Journal of Alzheimer's Disease - Volume 55, issue 3

Authors: Anderson, Maria | Xu, Feng | Ou-Yang, Ming-Hsuan | Davis, Judianne | Van Nostrand, William E. | Robinson, John K.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-β protein (Aβ) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of ‘brain-training games.’ In the present …study, we developed a highly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Aβ deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through a series of domain-specific tasks for an average of 4 months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to a measurable reduction in AD pathology or an improvement in general brain health. Show more

Keywords: Alzheimer’s disease, amyloid-beta, Barnes maze, cerebral amyloid angiopathy, cognitive training, transgenic mouse

DOI: 10.3233/JAD-160674

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1109-1121, 2017

Authors: Lin, Katherine Amy | Rundel, Colin | Doraiswamy, P. Murali | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Prior studies have noted gender differences in cognition, imaging, and pathological markers in mild cognitive impairment (MCI) subjects. Sex hormone-binding globulin (SHBG), a major controlling factor in the proportion of bioavailable versus bound testosterone and estrogen, has been proposed to contribute to links between hormones and dementia, but has not yet been investigated fully in a prospective biomarker trial. Objective: This study examined whether, among subjects with MCI, SHBG levels predict future rate of cognitive decline. Methods: We examine the effect of gender on cognitive decline and factors modulating potential gender differences in 378 …MCI subjects (134 females, 244 males) in the Alzheimer’s Disease Neuroimaging Initiative-1 (ADNI-1), followed for up to 8 years (mean ± SE, 4.0 ± 0.1 years). Cognition was assessed using the ADAS-cog-11. Multivariate models examined the effect of gender covarying for age, ApoE4, baseline cognition, years of education, and SHBG levels. Results: MCI women declined significantly faster than men in cognition over the follow up period. Baseline SHBG levels differed significantly between men and women (p  < 0.0001), and by age in men, but not by ApoE4 status. In the multivariate models, SHBG levels were not a significant predictor of cognitive decline in men or women but ApoE4 status, baseline cognition, years of education, and female gender were. Conclusion: SHBG levels did not influence the rate of cognitive decline in MCI. Further studies to confirm these findings and uncover other potential mechanisms of gender differences in the risk for AD may be warranted. Show more

Keywords: Amyloid-β, apolipoprotein E4, secondary prevention, sex differences, sex hormone-binding globulin

DOI: 10.3233/JAD-160513

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1123-1130, 2017

Authors: Cummings, Jeffrey | Scheltens, Philip | McKeith, Ian | Blesa, Rafael | Harrison, John E. | Bertolucci, Paulo H.F. | Rockwood, Kenneth | Wilkinson, David | Wijker, Wouter | Bennett, David A. | Shah, Raj C.

Article Type: Research Article

Abstract: Background: Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes. Objective: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. Methods: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer’s disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral …outcomes. Effect size was determined by calculating Cohen’s d statistic (or Cramér’s V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations. Results: In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: –0.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the co-primary outcome of Souvenir I (Wechsler memory scale delayed recall). No effect was shown on cognition in patients with mild-to-moderate AD (S-Connect). The number needed to treat (6 and 21 for Souvenir I and II, respectively) and high number needed to harm values indicate a favorable harm:benefit ratio for Souvenaid versus control in patients with mild AD. Conclusions: The favorable safety profile and impact on outcome measures converge to corroborate the putative mode of action and demonstrate that Souvenaid can achieve clinically detectable effects in patients with early AD. Show more

Keywords: Alzheimer’s disease, effect size, number-needed-to-treat, Souvenaid

DOI: 10.3233/JAD-160745

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1131-1139, 2017

Authors: Turnbull, Marion T. | Coulson, Elizabeth J.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disease that destroys memory and cognitive function. Aggregates of hyperphosphorylated tau protein are a prominent feature in the brain of patients with AD, and are a major contributor to neuronal toxicity and disease progression. However, the factors that initiate the toxic cascade that results in tau hyperphosphorylation in sporadic AD are unknown. Here we investigated whether degeneration of basal forebrain cholinergic neurons (BFCNs) and/or a resultant decrease in neurotrophin signaling cause aberrant tau hyperphosphorylation. Our results reveal that the loss of BFCNs in pre-symptomatic pR5 (P301L) tau transgenic mice results in a decrease in hippocampal brain-derived neurotrophic …factor levels and reduced TrkB receptor activation. However, there was no exacerbation of the levels of phosphorylated tau or its aggregation in the hippocampus of susceptible mice. Furthermore the animals’ performance in a hippocampal-dependent learning and memory task was unaltered, and no changes in hippocampal synaptic markers were observed. This suggests that tau pathology is likely to be regulated independently of BFCN degeneration and the corresponding decrease in hippocampal neurotrophin levels, although these features may still contribute to disease etiology. Show more

Keywords: Alzheimer’s disease, basal forebrain, brain-derived neurotrophic factor (BDNF), cholinergic neuron, hippocampus, lesion, neurotrophin, tau hyperphosphorylation

DOI: 10.3233/JAD-160805

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1141-1154, 2017

Authors: Beesley, Stephen | Olcese, James | Saunders, Charles | Bienkiewicz, Ewa A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the leading cause of dementia, and as its prevalence increases, so does its detrimental impact on society. The currently available therapies have limited efficacy, leaving AD patients on an irrevocably fatal path of this disease. Objective: The purpose of this study was to test efficacy of a novel combinatorial treatment approach to alleviate AD-like pathology. Methods: We selected four naturally occurring compounds and used them in different combinations to test their effect on AD-like pathology. Employing a well-established cell culture AD model system, we evaluated levels of several diverse biomarkers …associated with a number of cellular pathways associated with AD. The readouts included: amyloid-β peptides, anti-inflammatory and anti-apoptotic proteins, oxidative enzymes, and reactive oxygen species. Results: Using this approach, we demonstrated that the compounds delivered in combination had higher efficacy than individual treatments. Specifically, we observed significant reduction in levels of the amyloid-β peptides, as well as pro-inflammatory proteins and reactive oxygen species. Similarly, delivery of compounds in combination resulted in an increased expression of anti-apoptotic proteins and anti-oxidative enzymes. Collectively, these modifications in AD pathology biomarkers reflect a promising therapeutic and preventive strategy to combat this disease. Conclusion: The above findings support a novel therapeutic approach to address a currently unmet medical need, which would benefit not only AD patients and their caregivers, but also society as a whole. Show more

Keywords: Alzheimer’s disease, combinatorial treatment, (–)-epigallocatechin-3-gallate, melatonin, multi-target, N2aneuroblastoma cells, resveratrol, vitamin B12

DOI: 10.3233/JAD-160459

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1155-1166, 2017

Authors: Kuuluvainen, Liina | Pöyhönen, Minna | Pasanen, Petra | Siitonen, Maija | Rummukainen, Jaana | Tienari, Pentti J. | Paetau, Anders | Myllykangas, Liisa

Article Type: Research Article

Abstract: Mutations in the progranulin (GRN ) gene represent about 5–10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers’ blood samples. In conclusion, we describe a novel …GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype. Show more

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, mutation, progranulin (GRN), TDP-43

DOI: 10.3233/JAD-160647

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1167-1174, 2017

Authors: Lee, Moonhee | Guo, Jian-Ping | Kennedy, Krista | McGeer, Edith G. | McGeer, Patrick L.

Article Type: Research Article

Abstract: We have developed a non-invasive method of diagnosing Alzheimer’s disease (AD), which can also predict the risk of its future onset. It is based on measuring salivary levels of amyloid-β protein terminating at position 42 (Aβ42 ). Brain deposits of this peptide are characteristic of AD. Biomarker studies indicate that such brain deposits commence a decade or more prior to clinical onset of the disease. We report here that Aβ42 is produced in all peripheral organs tested, thus establishing the generality of its production. We used this information to develop simple and sensitive tests to determine salivary Aβ42 levels. The …levels were first stabilized by adding thioflavin S as an anti-aggregation agent and sodium azide as an anti-bacterial agent. We then quantitated the Aβ42 in a series of samples with ELISA type tests. Control cases showed almost identical levels of salivary Aβ42 regardless of sex or age. All AD cases secreted levels of Aβ42 more than double those of controls. Individuals at elevated risk of developing AD secreted levels comparable to the AD cases. The results establish that salivary Aβ42 levels can be used to diagnose AD as well as to predict the risk of its future onset. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, amyloid-β protein precursor, ELISA type assays, saliva, thioflavin S

DOI: 10.3233/JAD-160748

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1175-1182, 2017

Authors: Yates, Jennifer A. | Clare, Linda | Woods, Robert T. | in collaboration with The Cognitive Function and Ageing Study: Wales

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) often co-exists with mood problems, and both cognitive functioning and mood are known to be linked with health. This study aims to investigate how health, mood, and cognitive impairment interact. Health is often assessed using a single proxy measure, but the use of a range of measures can provide a more informative picture and allows for combination into a comprehensive measure of health. We report an analysis of data from the Cognitive Function and Ageing Study Wales (CFAS Wales, N = 3,173), in which structured interviews with older people captured measures of cognition, mood, and health. Each measure …of health was assessed independently in relation to cognition and mood, and then all measures were combined to form a latent health variable and tested using structural equation modeling (SEM). SEM confirmed the association between health and cognition, with depression acting as a mediator. All measures of health were individually associated with levels of anxiety and depression. Participants reporting mood problems were less likely to engage in physical activity and more likely to report poor or fair health, have more comorbid health conditions, use more services, and experience difficulties with instrumental activities of daily living. Perceived health was associated with cognitive status; participants with MCI were more likely to report fair or poor health than participants who were cognitively unimpaired. Careful intervention and encouragement to maintain healthy lifestyles as people age could help to reduce the risk of both mood problems and cognitive decline. Show more

Keywords: Anxiety, cognitive impairment, depression, health

DOI: 10.3233/JAD-160611

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1183-1193, 2017

Authors: Ochoa, John Fredy | Alonso, Joan Francesc | Duque, Jon Edinson | Tobón, Carlos Andrés | Mañanas, Miguel Angel | Lopera, Francisco | Hernández, Alher Mauricio

Article Type: Research Article

Abstract: Background: Recent studies report increases in neural activity in brain regions critical to episodic memory at preclinical stages of Alzheimer’s disease (AD). Although electroencephalography (EEG) is widely used in AD studies, given its non-invasiveness and low cost, there is a need to translate the findings in other neuroimaging methods to EEG. Objective: To examine how the previous findings using functional magnetic resonance imaging (fMRI) at preclinical stage in presenilin-1 E280A mutation carriers could be assessed and extended, using EEG and a connectivity approach. Methods: EEG signals were acquired during resting and encoding in 30 normal …cognitive young subjects, from an autosomal dominant early-onset AD kindred from Antioquia, Colombia. Regions of the brain previously reported as hyperactive were used for connectivity analysis. Results: Mutation carriers exhibited increasing connectivity at analyzed regions. Among them, the right precuneus exhibited the highest changes in connectivity. Conclusion: Increased connectivity in hyperactive cerebral regions is seen in individuals, genetically-determined to develop AD, at preclinical stage. The use of a connectivity approach and a widely available neuroimaging technique opens the possibility to increase the use of EEG in early detection of preclinical AD. Show more

Keywords: Alzheimer’s disease, autosomal-dominant, electroencephalography, functional neuroimaging, memory encoding, presenilin-1

DOI: 10.3233/JAD-160803

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1195-1205, 2017

Authors: Cohen-Manheim, Irit | Doniger, Glen M. | Sinnreich, Ronit | Simon, Ely S. | Murad, Havi | Pinchas-Mizrachi, Ronit | Kark, Jeremy D.

Article Type: Research Article

Abstract: Background: Whether life course anthropometric indices relate to cognitive function in midlife remains insufficiently explored. Rarely was socioeconomic position (SEP) adequately accounted for. Objective: To examine the association of the cumulative life course burden of high-ranked body mass index (BMI), its trajectory, and stature with cognitive function in midlife. Methods: Weight and height were measured from age 17 across a 33-year follow-up. 507 individuals completed a NeuroTrax computerized cognitive assessment at ages 48–52. Life course SEP was assessed by multiple methods. Using mixed models we calculated the area under the curve (AUC), representing both the life-course burden of BMI …(total AUC) and trends in BMI (incremental AUC) from age 17 to midlife. The associations of BMI and height with global cognition and its five component domains were assessed by multiple regression. Results: Higher BMI in late adolescence and total AUC over the life course were associated with poorer global cognition (Standardized beta (Beta) = –0.111, p  = 0.005 and Beta = –0.105, p  = 0.018, respectively), adjusted for childhood and adulthood SEP, and demographic characteristics. The associations with higher adolescent and midlife BMI were both restricted to those with low childhood SEP (p  < 0.05 for interaction). Short adolescent stature was related to poorer cognition (Beta = 0.115, p  = 0.040), whereas late final growth in women was associated with better cognition (Beta = 0.213, p  = 0.007). Conclusion: An adverse association of higher BMI with cognitive function began in adolescence and was restricted to low childhood SEP. Taller stature in both sexes and late growth in women were associated with better midlife cognitive performance. Show more

Keywords: Adolescence, body mass index, BMI change, cognition, cognitive aging, height, height change, life course epidemiology, obesity

DOI: 10.3233/JAD-160843

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1207-1221, 2017