Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Feng, Lei | Langsetmo, Lisa | Yaffe, Kristine | Sun, Ye | Fink, Howard A. | Shikany, James M. | Leung, P.C. | Lane, Nancy E. | Cauley, Jane A. | Osteoporotic Fractures in Men (MrOS) Study Group

Article Type: Research Article

Abstract: Background: Accumulating evidence supports the neuroprotective effects of bioactive compounds from tea leaves. There are limited data from black tea consumption populations. Objective: To determine whether black tea consumption is associated with cognitive decline among older men. Methods: We chose to study the association between black tea consumption and cognition using data from the Osteoporotic Fractures in Men (MrOS) cohort, which collected information on tea consumption at baseline and has repeatedly assessed cognitive function in 3,844 men aged 65+ years (mean = 72.4 years). We defined tea drinkers as those who drank black tea at least …once per week and further grouped them into weekly drinkers and daily drinkers. Cognitive function was assessed at baseline and approximately 7 years later using the Modified Mini-Mental State Examination (3MSE). Multivariable logistic regression and linear regression models were constructed to assess the association between black tea consumption and risk of fast cognitive decline as a binary variable and change in 3MSE scores as continuous variable. Fast cognitive decline was defined as decline in 3MSE >1.5 standard deviation of mean change score. Models were adjusted for age, education level, and baseline cognitive scores. Results: Weekly and daily black tea drinkers were 24.8% and 12.4% of the study cohort, respectively. Fast cognitive decline occurred in 243 (6.3%) participants. Tea consumption was not associated with risk of cognitive decline, nor was tea associated with cognitive decline measured by absolute change in 3MSE scores. Conclusions: There was no association of black tea consumption and cognitive decline among older men in the US. Show more

Keywords: Aging, black tea, cognitive decline, men

DOI: 10.3233/JAD-180103

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2018

Authors: Guzmán-Vélez, Edmarie | Jaimes, Sehily | Aguirre-Acevedo, Daniel C. | Norton, Daniel J. | Papp, Kathryn V. | Amariglio, Rebecca | Rentz, Dorene | Baena, Ana | Henao, Eliana | Tirado, Victoria | Muñoz, Claudia | Giraldo, Margarita | Sperling, Reisa A. | Lopera, Francisco | Quiroz, Yakeel T.

Article Type: Research Article

Abstract: Background: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer’s disease (AD), and that can be used to reliably measure cognitive decline. Objective: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1 ) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. Methods: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included …in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). Results: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals’ estimated age of clinical onset. Conclusions: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD. Show more

Keywords: Confirmatory factor analysis, cognitive factors, episodic memory, executive function, preclinical Alzheimer’s disease, processing speed, contstartabstract

DOI: 10.3233/JAD-180078

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2018

Authors: Watad, Abdulla | Bragazzi, Nicola L. | Tiosano, Shmuel | Yavne, Yarden | Comaneshter, Doron | D. Cohen, Arnon | Amital, Howard

Article Type: Research Article

Abstract: Background: Neurological features are often overlooked in systemic sclerosis (SSc) patients and little is known about the link between dementia and SSc. Objectives: We sought to investigate whether an association exists between Alzheimer’s disease (AD) and SSc, as well as assess the impact of a dual diagnosis on mortality rates, by performing an extensive data analysis on a large subject sample. Methods: We utilized the medical database of the Clalit-Health-Services in a case-control study. Patients with SSc were compared with age- and sex-matched controls with regard to the prevalence of AD and its impact on their …mortality. Results: Our study included 2,431 SSc patients and 12,377 age- and sex-matched controls. The mean age of the study population was 63.32±18.06 years and the female to male ratio was 4.5:1. 134 (5.5%) cases had AD as a co-morbidity in comparison with 749 (5.9%) of the controls. The mortality rate was 12.5% among controls and 26.2% among SSc cases. On the Cox multivariate survival analysis, diagnosis of SSc and AD demonstrated significant HRs (2.35 (95% CI 2.05–2.69, p < 0.0001) and 2.19 (95% CI 1.94–2.48, p < 0.0001), respectively). SSc patients with AD had a relative risk of death of 2.35 (95% CI: 1.44–3.83) in comparison with SSc patients without AD. Conclusion: AD is a predictor of death in SSc and therefore preemptive screening may be warranted. Further studies are needed to evaluate whether improvements in the medical regimen for SSc may lead to a reduction in AD development and possibly to increased survival as well. Show more

Keywords: Alzheimer’s disease, autoimmune diseases, dementia, scleroderma, systemic sclerosis

DOI: 10.3233/JAD-180516

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. -, 2018

Authors: Gámez-Valero, Ana | Canet-Pons, Julia | Urbizu, Aintzane | Anillo, Ana | Santos, Cristina | Ariza, Aurelio | Beyer, Katrin

Article Type: Research Article

Abstract: Lewy body diseases (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer’s disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB ) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB , perform haplotype analysis for SNCB , and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported …for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB , determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher’s exact, chi-square, ANOVA tests, and the Δ Δ Ct method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB. Show more

Keywords: α-synuclein gene (SNCA), β-synuclein gene (SNCB), dementia with Lewy bodies, haplotypes, INDEL variations, Parkinson’s disease

DOI: 10.3233/JAD-180074

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Pandareesh, Mirazkar D. | Chauhan, Ved | Chauhan, Abha

Article Type: Research Article

Abstract: Our previous study has shown beneficial effects of walnuts on memory and learning skills in transgenic mouse model of Alzheimer’s disease (AD-tg). To understand underlying mechanism, we studied here whether walnuts can reduce oxidative stress in AD. From 4 months of age, experimental AD-tg mice were fed diets containing 6% (T6) or 9% walnuts (T9) (equivalent to 1 or 1.5 oz, of walnuts per day in humans) for 5, 10, or 15 months. The control groups, i.e., AD-tg (T0) and wild-type (Wt) mice, were fed diets without walnuts. The free radicals i.e., reactive oxygen species (ROS), lipid peroxidation, protein oxidation, …and antioxidant enzymes, were assessed in these mice at different ages. AD-tg mice on control diet (T0) showed significant age-dependent increase in ROS levels, lipid peroxidation, and protein oxidation coupled with impaired activities of antioxidant enzymes [superoxide dismutase, catalase, and glutathione peroxidase] compared to Wt mice. Oxidative stress was significantly reduced in AD-tg mice on diets with walnuts (T6, T9), as evidenced by decreased levels of ROS, lipid peroxidation, and protein oxidation, as well as by enhanced activities of antioxidant enzymes compared to T0 mice. Long-term supplementation with walnuts for 10 or 15 months was more effective in reducing oxidative stress in AD-tg mice. Our findings indicate that walnuts can reduce oxidative stress, not only by scavenging free radicals, but also by protecting antioxidant status, thus leading to reduced oxidative damage to lipids and proteins in AD. Therefore, by reducing oxidative stress, a walnut-enriched diet may help reduce the risk or delay the onset and progression of AD. Show more

Keywords: Alzheimer’s disease, antioxidants, catalase, glutathione, lipid peroxidation, liver, oxidative stress, protein oxidation, reactive oxygen species, superoxide dismutase, walnuts

DOI: 10.3233/JAD-180361

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Shao, Yi | Jiang, Hong | Wei, Yantao | Shi, Yingying | Shi, Ce | Wright, Clinton B. | Sun, Xiaoyan | Vanner, Elizabeth A. | Rodriguez, Anny D. | Lam, Byron L. | Rundek, Tatjana | Baumel, Barry S. | Gameiro, Giovana Rosa | Dong, Chuanhui | Wang, Jianhua

Article Type: Research Article

Abstract: Background: A detailed analysis of the tomographic thickness of intraretinal layers may provide more information on neurodegeneration in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Objective: The goal was to analyze tomographic thickness patterns of intraretinal layers in patients with AD andMCI. Method: Forty-nine patients (25 AD and 24 MCI) and 21 cognitively normal (CN) controls were imaged using ultra-high-resolution optical coherence tomography to obtain volumetric data centered on the fovea. The segmented intraretinal layers were retinal nerve fiber layer (RNFL), ganglion cell– inner plexiform layer (GCIPL), inner nuclear layer (INL), outer nuclear …layer (ONL), outer plexiform layer (OPL), and retinal photoreceptor (PR), in addition to the total retinal thickness(TRT). Results: The thickness differences were negative (thinning) mainly in TRT, RNFL, and GCIPL in both AD and MCI groups in comparison to CN, while the thickness differences were positive (thickening) mainly in ONL and PR in AD. GCIPL of AD and MCI was thinner in superior, nasal superior, and temporal superior quadrants, compared to CN (p < 0.05). GCIPL of the inner superior, inner nasal superior, inner temporal superior, and outer nasal superior sectors was significantly thinner in AD than CN (p < 0.05). GCIPL of the outer superior, inner temporal superior, outer nasal, and temporal superior sectors was significantly thinner in MCI than CN (p < 0.05). Conclusion: Focal thinning of the GCIPL was visualized and quantified by detailed partitions in AD and MCI, which provides specific information about neurodegeneration in MCI and AD. Show more

Keywords: Alzheimer’s disease, ETDRS partition, ganglion-inner plexiform layer, hemispheric partition, mild cognitive impairment, retinal thickness mapping, ultrahigh-resolution OCT, Zeiss elliptical partition

DOI: 10.3233/JAD-180070

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. -, 2018

Authors: Chen, Rui | Shi, Jiangwei | Yin, Qingsheng | Li, Xiaojin | Sheng, Yanyuan | Han, Juan | Zhuang, Pengwei | Zhang, Yanjun

Article Type: Research Article

Abstract: Diabetes mellitus is a metabolic disease often accompanied by a series of complications, such as diabetic nephropathy, retinopathy, and diabetic foot. The survival time of diabetics has been significantly prolonged due to advancements in medicine. However, the prolonged survival time for diabetics can increase the prevalence of diabetic central nervous system disease. Diabetic encephalopathy (DE) has become one of the main complications of the disease, and the main clinical manifestation of DE is cognitive dysfunction. However, the typical morphological and pathological characteristics of the brain in DE are rarely systematically reported. Thus, this phenomenon severely restricts the diagnosis and treatment …of DE. This article presents a description of the pathology characteristics of DE, including atrophy of the brain (gray matter, white matter, and hippocampus), changes in cerebrovascular morphology and function, impairment of synaptic plasticity, and dysfunction of neuroglia. In addition, abnormalities in the glymphatic clearance system of the brain are closely related to the progression of DE. A review of typical brain morphological and pathological characteristics would aid in the diagnosis and treatment of DE. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, diabetic encephalopathy, pathological characteristics, vascular dementia

DOI: 10.3233/JAD-180314

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Vandermeeren, Marc | Borgers, Marianne | Van Kolen, Kristof | Theunis, Clara | Vasconcelos, Bruno | Bottelbergs, Astrid | Wintmolders, Cindy | Daneels, Guy | Willems, Roland | Dockx, Koen | Delbroek, Lore | Marreiro, André | Ver Donck, Luc | Sousa, Cristiano | Nanjunda, Rupesh | Lacy, Eilyn | Van De Casteele, Tom | Van Dam, Debby | Paul De Deyn, Peter | Kemp, John | Malia, Thomas J. | Mercken, Marc H.

Article Type: Research Article

Abstract: The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer’s disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we …describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstrated to be isoform-selective (PT18 and hTau56) or phospho-selective (PT84). Evaluation of the antibodies in cellular- and in vivo seeding assays revealed clear differences in maximal efficacy. Limited proteolysis experiments support the hypothesis that some epitopes are more exposed than others in the tau seeds. Moreover, antibody efficacy seems to depend on the structural properties of fibrils purified from tau Tg mice- and postmortem human AD brain. Show more

Keywords: Epitope mapping, immunotherapy, in vivo seeding, tau antibodies

DOI: 10.3233/JAD-180404

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2018

Authors: Piton, Morgane | Hirtz, Christophe | Desmetz, Caroline | Milhau, Jacqueline | Lajoix, Anne Dominique | Bennys, Karim | Lehmann, Sylvain | Gabelle, Audrey

Article Type: Research Article

Abstract: As of 2018, Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. It contributes to a progressive neuron loss, deterioration of memory, and cognitive impairment. Current therapies may provide a symptomatic benefit, but do not treat the underlying process. Ongoing researches focus on understanding the causal mechanisms and finding neuropathological hallmarks of AD. Therapeutic approaches targeting senile plaques or neurofibrillary tangles have not yet resulted in a significant cognitive improvement. However, recent data according to the analysis of AD clinical trials (clinicaltrials.gov database) show promising results. This literature review aims at summarizing the recent advances and at highlighting …the most promising results of the ongoing researches. It compares the merits of small-molecules, antibodies, cell, and gene-based therapies and emphasizes the need for treatment at earlier stages of the disease. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, amyloid-β protein precursor secretases, cell- and tissue-based therapy, early onset, genetic therapy, immunotherapy, tau proteins

DOI: 10.3233/JAD-180145

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Lamartinière, Yordenca | Boucau, Marie-Christine | Dehouck, Lucie | Krohn, Markus | Pahnke, Jens | Candela, Pietra | Gosselet, Fabien | Fenart, Laurence

Article Type: Research Article

Abstract: The role of ABCA7 in brain homeostasis and Alzheimer’s disease (AD) is currently under intense scrutiny, since it has been reported that polymorphisms in the Abca7 gene and a loss of function of the protein are closely linked to excessive accumulation of amyloid peptides and disturbed cholesterol homeostasis. The blood-brain barrier (BBB), which isolates the brain from the blood compartment, is involved in both of these processes. We therefore hypothesized that ABCA7 downregulation might affect cholesterol and amyloid exchanges at the BBB. Using siRNA and primary cultures of mouse endothelial cells purified from brain microvessels and seeded on Transwell …® inserts, we investigated the role of ABCA7 in cholesterol and amyloid exchanges across the BBB. Our results showed that a decrease in ABCA7 expression at the BBB provokes in vitro a reduction in ABCA1 and a decrease in APOE secretion. In vitro , these decreases reduce cholesterol exchange across the BBB, particularly for high-density lipoproteins and ApoA-I particles. When ABCA7 was absent, we observed a reduction in Aβ peptide basolateral-to-apical transport in the presence of ApoA-I, with non-significant changes in the expression levels of Rage , Lrp1 , Abcb1 , Abcc1 , and Abcg2 . Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein’s involvement in cholesterol metabolism and amyloid clearance at the BBB. Show more

Keywords: ABCA7, Aβ peptides, Alzheimer’s disease, blood-brain barrier, cholesterol metabolism

DOI: 10.3233/JAD-170883

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2018