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

Authors: Aguirre, Naiara | Costumero, Víctor | Marin-Marin, Lidón | Escudero, Joaquín | Belloch, Vicente | Parcet, María Antonia | Ávila, César

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) has been associated with memory impairment due to alterations in the medial temporal lobe (MTL) and the precuneus. Therefore, the goal of this study was to investigate the effects of AD on the brain networks associated with the hippocampus and precuneus during an encoding memory task. 68 mild cognitive impairment patients (MCI), 21 AD patients, and 20 healthy controls (HC) were included. Participants were instructed to memorize landscapes while undergoing fMRI scanning, followed by a recognition test. MCI were followed up clinically for 18 months to track conversion status. Independent component analysis (ICA) was performed to investigate …AD effects on precuneus and MTL networks during memory encoding. Behavioral analyses indicate that HC had a better performance than MCI converters (MCIc) and AD. ICA showed that MCIc had significantly higher activation in the MTL-associated network than MCI non converters (MCIn) and AD, including bilateral hippocampus, parahippocampus, and fusiform gyrus. Furthermore, the precuneus-associated network fitted the default mode network, showing a negative correlation with behavioral performance. These findings indicate that the hyperactivation of the hippocampal network displayed by MCIc has potential discrimination capacity to distinguish them of MCIn, and could be interpreted as a compensatory mechanism. Show more

Keywords: Alzheimer’s disease, hippocampus, independent component analysis, memory, precuneus

DOI: 10.3233/JAD-190421

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Smith, Patrick J. | Mabe, Stephanie | Sherwood, Andrew | Babyak, Michael A. | Doraiswamy, P. Murali | Welsh-Bohmer, Kathleen A. | Kraus, William | Burke, James | Hinderliter, Alan | Blumenthal, James A.

Article Type: Research Article

Abstract: Background: Greater body weight has been associated impairments in neurocognition and greater dementia risk, although the mechanisms linking weight and neurocognition have yet to be adequately delineated. Objective: To examine metabolic mechanisms underlying the association between obesity and neurocognition. Methods: We conducted a secondary analysis of weight, neurocognition, and the potentially mediating role of metabolic and inflammatory biomarkers among 160 participants from the ENLIGHTEN trial of vascular cognitive impairment, no dementia (CIND). Neurocognition was assessed using a 45-minute assessment battery assessing Executive Function, Verbal and Visual Memory. We considered three metabolic biomarkers: insulin resistance (homeostatic model …assessment [HOMA-IR]), plasma leptin, and insulin-like growth factor (IGF-1). Inflammation was assessed using C-reactive protein. Multiple regression analyses were used. Results: Participants included 160 sedentary older adults with CIND. Participants tended to be overweight or obese (mean BMI = 32.5 [SD = 4.8]). Women exhibited higher BMI (p  = 0.043), CRP (p  < 0.001), and leptin (p  < 0.001) compared with men. Higher BMI levels were associated with worse performance on measures of Executive Function (β= –0.16, p  = 0.024) and Verbal Memory (β= –0.16, p  = 0.030), but not Visual Memory (β= 0.05, p  = 0.500). Worse metabolic biomarker profiles also were associated with lower Executive Function (β= –0.12, p  = 0.050). Mediation analyses suggested leptin was a plausible candidate as a mediator between BMI and Executive Function. Conclusions: In overweight and obese adults with vascular CIND, the association between greater weight and poorer executive function may be mediated by higher leptin resistance. Show more

Keywords: Cognitive function, executive function, inflammation, insulin sensitivity, leptin, metabolic function, obesity

DOI: 10.3233/JAD-190569

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Elmaleh, David R. | Farlow, Martin R. | Conti, Peter S. | Tompkins, Ronald G. | Kundakovic, Ljiljana | Tanzi, Rudolph E.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that …aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, clinical trial design, combined modality therapy, inflammation, selection of subjects, tau protein, treatment outcomes

DOI: 10.3233/JAD-190507

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Moss, Donald E.

Article Type: Article Commentary

Abstract: The currently approved cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) produce gastrointestinal toxicity which limits dosing to that which produces only about 25% to 35% CNS cholinesterase inhibition in Alzheimer’s disease patients undergoing treatment, below the minimum therapeutic target of about 40% to 50% CNS inhibition considered necessary to treat cognitive impairment. A recent strategy for producing high-level CNS acetylcholinesterase (AChE) inhibition (50% or higher) is to co-administer a muscarinic anticholinergic with the AChE inhibitor to block the dose-limiting cholinergic overstimulation of the gastrointestinal system, allow more robust AChE inhibition in the CNS, and improve efficacy in the treatment of Alzheimer’s …disease. Unfortunately, most common muscarinic anticholinergics, including solifenacin, readily penetrate the CNS and are directly associated with long-term exacerbation of the underlying neuropathology of Alzheimer’s disease and increased brain atrophy. The co-administration of an anticholinergic with an AChE inhibitor is a rational strategy for improving efficacy in the symptomatic treatment of dementia, but there are significant long-term risks that have not yet been considered. For long-term safety against accelerating the underlying disease processes in Alzheimer’s disease, anticholinergics used to increase the tolerability of AChE inhibitors should not penetrate, or have very limited penetration, of the blood-brain barrier. Neurotrophic-mediated mechanisms by which cholinergic drugs may affect neurodegeneration in Alzheimer’s disease are explored and improved treatment options are suggested. Show more

Keywords: Alzheimer’s disease, anticholinergic, antimuscarinic, brain atrophy, cholinesterase inhibition, cognition, dementia, nerve growth factor, solifenacin, trospium

DOI: 10.3233/JAD-190626

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Pyun, Jung-Min | Kang, Min Ju | Youn, Young Chul | Park, Young Ho | Kim, Sang Yun

Article Type: Research Article

Abstract: Background: Although dementia with Lewy bodies (DLB) is a degenerative disease involving irreversible pathological changes and subsequent progressive cognitive decline, some patients have presented with improved cognitive function at follow-ups. Their clinical and neuropsychological characteristics and the factors influencing this improvement remain unclear. Objective: To investigate differences in clinical and neuropsychological characteristics between DLB patients with and without cognitive improvement at a one-year follow-up, and to identify predictive factors of cognitive improvement. Methods: This retrospective study included 60 DLB patients, 28 patients in the improved group, and 32 patients in the non-improved group. A multiple linear …regression model was used to compare changes in cognitive function test scores between groups over the course of one year. Binary logistic regression analysis was performed to determine the odds ratios (ORs) of depressive symptoms as a predictor for cognitive improvement. Results: The improved group showed significant increases in immediate and delayed verbal memory function in one year over the non-improved group. We also found that baseline depressive symptoms were associated with an increased probability of cognitive improvement (OR 1.234, CI 1.043– 1.460). Conclusion: Depressive symptoms at baseline were related to a higher probability of a cognitive improvement at one-year follow-up. In addition, immediate and delayed verbal memory function showed significant improvement during one year in improved patients compared to non-improved patients. Show more

Keywords: Cognitive improvement, dementia with Lewy bodies, depressive symptoms

DOI: 10.3233/JAD-190685

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Shaffer, Rachel M. | Sheppard, Lianne | Peskind, Elaine R. | Zhang, Jing | Adar, Sara D. | Li, Ge

Article Type: Research Article

Abstract: Background: Cerebrovascular diseases play an important role in dementia. Air pollution is associated with cardiovascular disease, with growing links to neurodegeneration. Prior studies demonstrate associations between fine particulate matter (PM2.5 ) and biomarkers of endothelial injury in the blood; however, no studies have evaluated these biomarkers in cerebrospinal fluid (CSF). Objective: We evaluate associations between short-term and long-term PM2.5 exposure with CSF vascular cell adhesion molecule-1 (VCAM-1) and e-selectin in cognitively normal and mild cognitive impairment (MCI)/Alzheimer’s disease (AD) individuals. Methods: We collected CSF from 133 community volunteers at VA Puget Sound …between 2001–2012. We assigned short-term PM2.5 from central monitors and long-term PM2.5 based on annual average exposure predictions linked to participant addresses. We performed analyses stratified by cognitive status and adjusted for key covariates with tiered models. Our primary exposure windows for the short-term and long-term analyses were 7-day and 1-year averages, respectively. Results: Among cognitively normal individuals, a 5μ g/m3 increase in 7-day and 1-year average PM2.5 was associated with elevated VCAM-1 (7-day: 35.4 (9.7, 61.1) ng/ml; 1-year: 51.8 (6.5, 97.1) ng/ml). A 5μ g/m3 increase in 1-year average PM2.5 , but not 7-day average, was associated with elevated e-selectin (53.3 (11.0, 95.5) pg/ml). We found no consistent associations among MCI/AD individuals. Conclusions: We report associations between short-term and long term PM2.5 and CSF biomarkers of vascular damage in cognitively normal adults. These results are aligned with prior research linking PM2.5 to vascular damage in other biofluids as well as emerging evidence of the role of PM2.5 in neurodegeneration. Show more

Keywords: Alzheimer’s disease, biomarkers, cellular adhesion molecules, cerebrospinal fluid, cerebrovascular disorders, dementia, particulate matter

DOI: 10.3233/JAD-190563

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Charil, Arnaud | Shcherbinin, Sergey | Southekal, Sudeepti | Devous, Michael D. | Mintun, Mark | Murray, Melissa E. | Miller, Bradley B. | Schwarz, Adam J.

Article Type: Research Article

Abstract: At autopsy, individuals with Alzheimer’s disease (AD) exhibit heterogeneity in the distribution of neurofibrillary tangles in neocortical and hippocampal regions. Subtypes of AD, defined using an algorithm based on the relative number of tangle counts in these regions, have been proposed—hippocampal sparing (relative sparing of the hippocampus but high cortical load), limbic predominant (high hippocampal load but lower load in association cortices), and typical (balanced neurofibrillary tangles counts in the hippocampus and association cortices) AD—and shown to be associated with distinct antemortem clinical phenotypes. The ability to distinguish these AD subtypes from the more typical tau signature in vivo …could have important implications for clinical research. Flortaucipir positron emission tomography (PET) images acquired from 45 amyloid-positive participants, defined clinically as mild cognitive impairment or AD, aged 50–92 years, 56% female, and estimated to be Braak V-VI based on their PET pattern of tau pathology, were studied. By translating the neuropathologic algorithm to flortaucipir PET scans, patterns of tau pathology consistent with autopsy findings, and with a similar prevalence, were identified in vivo . 6/45 (13%) participants were identified as hippocampal sparing and 6/45 (13%) as limbic predominant AD subtypes. Hippocampal sparing participants were significantly younger than those assigned to the other two subtypes. Worse performance on delayed recall was associated with increased hippocampal tau signal, and worse performance on the trail making test B-A was associated with lower values of the hippocampus to cortex ratio. Prospective studies can further validate the flortaucipir SUVR cut-points and the phenotype of the corresponding AD subtypes. Show more

Keywords: Hippocampal sparing, limbic predominant, subtype, tau

DOI: 10.3233/JAD-190264

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Schlegel, Petr | Novotny, Michal | Klimova, Blanka | Valis, Martin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is one of the most common forms of dementia, which cannot be cured at the moment. Therefore, researchers also look for the alternative approaches to its treatment. It is suggested that changes in human gut microbiome mediated by exercise could influence the development and progression of AD and a new term “muscle-gut-brain axis” is introduced. There is much evidence to support this assumption. The gut microbiology is closely related to a wide range of diseases of the nervous system and therefore any negative qualitative and quantitative changes in the composition of the gut microbiota can potentially contribute …to the pathophysiology of AD. Research shows that the treatment of intestinal dysbiosis with probiotics/synbiotics/eubiotics can prevent or alleviate the symptoms of these chronic neurological diseases. Studies also point to the positive effects of movement on the health of seniors. A positive correlation can be found between cognitive functions and physical stress, both in the elderly and in AD patients. Even short-term interventions with a relatively low frequency seem to produce positive results, while physical activities can be performed by using relatively simple and cost-effective means. In addition, physical activity can significantly modulate gut microbiome. Thus, it can be concluded that physical activity in humans seems to correlate with gut microbiome, which can prevent the incidence and development of AD. Show more

Keywords: Alzheimer’s disease, cognitive disorders, dementia, exercise, microbiome, physical activity, probiotics

DOI: 10.3233/JAD-190460

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Moazzami, Kasra | Wittbrodt, Matthew T. | Lima, Bruno B. | Kim, Jeong Hwan | Hammadah, Muhammad | Ko, Yi-An | Obideen, Malik | Abdelhadi, Naser | Kaseer, Belal | Gafeer, M. Mazen | Nye, Jonathon A. | Shah, Amit J. | Ward, Laura | Raggi, Paolo | Waller, Edmund K. | Bremner, J. Douglas | Quyyumi, Arshed A. | Vaccarino, Viola

Article Type: Research Article

Abstract: Background: Circulating progenitor cells (CPC) have been shown to be associated with memory function in healthy adults. However, the relationship between CPCs and memory function in patients with coronary artery disease (CAD) has not been assessed. Objective: To assess the association between CPCs and memory performance among subjects with CAD. Methods: We assessed cognitive function in 509 patients with CAD using the verbal and visual Memory subtests of the Wechsler Memory Scale-IV and the Trail Making Test Parts A and B. CPCs were enumerated with flow cytometry as CD45med /CD34+ blood mononuclear cells, those co-expressing other …epitopes representing populations enriched for hematopoietic and endothelial progenitors. Results: After adjusting for demographic and cardiovascular risk factors, lower number of endothelial progenitor cell counts were independently associated with lower visual and verbal memory scores (p for all <0.05). There was a significant interaction in the magnitude of this association with race, such that the association of verbal memory scores endothelial progenitor subsets was present in Black but not in White participants. No associations were present with the hematopoietic progenitor-enriched cells or with the Trail Making tests. Conclusion: Lower numbers of circulating endothelial progenitor cells are associated with poorer memory function in patients with CAD, suggesting a protective effect of repair/regeneration processes in the maintenance of cognitive status. Verbal memory function was more strongly associated with CPC counts in Blacks compared to whites with CAD. Whether strategies designed to improve regenerative capacity will improve cognition needs further study. Show more

Keywords: Black, circulating progenitor cell, coronary artery disease, memory

DOI: 10.3233/JAD-190217

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Tadokoro, Koh | Morihara, Ryuta | Ohta, Yasuyuki | Hishikawa, Nozomi | Kawano, Satoko | Sasaki, Ryo | Matsumoto, Namiko | Nomura, Emi | Nakano, Yumiko | Takahashi, Yoshiaki | Takemoto, Mami | Yamashita, Toru | Ueno, Setsuko | Wakutani, Yosuke | Takao, Yoshiki | Morimoto, Nobutoshi | Kutoku, Yumiko | Sunada, Yoshihide | Taomoto, Katsushi | Manabe, Yasuhiro | Deguchi, Kentaro | Higashi, Yasuto | Inufusa, Haruhiko | You, Fukka | Yoshikawa, Toshikazu | von Greiffenclau, Markus Matuschka | Abe, Koji

Article Type: Research Article

Abstract: Oxidative stress is part of the entire pathological process that underlies the development of Alzheimer’s disease (AD), including the mild cognitive impairment (MCI) stage. Twendee X (TwX) is a supplement containing a strong antioxidative mix of eight antioxidants, which has been shown to have a clinical and therapeutic benefit in AD model mice. Here, we conducted a multicenter, randomized, double-blind, and placebo-controlled prospective interventional study to evaluate the efficacy of TwX in mitigating MCI. The primary outcomes were differences in Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-revised (HDS-R) scores between baseline and six months for placebo and TwX groups. …Seventy-eight subjects with MCI were randomized into placebo (n  = 37) and TwX (n  = 41) groups. MMSE scores at six months differed significantly between the TwX and placebo groups (p  = 0.018), and HDS-R scores for the TwX group exhibited a significant improvement at six months relative to baseline (p  = 0.025). The TwX group did not show any change in affective or activities of daily living scores at six months. The present study indicates that strong antioxidative supplement TwX is clinical beneficial for cognitive function in subjects with MCI. Show more

Keywords: Dementia, dietary supplement, mild cognitive impairment, oxidative stress, randomized controlled trial

DOI: 10.3233/JAD-190644

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019