Journal of Alzheimer's Disease - Volume 75, issue 1

Authors: Bassendine, Margaret F. | Taylor-Robinson, Simon D. | Fertleman, Michael | Khan, Michael | Neely, Dermot

Article Type: Review Article

Abstract: Clinical specialization is not only a force for progress, but it has also led to the fragmentation of medical knowledge. The focus of research in the field of Alzheimer’s disease (AD) is neurobiology, while hepatologists focus on liver diseases and lipid specialists on atherosclerosis. This article on AD focuses on the role of the liver and lipid homeostasis in the development of AD. Amyloid-β (Aβ) deposits accumulate as plaques in the brain of an AD patient long before cognitive decline is evident. Aβ generation is a normal physiological process; the steady-state level of Aβ in the brain is determined by …balance between Aβ production and its clearance. We present evidence suggesting that the liver is the origin of brain Aβ deposits and that it is involved in peripheral clearance of circulating Aβ in the blood. Hence the liver could be targeted to decrease Aβ production or increase peripheral clearance. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, circadian, hepatitis C virus, liver, metabolic syndrome, small interfering RNAs

DOI: 10.3233/JAD-190848

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 1-14, 2020

Authors: Wilson, George D. | Wilson, Thomas G. | Hanna, Alaa | Fontanesi, Giovanni | Kulchycki, Justin | Buelow, Katie | Pruetz, Barbara L. | Michael, Daniel B. | Chinnaiyan, Prakash | Maddens, Michael E. | Martinez, Alvaro A. | Fontanesi, James

Article Type: Short Communication

Abstract: We have previously reported that low doses of external beam ionizing irradiation reduced amyloid-β (Aβ) plaques and improved cognition in APP/PS1 mice. In this study we investigated the effects of radiation in an age-matched series of 3xTg-AD mice. Mice were hemibrain-irradiated with 5 fractions of 2 Gy and sacrificed 8 weeks after the end of treatment. Aβ and tau were assessed using immunohistochemistry and quantified using image analysis with Definiens Tissue Studio. We observed a significant reduction in Aβ plaque burden and tau staining; these two parameters were significantly correlated. This preliminary data is further support that low doses of radiation …may be beneficial in Alzheimer’s disease. Show more

Keywords: Amyloid-β, radiation, reduction, tau

DOI: 10.3233/JAD-200030

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 15-21, 2020

Authors: Clay, Felix | Howett, David | FitzGerald, James | Fletcher, Paul | Chan, Dennis | Price, Annabel

Article Type: Research Article

Abstract: Background: Immersive virtual reality (iVR) allows seamless interaction with simulated environments and is becoming an established tool in clinical research. It is unclear whether iVR is acceptable to people with Alzheimer’s disease (AD) dementia or useful in their care. We explore whether iVR is a viable research tool that may aid the detection and treatment of AD. Objectives: This review examines the use of iVR in people with AD or mild cognitive impairment (MCI). Methods: Medline, PsycINFO, Embase, CINAHL, and Web of Science databases were searched from inception. PRISMA guidelines were used with studies selected by …at least two researchers. Results: Nine studies were eligible for inclusion. None reported any issues with iVR tolerability in participants with MCI and AD on assessment or treatment tasks. One study demonstrated capability for detecting prodromal AD and correlated with neuroanatomical substrates. Two studies showed iVR to have high accuracy in differentiating participants with AD from controls but were not hypothesis driven or with adequate controls measures. In a small validation study and two longitudinal case studies, iVR cognitive training was positively rated but did not demonstrate reliable benefit. Conclusion: iVR is emerging as a viable method of assessing older adults and people with AD. Strongest benefits were seen when closely integrated with theoretical models of neurodegeneration and existing screening methods. Further randomized controlled trials integrated with clinical populations are required. This will consolidate the power of iVR for assessment of MCI and clarify treatment efficacy beyond current applications in physical rehabilitation. Show more

Keywords: Alzheimer’s disease, cognitive remediation, mild cognitive impairment, spatial navigation, virtual reality

DOI: 10.3233/JAD-191218

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 23-43, 2020

Authors: Seita, Yasunari | Morimura, Toshifumi | Watanabe, Naoki | Iwatani, Chizuru | Tsuchiya, Hideaki | Nakamura, Shinichiro | Suzuki, Toshiharu | Yanagisawa, Daijiro | Tsukiyama, Tomoyuki | Nakaya, Masataka | Okamura, Eiichi | Muto, Masanaga | Ema, Masatsugu | Nishimura, Masaki | Tooyama, Ikuo

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia and understanding its pathogenesis should lead to improved therapeutic and diagnostic methods. Although several groups have developed transgenic mouse models overexpressing the human amyloid-β precursor protein (APP ) gene with AD mutations, with and without presenilin mutations, as well as APP gene knock-in mouse models, these animals display amyloid pathology but do not show neurofibrillary tangles or neuronal loss. This presumably is due to differences between the etiology of the aged-related human disease and the mouse models. Here we report the generation of two transgenic cynomolgus monkeys overexpressing the …human gene for APP with Swedish, Artic, and Iberian mutations, and demonstrated expression of gene tagged green fluorescent protein marker in the placenta, amnion, hair follicles, and peripheral blood. We believe that these nonhuman primate models will be very useful to study the pathogenesis of dementia and AD. However, generated Tg monkeys still have some limitations. We employed the CAG promoter, which will promote gene expression in a non-tissue specific manner. Moreover, we used transgenic models but not knock-in models. Thus, the inserted transgene destroys endogenous gene(s) and may affect the phenotype(s). Nevertheless, it will be of great interest to determine whether these Tg monkeys will develop tauopathy and neurodegeneration similar to human AD. Show more

Keywords: Amyloid-beta protein precursor, animal, cryopreservation, intracytoplasmic sperm injection (ICSI), primates, transgenic, vitrification, zygote

DOI: 10.3233/JAD-191081

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 45-60, 2020

Authors: Sonawane, Shweta Kishor | Chinnathambi, Subashchandrabose

Article Type: Research Article

Abstract: Background: Frontotemporal dementia and parkinsonism-linked to chromosome-17 are a group of diseases with tau mutations leading to primary tauopathies which include progressive supranuclear palsy, corticobasal syndrome, and frontotemporal lobar degeneration. Alzheimer’s disease is a non-primary tauopathy, which displays tau neuropathology of excess tangle formation and accumulation. FTDP-17 mutations are responsible for early onset of AD, which can be attributed to compromised physiological functions due to the mutations. Tau is a microtubule-binding protein that secures the integrity of polymerized microtubules in neuronal cells. It malfunctions owing to various insults and stress conditions-like mutations and post-translational modifications. Objective: In this …study, we modified the wild type and tau mutants by methyl glyoxal and thus studied whether glycation can enhance the aggregation of predisposed mutant tau. Methods: Tau glycation was studied by fluorescence assays, SDS-PAGE analysis, conformational evaluation, and transmission electron microscopy. Results: Our study suggests that FTDP-17 mutant P301 L leads to enhanced glycation-induced aggregation as well as advanced glycation end products formation. Glycation forms amorphous aggregates of tau and its mutants without altering its native conformation. Conclusion: The metabolic anomalies and genetic predisposition have found to accelerate tau-mediated neurodegeneration and prove detrimental for the early-onset of Alzheimer’s disease. Show more

Keywords: Advanced glycation end products, Alzheimer’s disease, FTDP-17, tau glycation

DOI: 10.3233/JAD-191348

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 61-71, 2020

Authors: Dion, Catherine | Arias, Franchesca | Amini, Shawna | Davis, Randall | Penney, Dana | Libon, David J. | Price, Catherine C.

Article Type: Research Article

Abstract: Background: A digital version of the clock drawing test (dCDT) provides new latency and graphomotor behavioral measurements. These variables have yet to be validated with external neuropsychological domains in non-demented adults. Objective: The current investigation reports on cognitive constructs associated with selected dCDT latency and graphomotor variables and compares performances between individuals with mild cognitive impairment (MCI) and non-MCI peers. Methods: 202 non-demented older adults (age 68.79 ± 6.18, 46% female, education years 16.02 ± 2.70) completed the dCDT and a comprehensive neuropsychological protocol. dCDT variables of interest included: total completion time (TCT), pre-first hand latency …(PFHL), post-clock face latency (PCFL), and clock face area (CFA). We also explored variables of percent time drawing (i.e., ‘ink time’) versus percent time not drawing (i.e., ‘think time’). Neuropsychological domains of interest included processing speed, working memory, language, and declarative memory. Results: Adjusting for age and premorbid cognitive reserve metrics, command TCT positively correlated with multiple cognitive domains; PFHL and PCFL negatively associated with worse performance on working memory and processing speed tests. For Copy, TCT, PCFL, and PFHL negatively correlated with processing speed, and CFA negatively correlated with language. Between-group analyses show MCI participants generated slower command TCT, produced smaller CFA, and required more command ‘think’ (% Think) than ‘ink’ (% Ink) time. Conclusion: Command dCDT variables of interest were primarily processing speed and working memory dependent. MCI participants showed dCDT differences relative to non-MCI peers, suggesting the dCDT may assist with classification. Results document cognitive construct validation to digital metrics of clock drawing. Show more

Keywords: Attention, cognition, cognitive aging, neuropsychology, processing speed

DOI: 10.3233/JAD-191089

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 73-83, 2020

Authors: Zhu, Xiangzhu | Borenstein, Amy R. | Zheng, Yinan | Zhang, Wei | Seidner, Douglas L. | Ness, Reid | Murff, Harvey J. | Li, Bingshan | Shrubsole, Martha J. | Yu, Chang | Hou, Lifang | Dai, Qi

Article Type: Research Article

Abstract: Background: Deterioration of ionized calcium (Ca2+ ) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC). Objective: To test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E (APOE). Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled …250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. Results: Among those aged > 65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p  = 0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged > 65 years old (p values = 0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e., cg13496662 and cg06750524) in APOE (p for indirect effect = 0.05). Conclusion: Our findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer’s disease. Clinical Trial Registry number and website : #100106 https://clinicaltrials.gov/ct2/show/NCT03265483 Show more

Keywords: APOE methylation, calcium, cognitive function, magnesium, mediation analysis, ratio

DOI: 10.3233/JAD-191223

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 85-98, 2020

Authors: Traschütz, Andreas | Enkirch, S. Jonas | Polomac, Nenad | Widmann, Catherine N. | Schild, Hans H. | Heneka, Michael T. | Hattingen, Elke

Article Type: Research Article

Abstract: Background: Structural magnetic resonance imaging (MRI) is routinely performed in patients with mild cognitive impairment (MCI), but diagnostic accuracy to detect early cerebral atrophy is limited. Objective: To validate the visual entorhinal cortex atrophy (ERICA) rating scale regarding diagnosis, biomarker status, neuropsychological profile, and dementia risk in MCI. Methods: The ERICA score was retrospectively assessed regarding its discrimination of MCI (n  = 80) from subjective cognitive decline and Alzheimer’s disease (AD) dementia (n  = 60, respectively), its prediction of conversion to dementia (median follow-up 28 months) and amyloid/tau biomarker status, and its association with neuropsychological tests. …Results: The ERICA score achieved 97% positive predictive value (PPV) for the presence of MCI. Discrimination between MCI and AD dementia (area under the curve: 0.71) was comparable to volumetry, and superior to the medial temporal lobe atrophy (MTA) score (p  = 0.006). The PPV of the ERICA score for conversion to dementia was 83%, equivalent to tau status. It achieved 90% PPV for conversion when combined with tau, and 100% negative predictive value with verbal recall. While no measure predicted the predominantly positive amyloid status, the ERICA score was at least comparable to volumetry, and superior to the MTA score in predicting tau positivity (92% PPV for phospho-tau). The ERICA score was associated with verbal learning and memory, and, unlike the MTA score, also with AD-specific deficits in cued verbal recall. Conclusion: The ERICA score is a simple and valuable tool to exploit structural MRI for diagnosis and prognosis in MCI and is non-inferior to volumetry. Show more

Keywords: Alzheimer’s disease, entorhinal cortex, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-181150

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 99-108, 2020

Authors: Kumar, Veena V. | Huang, Hanfeng | Zhao, Liping | Verble, Danielle D. | Nutaitis, Alexandra | Tharwani, Sonum D. | Brown, Alexandra L. | Zetterberg, Henrik | Hu, William | Shin, Ryan | Kehoe, Patrick G. | Quyyumi, Arshed | Nocera, Joe | Kippels, Andrea | Wharton, Whitney

Article Type: Research Article

Abstract: Background: The rate of AD for African Americans (AAs) is 64% higher than for non-Hispanic White Americans (Whites). It is hypothesized that poor peripheral vascular function, in combination with genetics, stress, and inflammation may directly contribute to the accumulation of AD pathologic biomarkers. These risk factors may disproportionately affect AAs. Objective: Our objective was to determine if in a healthy middle-aged cohort at risk for AD (1) AD biomarkers in CSF differ by race, (2) peripheral vascular dysfunction and cognition are related to a higher burden of CSF AD biomarkers, and (3) these relationships differ by race. …Methods: We enrolled 82 cognitively normal, middle-aged (45 and older) adults including AAs and Whites at high risk for AD due to parental history. Study procedures included lumbar puncture, vascular ultrasound, and cognitive testing. Results: While participants were in overall good health, AAs exhibited poorer indices of preclinical vascular health, including higher central SBP, central MAP, and EndoPAT AI, a marker of arterial stiffness. AAs also had significantly less cerebrospinal fluid tau burden than Whites. After polynomial regression analysis, adjusted for age, gender, education, and ApoE4 status, race significantly modified the relationship between total tau, phospho-tau, and Trails B, a marker of executive function. Small differences in tau correlated with poorer cognition in AAs. Conclusion: In a healthy middle-aged cohort at risk for AD, AAs had worse peripheral vascular health and worse cognition than Whites. Despite lower tau burden overall, race modified the relationship between tau and cognition, such that small differences in tau between AAs was related to worse cognition when compared to Whites. Show more

Keywords: Alzheimer’s disease, cognition, hypertension, parental history, prevention, tau, vascular risk

DOI: 10.3233/JAD-191103

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 109-117, 2020

Authors: Quintana, Dominic D. | Garcia, Jorge A. | Anantula, Yamini | Rellick, Stephanie L. | Engler-Chiurazzi, Elizabeth B. | Sarkar, Saumyendra N. | Brown, Candice M. | Simpkins, James W.

Article Type: Research Article

Abstract: Cerebrovascular pathology is pervasive in Alzheimer’s disease (AD), yet it is unknown whether cerebrovascular dysfunction contributes to the progression or etiology of AD. In human subjects and in animal models of AD, cerebral hypoperfusion and hypometabolism are reported to manifest during the early stages of the disease and persist for its duration. Amyloid-β is known to cause cellular injury in both neurons and endothelial cells by inducing the production of reactive oxygen species and disrupting intracellular Ca2+ homeostasis. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca2+ …uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. These observations provide a mechanism for the mitochondrial deficits that contribute to cerebrovascular dysfunction in patients with AD. Show more

Keywords: Amyloid-β, calcium, mitochondria, superoxide, vascular endothelial cells

DOI: 10.3233/JAD-190964

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 119-138, 2020