Journal of Alzheimer's Disease - Volume 40, issue 3

Authors: Del Campo, Marta | Teunissen, Charlotte E.

Article Type: Review Article

Abstract: Alzheimer's disease (AD), the most common form of dementia, shares clinical and pathological similarities with familial British and Danish dementias (FBD and FDD). Whereas the etiology of sporadic AD remains unclear, familial AD is linked to mutations in amyloid-β protein precursor (AβPP), presenilin 1 (PS1), and presenilin 2 (PS2). Similarly, FBD and FDD originate from mutations in the BRI2 gene (or ITM2b), causing amyloid angiopathy and neurofibrillary tangles analogous to those observed in AD. Recent studies on the role of BRI2 in FBD and FDD have revealed that the three diseases may share pathophysiological pathways leading to dementia. Interestingly, BRI2 …is a potential regulator of AβPP processing, and it can inhibit the production and fibrillation of Aβ. This suggests a role of BRI2 in the amyloid cascade, which is the prevailing hypothesis about AD pathogenesis. To understand a possible relationship of BRI2 with AD, we reviewed the relevant studies on this protein. The data included not only the protein's structure, expression pattern, function, and involvement in FBD and FDD, but also its relationship with memory deficits and the main pathological proteins involved in AD. Thus, we highlight and discuss the potential links between BRI2 and AD, leading to the formulation of a modified hypothesis about AD etiology. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, familial British dementia (FBD), familial Danish dementia (FDD), integral membrane protein 2B (ITM2B/BRI2)

DOI: 10.3233/JAD-131364

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 481-494, 2014

Authors: Abisambra, Jose F. | Scheff, Stephen

Article Type: Review Article

Abstract: Traumatic brain injury (TBI) is the most common form of head injury and is a leading cause of death worldwide. Due to the vast variability in the types and severity of trauma, the cellular consequences of head injury are not completely understood. The development of reliable models of TBI will aid in understanding the molecular consequences of head trauma, and they will assist in identifying biological surrogate markers of the degree of damage and prognosis. In doing so, effective therapeutic strategies can be applied. Current in vivo experimental models yield important information, but they too have a significant amount of …variation. The goal of this review is to re-evaluate the use of these in vivo models of TBI and assess whether they correlate with the consequence of TBI in humans from the perspective of tau, an axonal microtubule-stabilizing protein. We present and discuss the current models of traumatic head injury, and we focus on those that assess changes in tau. We evaluate reports of TBI in humans that measured changes in tau and that were detectable in serum and cerebrospinal fluid, and as a pathological consequence in brain tissue. Show more

Keywords: Alzheimer's disease, chronic traumatic encephalopathy, tau, tau post-translational modification, traumatic brain injury

DOI: 10.3233/JAD-131019

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 495-518, 2014

Authors: Saharan, Sumiti | Mandal, Pravat K.

Article Type: Review Article

Abstract: With millions of older individuals presently suffering from Alzheimer's disease (AD) worldwide, AD is an unduly common form of dementia that exacts a heavy toll on affected individuals and their families. One of the emerging causative factors associated with AD pathology is oxidative stress. This AD-related increase in oxidative stress has been attributed to decreased levels of the brain antioxidant, glutathione (GSH). In this article, we review the role of GSH in AD from a pathological as well as a diagnostic point of view. We recapitulate the literature that has assessed the role of GSH in AD onset and progression. …We discuss the various methodologies through which alterations in GSH levels might be monitored, and highlight the yet uncharted potential of assaying GSH levels in vivo with magnetic resonance spectroscopy in AD therapeutics and prognostics. Finally, the present manuscript integrates findings from various studies to elucidate the possible molecular mechanisms through which disruptions in GSH homeostasis may contribute to AD pathology. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, biomarker, glutathione, oxidative stress

DOI: 10.3233/JAD-132483

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 519-529, 2014

Authors: Pertl, Marie-Theres | Benke, Thomas | Zamarian, Laura | Martini, Caroline | Bodner, Thomas | Karner, Elfriede | Delazer, Margarete

Article Type: Research Article

Abstract: Patients with mild cognitive impairment (MCI) are by definition still autonomous in daily life and therefore make their own decisions, for example, concerning their own or their partners' health care. Health care information typically contains complex mathematical constructs like proportions, probabilities, and survival rates. The purpose of this study was to investigate whether patients with MCI have difficulties with understanding health numeracy questions and to explore the impact of declining cognitive functions. The performance of 25 patients with MCI in a health numeracy questionnaire was compared with the performance of a control sample including 164 healthy older adults, matched in …age and educational level. Participants were asked to convert percentages, assess different probabilities, or understand the dosage of a short patient information leaflet. Additionally, neuropsychological background tests were administered. Patients with MCI answered fewer items correctly than controls in the health numeracy questionnaire. A correlation analysis showed statistically significant associations between performance in the health numeracy task and mental arithmetic, executive functions (psychomotor speed, conceptualization), and global cognitive status, respectively. Patients with MCI show problems in understanding numerical information concerning health care. Since patients with MCI are confronted with several health care decisions, special attention has to be paid to presenting information in an easily understandable way, to make additional sources of information available, and to provide adequate support. Show more

Keywords: Advanced age, cognition, decision making, health numeracy, mental arithmetic, mild cognitive impairment

DOI: 10.3233/JAD-131895

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 531-540, 2014

Authors: Royall, Donald R. | Palmer, Raymond F.

Article Type: Research Article

Abstract: Neuritic plaque (NP) formation can be dated in vivo. This analysis attempts to “date” the progression of neurofibrillary tangles (NFT) using the spatial distribution of NP as a reference. Autopsy data from 471 participants in the Honolulu-Asia Aging Study (HAAS) were combined into latent factor measures of NFT and NP counts. The variance in “early” and “late” NP pathology was used to estimate the spatial distribution of “early” and “late” NFT formation. A third latent factor representing “non-NP-related NFT” was also constructed. “Early” NP and “late” NP correlated significantly with objectively early and later cognitive performance, respectively. In contrast to …our expectations, neocortical NFT correlated best with “early” NP pathology, while NFT in allocortical structures correlated best with “late” NP pathology. Therefore, the NP-related fraction of NFT appears to be co-localized spatially with NP. However, since the latter evolve corticofugally in time, this suggests that NP-related NFT do so as well. Corticotropic NFT formation must therefore be either unrelated to NP formation, a temporally distinct process, or both. Show more

Keywords: Alzheimer's disease, dementia, mild cognitive impairment, neuropathology

DOI: 10.3233/JAD-131733

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 541-549, 2014

Authors: Buckley, Rachel F. | Saling, Michael M. | Irish, Muireann | Ames, David | Rowe, Christopher C. | Lautenschlager, Nicola T. | Maruff, Paul | Macaulay, S. Lance | Martins, Ralph N. | Masters, Colin L. | Rainey-Smith, Stephanie R. | Rembach, Alan | Savage, Greg | Szoeke, Cassandra | Ellis, Kathryn A. | the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) Research Group

Article Type: Research Article

Abstract: Background: Autobiographical memory (ABM) refers to the recollection of individual experiences, while personal semantic memory (PSM) refers to personally relevant, but shared, facts. Mild cognitive impairment (MCI) is routinely diagnosed with the aid of neuropsychological tests, which do not tap the ABM and PSM domains. Objective: We aimed to characterize the nature of ABM and PSM retrieval in cognitively healthy (HC) memory complainers, non-memory complainers, and MCI participants, and to investigate the relationship between neuropsychological tests and personal memory. Methods: Gender- and education-matched participants (HC = 80 and MCI = 43) completed the Episodic ABM Interview …(EAMI) and a battery of neuropsychological tests. Results: ABM and PSM did not differ between complainers and non-complainers, but were poorer in MCI participants, after accounting for age and depressive symptomatology. There were significant associations between personal memory and objective memory measures were found in MCI participants, but standard cognitive measures were more sensitive to MCI. Conclusion: Personal memory was compromised in MCI, reflected by lower scores on the EAMI. Memory complaining, assessed by current approaches, did not have an impact on personal memory. Standard subjective questionnaires might not reflect the sorts of concerns that bring individuals to clinical attention. Understanding personal memory function in the elderly may aid in the development of a more sensitive measure of subjective memory concerns. Show more

Keywords: Aging, Alzheimer dementia, autobiographical memory, cognitive function, episodic memory, mild cognitive impairment, subjective cognitive decline, subjective memory complaint

DOI: 10.3233/JAD-131820

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 551-561, 2014

Authors: Cunningham, Rebecca L. | Singh, Meharvan | O'Bryant, Sid E. | Hall, James R. | Barber, Robert C.

Article Type: Research Article

Abstract: Background: The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy have been equivocal. Objective: Given our prior pre-clinical studies that reported a major influence of oxidative stress on testosterone’s neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load. Methods: In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone correlated with cognition in a subset of the Texas Alzheimer’s Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n = …116) and Mexican-American (n = 117) men. We also assessed whether oxidative stress (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 and glutathione S-transferase (GST), varied as a function of circulating testosterone. Results: In a low oxidative stress environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high oxidative stress (homocysteine levels >12 µmol/L), testosterone and luteinizing hormone were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans. Conclusion: While testosterone may be beneficial under conditions of low oxidative stress, testosterone appears to have negative consequences under conditions of elevated oxidative stress, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST. Show more

Keywords: Androgens, antioxidants, homocysteine, luteinizing hormone, Mexican American

DOI: 10.3233/JAD-131994

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 563-573, 2014

Authors: Sui, Xiaojing | Ren, Xiaohu | Huang, Peiwu | Li, Shuiming | Ma, Quan | Ying, Ming | Ni, Jiazuan | Liu, Jianjun | Yang, Xifei

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common fatal neurodegenerative disease affecting the elderly worldwide. There is an urgent need to identify novel biomarkers of early AD. This study aims to search for potential early protein biomarkers in serum from a triple transgenic (PS1M146V /APPSwe /TauP301L ) mouse model. Proteomic analysis via two-dimensional fluorescence difference gel electrophoresis was performed on serum samples from wild-type (WT) and triple transgenic mice that were treated with or without coenzyme Q10 (CoQ10) (800 mg/kg body weight/day), a powerful endogenous antioxidant displaying therapeutic benefits against AD pathology and cognitive impairment in multiple AD mouse models, for …a period of three months beginning at two months of age. A total of 15 differentially expressed serum proteins were identified between the WT and AD transgenic mice. The administration of CoQ10 was found to alter the changes in the differentially expressed serum proteins by upregulating 10 proteins and down-regulating 10 proteins. Among the proteins modulated by CoQ10, clusterin and α-2-macroglobulin were validated via ELISA assay. These findings revealed significant changes in serum proteins in the AD mouse model at an early pathological stage and demonstrated that administration of CoQ10 could modulate these changes in serum proteins. Our study suggested that these differentially expressed serum proteins could serve as potential protein biomarkers of early AD and that screening for potential candidate AD therapeutic drugs and monitoring of therapeutic effects could be performed via measurement of the changes in these differentially expressed serum proteins. Show more

Keywords: Alzheimer's disease, coenzyme Q10, serum, triple transgenic (PS1M146V/APPSwe/TauP301L) mice, two-dimensional fluorescence difference gel electrophoresis

DOI: 10.3233/JAD-131823

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 575-586, 2014

Authors: Steenland, Kyle | Zhao, Liping | Goldstein, Felicia | Cellar, Janet | Lah, James | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Most studies evaluating Alzheimer's disease (AD) biomarkers longitudinally have studied patients with mild cognitive impairment (MCI) who progress to AD; data on normal subjects are scarce. We studied which biomarkers best predict cognitive decline on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) among those with normal cognition at baseline, and derived cut points to predict decline. We studied 191 subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had normal cognition at baseline, 2 + visits (mean follow-up 3.1 years), and data on neuropsychological tests, cerebrospinal fluid (CSF) biomarkers, and structural MRI. We used repeated measures linear regression of log …ADAS-Cog on age, race, gender, education, APOE4 status, baseline biomarker values, and follow-up time; an interaction between biomarker and time assessed predictive power. Neuropsychological tests did not significantly predict ADAS-Cog decline, while both MRI variables and CSF biomarkers did; CSF markers were the strongest predictors. Optimal cut points for baseline CSF markers to distinguish decliners were < 220 pg/ml (Aβ42 ), ≥61 pg/ml (t-tau), ≥21 pg/ml (p-tau), ≥0.31 (t-tau/Aβ42 ), and ≥0.10 (p-tau/Aβ42 ). For progression to MCI/AD (n = 28), the best markers were t-tau, t-tau/Aβ42 , and p-tau/Aβ42 , with optimal cut points of 58, 0.31, and 0.08, respectively. The optimal cut points across all markers and cut points predicted decline in ADAS-Cog, as well as transition to MCI, with a 65% accuracy. Our findings support current models of AD progression and suggest it is feasible to establish biomarker criteria to predict cognitive decline in individuals with normal cognition. Larger studies will be needed to more accurately characterize optimal cut points. Show more

Keywords: biomarkers, cerebrospinal fluid, cognition, mild cognitive impairment

DOI: 10.3233/JAD-2014-131343

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 587-594, 2014

Authors: O'Caoimh, Rónán | Healy, Liam | Gao, Yang | Svendrovski, Anton | Kerins, David M. | Eustace, Joseph | Kehoe, Patrick Gavin | Guyatt, Gordon | Molloy, D. William

Article Type: Research Article

Abstract: Background: Centrally acting angiotensin converting enzyme inhibitors (CACE-Is) are associated with reduced rates of cognitive decline in patients with dementia. CACE-Is may also improve exercise tolerance in functionally impaired older adults with normal cognition, suggesting that CACE-Is may positively influence activities of daily living (ADL) in dementia. Objective: To compare rates of decline in patients with mild to moderate Alzheimer’s disease (AD) receiving CACE-Is to those not currently treated with CACE-Is (NoCACE-I), included in the Doxycycline and Rifampicin for Alzheimer’s Disease study (n = 406). Methods: Patients were included if baseline and end-point (twelve months apart) …scores were available for measures including the Standardized Alzheimer’s Disease Assessment Scale – Cognitive Subscale; Quick Mild Cognitive Impairment screen; Clinical Dementia Rating Scale (CDR-SB), and Lawton-Brody ADL Scale. Results: There was a significant, 25% difference (median one-point) in the 12-month rate of decline in ADL scores in patients taking CACE-Is (n = 91), compared to the NoCACE-I group (n = 274), p = 0.024. This remained significant after adjusting for age, gender, education, and blood pressure, p = 0.034. When individual CACE-Is were compared to the NoCACE-I group, a significant reduction in the rate of decline in ADLs (median one versus four points), were only observed for perindopril, p = 0.01. The CDR-SB was also reduced (median one-point) for the perindopril compared to the NoCACE-I group, p = 0.04. Conclusion: This observational study suggests that CACE-Is, and potentially perindopril in particular, are associated with a reduced rate of functional decline in patients with AD, without an association with mood or behavior. This suggests that CACE-Is may slow disease progression in AD. Show more

Keywords: ACE inhibitors, Alzheimer's disease, cognitive, dementia, function, psychological decline

DOI: 10.3233/JAD-131694

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 595-603, 2014