Journal of Alzheimer's Disease - Volume 40, issue 2

Authors: Wharton, Whitney | Gleason, Carey E. | Dowling, N. Maritza | Carlsson, Cynthia M. | Brinton, Eliot A. | Santoro, M. Nanette | Neal-Perry, Genevieve | Taylor, Hugh | Naftolin, Frederick | Lobo, Rogerio A. | Merriam, George | Manson, JoAnn E. | Cedars, Marcelle I. | Miller, Virginia M. | Black, Dennis M. | Budoff, Matthew | Hodis, Howard N. | Harman, S. Mitchell | Asthana, Sanjay

Article Type: Research Article

Abstract: Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group, clinical trial, investigating the efficacy of low-dose, transdermal 17β-estradiol and oral conjugated equine estrogen on cognition. …All results are cross-sectional and represent baseline data only. Analyses confirm that the KEEPS-Cog cohort (n = 571) was middle aged (mean 52.7 years, range 42–59 years), healthy, and free of cognitive dysfunction. Higher systolic BP was weakly related to poorer performance in auditory working memory and attention (p = 0.004; adjusted for multiple comparisons p = 0.10). This relationship was not associated with endogenous hormone levels, and systolic BP was not related to any other cognitive domain. BP levels may be more sensitive than other vascular risk factors in detecting subtle differences in cognitive task performance in healthy, recently menopausal women. Lower BP early in menopause may affect cognitive domains known to be associated with AD. Show more

Keywords: Attention, blood pressure, clinical trial, cognition, estradiol, estrogen, hormone therapy, memory, vascular risk

DOI: 10.3233/JAD-130245

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 331-341, 2014

Authors: Nielsen, Henrietta M. | Hall, Sara | Surova, Yulia | Nägga, Katarina | Nilsson, Christer | Londos, Elisabet | Minthon, Lennart | Hansson, Oskar | Wennström, Malin

Article Type: Research Article

Abstract: The proteoglycan NG2 plays a major role in proliferation, migration, and differentiation of pericytes and NG2 cells in the brain. We have previously reported decreased soluble NG2 (sNG2) levels in cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) and a relationship between sNG2 and AD biomarkers in these patients. To further investigate whether alterations in sNG2 is specific to AD pathology, we measured levels of sNG2 in CSF from a patient cohort consisting of non-demented controls (n = 51), patients with Parkinson's disease (PD) (n = 61), and patients with dementia with Lewy bodies (DLB) (n = 37), two …synucleinopathies whereof the latter disorder frequently coincides with amyloid-β pathology similar to AD. We found decreased sNG2 concentrations in DLB patients, but not in PD patients, compared to controls. Levels of sNG2 in controls and PD patients correlated to T-tau, P-tau, α-synuclein, and neurosin. Only one correlation, between sNG2 and neurosin, was found in DLB patients. Analysis of a second cohort consisting of controls (n = 23) and DLB patients (n = 31) showed that the result was reproducible, as lower levels of sNG2 again were found in DLB patients compared to controls. We conclude that lower levels of sNG2 levels indicate a DLB-related impact on NG2 expressing cells foremost associated with neuropathology linked to accumulation of amyloid-β and not α-synuclein. Show more

Keywords: α-synuclein, Alzheimer's disease markers, amyloid-β, biomarker, cerebrospinal fluid, dementia with Lewy bodies, NG2, neurosin, Parkinson's disease, synucleinopathies

DOI: 10.3233/JAD-132246

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 343-350, 2014

Authors: Mroczko, Barbara | Groblewska, Magdalena | Zboch, Marzena | Kulczyńska, Agnieszka | Koper, Olga M. | Szmitkowski, Maciej | Kornhuber, Johannes | Lewczuk, Piotr

Article Type: Research Article

Abstract: Background: A growing body of evidence shows the involvement of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in neurodegeneration processes, but reports of their concentrations in the cerebrospinal fluid (CSF) are inconsistent. Objective: Therefore, the aim of our study was to evaluate the CSF concentrations of MMP-2, MMP-3, MMP-9, and their inhibitors (TIMP-1 and TIMP-2) in carefully selected groups of patients with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and non-demented controls, whose clinical and neuropsychological diagnoses were confirmed by the corresponding CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aβ1-42 and/or Aβ42/40 ratio, …and increased concentrations of Tau and pTau181 proteins. Methods: The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of MMPs and TIMPs were determined with ELISAs. Results: CSF concentrations of MMP-9 were significantly lower, and the concentrations of MMP-3 significantly higher in AD patients compared to the controls. Neither MMP-2 nor TIMPs showed significant changes among the groups investigated. Conclusion: Altered concentrations of two out of three MMPs investigated in this study suggest that this family of biomolecules may play a role in the AD pathophysiology. Further studies are needed to establish their potential diagnostic utility. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases

DOI: 10.3233/JAD-131634

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 351-357, 2014

Authors: Gray, Nora E. | Morré, Jeff | Kelley, Jeremiah | Maier, Claudia S. | Stevens, Jan F. | Quinn, Joseph F. | Soumyanath, Amala

Article Type: Research Article

Abstract: The accumulation of amyloid-β (Aβ) is a hallmark of Alzheimer's disease and is known to result in neurotoxicity both in vivo and in vitro. We previously demonstrated that treatment with the water extract of Centella asiatica (CAW) improves learning and memory deficits in Tg2576 mice, an animal model of Aβ accumulation. However the active compounds in CAW remain unknown. Here we used two in vitro models of Aβ toxicity to confirm this neuroprotective effect and identify several active constituents of the CAW extract. CAW reduced Aβ-induced cell death and attenuated Aβ-induced changes in tau expression and phosphorylation in both the …MC65 and SH-SY5Y neuroblastoma cell lines. We confirmed and quantified the presence of several mono- and dicaffeoylquinic acids (CQAs) in CAW using chromatographic separation coupled to mass spectrometry and ultraviolet spectroscopy. Multiple dicaffeoylquinic acids showed efficacy in protecting MC65 cells against Aβ-induced cytotoxicity. Isochlorogenic acid A and 1,5-dicaffeoylquinic acid were found to be the most abundant CQAs in CAW, and the most active in protecting MC65 cells from Aβ-induced cell death. Both compounds showed neuroprotective activity in MC65 and SH-SY5Y cells at concentrations comparable to their levels in CAW. Each compound not only mitigated Aβ-induced cell death, but was able to attenuate Aβ-induced alterations in tau expression and phosphorylation in both cell lines, as seen with CAW. These data suggest that CQAs are active neuroprotective components in CAW, and therefore are important markers for future studies on CAW standardization, bioavailability, and dosing. Show more

Keywords: Amyloid-β toxicity, caffeoylquinic acids, Centella asiatica, neuroprotection, tau

DOI: 10.3233/JAD-131913

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 359-373, 2014

Authors: García-Casares, Natalia | Berthier, Marcelo L. | Jorge, Ricardo E. | Gonzalez-Alegre, Pedro | Gutiérrez Cardo, Antonio | Rioja Villodres, José | Acion, Laura | Ariza Corbo, María José | Nabrozidis, Alejandro | García-Arnés, Juan A. | González-Santos, Pedro

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) is an emerging risk factor for cognitive impairment. Whether this impairment is a direct effect of this metabolic disorder on brain function, a consequence of vascular disease, or both, remains unknown. Structural and functional neuroimaging studies in patients with T2DM could help to elucidate this question. Objective: We designed a cross-sectional study comparing 25 T2DM patients with 25 age- and gender-matched healthy control participants. Clinical information, APOE genotype, lipid and glucose analysis, structural cerebral magnetic resonance imaging including voxel-based morphometry, and F-18 fluorodeoxyglucose positron emission tomography were obtained in all subjects. …Methods: Gray matter densities and metabolic differences between groups were analyzed using statistical parametric mapping. In addition to comparing the neuroimaging profiles of both groups, we correlated neuroimaging findings with HbA1c levels, duration of T2DM, and insulin resistance measurement (HOMA-IR) in the diabetic patients group. Results: Patients with T2DM presented reduced gray matter densities and reduced cerebral glucose metabolism in several fronto-temporal brain regions after controlling for various vascular risk factors. Furthermore, within the T2DM group, longer disease duration, and higher HbA1c levels and HOMA-IR were associated with lower gray matter density and reduced cerebral glucose metabolism in fronto-temporal regions. Conclusion: In agreement with previous reports, our findings indicate that T2DM leads to structural and metabolic abnormalities in fronto-temporal areas. Furthermore, they suggest that these abnormalities are not entirely explained by the role of T2DM as a cardiovascular risk factor. Show more

Keywords: cognition, magnetic resonance imaging, neuroimaging, positron emission tomography, type 2 diabetes mellitus

DOI: 10.3233/JAD-131736

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 375-386, 2014

Authors: Liu, Xuena | Wang, Siqi | Zhang, Xinqing | Wang, Zhiqun | Tian, Xiaojie | He, Yong

Article Type: Research Article

Abstract: We used resting-state functional magnetic resonance imaging to measure the amplitude of low-frequency fluctuations (ALFF) of intrinsic brain activity in 23 patients with moderate Alzheimer's disease (AD) and 27 age- and gender-matched healthy controls. Two different frequency bands were analyzed (slow-5:0.01–0.027 Hz; slow-4:0.027–0.073 Hz). In many brain regions, widespread ALFF differences between the two frequency bands were observed, including predominantly the posterior cingulate cortex/precuneus (PCC/PCu), hippocampus/parahippocampal gyrus (Hip/PHG), insula, thalamus, and basal ganglia. Compared to controls, AD patients showed decreased ALFF values in the bilateral PCC/PCu, inferior parietal lobe, and several temporal regions, and increased ALFF values mainly in the …bilateral Hip/PHG, and middle and inferior temporal gyri. Intriguingly, the ALFF abnormalities in the left PCu, left supramarginal gyrus, and several temporal regions were greater in the slow-5 band compared to the slow-4 band. Moreover, correcting for gray matter volume loss significantly affected the functional analytical results, suggesting that gray matter loss can partially account for the functional imaging analytical results obtained in AD. Finally, we showed that regions with changes in ALFF demonstrated a significant correlation with patient cognitive performance as measured using Mini-Mental State Examination scores. The results also demonstrated a significant correlation between hippocampal volume and the ALFF in slow-5 band in the AD group. This study demonstrated widespread ALFF abnormalities of intrinsic brain activity in AD and revealed that the ALFF abnormalities in severe specific regions were frequency-dependent. Taken together, our findings provided novel insights into the pathophysiological mechanism of AD and may be helpful in the development of imaging biomarkers for disease diagnosis. Show more

Keywords: Alzheimer's disease, amplitude of low-frequency fluctuation, intrinsic brain activity, resting-state functional magnetic resonance imaging

DOI: 10.3233/JAD-131322

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 387-397, 2014

Authors: Dias, Irundika H.K. | Polidori, Maria Cristina | Li, Li | Weber, Daniela | Stahl, Wilhelm | Nelles, Gereon | Grune, Tilman | Griffiths, Helen R.

Article Type: Research Article

Abstract: Elevated serum cholesterol concentrations in mid-life increase risk for Alzheimer's disease (AD) in later life. However, lower concentrations of cholesterol-carrying high density lipoprotein (HDL) and its principal apolipoprotein A1 (ApoA1) correlate with increased risk for AD. As HDL transports oxocarotenoids, which are scavengers of peroxynitrite, we have investigated the hypothesis that lower HDL and oxocarotenoid concentrations during AD may render HDL susceptible to nitration and oxidation and in turn reduce the efficiency of reverse cholesterol transport (RCT) from lipid-laden cells. Fasting blood samples were obtained from subjects with 1) AD without cardiovascular comorbidities and risk factors (AD); 2) AD with …cardiovascular comorbidities and risk factors (AD Plus); 3) normal cognitive function; for carotenoid determination by HPLC, analysis of HDL nitration and oxidation by ELISA, and 3 H-cholesterol export to isolated HDL. HDL concentration in the plasma from AD Plus patients was significantly lower compared to AD or control subject HDL levels. Similarly, lutein, lycopene, and zeaxanthin concentrations were significantly lower in AD Plus patients compared to those in control subjects or AD patients, and oxocarotenoid concentrations correlated with Mini-Mental State Examination scores. At equivalent concentrations of ApoA1, HDL isolated from all subjects irrespective of diagnosis was equally effective at mediating RCT. HDL concentration is lower in AD Plus patients' plasma and thus capacity for RCT is compromised. In contrast, HDL from patients with AD-only was not different in concentration, modifications, or function from HDL of healthy age-matched donors. The relative importance of elevating HDL alone compared with elevating carotenoids alone or elevating both to reduce risk for dementia should be investigated in patients with early signs of dementia. Show more

Keywords: Aging, Alzheimer's disease, free radical scavenger, 3-nitrotyrosine, protein carbonyl formation, protein oxidation

DOI: 10.3233/JAD-131964

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 399-408, 2014

Authors: Schmand, Ben | Rienstra, Anne | Tamminga, Hyke | Richard, Edo | van Gool, Willem A. | Caan, Matthan W.A. | Majoie, Charles B.

Article Type: Research Article

Abstract: Background: Scales of global cognition and behavior, often used as endpoints for intervention trials in Alzheimer’s disease (AD) and mild cognitive impairment (MCI), are insufficiently responsive (i.e., relatively insensitive to change). Large patient samples are needed to detect beneficial drug effects. Therefore, magnetic resonance imaging (MRI) measures of cerebral atrophy have been proposed as surrogate endpoints. Objective: To examine how neuropsychological assessment compares to MRI in this respect. Methods: We measured hippocampal atrophy, cortical thickness, and performance on neuropsychological tests in memory clinic patients at baseline and after two years. Neurologists rated the patients as cognitively …normal (n = 28; Clinical Dementia Rating, CDR = 0) or as impaired (n = 34; CDR > 0). We administered five tests of memory, executive functioning, and verbal fluency. A composite neuropsychological score was calculated by taking the mean of the demographically corrected standard scores. MRI was done on a 3 Tesla scanner. Volumetric measurements of the hippocampus and surrounding cortex were made automatically using FreeSurfer software. Results: The composite neuropsychological score deteriorated 0.6 SD in the impaired group, and was virtually unchanged in the normal group. Annual hippocampal atrophy rates were 3.4% and 0.6% in the impaired and normal cognition groups, respectively. Estimates of required sample sizes to detect a 50% reduction in rate of change were larger using rate of hippocampal atrophy (n = 131) or cortical thickness (n = 488) as outcome compared to change scores on neuropsychological assessment (n = 62). Conclusion: Neuropsychological assessment is more responsive than MRI measures of brain atrophy for detecting disease progression in memory clinic patients with MCI or AD. Show more

Keywords: Alzheimer's disease, cognition, hippocampus, longitudinal design, magnetic resonance imaging, mild cognitive impairment, neuropsychological tests, responsiveness

DOI: 10.3233/JAD-131484

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 409-418, 2014

Authors: Liu, Xinghua | Wang, Zhihong | Xia, Yiyuan | Yu, Guang | Zeng, Kuan | Luo, Hongbin | Hu, Jichang | Gong, Cheng-Xin | Wang, Jian-Zhi | Zhou, Xin-Wen | Wang, Xiao-Chuan

Article Type: Research Article

Abstract: Recent studies have reported a correlation between dementia and low blood pressure. How hypotension is associated with the increased risk of Alzheimer's disease (AD) remains unclear. Here we show that one month treatment of losartan, an angiotensin II type 1 (AT1) receptor antagonist, causes chronic and sustained hypotension, along with oxidative stress in adult male Sprague-Dawley rats. Furthermore, we show that losartan treatment increases the level of inactivated protein phosphatase 2A (PP2A) and the hyperphosphorylation of tau at Ser 199 and Ser 396. Rats treated with losartan present memory deficits and decreases in spine-density. These findings suggest that losartan-induced hypotension …may increase the risk of AD-like pathological alteration and behavioral impairment through oxidative stress which leads to tau hyperphosphorylation and loss of dendritic spines. Show more

Keywords: Alzheimer's disease, hypotension, losartan, memory deficit, oxidative stress, tau hyperphosphorylation

DOI: 10.3233/JAD-131679

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 419-427, 2014

Authors: Dalby, Nils Ole | Volbracht, Christiane | Helboe, Lone | Larsen, Peter Hjørringaard | Jensen, Henrik Sindal | Egebjerg, Jan | Elvang, Anders Brandt

Article Type: Research Article

Abstract: The formation of neurofibrillary tangles from the assembly of hyperphosphorylated tau leads to dendritic and axonal instability, synaptic degeneration, and neuronal loss. To understand the early physiological consequences of aberrant tau expression, we characterized the physiology of CA1 pyramidal neurons in rTg4510 female mice and non-transgenic (wt) littermate controls. We studied mice at the age of 10–12 weeks where only minimal hyperphosphorylated pretangle tau was present, and 22–24 weeks old mice with significant neurofibrillary tangle pathology. Our electrophysiological analysis included input–output relation, paired-pulse facilitation, and whole cell patch-clamp recordings of neurons to measure action potential threshold and action potential properties, …chord-conductance, and characterization of AMPA receptor mediated synaptic transmission. We found that the input–output relation in field (excitatory postsynaptic potentials, EPSP) and whole cell recordings (excitatory postsynaptic currents, EPSC) were impaired in rTg4510 mice compared to wt controls at both ages. We measured a diminished tail current charge after depolarizing voltage input in rTg4510 mice compared to wt in both young and aged mice. Additionally, mini-EPSC properties (peak and decay time) were essentially similar between genotypes and age groups investigated. Surprisingly, in the 22–24 week old group, the mini-EPSC frequency was significantly increased (interevent interval 0.8 ± 0.1 in wt compared to 0.3 ± 0.1 in rTg4510 mice). These data indicate that the developmentally regulated expression of human P301L tau in CA1 pyramidal neurons coincide with changes in neuronal excitability but also that significant presynaptic changes occur late during the progression of tau pathology in this mouse model. Show more

Keywords: CA1, excitatory postsynaptic currents, hippocampus, postsynaptic, presynaptic, readily releasable pool, rTg4510 model, tauopathy

DOI: 10.3233/JAD-131358

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 429-442, 2014