The authors will present a comprehensive account of the neurological aspects of SARS-CoV-2 infect... more The authors will present a comprehensive account of the neurological aspects of SARS-CoV-2 infection. The aim is to provide a practical clinical book which will serve as a guide for clinicians from all specialties involved in the management of COVID-19 patients. The authors share the extensive clinical experience gained in major hospitals in Lombardy, the first European region to face the COVID-19 emergency in 2020. All are recognized international experts in their respective fields and have been involved in the management of COVID-19 cases from the very beginning of the Italian SARS-CoV-2 outbreak. The text begins with a description of pathobiological and pathophysiological aspects related to the involvement of the nervous system, moving on to the discussion of the neurological complications observed in COVID-19 patients; these range from central to peripheral symptoms, and can occur in the acute or post-acute phases of the disease. Further topics are: neuropathology, seizures and ...
ABSTRACT Background: Inflammation and excitotoxicity play important roles in the pathophysiology ... more ABSTRACT Background: Inflammation and excitotoxicity play important roles in the pathophysiology of ischemic brain damage. In previous studies we have shown a prolonged TNF-alpha (TNF-a) release, a long lasting high glutamate (glu) plasma concentration and an impaired platelet (plt) glu transport up to 3 months after the symptoms onset. Since high persisting plasmatic levels of TNF-a have been detected in stroke patients, we aimed to determine whether TNF-a administration could be sufficient to cause a defective plt glutamate uptake. Methods: Human blood plt were selected as a peripheral model of glutamate transport. 10 stroke patients and 20 control subjects were enrolled to test [H3]glu uptake after stimulation with increasing doses of TNF-a (10, 20 and 40ng/ml). Results: Plt from healthy subjects displayed a dose related reduction of glu uptake after TNF-a stimulation (total glu uptake decrease -35%). The reduction was less extensive in plt from stroke patients, possibly due to the demonstrated higher levels of plasmatic TNF-a in patients affected by stroke. Discussion: We showed that in-vitro administration of high concentration of TNF-a is able to effectively reduce glu uptake in human plt. The results suggest that the increase in plasmatic TNF-a in stroke patients may be responsible for the demonstrated reduction of plt glu uptake. Since decreased plt glu uptake could result in increased plasmatic glu levels, which in turn may generate a possible excitotoxic damage, pharmacological modulation of TNF-a levels might be helpful in the management of cerebrovascular patients.
Journal of Alzheimer's disease : JAD, Jan 28, 2017
The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumula... more The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer's disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation. Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia. We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP). In AD patients, the prevalence of epilepsy of unknown origin, ...
Journal of geriatric psychiatry and neurology, Jan 20, 2014
We analyzed scores obtained at the Neuropsychiatric Inventory (NPI) by 20 patients with posterior... more We analyzed scores obtained at the Neuropsychiatric Inventory (NPI) by 20 patients with posterior cortical atrophy (PCA) and contrasted it with 20 patients having Alzheimer disease (AD). Patients with hallucinations and delusions were not included due to the high probability of a diagnosis of Lewy body disease. Prevalence of behavioral and psychological symptoms (BPSD) was 95% in the PCA group, the most frequent being apathy and anxiety. Cluster analysis on NPI subscales highlighted a behavioral subsyndrome characterized by agitated temper and irritability. Depression, anxiety, and apathy did not cluster with any other BPSD nor with each other. The PCA group showed a significantly higher proportion of anxious patients and worse anxiety score than patients with AD. No correlation was found between NPI data and demographic, clinical, or neuropsychological features nor were there significant differences for the same variables between anxious and nonanxious cases with PCA. In agreement ...
Since the proposal that excessive glutamatergic stimulation could be responsible for neuronal suf... more Since the proposal that excessive glutamatergic stimulation could be responsible for neuronal suffering and death, excitotoxicity and glutamate uptake deficits have been repeatedly confirmed to play a key role in the pathogenesis of different neurological diseases. Therefore, it is conceivable that assessing the glutamatergic system function directly in patients could be extremely useful for early diagnosis, prognostic evaluation, and optimization of the therapy. A possibility is offered by assessing glutamate levels in biological fluid, such as plasma and CSF, where increased levels of this amino acid have been reported in patients affected by stroke, amyotrophic lateral sclerosis (ALS), and AIDS dementia complex. However, the metabolic role of this amino acid acts as a confounding factor, and the possibility of directly assessing glutamatergic functional parameters, such as amino acid reuptake, would probably mirror closely the actual excitotoxic damage operative in each patient. Here we will describe our findings obtained in peripheral ex vivo cells, such as platelets and fibroblasts, both displaying a functional glutamate reuptake system. Consistent with a systemic-impairment assumption, glutamate uptake was shown to be reduced in peripheral cells of Alzheimer's disease, Down syndrome, Parkinson's disease, ALS, and stroke patients. Different systemic factors might be responsible for this phenomenon, including genetic predisposition, oxidative stress, and inflammatory response, raising new, exciting questions about the relevance of their possible interactions for the pathogenesis of neurological disorders.
The unquestionable advantages provided by modern neuroimaging techniques have recently led some t... more The unquestionable advantages provided by modern neuroimaging techniques have recently led some to question the duty of the neurologist, traditionally struggling first and foremost to establish the semeiotic localization of brain lesions and only then to interpret them. The present brief report of six clinical patients who came recently to our attention aims to emphasize that the interpretation of neuroimaging results always requires integration with anamnestic, clinical and laboratory data, together with knowledge of nosography and the literature. The solutions of the reported cases always originated from close interaction between the neurologist and the neuroradiologist, based on the initial diagnostic uncertainty linked to the finding of isolated or multiple brain target or ring lesions, too often considered paradigmatic examples of the pathognomonic role of neuroimaging.
Genetic risk factors seem to play a role in sporadic Parkinson's disease (PD), maybe trig... more Genetic risk factors seem to play a role in sporadic Parkinson's disease (PD), maybe triggering oxidative stress and excitotoxicity within substantia nigra. However, genetic factors act at systemic level: reduced activity of mitochondrial enzymes and decreased glutamate uptake have been shown in platelets from PD patients. In this study we investigated glutamate uptake in platelets from 38 sporadic PD patients, 13 patients with parkinsonian syndromes and 28 controls and assessed polymorphisms of alpha-synuclein and ApoE genes. A 48% reduction of glutamate uptake p)<0.0001) was observed in PD patients which, with respect to control groups, correlated with the disease severity (r = -0.44, p < 0.05). Genetic studies of this population did not show differences between PD and controls, nor correlations with platelet glutamate uptake.
Background: It is conceivable that an early therapeutic intervention in amyotrophic lateral scler... more Background: It is conceivable that an early therapeutic intervention in amyotrophic lateral sclerosis (ALS) would lead to better results in terms of disease progression for these patients. One possible strategy to increase the sensitivity of the diagnosis is represented by the use of biological parameters reflecting, for example, oxidative stress alterations associated with ALS. Such biomarkers would be valuable tools both for a better diagnostic evaluation and for studying the impact of therapeutic interventions on the disease course. A special category of experimental models is represented by peripheral cells obtained directly from patients (ex vivo). Objective: In this study, primary fibroblasts obtained from 10 sporadic ALS (SALS) patients and 10 healthy matched controls were used to investigate a panel of parameters related to the oxidative status. Methods: Reactive oxygen species production, protein carbonylation and nitration, susceptibility to hydrogen peroxide exposure, p38...
The authors will present a comprehensive account of the neurological aspects of SARS-CoV-2 infect... more The authors will present a comprehensive account of the neurological aspects of SARS-CoV-2 infection. The aim is to provide a practical clinical book which will serve as a guide for clinicians from all specialties involved in the management of COVID-19 patients. The authors share the extensive clinical experience gained in major hospitals in Lombardy, the first European region to face the COVID-19 emergency in 2020. All are recognized international experts in their respective fields and have been involved in the management of COVID-19 cases from the very beginning of the Italian SARS-CoV-2 outbreak. The text begins with a description of pathobiological and pathophysiological aspects related to the involvement of the nervous system, moving on to the discussion of the neurological complications observed in COVID-19 patients; these range from central to peripheral symptoms, and can occur in the acute or post-acute phases of the disease. Further topics are: neuropathology, seizures and ...
ABSTRACT Background: Inflammation and excitotoxicity play important roles in the pathophysiology ... more ABSTRACT Background: Inflammation and excitotoxicity play important roles in the pathophysiology of ischemic brain damage. In previous studies we have shown a prolonged TNF-alpha (TNF-a) release, a long lasting high glutamate (glu) plasma concentration and an impaired platelet (plt) glu transport up to 3 months after the symptoms onset. Since high persisting plasmatic levels of TNF-a have been detected in stroke patients, we aimed to determine whether TNF-a administration could be sufficient to cause a defective plt glutamate uptake. Methods: Human blood plt were selected as a peripheral model of glutamate transport. 10 stroke patients and 20 control subjects were enrolled to test [H3]glu uptake after stimulation with increasing doses of TNF-a (10, 20 and 40ng/ml). Results: Plt from healthy subjects displayed a dose related reduction of glu uptake after TNF-a stimulation (total glu uptake decrease -35%). The reduction was less extensive in plt from stroke patients, possibly due to the demonstrated higher levels of plasmatic TNF-a in patients affected by stroke. Discussion: We showed that in-vitro administration of high concentration of TNF-a is able to effectively reduce glu uptake in human plt. The results suggest that the increase in plasmatic TNF-a in stroke patients may be responsible for the demonstrated reduction of plt glu uptake. Since decreased plt glu uptake could result in increased plasmatic glu levels, which in turn may generate a possible excitotoxic damage, pharmacological modulation of TNF-a levels might be helpful in the management of cerebrovascular patients.
Journal of Alzheimer's disease : JAD, Jan 28, 2017
The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumula... more The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer's disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation. Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia. We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP). In AD patients, the prevalence of epilepsy of unknown origin, ...
Journal of geriatric psychiatry and neurology, Jan 20, 2014
We analyzed scores obtained at the Neuropsychiatric Inventory (NPI) by 20 patients with posterior... more We analyzed scores obtained at the Neuropsychiatric Inventory (NPI) by 20 patients with posterior cortical atrophy (PCA) and contrasted it with 20 patients having Alzheimer disease (AD). Patients with hallucinations and delusions were not included due to the high probability of a diagnosis of Lewy body disease. Prevalence of behavioral and psychological symptoms (BPSD) was 95% in the PCA group, the most frequent being apathy and anxiety. Cluster analysis on NPI subscales highlighted a behavioral subsyndrome characterized by agitated temper and irritability. Depression, anxiety, and apathy did not cluster with any other BPSD nor with each other. The PCA group showed a significantly higher proportion of anxious patients and worse anxiety score than patients with AD. No correlation was found between NPI data and demographic, clinical, or neuropsychological features nor were there significant differences for the same variables between anxious and nonanxious cases with PCA. In agreement ...
Since the proposal that excessive glutamatergic stimulation could be responsible for neuronal suf... more Since the proposal that excessive glutamatergic stimulation could be responsible for neuronal suffering and death, excitotoxicity and glutamate uptake deficits have been repeatedly confirmed to play a key role in the pathogenesis of different neurological diseases. Therefore, it is conceivable that assessing the glutamatergic system function directly in patients could be extremely useful for early diagnosis, prognostic evaluation, and optimization of the therapy. A possibility is offered by assessing glutamate levels in biological fluid, such as plasma and CSF, where increased levels of this amino acid have been reported in patients affected by stroke, amyotrophic lateral sclerosis (ALS), and AIDS dementia complex. However, the metabolic role of this amino acid acts as a confounding factor, and the possibility of directly assessing glutamatergic functional parameters, such as amino acid reuptake, would probably mirror closely the actual excitotoxic damage operative in each patient. Here we will describe our findings obtained in peripheral ex vivo cells, such as platelets and fibroblasts, both displaying a functional glutamate reuptake system. Consistent with a systemic-impairment assumption, glutamate uptake was shown to be reduced in peripheral cells of Alzheimer's disease, Down syndrome, Parkinson's disease, ALS, and stroke patients. Different systemic factors might be responsible for this phenomenon, including genetic predisposition, oxidative stress, and inflammatory response, raising new, exciting questions about the relevance of their possible interactions for the pathogenesis of neurological disorders.
The unquestionable advantages provided by modern neuroimaging techniques have recently led some t... more The unquestionable advantages provided by modern neuroimaging techniques have recently led some to question the duty of the neurologist, traditionally struggling first and foremost to establish the semeiotic localization of brain lesions and only then to interpret them. The present brief report of six clinical patients who came recently to our attention aims to emphasize that the interpretation of neuroimaging results always requires integration with anamnestic, clinical and laboratory data, together with knowledge of nosography and the literature. The solutions of the reported cases always originated from close interaction between the neurologist and the neuroradiologist, based on the initial diagnostic uncertainty linked to the finding of isolated or multiple brain target or ring lesions, too often considered paradigmatic examples of the pathognomonic role of neuroimaging.
Genetic risk factors seem to play a role in sporadic Parkinson's disease (PD), maybe trig... more Genetic risk factors seem to play a role in sporadic Parkinson's disease (PD), maybe triggering oxidative stress and excitotoxicity within substantia nigra. However, genetic factors act at systemic level: reduced activity of mitochondrial enzymes and decreased glutamate uptake have been shown in platelets from PD patients. In this study we investigated glutamate uptake in platelets from 38 sporadic PD patients, 13 patients with parkinsonian syndromes and 28 controls and assessed polymorphisms of alpha-synuclein and ApoE genes. A 48% reduction of glutamate uptake p)<0.0001) was observed in PD patients which, with respect to control groups, correlated with the disease severity (r = -0.44, p < 0.05). Genetic studies of this population did not show differences between PD and controls, nor correlations with platelet glutamate uptake.
Background: It is conceivable that an early therapeutic intervention in amyotrophic lateral scler... more Background: It is conceivable that an early therapeutic intervention in amyotrophic lateral sclerosis (ALS) would lead to better results in terms of disease progression for these patients. One possible strategy to increase the sensitivity of the diagnosis is represented by the use of biological parameters reflecting, for example, oxidative stress alterations associated with ALS. Such biomarkers would be valuable tools both for a better diagnostic evaluation and for studying the impact of therapeutic interventions on the disease course. A special category of experimental models is represented by peripheral cells obtained directly from patients (ex vivo). Objective: In this study, primary fibroblasts obtained from 10 sporadic ALS (SALS) patients and 10 healthy matched controls were used to investigate a panel of parameters related to the oxidative status. Methods: Reactive oxygen species production, protein carbonylation and nitration, susceptibility to hydrogen peroxide exposure, p38...
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Papers by Carlo Ferrarese