concentration. 4. The IPSP was reversibly blocked by scopolamine and methoctramine, which has some selectivity for M2 subtype of muscarinic receptor. It was unaffected by 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM), DL-2-amino-phosphonovaleric acid (30 microM) and bicuculline (30 microM). 5. Exogenous acetylcholine and muscarine also hyperpolarized the neurones, and this was blocked by methoctramine by not by pirenzepine, which is an M1 receptor-selective antagonist. 6. The findings demonstrate that muscarinic IPSPs occur in the central nervous system. The IPSP may mediate an &amp;amp;amp;amp;#39;autoinhibition&amp;amp;amp;amp;#39; of striatal cholinergic neurone activity.
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Pathological oscillations characterize the firing discharge of different basal ganglia (BG) stations in rat models of... more
Pathological oscillations characterize the firing discharge of different basal ganglia (BG) stations in rat models of Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. Most recent literature focused on the prominence of the beta frequency band in awake rats. Yet, in 6-hydroxydopamine-lesioned animals, the firing discharge of the globus pallidus (GP) and the substantia nigra reticulata are in phase with urethane-induced slow wave cortical activity. The neuronal basis of this pathological synergy at low frequency is widely debated. In order to understand the role of substantia nigra pars compacta (SNc) signalling in the development of pathological synchronization, we performed a pharmacological inactivation of the medial forebrain bundle (MFB) through tetrodotoxin (TTX), which led to a dramatic, but reversible, reduction of the dopamine content in the striatum. This procedure caused a significant contralateral akinesia, detectable as soon as anaesthesia vanished, and lasting about 3-4 h. We sought to determine the electrophysiological counterpart of this transient Parkinsonian-like hypokinetic syndrome. Hence, we obtained the electrocorticogram (ECoG) and single unit recordings from GP and subthalamic nucleus (STN) in normal rats before and after the TTX injection in MFB. Intriguingly, the TTX-mediated inactivation of MFB induced a fast developing coherence between cortex and GP and a significant increase of the cortex/STN synchronization. The intra-GP iontophoretic delivery of haloperidol or the GABA(A) receptor antagonist bicuculline induced a short term cortex/GP synchronization. Strikingly, STN inactivation by local muscimol reversed both haloperidol- and TTX-mediated coherence between cortex and GP. Our data show that an abnormal cortical/BG synchronization, at low frequency, can be reproduced also without SNc neuronal loss and striatal cytoarchitectonic alterations. In addition, our results, which represent an acute and reversible Parkinsonism based upon impaired cable properties, seem compatible with the interpretation of acute changes of the functional interplay between cortex and the STN-GP pathway as a key factor mechanism underlying the fast deep brain stimulation-induced acute Off-On transitions.
Research Interests: Neuroscience, Physiology, Chemistry, Medicine, Subthalamic Nucleus, and 15 moreBiological Sciences, Cerebral Cortex, Animals, Male, Substantia nigra, The, Rats, Globus Pallidus, Basal ganglia, Wistar Rats, Tetrodotoxin, Neural pathways, Bicuculline, parkinsonian disorders, and Medical and Health Sciences
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The protective effects of riluzole against the neuronal damage caused by O2 and glucose deprivation (ischemia) was investigated in rat cortical slices by recording electrophysiologically the cortico-cortical field potential and by... more
The protective effects of riluzole against the neuronal damage caused by O2 and glucose deprivation (ischemia) was investigated in rat cortical slices by recording electrophysiologically the cortico-cortical field potential and by evaluating histologically the severity of neuronal death. Five minutes of ischemia determined an irreversible depression of the amplitude of the field potential. In addition, this insult caused a clear enhancement of the number of death cells that were specifically colored with trypan blue (a vital colorant which stains altered cells). We found that riluzole, which by itself depressed the synaptic transmission, neuroprotected when perfused 15-20 min before and during ischemia. In fact, due to the treatment with riluzole, the ischemia-induced irreversible depression of the field potential recovered and less cells were stained with trypan blue. These findings demonstrate that riluzole prevents neuronal death in an in vitro model of ischemia and suggest a therapeutic use of this drug in order to reduce the pathophysiological outcomes of stroke.
Research Interests: Neuroscience, Cognitive Science, Electrophysiology, Medicine, Neuroprotection, and 15 moreGlucose, Ischemia, Animals, Cell Death, Brain Ischemia, Neurons, Glial Fibrillary Acidic Protein, Cell Survival, Neurosciences, Frontal Lobe, Cortical Spreading Depression, Neuroprotective Agents, Excitatory Postsynaptic Potentials, Cell count, and In Vitro Techniques
Within the striatum, the gaseous neurotransmitter nitric oxide (NO) is produced by a subclass of interneurons containing the neuronal NO synthase (nNOS). NO promotes the second messenger cGMP through the activation of the soluble guanyl... more
Within the striatum, the gaseous neurotransmitter nitric oxide (NO) is produced by a subclass of interneurons containing the neuronal NO synthase (nNOS). NO promotes the second messenger cGMP through the activation of the soluble guanyl cyclase (sGC) and plays a crucial role in the integration of glutamate (GLU) and DA transmission. The aim of this study was to characterize the impact of 6-hydroxyDA (6-OHDA) lesion of the rat nigrostriatal pathway on NO/cGMP system. In vivo extracellular single units recordings were performed under urethane anesthesia to avoid any potentially misleading contributions of cortically-driven changes on endogenous NO. Hence, no electrical extrastriatal stimulation was performed and great attention was paid to the effects of 3-morpholinosydnonimine (SIN-1, a NO donor), N(G)-nitro-L-arginine methyl ester (L-NAME, a nonselective NOS inhibitor) and Zaprinast (a PDE inhibitor) delivered by iontophoresis upon the main striatal phenotypes. The latter were operationally distinguished in silent medium spiny-like neurons (MSN), with negligible spontaneous activity but displaying glutamate-induced firing discharge at rest and spontaneously active neurons (SAN), representing to a large extent nonprojecting interneurons. SANs were excited by SIN-1 and Zaprinast while MSNs showed a clear inhibition during local iontophoretic application of SIN-1 and Zaprinast. In 6-OHDA animals, SIN-1-induced excitation in SANs was significantly increased (on the contrary, the inhibitory effect of L-NAME was less effective). Interestingly, in DA-denervated animals, a subclass of MSNs (40%) displayed a peculiar excitatory response to SIN-1. These findings support the notion of an inhibitory modulatory role exerted by endogenous NO on control striatal projection cells. In addition, these findings suggest a functional cross-talk between NO, spontaneously active interneurons, and projection neurons that becomes critical in the parkinsonian state.
Research Interests: Cognitive Science, Chemistry, Enzyme Inhibitors, Medicine, Dopamine, and 15 moreNitric oxide, Animals, Male, Neurons, Denervation, Microdialysis, Rats, Analysis of Variance, Action Potentials, Neurosciences, Medium spiny neurons, cyclic GMP, Glutamate Receptor, Corpus striatum, and Electric stimulation
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Research Interests: Immunohistochemistry, Medicine, Corticotropin Releasing Hormone, Pathophysiology, Stroke, and 15 moreInternal Medicine, Caudate Nucleus, Ischemia, Animals, Male, Brain Ischemia, Rats, Time Factors, Cerebral Blood Flow, Blood Vessel, Middle Cerebral Artery, Cerebral Infarction, Axonal transport, Middle cerebral artery occlusion, and Medical and Health Sciences
Research Interests: Neuroscience, Cognitive Science, Motor Learning, Long Term Potentiation, Biology, and 15 moreMedicine, Neurodegenerative Diseases, Dopamine, Animals, Neuronal Plasticity, Central Nervous System, Animal Model, Acetylcholine, Neurons, Long Term Depression, Basal ganglia, Membrane Potential, High Sensitivity, cyclic GMP, and Nerve degeneration
Research Interests: Chemistry, Enzyme Inhibitors, Medicine, Blood Pressure, Nitric oxide, and 14 moreAnimals, Anaesthesia, Male, Anesthesia, Arterial Blood Pressure, Rats, Nitric Oxide Synthase, Pharmacological, Halothane, Cerebral Blood Flow, Brain Perfusion, Laser Doppler Flowmetry, Urethane, and Pharmacology and pharmaceutical sciences
The role of some chemical elements in neurodegeneration was suggested by various authors. To obtain a profile of chemical elements and oxidative status in complex neurological diseases, an unbiased... more
The role of some chemical elements in neurodegeneration was suggested by various authors. To obtain a profile of chemical elements and oxidative status in complex neurological diseases, an unbiased &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;omics&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; approach, i.e., quantification of 26 elements and oxidative stress parameters (serum oxidative status (SOS) and serum anti-oxidant capacity (SAC)), combined with multivariate statistical procedures (forward discriminant analysis, FDA) to analyse the vast amount of data, was applied to four groups of subjects (53 patients with Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD), 71 with Parkinson disease (PD), 60 with multiple sclerosis (MS) and 124 healthy individuals). Descriptive statistics revealed numerous differences between each disease and healthy status. A concordant imbalance (reduction in Fe, Zn and SAC, and increase in SOS) was shared by AD, PD and MS. The FDA yielded three significant discriminant functions based on age, SOS, Ca, Fe, Si, Sn, V, Zn and Zr, and identified disease-specific profiles of element imbalances, thus showing the appropriateness of the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;omics&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; approach. It may help assess the contribution of chemical elements and oxidative stress to disease causation and may provide complex predictors of disease evolution or treatment response.
Research Interests: Multivariate Statistics, Free Radicals, Multiple sclerosis, Neurodegeneration, Medicine, and 15 moreDiscriminant Analysis, Humans, Elements, Female, Disease, Male, Metals, Hydrogen Peroxide, Aged, Middle Aged, Analysis of Variance, Biological markers, Chemical Elements, Alzheimer Disease, and Discriminant Function
Research Interests: Electron Microscopy, Biology, Mitochondria, Medicine, Manganese, and 15 moreNeurotoxicology, Animals, Male, Astrocyte, Glial Cell, Neurons, Rats, Globus Pallidus, Analysis of Variance, Basal ganglia, Cytoplasm, Neurosciences, Electron Energy Loss Spectroscopy, Mitochondrion, and Pharmacology and pharmaceutical sciences
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NADPH diaphorase histochemical staining was investigated in rat brain and choroid plexuses. All epithelial cells of the latter as well as some sparse neurons in striatum and cerebral cortex showed strong NADPH reaction product. While... more
NADPH diaphorase histochemical staining was investigated in rat brain and choroid plexuses. All epithelial cells of the latter as well as some sparse neurons in striatum and cerebral cortex showed strong NADPH reaction product. While staining was homogeneous in neuronal cytoplasm, it was particulate in epithelial cells. Preincubation with EDTA (0.1 mM, 2h) prevented appearance of NADPH diaphorase reaction in neurons but not in choroid plexuses. These data show that in rat brain two forms of NADPH diaphorase are present; they are specifically localized in neurons and choroidal cells, respectively.
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A 10-min bilateral carotid occlusion (BCO) in Mongolian gerbils induces transient generalized epileptic discharges in the hippocampal and cortical regions, which are followed by long lasting interictal spiking activity. An initial peak of... more
A 10-min bilateral carotid occlusion (BCO) in Mongolian gerbils induces transient generalized epileptic discharges in the hippocampal and cortical regions, which are followed by long lasting interictal spiking activity. An initial peak of this activity occurs within 18-36 h after BCO, then it decreases slowly and completely disappears by the 6th-7th day. On the 7th day, morphological evidence shows a selective loss of CA1 hippocampal neurons. 4-(3-Phosphonopropyl)-2-piperazine-carboxylic acid (CPP), a competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor was administered (7 or 15 mg/kg i.p.) immediately after clamping, and again every 12 h for 3 consecutive days. It induced a dose-related depression of epileptic activity, while, on the other hand, at both dosages, it always prevented the loss of CA1 neurons. The results are discussed in view of the different mechanisms mediating cell damage and epileptic activity.
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In the CNS, nucleotide receptors termed P2 receptors are identified on neurons and glial cells, mediating neuron-neuron, glia-glia and glia-neuron communication. In the present work, we qualify in vivo in the adult rat CNS the... more
In the CNS, nucleotide receptors termed P2 receptors are identified on neurons and glial cells, mediating neuron-neuron, glia-glia and glia-neuron communication. In the present work, we qualify in vivo in the adult rat CNS the cellular/subcellular distribution of P2Y12 receptor protein in cerebral cortex, white matter and subcortical nuclei (striatum and substantia nigra), by means of immunofluorescence-confocal, electron microscopy and Western blot analysis. P2Y12 receptor immunoreactivity colocalizes neither with markers such as neuronal nuclei, neurofilament light chain, calbindin and tyrosine hydroxylase, nor with glial fibrillary acidic protein and isolectin B4, but with myelin basic protein and the oligodendrocyte marker RIP, in both cell bodies and processes, indicating therefore oligodendrocyte localization. Electron microscopy identifies P2Y12 receptors in both the perikaryon and under the plasmalemma of oligodendrocyte cell bodies and radiating processes, until the paranodal region of fibers. By Western blot analysis, P2Y12 receptor shows a specific band of 42-44 kDa, matching the molecular mass predicted from amino acid sequencing. Since in platelets P2Y12 receptor is known to regulate adhesion/activation and thrombus growth/stability, from our results we could speculate by analogy that, in oligodendrocytes, P2Y12 receptor signaling might contribute to the migration and adhesion of the glial processes to axons to be myelinated.
Research Interests: Neuroscience, Electron Microscopy, Biology, Membrane Proteins, Immunohistochemistry, and 15 moreCell Biology, Confocal Microscopy, Medicine, Brain, Cerebral Cortex, Animals, Glial Cell, Lectins, Glial Fibrillary Acidic Protein, Amino Acid Profile, Molecular Mass, Amino Acid Sequence, Neurosciences, Light chain, and myelin basic protein
Pre-embedding electron microscopic immunocytochemistry was used to examine the ultrastructure of neurons containing nitric oxide synthase and to evaluate their synaptic relationships with target neurons in the striatum and sensorimotor... more
Pre-embedding electron microscopic immunocytochemistry was used to examine the ultrastructure of neurons containing nitric oxide synthase and to evaluate their synaptic relationships with target neurons in the striatum and sensorimotor cerebral cortex. Intense nitric oxide synthase immunoreactivity was found by light and electron microscopy in a type of aspiny neuron scattered in these two regions. The intensity of the labeling was uniform in the soma, dendrites and axon terminals of these neurons. In both forebrain regions, nitric oxide synthase-immunoreactive neurons received synaptic contacts from unlabeled terminals, which were mostly apposed to small-caliber dendrites. The unlabeled symmetric contacts were generally about four times as abundant as the unlabeled asymmetric contacts on the nitric oxide synthase-immunoreactive neurons. Terminals labeled for nitric oxide synthase were filled with synaptic vesicles and were observed to contact unlabeled neurons. Only 54% (in the cerebral cortex) and 44.3% (in the striatum) of the nitric oxide synthase-immunoreactive terminals making apposition with the target structures were observed to form synaptic membrane specializations within the plane of the randomly sampled sections. The most common targets of nitric oxide synthase-immunoreactive terminals were thin dendritic shafts (54% of the immunoreactive terminals in the cortex and 75.7% of the immunoreactive terminals in the striatum), while dendritic spines were a common secondary target (42% of the immunoreactive terminals in the cortex and 20.6% of the immunoreactive terminals in the striatum). The spines contacted by nitric oxide synthase-immunoreactive terminals typically also received an asymmetric synaptic contact from an unlabeled axon terminal. These findings suggest that: (i) nitric oxide synthase-immunoreactive neurons in the cortex and striatum preponderantly receive inhibitory input; (ii) nitric oxide synthase-containing terminals commonly make synaptic contact with target structures in the cortex and striatum; (iii) spines targeted by nitric oxide synthase-containing terminals in the cortex and striatum commonly receive an asymmetric contact as well, which may provide a basis for a synaptic interaction of nitric oxide with excitatory input to individual spines.
Research Interests: Neuroscience, Electron Microscopy, Biology, Medicine, Axon, and 15 moreCerebral Cortex, Diffusion, Nitric oxide, Animals, Peripheral Nervous System, Male, Dendrites, Container Terminal, Neurons, Nitric Oxide Synthase, Neuropeptide Y, Neurosciences, Electron Microscope, Corpus striatum, and nicotinamide adenine dinucleotide phosphate
Research Interests: Neuroscience, Biology, Immunohistochemistry, Enzyme Inhibitors, Medicine, and 15 moreImmunocytochemistry, Cerebrospinal Fluid, Nitric oxide, Animals, Choroid Plexus, Neurons, Enzyme, Nitric Oxide Synthase, IDP, Isoenzymes, NAD, Neurosciences, Blood Vessel, nicotinamide adenine dinucleotide phosphate, and Nerve fibers
The corpus callosum (CC) has been shown to be susceptible to atrophy in Alzheimer disease (AD) as a correlate of wallerian degeneration or retrogenesis. However, when and where these 2 mechanisms intervene is still unclear. In 3 memory... more
The corpus callosum (CC) has been shown to be susceptible to atrophy in Alzheimer disease (AD) as a correlate of wallerian degeneration or retrogenesis. However, when and where these 2 mechanisms intervene is still unclear. In 3 memory clinics, we recruited 38 patients with amnestic mild cognitive impairment (MCI), 38 patients with mild AD, and 40 healthy controls (HC). Combining voxel-based morphometry and diffusion tensor imaging, we investigated CC white matter (WM) density and fractional anisotropy (FA), radial diffusivity (DR), and axial diffusivity (DA). Compared with HC, patients with amnestic MCI showed reduced WM density in the anterior CC subregion; however, FA, DR, and DA did not differ between the 2 groups. Significant changes were found in patients with mild AD compared with HC in the anterior and posterior CC regions. These differences were evident in both voxel-based morphometry and diffusion tensor imaging analyses. Specifically, we found reduced callosal WM density in the genu, posterior body, and splenium; decreased FA and increased DR in the anterior CC subregion; and increased DA, with no difference in the FA, in the posterior CC subregion. Callosal changes are already present in patients with amnestic mild cognitive impairment (MCI) and mild Alzheimer disease (AD). The precocious involvement of the anterior callosal subregion in amnestic MCI extends to posterior regions in mild AD. Two different mechanisms might contribute to the white matter changes in mild AD: wallerian degeneration in posterior subregions of the corpus callosum (suggested by increased axial diffusivity without fractional anisotropy modifications) and a retrogenesis process in the anterior callosal subregions (suggested by increased radial diffusivity without axial diffusivity modifications).
Research Interests: Cognitive Science, Magnetic Resonance Imaging, Diffusion Tensor Imaging, Medicine, Anisotropy, and 15 moreDiffusion MRI, Brain Mapping, Humans, Corpus Callosum, Cerebral Cortex, Diffusion, Female, Male, Clinical Sciences, Aged, Fractional Anisotropy, Biological markers, Disease Progression, Alzheimer Disease, and Cognition disorders
To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. In a group... more
To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. In a group of 34 HP-infected, motor-fluctuating patients with PD, the short-term (1-week) and long-term (3-month) beneficial effect of HP eradication (n = 17) was investigated in a double-blind fashion in comparison with a generic antioxidant treatment (n = 17), by means of pharmacokinetic, clinical, and gastrointestinal assessments. Results were compared with placebo treatment. Differently from the antioxidant-treated patients, the HP-eradicated patients showed a significant increase of l-dopa absorption, which was coupled with a significant improvement of clinical disability and with a prolonged &amp;amp;amp;amp;amp;amp;quot;on-time&amp;amp;amp;amp;amp;amp;quot; duration, whereas gastritis/duodenitis scores significantly decreased in line with a better l-dopa pharmacokinetics. These data demonstrate a reversible Helicobacter pylori (HP)-induced interference with l-dopa clinical response related to the impaired drug absorption, probably due to active gastroduodenitis. Therefore, the authors suggest that HP eradication may improve the clinical status of infected patients with Parkinson disease and motor fluctuations by modifying l-dopa pharmacokinetics.
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Without Abstract
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Research Interests: Neurology, Magnetic Resonance Imaging, Epilepsy, Medicine, Cerebrospinal Fluid, and 15 moreHumans, Neuroradiology, Male, Magnetic Resonance, Subarachnoid hemorrhage, Recurrence, Clinical Sciences, Adult, Hiv seropositivity, Laboratory Tests, Neurosciences, Bleed, Cerebral Angiography, Magnetic resonance image, and HIV infections
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We report that the area under the curve of L-dopa plasma concentration, following the administration of a single 250 mg L-dopa dose, is augmented after Helicobacter pylori (HP) eradication in six Parkinson&#39;s disease (PD) patients... more
We report that the area under the curve of L-dopa plasma concentration, following the administration of a single 250 mg L-dopa dose, is augmented after Helicobacter pylori (HP) eradication in six Parkinson&#39;s disease (PD) patients showing high IgG antibody titer against HP. A prolongation of L-dopa clinical benefit was also observed. We suggest that HP infection-activated gastric alterations may be responsible, at least in part, for the reported erratic efficacy of oral L-dopa therapy in some advanced PD patients. Given the high percentage of HP-positivity in the age cohorts including the largest prevalence of PD patients, we propose that HP eradication be recommended in all PD patients under L-dopa therapy.
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Extracellular ATP and P2 receptors may play a crucial role in the neurodegeneration of the CNS. Here, we investigated in neuronal cerebellar granule cultures the biological effect of the quite stable P2 receptor agonist ATPgammaS and... more
Extracellular ATP and P2 receptors may play a crucial role in the neurodegeneration of the CNS. Here, we investigated in neuronal cerebellar granule cultures the biological effect of the quite stable P2 receptor agonist ATPgammaS and compare it to the cytotoxic action of ATP. Time-course experiments showed that 500 microM ATPgammaS causes 50-100% cell death in 15-24 h. As proved by pharmacological means, ATPgammaS toxicity apparently involves neither indirect activation of NMDA receptors, nor ectonucleotidase activities, nor nucleoside transport and intracellular purine metabolism. Moreover, ATPgammaS induces detrimental effects without modifying the expression of several P2X and P2Y receptor proteins. Cell death instead occurs after extracellular release of the cytosolic enzyme lactic dehydrogenase and inhibition of the overall activity of the intracellular dehydrogenases. Moreover, ATPgammaS causes transient outflow of cytochrome c from mitochondria (maximal 2.5-fold stimulation in 4 h), it raises the intracellular reactive oxygen species (about four-fold in 1 h) and cAMP levels (about 40% in 15 min-4 h). Among several P2 receptor antagonists, only pyridoxal-phosphate-6-azophenyl-2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;,4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-disulphonic acid 4-sodium promotes 80-100% neuroprotection.
Research Interests: Biology, Neurochemistry, Oxidative Stress, Medicine, Cerebellum, and 15 moreAnimals, Cell Death, Cytochrome C, Neurons, Enzyme, Cell Survival, Neurosciences, Extracellular, Nucleotides, Cerebellar Granule Neuron, Adenosine Triphosphate, Intracellular, NMDA receptor, Medical biochemistry and metabolomics, and biological effect
Research Interests: Chemistry, Biology, Neurochemistry, Medicine, Energy Metabolism, and 15 moreNeuroprotection, Cerebellum, Glucose, Animals, Neurons, Enzyme, Neuronal Death, NAD, Mitochondrial Membrane Potential, Cell Survival, Cerebellar Granule Neuron, Adenosine Triphosphate, Medical biochemistry and metabolomics, nadp, and coloring agents
Research Interests: Neurobiology Of Disease, Biology, Cell Biology, Neurobiology, Medicine, and 15 moreCell Differentiation, Humans, Cell Death, Clinical Sciences, Neuroblastoma, Neuronal Differentiation, Receptor, Div, Neurosciences, Brain Neoplasms, Nucleotides, Phase Contrast, Neurofilament proteins, Bucladesine, and biological effect
A complete survey of the immunofluorescence distribution of the cytoskeletal protein vinculin in the normal skeletal muscle and peripheral nerve of humans and of different rodent species was performed. Our results enable us to localize... more
A complete survey of the immunofluorescence distribution of the cytoskeletal protein vinculin in the normal skeletal muscle and peripheral nerve of humans and of different rodent species was performed. Our results enable us to localize vinculin in different types of adhesion plaques such as sarcolemmal costameres and neuromuscular and myotendinous junctions, but also in a fine intermyofibrillar lattice, possibly associated with intermediate filaments and/or with the triads. Moreover, we describe the presence of vinculin in junctional domains of several, previously unrecognized, specialized cells such as: the outer sheath of the muscle spindle capsule, the multilayered flat cells of the perineurium, the smooth muscle cells of epineurial blood vessels, and the endothelial cells in the endoneurium. These data call for a major role of vinculin in mechanisms of adhesion between cells, between cell and substrate and between intermyofibrillar components in the neuromuscular system. Such kn...
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Dear Sirs, Although the origin of MS remains elusive, several studies have focused on different genetic-environmental factors; in particular, the role of Epstein–Barr Virus (EBV) infection and virus-triggered immunopathology have been... more
Dear Sirs, Although the origin of MS remains elusive, several studies have focused on different genetic-environmental factors; in particular, the role of Epstein–Barr Virus (EBV) infection and virus-triggered immunopathology have been investigated.1–2 We report on a 64-year-old male presenting with fever, lethargy, stiff neck, left-trigeminal and right-facial nerves deficit, astasia, sensory loss in lower limbs, hypotonic and areflexic paraparesis. CSF analysis showed lymphocytic and mononuclear pleocytosis, amplifiable EBVDNA and EBV IgM and IgG. Brain MRI was unremarkable; spinal MRI showed a diffuse T2-weighted high-signal intensity (T2HSI) along the thoracic cord with gadolinium enhancement, and lumbosacral impingement of nerve roots and meninges. The patient achieved a full recovery after intravenous (i.v.) therapy with acyclovir 10 mg/kg t.i.d. and methylprednisolone 1000 mg/day. Combined clinical, CSF and MRI findings led to the diagnosis of encephalomyelomeningoradiculitis related to EBV infection. After a long period of total well-being, the patient presented two acute episodes of lower limbs sensory-motor deficit and severe sphinteric retention. The episodes were separated by a considerable time and each was followed by almost complete recovery. Neurological examination showed in both episodes brisk tendon reflexes in the lower limbs, bilateral Babinski sign and clonus in Achilles tendon reflexes. On both occasions normal cell count and mild increment of protein, lactate and IgG were detected in the CSF, but intrathecal synthesis of oligoclonal bands (OCBs) was unexpectedly evident at the immunoelectrofocusing. Virology from CSF and serum, as vasculitic and rheumatological screens, was negative. Brain and spinal MRI documented the progressive increment in size and number of T2HSI lesions, not evident previously. Somatosensory and visual evoked potentials (SEPs; VEPs) showed bilateral delay of the P40, N20 and P100 waves. In both episodes, a five-day treatment with i.v. methylprednisolone 1000 mg/day produced a full recovery, except for a residual numbness in the feet and sphinteric retention. Therefore, episodes were notably associated to: i) neuraxis-MRI documenting the progressive dissemination in time and space of the white matter lesions; ii) CSF intrathecal synthesis of OCBs; iii) altered evoked potentials; iv) response to i.v. corticosteroids. On this evidence the diagnosis of a demyelinating process occurring after an EBV neuraxis infection was postulated. MS aetiology is still unknown, but one of the most interesting conjectures is that MS may be primed and perpetuated by a neurotropic agent, possibly a virus, in genetically susceptible subjects, suggesting that a virus may initiate or trigger immunopathological demyelinating processes.1 Different neurotropic viruses have been variously invoked as the possible cause of MS and EBV is considered the outstanding candidate.2 In fact, there is ample documentation that a history of symptomatic primary EBV infection increases the risk of developing MS; moreover, it has been recently hypothesized that EBV can promote inflammatory processes by activating innate immune responses, for example IFNα production,3 although these data are still debated.4 The present case documents a clear relationship between an EBV-CNS infection and the subsequent development of a CNS demyelinating process, probably due to an immunological cross-reaction, showing clinical and paraclinical features in agreement with the McDonald criteria for MS diagnosis.5 Hence, we propose that EBV should be considered as playing a possible crucial role as a trigger in the pathogenesis of demyelinating processes.
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The aetiology of Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) is still unknown,... more
The aetiology of Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) is still unknown, but some hypotheses have focused on the imbalances in body levels of metals as co-factors of risk. To assess whether hair could be a reliable marker of possible changes, calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), silicon (Si) and zinc (Zn) were determined in hair from 81 patients affected by PD and 17 age-matched controls. Care was taken to eliminate external contamination of the hair by thorough washing. Digestion of the matrix was achieved by an acid-assisted microwave procedure. Quantification of the elements was performed by inductively coupled plasma atomic emission spectrometry. Results indicated significantly lower levels of Fe in the hair of patients (p=0.018) compared with controls. Ca and Mg levels were slightly lower while Zn levels were higher in patients, although these differences were not significant; neither were variations in Cu and Si. Ca and Mg were at least 1.5 times higher in females than in males in both controls and patients. In addition, Ca correlated positively with Mg in both groups and in both sexes (p-value always less than 0.03), and negatively with age in patients (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). Finally, element levels did not correlate with either the duration or the severity of the disease or with anti-Parkinson treatment.
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The in vivo diagnosis of... more
The in vivo diagnosis of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) may be facilitated by cerebro-spinal fluid (CSF) biomarkers in combination with imaging and clinical assessments. By determining the concentration of beta amyloid fragments, total tau (t-tau) and phospho-tau (p-tau), it is possible to detect the conversion of mild cognitive impairment (MCI) to AD or distinguish AD vs. pseudo-dementia. However, these markers are poorly sensitive to the progressive disease stages. And far from clear is their role in &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;mixed&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; forms of dementia, as far as hemodynamic deficits complicate the clinical history. We have studied cerebral hemodynamic impairment in AD patients, relative to control subjects. Mean flow velocity (MFV), pulsatility index (PI) and cerebrovascular reactivity (assayed as breath-holding index, BHI) were evaluated by bilateral transcranial Doppler (TCD) monitoring of middle cerebral arteries. MFV and BHI were significantly lower and PI was significantly higher in AD patients with respect to control subjects. The presence of white-matter changes (WMC) in the AD cases did not influence any of the hemodynamic variables. Noticeably, MMSE score was correlated to BHI reduction (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.005). Our results, consistent with the recent literature indicate that hemodynamic impairment is a critical marker of cognitive decline and supports once more the hypothesis of a significant pathigenic role of vascular damage in AD. Similar functional alterations might be early hallmarks in a variety of dementia subtypes, including &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;mixed&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; dementia, whose prevalence is undoubtedly increased. Assessment of hemodynamic reactivity could provide valuable correlations with individual patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s cognitive profile, which in turn would assist in the identification of critical steps in disease progression and the validation of effective therapies.
Research Interests: Cardiology, Dementia, Cognition, Magnetic Resonance Imaging, Brain, and 15 moreHumans, Internal Medicine, Hemodynamics, Female, Clinical Sciences, Aged, Clinical Assessment, Biological markers, Disease Progression, Indexation, Cognitive Decline, Alzheimer Disease, Blood Flow Velocity, Cognition disorders, and Cohort Studies
Involvement of metals in the risk of developing Parkinson&amp;amp;#39;s disease (PD) has been suggested. In the present study, concentration of metals in cerebrospinal fluid (CSF), blood, serum, urine and hair of 91 PD patients and 18... more
Involvement of metals in the risk of developing Parkinson&amp;amp;#39;s disease (PD) has been suggested. In the present study, concentration of metals in cerebrospinal fluid (CSF), blood, serum, urine and hair of 91 PD patients and 18 controls were compared. Blood and hair were microwave digested, while CSF, serum and urine were water-diluted. Elements quantification was achieved by Inductively Coupled Plasma Atomic Emission Spectrometry and Sector Field Inductively Coupled Plasma Mass Spectrometry. Some metal imbalances in PD were observed: i), in CSF, lower Fe and Si; ii), in blood, higher Ca, Cu, Fe, Mg and Zn; iii), in serum, lower Al and Cu; iv), in urine, lower Al and Mn, higher Ca and Fe; and v), in hair, lower Fe. The ROC analysis suggested that blood Ca, Fe, Mg and Zn were the best discriminators between PD and controls. In addition, hair Ca and Mg were at least 1.5 times higher in females than in males of patients and controls. A decrement with age of patients in hair and urine Ca and, with less extent, in urine Si was observed. Magnesium concentration in CSF decreased with the duration and severity of the disease. Elements were not influenced by the type of antiparkinsonian therapy. Variation in elements with the disease do not exclude their involvement in the neurodegeneration of PD.
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P2X receptors are a family of seven (P2X(1-7)) cation channels gated by extracellular ATP, widely expressed in neurons and nonneuronal cells. Lipid rafts are cholesterol/sphingolipid-rich membrane domains, involved in many cellular... more
P2X receptors are a family of seven (P2X(1-7)) cation channels gated by extracellular ATP, widely expressed in neurons and nonneuronal cells. Lipid rafts are cholesterol/sphingolipid-rich membrane domains, involved in many cellular processes, including transmembrane receptor signaling, vesicle traffic, and protein sorting. We provide direct biochemical evidence that P2X3 receptor localizes into lipid rafts, in primary cultures of cerebellar granule neurons as well as in brain and dorsal root ganglia extracts. We show that P2X3 exhibits all the characteristics distinctive of a protein associated with lipid rafts. These characteristics include resistance to detergent extraction at 4 degrees C, solubility after extraction of cholesterol from membranes with either saponin or methyl-beta-cyclodextrin, and partitioning to low buoyant density fractions after sucrose gradient centrifugation in both detergent-containing and detergent-free conditions. Furthermore, P2X3 localizes in raft-containing fractions in transiently transfected SH-SY5Y neuroblastoma cells. The present finding contributes to the characterization of the functional localization of P2X3 in neurons and provides a novel potential mechanism for correct targeting and dynamic activation of this receptor.
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Research Interests: Endocrinology, Psychology, Chemistry, Mass Spectrometry, Medicine, and 15 moreCerebrospinal Fluid, Humans, Internal Medicine, Copper, Female, Male, Inductively Coupled Plasma Mass Spectrometry, Metals, Aged, Middle Aged, Oxidative Damage, Biological markers, Neural, Neurosciences, and Parkinson Disease
Research Interests: Endocrinology, Psychology, Pathogenesis, Biology, Medicine, and 15 moreHumans, Female, Male, Phosphorylation, Plasminogen, Aged, Middle Aged, Biological markers, Alzheimer Disease, Fibrinolysis, Neurosciences, Plasminogen Activator Inhibitor, Plasminogen Activator, Neuropsychological Tests, and plasmin
In... more
In Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD), transcranial magnetic stimulation (TMS) studies have shown abnormalities of motor cortical excitability, such as a decreased intra-cortical inhibition (ICI) and changes in resting motor threshold (rMT). We studied the effects of L-dopa on rMT and ICI in a cohort of moderate AD patients after paired-pulse TMS. Results were compared with a control group of healthy subjects. As expected, AD patients showed a significant reduction in ICI and a lower rMT. L-dopa administration (soluble form, melevodopa 200 mg) promptly reversed the ICI impairment up to normalization. This effect was specific, since it was not mimicked in control subjects. These results indicate a possible role of dopamine in modulating AD cortical excitability, thus suggesting an interaction between dopaminergic ascending pathways and endogenous intracortical transmitters. In addition, considering that L-dopa showed a pharmacological profile similar to the one of cholinomimetics, L-dopa might represent a reliable tool to study new therapeutic perspective and strategies for AD.
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A 64-year-old man with idiopathic CD4(+) lymphocytopenia developed cognitive impairment and gait ataxia with isolated obstructive hydrocephalus, which was fatal. Cerebrospinal fluid showed mild pleocytosis, but the etiology was not... more
A 64-year-old man with idiopathic CD4(+) lymphocytopenia developed cognitive impairment and gait ataxia with isolated obstructive hydrocephalus, which was fatal. Cerebrospinal fluid showed mild pleocytosis, but the etiology was not revealed by extensive analysis. At autopsy, inflammatory cells, CD8(+) lymphocytes and abundant macrophages but not CD4(+) lymphocytes were infiltrating the meninges at the base of the brain. Electron microscopy demonstrated that inflammation was caused by Cryptococcus neoformans, which was localized exclusively within macrophages, where it grew with budding. Our study suggests that, in idiopathic CD4(+) lymphocytopenia, macrophages can efficiently phagocytize but inefficiently digest C. neoformans, thus representing a vehicle of chronic intracellular infection.
Research Interests: Immunology, Electron Microscopy, Biology, Medicine, Cerebrospinal Fluid, and 15 moreHydrocephalus, Humans, Cryptococcus Neoformans, Chronic Disease, Male, Differential Diagnosis, Clinical Sciences, Neurological, Middle Aged, Cognitive impairment, Meningitis, Meninges, Neurological Sciences, Lymphocytopenia, and Fatal outcome
Research Interests: Chemistry, Cryopreservation, Clinical Chemistry, Cerebrospinal Fluid, Humans, and 15 moreFemale, Male, Amyloid Beta, Clinical Sciences, Aged, Cognitive impairment, Biological markers, Low Temperature, Experimental Neurology, Alzheimer Disease, Epitopes, Enzyme Linked Immunosorbent Assay, Conformational Change, Control Group, and lumbar puncture
Research Interests: Biology, Cell Biology, Medicine, Cell line, Glutamate, and 15 moreHumans, Glucose, Animals, Cell Death, Hypoglycemia, Immunoprecipitation, Clinical Sciences, Epithelial cells, Div, Glutamic Acid, Cerebellar Granule Neuron, Biochemistry and cell biology, Cellular system, Adenosine Triphosphate, and Cell Membrane
The possible acute morphological changes induced by electrical transcranial unifocal stimulation (eTCS) in the rabbit extracerebral tissues were studied by light and scanning electron microscopy. In order to do this, a wide range of... more
The possible acute morphological changes induced by electrical transcranial unifocal stimulation (eTCS) in the rabbit extracerebral tissues were studied by light and scanning electron microscopy. In order to do this, a wide range of electric stimuli with respect to those employed in the clinical practice were utilized. Either surface electrodes were attached to the scalp, or needle electrodes were infixed in the subcutaneous tissue. Beneath the cathode a blood extravasation was constantly observed in the subcutaneous tissue of the scalp; the different electrode arrays produced either a large hemorrhagic lesion or a few petechiae. Beneath the anode, the damage was limited to the scalp, or reached the meninges when stimuli longer than 0.2 ms were used. Irrespective of the electrode arrays, the scalp and the dura mater displayed hemorrhagic petechiae over a limited area about 2-3 mm in extent. Moreover, the leptomeningeal membrane was microscopically disrupted over an area less than 1 mm large; therein the squamous, overlapping cells were transformed into fusiform or macrophage-like cells. Unduly intense eTCS produces evident hemorrhagic lesions in the scalp and in the dura mater, whereas it induces microscopic, reactive changes in the leptomeninx.
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We have examined whether the cardiovascular effects of 7-nitroindazole, a reportedly selective inhibitor of neuronal nitric oxide (NO) synthase, are induced without inhibition of endothelial NO synthase. A significant increase in mean... more
We have examined whether the cardiovascular effects of 7-nitroindazole, a reportedly selective inhibitor of neuronal nitric oxide (NO) synthase, are induced without inhibition of endothelial NO synthase. A significant increase in mean arterial blood pressure but no change in heart rate was observed after 7-nitroindazole administration (50 mg/kg i.p.) in rats anesthetized with urethane or urethane and chloralose, while both an elevation in mean arterial blood pressure and bradycardia were observed in conscious animals after 7-nitroindazole administration (50 mg/kg i.p.). No enhancements in these effects on mean arterial blood pressure and heart rate were observed in urethane-chloralose anesthetized rats treated with a higher dose of 7-nitroindazole (75 mg/kg i.p.). Use of halothane to induce anesthesia abolished the pressor effect of 7-nitroindazole in rats studied under urethane anesthesia. 7-Nitroindazole shortened the duration of the acetylcholine (3 micrograms or 30 micrograms i.v.) but not the sodium nitroprusside (2 micrograms i.v.) induced hypotension in urethane-anesthetized rats. Pretreatment with L-arginine (300 mg/kg i.v.) inhibited the effects of 7-nitroindazole on mean arterial blood pressure and acetylcholine induced hypotension, suggesting involvement of the L-arginine-NO pathway in the effects of 7-nitroindazole. The effects of 7-nitroindazole on blood pressure and on the depressor responses to acetylcholine and sodium nitroprusside are similar to the effects previously observed after non-selective NO synthase inhibition by L-arginine analogs. Our results suggest, therefore, that 7-nitroindazole affects basal endothelial NO formation in vivo. The suppressive action of halothane on the cardiovascular effects of 7-nitroindazole suggests that the influence of anesthetics should be taken into consideration in studies of the cardiovascular effects of NO synthase inhibitors, particularly 7-nitroindazole.
Research Interests: Chemistry, Enzyme Inhibitors, Medicine, Blood Pressure, Nitric oxide, and 14 moreAnimals, Male, Heart rate, Vascular endothelium, Acetylcholine, European, In Vivo, Rats, Nitric Oxide Synthase, Arginine, Sodium Nitroprusside, Arterial pressure, Endothelial nitric oxide synthase, and Pharmacology and pharmaceutical sciences
Dysregulation of dopamine receptors is thought to underlie levodopa‐induced dyskinesias in experimental models of Parkinson’s disease. It is unknown whether an imbalance of the second messengers, cyclic adenosine monophosphate (cAMP) and... more
Dysregulation of dopamine receptors is thought to underlie levodopa‐induced dyskinesias in experimental models of Parkinson’s disease. It is unknown whether an imbalance of the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is involved in the alterations of levodopa/dopamine signal transduction. We examined cAMP and cGMP signalling in the interconnected cortico‐striatal‐pallidal loop at the peak of levodopa‐induced dyskinesias in rats with 6‐hydroxydopamine lesions in the substantia nigra. In addition, we examined the role of phosphodiesterase (PDE) and the rate of cAMP and cGMP degradation on the severity of levodopa‐induced dyskinesias in animals pretreated with PDE inhibitor, zaprinast. Unilateral lesion of substantia nigra led to an increase in cAMP but a decrease in cGMP levels in the ipsilateral basal ganglia. After chronic levodopa treatment, cAMP and cGMP were differentially regulated in eukinetic animals: the cAMP level i...
Research Interests: Endocrinology, Psychology, Cognitive Science, Biology, Medicine, and 15 moreDopamine, Brain, Internal Medicine, Cerebral Cortex, cyclic AMP, Animals, Male, Phosphorylation, Levodopa, Phosphodiesterase Inhibitors, Globus Pallidus, Neurosciences, Cyclic nucleotide, cyclic GMP, and parkinsonian disorders
Recent evidence has shown that the activity of cAMP responsive element-binding protein (CREB) and of CREB-binding protein (CBP) is decreased in... more
Recent evidence has shown that the activity of cAMP responsive element-binding protein (CREB) and of CREB-binding protein (CBP) is decreased in Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (HD) [Steffan et al. (2000)Proc. Natl Acad. Sci. USA, 97, 6763-6768; Gines et al. (2003)Hum. Mol. Genet., 12, 497-508; Rouaux et al. (2004) Biochem. Pharmacol., 68, 1157-1164; Sugars et al. (2004)J. Biol. Chem., 279, 4988-4999]. Such decrease is thought to reflect the impaired energy metabolism observed in a HD mouse model, where a decline in striatum cAMP levels has been observed [Gines et al. (2003)Hum. Mol. Genet., 12, 497-508]. Increased levels of CREB have also been demonstrated to exert neuroprotective functions [Lonze &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp; Ginty (2002)Neuron, 35, 605-623; Lonze et al. (2002)Neuron, 34, 371-385]. Our study aimed to investigate the distribution of CREB in the neuronal subpopulations of the striatum in normal rats compared to the HD model of quinolinic acid lesion. Twenty-five Wistar rats were administered quinolinic acid 100 mm into the right striatum, and killed after 24 h, 48 h, 1 week, 2 weeks, and six weeks, respectively. The contralateral striata were used as controls. Dual-label immunofluorescence was employed using antibodies against phosphorylated CREB and each of the different neuronal subpopulations markers. Our results show that activated CREB levels decrease progressively in projection neurons and parvalbumin (PARV) and calretinin (CALR) interneurons, whereas such levels remain stable in cholinergic and somatostatin interneurons. Thus, we speculate that the ability of cholinergic interneurons to maintain their levels of CREB after excitotoxic lesions is one of the factors determining their protection in Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease.
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Transient receptor potential channels (TRPC) are plasma membrane, non‐selective cationic channels and have been proposed as candidates involved in the regulation of cellular Ca2+ influx. The expression, at mRNA level, of several TRPCs has... more
Transient receptor potential channels (TRPC) are plasma membrane, non‐selective cationic channels and have been proposed as candidates involved in the regulation of cellular Ca2+ influx. The expression, at mRNA level, of several TRPCs has been demonstrated recently in dopaminergic neurons of the substantia nigra (SN). The aim of the present study was to characterize the expression of TRPC1, at a protein level, in the substantia nigra neurons and non‐excitable cells of Wistar rats. Single‐label immunohistochemistry and double‐label immunofluorescence were used to study the expression of TRPC1 among substantia nigra dopamine neurons and cellular processes using antibodies against tyrosine hydroxylase (TH), substance P (SP), enkephalin, synaptophysin, vesicular glutamate transporter‐2 (Vglut‐2), microtubule associated protein‐2 and metabotropic glutamate receptor 1 (mGluR1). Moreover, the ultrastructural localization of TRPC1 was investigated by means of electron microscopy. A set of d...
Research Interests: Psychology, Cognitive Science, Electron Microscopy, Biology, Immunohistochemistry, and 15 moreTransmission Electron Microscopy, Confocal Microscopy, Medicine, Dopamine, Animals, Metabotropic Glutamate Receptors, Male, Substantia nigra, Dendrites, Synaptic Transmission, European, Rats, SYNAPSES, Biological markers, and Neurosciences
We have studied the effects of dopamine and the D2‐like agonist quinpirole on calcium currents of neurons isolated from the striatum and the globus pallidus (GP). Experiments were performed in young adult rats, either in control... more
We have studied the effects of dopamine and the D2‐like agonist quinpirole on calcium currents of neurons isolated from the striatum and the globus pallidus (GP). Experiments were performed in young adult rats, either in control conditions or following lesion of the nigrostriatal pathway by the unilateral injection of 6‐hydroxydopamine (6‐OHDA) in the substantia nigra. Apomorphine‐driven contralateral turning, 15 days after lesioning, assessed the severity of the dopamine denervation. In addition, the loss of tyrosine hydroxylase immunohistochemistry confirmed the extent of the toxin‐induced damage. In both striatal medium spiny (MS) and GP neurons of control animals dopamine and quinpirole promoted a very modest inhibition of calcium conductance. Following 6‐OHDA, the inhibition was unaltered in MS (from 10 to 12%), but significantly augmented in GP neurons (21% vs. 9%). Interestingly, analogous inhibition was observed in GP neurons dissociated 20 h after reserpine treatment. Furth...
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Combination of morphological and electrophysiological techniques provided data, suggesting existence in the young rat striatum of a peculiar class of neurons, the neurogliaform or dwarf neurons. Striatal neurons (n = 92), intracellularly... more
Combination of morphological and electrophysiological techniques provided data, suggesting existence in the young rat striatum of a peculiar class of neurons, the neurogliaform or dwarf neurons. Striatal neurons (n = 92), intracellularly recorded from rat brain slices, were filled (one in each slice) with the intracellular marker biocytin, to compare physiological and morphological properties in the same cell. Moreover, some neurons (n = 7) were filled with biocytin plus the fluorescent calcium indicator fura-2, identifying cells during electrophysiological recording. Electrophysiological recording showed that striatal neurons had different firing patterns, suggestive in most cases (n = 80) of spiny neuron class and in others (n = 12) of interneuron class. Fura-2 injection clearly identified the body of six medium-sized cells and of one distinctive tiny cell. This small cell, however, showed a resting membrane potential and spontaneous and evoked firing pattern characteristic of striatal interneurons. Moreover, the fura-2 injected in such small neuron also completely filled the cell body of a near large neuron; the fura-2 fluorescence changed synchronously in the two paired neurons after electrical stimulation of the impaled small one. Accordingly, the biocytin staining identified the morphology of the small recorded neuron as a neurogliaform-like cell apposed to a dendrite of an aspiny neuron, suggesting that the dye injected in one neuron had diffused to the other of a different type. Furthermore, such heterologous dye coupling unexpectedly involved seven pairs of cells detected with biocytin staining (7.6% of the recorded neurons), invariably represented by a medium or large neuron on one side, and on the other side by a small (5.44 +/- 0.15 x 9.14 +/- 0.7 microns, mean +/- SD; n = 7) neurogliaform cell, roundish in shape with few slender and short processes, usually apposed to a dendrite of the companion neurons (six out of seven). In the other cases, the biocytin staining revealed in each slice either the morphology of single spiny or aspiny neurons (80.4% of recorded neurons), or of two-three medium-sized spiny neurons detected near to each other, suggesting that dye coupling had occurred typically between similar neurons (11.9% of the recorded neurons). These data suggest that some neurogliaform cells in the striatum of young rat can be identified as dwarf interneurons, that may be dye-coupled with neurons of different classes.
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Epileptic activity is an underdiagnosed cause that can determine a disruption of memory and cognitive performance, leading an incorrect diagnosis of dementia. We report a 68‐year‐old man, referred with a 5‐year history of subtle... more
Epileptic activity is an underdiagnosed cause that can determine a disruption of memory and cognitive performance, leading an incorrect diagnosis of dementia. We report a 68‐year‐old man, referred with a 5‐year history of subtle behavioral changes and a subjective memory impairment, who was admitted to our department because of recurrent episodes of confusional state lasting from 1 week. Neuropsychological evaluation demonstrated a marked impairment of all cognitive domains examined. Electroencephalogram (EEG) recording showed frequent almost continuous sharp waves localized on the bilateral posterior temporal regions with mild right side predominance. Treatment with phenytoin reversed his cognitive dysfunction and behavioral disturbances. We presume that ictal temporal lobe epileptiform activity is the cause of his confusional episodes and cognitive dysfunction, showing an electroclinical picture of complex partial status epilepticus. However, we hypothesize that the interictal dis...
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Research Interests: Epilepsy, Medicine, Humans, Male, Clinical Sciences, and 3 moreIctal, Seizures, and Functional Laterality
Summary: GP 47779, the active metabolite of oxcarbazepine (OCBZ) inhibits glutamatergic excitatory postsynaptic potentials (EPSPs) in rat striatum (described in the accompanying article). This effect was presumed to involve the modulation... more
Summary: GP 47779, the active metabolite of oxcarbazepine (OCBZ) inhibits glutamatergic excitatory postsynaptic potentials (EPSPs) in rat striatum (described in the accompanying article). This effect was presumed to involve the modulation of the calcium (Ca2+) signals at either pre‐ or postsynaptic level. Therefore, we directly tested whether GP 47779 could modulate Ca2+ conductances in cortical as well as in striatal neurons. GP 47779 produced a reversible dose‐dependent decrease in high‐voltage‐activated (HVA) Ca2+ currents evoked by membrane depolarization in isolated cortical pyramidal cells. GP 47779‐mediated reduction in HVA Ca2+ currents, if occurring also at corticostriatal axon terminals, might explain the reduction of glutamate release in the striatum. An inhibitory action of GP 47779 on HVA Ca2+ currents was also observed in isolated striatal neurons. The effect on HVA Ca2+ currents in cortical and striatal neurons persisted in the presence of nifedipine, suggesting that ...
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While many studies have investigated electroencephalographic (EEG) features of dementia, few have analysed the relationship between EEG and cerebrospinal fluid biomarkers in cognitive impairment. Seizures are frequently observed at the... more
While many studies have investigated electroencephalographic (EEG) features of dementia, few have analysed the relationship between EEG and cerebrospinal fluid biomarkers in cognitive impairment. Seizures are frequently observed at the end stage of Alzheimer disease, and experimental animal studies support the view that epileptiform activity may contribute to the cognitive decline. In this paper, after reviewing literature findings concerning the role of EEG in dementia, we show the preliminary results of our study aimed to correlate the presence of epileptiform EEG patterns with cerebrospinal fluid biomarkers in order to better define the prognosis of dementia. Our study shows a clear relationship between phospho-tau protein levels and epileptiform EEG pattern. This finding seems to suggest in humans the observation made in animal models that not only β-amyloid protein, but also tau and phospho-tau proteins, are involved in the aberrant regulation of neural transmission possibly contributing to EEG deterioration, cognitive decline and worse prognosis. On the basis of the relationship between phospho-tau protein, cognitive decline and epileptogenicity we suspect that high liquoral phospho-tau levels and epileptiform EEG pattern may provide an early identification of patients with dementia and/or represent an aggressive phenotype of dementia. We propose that qualitative EEG analysis integrated with cerebrospinal biomarkers may be extensively used to better define dementia.
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Frailty is an evolving concept that is generally defined in biomedical or psychosocial terms. It is not necessarily related to a specific single disease process. Passing by the theories of Selye (1936) on the exhaustion of the General... more
Frailty is an evolving concept that is generally defined in biomedical or psychosocial terms. It is not necessarily related to a specific single disease process. Passing by the theories of Selye (1936) on the exhaustion of the General Adaptation Syndrome,until reaching to the studies of Fried (2001) who, firstly, proposed diagnostic criteria for frailty, in this paper are explored different ways to understand this concept, until endeavour to give a possible modern view. The definition of a frailty syndrome characterized by a multi-system reduction in ?reserve capacity? remains widely accepted.
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Research Interests: Medicine, Humans, Male, Intraocular Pressure, Clinical Sciences, and 10 moreAged, Optometry and Ophthalmology, Public health systems and services research, Visual Fields, Disease Progression, Alzheimer Disease, Clinical and Experimental Ophthalmology, Indian Journal of Clinical and Experimental Ophthalmology, Primary Open Angle Glaucoma, and Tau proteins
The cholinergic innervation of coronary arteries and veins has been studied in the human. Structures resembling cholinergic nerve fibres are localised at the level of the extraparenchymal branches of the coronary arteries, organised in... more
The cholinergic innervation of coronary arteries and veins has been studied in the human. Structures resembling cholinergic nerve fibres are localised at the level of the extraparenchymal branches of the coronary arteries, organised in the adventitial plexus. Neither the coronary veins nor the intraparenchymal blood vessels are provided with a cholinergic innervation. Those findings are discussed.
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Manganese (Mn) is a cofactor for some metalloprotein enzymes, including Mn-superoxide dismutase (Mn-SOD), a mitochondrial enzyme predominantly localized in neurons, and glutamine synthetase (GS), which is selectively expressed in... more
Manganese (Mn) is a cofactor for some metalloprotein enzymes, including Mn-superoxide dismutase (Mn-SOD), a mitochondrial enzyme predominantly localized in neurons, and glutamine synthetase (GS), which is selectively expressed in astroglial cells. The detoxifying effects of GS and Mn-SOD in the brain, involve catabolizing glutamate and scavenging superoxide anions, respectively. Mn intoxication is characterized by impaired function of the basal ganglia. However, it is unclear whether regional central nervous system expression of manganoproteins is also affected. Here, we use immunocytochemistry in the adult rat brain, to examine whether Mn overload selectively affects the expression of GS, Mn-SOD, Cu/Zn-SOD, another component of the SOD family, and glial fibrillary acid protein (GFAP), a specific marker of astrocytes. After chronic Mn overload in drinking water for 13 weeks, we found that the number and immunostaining intensity of GS- and Mn-SOD-positive cells was significantly decreased in the striatum and globus pallidus, but not in the cerebral frontal cortex. In addition, we found that GS enzymatic activity was decreased in the strio-pallidal regions but not in the cerebral cortex of Mn-treated animals. In contrast, Cu/Zn-SOD- and GFAP-immunoreactivity was unchanged in both the cerebral cortex and basal ganglia of Mn-treated rats. Thus, we conclude that in response to chronic Mn overload, a down-regulation of some manganoproteins occurs in neurons and astrocytes of the striatum and globus pallidus, probably reflecting the vulnerability of these regions to Mn toxicity.
Research Interests: Cognitive Science, Biology, Immunohistochemistry, Manganese, Glutamate, and 15 moreBrain, Cerebral Cortex, Animals, Male, Drinking Water, Astrocyte, Frontal Cortex, Central Nervous System, Enzyme, Globus Pallidus, Basal ganglia, Glial Fibrillary Acidic Protein, Cytochemistry, Glutamine Synthetase, and Enzymatic Activity
Single- and double-label electron microscopic immunocytochemistry was used to examine the ultrastructure of striatal neurons containing nitric oxide synthase (NOS+) and evaluate the synaptic relationship of NOS+ striatal neurons with... more
Single- and double-label electron microscopic immunocytochemistry was used to examine the ultrastructure of striatal neurons containing nitric oxide synthase (NOS+) and evaluate the synaptic relationship of NOS+ striatal neurons with those containing parvalbumin (PV+). In both the single-label and double-label studies, NOS+ perikarya were observed to possess polylobulated nuclei. In the single-label studies, NOS+ terminals were seen forming synaptic contacts with dendritic shafts and dendritic spines that did not contain NOS, but not with NOS+ perikarya or dendrites. In the double-label studies (using diaminobenzidine and silver intensified immunogold as markers), nitric oxide synthase and parvalbumin immunoreactions were found in two different populations of medium-sized aspiny striatal neurons. The PV+ axon terminals were seen forming symmetric synapses on the dendritic spines of neurons devoid of PV or NOS labeling, on PV+ dendrites, and on NOS+ soma and dendrites. In contrast, NOS+ terminals were not observed to form synaptic contacts with the dendrites or soma of either PV+ or NOS+ neurons. These findings suggest that NOS+ striatal interneurons form synaptic contact with the spines and presumably the dendrites of striatal projection neurons, but not with the dendrites or soma of PV+ or NOS+ striatal interneurons. NOS+ neurons do, however, receive synaptic input from PV+ neurons.
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Research Interests: Cognitive Science, Chemistry, Fluorescence Microscopy, Biology, Medicine, and 15 moreBrain, Population, Animals, Male, Medical Physiology, Enzyme, Nitric Oxide Synthase, Neuropeptide Y, Basal ganglia, Confocal Laser Scanning Microscopy, Enzymatic Activity, Neurosciences, Corpus striatum, Colocalization, and Neuropeptide
Research Interests: Fluorescence Microscopy, Biology, Medicine, Cell Culture, Cell line, and 15 moreAnimals, Cell Death, Glial Cell, Kinase inhibitor, Biochemical, Neurons, Enzyme, High Pressure Liquid Chromatography, NBTI, BIOCHEMICAL PHARMACOLOGY, Cell Cycle Arrest, Cell Survival, Antineoplastic Agents, Adenosine Triphosphate, and Cell count
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The incidence of leprosy is nowa-days very low in developed coun-tries,2 but immigrants from endemic areas3 may develop the disease even after a very long incubation, as in the case of this patient. It is worth not-ing that lepromatous... more
The incidence of leprosy is nowa-days very low in developed coun-tries,2 but immigrants from endemic areas3 may develop the disease even after a very long incubation, as in the case of this patient. It is worth not-ing that lepromatous leprosy may pre-sent with little or no skin ...
Research Interests: Cognitive Science, Archives, Medicine, Humans, Leprosy, and 8 moreFemale, Skin Diseases, Clinical Sciences, Adult, Foot, Foot Diseases, Neurosciences, and toes
Striatal spiny neurons are selectively vulnerable in Huntington's disease (HD) and ischemia, whereas large aspiny (LA) cholinergic interneurons of the striatum are spared in these pathological conditions. We have investigated whether... more
Striatal spiny neurons are selectively vulnerable in Huntington's disease (HD) and ischemia, whereas large aspiny (LA) cholinergic interneurons of the striatum are spared in these pathological conditions. We have investigated whether a different sensitivity to ionotropic glutamatergic agonists might account for this differential vulnerability. Intracellular recordings were obtained from morphologically identified striatal spiny neurons and LA cholinergic interneurons by using a rat brain slice preparation. The two striatal neuronal subtypes had strikingly different intrinsic membrane properties. Both subtypes responded to cortical stimulation with excitatory postsynaptic potentials: these potentials, however, had a different time course and pharmacology in the two classes of cells. Interestingly, membrane depolarizations and inward currents produced by exogenous glutamate receptor agonists (AMPA, kainate, and NMDA) were remarkably larger in spiny neurons than in LA interneurons....
Research Interests: Neuroscience, Electrophysiology, Biology, Medicine, Cerebral Cortex, and 15 moreAnimals, Metabotropic Glutamate Receptors, Brain Ischemia, Synaptic Transmission, Neurotoxins, Clinical Sciences, Rats, Huntington disease, Annals, Neurosciences, Interneurons, Glutamate Receptor, Excitatory Postsynaptic Potentials, Corpus striatum, and Kainic acid
We occasionally observed a consistent clinical improvement in an advanced Parkinson’s disease (PD) patient (Hoehn and Yahr [H and Y], stage 4, 10-year disease history) under stable levodopa (L-dopa) therapy, immediately after eradicating... more
We occasionally observed a consistent clinical improvement in an advanced Parkinson’s disease (PD) patient (Hoehn and Yahr [H and Y], stage 4, 10-year disease history) under stable levodopa (L-dopa) therapy, immediately after eradicating Helicobacter pylori (Hp) infection. We hypothesised that Hpinduced changes of the gastric environment (ie, pH variations or increase of oxidant agents) affecting L-dopa absorption might be reversed by eradicating Hp infection. Therefore, we measured the acute plasma L-dopa concentration–time curve in 7 advanced PD patients (mean age, 70.4 6 6.3 years; mean disease duration, 6.8 6 2.4 years; H and Y $ 2.5) who were Hp-positive (IgG antibody titer higher than 1,000 Pyloryset; Orion Diagnostica, Espoo, Finland), and had no history of previous Hp eradication attempts. Measurements were made in a blind fashion at baseline, 1 week after a 7-day cycle with placebo and 1 week after a standard cycle of a 7-day therapy with omeprazole, amoxicillin, and chlarithromycin. In each condition studied, plasma L-dopa concentration was monitored every 0.5 hour up to 4.0 hours, beginning with a fasting oral dose of L-dopa (250mg Sinemet) administered after an overnight withdrawal. L-dopa blood content was determined by highperformance liquid chromatography coupled to electrochemical detection. Data are expressed as mean 6 standard error. Area under the concentration time curve (AUC) was calculated for each patient, each acting as his or her own control, using the Pharmacologic Calculation System v 4.0 according to the trapezoidal rule. Patient clinical scores were evaluated by a blinded neurologist using the Unified Parkinson’s Disease Rating Scale (UPDRS) motor examination III (min, 0; max, 108). The clinical score was assessed immediately before L-dopa administration and then repeated at 1 and 2-hour intervals thereafter (Table). The mean AUC significantly increased after antibiotic therapy from 6,584.7 6 830.2 to 7,871.0 6 1,169.5ng/mL (p , 0.01, two-way analysis of variance [ANOVA] for repeated measures; factor interaction: treatment [pre/post] vs drugs, placebo/antibiotic therapy; posthoc Tukey test, p , 0.05) but not after placebo (from 6,584.7 6 830 to 6,624.3 6 970ng/mL; Fig, insets). Single values of the plasma L-dopa concentration–time curves showed no significant variations (three-way ANOVA). However, after antibiotic therapy, L-dopa levels seemed to increase mostly at late intervals (.1.5 hours; see Fig; A). In fact, the expected L-dopa-induced antiparkinsonian effect over the following 2 hours (p , 0.01, Friedman ANOVA) was significantly larger after antibiotic therapy than after placebo only at the second hour (UPDRS III, 23.1 6 8.8 vs 33.9 6 10.7; p , 0.01, Wilcoxon test). These data suggest that Hp infection may interfere with L-dopa absorption in PD patients. Moreover, they indicate that Hp eradication procedure may increase drug availability by about 20%, prolonging the tail of the plasma L-dopa conFig. Effects of (A) placebo or (B) antibiotic treatment on L-dopa plasma concentrations in Parkinsons’s disease patients affected by HP infection.
Research Interests: Gastroenterology, Treatment Outcome, Helicobacter pylori, Medicine, Humans, and 14 moreLevodopa, Clinical Sciences, Intestinal absorption, Aged, Anti-Bacterial Agents, Analysis of Variance, Combination drug therapy, Parkinson´s Disease, Biological Availability, Neurosciences, Area Under Curve, Parkinson Disease, Severity of Illness Index, and Omeprazole
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Here we investigated the effect of the rivastigmine patch alone on depression in 50 mild... more
Here we investigated the effect of the rivastigmine patch alone on depression in 50 mild Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) patients with comorbid major depressive episode (MDE). First diagnosis acetyl-cholinesterase inhibitor and psychoactive drug-free outpatients (n=50) were recruited in memory clinics and reassessed after 3 and 6 months. Global cognitive functioning, depressive symptoms and MDE frequency were evaluated with the Mini Mental State Examination, the CERAD Dysphoria scale and the modified DSM-IV criteria for MDE in AD. MDE frequency reduced significantly from the first diagnostic visit (100%) to the 6-month follow-up (62%). We also found a significant reduction in CERAD Dysphoria scores that decreased from 6.2±3.9 mean±standard deviation to 4.9±4.5 at the 6-month follow-up. In AD patients with MDE rivastigmine alone can have a positive impact on depressive phenomena. Thus, future controlled study are justified to definitively verify if rivastigmine alone may improve depression in AD.
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A late-onset, myopathic variant of phosphofructokinase (PFK) deficiency has been previously described in two patients of Ashkenazic descent. We report here on a non-Ashkenazic woman with the onset, at the age of 48 years, of a progressive... more
A late-onset, myopathic variant of phosphofructokinase (PFK) deficiency has been previously described in two patients of Ashkenazic descent. We report here on a non-Ashkenazic woman with the onset, at the age of 48 years, of a progressive limb girdle myopathy that was not preceded by a history of exercise intolerance. Muscle biopsy findings at the age of 58 years showed deposition of amylopectin-like material in muscle fibers and the absence of histochemical PFK activity. Enzymatic PFK activity in vitro was only 4% of normal. Since the forearm ischemic exercise test induced a sub-normal production of serum lactate, the patient underwent phosphorus magnetic resonance spectroscopy (31P-MRS), a non-invasive method that allows in vivo assessment of the functional status of the glycolytic pathway and mitochondrial oxidative metabolism by measuring the high-energy phosphates and cytosolic pH. In vivo, 31P-MRS disclosed a residual glycolytic flux and a normal rate of ATP production both at rest and during exercise. These results suggest that, in some patients, muscle PFK deficiency may be partial in vivo, and more severe in vitro, possibly due to protein or mRNA instability rather than absence. The presence of these findings in a patient with the late-onset myopathic form is compatible with a distinct pathogenetic mechanism, relying on progressive polysaccharide accumulation, rather than on acute energetic shortage in muscle fibers.
Research Interests: Endocrinology, Biology, Magnetic Resonance Spectroscopy, Medicine, Energy Metabolism, and 15 morePhosphorus, Humans, Internal Medicine, Phosphofructokinase, Female, Glycolysis, Clinical Sciences, Middle Aged, In Vivo, Exercise Test, Neurosciences, Functional Status, High energy, Oxidative Metabolism, and Muscle Biopsy
Aggregation states of amyloid beta peptides for amyloid beta A β 1 – 40 to A β 1 – 42 and A β p 3 – 42 are investigated through small angle neutron scattering (SANS). The knowledge of these small peptides and their aggregation state are... more
Aggregation states of amyloid beta peptides for amyloid beta A β 1 – 40 to A β 1 – 42 and A β p 3 – 42 are investigated through small angle neutron scattering (SANS). The knowledge of these small peptides and their aggregation state are of key importance for the comprehension of neurodegenerative diseases (e.g., Alzheimer’s disease). The SANS technique allows to study the size and fractal nature of the monomers, oligomers and fibrils of the three different peptides. Results show that all the investigated peptides have monomers with a radius of gyration of the order of 10 Å, while the oligomers and fibrils display differences in size and aggregation ability, with A β p 3 – 42 showing larger oligomers. These properties are strictly related to the toxicity of the corresponding amyloid peptide and indeed to the development of the associated disease.
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... Short Communication. Dopamine denervation induces neurotensin immunoreactivity in GABA-parvalbumin striatal neurons. Alessandro Martorana 1,2,* ,; Francesca Romana Fusco 2 ,; Barbara Picconi 1 ,; Roberto Massa 1 ,; Giorgio Bernardi... more
... Short Communication. Dopamine denervation induces neurotensin immunoreactivity in GABA-parvalbumin striatal neurons. Alessandro Martorana 1,2,* ,; Francesca Romana Fusco 2 ,; Barbara Picconi 1 ,; Roberto Massa 1 ,; Giorgio Bernardi 1,2 ,; Giuseppe Sancesario 1. ...
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Research Interests: Neurology, Psychiatry, Neurosurgery, Magnetic Resonance Imaging, Electroencephalography, and 15 moreAdolescent, Medicine, Brain, Humans, Mutation, Neuroradiology, Female, Calcium channels, Migraine, Mental Disorders, Clinical Sciences, Migraine With Aura, Neurosciences, Calcium Channel Blockers, and Neurological Sciences
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Prolonged exposure to manganese in mammals may cause an extrapyramidal disorder characterized by dystonia and rigidity. Gliosis in the pallidal segments underlies the well-established phase of the intoxication. The early phase of the... more
Prolonged exposure to manganese in mammals may cause an extrapyramidal disorder characterized by dystonia and rigidity. Gliosis in the pallidal segments underlies the well-established phase of the intoxication. The early phase of the intoxication may be characterized by psychic, nonmotor signs, and its morphological and electrophysiological correlates are less defined. In a rat model of manganese intoxication (20 mg/ml in drinking water for 3 months), neither neuronal loss nor gliosis was detected in globus pallidus (GP). However, a striking vulnerability of manganese-treated GP neurons emerged. The majority of GP neurons isolated from manganese-treated rats died following brief incubation in standard dissociation media. In addition, patch-clamp recordings in the whole-cell configuration were not tolerated by surviving GP neurons. Neither coeval but untreated GP neurons nor striatal ones manifested analogous susceptibility. Using the perforated-patch mode of recording we attempted at identifying the functional hallmarks of GP vulnerability: in particular, voltage-gated calcium currents and glutamate-induced currents were examined. Manganese-treated GP neurons exhibited calcium currents similar to control cells aside from a slight reduction in the dihydropyridine-sensitive current facilitation. Strikingly, manganese-treated GP cells--but not striatal ones--manifested peculiar responses to glutamate, since repeated applications of the excitatory amino acid, at concentrations which commonly promote desensitizing responses, produced instead an irreversible cell damage. Possible mechanisms are discussed.
Research Interests: Neuroscience, Electrophysiology, Calcium, Neurodegeneration, Medicine, and 15 moreGlutamate, Animals, Calcium channels, Male, Drinking Water, Neurons, Globus Pallidus, Glutamic Acid, Parkinson Disease, Glutamate Receptor, Gliosis, Bursting, parkinsonian disorders, Medical and Health Sciences, and Nerve degeneration
In Huntington's disease neuronal degeneration mainly involves medium‐sized spiny neurons. It has been postulated that both excitotoxic mechanisms and energy metabolism failure are implicated in the neuronal degeneration observed in... more
In Huntington's disease neuronal degeneration mainly involves medium‐sized spiny neurons. It has been postulated that both excitotoxic mechanisms and energy metabolism failure are implicated in the neuronal degeneration observed in Huntington's disease. In central neurons, >40% of the energy released by respiration is used by Na+/K+ ATPase to maintain ionic gradients. Considering that impairment of Na+/K+ ATPase activity might alter postsynaptic responsivity to excitatory amino acids (EAAs), we investigated the effects of the Na+/K+ ATPase inhibitors, ouabain and strophanthidin, on the responses to different agonists of EAA receptors in identified medium‐sized spiny neurons electrophysiologically recorded in the current‐ and voltage‐clamp modes. In most of the cells both ouabain and strophanthidin (1–3 μM) did not cause significant change in the membrane properties of the recorded neurons. Higher doses of either ouabain (30 μM) or strophanthidin (30 μM) induced, per se, a...
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BackgroundThe cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in... more
BackgroundThe cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories.MethodsData from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single‐analyte enzyme‐linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection.ResultsA total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within‐run CVs, less than 5% to 10%; and longitudinal within‐laboratory CVs, 5% to 19%. Interestingly, longitudinal within‐laboratory CV differed between bioma...
Research Interests: Biomarkers, Medicine, Quality Control, Clinical Chemistry, Cerebrospinal Fluid, and 15 moreHumans, Clinical, Hospital, Phosphorylation, Proficiency testing, Clinical Sciences, Biomarker, Immunoassay, Reproducibility of Results, Biological markers, Elsevier, Alzheimer Disease, Neurosciences, Enzyme Linked Immunosorbent Assay, and Medical
Mechanisms of tissue damage in Huntington’s disease involve excitotoxicity, mitochondrial damage, and neuroinflammation, including microglia activation. In the present study, we investigate the role of pyroptosis process in the striatal... more
Mechanisms of tissue damage in Huntington’s disease involve excitotoxicity, mitochondrial damage, and neuroinflammation, including microglia activation. In the present study, we investigate the role of pyroptosis process in the striatal neurons of the R6/2 mouse model of Huntington’s disease. Transgenic mice were sacrificed at 4 and 13 weeks of age. After sacrifice, histological and immunohistochemical studies were performed. We found that NLRP3 and Caspase-1 were intensely expressed in 13-week-old R6/2 mice. Moreover, NLRP3 expression levels were higher in striatal spiny projection neurons and in parvalbumin interneurons, which are prone to degenerate in HD.
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Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as “bioactive lipids”. Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and... more
Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as “bioactive lipids”. Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between the immune and nervous systems, and lipids can interact particularly with the aggregation and propagation of many pathogenic proteins that are well-renowned hallmarks of several neurodegenerative disorders, including Alzheimer’s (AD) and Parkinson’s (PD) diseases. In this review, we summarize the current knowledge about the presence and quantification of the main classes of endogenous bioactive lipids, namely glycerophospholipids/sphingolipids, classical eicosanoids, pro-resolving lipid mediators, and endocannabinoids, in AD and PD patients, as well as their most-used animal models, by means of lipidomic analyses, advocating for these lipid mediat...
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We aimed to investigate A2A receptors in the basal ganglia of a DYT1 mouse model of dystonia. A2A was studied in control Tor1a+/+ and Tor1a+/− knock-out mice. A2A expression was assessed by anti-A2A antibody immunofluorescence and Western... more
We aimed to investigate A2A receptors in the basal ganglia of a DYT1 mouse model of dystonia. A2A was studied in control Tor1a+/+ and Tor1a+/− knock-out mice. A2A expression was assessed by anti-A2A antibody immunofluorescence and Western blotting. The co-localization of A2A was studied in striatal cholinergic interneurons identified by anti-choline-acetyltransferase (ChAT) antibody. A2A mRNA and cyclic adenosine monophosphate (cAMP) contents were also assessed. In Tor1a+/+, Western blotting detected an A2A 45 kDa band, which was stronger in the striatum and the globus pallidus than in the entopeduncular nucleus. Moreover, in Tor1a+/+, immunofluorescence showed A2A roundish aggregates, 0.3–0.4 μm in diameter, denser in the neuropil of the striatum and the globus pallidus than in the entopeduncular nucleus. In Tor1a+/−, A2A Western blotting expression and immunofluorescence aggregates appeared either increased in the striatum and the globus pallidus, or reduced in the entopeduncular ...
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Pyroptosis is a type of cell death that is caspase-1 (Casp-1) dependent, which leads to a rapid cell lysis, and it is linked to the inflammasome. We recently showed that pyroptotic cell death occurs in Huntington’s disease (HD). Moreover,... more
Pyroptosis is a type of cell death that is caspase-1 (Casp-1) dependent, which leads to a rapid cell lysis, and it is linked to the inflammasome. We recently showed that pyroptotic cell death occurs in Huntington’s disease (HD). Moreover, we previously described the beneficial effects of a PARP-1 inhibitor in HD. In this study, we investigated the neuroprotective effect of Olaparib, an inhibitor of PARP-1, in the mouse model of Huntington’s disease. R6/2 mice were administered Olaparib or vehicle from pre-symptomatic to late stages. Behavioral studies were performed to investigate clinical effects of the compound. Immunohistochemical and Western blotting studies were performed to evaluate neuroprotection and the impact of the compound on the pathway of neuronal death in the HD mice. Our results indicate that Olaparib administration starting from the pre-symptomatic stage of the neurodegenerative disease increased survival, ameliorated the neurological deficits, and improved clinical...
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Dystonia pathophysiology has been partly linked to downregulation and dysfunction of dopamine D2 receptors in striatum. We aimed to investigate the possible morpho-structural correlates of D2 receptor downregulation in the striatum of a... more
Dystonia pathophysiology has been partly linked to downregulation and dysfunction of dopamine D2 receptors in striatum. We aimed to investigate the possible morpho-structural correlates of D2 receptor downregulation in the striatum of a DYT1 Tor1a mouse model. Adult control Tor1a+/+ and mutant Tor1a+/− mice were used. The brains were perfused and free-floating sections of basal ganglia were incubated with polyclonal anti-D2 antibody, followed by secondary immune-fluorescent antibody. Confocal microscopy was used to detect immune-fluorescent signals. The same primary antibody was used to evaluate D2 receptor expression by western blot. The D2 receptor immune-fluorescence appeared circumscribed in small disks (~0.3–0.5 µm diameter), likely representing D2 synapse aggregates, densely distributed in the striatum of Tor1a+/+ mice. In the Tor1a+/− mice the D2 aggregates were significantly smaller (µm2 2.4 ± SE 0.16, compared to µm2 6.73 ± SE 3.41 in Tor1a+/+) and sparse, with ~30% less nu...
Research Interests: Genetics, Chemistry, Medicine, Dopamine, Striatum, and 3 moreMolecular sciences, Basal ganglia, and Receptor
The role of noradrenergic neurotransmission was analyzed in striatal cholinergic interneurons. Conventional intracellular and whole-cell patch-clamp recordings were made of cholinergic interneurons in rat brain slice preparations.... more
The role of noradrenergic neurotransmission was analyzed in striatal cholinergic interneurons. Conventional intracellular and whole-cell patch-clamp recordings were made of cholinergic interneurons in rat brain slice preparations. Bath-applied noradrenaline (NA) (1–300 μm) dose-dependently induced both an increase in the spontaneous firing activity and a membrane depolarization of the recorded cells. In voltage-clamped neurons, an inward current was induced by NA. This effect was not prevented by α-adrenoceptor antagonists, whereas it was mimicked by the β-adrenoceptor agonist isoproterenol and blocked by the β1 antagonists propranolol and betaxolol. Interestingly, forskolin, activator of adenylate cyclase, mimicked and occluded the membrane depolarization obtained at saturating doses of both dopamine and NA. Accordingly, SQ22,536, a selective adenylate cyclase inhibitor, reduced the response to NA. Analysis of the reversal potential of the NA-induced current did not provide homogen...
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High-frequency stimulation (HFS) of corticostriatal glutamatergic fibers induces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of LTD can be mimicked by zaprinast, a selective... more
High-frequency stimulation (HFS) of corticostriatal glutamatergic fibers induces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of LTD can be mimicked by zaprinast, a selective inhibitor of cGMP phosphodiesterases (PDEs). Biochemical analysis shows that most of the striatal cGMP PDE activity is calmodulin-dependent and inhibited by zaprinast. The zaprinast-induced LTD occludes further depression by tetanic stimulation and vice versa. Both forms of synaptic plasticity are blocked by intracellular 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, indicating that an increased cGMP production in the spiny neuron is a key step. Accordingly, intracellular cGMP, activating protein kinase G (PKG), also induces LTD. Nitric oxide synthase (NOS) inhibitorsN(G)-nitro-l-arginine methyl ester hydrochloride (L-NAME) and 7-nitroindazole monosodium salt (7-NINA) block LTD induced by eith...
Research Interests: Neuroscience, Chemistry, Electron Microscopy, Immunohistochemistry, Medicine, and 15 moreCerebral Cortex, Animals, Neuronal Plasticity, Dendrites, Neurons, Long Term Depression, Calmodulin, Methyl Ester, cyclic GMP, Corpus striatum, High Frequency Stimulation, Intracellular recording, intracellular recordings, Medical and Health Sciences, and Feed Forward
Late-life depression (LLD) and Alzheimer's Disease (AD) are the two most frequent neuropsychiatric disorders affecting elderly. LLD and AD may clinically present with depressive and cognitive symptoms. Therefore, when cognitive... more
Late-life depression (LLD) and Alzheimer's Disease (AD) are the two most frequent neuropsychiatric disorders affecting elderly. LLD and AD may clinically present with depressive and cognitive symptoms. Therefore, when cognitive decline is coupled with depression in the elderly, the differential diagnosis between LLD and AD could be challenging. The aim of the present study was to evaluate in a population of elderly patients affected by depression and dementia the usefulness of CSF AD biomarkers (tau proteins and β-amyloid-Aβ) and 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (18FFDG-PET) in early differentiating LLD from AD. Two hundred and fifty-six depressed and demented patients, after performing CSF AD biomarkers and 18FFDG-PET, were distributed in two groups on the basis of the current diagnostic guidelines for AD (= 201) and LLD (= 55). Patients were then observed for 2 years to verify the early diagnosis. After the 2 year follow-up we compared AD and LLD pa...
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Background/Aims: To investigate the differences in brain glucose consumption between patients with early onset of Alzheimer's disease (EOAD, aged ≤65 years) and patients with late onset of Alzheimer's disease (LOAD, aged >65... more
Background/Aims: To investigate the differences in brain glucose consumption between patients with early onset of Alzheimer's disease (EOAD, aged ≤65 years) and patients with late onset of Alzheimer's disease (LOAD, aged >65 years). Methods: Differences in brain glucose consumption between the groups have been evaluated by means of Statistical Parametric Mapping version 8, with the use of age, sex, Mini-Mental State Examination and cerebrospinal fluid values of Aβ1-42, phosphorylated Tau and total Tau as covariates in the comparison between EOAD and LOAD. Results: As compared to LOAD, EOAD patients showed a significant decrease in glucose consumption in a wide portion of the left parietal lobe (BA7, BA31 and BA40). No significant differences were obtained when subtracting the EOAD from the LOAD group. Conclusions: The results of our study show that patients with EOAD show a different metabolic pattern as compared to those with LOAD that mainly involves the left parietal l...
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Research Interests: Psychology, Cognitive Science, Dementia, Medicine, Cerebrospinal Fluid, and 15 moreNeuropeptides, Humans, Internal Medicine, Female, Male, Clinical Sciences, Polysomnography, Aged, Middle Aged, Orexin, Alzheimer Disease, Neurosciences, Cognition disorders, Case Control Studies, and Severity of Illness Index
Nitric oxide may influence pathophysiology of brain ischemia in a complex way depending on the sources of its production either from neurons or endothelial cells. We investigated whether inhibition of nitric oxide synthesis affects... more
Nitric oxide may influence pathophysiology of brain ischemia in a complex way depending on the sources of its production either from neurons or endothelial cells. We investigated whether inhibition of nitric oxide synthesis affects postischemic neuronal death in hippocampus. Moreover, we evaluated whether the presence of nitric oxide synthase activity in specific neurons protects these against ischemia in the hippocampus, striatum, and sensorimotor cortex. To inhibit nitric oxide synthase, several dosing regimens of NG-nitro-L-arginine methyl ester (L-NAME) were used (5 or 50 mg/kg IP, twice a day for 4 days, or 30 mg/kg IV) in gerbils. Control animals received either the isomer NG-nitro-D-arginine methyl ester or the vehicle. The gerbils underwent 10-minute occlusion of carotid arteries under ether anesthesia and controlled body temperature while physiological parameters were monitored. Neuronal damage was assessed 5 days after ischemia using Nissl-stained sections of hippocampus. ...
Research Interests: Medicine, Hippocampus, Ischemia, Nitric oxide, Female, and 15 moreAnimals, Male, Anesthesia, Neurons, Body Temperature, Clinical Sciences, Nitric Oxide Synthase, Arginine, NAD, Neurosciences, Hippocampal formation, Arterial Occlusive Diseases, Gerbillinae, nicotinamide adenine dinucleotide phosphate, and Cardiovascular medicine and haematology
Research Interests: Endocrinology, Neuroscience, Immunohistochemistry, Medicine, Multidisciplinary, and 15 moreDopamine, Striatum, Internal Medicine, Animals, Male, Dyskinesia, Levodopa, PLoS one, Rats, Analysis of Variance, Muscle contraction, Rat Model, Corpus striatum, real time polymerase chain reaction, and reverse transcriptase polymerase chain reaction
Research Interests: Depression, Neuropsychopharmacology, Medicine, Dopamine, Humans, and 15 moreCerebral Cortex, Exploration, Cognitive Process, Acetylcholine, Levodopa, Aged, Cognitive Decline, Alzheimer Disease, Healthy Subjects, Cortical Excitability, Neuropsychological Tests, dopaminergic, Cognitive dysfunction, Medical and Health Sciences, and Electric stimulation
In the present study, we found that PDE10A inhibitor papaverine, alone or in combination with the D1 receptor agonist SKF38393, did not change spontaneous IPSCs (sIPSCs) frequency or amplitude in the substantia nigra pars reticulata... more
In the present study, we found that PDE10A inhibitor papaverine, alone or in combination with the D1 receptor agonist SKF38393, did not change spontaneous IPSCs (sIPSCs) frequency or amplitude in the substantia nigra pars reticulata (SNpr). An increase in frequency, but not in amplitude, of sIPSCs was only observed when SKF38393 and PDE10A inhibitors were associated to perfusion with higher extracellular K(+). On the other hand, the amplitude of evoked IPSCs (eIPSCs) of the striato-nigral projection to SNpr, was increased in response to co-administration of SKF38393 and papaverine in normal extracellular potassium. Of note, both an increase in sIPSCs frequency and eIPSC amplitude could be obtained either by a robust stimulation of adenylyl cyclase (AC) with forskolin (10 μM) or by a lower dose of forskolin (1 μM) associated to PDE inhibition. We next investigated the effects produced by dopamine (DA) depletion in the striatum. Under this condition, SKF38393 alone increased either sIPSCs frequency and eIPSC amplitude. In addition, in the striatum of DA-depleted mice we found reduced PDE10A levels and higher cAMP-dependent phosphorylation in response to D1 receptor stimulation. In accordance with these biochemical data, perfusion with papaverine had no effect on the SKF38393-induced changes of IPSCs in slices of DA-depleted mice. These findings reveal a dynamic interplay between PDE10A activity, level of neuronal network depolarization and degree of dopaminergic tone in the ability of D1 receptors to facilitate the GABAergic transmission to SNpr neurons from the direct nigro-striatal pathway. This article is part of the Special Issue entitled &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;The Synaptic Basis of Neurodegenerative Disorders&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;.
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Research Interests: Biology, Medicine, Manganese, Learning, Dopamine, and 15 moreLiver, Animals, Male, Behavior change, Dopamine Receptors, Inhibitory Control, Clinical Sciences, Basal ganglia, Exploratory Behavior, Brain Chemistry, Maze Learning, Motor activity, Excitatory Postsynaptic Potentials, dopaminergic, and Electric stimulation
The P2X7 receptor for extracellular ATP is the main candidate, among P2 receptors, inducing cell death in the immune system. Here, we demonstrate the direct participation of this receptor to cell damage induced by oxygen/glucose... more
The P2X7 receptor for extracellular ATP is the main candidate, among P2 receptors, inducing cell death in the immune system. Here, we demonstrate the direct participation of this receptor to cell damage induced by oxygen/glucose deprivation, in the ex vivo model of organotypic hippocampal cultures. By pharmacological and immunological approaches, we show that P2X7 is rapidly and transiently up regulated in hippocampal areas eliciting metabolism impairment. Moreover, the P2 antagonists 2′,3′,-dialdehyde ATP and reactive blue 2 prevent both up regulation of this receptor and hypoxic/hypoglycemic damage. By confocal laser microscopy, we show that P2X7 is present at the synaptic level of fibers extending from the CA1–2 pyramidal cell layer throughout the strata oriens and radiatum, but absent on oligodendrocytes, astrocytes or neuronal cell bodies. Colocalization of P2X7 is obtained with neurofilament-L protein and with synaptophysin, not with myelin basic protein, glial fibrillary acid...
Research Interests: Metabolism, Biology, Cell Biology, Confocal Microscopy, Medicine, and 15 moreHippocampus, Glucose, Flow, Brain Circulation, Animals, Cell Death, Astrocyte, Clinical Sciences, Immune system, Glial Fibrillary Acidic Protein, Culture Media, Extracellular, Hippocampal formation, Colocalization, and Cardiovascular medicine and haematology
Research Interests: Neuroscience, Biology, Medicine, Cerebrospinal Fluid, Corpus Callosum, and 15 moreNitric oxide, Female, Animals, Male, Rat Brain, Neurons, Clinical Sciences, Free Surface, Cerebral, Nitric Oxide Synthase, Neural pathways, Cerebral Blood Flow, Neurosciences, Ependyma, and Cardiovascular medicine and haematology
Research Interests: Endocrinology, Biology, Immunohistochemistry, Confocal Microscopy, Medicine, and 15 moreNeuropeptides, Internal Medicine, Animals, Male, Neurons, Clinical Sciences, Fluorescent Antibody Technique, Experimental, Globus Pallidus, Basal ganglia, Lesion, Experimental Neurology, Neurosciences, dopaminergic, and Neuropeptide
Dopamine and NO are physiological stimulators of synthesis of cAMP and cGMP, respectively, and NO synthase-containing interneurons in the striatum are physiologically activated by dopamine-containing neurons in the substantia nigra. This... more
Dopamine and NO are physiological stimulators of synthesis of cAMP and cGMP, respectively, and NO synthase-containing interneurons in the striatum are physiologically activated by dopamine-containing neurons in the substantia nigra. This study investigated whether lesioning dopamine neurons has multiple consequences in the striatum consistent with the reported sensitization of cAMP synthesis, including alteration of the NO-cGMP pathway and phosphodiesterase-dependent metabolism of cyclic nucleotides. The substantia nigra of adult Sprague-Dawley rats was unilaterally lesioned with 6-hydroxydopamine. Two months later, we determined expression of NO synthase and evaluated cGMP and cAMP levels of intact and deafferented striatum. Moreover, we evaluated cAMP- and cGMP-phosphodiesterase activities in basal conditions and after Ca2+-calmodulin stimulation and determined the expression of the phosphodiesterase-1B isoform and the levels of phosphodiesterase-1B mRNA. Using immunocytochemistry we characterized the distribution of NO synthase and phosphodiesterase-1B within striatal neurons. In the dopamine-deafferented striatum, NO synthase levels were decreased by 42% while NO synthase-immunopositive intrastriatal fibres but not NO synthase neuronal bodies were reduced in number. In the deafferented striatum basal cGMP levels were reduced, and cAMP levels were increased, but cGMP-phosphodiesterase and cAMP-phosphodiesterase activities were both increased in basal and Ca2+-calmodulin-stimulated conditions. Accordingly, phosphodiesterase-1B expression and phosphodiesterase-1B mRNA were upregulated while a large population of medium-sized striatal neurons showed increased phosphodiesterase-1B immunoreactivity. Dopamine deafferentation led to a complex down-regulation of the NO-cGMP pathway in the striatum and to an up-regulation of phosphodiesterase-1B-dependent cyclic nucleotide metabolism, showing new aspects of neuronal plasticity in experimental hemiparkinsonism.
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Background In the CNS, several P2 receptors for extracellular nucleotides are identified on neurons and glial cells to participate to neuron-neuron, glia-glia and glia-neuron communication. Results In this work, we describe the cellular... more
Background In the CNS, several P2 receptors for extracellular nucleotides are identified on neurons and glial cells to participate to neuron-neuron, glia-glia and glia-neuron communication. Results In this work, we describe the cellular and subcellular presence of metabotropic P2Y1 receptor in rat cerebellum at two distinct developmental ages, by means of immunofluorescence-confocal and electron microscopy as well as western blotting and direct membrane separation techniques. At postnatal day 21, we find that P2Y1 receptor in addition to Purkinje neurons, is abundant on neuronal specializations identified as noradrenergic by anatomical, morphological and biochemical features. P2Y1 receptor immunoreactivity colocalizes with dopamine β-hydroxylase, tyrosine hydroxylase, neurofilament light chain, synaptophysin and flotillin, but not with glial fibrillary acidic protein for astrocytes. P2Y1 receptor is found enriched in membrane microdomains such as lipid rafts, in cerebellar synaptic ...
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Research Interests: Psychology, Dementia, Mild Cognitive Impairment, Medicine, Humans, and 15 moreInternal Medicine, Female, Disease, Male, Clinical Sciences, Dementia and the arts, Aged, Biological markers, Neurotrophic Factors, Alzheimer Disease, Neurosciences, Enzyme Linked Immunosorbent Assay, Cognition disorders, Brain-derived neurotrophic factor (BDNF), and Neuropsychological Tests
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Dystrophin is localized, in normal muscle fibers, on the cytoplasmic surface of the sarcolemma. The function of this protein is not known but, according to its structure and intracellular distribution, it seems likely that dystrophin... more
Dystrophin is localized, in normal muscle fibers, on the cytoplasmic surface of the sarcolemma. The function of this protein is not known but, according to its structure and intracellular distribution, it seems likely that dystrophin interacts with other cytoskeletal proteins to form a complex linkage between myofibrils, sarcolemma and extracellular matrix. To evaluate the possibility that dystrophin deficiency induces, per se, a disarray in the cytoskeleton, we studied three components of this structure in muscle fibers of the dystrophic mdx mouse in a phase preceding the onset of necrosis. Vinculin, abundant in sarcolemmal structures called costameres, desmin, the principal component of intermediate filaments and nebulin, constituent of the so-called &quot;third filament&quot; within the sarcomere, were stained with the indirect immunofluorescence technique in cryostat sections. The same monoclonal antibodies were used in Western blots of proteins extracted from the same muscles. No difference was observed in the distribution or in the relative abundance of the three proteins, comparing muscles from 18 day-old mdx and control mice. Our results indicate that the lack of dystrophin does not induce, per se, alterations in the structures linking the sarcolemma to the contractile apparatus. It is likely that the structural damage in dystrophin-less muscle fibers is initially confined to limited portions of the plasma membrane. These focal lesions, impairing intracellular calcium homeostasis, can lead to muscle fiber necrosis.
Research Interests: Fluorescence Microscopy, Biology, Cell Biology, Medicine, Extracellular Matrix, and 15 moreCytoskeleton, Mice, Muscular Dystrophy, Female, Animals, Male, Duchenne Muscular Dystrophy, Clinical Sciences, Fluorescent Antibody Technique, ACTA, Monoclonal Antibody, Dystrophin, Neurosciences, Intracellular Calcium, and Immunoblotting
Loss of dopamine neurons in experimental parkinsonism results in altered cyclic nucleotide cAMP and cGMP levels throughout the basal ganglia. Our objective was to examine whether expression of phosphodiesterase 10A (PDE10A), an isozyme... more
Loss of dopamine neurons in experimental parkinsonism results in altered cyclic nucleotide cAMP and cGMP levels throughout the basal ganglia. Our objective was to examine whether expression of phosphodiesterase 10A (PDE10A), an isozyme presenting a unique distribution in basal ganglia, is altered after unilateral injection of 6-hydroxydopamine in the medial forebrain bundle, eliminating all midbrain dopaminergic neurons, such that cyclic nucleotide catabolism and steady state could be affected. Our study demonstrates that PDE10A mRNA levels were decreased in striatal neurons 10 weeks after 6-hydroxydopamine midbrain lesion. Such changes occurred in the striatum ipsilateral to lesion and were paralleled by decreased PDE10A protein levels and activity in striatal neurons and in striato-pallidal and striato-nigral projections. However, PDE10A protein and activity were increased while PDE10A mRNA was unchanged in the nucleus accumbens ipsilateral to the 6-hydroxydopamine midbrain lesion. Accordingly, cAMP levels were down-regulated in the nucleus accumbens, and up-regulated in the striatum ipsilateral to the lesion, but they were not significantly changed in substantia nigra and globus pallidus. Unlike cAMP, cGMP levels were decreased in all dopamine-deafferented regions. The opposite variations of cAMP steady state in striatum and nucleus accumbens are concordant and likely dependent, at least in part, on the down-regulation of PDE10A expression and activity in the former and its up-regulation in the latter. On the other hand, the down-regulation of cGMP steady state in the striato-nigral and striato-pallidal complex is not consistent with and is likely independent from the concomitant down-regulation of PDE10A. Therefore, dopamine loss inversely regulates PDE10A gene expression in the striatum and PDE10A post-transcription in the nucleus accumbens, therein differentially modulating PDE10A-dependent cAMP catabolism.
Research Interests: Endocrinology, Chemistry, Neurobiology Of Disease, Metabolism, Medicine, and 15 moreGene expression, Dopamine, Internal Medicine, cyclic AMP, Animals, Male, Neurons, Clinical Sciences, Globus Pallidus, Cyclic nucleotides, Basal ganglia, Neural pathways, Midbrain, cyclic GMP, and Gene Expression Regulation
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Adenosine 5'-triphosphate outflow increases after an ischemic insult in the brain and may induce the expression of P2X 7 receptors in resting microglia, determining its modification into an activated state. To assess the effects of... more
Adenosine 5'-triphosphate outflow increases after an ischemic insult in the brain and may induce the expression of P2X 7 receptors in resting microglia, determining its modification into an activated state. To assess the effects of P2X 7 receptor blockade in preventing microglia activation ...
Research Interests: Neuroscience, Neurology, Metabolism, Medicine, Flow, and 15 moreBrain Circulation, Animals, Microglia, Male, Astrocyte, Frontal Cortex, Brain Ischemia, Clinical Sciences, Cerebral, And, Cerebral Ischemia, Brain Damage, Cerebral Infarction, Middle cerebral artery occlusion, and Cardiovascular medicine and haematology
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A deficit in facial emotion recognition was described in patients with Alzheimer disease (AD). However, this issue has been underexplored in subjects with amnestic mild cognitive impairment (a-MCI). Thus, the authors aimed to determine... more
A deficit in facial emotion recognition was described in patients with Alzheimer disease (AD). However, this issue has been underexplored in subjects with amnestic mild cognitive impairment (a-MCI). Thus, the authors aimed to determine whether a deficit in facial emotion recognition is present in a-MCI phase and whether this is intensity dependent. A secondary aim was to investigate relationships between facial emotion recognition and cognitive performances. Case-control study. Memory clinic. Fifty a-MCI patients, 50 mild AD patients, and 50 comparison subjects (COM) were enrolled. Information about facial emotion recognition was obtained from Penn Emotion Recognition Test. The Mental Deterioration Battery was used to measure cognitive impairment. Mild AD patients were more impaired in the recognition of almost all emotional stimuli of all intensities than a-MCI and COM subjects. However, there was an increased progression only in low-intensity facial emotion recognition deficit fro...
Research Interests: Cognition, Face recognition (Psychology), Facial expression, Emotions, Speech, and 15 moreMemory, Humans, Emotion Recognition, Female, Prosopagnosia, Male, American, Clinical Sciences, Aged, Public health systems and services research, Educational Status, Alzheimer Disease, Cognition disorders, Severity of Illness Index, and Neuropsychological Tests
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Synapses are ultrastructural sites for memory storage in brain, and synaptic damage is the best pathologic correlate of cognitive decline in Alzheimer's disease (AD). Post-translational hyperphosphorylation, enzyme-mediated... more
Synapses are ultrastructural sites for memory storage in brain, and synaptic damage is the best pathologic correlate of cognitive decline in Alzheimer's disease (AD). Post-translational hyperphosphorylation, enzyme-mediated truncation, conformational modifications, and aggregation of tau protein into neurofibrillary tangles (NFTs) are hallmarks for a heterogeneous group of neurodegenerative disorders, so-called tauopathies. AD is a secondary tauopathy since it is pathologically distinguished by the presence of amyloid-beta (Abeta)-containing senile plaques and the presence of tau-positive NFTs in the neocortex and hippocampus. Here, we report that a 20-22 kDa NH2-truncated tau fragment is largely enriched in human mitochondria from cryopreserved synaptosomes of AD brains and that its amount in terminal fields correlates with the pathological synaptic changes and with the organelle functional impairment. This NH2-truncated tau form is also found in other human, not AD-tauopathies...
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Daytime somnolence and sleep-wake cycle disturbances are commonly encountered symptoms in Frontotemporal Dementia (FTD). Orexin-A (Hypocretin-1) is a hypothalamic neuropeptide regulating the sleep-wake rhythm. We investigated the... more
Daytime somnolence and sleep-wake cycle disturbances are commonly encountered symptoms in Frontotemporal Dementia (FTD). Orexin-A (Hypocretin-1) is a hypothalamic neuropeptide regulating the sleep-wake rhythm. We investigated the cerebrospinal-fluid (CSF) orexin levels in a population of FTD patients and evaluated whether there is a relationship between daytime somnolence and CSF orexin concentrations. CSF orexin levels were measured in a sample of FTD patients (n = 11) compared to a population of non-demented controls (n = 13) similar for age and sex. Moreover, CSF orexin concentrations were correlated with daytime somnolence investigated by means of the Epworth Sleepiness Scale (ESS) in both FTD patients and controls. FTD patients showed CSF orexin concentrations (164.3 ± 66.45 vs 170.81 ± 42.73 pg/mL) and ESS scores (7.45 ± 4.36 vs 3.84 ± 1.82) not different from controls. However, three FTD patients showed pathological daytime sleepiness (ESS &amp;amp;gt; 10) coupled with the lowest CSF orexin levels. In addition, we found a significant negative correlation between CSF orexin levels and ESS scores in the FTD population (R = -0.91; p &amp;amp;lt; 0.0001), which was not evident in the control group (R = 0.16; p &amp;amp;gt; 0.05). This is the first study investigating CSF orexin concentrations in FTD. We did not find differences in CSF orexin concentrations between FTD patients and controls. However, a significant negative correlation between daytime somnolence and CSF orexin levels was evident in FTD patients. Moreover, we have found that pathological daytime somnolence was evident in those FTD patients with the lowest CSF orexin levels. Based on these findings, we argued that lower orexin levels may be permissive for increased daytime somnolence in FTD.
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Awareness of cognitive deficits may be reduced in mild cognitive impairment (MCI). This may have a detrimental effect on illness course and may be a predictor of subsequent conversion to AD. Although neuropsychological correlates have... more
Awareness of cognitive deficits may be reduced in mild cognitive impairment (MCI). This may have a detrimental effect on illness course and may be a predictor of subsequent conversion to AD. Although neuropsychological correlates have been widely investigated, no evidence of a neuroanatomical basis of the phenomenon has been reported yet. This study was aimed at investigating the neuroanatomical correlates of deficit awareness in amnestic MCI to determine whether they constitute risk factors for conversion to AD. A sample of 36 first-diagnosis amnestic MCI patients were followed for five years. At the first diagnostic visit they were administered an extensive diagnostic and clinical procedure and the Memory Insight Questionnaire (MIQ), measuring a total index and four sub-indices, to investigate awareness of deficits in dementia; they also underwent a high resolution T1-weighted Magnetic Resonance Imaging (MRI) investigation. Grey matter brain volumes were analysed on a voxel-by-voxel basis using Statistical Parametric Mapping 8. Data of 10 converter patients (CONV) and those of 26 non converter patients (NOCONV) were analysed using multiple regression models. At baseline, self-awareness of memory deficits was poorer in CONV compared to NOCONV. Furthermore, reduced awareness of cognitive deficits in CONV correlated with reduced grey matter volume of the anterior cingulate (memory deficit awareness), right pars triangularis of the inferior frontal cortex (memory deficit awareness) and cerebellar vermis (total awareness), whereas in NOCONV it correlated with reduced grey matter volume of left superior (total awareness) and middle (language deficit awareness) temporal areas. Further, at baseline self-awareness of memory deficits were poorer in CONV than in NOCONV. Defective awareness of cognitive deficits is underpinned by different mechanisms in CONV and NOCONV amnestic MCI patients. Our data support the hypothesis that poor awareness of cognitive deficit is a predictor of subsequent conversion to AD.
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The subventricular zone (SVZ) is a region that lies immediately beneath the ependymal layer on the lateral wall of the lateral ventricles, and is separated from the caudate nucleus by a layer of myelin. It contains multipotent neural stem... more
The subventricular zone (SVZ) is a region that lies immediately beneath the ependymal layer on the lateral wall of the lateral ventricles, and is separated from the caudate nucleus by a layer of myelin. It contains multipotent neural stem cells. The aim of this study was to investigate the tissue around the SVZ, with the hypothesis that multimodal MRI is able to highlight the progressive disruption of tissue caused by the neurodegenerative disease in this area. We combined volumetric and diffusion tensor (DTI) imaging using a 3T imager in a cross-sectional study including 30 patients with amnestic-mild cognitive impairment (a-MCI), 30 patients with Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) and 30 age- and gender-matched healthy controls (HC). Our data indicate that mean diffusivity (MD) values increase continuously from HC through a-MCI to AD in the bilateral SVZ, where most of the proliferating stem cells in the adult brain are located. This result was specific for the SVZ and could not be observed in other periventricular areas. Multimodal MRI, being able to highlight structural changes of microscopic tissue in humans in vivo, could represent a precious tool to complement histological studies of neurogenesis.
Research Interests: Neuroscience, Cognitive Science, Magnetic Resonance Imaging, Diffusion Tensor Imaging, Mild Cognitive Impairment, and 15 moreNeural stem cell, Brain, Humans, Caudate Nucleus, Female, Male, Aged, Analysis of Variance, Neurodegenerative Disease, Neural pathways, Cross sectional Study, Cross Sectional Studies, Alzheimer Disease, Cognition disorders, and Mean Diffusivity
Research Interests: Culture, Neuropharmacology, Apoptosis, Modulation, Hippocampus, and 15 moreGlutamate, Cerebellum, Animals, Cell Death, Central Nervous System, Function, Microelectrodes, Neurons, Degeneration, Neurosciences, Nucleotides, Cerebellar Granule Neuron, Adenosine Triphosphate, NMDA receptor, and Pharmacology and pharmaceutical sciences
To ascertain the potential role of chemical elements (namely, Al, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Hg, Li, Mg, Mn, Mo, Ni, Pb, Sb, Si, Sn, Sr, Tl, V, W, Zn and Zr) as markers in the... more
To ascertain the potential role of chemical elements (namely, Al, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Hg, Li, Mg, Mn, Mo, Ni, Pb, Sb, Si, Sn, Sr, Tl, V, W, Zn and Zr) as markers in the Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD), the elemental concentration of cerebrospinal fluid (CSF) of 42 patients with PD and 20 age-matched controls was assessed. Analyses were performed by Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES) and Sector Field Inductively Coupled Plasma Mass Spectrometry (SF-ICP-MS). Significantly lower levels of Co, Cr, Fe, Pb, Si and Sn were observed in the CSF of PD patients compared with those in controls, with a percentage of depletion up to 50% for Cr and Pb. No such variations were detected for all the other elements. Results suggested that Pb, Cr, Fe were the most suitable elements to distinguish between normality and PD. Different cut-off concentrations for these elements could be tentatively proposed as a predictive tool for the PD condition.
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Among mediators of inflammation, chemokines play a pivotal role in the neuroinflammatory process related to Alzheimer’s disease (AD). The chemokine Bv8/prokineticin 2 (PROK2) is a critical player in inflammatory and neuroinflammatory... more
Among mediators of inflammation, chemokines play a pivotal role in the neuroinflammatory process related to Alzheimer’s disease (AD). The chemokine Bv8/prokineticin 2 (PROK2) is a critical player in inflammatory and neuroinflammatory diseases and has been demonstrated to be involved in Aβ toxicity. The aim of the present study was to extend the research to rats chronically intracerebroventricularly (i.c.v.) injected with Aβ, to an AD transgenic mouse model, and subsequently to AD patients, mainly with the aim of detecting a potential biomarker. Real-time PCR and immunofluorescence analysis were used to evaluate Prokineticin-2 (PROK2) mRNA and the corresponding protein levels in both animal and human AD brain extracts, and the ELISA test was used to measure the amount of PROK2 in the serum of AD patients. We demonstrated a significant upregulation of PROK2 levels in brain tissues of Aβ1–42 i.c.v. injected rats, transgenic AD mice (Tg2576), and in the hippocampus of AD patients. Addit...
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Experimental data suggest that the cerebrospinal fluid (CSF) dynamic is involved in the clearance of beta-amyloid, a key event in the pathogenesis of Alzheimer&#39;s disease (AD). At this regard no evidence still exists in vivo. In... more
Experimental data suggest that the cerebrospinal fluid (CSF) dynamic is involved in the clearance of beta-amyloid, a key event in the pathogenesis of Alzheimer&#39;s disease (AD). At this regard no evidence still exists in vivo. In this study we explored the relationships between CSF pressure and AD pathology, as measured with CSF core biomarkers. We enrolled 16 patients with probable AD and 21 controls, collecting demographics, clinical data, CSF opening pressure and CSF levels of beta-amyloid-42 fragment (Aβ42), total-tau (t-tau), phosphorylated-tau-181 (p-tau), albumin and albumin ratio. Differences between the groups were calculated with non-parametric tests, while correlations among all parameters were separately calculated with Spearman&#39;s test in each group. The groups significantly differed in biomarkers&#39; concentration with lower Aβ42, and higher t-tau and p-tau in AD patients. Moreover, CSF pressure was significantly lower in AD group (11.0 ± 2.8 vs. 13.3 ± 3.0 mmHg, p &lt; 0.05) and directly correlated with Aβ42 levels (R = 0.512; p &lt; 0.05), but not with other biomarkers or parameters. No significant correlations emerged for biomarkers in control group. AD patients exhibit low CSF pressure whose values are directly and selectively related to CSF Aβ42 levels. This interesting correlation may confirm in vivo the association between CSF dynamic and beta-amyloid metabolism occurring in AD.
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The distribution of 3H-spiroperidol binding sites within rabbit superior mesenteric artery was studied in normal as well as 6-hydroxydopamine (6-OHDA) sympathectomized animals using a histoautoradiographic technique. The labelled drug was... more
The distribution of 3H-spiroperidol binding sites within rabbit superior mesenteric artery was studied in normal as well as 6-hydroxydopamine (6-OHDA) sympathectomized animals using a histoautoradiographic technique. The labelled drug was located in the three layers of the artery (adventitia, media and intima), with the greater density in the media. In the adventitia the radiolabelled drug was located at the level of fibrous and connective cells. In the media 3H-spiroperidol was bound by smooth muscle cells and is found in the cellular membrane of the same cells. 6-OHDA administration causes an increase in the number of 3H-spiroperidol binding sites in the adventitia and as well as a 20-25% increase in the media. The possible existence of a direct dopaminergic innervation of the superior mesenteric artery is discussed.
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We have studied the electrophysiological effects of glucose deprivation on morphologically identified striatal neurons recorded from a corticostriatal slice preparation. The large majority of the recorded cells were spiny neurons and... more
We have studied the electrophysiological effects of glucose deprivation on morphologically identified striatal neurons recorded from a corticostriatal slice preparation. The large majority of the recorded cells were spiny neurons and responded to aglycemia with a slow membrane depolarization coupled with a reduction of the input resistance. In voltage-clamp experiments aglycemia caused an inward current. This current was associated with a conductance increase and reversed at -40 mV. The aglycemia-induced membrane depolarization was not affected by tetrodotoxin (TTX) or 6-cyano-7-nitroquinoxaline-2,3-dione plus aminophosphonovalerate, antagonists acting respectively on AMPA and NMDA glutamate receptors. Also, the intracellular injection of bis(2-aminophenoxy)ethane-N,N, N',N'-tetra-acetic acid, a calcium (Ca2+) chelator, and low Ca2+/high Mg2+-containing solutions failed to reduce this phenomenon. Conversely, it was reduced by lowering external sodium (Na+) concentration. A m...
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Research Interests: Spatial Memory, Hippocampus, cyclic AMP, Animals, Male, and 13 moreReaction Time, Phosphodiesterase Inhibitors, Rats, Analysis of Variance, Time Factors, Wistar Rats, Memory Disorders, Maze Learning, cyclic GMP, Motor activity, Psychology and Cognitive Sciences, Medical and Health Sciences, and In Vitro Techniques
The aim of this work was to investigate the hypothesis that multimodal MRI is able to detect the progressive disruption of volume and microstructure of subcortical structures in patients with amnestic mild cognitive impairment (a-MCI) and... more
The aim of this work was to investigate the hypothesis that multimodal MRI is able to detect the progressive disruption of volume and microstructure of subcortical structures in patients with amnestic mild cognitive impairment (a-MCI) and mild Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) in comparison with healthy controls (CTRL). We combined volumetric and diffusion tensor imaging (DTI) techniques in a cross-sectional study including 30 a-MCI, 30 AD patients, and 30 age-matched CTRL. We employed a fully automated model-based segmentation algorithm on 3 Tesla MRI anatomical images and accurate coregistration of DTI to anatomical images to extract regional values of DTI parameters. Both the hippocampi significantly and progressively decreased in volume from CTRL through MCI to AD. Both the thalami showed a progressive and significant decrease in volume from CTRL to AD. Mean diffusivity (MD) values increased progressively across the three groups in the bilateral hippocampus, amygdala, and in the right caudate. No differences in fractional anisotropy (FA) values were found. Two distinct but overlapping patterns of progression of structural (i.e., atrophy) and microstructural (i.e., MD increase) damage were observed. Particularly, the pattern of atrophy was mirrored by the increasing value of the averaged MD, which provided a further indicator of subtle tissue disruption in the hippocampal structure in mild AD patients. Combining different MRI modalities can allow identifying sensitive indicators of the subtle pathogenic mechanisms that occur in subcortical areas of AD patients.
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Research Interests:
Research Interests: Neurochemistry, Membrane Proteins, Apoptosis, Caspases, Glutamate, and 15 moreCerebellum, Glucose, Animals, Cell Death, Cytochrome C, Hypoglycemia, Neurons, Enzyme, Biological markers, Heat Shock Protein, Lactate dehydrogenase, Neurosciences, Cerebellar Granule Neuron, Neuroprotective Agents, and Medical biochemistry and metabolomics
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6 cases of brainstem hematoma were studied utilizing CT scan and brainstem auditory evoked potential (BAEP) recordings. CT scan did not contribute to an early discrimination between primary and secondary hematomas. Size of the hematoma... more
6 cases of brainstem hematoma were studied utilizing CT scan and brainstem auditory evoked potential (BAEP) recordings. CT scan did not contribute to an early discrimination between primary and secondary hematomas. Size of the hematoma and the presence of blood in the CSF did not represent evident signs in differentiating benign from unfavourable brainstem hematomas or hemorrhages. BAEP recordings showed the presence of electrophysiological anomalies at the level of the lesion, demonstrating that bleeding as well as tumor in the brainstem can provoke a focal damage.
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Truncation at N-terminal domain of tau protein is early associated with neurofibrillary pathology in several human tauopathies, including Alzheimer's disease (AD). In affected subjects, the monitoring of total (t-tau) and/or... more
Truncation at N-terminal domain of tau protein is early associated with neurofibrillary pathology in several human tauopathies, including Alzheimer's disease (AD). In affected subjects, the monitoring of total (t-tau) and/or phosphorylated tau (p-tau) levels in cerebrospinal fluid (CSF) provides a reliable, indirect evaluation of cellular changes occurring in vivo and the identification of additional CSF biomarkers would better assist with the clinical practice, allowing a broader profile of underlying ongoing neurodegeneration. Here we show that a 20-22 kDa NH2-truncated form of human tau (i.e., NH2htau), a neurotoxic fragment of the full length protein (htau40) that we previously found in synapses from subjects affected by different tauopathies: (i) is not a normal constituent of CSF, unlike t-tau and p-tau, being exceptionally detected in patients without cognitive impairment; (ii) discriminates, with a weak specificity of 65% but a high sensitivity of 85%, patients carrying ...
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Cytotoxic brain edema has been produced in rats by subacute intoxication with triethyltin (TET). Some animals were allowed to recover spontaneously, others were post-treated with an extract of Ginkgo biloba (EGB) for 1 to 4 weeks,... more
Cytotoxic brain edema has been produced in rats by subacute intoxication with triethyltin (TET). Some animals were allowed to recover spontaneously, others were post-treated with an extract of Ginkgo biloba (EGB) for 1 to 4 weeks, beginning 3 days after intoxication was stopped. The time course of the resolution of the edema was studied biochemically and morphologically by light microscopy, histochemistry and electron microscopy (EM). Morphometric evaluation showed that the spontaneous reabsorption of TET-induced edema was very slow: it was evident only 2 weeks after ending TET administration and it required more than 4 weeks to be completed. EGB therapy markedly decreased the vacuolation, as well as the abnormal levels of water and sodium contents, 1 week after beginning the treatment. Less influence of EGB was observed at the later stages. During spontaneous recovery, astroglial cells in the edematous white matter of TET-intoxicated animals showed short and swollen processes containing few organelles, low levels of NADH- and NADPH-tetrazolium reductase activities and glial fibrillary acidic protein (GFAP)-immunofluorescence for about 2 weeks. During EGB therapy the astrocytes regained their cellular processes, containing intense oxidative enzyme activities and GFAP-immunofluorescence as early as after 1 week of treatment. In the EM, astrocytes often appeared hypertrophic, surrounding myelin vacuoles and displaying phagocytosis of myelin debris. We conclude that EGB can accelerate the reabsorption of TET-induced cerebral edema and improve the astroglial reaction.