Journal of Alzheimer's Disease - Volume 76, issue 2

Authors: Xiao, Zhenxu | Wu, Wanqing | Zhao, Qianhua | Liang, Xiaoniu | Luo, Jianfeng | Ding, Ding

Article Type: Research Article

Abstract: Background: Growing evidence has shown the association between ophthalmic disorders and the risk of cognitive decline, but the conclusions were inconsistent. Objective: This study aimed to verify the hypothesis that glaucoma or cataract or their combination is associated with incident dementia in Chinese older adults. Methods: We followed up 1,659 non-demented community residents aged ≥60 years for an average of 5.2 years in the Shanghai Aging Study. Histories of glaucoma and cataract were collected based on self-report and medical record confirmation. Consensus diagnoses of incident dementia and Alzheimer’s disease (AD) were made based on neurological and …neuropsychological assessments. Results: During the follow-up, 168 cases (10.1%) of incident dementia and 124 cases (7.5%) of incident AD were identified. Participants with glaucoma at baseline had a significant risk of incident dementia (hazard ratio [HR] = 2.38, 95% confidence interval [CI] 1.08–5.23) and incident AD (HR = 2.77, 95% CI 1.17–6.56) after adjusting for confounders. There was no association between cataract and incident dementia (HR = 1.23, 95% CI 0.85–1.79) or AD (HR = 1.14, 95% CI 0.73–1.77). Those who had both glaucoma and cataract were more likely to develop dementia (HR = 3.08, 95% CI 1.29–7.37) and AD (HR = 3.72, 95% CI 1.52–9.14), compared to those without ophthalmic conditions. Conclusion: Glaucoma is an independent risk factor of incident dementia and AD. The comorbidity of glaucoma and cataract may significantly increase the risk of dementia and AD. Show more

Keywords: Alzheimer’s disease, cohort studies, cataract, dementia, glaucoma, ophthalmology

DOI: 10.3233/JAD-200295

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 529-537, 2020

Authors: Beam, Christopher R. | Kaneshiro, Cody | Jang, Jung Yun | Reynolds, Chandra A. | Pedersen, Nancy L. | Gatz, Margaret

Article Type: Research Article

Abstract: Background: While sex differences in incidence of Alzheimer’s disease (AD) and potential explanations have received considerable attention, less attention has been paid to possible sex differences in genetic risk for AD. Objective: We examined sex differences in genetic and environmental influences on disease risk and age at onset for All Dementia, AD Only, and Non-AD Dementia. Methods: Twin pairs were drawn from the Swedish Twin Registry. All Dementia analysis included 9,467 pairs; AD only, 8,696 pairs; and non-AD dementia, 8,195 pairs. APOE analyses included 1,740 individual twins with measured ɛ 4 alleles. Dementia diagnoses were …based on clinical workup and national health registry linkage. Results: Although within-pair correlations for All Dementia and AD Only were higher for women than for men, sex differences did not statistically differ for genetic or environmental etiology of All Dementia, AD Only, and Non-AD dementia. Similar results were observed when looking at specific genetic effects (APOE ɛ 4). Co-twin control analyses indicated that among twin pairs discordant for dementia, female twins without dementia had approximately 40% greater risk of developing dementia, compared with their male counterparts, in the 2–5 years following the first twin’s diagnosis. Conclusion: For All Dementia, AD Only, and Non-AD Dementia, genetic influences could be equated across sex. Co-twin analyses, however, suggest greater risk to female than to male co-twins of dementia cases even though sex differences in either genetic or shared environmental influences on the risk of dementia could not be differentiated. Show more

Keywords: Alzheimer’s disease, APOE ɛ4, sex differences, twin studies

DOI: 10.3233/JAD-191192

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 539-551, 2020

Authors: Hernandes-Alejandro, Mario | Montaño, Sarita | Harrington, Charles R. | Wischik, Claude M. | Salas-Casas, Andrés | Cortes-Reynosa, Pedro | Pérez Salazar, Eduardo | Cazares-Apatiga, Javier | Apatiga-Perez, Ricardo | Ontiveros Torres, Miguel Ángel | Perry, George | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: Background: Neurofibrillary tangles (NFTs) and amyloid plaques are the neuropathological hallmarks in brains with Alzheimer’s disease (AD). Post-translational modifications of tau, such as phosphorylation and truncation, have been proposed as initiators in the assembly of the abnormal paired helical filaments that constitute the NFTs. Neurons and NFTs are sites of matrix metalloproteinases (MMPs). Objective: The aim of this study was to analyze the relationship of MMP-9 and tau protein in brain samples with AD. Methods: This study was performed on brain tissue samples from patients with early, moderate, and late AD. MMPs and tau levels were …analyzed by western blot and gelatin-substrate zymography. Immunofluorescence techniques and confocal microscopy were used to analyze the presence of both proteins in NFTs. Further, molecular dynamics simulations (MDS) and protein-protein docking were conducted to predict interaction between MMP-9 and tau protein. Results: MMP-9 expression was greatest in moderate and late AD, whereas MMP-2 expression was only increased in late-stage AD. Interestingly, confocal microscopy revealed NFTs in which there was co-localization of MMP-9 and tau protein. MDS and protein-protein docking predictions indicate that a high-affinity complex can be formed between MMP-9 and full-length tau protein. Conclusion: These observations provide preliminary evidence of an interaction between these two proteins. Post-translational modifications of tau protein, such as C-terminal truncation or phosphorylation of amino acid residues in the MMP-9 recognition site and conformational changes in the protein, such as folding of the N-terminal sequence over the three-repeat domain, could preclude the interaction between MMP-9 and tau protein during stages of NFT development. Show more

Keywords: Alzheimer’s disease, matrix metalloproteinase-9, molecular dynamics simulation, protein-protein docking, tau protein

DOI: 10.3233/JAD-200146

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 553-569, 2020

Authors: Fazlollahi, Amir | Raniga, Parnesh | Bourgeat, Pierrick | Yates, Paul | Bush, Ashley I. | Salvado, Olivier | Ayton, Scott

Article Type: Research Article

Abstract: Background: Cortical iron accumulation has been reported as a pathological feature of Alzheimer’s disease (AD). The cause of cortical iron elevation in AD is unknown but may be contributed by hemosiderin deposits in cerebral microbleeds that frequently occur in this disease. Objective: To investigate the impact of cerebral microbleeds (which are more frequent in AD) on the magnetic susceptibility of the surrounding brain tissue. Methods: 32 MRI scans from the Australian Imaging, Biomarker and Lifestyle (AIBL) study were found to have cerebral microbleeds by manual assessment of susceptibility weighted images. Quantitative susceptibility mapping (QSM; an MRI …technique that is sensitive to iron) was used to estimate iron content in the tissue surrounding the microbleed in four concentric radii. Furthermore, the mirror regions on the contralateral hemisphere were also demarcated. A simulation analysis was conducted to investigate the effect of QSM imaging on cerebral microbleeds with varying sizes. Results: 77 microbleeds were identified from the available scans. The immediate proximal region to the cerebral microbleeds had enhanced tissue susceptibility (∼0.02 PPM), but importantly, this did not extend beyond one voxel radius. This finding with in vivo data was also replicated in a simulation study. However, the presence of microbleeds could lead to over-estimation of tissue QSM in unsupervised quantification, therefore processing methods to avoid this artefact without the need for their manual identification are proposed. Conclusion: The local changes in susceptibility due to microbleeds outside the focal lesion are restricted to 1 voxel and may be explained by partial voluming artefacts caused by limited imaging resolution. The susceptibly change induced by the microbleed is a relatively small proportion of tissue and could not account for regional iron changes observed in AD cortex. Show more

Keywords: Alzheimer’s disease, cerebral microbleeds, iron, magnetic resonance imaging, quantitative susceptibility mapping

DOI: 10.3233/JAD-200076

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 571-577, 2020

Authors: Barthold, Douglas | Joyce, Geoffrey | Ferido, Patricia | Drabo, Emmanuel F. | Marcum, Zachary A. | Gray, Shelly L. | Zissimopoulos, Julie

Article Type: Research Article

Abstract: Background: Four prescription drugs (donepezil, galantamine, memantine, and rivastigmine) are approved by the US FDA to treat symptoms of Alzheimer’s disease (AD). Even modest effectiveness could potentially reduce the population-level burden of AD and related dementias (ADRD), especially for women and racial/ethnic minorities who have higher incidence of ADRD. Objective: Describe the prevalence of antidementia drug use and timing of initiation relative to ADRD diagnosis among a nationally representative group of older Americans, and if there are disparities in prevalence and timing by sex and race/ethnicity. Methods: Descriptive analyses and logistic regressions of Medicare claims (2008–2016) …for beneficiaries who had an ADRD or dementia-related symptom diagnosis, or use of an FDA approved drug for AD. We investigate prevalence of use and timing of treatment initiation relative to ADRD diagnosis across time and beneficiary characteristics (age, sex, race/ethnicity, socioeconomic status, comorbidities). Results: Among persons diagnosed with ADRD or related symptoms, 33.3% used an approved drug over the study period. Odds of use was higher among Whites than non-Whites. Among ADRD drug users, 40% initiated use within 6 months of the initial ADRD or related symptoms diagnosis, and 16% initiated prior to a diagnosis. We observed disparities by race/ethnicity: 28% of Asians, 24% of Hispanics, 16% of Blacks, and 15% of Whites initiated prior to diagnosis. Conclusions: The use of antidementia drugs is relatively low and varies widely by race/ethnicity. Heterogeneity in timing of initiation and use may affect health and cost outcomes, but these effects merit further study. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease and related dementias, disparities, donepezil, galantamine, memantine, rivastigmine

DOI: 10.3233/JAD-200133

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 579-589, 2020

Authors: Prieto, Sarah | Valerio, Kate E. | Moody, Jena N. | Hayes, Scott M. | Hayes, Jasmeet P. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: A complex set of interactions between biological, genetic, and environmental factors likely underlies the development of Alzheimer’s disease (AD). Identifying which of these factors is most associated with AD is important for early diagnosis and treatment. Objective: We sought to examine genetic risk and structural brain volume on episodic memory in a sample of older adults ranging from cognitively normal to those diagnosed with AD. Methods: 686 adults (55–91 years old) completed a 3T MRI scan, baseline cognitive assessments, and biospecimen collection through the Alzheimer’s Disease Neuroimaging Initiative. Hierarchical linear regression analyses examined main and …interaction effects of medial temporal lobe (MTL) volume and polygenic hazard score (PHS), indicating genetic risk for AD, on a validated episodic memory composite score. Results: Genetic risk moderated the relationship between MTL volume and memory, such that individuals with high PHS and lower hippocampal and entorhinal volume had lower memory composite scores [Δ F (1,677) = 4.057, p  = 0.044, Δ R2  = 0.002]. Further analyses showed this effect was driven by the left hippocampus [Δ F (1,677) = 5.256, p  = 0.022, Δ R 2  = 0.003] and right entorhinal cortex [Δ F (1,677) = 6.078, p  = 0.014, Δ R 2  = 0.003]. Conclusions: Among those with high genetic risk for AD, lower volume was associated with poorer memory. Results suggest that the interaction between AD genetic risk and MTL volume increases the likelihood for memory impairment among older adults. Results from this study suggest that genetic risk and brain volume should be considered key factors in tracking cognitive decline. Show more

Keywords: Alzheimer’s disease, atrophy, entorhinal cortex, episodic memory, hippocampus, medial temporal lobe, polygenic risk

DOI: 10.3233/JAD-191312

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 591-600, 2020

Authors: Isaacs-Trepanier, Cameron | Saleem, Mahwesh | Herrmann, Nathan | Swardfager, Walter | Oh, Paul I. | Goldstein, Benjamin I. | Mitchell, Jane | Sugamori, Kim S. | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Patients with coronary artery disease have an increased risk for developing vascular cognitive impairment. Endothelial function is often diminished and has been associated with lower cognitive performance in these patients. The link between endothelial function and cognition in coronary artery disease is not fully understood. Angiogenesis may play a role in mediating the association between endothelial function and cognition since angiogenic processes rely heavily on the endothelium. Objective: The aim of this study was to determine if markers of angiogenesis mediate the relationship between endothelial function and cognition in coronary artery disease patients. Methods: In …50 participants with coronary artery disease, endothelial function was assessed using peripheral arterial tonometry. Vascular endothelial growth factor (pro-angiogenic) and endostatin (anti-angiogenic) were measured in peripheral serum samples. Cognition was assessed using the Montreal Cognitive Assessment. A mediation analysis, using a bias corrected inferential bootstrapping method with 10,000 permutations, was used to determine if vascular endothelial growth factor or endostatin mediated an association between peripheral arterial tonometry measures and cognitive performance on the Montreal Cognitive Assessment. Results: Endostatin, but not vascular endothelial growth factor, mediated a relationship between endothelial function and cognitive performance when controlling for total years of education, body mass index, coronary artery bypass graft, stent, diabetes, and diuretic use. This analysis was also significant when delayed recall was substituted for the overall score on the Montreal Cognitive Assessment. Conclusion: These results suggest that endostatin mediates an association between endothelial function and cognitive performance in coronary artery disease. Show more

Keywords: Cognition, cognitive dysfunction, coronary artery disease, endothelium, endostatin, vascular endothelial growth factor

DOI: 10.3233/JAD-200058

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 601-611, 2020

Authors: Wood, Ryan M. | Garcia, Zacnite | Daniels, Nathan | Landon, Shannon M. | Humayun, Saima | Lee, Hyoung-gon | Macpherson, Lindsey J.

Article Type: Research Article

Abstract: Background: Previous studies indicate that taste dysfunction occurs early in the development of Alzheimer’s disease. It is debatable whether the deficit in taste is due primarily to peripheral sensory mechanisms or to central processing, or a combination of the two. Objective: The aim of our current study is to combine behavior and histological data in APP/PS1 transgenic mice to determine whether APP/PS1 transgenic mice show deficits in unconditioned taste preference and avoidance behaviors and whether taste impairments are due to defects in the peripheral taste system and/or problems with central processing of taste information. Methods: The …APP/PS1 transgenic mutant mice were used as a model of Alzheimer’s disease. We employed a brief-access gustometer test to assess immediate orosensory taste responses of APP/PS1 mice. We used immunohistochemistry to examine tongue, gustatory ganglion, and brain tissues to determine a cytological basis for behavioral deficits. Results: There is a significant, selective reduction of bitter taste sensitivity in APP/PS1 mice. These mice also have a loss of TRPM5-expressing taste receptor cells in the circumvallate papillae of the tongue. While we observed no overt loss of neuron cell bodies within the primary gustatory sensory neurons, degeneration of the neurons’ peripheral axons innervating the taste bud may play a role in the observed loss of TRPM5-expressing taste receptor cells. Conclusion: This data supports a potential role for peripheral taste dysfunction in AD through the selective loss of taste receptor cells. Further study is necessary to delineate the mechanisms and pathological significance of this deficit in AD. Show more

Keywords: APP/PS1 mutant, taste dysfunction, taste receptor cells

DOI: 10.3233/JAD-200376

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 613-621, 2020

Authors: Si, Zizhen | Wang, Xue | Kang, Yuchun | Wang, Xidi | Sun, Changhui | Li, Yuanxin | Xu, Jiakun | Wu, Jiajia | Zhang, Zhujun | Li, Ling | Peng, Yahui | Li, Jihong | Sun, Chongran | Hui, Yang | Gao, Xu

Article Type: Research Article

Abstract: Background: Adult hippocampal neurogenesis is critical for renewing hippocampal neural circuits and maintaining hippocampal cognitive function and is closely associated with age-related neurodegenerative diseases. Heme oxygenase 1 (HO-1) is a stress protein that catalyzes the degradation of heme into free iron, biliverdin, and carbon monoxide. Elevated HO-1 level constitutes a pathological feature of Alzheimer’s disease, Parkinson’s disease, and many other age-related neurodegenerative diseases. Objective: Here we research the precise role of HO-1 in adult hippocampal neurogenesis. Methods: To explore the effect of HO-1 overexpression on adult neural stem cells (aNSCs) and elucidate its mechanisms, Tg(HO-1) was …constructed. The transgenic mice and aNSCs were subjected to neurosphereing assay, clonal analysis, and BrdU labelling to detect the proliferation and self-renewal ability. LiCl, MG132, CHX, and IGF-1 treatment were used to research the signaling pathways which regulated by HO-1. Results: HO-1 overexpression decreased proliferation ability and induced apoptosis of aNSCs in subgranular zoon (SGZ) in vivo and in vitro . Furthermore, HO-1 overexpression inactivated canonical WNT/β-catenin pathway. Re-activate canonical WNT/β-catenin pathway rescued aNSCs proliferation and survival upon HO-1 overexpression. More importantly, phosphorylation of AKTS473 and GSK3βS9 was found to be significantly decreased in HO-1 overexpressed aNSCs. Re-activation of AKT signaling proved that HO-1 inhibited Wnt/β-catenin signaling pathway via AKT/GSK3β signaling pathway. Conclusion: These results demonstrated a critical role of HO-1 in regulating aNSCs survival and proliferation by inhibiting Wnt/β-catenin pathway through repression of AKT/GSK3β, which provide a novel insight into the role of HO-1 in Alzheimer’s disease pathogenesis. Show more

Keywords: Adult hippocampal neurogenesis, age-related neurodegenerative diseases, canonical Wnt/β-catenin pathway, heme oxygenase 1, neural stem cell

DOI: 10.3233/JAD-200114

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 623-641, 2020

Authors: Iriondo, Ane | García-Sebastian, Maite | Arrospide, Arantzazu | Arriba, Maria | Aurtenetxe, Sara | Barandiaran, Myriam | Clerigue, Montserrat | Ecay-Torres, Mirian | Estanga, Ainara | Gabilondo, Alazne | Izagirre, Andrea | Saldias, Jon | Tainta, Mikel | Villanua, Jorge | Blennow, Kaj | Zetterberg, Henrik | Mar, Javier | Abad-García, Beatriz | Dias, Irundika H.K. | Goñi, Felix M. | Martínez-Lage, Pablo

Article Type: Research Article

Abstract: Background: Abnormal cholesterol metabolism changes the neuronal membrane and may promote amyloidogenesis. Oxysterols in cerebrospinal fluid (CSF) are related to Alzheimer’s disease (AD) biomarkers in mild cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance. Objective: We aim to demonstrate that the association of oxysterols, AD biomarkers, and WM microstructure occurs early in asymptomatic individuals. Methods: We studied the association of inter-individual variability of CSF 24-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), 7-ketocholesterol (7-KC), 7β-hydroxycholesterol (7β-OHC), amyloid-β42 (Aβ42 ), total-tau (t-tau), phosphorylated-tau (p-tau), neurofilament (NfL), and WM microstructure using diffusion tensor …imaging, generalized linear models and moderation/mediation analyses in 153 healthy adults. Results: Higher 7-KC levels were related to lower Aβ42 , indicative of greater AD pathology (p  = 0.041) .  Higher 7-KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD), and radial (RD) diffusivity. 7-KC modulated the association between AxD and NfL in the corpus callosum splenium (B  = 39.39, p  = 0.017), genu (B  = 68.64, p  = 0.000), and fornix (B  = 10.97, p  = 0.000). Lower Aβ42 levels were associated to lower FA and higher MD, AxD, and RD in the fornix, corpus callosum, inferior longitudinal fasciculus, and hippocampus. The association between AxD and Aβ42 was moderated by 7K-C (p  = 0.048). Conclusion: This study adds clinical evidence to support the role of 7K-C on axonal integrity and the involvement of cholesterol metabolism in the Aβ42 generation process. Show more

Keywords: Amyloid-β , cerebrospinal fluid, diffusion tensor imaging, oxysterols, white matter

DOI: 10.3233/JAD-200105

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 643-656, 2020

Authors: Lv, Ling-Li | Liu, Bo | Liu, Jing | Li, Li-Sheng | Jin, Feng | Xu, Yun-Yan | Wu, Qin | Liu, Jie | Shi, Jing-Shan

Article Type: Research Article

Abstract: Background: Dendrobium nobile is a well-known traditional Chinese herbal medicine used for age-related diseases. Dendrobium nobile Lindl. alkaloid (DNLA) is the active ingredient to improve learning and memory deficits in laboratory animals. Objective: The aim of the present study was to examine the anti-aging effects of long-term administration of DNLA and metformin during the aging process in senescence-accelerated mouse-prone 8 (SAMP8) mice. Methods: SAMP8 mice were orally given DNLA (20 and 40 mg/kg) or metformin (80 mg/kg) starting at 6 months of age until 12 months of age. Age-matched SAMR1 mice were used as controls. DNLA …and metformin treatments ameliorated behavioral deficits of 12-month-old SAMP8 mice, as determined by Rotarod, Y-maze, and Open-field tests. Results: DNLA and metformin treatments prevented brain atrophy and improved morphological changes in the hippocampus and cortex, as evidenced by Nissl and H&E staining for neuron damage and loss, and by SA-β-gal staining for aging cells. DNLA and metformin treatments decreased amyloid-β1–42 , AβPP, PS1, and BACE1, while increasing IDE and neprilysin for Aβ clearance. Furthermore, DNLA and metformin enhanced autophagy activity by increasing LC3-II, Beclin1, and Klotho, and by decreasing p62 in the hippocampus and cortex. Conclusion: The beneficial effects of DNLA were comparable to metformin in protecting against aging-related cognitive deficits, neuron aging, damage, and loss in SAMP8 mice. The mechanisms could be attributed to increased Aβ clearance, activation of autophagy activity, and upregulation of Klotho. Show more

Keywords: Aging, amyloid-β, autophagy, Dendrobium nobile Lindl. alkaloid (DNLA), metformin, senescence accelerated mouse prone 8 (SAMP8)

DOI: 10.3233/JAD-200308

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 657-669, 2020

Authors: Staekenborg, Salka S. | Kelly, Naomi | Schuur, Jacqueline | Koster, Pieter | Scherder, Erik | Tielkes, Caroline E.M. | Scheltens, Philip | Claus, Jules J.

Article Type: Research Article

Abstract: Background: The role of cognitive reserve (CR) to explain individual differences in cognitive functioning is unclear in memory clinic patients. Objective: To examine the cross-sectional effect of CR on cognition in relation to levels of neurodegeneration in a large elderly single-center memory clinic population. Methods: We included patients with subjective cognitive impairment (SCI, n  = 481), mild cognitive impairment (MCI, n  = 628) or Alzheimer’s disease (AD, n  = 1,099). Education was used as proxy for CR and visually rated medial temporal lobe atrophy (MTA) on CT was used as parameter of neurodegeneration. Relations between CR, cognition, and MTA …were analyzed with multiple linear regression adjusted for age, sex, and cerebral atrophy. In addition, we examined if education affects the relation between MTA and cognition using an interaction variable. Results: Education was significantly related to all measures of cognition including subtests with an explained variance of education as a determinant of cognition of 11%. More highly educated patients had more advanced levels of MTA at the same level of cognition. All these results were stronger or only present in demented compared to non-demented patients but appeared no longer significant in those with lowest overall cognition. The interaction effect was significant indicating that with more advanced MTA, less cognitive decline was shown in higher educated patients. Conclusion: Education is a very strong determinant of cognition in an elderly memory clinic population. The positive effect of education was stronger in demented than in non-demented patients but disappeared in those with the lowest cognitive scores indicating a “window of CR benefit”. Show more

Keywords: Cognitive reserve, dementia, education, medial temporal lobe atrophy, memory clinic

DOI: 10.3233/JAD-191332

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 671-679, 2020

Authors: Motta, Caterina | Finardi, Annamaria | Toniolo, Sofia | Di Lorenzo, Francesco | Scaricamazza, Eugenia | Loizzo, Stefano | Mercuri, Nicola Biagio | Furlan, Roberto | Koch, Giacomo | Martorana, Alessandro

Article Type: Research Article

Abstract: Background: Neuroinflammatory cytokines can play a pivotal role in Alzheimer’s disease (AD) contributing to the evolution of degenerative processes. Objective: We aimed at evaluating the levels of cerebrospinal fluid (CSF) inflammatory cytokines, chemokines, and growth factors in subjects with diagnosis of amnestic mild cognitive impairment and mild AD. Methods: We evaluated CSF contents of inflammatory cytokines in 66 patients divided according to the NIA-AA research framework and the APOE genotype. CSF of a group of cognitively unimpaired individuals (n  = 23) was evaluated as control. All patients were evaluated for 24 months using Mini-Mental State Examination …(MMSE). Results: We found significant increased levels of IL-4, IL-6, IL-8, and G-CSF in the CSF of A+/T–APOE4 carriers, respect to A+/T–patients homozygous for APOE3 , respect to A+/T+ patients, regardless the APOE status, and respect to controls. Over a period of 24 months, A+/T–APOE4 carriers, with increased levels of cytokines, showed a preserved cognitive evaluation when compared to the other subgroups of patients (delta MMSE at 24 months respect to baseline: 0.10±0.35; p  < 0.05). Conclusion: Our data suggest that during early phases of AD, in APOE4 carriers, Aβ pathology likely induces a specific cytokines pattern synthesis associated to cognitive preservation. These data highlight the different role that neuroinflammation can play in AD pathology based on the presence of specific CSF biomarkers and on the APOE status. Show more

Keywords: Amyloid-β 42, APOE , cognitive decline, G-CSF, interleukins, tau

DOI: 10.3233/JAD-191250

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 681-689, 2020

Authors: Fowler, Mackenzie E. | Triebel, Kristen L. | Cutter, Gary R. | Schneider, Lon S. | Kennedy, Richard E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cross-sectional studies suggest self-reported cancer history is associated with decreased risk of Alzheimer’s disease (AD). However, little is known about how self-reported cancer affects longitudinal AD progression, the primary outcome in clinical trials and observational studies. Objective: To determine self-reported cancer history’s effect on longitudinal AD progression in an observational study. Methods: We utilized data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to evaluate progression to AD by self-reported all-cancer, breast, prostate, colorectal, or non-melanoma skin cancer history. Linear mixed effects models were used to examine baseline differences and rates of progression on the Alzheimer’s …Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) by self-reported cancer history. Age at AD onset was examined using consensus clinical diagnoses with Cox proportional hazards regression. Results: Among 1,271 participants, models revealed no significant differences in progression over time but did reveal significantly lower baseline ADAS-Cog score, indicating better cognition at a given age in those with self-reported cancer history. Cox models indicated those with self-reported cancer history had significantly later age of AD onset (HR: 0.67, 95% CI: 0.53–0.85) after adjustment for covariates. Conclusion: Participants with self-reported cancer history entered ADNI with better cognition and later age of AD onset, but progressed similarly to participants without such history, indicating differences in AD between those with and without self-reported cancer history emerge early in the disease course. Such differences in longitudinal progression by self-reported cancer history could affect AD trials and observational studies, given the current focus on early disease course. Further investigation is warranted with detailed longitudinal assessment of cancer and AD. Show more

Keywords: Alzheimer’s disease, cancer, cognitive impairment, disease progression, mild cognitive impairment

DOI: 10.3233/JAD-200108

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 691-701, 2020

Authors: Makino, Keitaro | Lee, Sangyoon | Bae, Seongryu | Shinkai, Yohei | Chiba, Ippei | Shimada, Hiroyuki

Article Type: Research Article

Abstract: Background: Both pain interference and depressive symptoms have certain effects on dementia, and these are reciprocally related. However, comorbid effects of pain interference and depressive symptoms on dementia have not been examined in detail. Objective: This longitudinal study aimed to examine the combined effects of pain interference and depressive symptoms on the incidence of dementia in community-dwelling elderly individuals. Methods: This prospective cohort study with a 36-month follow-up period included 4,326 community-dwelling elderly individuals without dementia at baseline. Pain interference and depressive symptoms were assessed for every participant at baseline. We collected medical records in the …Japanese public health insurance system to identify the incidence of dementia for 36 months. Results: The incidence rates of dementia during the follow-up period in the control, pain-interference, depressive-symptoms, and comorbid group were 3.2%, 6.2%, 7.9%, and 11.3%, respectively. A Cox regression analysis showed that the hazard ratios for the incidence of dementia were 1.85 (95% CI: 1.13–3.03) in the pain interference group, 1.87 (95% CI: 1.27–2.76) in the depressive symptoms group, and 2.20 (95% CI: 1.26–3.84) in the comorbid group, after adjusting for covariates. Conclusion: The coexistence of pain interference and depressive symptoms had a greater effect on the incidence of dementia than either condition alone in community-dwelling elderly individuals. Pain interference and depressive symptoms are known as common comorbid conditions and often form a negative cycle that accelerates the worsening of the individual symptoms of both. Thus, the comorbidity of these conditions may require monitoring for the prevention of dementia. Show more

Keywords: Activity limitation, community, dementia, depression, pain, prevention

DOI: 10.3233/JAD-191139

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 703-712, 2020

Authors: He, Yating | Zhang, Haihua | Wang, Tao | Han, Zhifa | Ni, Qing-bin | Wang, Kun | Wang, Longcai | Zhang, Yan | Hu, Yang | Jin, Shuilin | Sun, Bao-liang | Liu, Guiyou

Article Type: Research Article

Abstract: Background: Altered calcium homeostasis is hypothesized to underlie Alzheimer’s disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. Objective: To develop effective therapies, we should establish the causal link between serum calcium levels and AD. Methods: Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 …controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. Results: IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35–0.95, p  = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. Conclusion: In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD. Show more

Keywords: Alzheimer’s disease, genome-wide association study, inverse-variance weighted, Mendelian randomization, serum calcium

DOI: 10.3233/JAD-191249

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 713-724, 2020

Authors: Piamonte, Bernadeth Lyn C. | Espiritu, Adrian I. | Anlacan, Veeda Michelle M.

Article Type: Research Article

Abstract: Background: A critical strategy in the management of Alzheimer’s disease (AD) is optimizing the effects of currently available pharmacologic therapies such as citicoline (CC). Objective: The purpose of this study was to determine the effects of CC as adjunct therapy to cholinesterase inhibitors (AChEI) in the treatment of AD. Methods: We identified relevant studies by electronic search until April 2020. We considered studies with a comparator group that enrolled elderly patients with a diagnosis of AD and employed CC as an adjunct therapy to AChEIs compared to AChEI monotherapy or comparisons of different AChEIs combined with …CC. Methodological quality assessment was done using the Newcastle-Ottawa Scale. Results: Out of 149 articles identified, two retrospective cohort studies involving 563 elderly patients affected with AD were included. After 3 months and 9 months, better Mini-Mental Status Examination scores were observed in the “AChEIs + CC” group versus “AChEIs alone” group. CC combined with donepezil may be better in improving cognition than when combined with rivastigmine. No significant difference was noted in terms of activities of daily living (ADL) and instrumental-ADL. Neuropsychiatric Inventory and Geriatric Depression Scale-short form scores appeared to be lower in the combination treatment versus monotherapy. The adverse events of combined treatment were self-limiting and included occasional excitability, gastric intolerance, and headache. Conclusion: Limited evidence from pooled data of two observational studies suggests that CC used in adjunct with AChEIs in the treatment of AD was well-tolerated and showed improvement in cognition, mood, and behavioral symptoms compared to treating with AChEIs alone. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, citicoline, systematic review

DOI: 10.3233/JAD-200378

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 725-732, 2020

Authors: Rajji, Tarek K. | Bowie, Christopher R. | Herrmann, Nathan | Pollock, Bruce G. | Bikson, Marom | Blumberger, Daniel M. | Butters, Meryl A. | Daskalakis, Zafiris J. | Fischer, Corinne E. | Flint, Alastair J. | Golas, Angela C. | Graff-Guerrero, Ariel | Kumar, Sanjeev | Lourenco, Lillian | Mah, Linda | Ovaysikia, Shima | Thorpe, Kevin E. | Voineskos, Aristotle N. | Mulsant, Benoit H. | for the PACt-MD Study Group

Article Type: Research Article

Abstract: Background: By the time Alzheimer’s disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed. Objective: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups. Methods: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI. Results: PACt-MD (Prevention of Alzheimer’s dementia with Cognitive …remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants. Conclusion: PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD. Show more

Keywords: Alzheimer’s disease and related disorders, cognitive remediation, major depressive disorder, mild cognitive disorder, PACt-MD, prevention, transcranial direct current stimulation, NCT02386670

DOI: 10.3233/JAD-200141

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 733-751, 2020

Authors: Cuttler, Katelyn | Bignoux, Monique J. | Otgaar, Tyrone C. | Chigumba, Stephanie | Ferreira, Eloise | Weiss, Stefan F.T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently, it has been demonstrated that the 37 kDa/67 kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aβ pathology. Since both LRP/LR and telomerase are known to play a role in the Aβ facet of AD, we hypothesized that they might also play a role in tauopathy. Objective: This study aimed …to determine if LRP/LR has a relationship with tau and whether overexpression of LRP::FLAG has an effect on tauopathy-related proteins. Methods: We employed confocal microscopy and FRET to determine whether LRP/LR and tau co-localize and interact. LRP::FLAG overexpression in HEK-293 and SH-SY5Y cells as well as analysis of tauopathy-related proteins was assessed by western blotting. Results: We demonstrate that LRP/LR co-localizes with tau in the perinuclear cell compartment and confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Overexpression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrPc levels, a tauopathy-related protein. LRP::FLAG overexpression also resulted in increased hTERT levels. Conclusion: This data suggest that LRP/LR extends its role in AD through a direct interaction with tau, and recommend LRP::FLAG as a possible alternative AD therapeutic via decreasing phosphorylated tau levels. Show more

Keywords: Alzheimer’s disease, 37 kDa/67 kDa laminin receptor (LRP/LR), PrPc , tau, telomerase

DOI: 10.3233/JAD-200244

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 753-768, 2020

Authors: Takemoto, Mami | Ohta, Yasuyuki | Hishikawa, Nozomi | Yamashita, Toru | Nomura, Emi | Tsunoda, Keiichiro | Sasaki, Ryo | Tadokoro, Koh | Matsumoto, Namiko | Omote, Yoshio | Abe, Koji

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms of dementia such as depression and apathy in patients with Alzheimer’s disease (AD) are associated with a lower quality of life. Objective: We aimed to determine the efficacy of two antidepressants and one antipathy drug in the treatment of depression and apathy in AD patients. Methods: In the present study, we evaluated the efficacy of sertraline (n  = 11; average dose = 31.8 mg), escitalopram (n  = 13; average dose = 7.3 mg), and nicergoline (n  = 9; average dose = 14.5 mg) in treating depression and apathy over a period of 3 months (M).The 33 patients with AD demonstrated high Geriatric Depression Scale (GDS) …(>5) or a high Apathy Scale (AS) (>16) scores. Results: The patients receiving escitalopram treatment showed a significant improvement in GDS score from baseline (8.2±3.5) to 3 M (5.7±2.6, p  = 0.04), and the patients receiving sertraline treatment showed a significant improvement in AS score from baseline (20.8±5.2) to 3 M (16.8±6.1, p  = 0.05); however, no significant changes were noted in patients receiving nicergoline. Conclusion: These results provide novel information on the efficacy of sertraline and escitalopram in the treatment of apathy and depression, respectively, in patients with AD. Show more

Keywords: Alzheimer’s disease, apathy, depression, escitalopram, nicergoline, sertraline

DOI: 10.3233/JAD-200247

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 769-772, 2020