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

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: 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. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Yamoah, Alfred | Tripathi, Priyanka | Sechi, Antonio | Köhler, Christoph | Guo, Haihong | Chandrasekar, Akila | Nolte, Kay Wilhelm | Wruck, Christoph Jan | Katona, Istvan | Anink, Jasper | Troost, Dirk | Aronica, Eleonora | Steinbusch, Harry | Weis, Joachim | Goswami, Anand

Article Type: Research Article

Abstract: Granulovacuolar degeneration (GVD) occurs in Alzheimer’s disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones GRP78/BiP, Sigma receptor 1 (SigR1), and VAPB were elevated in many AD patients’ subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly …co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-β in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis. Show more

Keywords: Endoplasmic reticulum chaperones, exosomes, FUS, granulovacuolar degeneration, Matrin 3, Sigma receptor 1 (SigR1), stress granules

DOI: 10.3233/JAD-190722

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Horvath, Alexandra | Salman, Zeinab | Quinlan, Patrick | Wallin, Anders | Svensson, Johan

Article Type: Research Article

Abstract: Background: Insulin-like growth factor-I (IGF-I) is important for amyloid-β (Aβ) metabolism, and also interacts with the brain vasculature. In previous IGF-I studies, it has not been evaluated whether Alzheimer’s disease (AD) patients had vascular comorbidities. Objective and Methods: A cross-sectional study of 40 consecutive non-diabetic AD patients and 36 healthy controls. We measured IGF-I in serum and cerebrospinal fluid (CSF) and also serum insulin. Mixed forms of AD and vascular dementia were excluded. Results: After adjustment for covariates including age, serum IGF-I level was higher in the AD group than in the controls, whereas CSF IGF-I …and serum insulin were unchanged. Binary logistic regression confirmed that high serum IGF-I was associated with increased prevalence of AD [adjusted Odds Ratio (OR) = 1.83, 95% confidence interval (CI): 1.005–3.32 per standard deviation (SD) increase in serum IGF-I]. This association was more robust after exclusion of patients receiving treatment with acetylcholinesterase inhibitors or N-methyl D-aspartate (NMDA) receptor antagonists (OR = 2.23, 95 % CI: 1.10–4.48). In the total study population (n  = 76) as well in the AD group (n  = 40), serum IGF-I correlated negatively with CSF Aβ1-42 , and CSF IGF-I correlated positively with CSF/serum albumin ratio, CSF total tau, and CSF phosphorylated tau. Conclusion: In AD patients without major brain vascular comorbidities, serum but not CSF levels of IGF-I were increased after correction for covariates. This association was strengthened by exclusion of patients receiving medical treatment. Overall, the results support the notion of IGF-I resistance in mild AD dementia. Show more

Keywords: Alzheimer’s disease, cerebral vascular pathology, cerebrospinal fluid, CSF AD biomarkers, IGF-I, serum

DOI: 10.3233/JAD-190921

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Qiao, Yuan | Xie, Xin-Yi | Lin, Guo-Zhen | Zou, Yang | Chen, Sheng-Di | Ren, Ru-Jing | Wang, Gang

Article Type: Research Article

Abstract: Background: Language dysfunction is a frequently reported symptom in Alzheimer’s disease (AD). However, computer-assisted analysis of spontaneous speech in AD and mild cognitive impairment (MCI) is rarely used to date. Objective: To characterize the language impairment in AD and amnestic MCI (aMCI) with computer-based automatic analysis via the “Automatic Speech Recognition (ASR) software for cognitive impairment V1.3”. Methods: A total of 64 subjects, including 20 AD patients, 20 aMCI patients, and 24 healthy controls were recruited. All subjects underwent neuropsychological testing, and spontaneous speech samples were recorded through the description of the “Cookie-Theft Picture” and then …analyzed by the computerized software. Subsequently, we compared the speech parameters between the subjects and the controls. Results: We identified seven spontaneous speech parameters (percentage of silence duration, average duration of phrasal segments, average duration of silence segments, number of speech segments, number of long pauses, ratio of hesitation/speech counts and ratio of short pause/speech counts) demonstrating significant differences between the three groups (p  < 0.05). All seven speech parameters significantly correlated with cognitive performance, with average duration of silence segments demonstrating the best correlation to cognitive performance on stepwise multiple linear regression analysis. Conclusion: Computer-assisted automated analysis of speech/silence segments demonstrated the potential to reflect the intrinsic linguistic impairment associated with MCI and AD. It has a promising prospect in the early detection of AD and assessment of disease severity. Show more

Keywords: Alzheimer’s disease, computer-assisted speech analysis, language impairment, mild cognitive impairment, spontaneous speech

DOI: 10.3233/JAD-191056

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-20, 2020

Authors: Daly, Timothy | Houot, Marion | Barberousse, Anouk | Agid, Yves | Epelbaum, Stéphane

Article Type: Research Article

Abstract: The amyloid cascade hypothesis (ACH) has dominated contemporary biomedical research into Alzheimer’s disease (AD) since the 1990 s but still lacks definitive confirmation by successful clinical trials of anti-amyloid medicines in human AD. In this uncertain period regarding the centrality of amyloid-β (Aβ) in AD pathophysiology, and with the community apparently divided about the ACH’s validity, we used citation practices as a proxy for measuring how researchers have invested their belief in the hypothesis between 1992 and 2019. We sampled 445 articles citing Hardy & Higgins (1992, “HH92”) and classified the polarity of their HH92 citation according to Greenberg (2009)’s citation …taxonomy of positive, neutral, and negative citations, and then tested four hypotheses. We identified two major attitudes towards HH92: a majority (62%) of neutral attitudes with consistent properties across the time period, and a positive attitude (35%), tending to cite HH92 earlier on within the bibliography as time went by, tending to take HH92 as an established authority. Despite the majority of neutral HH92 citations, there was a positive majority of attitudes toward different versions of the ACH and anti-amyloid therapeutic strategies (65%), suggesting that the ACH has been dominant and has undergone significant refinement since 1992. Finally, of those 110 original articles within the sample also testing the ACH empirically, an overwhelming majority (89%) returned a pro-ACH test result, suggesting that the ACH’s central claim is reproducible. Further studies will quantify the extent to which results from different methods within such original studies convergence to provide a robust conclusion vis-à-vis Aβ’s pathogenicity in AD. Show more

Keywords: Alzheimer’s disease, amyloid cascade hypothesis, amyloid-β, belief, bibliometrics, citations, confirmation, Karl Popper, reproducibility, scientific bias

DOI: 10.3233/JAD-191321

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Racine, Annie M. | Touroutoglou, Alexandra | Abrantes, Tatiana | Wong, Bonnie | Fong, Tamara G. | Cavallari, Michele | Travison, Thomas G. | Gou, Yun | Marcantonio, Edward R. | Alsop, David C. | Jones, Richard N. | Inouye, Sharon K. | Dickerson, Bradford C. | for the SAGES study group

Article Type: Research Article

Abstract: Background: Older surgical patients with Alzheimer’s disease (AD) dementia and delirium are at increased risk for accelerated long-term cognitive decline. Objective: Investigate associations between a probabilistic marker of preclinical AD, delirium, and long-term cognitive decline. Methods: The Successful Aging after Elective Surgery cohort includes older adults (≥70 years) without dementia who underwent elective surgery. 140 patients underwent preoperative magnetic resonance imaging and had≥6 months cognitive follow-up. Cortical thickness was measured in ‘AD-Signature’ regions. Delirium was evaluated each postoperative day by the Confusion Assessment Method. Cognitive performance was assessed using a detailed neuropsychological battery at baseline; months …1, 2, and 6; and every 6 months thereafter until 36 months. Using either a General Cognitive Performance composite (GCP) or individual test scores as outcomes, we performed linear mixed effects models to examine main effects of AD-signature atrophy and the interaction of AD-signature atrophy and delirium on slopes of cognitive change from post-operative months 2–36. Results: Reduced baseline AD-signature cortical thickness was associated with greater 36-month cognitive decline in GCP (standardized beta coefficient, β = –0.030, 95% confidence interval [–0.060, –0.001]). Patients who developed delirium who also had thinner AD signature cortex showed greater decline on a verbal learning test (β = –0.100 [–0.192, –0.007]). Conclusion: Patients with the greatest baseline AD-related cortical atrophy who develop delirium after elective surgery appear to experience the greatest long-term cognitive decline. Thus, atrophy suggestive of preclinical AD and the development of delirium may be high-risk indicators for long-term cognitive decline following surgery. Show more

Keywords: aging signature, Alzheimer’s disease signature, cognitive decline, cortical thickness, delirium, preclinical Alzheimer’s disease, post-operative, surgery

DOI: 10.3233/JAD-190380

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Article Type: Correction

DOI: 10.3233/JAD-200002

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Robinson, Rebecca L. | Rentz, Dorene M. | Andrews, Jeffrey Scott | Zagar, Anthony | Kim, Yongin | Bruemmer, Valerie | Schwartz, Ronald L. | Ye, Wenyu | Fillit, Howard M.

Article Type: Research Article

Abstract: Background: Costs associated with early stages of Alzheimer’s disease (AD; mild cognitive impairment [MCI] and mild dementia [MILD]) are understudied. Objective: To compare costs associated with MCI and MILD due to AD in the United States. Methods: Data included baseline patient/study partner medical history, healthcare resource utilization, and outcome assessments as part of a prospective cohort study. Direct, indirect, and total societal costs were derived by applying standardized unit costs to resources for the 1-month pre-baseline period (USD2017). Costs/month for MCI and MILD cohorts were compared using analysis of variance models. To strengthen the confidence of …diagnosis, amyloid-β (Aβ ) tests were included and analyses were replicated stratifying within each cohort by amyloid status [+ /−]. Results: Patients (N  = 1327) with MILD versus MCI had higher total societal costs/month ($4243 versus $2816; p  <  0.001). These costs were not significantly different within each severity cohort by amyloid status. The largest fraction of overall costs were informal caregiver costs (45.1%) for the MILD cohort, whereas direct medical patient costs were the largest for the MCI cohort (39.0%). Correspondingly, caregiver time spent on basic activities of daily living (ADLs), instrumental ADLs, and supervision time was twice as high for MILD versus MCI (all p  <  0.001). Conclusion: Early AD poses a financial burden, and despite higher functioning among those with MCI, caregivers were significantly impacted. The major cost driver was the patient’s clinical cognitive-functional status and not amyloid status. Differences were primarily due to rising need for caregiver support. Show more

Keywords: Amyloid, burden of illness, dementia, economic burden, florbetapir F18, mild cognitive impairment, societal burden, H8A-US-B004, NCT02951598

DOI: 10.3233/JAD-191212

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

Authors: Blattner, Margaret S. | Panigrahi, Sunil K. | Toedebusch, Cristina D. | Hicks, Terry J. | McLeland, Jennifer S. | Banks, Ian R. | Schaibley, Claire | Ovod, Vitaliy | Mawuenyega, Kwasi G. | Bateman, Randall J. | Wardlaw, Sharon L. | Lucey, Brendan P.

Article Type: Research Article

Abstract: Background: Concentrations of soluble amyloid-β (Aβ ) oscillate with the sleep-wake cycle in the interstitial fluid of mice and cerebrospinal fluid (CSF) of humans. Further, the concentration of Aβ in CSF increases during sleep deprivation. Stress and disruption of the circadian clock are additional mechanisms hypothesized to increase CSF Aβ levels. Cortisol is a marker for both stress and has an endogenous circadian rhythm. Other factors such as glucose and lactate have been associated with changes in sleep-wake activity and/or Aβ . Objective: In this exploratory study, we used samples collected in a previous study …to examine how sleep deprivation affects Aβ , cortisol, lactate, and glucose in plasma and CSF from healthy middle-aged adults (N = 11). Methods: Eleven cognitively normal participants without evidence of sleep disturbance were randomized to sleep deprivation or normal sleep control. All participants were invited to repeat the study. Cortisol, lactate, glucose, and Aβ were measured in 2-h intervals over a 36-h period in both plasma and CSF. All concentrations were normalized to the mean prior to calculating mesor, amplitude, acrophase, and other parameters. Results: One night of sleep deprivation increases the overnight concentration of Aβ in CSF approximately 10%, but does not significantly affect cortisol, lactate, or glucose concentrations in plasma or CSF between the sleep-deprived and control conditions. Conclusion: These data suggest that sleep deprivation-related changes in CSF Aβ are not mediated by stress or circadian disruption as measured by cortisol. Show more

Keywords: Amyloid-β, cortisol, sleep deprivation

DOI: 10.3233/JAD-191122

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Pereira, Marta Luísa Gonçalves de Freitas | Camargo, Marina von Zuben de Arruda | Bellan, Ariella Fornachari Ribeiro | Tahira, Ana Carolina | dos Santos, Bernardo | dos Santos, Jéssica | Machado-Lima, Ariane | Nunes, Fátima L.S. | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: Background: Visual search abilities are essential to everyday life activities and are known to be affected in Alzheimer’s disease (AD). However, little is known about visual search efficiency in mild cognitive impairment (MCI), a transitive state between normal aging and dementia. Eye movement studies and machine learning methods have been recently used to detect oculomotor impairments in individuals with dementia. Objective: The aim of the present study is to investigate the association between eye movement metrics and visual search impairment in MCI and AD. Methods: 127 participants were tested: 43 healthy controls, 51 with MCI, and …33 with AD. They completed an eyetracking visual search task where they had to find a previously seen target stimulus among distractors. Results: Both patient groups made more fixations on the screen when searching for a target, with longer duration than controls. MCI and AD fixated the distractors more often and for a longer period of time than the target. Healthy controls were quicker and made less fixations when scanning the stimuli for the first time. Machine-learning methods were able to distinguish between controls and AD subjects and to identify MCI subjects with a similar oculomotor profile to AD with a good accuracy. Conclusion: Results showed that eye movement metrics are useful for identifying visual search impairments in MCI and AD, with possible implications in the early identification of individuals with high-risk of developing AD. Show more

Keywords: Alzheimer’s disease, eye movements, eyetracking, machine learning, mild cognitive impairment, visual attention, visual impairments, visual search

DOI: 10.3233/JAD-190690

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

Authors: Chuang, Yi-Fang | Varma, Vijay | An, Yang | Tanaka, Toshiko | Davatzikos, Christos | Resnick, Susan M. | Thambisetty, Madhav

Article Type: Research Article

Abstract: Background: An epistatic interaction between the ɛ 4 allele of apolipoprotein E (APOE ɛ 4) gene and the K-variant of butyrylcholinesterase (BCHE-K ) genes has been previously reported to increase risk of Alzheimer’s disease (AD). However, these observations were largely from case-control studies with small sample sizes. Objective: To examine the interaction between APOE ɛ 4 and BCHE-K on: 1) the risk of incident AD and 2) rates of change in brain volumes and cognitive performance during the preclinical stages of AD in a prospective cohort study. Methods: The study sample for survival …analysis included 691 Caucasian participants (age at baseline, 58.4±9.9 years; follow-up time,16.9±9.7 years) from the Baltimore Longitudinal Study of Aging. The neuroimaging sample included 302 participants with 1,388 magnetic resonance imaging (MRI) scans. Cognitive performance was assessed in 703 participants over 4,908 visits. Results: A total of 122 diagnoses (79 AD, 43 mild cognitive impairment [MCI]) were identified. Participants with both APOE ɛ 4 and BCHE-K variants had a 3.7-fold greater risk of AD (Hazard ratio [HR] 95% CI=1.99–6.89, p  <  0.001) compared to non-carriers of both genes (APOE ɛ 4 x BCHE-K interaction p  = 0.025). There was no APOE ɛ 4-BCHE-K interaction effect on rate of cognitive decline and brain atrophy. Conclusion: The APOE and BCHE genes interact to influence risk of incident AD/MCI but not rates of brain atrophy and decline in cognitive performance before onset of cognitive impairment. This may suggest the epistatic interaction between APOE ɛ 4 and BCHE-K on AD risk is disease stage-dependent. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E4, Butyrylcholinesterase, epistaxis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-191335

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Gill, Sascha | Mouches, Pauline | Hu, Sophie | Rajashekar, Deepthi | MacMaster, Frank P. | Smith, Eric E. | Forkert, Nils D. | Ismail, Zahinoor | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Machine learning (ML) is a promising technique for patient-specific prediction of mild cognitive impairment (MCI) and dementia development. Neuropsychiatric symptoms (NPS) might improve the accuracy of ML models but have barely been used for this purpose. Objectives: To investigate if baseline mild behavioral impairment (MBI) status used for NPS quantification along with brain morphology features are predictive of follow-up diagnosis, median 40 months later in patients with normal cognition (NC) or MCI. Method: Baseline neuroimaging, neuropsychiatric, and clinical data from 102 individuals with NC and 239 with MCI were extracted from the Alzheimer’s Disease Neuroimaging …Initiative database. Neuropsychiatric inventory questionnaire items were transformed to MBI domains using a published algorithm. Diagnosis at latest follow-up was used as the outcome variable and ground truth classification. A logistic model tree classifier combined with information gain feature selection was trained to predict follow-up diagnosis. Results: In the binary classification (NC versus MCI/AD), the optimal ML model required only two features from over 200, MBI total score and left hippocampal volume. These features correctly classified participants as remaining normal or developing cognitive impairment with 84.4% accuracy (area under the receiver operating characteristics curve [ROC-AUC] = 0.86). Seven features were selected for the three-class model (NC versus MCI versus dementia) achieving an accuracy of 58.8% (ROC-AUC=0.73). Conclusion: Baseline NPS, categorized for MBI domain and duration, have prognostic utility in addition to brain morphology measures for predicting diagnosis change using ML. MBI total score, followed by impulse dyscontrol and affective dysregulation were most predictive of future diagnosis. Show more

Keywords: Alzheimer’s disease, artificial intelligence, magnetic resonance imaging, mild behavioral impairment, mild cognitive impairment

DOI: 10.3233/JAD-191169

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: He, Wenting | Tu, Man | Du, Yehong | Li, Junjie | Pang, Yayan | Dong, Zhifang

Article Type: Research Article

Abstract: Background: Accumulation of amyloid-β (Aβ ) peptides, generated from amyloid-β precursor protein (Aβ PP) amyloidogenic processing, is one of the most salient disease hallmarks of Alzheimer’s disease (AD). Nicotine is able to promote α -secretase-mediated Aβ PP nonamyloidogenic processing and increase the release of sAβ PPα and C-terminal fragment of 83 amino acids (C83). However, the potential molecular mechanism remains elusive. Objective: The aim of the present study was to investigate the effect of nicotine on Aβ PP processing in SH-SY5Y cells that stably express human Swedish mutant Aβ PP695 (SH-SY5Y-Aβ PP695). Methods: …The expression of Aβ PP and its C-terminal fragments including C99, C89, and C83, was measured in SH-SY5Y-Aβ PP695 cells treated with nicotine for 6 h. Protein kinase C (PKC) antagonist Ro30-8220 or agonist PMA was used to determine the role of PKC in Aβ PP processing. Lentivirus-mediated shRNA targeting receptor for activated C-kinase 1 (RACK1) gene was added into the media to knockdown RACK1 expression, and then Aβ PP processing was examined. Results: The results showed that 6 h of nicotine exposure increased the expression of α -secretase (ADAM10) and C83 in a dose dependent manner. While the β -secretase (BACE1), Aβ PP amyloidogenic processing products C89 and C99 as well as Aβ peptides (including Aβ 40 and Aβ 42 ) remained unchanged. We also found that nicotine elevated the expression of phosphorylated PKC (P-PKC) and RACK1 on the cytomembrane. PKC antagonist Ro30-8220 treatment prevented the increase of ADAM10 and C83 by nicotine. Genetic knockdown RACK1 significantly inhibited P-PKC, and consequently abolished the increase of ADAM10 and C83 by nicotine. Conclusion: Taken together, these results indicate that nicotine effectively promotes Aβ PP nonamyloidogenic processing via RACK1-dependent activation of PKC in SH-SY5Y-Aβ PP695 cells and could be a potential molecule for AD treatment. Show more

Keywords: Alzheimer’s disease, nicotine, protein kinase C, receptor for activated C-kinase 1

DOI: 10.3233/JAD-200003

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Zhang, Weiwei | Liu, Yiming | Bao, Hong | Zhang, Mengguo | Gao, Feng | Kang, Dongmei | Shen, Yong

Article Type: Research Article

Abstract: Background: Recent studies showed that type 2 diabetes mellitus (T2DM) may increase the risk of cognitive impairment, but there are few biomarkers to diagnostically discriminate T2DM-associated cognitive impairment and cognitive impairment alone. In this study, we assessed certain cytokines involved in inflammation and vascular diseases and identified special panel of cytokines that could differentiate between T2DM and cognitive impairment. Objective: To investigate associations and differences between T2DM and cognitive impairment by cytokines analysis. Methods: A total of 264 participants were recruited, their blood samples were collected, and plasma and serum were separated and stored at – …80°C until the assessment of amyloid-β (Aβ )42 , Aβ 40 and 8 kinds of cytokines by Luminex multiplex assays. Results: Plasma Aβ 40 is higher whereas Aβ 42/40 ratio is lower in cognitive impairment and T2DM-associated cognitive impairment compared to other groups. As compared to health control, YKL-40 level was upregulated in cognitive impairment, PRGN was downregulated in T2DM associated cognitive impairment, OPN was substantially decreased in T2DM, and IL-6 was elevated in cognitive impairment and T2DM-associated cognitive impairment. Interestingly, VEGF and S100B were induced in T2DM when compared with cognitive impairment, and NSE level in T2DM-associated cognitive impairment is significantly lower than in T2DM or cognitive impairment. Conclusion: Aβ 42 , Aβ 40 , and Aβ 42/40 ratio cannot distinguish T2DM-associated cognitive impairment from cognitive impairment. Certain cytokines (YKL-40, NSE, and VEGF) have good performance in distinguishing T2DM-associated cognitive impairment from simple cognitive impairment. Taken together, this may improve the accuracy of the diagnosis and establishment of individualized therapy. Show more

Keywords: Biomarkers, cognitive impairment, serum cytokines, type 2 diabetes mellitus

DOI: 10.3233/JAD-200095

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Portacolone, Elena | Halpern, Jodi | Luxenberg, Jay | Harrison, Krista L. | Covinsky, Kenneth E.

Article Type: Review Article

Abstract: Due to the high costs of providing long-term care to older adults with cognitive impairment, artificial companions are increasingly considered as a cost-efficient way to provide support. Artificial companions can comfort, entertain, and inform, and even induce a sense of being in a close relationship. Sensors and algorithms are increasingly leading to applications that exude a life-like feel. We focus on a case study of an artificial companion for people with cognitive impairment. This companion is an avatar on an electronic tablet that is displayed as a dog or a cat. Whereas artificial intelligence guides most artificial companions, this application …also relies on technicians “behind” the on-screen avatar, who via surveillance, interact with users. This case is notable because it particularly illustrates the tension between the endless opportunities offered by technology and the ethical issues stemming from limited regulations. Reviewing the case through the lens of biomedical ethics, concerns of deception, monitoring and tracking, as well as informed consent and social isolation are raised by the introduction of this technology to users with cognitive impairment. We provide a detailed description of the case, review the main ethical issues and present two theoretical frameworks, the “human-driven technology” platform and the emancipatory gerontology framework, to inform the design of future applications. Show more

Keywords: Dementia, ethics, robots, technology

DOI: 10.3233/JAD-190952

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Harrison, Judith R. | Mistry, Sumit | Muskett, Natalie | Escott-Price, Valentina

Article Type: Research Article

Abstract: Background: Late-onset Alzheimer’s disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual’s risk alleles, have been used to draw inferences about the pathological processes underpinning AD. Objective: This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration. Methods: We searched the literature from July 2008–July 2018 following PRISMA …guidelines. Results: 57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes. Conclusion: PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity. Show more

Keywords: alleles, Alzheimer’s disease, amyloid-beta peptides, cognitive dysfunction, genome-wide association study, multifactorial inheritance, neuroimaging, phenotype, precision medicine, single nucleotide polymorphism

DOI: 10.3233/JAD-191233

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Luchsinger, José A. | Palta, Priya | Rippon, Brady | Soto, Luisa | Ceballos, Fernando | Pardo, Michelle | Laing, Krystal | Igwe, Kay | Johnson, Aubrey | Tomljanovic, Zeljko | He, Hengda | Reitz, Christiane | Kreisl, William | Razlighi, Qolamreza | Teresi, Jeanne | Moreno, Herman | Brickman, Adam M.

Article Type: Research Article

Abstract: Background: Females may have a higher risk of dementia than males. It is not clear if sex differences in Alzheimer’s disease (AD) neuropathology explain the higher risk of dementia in females. Sex differences in AD neuropathology might begin in middle age, decades before the sex differences in dementia are apparent. Objective: To examine sex differences in in vivo AD neuropathology in late middle age. Methods: We conducted a cross-sectional comparison of AD biomarkers among 266 Hispanic males and females (mean age: 64.0; 71.8% females) without dementia. Amyloid burden was measured as global standardized uptake value ratio …(SUVR) with18 F-Florbetabenpositron emission tomography (PET). Neurodegeneration was ascertained as cortical thickness in AD signature areasusingbrain magnetic resonance imaging. Tau burden was measured as tau SUVR in the middle/inferior temporal gyri and medial temporal cortex with 18 F-MK-6240 in 75 of the 266 participants. Results: Females had higher amyloid SUVR and tau SUVR in the middle/inferior temporal gyri thanmales. However, femaleshad higher cortical thickness than males and performed better in a test of verbal memory despite having higher AD neuropathology burden. Conclusion: Higher amyloid and tauin femalescompared tomalesin late middle-agemay explainthe reported higher dementia risk in elderly females compared to males. Longitudinal follow-up is necessary to examine whether higher amyloid and tau burden in late middle age is followed by increased neurodegeneration and cognitive decline in females as compared with males. Show more

Keywords: Amyloid, cognition, Hispanics, neurodegeneration, sex differences, tau

DOI: 10.3233/JAD-191183

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Li, Lily | Cavuoto, Marina | Biddiscombe, Karen | Pike, Kerryn E.

Article Type: Research Article

Abstract: Background: Dementia is a devastating condition for older adults, with both modifiable (e.g., diabetes mellitus) and unmodifiable risk factors (e.g., APOE ɛ 4 allele). It remains unclear how, and to what extent, diabetes impacts dementia risk via both cerebrovascular and amyloid-β pathways. Objective: We conducted a quantitative meta-analysis to investigate the contribution of diabetes to incident dementia risk in people with ɛ 4 and, based on the vascular-related neuropathology of diabetes, whether the combination of these factors increases risk for vascular dementia versus Alzheimer’s disease (AD). Methods: Systematic literature searches were conducted using EMBASE, MEDLINE, …PsychINFO, and CINHAL databases. Pooled relative risk (RR) estimates were calculated using a random effects model, and subgroup analyses conducted across dementia subtypes. Results: Twelve studies were included, with a total of 16,200 participants. Considered concurrently, diabetes increased incident dementia risk an additional 35% for those with ɛ 4 (RR = 1.35, 95% CI = 1.13–1.63). Similar patterns were observed for AD and vascular dementia. Conclusion: Interventions to prevent co-morbid diabetes, and diabetes-related complications and neuropathological changes, may be one way of modifying dementia risk in the vulnerable ɛ 4 population. Show more

Keywords: Alzheimer’s disease, Apolipoproteins E, dementia, diabetes mellitus, risk factors, vascular dementia

DOI: 10.3233/JAD-191068

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 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. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Mandal, Pravat K. | Shukla, Deepika

Article Type: Editorial

Abstract: Magnetic resonance spectroscopy (MRS) plays a substantial role in the non-invasive detection of brain neurochemicals, antioxidants, and neurotransmitters. Quantitative monitoring of these neurochemicals and neurotransmitters in the brain has a profound application for the understanding of brain disorders. Significant progress in the MR scanner as well as MR pulse sequence development to detect in vivo neurochemicals has been accomplished. The processing of MR signal from these low abundant neurochemicals/neurotransmitters should be very robust and sensitive in order to provide distinctive observations of disease-related neurochemical alterations and their absolute quantitation to aid in early clinical diagnosis. We highlight the diversity …in currently available MRS processing tools, and recently introduced, KALPANA, a promising package integrating the end-to-end processing as well as robust quantitation of neurochemicals in a user-friendly approach through a graphical user interface. This further necessitates the futuristic need for advanced MRS processing pipeline and the respective readout can help in early diagnosis and prognosis of diseases in the clinical environment. Show more

Keywords: Absolute quantitation, clinical study, KALPANA, magnetic resonance spectroscopy, Matlab, platform, signal processing

DOI: 10.3233/JAD-191351

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Yang, Hyun Ju | Kang, Na Ri | Jung, Young Eun | Kim, Moon Doo | Jeong, Hyun Ghang | Lee, Tae Jin | Han, Ji Won | Kim, Ki Woong | Park, Joon Hyuk

Article Type: Research Article

Abstract: Background: Apolipoprotein E (APOE ) ɛ 4 allele carriers have an increased risk of late-onset Alzheimer’s disease (AD). However, in the “Choosing Wisely” campaign for avoiding unnecessary medical tests, treatments, and procedures, APOE genetic testing is not recommended as a predictive test for AD. Objective: The aim of this study was to investigate the potential value of APOE genetic testing in a specific clinical context. Methods: Subjects with poor performance in the Korean version of the Mini-Mental Status Examination for dementia screening (MMSE-DS) with a Z-score of less than –1.5 were recruited from the …public health centers. All participants underwent APOE genetic testing. Family history of dementia (FHx) was confirmed if one or more first-degree relatives had dementia. Results: Among 349 subjects, 162 (46.4%) were diagnosed with AD. APOE ɛ 4 allele carriers had a much higher risk of AD in the group with FHx than in the group without FHx (OR = 15.81, 95% CI = 2.74–91.21 versus OR = 1.82, 95% CI = 1.00–3.27, z  = 2.293, p  = 0.011). The sensitivity, specificity, positive predictive value, and negative predictive value for the APOE ɛ 4 allele were 47.7%, 90.9%, 91.3%, and 46.5% in the group with FHx. Conclusion: It would be a wise choice to perform the APOE genetic testing for the diagnosis of AD in subjects with poor performance in a screening test and a family history of dementia. Show more

Keywords: Alzheimer’s disease, apolipoprotein genetic testing, odds ratio, sensitivity, specificity

DOI: 10.3233/JAD-190983

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Alifier, Marek | Olsson, Bob | Andreasson, Ulf | Cullen, Nicholas C. | Czyżewska, Jolanta | Jakubów, Piotr | Sieśkiewicz, Andrzej | Stasiak-Barmuta, Anna | Hirnle, Tomasz | Kornhuber, Johannes | Zetterberg, Henrik | Lewczuk, Piotr | Blennow, Kaj

Article Type: Research Article

Abstract: Background: Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures. Objective: Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma. Methods: Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aβ40 …, and Aβ42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery. Results: Tau increased during surgery (1752%, p  = 0.0001) and NFL rose seven days post-surgery (1090%, p  < 0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aβ40 and Aβ42 . Conclusion: Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia. Show more

Keywords: Cardiac surgery, cognitive impairment, dementia, extracorporeal circulation, neurofilament light protein, plasma, tau

DOI: 10.3233/JAD-191165

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Feinkohl, Insa | Schipke, Carola G. | Kruppa, Jochen | Menne, Felix | Winterer, Georg | Pischon, Tobias | Peters, Oliver

Article Type: Research Article

Abstract: Background: Collection of cerebrospinal fluid (CSF) for measurement of amyloid-β (Aβ) species is a gold standard in Alzheimer’s disease (AD) diagnosis, but has risks. Thus, establishing a low-risk blood Aβ test with high AD sensitivity and specificity is of outmost interest. Objective: We evaluated the ability of a commercially available plasma Aβ assay to distinguish AD patients from biomarker-healthy controls. Method: In a case-control design, we examined plasma samples from 44 AD patients (A + N+) and 49 controls (A–N–) from a memory clinic. AD was diagnosed using a combination of neuropsychological examination, CSF biomarker analysis and brain …imaging. Total Aβ40 and total Aβ42 in plasma were measured through enzyme-linked immunosorbent assay (ELISA) technology using ABtest40 and ABtest42 test kits (Araclon Biotech Ltd.). Receiver operating characteristic (ROC) analyses with outcome AD were performed, and sensitivity and specificity were calculated. Results: Plasma Aβ42/40 was weakly positively correlated with CSF Aβ42/40 (Spearman’s rho 0.22; p  = 0.037). Plasma Aβ42/40 alone was not able to statistically significantly distinguish between AD patients and controls (AUC 0.58; 95% CI 0.46, 0.70). At a cut-point of 0.076 maximizing sensitivity and specificity, plasma Aβ42/40 had a sensitivity of 61.2% and a specificity of 63.6%. Conclusion: In this sample, the high-throughput blood Aβ assay was not able to distinguish well between AD patients and controls. Whether or not the assay may be useful in large-scale epidemiological settings remains to be seen. Show more

Keywords: Alzheimer’s disease, amyloid, diagnosis, high-throughput assay, plasma

DOI: 10.3233/JAD-200046

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Banerjee, Gargi | Ambler, Gareth | Keshavan, Ashvini | Paterson, Ross W. | Foiani, Martha S. | Toombs, Jamie | Heslegrave, Amanda | Dickson, John C. | Fraioli, Francesco | Groves, Ashley M. | Lunn, Michael P. | Fox, Nick C. | Zetterberg, Henrik | Schott, Jonathan M. | Werring, David J.

Article Type: Research Article

Abstract: Background: There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA). Objective: To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA. Methods: We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer’s disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service. Results: We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, …CAA patients had a distinctive CSF biomarker profile, with significantly lower (p  < 0.01) median concentrations of Aβ38 , Aβ40 , Aβ42 , sAβPPα , and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p  < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38 , Aβ40 , Aβ42 , and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n  = 5) and negative (n  = 5) scans, PET positive individuals had lower (p  < 0.05) concentrations of CSF Aβ42 , and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an “AD-like” profile. Conclusion: CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed. Show more

Keywords: Alzheimer’s disease, amyloid-β , biomarkers, cerebral amyloid angiopathy, cerebrospinal fluid

DOI: 10.3233/JAD-191254

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Wang, Ya-Juan | Hu, Hao | Yang, Yu-Xiang | Zuo, Chuan-Tao | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Recent studies have shown that amyloid-β (Aβ) burden influenced white matter (WM) integrity before the onset of dementia. Objective: To assess whether the effects of Aβ burden on WM integrity in cognitively normal (CN) individuals were regionally specific. Methods: Our cohort consisted of 71 CNs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database who underwent both AV45 amyloid-PET and diffusion tensor imaging. Standardized uptake value ratio (SUVR) was computed across four bilateral regions of interest (ROIs) corresponding to four stages of in vivo amyloid staging model (Amyloid stages I–IV). Linear regression models were conducted …in entire CN group and between APOE ɛ 4 carriers and non-carriers. Results: Our results indicated that higher global Aβ-SUVR was associated with higher mean diffusivity (MD) in the entire CN group (p  = 0.023), and with both higher MD (p  = 0.015) and lower fractional anisotropy (FA) (p  = 0.026) in APOE ɛ 4 carriers. Subregion analysis showed that higher Amyloid stage I-II Aβ-SUVRs were associated with higher MD (Stage-1: p  = 0.030; Stage-2: p  = 0.016) in the entire CN group, and with both higher MD (Stage-1: p  = 0.004; Stage-2: p  = 0.010) and lower FA (Stage-1: p  = 0.022; Stage-2: p  = 0.014) in APOE ɛ 4 carriers. No associations were found in APOE ɛ 4 non-carriers and in Amyloid stage III-IV ROIs. Conclusions: Our results indicated that the effects of Aβ burden on WM integrity in CNs might be regionally specific, particularly in Amyloid stage I-II ROIs, and modulated by APOE ɛ 4 status. Show more

Keywords: Amyloid PET, cognitively normal elders, diffusion tensor imaging, in vivo amyloid staging model, white matter integrity

DOI: 10.3233/JAD-191350

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Counil, Hermine | Krantic, Slavica

Article Type: Research Article

Abstract: Nanosized extracellular vesicles, known as exosomes, are produced by all cell types in mammalian organisms and have been recently involved in neurodegeneration. In the brain, both glia and neurons give rise to exosomes, which contribute to their intercellular communication. In addition, brain-derived exosomes have a remarkable property to cross the blood-brain-barrier bi-directionally. In this line, exosomes of central origin have been identified in peripheral circulation and already considered as putative blood biomarkers of neurodegenerative diseases, including Alzheimer’s disease (AD). Moreover, tentative use of exosomes as vehicle for the clearance of brain-born toxic proteins or, conversely, neuroprotective drug delivery, was also …envisaged. However, little is known about the precise role of exosomes in the control and regulation of neuronal functions. Based on the presence of subunits of glutamate receptors in neuron-derived exosomes on one hand, and complement proteins in astrocyte-derived exosomes on the other hand, we hypothesize that exosomes may participate in the control of neuronal excitability via inflammatory-like mechanisms both at the central level and from the periphery. In this review, we will focus on AD and discuss the mechanisms by which exosomes of neuronal, glial, and/or peripheral origin could impact on neuronal excitability either directly or indirectly. Show more

Keywords: Alzheimer’s disease, exosomes, glial cells, neuronal excitability, synaptic activity

DOI: 10.3233/JAD-191237

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

Authors: Terrera, Graciela Muniz | Harrison, John E. | Ritchie, Craig W. | Ritchie, Karen

Article Type: Research Article

Abstract: Alterations in Alzheimer’s disease (AD) biomarkers have been observed decades before the onset of dementia. Cognitive dysfunction, while central to the clinical diagnosis of AD, has long been considered as a late-stage phenomenon. This assumption is currently challenged and signals on some cognitive tests are now being observed within the preclinical stage. As part of the European Prevention of Alzheimer’s Dementia (EPAD) project, a battery of cognitive tests has been proposed (the EPAD Neuropsychological Examination, ENE) which is designed to detect cognitive changes in persons without clinical signs of AD but who are at high risk. Analysis of results from …the 361 participants with complete measures and without dementia recruited into the EPAD Longitudinal Cohort Study that the majority have elevated biomarker levels, with significant associations between an episodic verbal memory task and tau, while amyloid-β (Aβ) was associated with a central executive task. These preliminary findings suggest that profiles of cognitive performance may be specific to a given biomarker, with a primarily hippocampal task being associated with higher levels of tau and a frontal executive task being associated with higher levels of Aβ. While previous research has focused on the relationship between cognition and levels of Aβ, our findings suggest that p-tau may potentially be a more significant correlate. Show more

Keywords: Alzheimer’s disease, amyloid-β , biomarkers, cognition, diagnosis, neuropsychology, tau

DOI: 10.3233/JAD-191108

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Oesterhus, Ragnhild | Dalen, Ingvild | Bergland, Anne K. | Aarsland, Dag | Kjosavik, Svein R.

Article Type: Research Article

Abstract: Background: Patients with dementia are at high risk of being hospitalized, but there is little knowledge whether this applies to all forms of dementia. Objective: To investigate if there are differences in hospitalization between patients with Alzheimer’s disease (AD) and Lewy body disease (LBD), and further, to compare admission rate with the general age-matched population. Methods: Patients (age 75.7±7.4) recently diagnosed with mild form of AD (n  = 110) or LBD (n  = 91) were included from outpatient clinics. The participants were followed from time of diagnosis, for five years or until death. Study outcomes were time to …first hospitalization after diagnosis, number of admissions, total number of hospital days, and length of stay. Age-standardized admission ratios were calculated. Time to first admission was analyzed using competing risks regression models, and differences in number of hospitalizations and hospital days were addressed using negative binomial regression models. Results: More than 77% of the patients were admitted, largely as unplanned hospitalizations. Patients with LBD had significantly shorter time until first hospitalization (median 1.28 years, 95% CI 0.93–1.67 versus AD: 2.32 years, 95% CI 1.74–3.31) and more unplanned hospital days (median 7 days, IQR 2–26), than patients with AD (2 days, IQR 0–11). Conclusion: Our data indicates that patients with LBD have shorter time until first admission and higher admission rate than AD patients. This imposes a great burden on patients, their family, and the health care system. More knowledge about hospital admissions of people with dementia is needed. Future studies should investigate strategies to avoid potentially preventable admissions. Show more

Keywords: Alzheimer’s disease, dementia, hospitalization, length of stay, Lewy body dementia, patient admission

DOI: 10.3233/JAD-191141

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Huang, Yaowei | Huang, Wei | Huang, Yingwei | Song, Pingping | Zhang, Melanie | Zhang, Han-Ting | Pan, Suyue | Hu, Yafang

Article Type: Research Article

Abstract: Background: Accumulation of p25 is thought to be a causative risk factor for Alzheimer’s disease (AD). As a cleaved product of p35, p25 binds to cyclin-dependent kinase 5 (Cdk5) and leads to the hyperactivity of Cdk5. Then, Cdk5/p25 phosphorylates many pathological substrates related to neurodegenerative diseases. p25 transgenic (Tg) mouse model recaptures some pathological changes of AD, including tau hyperphosphorylation, neurofibrillary tangles, neuroinflammation, and neuronal death, which can be prevented by transgenic expression of Cdk5 inhibitory peptide (CIP) before the insult of p25. Objective: In the present study, we would like to know whether adeno-associated virus serotype-9 (AAV9)-mediated …CIP can protect neurons after insult of p25 in p25Tg mice. Methods: Administration of AAV9-CIP or control virus were delivered in the brain of p25Tg mice via intracerebroventricular infusions following the induction of p25. Western blotting, immunohistochemistry and immunofluorescence assessment, and animal behavioral evaluation were performed. Results: Brain atrophy, neuronal death, tau phosphorylation and inflammation in the hippocampus, and cognitive decline were observed in p25Tg mice. Administration of CIP but not the control virus in p25Tg mice reduced levels of tau phosphorylation and inflammation in the hippocampus, which is correlated with inhibition of brain atrophy and neuronal apoptosis in the hippocampus, and improvement of cognitive decline. Conclusion: Our results provide further evidence that the neurotoxicity of p25 can be alleviated by CIP. Show more

Keywords: Cdk5, Cdk5 inhibitory peptide, p25 transgenic mice, tau phosphorylation, neurodegeneration

DOI: 10.3233/JAD-191098

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Kiss, Eva | Groeneweg, Femke | Gorgas, Karin | Schlicksupp, Andrea | Kins, Stefan | Kirsch, Joachim | Kuhse, Jochen

Article Type: Research Article

Abstract: Early changes in inhibitory synapse connectivities are thought to contribute to the excitation/inhibition imbalance preceding neurodegeneration in Alzheimer’s disease (AD). Recently, we reported a robust increase in the level of different key-proteins of inhibitory synapses in hippocampal subregions of pre-symptomatic APPswe-PS1 mice, a model of cerebral amyloidosis. Besides increased inhibitory synaptic clusters on parvalbumin-positive projections in CA1 and CA3, we observed impaired communication between these two hippocampal areas of young APP-PS1 mice. Interestingly, the phosphorylation of gephyrin, a major organizer of inhibitory synapses, was also increased. Here, we demonstrate that the protein levels of CDK5, a kinase involved in the …phosphorylation of gephyrin, and its regulatory protein p35 are also significantly increased in hippocampal subregions of young APP-PS1 mice. Consistently, the expression of hAPP-swe in cultured hippocampal neurons resulted in higher p35-protein levels, indicating a possible molecular link between increased Aβ-production and the elevated p35/CDK5 levels seen in vivo . Further, a shRNA mediated downregulation of p35-expression in hippocampal neurons correlated with a decrease in gephyrin phosphorylation and in a reduced density of synaptic γ 2-GABAA -receptor clusters. These findings, together with the detection of gephyrin colocalization with CDK5 and p35 by immunostaining and proximity ligation experiments in vivo and in vitro , are supporting our hypothesis that Aβ has a profound impact on inhibitory network properties, likely mediated at least in part by p35/CDK5 signaling. This further underscores the impact of altered inhibitory synaptic transmission in AD. Show more

Keywords: Alzheimer’s disease, APP-PS1, CDK5, CDK5r1, γ2-GABAA receptor, inhibitory synapse, p35

DOI: 10.3233/JAD-190976

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

Authors: Ihara, Masafumi | Saito, Satoshi

Article Type: Review Article

Abstract: Although more than 100 years have passed since Alois Alzheimer reported a case of Alzheimer’s disease (AD), a definitive answer to the causes of cognitive impairment in the disease remains elusive. Despite significant enthusiasm and investment from the pharmaceutical industry, clinical trials of many disease-modifying drugs for AD have been largely unsuccessful. Drug repositioning (DR) or repurposing approaches are relatively inexpensive and more reliable compared to de novo drug development in AD. About 30% of clinical trials for AD in progress around the world use the DR method and hold potential in halting the current deadlock in treatment options. …By using drugs approved for other indications, these clinical trials target dysregulated pathways in AD with different or a combination of modes of action, including anti-amyloid, cardiovascular, anti-tau, anti-inflammatory, immunomodulatory, metabolic, neuroprotective, and neurotransmission-based approaches. For instance, anti-diabetic drugs, such as insulin, metformin, liraglutide, and dapagliflozin, and cardiovascular drugs, such as cilostazol, candesartan, telmisartan, prazosin, and dabigatran, could serendipitously provide previously unearthed benefits in AD. This is in line with recent thinking, which views AD as a complex multifactorial disorder, not dominated by one dominant biological factor, such as amyloid-β, and likely a confluence of many pathobiological mechanisms, including vascular dysregulation. Such increasingly available knowledge of phenotyping may be used to design ‘tailor-made’ DR and relatively homogeneous AD subpopulations specifically targeted with existing drugs based on known modes of action. It is thus expected that DR approaches will create a major paradigm shift in AD research and development. Show more

Keywords: Clinical trial, drug repositioning, drug reprofiling, drug repurposing, drug rescue

DOI: 10.3233/JAD-200049

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Kresge, Hailey A. | Liu, Dandan | Gupta, Deepak K. | Moore, Elizabeth E. | Osborn, Katie E. | Acosta, Lealani Mae Y. | Bell, Susan P. | Pechman, Kimberly R. | Gifford, Katherine A. | Mendes, Lisa A. | Wang, Thomas J. | Blennow, Kaj | Zetterberg, Henrik | Hohman, Timothy J. | Jefferson, Angela L.

Article Type: Research Article

Abstract: Background: Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer’s disease (AD) pathology and neurodegeneration. Objective: This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration. Methods: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n  = 152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42 ), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions …related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ɛ 4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognitive (NC), mild cognitive impairment (MCI)). Results: Higher LVEF related to decreased CSF Aβ42 levels (β= –6.50, p  = 0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p  = 0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p  = 0.004) and p-tau levels (p  = 0.002), whereas lower LVEF was associated with increased CSF t-tau (β= –9.74, p  = 0.01) and p-tau in the NC (β= –1.41, p  = 0.003) but not MCI participants (p -values>0.13). Conclusions: Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life. Show more

Keywords: Aging, Alzheimer’s disease, atrophy, cerebrospinal fluid proteins, echocardiography, tau proteins

DOI: 10.3233/JAD-190813

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Morin, Alexandre | Samper-Gonzalez, Jorge | Bertrand, Anne | Ströer, Sébastian | Dormont, Didier | Mendes, Aline | Coupé, Pierrick | Ahdidan, Jamila | Lévy, Marcel | Samri, Dalila | Hampel, Harald | Dubois, Bruno | Teichmann, Marc | Epelbaum, Stéphane | Colliot, Olivier

Article Type: Research Article

Abstract: Background: Automated volumetry software (AVS) has recently become widely available to neuroradiologists. MRI volumetry with AVS may support the diagnosis of dementias by identifying regional atrophy. Moreover, automatic classifiers using machine learning techniques have recently emerged as promising approaches to assist diagnosis. However, the performance of both AVS and automatic classifiers has been evaluated mostly in the artificial setting of research datasets. Objective: Our aim was to evaluate the performance of two AVS and an automatic classifier in the clinical routine condition of a memory clinic. Methods: We studied 239 patients with cognitive troubles from a …single memory center cohort. Using clinical routine T1-weighted MRI, we evaluated the classification performance of: 1) univariate volumetry using two AVS (volBrain and Neuroreader™); 2) Support Vector Machine (SVM) automatic classifier, using either the AVS volumes (SVM-AVS), or whole gray matter (SVM-WGM); 3) reading by two neuroradiologists. The performance measure was the balanced diagnostic accuracy. The reference standard was consensus diagnosis by three neurologists using clinical, biological (cerebrospinal fluid) and imaging data and following international criteria. Results: Univariate AVS volumetry provided only moderate accuracies (46% to 71% with hippocampal volume). The accuracy improved when using SVM-AVS classifier (52% to 85%), becoming close to that of SVM-WGM (52 to 90%). Visual classification by neuroradiologists ranged between SVM-AVS and SVM-WGM. Conclusion: In the routine practice of a memory clinic, the use of volumetric measures provided by AVS yields only moderate accuracy. Automatic classifiers can improve accuracy and could be a useful tool to assist diagnosis. Show more

Keywords: All cognitive disorders/dementia, Alzheimer’s disease, assessment of cognitive disorders/dementia, magnetic resonance imaging, volumetric MRI

DOI: 10.3233/JAD-190594

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Yang, Aimin | Wang, Hongwei | Zuo, Xiaoxiao | Yang, Jianjun

Article Type: Research Article

Abstract: Persistent neuropathic pain (NP) causes future development of neurodegenerative diseases, e.g., Alzheimer’ disease, and thus needs to be optimally treated. Surgically-induced neuropathic pain (SNPP) is a persistent pain that occurs in nearly half of the individuals after common operations. Here, we showed that specific activation of 5-hydroxytryptamine (5-HT) type 2A receptors by systemic administration of TCB-2 [(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide] improved the function of potassium chloride cotransporter 2 (KCC2), resulting in reduction in neuropathic pain after chronic constriction injury (CCI), a rat model that mimics SNPP. Moreover, TCB-2 administration attenuated both mechanical and thermal hyperalgesia, likely through augmentation of dorsal horn …KCC2 levels, since this effect was abolished by intrathecal provision of dihydroindenyl oxy alkanoic acid (DIOA), which blocked the effects of KCC2. Furthermore, TCB-2-mediated re-activation of KCC2 likely reduces future development of neurodegeneration in rats. Together, our data support further studies on the possibility of using this strategy to reduce postoperative pain and future neurodegenerative disorders in clinic. Show more

Keywords: Alzheimer’ disease, neurodegeneration, potassium chloride cotransporter 2 (KCC2), surgically-induced neuropathic pain

DOI: 10.3233/JAD-200027

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Aschenbrenner, Andrew J. | Gordon, Brian A. | Fagan, Anne M. | Schindler, Suzanne E. | Balota, David A. | Morris, John C. | Hassenstab, Jason J.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid tau and neurofilament light (NfL) are two biomarkers of neurodegeneration in Alzheimer’s disease. Previous reports have shown that the influence of tau on cognitive decline depends on levels of amyloid burden whereas NfL predicts decline independently of amyloid. Most studies use a global cognitive composite as the primary outcome, and it is unknown if critical cognitive domain scores are similarly sensitive to rates of decline due to neurodegeneration. Objective: To examine the unique contribution of amyloid, tau, and NfL to rates of cognitive decline in multiple cognitive composites in a cognitively healthy, middle-aged to older …adult cohort. Methods: A total of 255 participants (55% female; mean age = 66.2 years, range = 42.5–86.7 years) completed CSF studies and serial cognitive assessments to measure global cognition, episodic memory, and attentional control. Linear mixed effects models were used to examine rates of change on each composite score as a function of baseline biomarker levels. Results: Total tau predicted decline in attention regardless of amyloid status, but the relationship to global cognition and episodic memory was dependent on amyloid, replicating prior literature. NfL predicted decline in attention and global cognition, but not memory, and this effect was independent of amyloid status. Conclusions: These findings suggest that NfL can be used to monitor cognitive decline in aging and Alzheimer’s disease and that an attentional control composite may be a better outcome for tracking general neurodegenerative effects on cognition. Show more

Keywords: Alzheimer’s disease, attention, cerebrospinal fluid, memory, neurofilament light

DOI: 10.3233/JAD-200018

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Gallucci, Maurizio | Pallucca, Claudia | Di Battista, Maria Elena | Bergamelli, Cristina | Fiore, Vittorio | Boccaletto, Franco | Fiorini, Michele | Perra, Daniela | Zanusso, Gianluigi | Fenoglio, Chiara | Serpente, Maria | Galimberti, Daniela | Bonanni, Laura

Article Type: Research Article

Abstract: We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old patient, followed by psychiatrists for depression and behavioral disorders, received a diagnosis of dementia with Lewy bodies (DLB) at another Center due to auditory hallucinations, gait impairment, and tendency to fall. He was then admitted to our Memory Clinic Unit for behavioral disturbances, such as delusional thinking, auditory hallucinations, and memory complaints. At that time, the patient’s therapy included Lorazepam, Quetiapine, Promazine, and Biperiden. The latter was immediately suspended for the absence of extrapyramidal …signs and to avoid the anticholinergic cognitive side effects. A 18 F-FDG PET showed a derangement of cortical metabolism with diffusely reduced activity, and limited areas of hyperactivity involving lateral frontal and lateral temporal inferior regions bilaterally. The patient underwent a series of exams, including neuropsychological tests, 123 I-MIBG scintigraphy, cerebrospinal fluid examination, and genetic analysis. A second 18 F-FDG PET showed an extensive remodulation of metabolic activity: relative higher concentration of the tracer in the prefrontal and inferior temporal cortex was no more detectable. Similarly, the diffuse reduced metabolic activity could not be traced anymore. Nonetheless, the metabolic activity still appeared reduced in the frontal lobe, in the anterior cingulate bilaterally, and in the anterior part of the hemispheric fissure. Taken together, clinical and neuroimaging features would point to a FTLD-like form. Furthermore, the diagnostic work-up was likely confounded by the anticholinergic drug on 18 F-FDG PET, highlighting the importance of carefully checking the patient’s pharmacology during the diagnostic process. Show more

Keywords: Anti-cholinergics, cerebral cortex, frontotemporal dementia, PET scan, TREDEM

DOI: 10.3233/JAD-191290

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Mehder, Rasha H. | Bennett, Brian M. | Andrew, R. David

Article Type: Research Article

Abstract: The study of late-onset (sporadic) Alzheimer’s disease (LOAD) has lacked animal models where impairments develop with aging. Oxidative stress promotes LOAD, so we have developed an oxidative stress-based model of age-related cognitive impairment based on gene deletion of aldehyde dehydrogenase 2 (ALDH2). This enzyme is important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit a progressive decline in recognition and spatial memory and AD-like pathologies. Here we performed morphometric analyses in the dorsal and ventral hippocampal CA1 regions (dCA1 and vCA1) as well as in overlying primary sensory …cortex to determine if altered neuronal structure can help account for the cognitive impairment in 12-month old KO mice. Dendritic morphology was quantitatively analyzed following Golgi-Cox staining using 9 WT mice (108 neurons) and 15 KO mice (180 neurons). Four pyramidal neurons were traced per mouse in each region, followed by branched structured analysis and Sholl analysis. Compared to WT controls, the morphology and complexity of dCA1 pyramidal neurons from KOs showed significant reductions in apical and basal dendritic length, dendrite intersections, ends, and nodes. As well, spine density along dorsal CA1 apical dendrites was significantly lower in KO versus WT. In contrast, pyramidal arborization in the vCA1 and primary sensory cortex were only minimally reduced in KO versus WT mice. These data suggest a region-specific vulnerability to oxidative stress-induced damage and/or a major and specific reduction in synaptic input to the pyramidal neurons of the dorsal hippocampus. This is in keeping with studies showing that lesions to the dorsal hippocampus impair primarily cognitive memory whereas ventral hippocampal lesions cause deficits in stress, emotion, and affect. Show more

Keywords: CA1, dendrite, hippocampus, morphometry, oxidative stress, pyramidal neurons, spatial memory, spines

DOI: 10.3233/JAD-191067

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

Authors: Dominguez, Sky | Rodriguez, Guadalupe | Fazelinia, Hossein | Ding, Hua | Spruce, Lynn | Seeholzer, Steven H. | Dong, Hongxin

Article Type: Research Article

Abstract: Approximately two-thirds of those suffering with Alzheimer’s disease (AD) are women, however, the biological mechanisms underlying this sex divergence of AD prevalence remain unknown. Previous research has shown sex-specific biochemical differences that bias female mice toward pro-AD signaling on the phosphoproteomic level via corticotropin releasing factor (CRF) receptor 1 activation after CRF overexpression. Here we aimed to determine if chronic stress would induce a similar response in AD mouse models. We stressed 4-month-old APP/PS1 mice using a chronic unpredictable mild stress (CUMS) paradigm for up to 1 month. Following CUMS and behavioral assessments, we quantified whole protein and phosphoprotein levels …in the cortex of stressed and non-stressed APP/PS1 mice using mass spectrometry-based proteomics. While there were no statistically significant differences at the total protein and peptide abundance levels, we found 909 and 841 statistically significant phosphopeptides between stressed and unstressed females and males, respectively, using a false discovery rate of 5%. Of these significant phosphopeptides, only 301 were the same in males and females. These results indicate that while both males and females undergo protein phosphorylation changes following stress, the peptides that are phosphorylated differ between sexes. We then used Metacore analysis to determine which biological pathways were affected. We found that several pathways were changed differently between male and female mice including NMDA receptor trafficking, cytoskeleton organization, and tau pathology. The differing biological pathways affected between males and females in response to chronic stress may help us to better understand why women are at a higher risk of AD. Show more

Keywords: Alzheimer’s disease, APP/PS1 mice, chronic stress, phosphoproteomics, sex differences

DOI: 10.3233/JAD-191009

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Babulal, Ganesh M. | Roe, Catherine M. | Stout, Sarah H. | Rajasekar, Ganesh | Wisch, Julie K. | Benzinger, Tammie L.S. | Morris, John C. | Ances, Beau M.

Article Type: Research Article

Abstract: Background: Depression is also common with older age. Alzheimer’s disease (AD) studies suggest that both cerebrospinal fluid and positron emission tomography (PET) amyloid biomarkers are associated with more depressive symptoms in cognitively normal older adults. The recent availability of tau radiotracers offers the ability to examine in vivo tauopathy. It is unclear if the tau biomarker is associated with depression diagnosis. Objective: We examined if tau and amyloid imaging were associated with a depression diagnosis among cognitively normal adults (Clinical Dementia Rating = 0) and whether antidepressants modified this relationship. Methods: Among 301 participants, logistic regression models …evaluated whether in vivo PET tau was associated with depression, while another model tested the interaction between PET tau and antidepressant use. A second set of models substituted PET amyloid for PET tau. A diagnosis of depression (yes/no) was made during an annual clinical assessment by a clinician. Antidepressant use (yes/no) was determined by comparing medications the participants used to a list of 30 commonly used antidepressants. All models adjusted for age, sex, education, race, and apolipoprotein ɛ 4. Similar models explored the association between the biomarkers and depressive symptoms. Results: Participants with elevated tau were twice as likely to be depressed. Antidepressant use modified this relationship where participants with elevated tau who were taking antidepressants had greater odds of being depressed. Relatedly, elevated amyloid was not associated with depression. Conclusions: Our results demonstrate that tau, not amyloid, was associated with a depression diagnosis. Additionally, antidepressant use interacts with tau to increase the odds of depression among cognitively normal adults. Show more

Keywords: Alzheimer’s disease, antidepressants, biomarkers, depression, older adults

DOI: 10.3233/JAD-191078

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Wisch, Julie K. | Roe, Catherine M. | Babulal, Ganesh M. | Schindler, Suzanne E. | Fagan, Anne M. | Benzinger, Tammie L. | Morris, John C. | Ances, Beau M.

Article Type: Research Article

Abstract: Background: Changes in resting state functional connectivity (rs-fc) occur in Alzheimer’s disease (AD), but few longitudinal rs-fc studies have been performed. Most studies focus on single networks and not a global measure of rs-fc. Although the amyloid tau neurodegeneration (AT(N)) framework is increasingly utilized by the AD community, few studies investigated when global rs-fc signature changes occur within this model. Objective: 1) Identify a global rs-fc signature that differentiates cognitively normal (CN) individuals from symptomatic AD. 2) Assess when longitudinal changes in rs-fc occur relative to conversion to symptomatic AD. 3) Compare rs-fc with amyloid, tau, and neurodegeneration …biomarkers. Methods: A global rs-fc signature composed of intra-network connections was longitudinally evaluated in a cohort of cognitively normal participants at baseline (n  = 335). Biomarkers, including cerebrospinal fluid (Aβ42 and tau), structural magnetic resonance imaging, and positron emission tomography were obtained. Results: Global rs-fc signature distinguished CN individuals from individuals who developed symptomatic AD. Changes occurred nearly four years before conversion to symptomatic AD. The global rs-fc signature most strongly correlated with markers of neurodegeneration. Conclusion: The global rs-fc signature changes near symptomatic onset and is likely a neurodegenerative biomarker. Rs-fc changes could serve as a biomarker for evaluating potential therapies for symptomatic conversion to AD. Show more

Keywords: Alzheimer’s disease, biomarkers, neuroimaging, observational studies

DOI: 10.3233/JAD-191039

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Tadayon, Ehsan | Moret, Beatrice | Sprugnoli, Giulia | Monti, Lucia | Pascual-Leone, Alvaro | Santarnecchi, Emiliano | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Recent studies have revealed the possible role of choroid plexus (ChP) in Alzheimer’s disease (AD). T1-weighted MRI is the modality of choice for the segmentation of ChP in humans. Manual segmentation is considered the gold-standard technique, but given its time-consuming nature, large-scale neuroimaging studies of ChP would be impossible. In this study, we introduce a lightweight segmentation algorithm based on the Gaussian Mixture Model (GMM). We compared its performance against manual segmentation as well as automated segmentation by Freesurfer in three separate datasets: 1) patients with structural MRIs enhanced with contrast (n  = 19), 2) young healthy subjects (n  = 20), and …3) patients with AD (n  = 20). GMM outperformed Freesurfer and showed high similarity with manual segmentation. To further assess the algorithm’s performance in large scale studies, we performed GMM segmentations in young healthy subjects from the Human Connectome Project (n  = 1,067), as well as healthy controls, mild cognitive impairment (MCI), and AD patients from the Alzheimer’s Disease Neuroimaging Initiative (n  = 509). In both datasets, GMM segmented ChP more accurately than Freesurfer. To show the clinical importance of accurate ChP segmentation, total AV1451 (tau) PET binding to ChP was measured in 108 MCI and 32 AD patients. GMM was able to reveal the higher AV1451 binding to ChP in AD compared with MCI. Our results provide evidence for the utility of the GMM in accurately segmenting ChP and show its clinical relevance in AD. Future structural and functional studies of ChP will benefit from GMM’s accurate segmentation. Show more

Keywords: Alzheimer’s disease, choroid plexus, magnetic resonance imaging, tau PET

DOI: 10.3233/JAD-190706

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Cicognola, Claudia | Satir, Tugce Munise | Brinkmalm, Gunnar | Matečko-Burmann, Irena | Agholme, Lotta | Bergström, Petra | Becker, Bruno | Zetterberg, Henrik | Blennow, Kaj | Höglund, Kina

Article Type: Research Article

Abstract: Background: Tau aggregation in neurons and glial cells characterizes tauopathies as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Tau proteolysis has been proposed as a trigger for tau aggregation and tau fragments have been observed in brain and cerebrospinal fluid (CSF). Our group identified a major tau cleavage at amino acid (aa) 224 in CSF; N-terminal tau fragments ending at aa 224 (N-224) were significantly increased in AD and lacked correlation to total tau (t-tau) and phosphorylated tau (p-tau) in PSP and CBD. Objective: Previous studies have shown cleavage from calpain proteases at sites …adjacent to aa 224. Our aim was to investigate if calpain-1 or -2 could be responsible for cleavage at aa 224. Methods: Proteolytic activity of calpain-1, calpain-2, and brain protein extract was assessed on a custom tau peptide (aa 220–228), engineered with fluorescence resonance energy transfer (FRET) technology. Findings were confirmed with in-gel trypsination and mass spectrometry (MS) analysis of brain-derived bands with proteolytic activity on the FRET substrate. Finally, knock-down of the calpain-2 catalytic subunit gene (CAPN2 ) was performed in a neuroblastoma cell line (SH-SY5Y). Results: Calpain-2 and brain protein extract, but not calpain-1, showed proteolytic activity on the FRET substrate. MS analysis of active gel bands revealed presence of calpain-2 subunits, but not calpain-1. Calpain-2 depletion and chemical inhibition suppressed proteolysis of the FRET substrate. CAPN2 knock-down caused a 76.4% reduction of N-224 tau in the cell-conditioned media. Conclusions: Further investigation of the calpain-2 pathway in the pathogenesis of tauopathies is encouraged. Show more

Keywords: Alzheimer’s disease, calpain, fragments, tau, tauopathy

DOI: 10.3233/JAD-191130

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

Authors: Zhang, Jingtian | Zhao, Zhizhuang Joe | Fu, Xueqi | Niu, Han | Hu, Chen | Dong, Yunzhou | Cui, Mei-Zhen | Zhang, Fuqiang | Zeng, Linlin | Xu, Xuemin

Article Type: Research Article

Abstract: Presenilin-associated protein (PSAP) was originally identified as a mitochondrial proapoptotic protein. To further explore the apoptotic pathway that involves PSAP, our yeast two-hybrid screen revealed that PSAP interacts with a death receptor, DR6. DR6 is a relatively less common member of the death receptor family and has been shown to mediate the neurotoxicity of amyloid-β, mutant SOD1, and prion proteins and has also been implicated in the regulation of immune cell proliferation and differentiation. Our previous study showed that DR6 induces apoptosis via a unique mitochondria-dependent pathway different from the conventional death receptor-mediated extrinsic apoptotic pathways. Thus, the interaction of …DR6 with PSAP established a direct molecular link between DR6 and mitochondrial apoptotic pathway. We investigated the possible role of PSAP in DR6-induced apoptosis. Interestingly, it was discovered that knockdown of PSAP strongly inhibited DR6-induced apoptosis. To further elucidate the mechanism by which PSAP mediates DR6-induced mitochondria-dependent apoptosis, our data demonstrated that knockdown of PSAP blocked DR6-induced Bax translocation and cytochrome c release from the mitochondria. Moreover, it was found that both PSAP and DR6 form complexes with Bax, but at different subcellular locations. The DR6-Bax complex was detected in the cytosolic fraction while the PSAP-Bax complex was detected in the mitochondrial fraction. The observation that knockdown of DR6 significantly reduced the amount of PSAP-Bax complex detected in mitochondria suggests a possibility that DR6-bound Bax is transferred to PSAP upon interaction with PSAP at the mitochondria, leading to cytochrome c release and eventually apoptosis. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, apoptosis, DR6, mitochondria, neurodegenerative disease, PSAP

DOI: 10.3233/JAD-191086

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Mariano, Luciano Inácio | Caramelli, Paulo | Guimarães, Henrique Cerqueira | Gambogi, Leandro Boson | Moura, Millena Vieira Brandão | Yassuda, Mônica Sanches | Teixeira, Antônio Lúcio | de Souza, Leonardo Cruz

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) share cognitive and behavioral symptoms, such as apathy. Social cognition measurements are useful in distinguishing bvFTD from AD, but their accuracies may be affected by apathy. Objective: To investigate whether social cognition measurements can distinguish bvFTD from either apathetic or non-apathetic AD patients. Methods: Three groups of participants were enrolled in the present study: bvFTD (n  = 22), AD (n  = 20), and healthy controls (HC, n  = 23). The AD group was divided into apathetic (n  = 10) and non-apathetic (n  = 10). All subjects underwent comprehensive neuropsychological examination, including …the short version of the Social and Emotional Assessment (Mini-SEA), which comprises the facial emotion recognition test and the faux-pas recognition test (Faux-Pas Test). Apathy was assessed according to the Starkstein’s Apathy (SA) Scale. Results: The bvFTD and AD groups did not differ on global cognitive efficiency and on executive functions. In comparison to the whole AD group, bvFTD displayed lower Faux-Pas Test and Mini-SEA scores. Both AD subgroups, apathetic or non-apathetic, exhibited similar performance on all social cognition measurements. In comparison to either apathetic AD or non-apathetic AD, bvFTD patients underperformed on the Faux-Pas Test and on the Mini-SEA. The area under the curve values for the Mini-SEA total score were 0.87 (bvFTD versus AD), 0.90 (bvFTD versus apathetic AD), and 0.83 (bvFTD versus non-apathetic AD). Conclusion: Social cognition tests provide accurate distinction between bvFTD against either apathetic AD or non-apathetic AD. Social cognition measurements did not correlate with apathy severity. Show more

Keywords: Alzheimer’s disease, apathy, frontotemporal dementia, social cognition

DOI: 10.3233/JAD-190861

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Zhang, Haihua | Wang, Tao | Han, Zhifa | Wang, Longcai | Zhang, Yan | Wang, Lijun | Liu, Guiyou

Article Type: Research Article

Abstract: Until now, observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have explored the impact of vitamin D on Alzheimer’s disease (AD), and reported inconsistent findings. In MR studies, the sensitivity analysis by removing GC rs2282679 variant highlighted no association of 25OHD levels with AD risk, which indicates that vitamin D-binding protein (DBP) encoded by GC may have distinct effects on AD risk. Here, we aim to clarify this assumption. We selected the GC rs2282679 variant associated with DBP levels (p  = 3.30E-76) as the instrumental variable, and extracted the summary statistics of rs2282679 variant in multiple …AD GWAS datasets from IGAP, Complex Trait Genetics (CTG) lab, and UK Biobank. We then performed a MR study to investigate the causal association between DBP levels and AD. In IGAP, MR analysis showed that the genetically DBP levels (per 1 standard deviation (SD) increase 50 mg/L) were significantly associated with reduced AD risk (OR = 0.63, 95% CI: 0.45-0.89, p  = 0.009). Importantly, the estimates from two sensitivity analyses were consistent with the main estimate in terms of direction and magnitude. Meanwhile, we found no causal association between DBP levels and other four AD phenotypes in CTG lab and UK Biobank. In summary, we highlight the role of DBP levels in AD risk, and provide strong support evidence that DBP may be the therapeutic agent for the treatment of AD. Meanwhile, our findings clarify the assumption that DBP may drive the observed relationship between 25OHD levels and AD. Show more

Keywords: Alzheimer’s disease, genome-wide association study, Mendelian randomization, vitamin D, vitamin D-binding protein

DOI: 10.3233/JAD-191051

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Tomaszewski, Natalie | He, Xulei | Solomon, Victoria | Lee, Mitchell | Mack, Wendy J. | Quinn, Joseph F. | Braskie, Meredith N. | Yassine, Hussein N.

Article Type: Research Article

Abstract: Background: Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) play key roles in several metabolic processes relevant to Alzheimer’s disease (AD) pathogenesis and neuroinflammation. Carrying the APOE ɛ 4 allele (APOE4 ) accelerates omega-3 polyunsaturated fatty acid (PUFA) oxidation. In a pre-planned subgroup analysis of the Alzheimer’s Disease Cooperative Study-sponsored DHA clinical trial, APOE4 carriers with mild probable AD had no improvements in cognitive outcomes compared to placebo, while APOE 4 non-carriers showed a benefit from DHA supplementation. Objective: We sought to clarify the effect of APOE ɛ 4/ɛ 4 on both …the ratio of plasma DHA and EPA to AA, and on hippocampal volumes after DHA supplementation. Methods: Plasma fatty acids and APOE genotype were obtained in 275 participants randomized to 18 months of DHA supplementation or placebo. A subset of these participants completed brain MRI imaging (n  = 86) and lumbar punctures (n  = 53). Results: After the intervention, DHA-treated APOE ɛ 3/ɛ 3 and APOE ɛ 2/ɛ 3 carriers demonstrated significantly greater increase in plasma DHA/AA compared to ɛ 4/ɛ 4 carriers. APOE ɛ 2/ɛ 3 had a greater increase in plasma EPA/AA and less decline in left and right hippocampal volumes compared to compared to ɛ 4/ɛ 4 carriers. The change in plasma and cerebrospinal fluid DHA/AA was strongly correlated. Greater baseline and increase in plasma EPA/AA was associated with a lower decrease in the right hippocampal volume, but only in APOE 4 non-carriers. Conclusion: The lower increase in plasma DHA/AA and EPA/AA in APOE ɛ 4/ɛ 4 carriers after DHA supplementation reduces brain delivery and affects the efficacy of DHA supplementation. Show more

Keywords: Arachidonic acid, Alzheimer’s disease, apolipoprotein E, docosahexaenoic acid, eicosapentaenoic acid

DOI: 10.3233/JAD-191017

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Stozicka, Zuzana | Korenova, Miroslava | Uhrinova, Ivana | Cubinkova, Veronika | Cente, Martin | Kovacech, Branislav | Babindakova, Nikoleta | Matyasova, Katarina | Vargova, Greta | Novak, Michal | Novak, Petr | Zilka, Norbert | Jadhav, Santosh

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder, affecting over 44 million people worldwide. There are no effective pharmaco-therapeutic options for prevention and treatment of AD. Non-pharmacological approaches may help patients suffering from AD to significantly ameliorate disease progression. In this study, we exposed a transgenic rat model (tg) of human tauopathy to enriched environment for 3 months. Behavioral testing at 6 months of age revealed improvement in functional deficits of tg rats reared under enriched conditions, while sedentary tg rats remained severely impaired. Interestingly, enriched environment did not reduce tau pathology. Analysis of neurotrophic factors revealed an increase …of nerve growth factor (NGF) levels in the hippocampus of both enriched groups (tg and non-tg rats), reflecting a known effect of enriched environment on the hippocampal formation. On the contrary, NGF levels decreased markedly in the brainstem of enriched groups. The non-pharmacological treatment also reduced levels of tissue inhibitor of metalloproteinase 1 in the brainstem of transgenic rats. Expression analysis of inflammatory pathways revealed upregulation of microglial markers, such as MHC class II and Cd74, whereas levels of pro-inflammatory cytokines remained unaffected by enriched environment. Our results demonstrate that exposure to enriched environment can rescue functional impairment in tau transgenic rats without reducing tau pathology. We speculate that non-pharmacological treatment modulates the immune response to pathological tau protein inclusions, and thus reduces the damage caused by neuroinflammation. Show more

Keywords: Enriched environment, nerve growth factor, neuroinflammation, non-pharmacological intervention, tauopathy

DOI: 10.3233/JAD-191112

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

Authors: Sado, Mitsuhiro | Funaki, Kei | Ninomiya, Akira | Knapp, Martin | Mimura, Masaru

Article Type: Research Article

Abstract: Background: Although the effects of various types of cognitive interventions have been evaluated, effectiveness and cost-saving effect of the combination of the different cognitive interventions is unknown. Objective: This study aimed to evaluate the feasibility of conducting a definitive trial to assess the effectiveness of combined cognitive intervention. Methods: A matched controlled trial of learning therapy (LT), a combination of cognitive training and stimulation, was conducted. The samples were recruited from the nursing homes. Inclusion criteria were as follows: age 65 years or older, clinical diagnosis of dementia, level of activities of daily living at II …or above, Mini-Mental State Examination score between 10 and 26, receiving long-term-care services without history of LT, and provision of written consent. The primary outcomes were safety, validity of eligibility, retention rate, and effect on the functions of daily living represented by Criterion Time for Certification of Needed Long-Term-Care (CT for CNLTC) at 12 months. Cost-benefit analysis was also conducted to assess the cost saving effect of LT. Results: No serious adverse events were detected. The exclusion rate at the screening phase was 5% and the retention rate was 77% at 12 months. LT demonstrated statistically significant improvement in CT for CNLTC at 12 months (Δ =18.8, almost equivalent to “one” degree of the care needed level) and saved the long-term-care cost by JPY 200,000 (USD 1,618). Conclusions: LT is effective for improving care recipients’ level of care needed and has a cost saving effect. A randomized controlled trial is required to verify these findings. Clinical Trial Registration: This study was approved by the ethics committee at Keio University School of Medicine (ID: 20150061). This trial was registered at University hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID: UMIN000018223). Show more

Keywords: Activities of daily living, cost-benefit analysis, cognitive training, dementia, long term care

DOI: 10.3233/JAD-190886

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Richardson, Kathryn | Wharton, Stephen B. | Grossi, Carlota M. | Matthews, Fiona E. | Fox, Chris | Maidment, Ian | Loke, Yoon K. | Steel, Nicholas | Arthur, Antony | Myint, Phyo Kyaw | Boustani, Malaz | Campbell, Noll | Robinson, Louise | Brayne, Carol | Savva, George M.

Article Type: Research Article

Abstract: Background: Benzodiazepines and anticholinergic drugs have been implicated in causing cognitive decline and potentially increasing dementia risk. However, evidence for an association with neuropathology is limited. Objective: To estimate the correlation between neuropathology at death and prior use of benzodiazepines and anticholinergic drugs. Methods: We categorized 298 brain donors from the population-based Medical Research Council Cognitive Function and Ageing Study, according to their history of benzodiazepine (including Z-drugs) or anticholinergic medication (drugs scoring 3 on the Anticholinergic Cognitive Burden scale) use. We used logistic regression to compare dichotomized neuropathological features for those with and without history …of benzodiazepine and anticholinergic drug use before dementia, adjusted for confounders. Results: Forty-nine (16%) and 51 (17%) participants reported benzodiazepine and anticholinergic drug use. Alzheimer’s disease neuropathologic change was similar whether or not exposed to either drug, for example 46% and 57% had intermediate/high levels among those with and without anticholinergic drug use. Although not significant after multiple testing adjustments, we estimated an odds ratio (OR) of 0.40 (95% confidence interval [95% CI] 0.18–0.87) for anticholinergic use and cortical atrophy. For benzodiazepine use, we estimated ORs of 4.63 (1.11–19.24) and 3.30 (1.02–10.68) for neuronal loss in the nucleus basalis and substantial nigra. There was evidence of neuronal loss in the nucleus basalis with anticholinergic drug use, but the association reduced when adjusted for confounders. Conclusions: We found no evidence that benzodiazepine or anticholinergic drug use is associated with typical pathological features of Alzheimer’s disease; however, we cannot rule out effects owing to small numbers. Show more

Keywords: Alzheimer’s disease, basal nucleus of Meynert, benzodiazepines, cholinergic antagonists, neurofibrillary tangles, neuritic plaques, neuropathology

DOI: 10.3233/JAD-191199

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Basta, Maria | Koutentaki, Eirini | Vgontzas, Alexandros | Zaganas, Ioannis | Vogiatzi, Emmanouela | Gouna, Garyfalia | Bourbouli, Mara | Panagiotakis, Symeon | Kapetanaki, Stefania | Fernandez-Mendoza, Julio | Simos, Panagiotis

Article Type: Research Article

Abstract: Background: Patients with dementia report excessive daytime sleep/sleepiness, which is associated with worse cognitive performance. Inflammatory markers may be elevated in patients with dementia and have been proposed as mediators of sleep/sleepiness. Objective: To examine the association of objective daytime napping with cognitive performance and peripheral markers of inflammation in patients with dementia as compared to not cognitively impaired (NCI) controls. Methods: A sub-sample of 46 patients with mild-to-moderate dementia and 85 NCI controls, were recruited from a large, population-based cohort of 3,140 elders (≥60 years) in Crete, Greece. All participants underwent medical history/physical examination, extensive …neuropsychiatric and neuropsychological evaluation, 3-day 24 h actigraphy and a single morning measure of IL-6 and TNFα plasma levels. Comparisons of sleep parameters and inflammation markers between diagnostic groups, and between nappers and non-nappers within each diagnostic group, were conducted using ANCOVA controlling for demographics/related clinical factors. Associations between inflammatory markers, sleep variables, and neuropsychological performance were assessed within each group using partial correlation analysis controlling for confounders. Results: Patients with dementia slept 15 minutes longer during the day than NCI. Within dementia patients, nappers had significantly worse performance on autobiographic memory (p  = 0.002), working memory (p  = 0.007), episodic memory (p  = 0.010), and assessment of daily function (p  = 0.012) than non-nappers. Finally, IL-6 levels were significantly associated with nap duration within dementia patients who napped (r  = 0.500, p  = 0.01). Conclusions: Daytime napping in patients with dementia is associated with worse cognitive performance and increased IL-6 levels. In dementia, objective daytime napping, may be a marker of the severity of the disease. Show more

Keywords: Actigraphy, cognitive performance, cytokines, dementia, inflammation, objective daytime napping

DOI: 10.3233/JAD-190483

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Arnaldi, Dario | Donniaquio, Andrea | Mattioli, Pietro | Massa, Federico | Grazzini, Matteo | Meli, Riccardo | Filippi, Laura | Grisanti, Stefano | Famà, Francesco | Terzaghi, Michele | Girtler, Nicola | Brugnolo, Andrea | Doglione, Elisa | Pardini, Matteo | Villani, Flavio | Nobili, Flavio

Article Type: Research Article

Abstract: Background: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking. Objective: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer’s disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR). Methods: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent …baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender. Results: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients. Conclusion: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients. Show more

Keywords: Alzheimer’s disease, dementia, EEG, epilepsy, seizure

DOI: 10.3233/JAD-191315

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Zhang, Jin | Hua, Xue-feng | Gu, Jinhua | Chen, Feng | Gu, Jianlan | Gong, Cheng-Xin | Liu, Fei | Dai, Chun-Ling

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia. Studies indicate that neuroinflammation plays an important role in the pathophysiology of AD. High-mobility group box 1 (HMGB1) is an important chromatin protein. It can be secreted by immune cells and passively released from damaged cells to promote inflammation. HMGB1 also can recruit stem cells and promote their proliferation and tissue repairing. However, the role of HMGB1 in the progression of AD is currently unknown. Objective: The aims were to investigate the effect of HMGB1 on the AD-related pathologies and cognitive function using 3×Tg-AD mouse model. …Methods: Female 5-6-month-old 3×Tg-AD mice were intracerebroventricularly injected with 4.5 μg of HMGB1 or with saline as a control. The levels of interesting protein were assessed by western blots or immunofluorescence. The effect of HMGB1 on the cognitive function was evaluated by one-trial novel object recognition test and Morris water maze. Results: Intracerebroventricular injection of recombinant HMGB1 ameliorated cognitive impairment in 5–6-month-old 3×Tg-AD mice. The levels of synapsin 1, synaptophysin, MAP2, NeuN, and phosphorylated CREB were increased in HMGB1-treated 3×Tg-AD mouse brains. HMGB1 decreased intracellular amyloid-β level but did not affect tau phosphorylation. HMGB1 treatment also promoted neurogenesis in the dentate gyrus and increased the level of GFAP in the 3×Tg-AD mouse brains. Conclusion: These results reveal a novel function of HMGB1 in enhancing neuroplasticity and improving cognitive function in 3×Tg-AD mice. Show more

Keywords: Alzheimer’s disease, amyloid-β , cognition, HMGB1, inflammation, neurogenesis, tau

DOI: 10.3233/JAD-191110

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

Authors: Popovac, Aleksandra | Mladenović, Irena | Krunić, Jelena | Trifković, Branka | Todorović, Ana | Milašin, Jelena | Despotović, Nebojša | Stančić, Ivica

Article Type: Research Article

Abstract: Compromised dentition has been suggested to pose a significant risk factor for dementia. It was mainly investigated through insufficient tooth number, disregarding contact between opposing teeth (dental occlusion). The E4 allele of apolipoprotein (APOE4 ) is the primary genetic marker for the late onset of Alzheimer’s disease (AD). However, APOE4 and dental occlusion have not yet been investigated as possible associated risk factors for AD. The study was aimed to examine the impact of dental status and different APOE gene variants on AD occurrence. Secondly, sociodemographic variables were investigated as factors potentially associated with AD. The case-control study …included two groups: 116 patients with AD (according to the NINDS-ADRDA criteria) and 63 controls (Mini-Mental State Examination scores ≥24). The analysis of APOE gene polymorphism was conducted through PCR reaction. Dental examination included recording of number of teeth, presence of fixed or removable dentures, and number of functional tooth units (FTU). Regression analysis was used to investigate the joint effect of the clinical and genetic variables on AD. Results showed that patients with AD were more often carriers of E3/E4 genotype and E4 allele, had lower number of teeth and FTU, and were less likely to be married, live in home, and had less chronic diseases, compared to the controls. Regression analysis showed that presence of APOE4 allele and the number of total FTU remained associated with AD, even when adjusted for age, sex, and level of education. In conclusion, deficient dental occlusion and presence of APOE4 may independently increase risk for AD. Show more

Keywords: Alzheimer’s disease, apolipoproteins E, dental occlusion, tooth loss

DOI: 10.3233/JAD-191283

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Kapoor, Arunima | Bartha, Robert | Black, Sandra E. | Borrie, Michael | Freedman, Morris | Gao, Fuqiang | Herrmann, Nathan | Mandzia, Jennifer | Ozzoude, Miracle | Ramirez, Joel | Scott, Christopher J.M | Symons, Sean | Fischer, Corinne E. | Frank, Andrew | Seitz, Dallas | Wolf, Michael Uri | Verhoeff, Nicolaas Paul L.G. | Naglie, Gary | Reichman, William | Masellis, Mario | Mitchell, Sara Berman | Tang-Wai, David F. | Tartaglia, Carmela | Kumar, Sanjeev | Pollock, Bruce G. | Rajji, Tarek K. | Finger, Elizabeth | Pasternak, Stephen H. | ONDRI Investigators | Swartz, Richard H.

Article Type: Research Article

Abstract: Background/Objective: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer’s disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. Methods: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. Results: Of …210 AD clinical trials, 105 (50%) included brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. Discussion: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity. Show more

DOI: 10.3233/JAD-191097

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Arroyo-Anlló, Eva M. | Sánchez, Jorge Chamorro | Ventola, Alejandra R. Melero | Ingrand, Pierre | Neau, Jean-Philippe | Gil, Roger

Article Type: Research Article

Abstract: Background: Multiple sclerosis (MS) is considered a neurodegenerative disease and an inflammatory demyelinating neuropathology in young population. Procedural memory has been poorly investigated in MS. Objective: We assessed whether the MS group was able to develop a motor-cognitive skill, using a procedural task (PLSC) developed in our laboratory, applying a manual and serial reaction time (RT) paradigm to semantic categorization. Methods: We evaluated 26 MS patients and 26 socio-demographic matched control participants using the PLSC task. Results: Using non-parametric statistical analyses, we observed a significant improvement of semantic categorization RTs with practice (p  = 0.002), …even with new verbal material to categorize in MS patients (p  = 0.006), despite their motor and executive moderate deficits. This same profile of semantic procedural learning in MS was observed in previous studies carried out with Alzheimer’s and Parkinson’s diseases. Moreover, the visual-motor RTs remained stable or slightly improved over the five blocks in both groups, as well as in the AD groups of previous studies. The MS group showed longer visual-motor reaction times than those of the control group (p  < 0.042), except in motor initiation aspect (p  = 0.064). Both groups showed no significant differences for any type of error. Additionally, disability level and cognitive performances were not associated with the ratio of semantic procedural learning. Conclusion: The present results support the notion that MS patients may be capable of acquiring semantic skill, despite their motor disabilities and executive troubles. This work also addresses the possibilities to improve motor-cognitive skill RTs in neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, dementia, language, multiple sclerosis, neurodegenerative diseases, Parkinson’s disease, procedural memory, reaction time, skill

DOI: 10.3233/JAD-191083

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Watt, Georgia | Shang, Kani | Zieba, Jerzy | Olaya, Juan | Li, Henry | Garner, Brett | Karl, Tim

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive cognitive decline and pathologically by the accumulation of amyloid-β (Aβ) and tau hyperphosphorylation causing neurodegeneration and neuroinflammation. Current AD treatments do not stop or reverse the disease progression, highlighting the need for more effective therapeutics. The phytocannabinoid cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory, and neuroprotective properties. Furthermore, chronic CBD treatment (20 mg/kg) reverses social and object recognition memory deficits in the A βPPxPS1 transgenic mouse model with only limited effects on AD-relevant brain pathology. Importantly, studies have indicated that CBD works in a dose-dependent manner. Thus, this study determined the chronic effects of …50 mg/kg CBD in male A βPPxPS1 mice. 12-month-old mice were treated with 50 mg/kg CBD or vehicle via daily intraperitoneal injections for 3 weeks prior to behavioral testing. A variety of cognitive domains including object and social recognition, spatial and fear-associated memory were evaluated. Pathological brain analyses for AD-relevant markers were conducted using ELISA and western blot. Vehicle-treated male A βPPxPS1 mice demonstrated impaired social recognition memory and reversal spatial learning. These deficits were restored after CBD treatment. Chronic CBD tended to reduce insoluble Aβ40 levels in the hippocampus of A βPPxPS1 mice but had no effect on neuroinflammation, neurodegeneration, or PPARγ markers in the cortex. This study demonstrates that therapeutic-like effects of 50 mg/kg CBD on social recognition memory and spatial learning deficits in A βPPxPS1 mice are accompanied by moderate brain region-specific reductions in insoluble Aβ40 levels. The findings emphasize the clinical relevance of CBD treatment in AD; however, the underlying mechanisms involved require further investigation. Show more

Keywords: Alzheimer’s disease, amyloid-β , BDNF, cannabidiol, cognition, IBA1, neuroinflammation, PPARγ , transgenic AβPPswe/PS1 E9 mice

DOI: 10.3233/JAD-191242

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

Authors: Atayde, Adrienne L. | Fischer, Corinne E. | Schweizer, Tom A. | Munoz, David G.

Article Type: Research Article

Abstract: Background: The relationship between sleep, neuropathology, and clinical manifestations of Alzheimer’s disease (AD) remains controversial. Objective: To determine whether nighttime behaviors (NTB) are associated with the development of AD histopathology or cognitive decline. Methods: We compared NTB prevalence in subjects with or without AD lesions, and with or without progressive cognitive decline. Subjects with either absent or severe plaques and tangles were identified from the National Alzheimer’s Disease Coordinating Center data sets and classified as cognitively declining if the standard deviation from their individual mean Mini-Mental Status Examination score was ≥2, and stable if <2 regardless …of their initial score. NTB was assessed using the Neuropsychiatric Inventory Questionnaire Quick Version (NPI-Q). Results: NTB was significantly greater in decliners than stable subjects in the group with severe histopathology as determined by frequent plaques (p  = 0.003) or high Braak stage (p  = 0.002). A similar significant trend was observed in subjects with absent plaques (p  = 0.019) or tangles (p  = 0.006). The prevalence of NTB was comparable between stable AD and non-AD subjects. NTB severity scores showed a similar pattern. Conclusion: The development of NTB as assessed by NPI-Q in subjects with or without AD lesions occurred concurrently with cognitive decline. Among cognitively stable subjects, the presence of AD histopathology did not alter NTB prevalence. Thus, NTB disruptions at the gross granularity level assessed by NPI-Q were much more closely related to cognitive decline than the formation of pathological lesions. Factors other than AD histopathology may mediate the association between NTB and cognitive decline. Show more

Keywords: Alzheimer’s disease, amyloid plaque, cognitive decline, neurofibrillary tangles, sleep

DOI: 10.3233/JAD-190907

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Grøntvedt, Gøril Rolfseng | Lauridsen, Camilla | Berge, Guro | White, Linda R. | Salvesen, Øyvind | Bråthen, Geir | Sando, Sigrid Botne

Article Type: Research Article

Abstract: Background: The unbiased amyloid, tau, and neurodegeneration (A/T/N) classification is designed to characterize individuals in the Alzheimer continuum and is currently little explored in clinical cohorts. Objective: A retrospective comparison of the A/T/N classification system with the results of a two-year clinical study, with extended follow-up up to 10 years after inclusion. Methods: Patients (n  = 102) clinically diagnosed as Alzheimer’s disease (AD) with dementia or amnestic mild cognitive impairment (MCI), and 61 cognitively healthy control individuals were included. Baseline cerebrospinal fluid core biomarkers for AD (Aβ42 , phosphorylated tau, and total tau) were applied to the …A/T/N classification using the final clinical diagnosis at extended follow-up as the gold standard. Results: A + T + N+ was a strong predictor for AD dementia, even among cognitively healthy individuals. Amnestic MCI was heterogenous, considering both clinical outcome and distribution within A/T/N. Some individuals with amnestic MCI progressed to clinical AD dementia within all four major A/T/N groups. The highest proportion of progression was among triple positive cases, but progression was also common in individuals with suspected non-Alzheimer pathophysiology (A-T + N+), and those with triple negative status. A-T-N- individuals who were cognitively healthy overwhelmingly remained cognitively intact over time, but in amnestic MCI the clinical outcome was heterogenous, including AD dementia, other dementias, and recovery. Conclusion: The A/T/N framework accentuates biomarkers over clinical status. However, when selecting individuals for research, a combination of the two may be necessary since the prognostic value of the A/T/N framework depends on clinical status. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, classification, mild cognitive impairment, tau

DOI: 10.3233/JAD-191227

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Almansoub, Hasan A.M.M. | Tang, Hui | Wu, Ying | Wang, Ding-Qi | Mahaman, Yacoubou Abdoul Razak | Salissou, Maibouge Tanko Mahamane | Lu, Youming | Hu, Fan | Zhou, Lan-Ting | Almansob, Yusra A.M. | Liu, Dan

Article Type: Research Article

Abstract: Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice …are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α -synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro . Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT. Show more

Keywords: Alpha-synuclein, behavior deficit, MPTP, neurotoxicity, oxidative stress, oxytocin, Parkinson’s disease

DOI: 10.3233/JAD-191091

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Marelli, Cecilia | Hourregue, Claire | Gutierrez, Laure-Anne | Paquet, Claire | Menjot de Champfleur, Nicolas | De Verbizier, Delphine | Jacob, Melissa | Dubois, Jonathan | Maleska, Aleksandra Maceski | Hirtz, Christophe | Navucet, Sophie | Bennys, Karim | Dumurgier, Julien | Cognat, Emmanuel | Berr, Claudine | Magnin, Eloi | Lehmann, Sylvain | Gabelle, Audrey

Article Type: Research Article

Abstract: Background: Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant frontotemporal dementia (bvFTD). Objective: To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD. Methods: Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD. Results: This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n  = 11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: 3 …[0–4] versus 1 [0–3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aβ1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age. Conclusion: The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer’s disease in the late-onset group (comparable and within normal range CSF Aβ1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD. Show more

Keywords: Biomarkers, cerebrospinal fluid, frontotemporal dementia, glial fibrillary acid protein, late-onset, neurofilament light chain

DOI: 10.3233/JAD-190378

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Pasha, Evan P. | Rutjes, Elmer | Tomoto, Tsubasa | Tarumi, Takashi | Stowe, Ann | Claassen, Jurgen A.H.R. | Munro Cullum, C. | Zhu, David C. | Zhang, Rong

Article Type: Research Article

Abstract: Background: Vascular dysfunction has been implicated in the onset and progression of Alzheimer’s disease (AD), yet the relationship of arterial stiffening with brain amyloid-β (Aβ) burden in at risk patients is unclear. Objective: We aimed to determine the relationship of aortic and carotid arterial stiffening with Aβ burden in patients with amnestic mild cognitive impairment (aMCI), a proposed transitional stage between normal aging and AD. Methods: Thirty-two older adults with aMCI underwent 18 Florbetapir PET amyloid imaging to ascertain Aβ burden via standardized uptake value ratio (SUVR). Carotid-femoral pulse wave velocity (cfPWV), which reflects aortic stiffness, …and carotid β stiffness index and distensibility, which reflect local cerebral arterial stiffness, thus having direct impact on the cerebral circulation, were measured using applanation tonometry and ultrasonography. Results: Region-of-interest based analysis showed that precuneus and mean cortex Aβ SUVR were correlated positively with carotid β stiffness index and negatively with carotid distensibility after adjusting for age, sex, mean arterial pressure (MAP), pulse pressure (PP), and APOE4 status. Whole-brain voxel-wise analysis showed that Aβ SUVR was positively correlated with carotid β stiffness index, and negatively with carotid distensibility at the precuneus/cingulate gyrus after multiple comparison correction. cfPWV was not correlated with Aβ SUVR. Conclusions: Carotid rather than aortic stiffening is independently associated with brain Aβ burden in patients with aMCI after adjusting for age, sex, MAP, PP, and APOE4 status. These findings provide evidence that arterial stiffening, particularly carotid artery stiffening, may contribute to AD pathology in patients with aMCI. Show more

Keywords: Arterial stiffness, amyloid, mild cognitive impairment, ClinicalTrials.gov identifier: NCT01146717

DOI: 10.3233/JAD-191073

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Sundström, Anna | Sörman, Daniel Eriksson | Hansson, Patrik | Ljungberg, Jessica Körning | Adolfsson, Rolf

Article Type: Short Communication

Abstract:  High mental demands at work was examined as a possible protective factor to reduce the risk of dementia in 1,277 initially dementia-free participants, aged 60 years and older. The cohort was followed for a mean of 13.6 years. During follow-up, 376 participants developed all-cause dementia (Alzheimer’s disease = 199; vascular dementia = 145). The association between mental demands at work and dementia was analyzed with Cox hazard models, adjusted for a range of covariates. The results revealed no significant association between mental demands at work and incidence of dementia. Based on the measures used in this study, it was concluded that high mental demands …at work may not reduce the risk of dementia later on in life. Show more

Keywords: Aging, Alzheimer’s disease, cognitive occupation complexity, cognitive reserve, dementia, mental demands at work, vascular dementia

DOI: 10.3233/JAD-190920

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Tabara, Yasuharu | Yamanaka, Mikihiro | Setoh, Kazuya | Segawa, Hiroaki | Kawaguchi, Takahisa | Kosugi, Shinji | Nakayama, Takeo | Matsuda, Fumihiko | the Nagahama Study Group

Article Type: Short Communication

Abstract: Accumulation of advanced glycation end products (AGEs) has been linked with cognitive decline as a risk factor based on the analysis in small populations. We investigated the association between skin autofluorescence of AGEs and global cognitive function in a Japanese older (≥60 years) population (n  = 4,041). The AGEs quartiles were inversely associated with the Revised Hasegawa’s Dementia Scale score (Q1: reference, Q2: β= –0.011, p  = 0.537, Q3: β= –0.043, p  = 0.016, Q4: β= –0.064, p  < 0.001) independent of major risk factors. Accumulation of AGEs was associated with lower cognitive performance in older adults.

Keywords: Advanced glycation end products, cognitive function, epidemiological studies, population at risk

DOI: 10.3233/JAD-190878

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Liu, Peng | Zhao, Beiyu | Wei, Meng | Li, Yanbo | Liu, Jie | Ma, Louyan | Shang, Suhang | Huo, Kang | Wang, Jin | Li, Rui | Qu, Qiumin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common age-associated neurodegenerative disease featured by progressive learning and memory deficit, and Aβ was identified as playing a key role in the process of AD and was theorized to be caused by the imbalance of production and clearance. Increasing evidence suggested an association between sleep deprivation and AD. Our recent study found that chronic sleep restriction (CSR) caused cognitive impairment and Aβ accumulation in rats, but the underlining mechanism was unclear. In the present study, we investigated the effects of inflammation on Aβ accumulation induced by CSR. We found that CSR significantly increased the …expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α ), inducible nitric oxide synthase (iNOS), and nitric oxide (NO) in brain, and the inflammatory factors levels were positively correlated with Aβ42 deposition. Additionally, the inflammatory factors were correlated with BACE1, LRP-1, and RAGE levels in both the hippocampus and the prefrontal cortex. Furthermore, the plasma levels of IL-1β, TNF-α , and NO were elevated after CSR, and the concentration of plasma inflammatory mediators were correlated with plasma levels of sLRP1 and sRAGE. These results suggested that the inflammation in brain and plasma might be involved in the CSR-induced Aβ accumulation. Show more

Keywords: Alzheimer’s disease, amyloid-β, chronic sleep restriction, inflammation, risk factor

DOI: 10.3233/JAD-191317

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

Authors: Silva, Dina | Cardoso, Sandra | Guerreiro, Manuela | Maroco, João | Mendes, Tiago | Alves, Luísa | Nogueira, Joana | Baldeiras, Inês | Santana, Isabel | de Mendonça, Alexandre

Article Type: Research Article

Abstract: Background: Diagnosis of Alzheimer’s disease (AD) confirmed by biomarkers allows the patient to make important life decisions. However, doubt about the fleetness of symptoms progression and future cognitive decline remains. Neuropsychological measures were extensively studied in prediction of time to conversion to dementia for mild cognitive impairment (MCI) patients in the absence of biomarker information. Similar neuropsychological measures might also be useful to predict the progression to dementia in patients with MCI due to AD. Objective: To study the contribution of neuropsychological measures to predict time to conversion to dementia in patients with MCI due to AD. …Methods: Patients with MCI due to AD were enrolled from a clinical cohort and the effect of neuropsychological performance on time to conversion to dementia was analyzed. Results: At baseline, converters scored lower than non-converters at measures of verbal initiative, non-verbal reasoning, and episodic memory. The test of non-verbal reasoning was the only statistically significant predictor in a multivariate Cox regression model. A decrease of one standard deviation was associated with 29% of increase in the risk of conversion to dementia. Approximately 50% of patients with more than one standard deviation below the mean in the z score of that test had converted to dementia after 3 years of follow-up. Conclusion: In MCI due to AD, lower performance in a test of non-verbal reasoning was associated with time to conversion to dementia. This test, that reveals little decline in the earlier phases of AD, appears to convey important information concerning conversion to dementia. Show more

Keywords: Alzheimer’s disease (AD), amyloid-β, cognitive impairment, dementia, mild cognitive impairment due to AD, neuropsychological assessment, prodromal AD, Raven Coloured Progressive Matrices

DOI: 10.3233/JAD-191133

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Teimouri, Elham | Rainey-Smith, Stephanie R. | Bharadwaj, Prashant | Verdile, Giuseppe | Martins, Ralph N.

Article Type: Review Article

Abstract:  There is currently no effective treatment for Alzheimer’s disease (AD), the most common form of dementia. It has been proposed, however, that a modest delay in onset can significantly reduce the number of cases. Thus, prevention and intervention strategies are currently the focus of much research. In the search for compounds that potentially confer benefit, the Amla fruit and its extracts have drawn attention. Amla preparations have been used for centuries in traditional Indian medicine systems such as Ayurveda, with various parts of the plant used to treat a variety of diseases. Here we review many animal-based studies, and some …clinical trials, which have shown that Amla, and its extracts, exert many positive effects on dyslipidemia, hyperglycemia, inflammation, oxidative stress, apoptosis, and autophagy, that contribute to AD risk. Collectively, this evidence suggests that Amla may be of value as part of an effective disease-delaying treatment for AD. Show more

Keywords: Amla, Alzheimer’s disease, anti-inflammatory, antioxidant, cardiovascular disease, type 2 diabetes

DOI: 10.3233/JAD-191033

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

Authors: Marino Gammazza, Antonella | Restivo, Vincenzo | Baschi, Roberta | Caruso Bavisotto, Celeste | Cefalù, Angelo B. | Accardi, Giulia | Conway de Macario, Everly | Macario, Alberto J.L. | Cappello, Francesco | Monastero, Roberto

Article Type: Research Article

Abstract: Molecular chaperones play essential roles in many processes such as cell differentiation, tissue homeostasis, and organ remodeling. Recent data indicate that chaperones can act as cytoprotectants for brain cells during the progression of neurodegenerative diseases, including Alzheimer’s disease (AD). However, very few data on the levels of chaperones in dementia, including its prodromal phases, have been reported. In this study, we used biological samples and epidemiological data collected during the Zabùt Aging Project (a prospective, community-based, cohort study of normal/pathological aging conducted in Sicily, Italy, with a follow-up of ten years) to determine if there is an association between plasma …levels of the chaperones Hsp60, Hsp70, and Hsp90 with amnestic mild cognitive impairment (aMCI) and AD. Twenty-six aMCI individuals, 26 AD and 26 controls, matched for age and sex, were enrolled. After adjustment for education subjects with AD showed significantly higher levels of Hsp60 than aMCI (OR = 1.16, 95% CI 1.04–1.30) and controls (OR = 1.12, 95% CI 1.03–1.22), while Hsp70 was significantly higher only in AD (OR = 1.84, 95% CI 1.09–3.10) than controls. In contrast, circulating levels of Hsp90 were significantly diminished in aMCI (OR = 0.69, 95% CI 0.52–0.91) and AD (OR = 0.51, 95% CI 0.35–0.75) compared to controls. However, these results were no longer significant after adjustment for multiple comparisons. Although the results lost significance after adjustment for multiple comparisons, they are encouraging despite the smallness of the sample and new studies should be carried out with larger populations to determine to what extent sequential measurement of serum chaperones in aMCI and AD can be trusted as indicators of disease status and progression. Show more

Keywords: Alzheimer’s disease, cognitive impairment, Hsp60, Hsp70, Hsp90, molecular chaperones, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-180825

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018