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

Authors: Lehingue, Elsa | Gueniat, Julien | Jourdaa, Sandra | Hardouin, Jean Benoît | Pallardy, Amandine | Courtemanche, Hélène | Rocher, Laëtitia | Etcharry-Bouyx, Frédérique | Auriacombe, Sophie | Mollion, Hélène | Formaglio, Maité | Rouaud, Olivier | Bretonnière, Cédric | Antérion, Catherine Thomas | Boutoleau-Bretonnière, Claire

Article Type: Research Article

Abstract: Background: The frontal variant of Alzheimer’s disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD. Objective: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD. …Methods: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients. Results: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18 FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion. Conclusion: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD. Show more

Keywords: Alzheimer’s disease, behavioral disorders, frontotemporal dementia, scale

DOI: 10.3233/JAD-201088

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Martínez-Maldonado, Alejandra | Ontiveros-Torres, Miguel Ángel | Harrington, Charles R. | Montiel-Sosa, José Francisco | Prandiz, Raúl García-Tapia | Bocanegra-López, Patricia | Sorsby-Vargas, Andrew Michael | Bravo-Muñoz, Marely | Florán-Garduño, Benjamín | Villanueva-Fierro, Ignacio | Perry, George | Garcés-Ramírez, Linda | de la Cruz, Fidel | Martínez-Robles, Sandra | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with the repeated microtubule-binding domains of three (3R) or four (4R) repeats. Under normal conditions, the 4R:3R ratio is 1:1. In PSP, the 4R isoform is predominantly expressed. The lesions in PSP brains are phosphorylated tau aggregates in both neurons and glial cells. These neurodegenerative diseases with abnormal tau inclusions are called tauopathies, including Alzheimer’s disease (AD). AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. …Objective: Our objective was to evaluate and compare the pathological tau processing in PSP and AD. Methods: Double and triple immunofluorescence with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) were carried out and analyzed by confocal microscopy. Results: Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Truncated tau at Glu391 and Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR and the absence of intact or phosphorylated tau. Conclusion: Phosphorylated tau was abundantly evidenced in PSP as in AD. The presence of eNFTs in glial cells and neuronal bodies suggest that other truncated tau species different from those observed in AD could be present in PSP. Additional studies on truncated tau within PSP lesions could improve understanding of tau’s pathological processing and help identify a discriminatory biomarker for AD and PSP. Show more

Keywords: Alzheimer’s disease, neurofibrillary tangle, progressive supranuclear palsy, tau protein, truncation Glu391

DOI: 10.3233/JAD-201139

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

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

Article Type: Research Article

Abstract: Background: Neuronal damage resulting from increased oxidative stress is important in the development of late onset/age-related Alzheimer’s disease (LOAD). We have developed an oxidative stress–related mouse model of LOAD based on gene deletion of aldehyde dehydrogenase 2 (ALDH2), an enzyme important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit AD-like pathologies and a progressive decline in recognition and spatial memory. This progression presumably has a morphological basis induced by oxidative damage. Objective: We performed morphometric analyses in the dorsal hippocampal CA1 region (dCA1) to determine if …altered neuronal structure can help account for the progressive cognitive impairment in 3- to 12-month-old KO mice. Methods: Dendritic morphology was quantitatively analyzed by branched structured analysis and Sholl analysis following Golgi-Cox staining in WT mice (148 neurons) versus KO mice (180 neurons). Results: The morphology and complexity of dCA1 pyramidal neurons were similar at age 3 months in WTs and KOs. However, by 6 months there were significant reductions in apical and basal dendritic length, dendrite complexity, and spine density in KO versus WT mice that were maintained through ages 9 and 12 months. Immunostaining for protein adducts of the lipid peroxidation product 4-hydroxynonenal revealed significant increases in staining in dCA1 (but not ventral CA1) by 3 months, increasing through 12 months. Conclusion: This specific and progressive increase in dCA1 oxidative damage preceded detectable synaptic trimming in KO mice, in keeping with studies showing that lesions to dorsal hippocampus primarily impair cognitive memory. Show more

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

DOI: 10.3233/JAD-201024

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Rodriguez, Francisca S. | Pabst, Alexander | Heser, Kathrin | Kleineidam, Luca | Hajek, Andre | Eisele, Marion | Röhr, Susanne | Löbner, Margrit | Wiese, Birgitt | Angermeyer, Matthias C. | Maier, Wolfgang | Scherer, Martin | Wagner, Michael | König, Hans-Helmut | Riedel-Heller, Steffi G.

Article Type: Research Article

Abstract: Background: Only little evidence is available on disorientation, one of the most challenging symptoms of Alzheimer’s disease and related dementias. Objectives: The aim of this study was to investigate the prevalence of disorientation in older age in association with the level of cognitive status, personal characteristics, and life events. Methods: Three longitudinal population-based cohort studies on cognitive health of elderly adults were harmonized (LEILA 75 + , AgeCoDe/AgeQualiDe, AgeMooDe). Participants who completed a baseline and at least one follow-up assessment of cognitive functioning and who did not have stroke, Parkinson’s disease, atherosclerosis, kidney disease, and/or alcoholism were included …in the analysis (n  = 2135, 72.6% female, mean age 80.2 years). Data was collected in standardized interviews and questionnaires with the participant, a proxy informant, and the participant’s general practitioner. Results: Making three errors in the MMSE other than in the questions on orientation (MMSEwo ) came with a probability of 7.8% for disorientation, making ten errors with a probability of 88.9%. A lower MMSEwo score (HR 0.75, CI 95 0.71–0.79, p  < 0.001), older age (HR 1.11, CI 95 1.08–1.14, p  < 0.001), and living in a nursing home (HR 1.64, CI 95 1.02–2.64, p  = 0.042) were associated with incident disorientation. Impairments in walking (OR 2.41, CI 95 1.16–4.99, p  = 0.018) were associated with a greater probability for prevalent disorientation. None of the life events were significant. Conclusion: Our findings suggest that disorientation is primarily associated with cognitive status. Regular walking activities might possibly reduce the risk for disorientation but further research is necessary. Show more

Keywords: Cognitive functioning, cognitive status, dementia, longitudinal cohort, orientation, symptoms

DOI: 10.3233/JAD-201008

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Arendt, Johan Frederik Håkonsen | Horváth-Puhó, Erzsébet | Sørensen, Henrik Toft | Nexø, Ebba | Pedersen, Lars | Ording, Anne Gulbech | Henderson, Victor W.

Article Type: Research Article

Abstract: Background: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia. Objective: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer’s disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes). Methods: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000–2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients …with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200–600 pmol/L). We used multivariable Cox regression to compute 0–15-year hazard ratios for dementia. Results: For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia. Conclusion: We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia. Show more

Keywords: Alzheimer’s disease, cobalamin, cohort studies, clinical nutrition, registries

DOI: 10.3233/JAD-201096

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Hayashi, Tetsuo | Shimonaka, Shotaro | Elahi, Montasir | Matsumoto, Shin-Ei | Ishiguro, Koichi | Takanashi, Masashi | Hattori, Nobutaka | Motoi, Yumiko

Article Type: Research Article

Abstract: Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective: To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods: We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of …the AD brain into the unilateral hippocampus. Results: After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion: These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions. Show more

Keywords: Microglia, neurodegeneration, propagation, tau protein, tauopathies

DOI: 10.3233/JAD-201002

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Lu, Yifei | Pike, James R. | Selvin, Elizabeth | Mosley, Thomas | Palta, Priya | Richey Sharrett, A. | Thomas, Alvin | Loehr, Laura | Sidney Barritt, A. | Hoogeveen, Ron C. | Heiss, Gerardo

Article Type: Research Article

Abstract: Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. …Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values <10th percentile were associated with a higher risk of dementia (hazard ratio [HR] 1.34, 95% CI 1.08–1.65). The corresponding HR was 1.22 (0.99–1.51) for AST. Conclusion: Plasma aminotransferases <10th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia, advocating for attention to the putative role of hepatic function in the pathogenesis of dementia. Show more

Keywords: ALT, Alzheimer’s disease, AST, dementia, liver hypometabolism

DOI: 10.3233/JAD-201241

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Gnanaprakash, Madhumathi | Staniszewski, Agnieszka | Zhang, Hong | Pitstick, Rose | Kavanaugh, Michael P. | Arancio, Ottavio | Nicholls, Russell E.

Article Type: Research Article

Abstract: Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ). Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in …vivo . Methods: To do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice. Results: We found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments. Conclusion: These data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive impairment, leucine carboxyl methyltransferase, long-term potentiation, MAPT protein, protein phosphatase 2A, protein phosphatase methylesterase

DOI: 10.3233/JAD-200462

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Iliadou, Paraskevi | Paliokas, Ioannis | Zygouris, Stelios | Lazarou, Eftychia | Votis, Konstantinos | Tzovaras, Dimitrios | Tsolaki, Magdalini

Article Type: Research Article

Abstract: Background: Electroencephalography (EEG) has been used to assess brain activity while users are playing an immersive serious game. Objective: To assess differences in brain activation as measured with a non-intrusive wearable EEG device, differences in game performance and correlations between EEG power, game performance and global cognition, between cognitively impaired and non-impaired older adults, during the administration of a novel self-administered serious game-based test, the Virtual Supermarket Test (VST). Methods: 43 older adults with subjective cognitive decline (SCD) and 33 older adults with mild cognitive impairment (MCI) were recruited from day centers for cognitive disorders. Global …cognition was assessed with the Montreal Cognitive Assessment (MoCA). Brain activity was measured with a non-intrusive wearable EEG device in a resting state condition and while they were administered the VST. Results: During resting state condition, the MCI group showed increased alpha, beta, delta, and theta band power compared to the SCD group. During the administration of the VST, the MCI group showed increased beta and theta band power compared to the SCD group. Regarding game performance, alpha, beta, delta, and theta rhythms correlated with average duration, while delta rhythm was positively correlated with mean errors. MoCA correlated with alpha, beta, delta, and theta rhythms and with average game duration and mean game errors indicating that elevated EEG rhythms in MCI may be associated with an overall cognitive decline. Conclusion: VST performance can be used as a digital biomarker. Cheap commercially available wearable EEG devices can be used for obtaining brain activity biomarkers. Show more

Keywords: Age-related memory disorders, cognitive assessment screening instrument, computer games, dementia, EEG, mild cognitive impairment, neurocognitive tests, screening, self-evaluation

DOI: 10.3233/JAD-201300

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Martínez-García, Ignacio | Hernández-Soto, Rebeca | Villasana-Salazar, Benjamín | Ordaz, Benito | Peña-Ortega, Fernando

Article Type: Research Article

Abstract: Background: Deficits in odor detection and discrimination are premature symptoms of Alzheimer’s disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility was not directly tested before. Objective: To characterize the effects of Aβ on OB and PCx excitability/coupling and …on olfaction. Methods: Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in vitro . Olfaction was assessed through the habituation/dishabituation test. Results: Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo . Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in vitro . Conclusion: Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD. Show more

Keywords: Alzheimer’s disease, coherence, hyperexcitability, local field potential, main olfactory bulb, olfactory function, piriform cortex

DOI: 10.3233/JAD-201392

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Lao, Kejing | Zhang, Ruisan | Luan, Jing | Zhang, Yuelin | Gou, Xingchun

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that has been recognized as one of the most intractable medical problems with heavy social and economic costs. Amyloid-β (Aβ) has been identified as a major factor that participates in AD progression through its neurotoxic effects. The major mechanism of Aβ-induced neurotoxicity is by interacting with membrane receptors and subsequent triggering of aberrant cellular signaling. Besides, Aβ transporters also plays an important role by affecting Aβ homeostasis. Thus, these Aβ receptors and transporters are potential targets for the development of AD therapies. Here, we summarize the reported therapeutic strategies targeting Aβ receptors …and transporters to provide a molecular basis for future rational design of anti-AD agents. Show more

Keywords: Aβ receptors, Aβ transporter, EphB2, LilrB2, LRP-1, NgR, p75NTR, PrPc, RAGE

DOI: 10.3233/JAD-200851

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Loeffler, David A.

Article Type: Research Article

Abstract: There is an extensive literature relating to factors associated with the development of Alzheimer’s disease (AD), but less is known about factors which may contribute to its progression. This review examined the literature with regard to 15 factors which were suggested by PubMed search to be positively associated with the cognitive and/or neuropathological progression of AD. The factors were grouped as potentially modifiable (vascular risk factors, comorbidities, malnutrition, educational level, inflammation, and oxidative stress), non-modifiable (age at clinical onset, family history of dementia, gender, Apolipoprotein E ɛ4, genetic variants, and altered gene regulation), and clinical (baseline cognitive level, neuropsychiatric symptoms, …and extrapyramidal signs). Although conflicting results were found for the majority of factors, a positive association was found in nearly all studies which investigated the relationship of six factors to AD progression: malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs. Whether these or other factors which have been suggested to be associated with AD progression actually influence the rate of decline of AD patients is unclear. Therapeutic approaches which include addressing of modifiable factors associated with AD progression should be considered. Show more

Keywords: Alzheimer’s disease, baseline cognition, extrapyramidal signs, genetic factors, malnutrition, neuropsychiatric symptoms, progression

DOI: 10.3233/JAD-201182

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-27, 2021

Authors: Ferini-Strambi, Luigi | Hensley, Michael | Salsone, Maria

Article Type: Research Article

Abstract: Obstructive sleep apnea (OSA) and Alzheimer’s disease (AD) are two common chronic diseases with a well-documented association. Whether the association is causal has been highlighted by recent evidence reporting a neurobiological link between these disorders. This narrative review discusses the brain regions and networks involved in OSA as potential vulnerable areas for the development of AD neuropathology with a particular focus on gender-related implications. Using a neuroimaging perspective supported by neuropathological investigations, we provide a new model of neurodegeneration common to OSA and AD, that we have called OSA-AD neurodegeneration in order to decode the causal links between these two …chronic conditions. Show more

Keywords: Alzheimer’s disease, amygdala, cingulate gyrus, hippocampus, insula, magnetic resonance imaging, obstructive sleep apnea

DOI: 10.3233/JAD-201066

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Borda, Miguel Germán | Ayala Copete, Ana María | Tovar-Rios, Diego Alejandro | Jaramillo-Jimenez, Alberto | Giil, Lasse Melvær | Soennesyn, Hogne | Gómez-Arteaga, Camilo | Venegas-Sanabria, Luis Carlos | Kristiansen, Ida | Chavarro-Carvajal, Diego Andrés | Caicedo, Sandra | Cano-Gutierrez, Carlos Alberto | Vik-Mo, Audun | Aarsland, Dag

Article Type: Research Article

Abstract: Background: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline. Objective: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia. Methods: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer’s disease (AD) (n  = 103), Lewy body dementia (LBD) (n … = 74), and other dementias (OD) (n  = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models. Results: At baseline, the prevalence of general malnutrition was 28.7%; 17.32% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline. Conclusion: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis. Show more

Keywords: Activities of daily living, Alzheimer’s disease, dementia, Lewy body dementia, malnutrition

DOI: 10.3233/JAD-200961

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Dennison, Jessica L. | Ricciardi, Natalie R. | Lohse, Ines | Volmar, Claude-Henry | Wahlestedt, Claes

Article Type: Research Article

Abstract: Female sex is a leading risk factor for developing Alzheimer’s disease (AD). Sexual dimorphism in AD is gaining attention as clinical data show that women are not only more likely to develop AD but also to experience worse pathology and faster cognitive decline. Pre-clinical AD research in animal models often neglects to address sexual dimorphism in evaluation of behavioral or molecular characteristics and outcomes. This can compromise its translation to a clinical setting. The triple-transgenic AD mouse model (3xTg-AD) is a commonly used but unique AD model because it exhibits both amyloid and tau pathology, essential features of the human …AD phenotype. Mounting evidence has revealed important sexually dimorphic characteristics of this animal model that have yet to be reviewed and thus, are often overlooked in studies using the 3xTg-AD model. In this review we conduct a thorough analysis of reports of sexual dimorphism in the 3xTg-AD model including findings of molecular, behavioral, and longevity-related sex differences in original research articles through August 2020. Importantly, we find results to be inconsistent, and that strain source and differing methodologies are major contributors to lack of consensus regarding traits of each sex. We first touch on the nature of sexual dimorphism in clinical AD, followed by a brief summary of sexual dimorphism in other major AD murine models before discussing the 3xTg-AD model in depth. We conclude by offering four suggestions to help unify pre-clinical mouse model AD research inspired by the NIH expectations for considering sex as a biological variable. Show more

Keywords: Alzheimer’s disease, mouse models, sex as a biological variable (SABV), sexual dimorphism, triple transgenic, 3xTg-AD

DOI: 10.3233/JAD-201014

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Qian, Xueshen | Zhang, Shuang | Duan, Lian | Yang, Fengchun | Zhang, Kun | Yan, Fuhua | Ge, Song

Article Type: Research Article

Abstract: Background: Although periodontitis is reportedly associated with increased cognitive decline in Alzheimer’s disease, the mechanisms underlying this process remain unknown. Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) is an endotoxin associated with periodontal disease. Objective: We investigated the effect of periodontitis on learning capacity and memory of amyloid-β protein precursor (AβPP)/presenilin (PS1) transgenic mice along with the mechanisms underlying these effects. Methods: Mice were randomly assigned to three groups, namely AβPP/PS1 (control), P.g-LPS Injection, and P.g-LPS Injection + Ligation. Mice from the P.g-LPS Injection group were injected with P.g-LPS in the periodontal tissue three times per week for …8 weeks, while mice from the P.g-LPS Injection + Ligation group were injected with P.g-LPS and subjected to ligation of the gingival sulcus of the maxillary second molar. Results: Expression of gingival proinflammatory cytokines as well as alveolar bone resorption in P.g-LPS-injected and ligatured mice was increased compared to that in control mice. Mice in the P.g-LPS Injection + Ligation group exhibited cognitive impairment and a significant reduction in the number of neurons. Glial cell activation in the experimental groups with significantly increased amyloid-β (Aβ) levels was more pronounced relative to the control group. Induction of periodontitis was concurrent with an increase in cyclooxygenase-2, inducible nitric oxide synthase, AβPP, and beta-secretase 1 expression and a decrease in A disintegrin and metalloproteinase domain-containing protein 10 expression. Conclusion: These findings indicated that periodontitis exacerbated learning and memory impairment in AβPP/PS1 mice and augmented Aβ and neuroinflammatory responses. Our study provides a theoretical basis for risk prediction and early intervention of Alzheimer’s disease and periodontitis. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, lipopolysaccharide, periodontitis, Porphyromonas gingivalis

DOI: 10.3233/JAD-201007

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Shaffer, Rachel M. | Li, Ge | Adar, Sara D. | Dirk Keene, C. | Latimer, Caitlin S. | Crane, Paul K. | Larson, Eric B. | Kaufman, Joel D. | Carone, Marco | Sheppard, Lianne

Article Type: Research Article

Abstract: Background: Evidence links fine particulate matter (PM2.5 ) to Alzheimer’s disease (AD), but no community-based prospective cohort studies in older adults have evaluated the association between long-term exposure to PM2.5 and markers of AD neuropathology at autopsy. Objective: Using a well-established autopsy cohort and new spatiotemporal predictions of air pollution, we evaluated associations of 10-year PM2.5 exposure prior to death with Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC score). Methods: We used autopsy specimens (N = 832) from the Adult Changes in Thought (ACT) study, with …enrollment ongoing since 1994. We assigned long-term exposure at residential address based on two-week average concentrations from a newly developed spatiotemporal model. To account for potential selection bias, we conducted inverse probability weighting. Adjusting for covariates with tiered models, we performed ordinal regression for Braak and CERAD and logistic regression for dichotomized ABC score. Results: 10-year average PM2.5 from death across the autopsy cohort was 8.2 (1.9) μg/m3 . Average age at death was 89 (±7) years. Each 1μg/m3 increase in 10-year average PM2.5 prior to death was associated with a suggestive increase in the odds of worse neuropathology as indicated by CERAD score (OR: 1.35 (0.90, 1.90)) but a suggestive decreased odds of neuropathology as defined by the ABC score (OR: 0.79 (0.49, 1.19). There was no association with Braak stage (OR: 0.99 (0.64, 1.47). Conclusion: We report inconclusive associations between PM2.5 and AD neuropathology at autopsy among a cohort where 94% of individuals experienced 10-year exposures below the current EPA standard. Prior studies of AD risk factors and AD neuropathology are similarly inconclusive, suggesting alternative mechanistic pathways for disease or residual confounding. Show more

Keywords: Air pollution, Alzheimer’s disease, autopsy, dementia, neuropathology, particulate matter

DOI: 10.3233/JAD-201005

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Ly, Maria | Raji, Cyrus A. | Yu, Gary Z. | Wang, Qing | Wang, Yong | Schindler, Suzanne E. | An, Hongyu | Samara, Amjad | Eisenstein, Sarah A. | Hershey, Tamara | Smith, Gordon | Klein, Samuel | Liu, Jingxia | Xiong, Chengjie | Ances, Beau M. | Morris, John C. | Benzinger, Tammie L.S.

Article Type: Research Article

Abstract: Background: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood. Objective: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer’s disease (AD) dementia. Methods: We analyzed brain MRIs from 104 cognitively normal participants (CDR = 0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI <25, N = 62) or …overweight and obese (BMI ≥25, N = 42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL. Results: Participants with BMI <25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR correc-ted for multiple comparisons to alpha = 0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI ≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers. Conclusion: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly. Show more

Keywords: Alzheimer’s disease, neuroinflammation imaging, obesity

DOI: 10.3233/JAD-201242

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Mercerón-Martínez, Daymara | Ibaceta-González, Cristobal | Salazar, Claudia | Almaguer-Melian, William | Bergado-Rosado, Jorge A. | Palacios, Adrian G.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common and devastating neurodegenerative condition worldwide, characterized by the aggregation of amyloid-β and phosphorylated tau protein, and is accompanied by a progressive loss of learning and memory. A healthy nervous system is endowed with synaptic plasticity, among others neural plasticity mechanisms, allowing structural and physiological adaptations to changes in the environment. This neural plasticity modification sustains learning and memory, and behavioral changes and is severely affected by pathological and aging conditions, leading to cognitive deterioration. This article reviews critical aspects of AD neurodegeneration as well as therapeutic approaches that restore neural plasticity to provide …functional recoveries, including environmental enrichment, physical exercise, transcranial stimulation, neurotrophin involvement, and direct electrical stimulation of the amygdala. In addition, we report recent behavioral results in Octodon degus , a promising natural model for the study of AD that naturally reproduces the neuropathological alterations observed in AD patients during normal aging, including neuronal toxicity, deterioration of neural plasticity, and the decline of learning and memory. Show more

Keywords: Neural plasticity, neurorestauration, non-transgenic animal models of neurodegeneration

DOI: 10.3233/JAD-201178

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Prakash, Mithilesh | Abdelaziz, Mahmoud | Zhang, Linda | Strange, Bryan A. | Tohka, Jussi | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Quantitatively predicting the progression of Alzheimer’s disease (AD) in an individual on a continuous scale, such as the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) scores, is informative for a personalized approach as opposed to qualitatively classifying the individual into a broad disease category. Objective: To evaluate the hypothesis that the multi-modal data and predictive learning models can be employed for future predicting ADAS-cog scores. Methods: Unimodal and multi-modal regression models were trained on baseline data comprised of demographics, neuroimaging, and cerebrospinal fluid based markers, and genetic factors to predict future ADAS-cog scores for 12, 24, and …36 months. We subjected the prediction models to repeated cross-validation and assessed the resulting mean absolute error (MAE) and cross-validated correlation (ρ) of the model. Results: Prediction models trained on multi-modal data outperformed the models trained on single modal data in predicting future ADAS-cog scores (MAE12, 24 & 36 months = 4.1, 4.5, and 5.0, ρ 12, 24 & 36 months = 0.88, 0.82, and 0.75). Including baseline ADAS-cog scores to prediction models improved predictive performance (MAE12, 24 & 36 months = 3.5, 3.7, and 4.6, ρ 12, 24 & 36 months = 0.89, 0.87, and 0.80). Conclusion: Future ADAS-cog scores were predicted which could aid clinicians in identifying those at greater risk of decline and apply interventions at an earlier disease stage and inform likely future disease progression in individuals enrolled in AD clinical trials. Show more

Keywords: Alzheimer’s disease, machine learning, magnetic resonance imaging, multi-modal imaging, neuropsychology

DOI: 10.3233/JAD-200906

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Farugia, Taya L. | Cuni-Lopez, Carla | White, Anthony R.

Article Type: Research Article

Abstract: Australia often experiences natural disasters and extreme weather conditions such as: flooding, sandstorms, heatwaves, and bushfires (also known as wildfires or forest fires). The proportion of the Australian population aged 65 years and over is increasing, alongside the severity and frequency of extreme weather conditions and natural disasters. Extreme heat can affect the entire population but particularly at the extremes of life, and patients with morbidities. Frequently identified as a vulnerable demographic in natural disasters, there is limited research on older adults and their capacity to deal with extreme heat and bushfires. There is a considerable amount of literature that …suggests a significant association between mental disorders such as dementia, and increased vulnerability to extreme heat. The prevalence rate for dementia is estimated at 30% #x0025;by age 85 years, but there has been limited research on the effects extreme heat and bushfires have on individuals living with dementia. This review explores the differential diagnosis of dementia, the Australian climate, and the potential impact Australia’s extreme heat and bushfires have on individuals from vulnerable communities including low socioeconomic status Indigenous and Non-Indigenous populations living with dementia, in both metropolitan and rural communities. Furthermore, we investigate possible prevention strategies and provide suggestions for future research on the topic of Australian bushfires and heatwaves and their impact on people living with dementia. This paper includes recommendations to ensure rural communities have access to appropriate support services, medical treatment, awareness, and information surrounding dementia. Show more

Keywords: Bushfire, climate change, dementia, extreme heat, wildfire

DOI: 10.3233/JAD-201388

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Delic, Vedad | Ratliff, Whitney A. | Citron, Bruce A.

Article Type: Research Article

Abstract: An estimated 5 million Americans are living with Alzheimer's disease (AD), and there is also a significant impact on caregivers, with an additional 16 million mericans providing unpaid care for individuals with AD and other dementias. These numbers are projected to increase in the coming years. While AD is still without a cure, continued research efforts have led to better understanding of pathology and potential risk factors that could be exploited to slow disease progression. A bidirectional relationship between sleep deprivation and AD has been suggested and is well supported by both human and animal studies. Even brief episodes of …inadequate sleep have been shown to cause an increase in amyloidβ and tau proteins, both well-established contributors toAD pathology. Sleep deprivation is also the most common consequence of post-traumatic stress disorder (PTSD). Patients with PTSD frequently present with sleep disturbances and also develop dementia at twice the rate of the general population accounting for a disproportionate representation of AD among U.S. Veterans. The goal of this review is to highlight the relationship triad between sleep deprivation, AD, and PTSD as well as their impact on molecular mechanisms driving AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β, post-traumatic stress disorder, sleep deprivation, tau

DOI: 10.3233/JAD-201378

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Mai, Yingren | Yu, Qun | Zhu, Feiqi | Luo, Yishan | Liao, Wang | Zhao, Lei | Xu, Chunyan | Fang, Wenli | Ruan, Yuting | Cao, Zhiyu | Lei, Ming | Au, Lisa | Mok, Vincent C.T. | Shi, Lin | Liu, Jun

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) provides objective information about brain structural atrophy in patients with Alzheimer’s disease (AD). This multi-structural atrophic information, when integrated as a single differential index, has the potential to further elevate the accuracy of AD identification from normal control (NC) compared to the conventional structure volumetric index. Objective: We herein investigated the performance of such an MRI-derived AD index, AD-Resemblance Atrophy Index (AD-RAI), as a neuroimaging biomarker in clinical scenario. Method: Fifty AD patients (19 with the Amyloid, Tau, Neurodegeneration (ATN) results assessed in cerebrospinal fluid) and 50 age- and gender-matched NC …(19 with ATN results assessed using positron emission tomography) were recruited in this study. MRI-based imaging biomarkers, i.e., AD-RAI, were quantified using AccuBrain® . The accuracy, sensitivity, specificity, and area under the ROC curve (AUC) of these MRI-based imaging biomarkers were evaluated with the diagnosis result according to clinical criteria for all subjects and ATN biological markers for the subgroup. Results: In the whole groups of AD and NC subjects, the accuracy of AD-RAI was 91%, sensitivity and specificity were 88% and 96%, respectively, and the AUC was 92%. In the subgroup of 19 AD and 19 NC with ATN results, AD-RAI results matched completely with ATN classification. AD-RAI outperforms the volume of any single brain structure measured. Conclusion: The finding supports the hypothesis that MRI-derived composite AD-RAI is a more accurate imaging biomarker than individual brain structure volumetry in the identification of AD from NC in the clinical scenario. Show more

Keywords: AD-Resemblance atrophy index, Alzheimer’s disease, ATN biological markers, automated brain volumetry, magnetic resonance imaging

DOI: 10.3233/JAD-201033

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

Authors: Underlien Kristensen, Rachel | Jensen-Dahm, Christina | Gasse, Christiane | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Studies have shown declining use of potentially inappropriate medication (PIM), medication where risks associated with use outweigh potential benefits in older people. However, the trend in people with dementia remains unknown. Objective: To test the hypothesis that the use of PIM has decreased in people with dementia in line with the declining use in the general older population. Methods: Repeated cross-sectional register-based study of the entire Danish population aged ≥65 years (2000: N = 802,106; 2015: N = 1,056,476). PIM was identified using the Danish “Red-yellow-green list”. Changes in the use of PIM were examined by calculating the annual …prevalence of filling prescriptions for at least one PIM in older people with and without dementia. Characteristics of the study population were examined annually including comorbidity. Results: From 2000 to 2015, the prevalence of PIM use decreased from 54.7%to 43.5%in people with dementia and from 39.5%to 28.8%in people without dementia; the decrease was significant across all age groups and remained so in a sensitivity analysis where antipsychotics were removed. During the same period, comorbidity scores increased in people with and without dementia. Conclusion: The declining use of PIM in people with dementia from 2000 to 2015 parallels the trend in the general older population. The use of PIM decreased despite increasing levels of comorbidity and was not solely attributable to the decreasing use of antipsychotics in people with dementia. However, PIM use remained more widespread in people with dementia who may be more vulnerable to the risks associated with PIM. Show more

Keywords: Dementia, inappropriate prescribing, pharmacoepidemiology, potentially inappropriate medication, time trend

DOI: 10.3233/JAD-200627

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: de la Torre, Jack C.

Article Type: Research Article

Abstract: This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer’s disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993. New biomolecular findings reveal the interplay of CBH in increasing tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice, damaging fast axonal transport, increasing signaling of mammalian target of rapamycin (mTOR), impairing learning-memory function, and promoting …the formation of neurofibrillary tangles, a neuropathologic hallmark of AD. These pathologic elements have been singularly linked with neurodegeneration and AD but their abnormal, collective participation during brain aging have not been fully examined. The format for this review will provide a consolidated analysis of each pathologic phase contributing to cognitive decline and AD onset, summarized in nine chronological steps. These steps galvanize each factor’s active participation and contribution in constructing a biomolecular pathway to AD onset generated by CBH. Show more

Keywords: Axonal transport, brain hypoperfusion, cognition, mammalian target of rapamycin, neurofibrillary tangles, tau, vascular hypothesis of Alzheimer’s

DOI: 10.3233/JAD-201165

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Baril, Andrée-Ann | Beiser, Alexa S. | Redline, Susan | McGrath, Emer R. | Gottlieb, Daniel J. | Aparicio, Hugo | Seshadri, Sudha | Himali, Jayandra J. | Pase, Matthew P.

Article Type: Short Communication

Abstract: Because of their roles as potential risk factors, we evaluated whether obstructive sleep apnea (OSA) severity interacts with interleukin-6 (IL-6) in predicting incident dementia of the Alzheimer’s type (DAT). In 269 dementia-free participants, IL-6 and the apnea-hypopnea index (AHI) were measured at baseline and incident DAT was surveilled for up to 22.8 years. Cox models revealed a significant interaction: In the lowest IL-6 quartile only, a higher AHI was associated with an elevated risk of DAT. The association between OSA severity and incident DAT might be especially apparent in the absence of inflammation or absence of potential benefits from IL-6.

Keywords: Alzheimer’s disease, dementia, inflammation, interleukin-6, sleep apnea, sleep-disordered breathing, sleep disorders

DOI: 10.3233/JAD-200545

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Clark, Ian Albert | Vissel, Bryce

Article Type: Review Article

Abstract: Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post- traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia …chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer’s disease and Parkinson’s disease sufferers. In contrast, Alzheimer’s disease and Parkinson’s disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this. Show more

Keywords: Alzheimer’s disease, cardiac arrest survival, locus coeruleus, neurological COVID-19, norepinephrine, parkinson’s disease, stroke, traumatic brain injury, tumor necrosis factor

DOI: 10.3233/JAD-201186

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

Authors: Schonfeld, Ethan | Schonfeld, Elan | Aman, Casey | Gill, Navroop | Kim, Dami | Rabin, Sydney | Shamshuddin, Bushraa | Sealey, Lloyd | Senno, Ricardo Gabriel

Article Type: Research Article

Abstract: Background: There exist functional deficits in motor, sensory, and olfactory abilities in dementias. Measures of these deficits have been discussed as potential clinical markers. Objective: We measured the deficit of motor, sensory, and olfactory functions on both the left and right body side, to study potential body lateralizations. Methods: This IRB-approved study (N = 84) performed left/right clinical tests of gross motor (dynamometer test), sensory (Von Frey test), and olfactory (peppermint oil test) ability. The Mini-Mental Status Exam was administered to determine level of dementia; medical and laboratory data were collected. Results: Sensory and olfactory deficits …lateralized to the left side of the body, while motor deficits lateralized to the right side. We found clinical correlates of motor lateralization: female, depression, MMSE <15, and diabetes. While clinical correlates of sensory lateralization: use of psychotherapeutic agent, age ≥85, MMSE <15, and male. Lastly, clinical correlates of olfactory lateralization: age <85, number of medications >10, and male. Conclusion: These lateralized deficits in body function can act as early clinical markers for improved diagnosis and treatment. Future research should identify correlates and corresponding therapies to strengthen at-risk areas. Show more

Keywords: Alzheimer’s disease, clinical markers, functional laterality, motor skills, olfactory perception, sensory thresholds, therapeutics

DOI: 10.3233/JAD-201216

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

Authors: Castagna, Alberto | Fabbo, Andrea | Manzo, Ciro | Lacava, Roberto | Ruberto, Carmen | Ruotolo, Giovanni

Article Type: Research Article

Abstract: Background: Background: Citicoline has been proven to have beneficial effects in patients with cognitive impairment. In previous studies, combined treatment with memantine and acetylcholinesterase inhibitors (AChEIs) maintained cognitive function in patients with Alzheimer’s disease (AD) better than memantine or AChEIs alone. Objective: To evaluate the effectiveness and safety of a combination therapy of oral citicoline, memantine, and an AChEI in AD when compared with memantine and an AChEI without citicoline. Methods: This was a retrospective multi-centric case-control study, conducted in Italian Centers for Cognitive Impairment and Dementia. Overall, 170 patients were recruited (34.11%of men, mean …age 76,81±4.93 years): 48.8%treated with memantine and donepezil; 48.2%with memantine and rivastigmine; 2.9%with memantine and galantamine. 89 patients (control-group) were treated with memantine and an AChEI, whereas 81 patients (case-group) were treated with oral citicoline 1000 mg/day added to memantine and an AChEI given orally. Cognitive functions, activities of daily living, instrumental activities of daily living, comorbidities, mood and behavioral disturbances were assessed at baseline, month 6, and month 12. Results: In the case group, MMSE score had a statistically significant increasing trend between T0 and T2 (14.88±2.95 versus 15.09±3.00; p  = 0.040), whereas in the control group, MMSE score showed a statistically significant decrease trend (14.37±2.63 versus 14.03±2.92 p  = 0.024). Conclusion: In older patients with AD, a triple therapy with citicoline, memantine, and AChEI was more effective than memantine and AChEI without citicoline in maintaining the MMSE total score after 12 months. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, citicoline, combined treatment, memantine

DOI: 10.3233/JAD-201211

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Bohlken, Jens | Riedel-Heller, Steffi | Steininger, Gilles | Kostev, Karel | Michalowsky, Bernhard

Article Type: Research Article

Abstract: Background: The number of patients with dementia is forecast to grow continuously. However, there are indications that the incidence and prevalence is falling in high-income countries. Objective: To examine whether any effects of declining incidence and prevalence rates of dementia and mild cognitive impairment (MCI) were evident in Germany between 2015 and 2019. Methods: The analysis was based on 797 general and 132 specialists (neurological/psychiatric) practices and included 10.1 million patients aged 18 years and older who visited between January 2014 and December 2019 one of the practitioners. The prevalence and incidence of dementia and MCI …were demonstrated descriptively. Results: Between 2015 and 2019, the prevalence (incidence) of dementia decreased from 2.18%(0.44%) in 2015 to 2.07%(0.35%) in 2019. A relatively large decrease in the prevalence (incidence) of dementia was observed in patients aged 80 and older, at –1.47%(–0.62%), compared to younger patients, at –0.40%(–0.18%). By contrast, the prevalence and incidence of MCI have remained constant over the years (0.19%to 0.22%and 0.06%, respectively). Overall, the number of patients diagnosed with dementia decreased slightly by 1%while the number of patients diagnosed with MCI increased by 17%, which is caused by continued demographic changes. Conclusion: Our results confirmed the reduction in the prevalence and incidence of dementia and revealed a decrease in the number of patients with dementia despite continued demographic changes. Future studies are warranted to determine whether the results are caused by changing risk and lifestyle factors or changes in medical diagnosis and treatment behavior of the practitioners. Show more

Keywords: Cognitive dysfunction, dementia, diagnosis, incidence, prevalence

DOI: 10.3233/JAD-201385

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Peng, Zhouyuan | Nishimoto, Hiroyuki | Kinoshita, Ayae

Article Type: Research Article

Abstract: Background: With the rapid aging of the population, the issue of driving by dementia patients has been causing increasing concern worldwide. Objective: To investigate the driving difficulties faced by senior drivers with cognitive impairment and identify the specific neuropsychological test that can reflect specific domains of driving maneuvers. Methods: Senior drivers with cognitive impairment were investigated. Neuropsychological tests and a questionnaire on demographic and driving characteristics were administered. Driving simulator tests were used to quantify participants’ driving errors in various domains of driving. Results: Of the 47 participants, 23 current drivers, though they had …better cognitive functions than 24 retired drivers, were found to have impaired driving performance in the domains of Reaction, Starting and stopping, Signaling, and Overall (wayfinding and accidents). The parameters of Reaction were significantly related to the diagnosis, and the scores of MMSE, TMT-A, and TMT-B. As regards details of the driving errors, “Sudden braking” was associated with the scores of MMSE (ρ = –0.707, p  <  0.01), BDT (ρ = –0.560, p  <  0.05), and ADAS (ρ = 0.758, p  <  0.01), “Forgetting to use turn signals” with the TMT-B score (ρ = 0.608, p  <  0.05), “Centerline crossings” with the scores of MMSE (ρ = –0.582, p  <  0.05) and ADAS (ρ = 0.538, p  <  0.05), and “Going the wrong way” was correlated with the score of CDT (ρ = –0.624, p  <  0.01). Conclusion: Different neuropsychological factors serve as predictors of different specific driving maneuvers segmented from driving performance. Show more

Keywords: Automobile driving, cognitive impairment, computer simulation, dementia, neuropsychological tests

DOI: 10.3233/JAD-201323

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Darst, Burcu F. | Huo, Zhiguang | Jonaitis, Erin M. | Koscik, Rebecca L. | Clark, Lindsay R. | Lu, Qiongshi | Kremen, William S. | Franz, Carol E. | Rana, Brinda | Lyons, Michael J. | Hogan, Kirk J. | Zhao, Jinying | Johnson, Sterling C. | Engelman, Corinne D.

Article Type: Research Article

Keywords: Alzheimer’s disease, amino acids, cognition, executive function, fatty acids, longitudinal analysis, metabolomics

DOI: 10.3233/JAD-200176

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

Authors: Russ, Tom C. | Cherrie, Mark P.C. | Dibben, Chris | Tomlinson, Sam | Reis, Stefan | Dragosits, Ulrike | Vieno, Massimo | Beck, Rachel | Carnell, Ed | Shortt, Niamh K. | Muniz-Terrera, Graciela | Redmond, Paul | Taylor, Adele M. | Clemens, Tom | van Tongeren, Martie | Agius, Raymond M. | Starr, John M. | Deary, Ian J. | Pearce, Jamie R.

Article Type: Research Article

Keywords: Aging, air pollution, Alzheimer’s disease, atmosphere, cognition, dementia, epidemiologic methods

DOI: 10.3233/JAD-200910

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

Authors: Jobin, Benoît | Zahal, Rayane | Bussières, Eve-Line | Frasnelli, Johannes | Boller, Benjamin

Article Type: Research Article

Keywords: Alzheimer’s disease, biomarker, meta-analysis, olfaction, olfactory identification, smell, subjective cognitive decline

DOI: 10.3233/JAD-201022

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Huang, Lei | Zhang, Yang | Wang, Yongwei | Lan, Yajia

Article Type: Research Article

Abstract: Degenerative dementia, of which Alzheimer’s disease is the most common form, is characterized by the gradual deterioration of cognitive function. The events that trigger and promote degenerative dementia are not clear, and treatment options are limited. Experimental and epidemiological studies have revealed chronic noise exposure (CNE) as a potential risk factor for cognitive impairment and degenerative dementia. Experimental studies have indicated that long-term exposure to noise might accelerate cognitive dysfunction, amyloid-β deposition, and tau hyperphosphorylation in different brain regions such as the hippocampus and cortex. Epidemiological studies are increasingly examining the possible association between external noise exposure and dementia. In …this review, we sought to construct a comprehensive summary of the relationship between CNE, cognitive dysfunction, and degenerative dementia. We also present the limitations of existing evidence as a guide regarding important prospects for future research. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognition, dementia, neuropathology, noise, tau

DOI: 10.3233/JAD-201037

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2021

Authors: Park, Jin-Hyuck | Ah Lee, Sang

Article Type: Research Article

Abstract: Background: Although episodic memory impairment is one of the hallmarks of Alzheimer’s disease (AD), the relative decline in the components of episodic memory (What, Where , and When ) and the effects of cognitive training on each of them are still unknown. Objective: We aimed to independently assess the impairment in each component of episodic memory in early to moderate AD and address whether it can be enhanced through active, spatiotemporal episodic training. Methods: A non-verbal scene-based episodic memory task was developed to assess the ability to remember What, Where, and When information. Experiment …1 tested whether this task can differentiate AD subjects (N = 16) from healthy controls (N = 16). In Experiment 2, 13 AD subjects underwent 16 training sessions, followed by a re-administration of the scene-based memory task. Experiment 3 tested 42 healthy older adults and 51 younger adults on the same task to investigate the effects of normal aging. Results: Of the three components, When memory had the highest predictive power in distinguishing AD from normal aging. Following training of AD subjects, only Where memory improved. Only What memory revealed a significant decline in healthy subjects from 65–85 years of age. Conclusion: These findings shed new light on the importance of the temporal component of episodic memory as a behavioral marker of AD. The selective improvement of spatial but not temporal memory through training further demonstrates the fragility of temporal memory even in early AD. Neuroscientific research is needed to distinguish whether the Where component was enhanced by improvements in hippocampal spatial representation or by other compensatory mechanisms. Show more

Keywords: Alzheimer’s disease, cognitive training, episodic memory, temporal order memory, visual scene memory, What-Where-When memory

DOI: 10.3233/JAD-200892

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Hassanin, Hany I. | Tawfik, Heba M. | Zygouris, Stelios | Tsatali, Marianna | Sweed, Hala S. | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: With greying of nations, dementia becomes a public health priority. The rising dementia prevalence escalates both health care expenses and burden, placing the entire healthcare system and caregivers under huge stress. Cognition-oriented interventions have been shown to enhance the overall cognitive performance among healthy and cognitively impaired older adults. Objective: This article is assumed to be a steppingstone for the introduction and establishment of cognition- oriented interventions in Egypt. In addition, it aims to offer provisional guidance for health care providers in Arab speaking countries in a stepwise approach in order to establish cognition-oriented intervention services and …help them to evaluate and monitor their efficacy. Methods: Aconsortium of Egyptian and Greek specialists developed a protocol for the operations of the Ain Shams Cognitive Training Lab and the provision of cognition-oriented interventions. This protocol is based on a previous successful protocol that has been implemented in Greece for more than 10 years and is co-designed to fit the needs of older adults in Arabic speaking countries. Results: The types of services offered, their objectives, recruitment of participants, delivery of interventions, measurement of outcomes and privacy policy are all outlined in the policy. Conclusion: Establishing the appropriate framework in which cognitive training strategies can be adapted and implemented in Arabic population, constitutes an inevitable achievement in healthy ageing and can be also assumed as a dementia prevention strategy. Moreover, setting up the first cognitive laboratory in Egypt older adults, can be a model of good practice across the Arabic countries. Show more

Keywords: Aging, Alzheimer’s disease, cognitive remediation, computers, dementia, memory disorders, mild cognitive impairment, psychosocial support systems, web-based intervention

DOI: 10.3233/JAD-201278

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Hyun Lee, Yang | Jeon, Seun | Soo Yoo, Han | Jong Chung, Seok | Ho Jung, Jin | Baik, Kyoungwon | Sohn, Young H. | Hyu Lee, Phil | Yun, Mijin | Evans, Alan C. | Seok Ye, Byoung

Article Type: Research Article

Abstract: Background: The relationship among amyloid-β (Aβ) deposition on amyloid positron emission tomography (PET), cortical metabolism on 18 F-fluoro-2-deoxy-D-glucose (FDG)-PET, and clinical diagnosis has not been elucidated for both Alzheimer’s disease (AD) and Lewy body disease (LBD). Objective: We investigated the patterns of cerebral metabolism according to the presence of AD and LBD. Methods: A total of 178 subjects were enrolled including 42 pure AD, 32 pure LBD, 34 Lewy body variant AD (LBVAD), 15 LBD with amyloid, 26 AD with dementia with Lewy bodies (DLB), and 29 control subjects. Pure AD, LBVAD, and AD with DLB …groups had biomarker-supported diagnoses of typical AD, while pure LBD, LBD with amyloid, and AD with DLB groups had biomarker-supported diagnoses of typical LBD. Typical AD and LBD with amyloid showed amyloid-positivity on 18 F-florbetaben (FBB) PET, while typical LBD and LBVAD had abnormalities on dopamine transporter PET. We measured regional patterns of glucose metabolism using FDG-PET and evaluated their relationship with AD and LBD. Results: Compared with control group, typical AD and typical LBD commonly exhibited hypometabolism in the bilateral temporo-parietal junction, precuneus, and posterior cingulate cortex. Typical AD showed an additional hypometabolism in the entorhinal cortex, while patients with dopamine transporter abnormality-supported diagnosis of LBD showed diffuse hypometabolism that spared the sensory-motor cortex. Although the diffuse hypometabolism in LBD also involved the occipital cortex, prominent occipital hypometabolism was only seen in LBD with amyloid group. Conclusion: Combining clinical and metabolic evaluations may enhance the diagnostic accuracy of AD, LBD, and mixed disease cases. Show more

Keywords: Alzheimer’s disease, amyloid, glucose metabolism, lewy body disease

DOI: 10.3233/JAD-201094

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Li, Sen | Yi, Yushan | Cui, Ke | Zhang, Yanqiu | Chen, Yange | Han, Dou | Sun, Ling | Zhang, Xiaohui | Chen, Fei | Zhang, Yixin | Yang, Yufeng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a common cause of dementia among elderly people. Hyperphosphorylation and aggregation of tau correlates with the clinical progression of AD; therefore, therapies targeting the aggregation of tau may have potential applications for anti-AD drug development. Several inhibitors of tau aggregation, including small molecules and antibodies, have been found to decrease the aggregation of tau and the corresponding pathology. Objective: To screen one kind of single-chain variable fragment (scFv) antibody which could inhibit the aggregation of tau and ameliorate its cytotoxicity. Methods/Results: Using phosphorylated tau (pTau) as an antigen, we obtained a …scFv antibody via the screening of a high-capacity phage antibody library. Biochemical analysis revealed that this scFv antibody (scFv T1) had a strong ability to inhibit pTau aggregation both in dilute solutions and under conditions of macromolecular crowding. ScFv T1 could also depolymerize preformed pTau aggregates in vitro . Furthermore, scFv T1 was found to be able to inhibit the cytotoxicity of extracellular pTau aggregates and ameliorate tau-mediated toxicity when coexpressed with a hTauR406W mutant in the eye of transgenic Drosophila flies. Conclusion: This scFv T1 antibody may be a potential new therapeutic agent against AD. Our methods can be used to develop novel strategies against protein aggregation for the treatment of neurodegenerative diseases. Show more

Keywords: Aggregation, Alzheimer’s disease, Drosophila , single-chain variable fragment antibody, tau, tauopathy, toxicity

DOI: 10.3233/JAD-191266

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Magnin, Eloi

Article Type: Research Article

Abstract: Neurodevelopmental and neurodegenerative disorders are both growing major public health topics with similarities and frequent complex interactions with each other. Taking these aspects into account can provide a new point of view on lifelong neurocognitive trajectories. Assessing both neurodevelopmental and neurodegenerative dimensions during cognitive and behavioral clinical assessments is challenging but might improve diagnostic accuracy and physiopathological understanding. It is therefore necessary to understand the lifelong specific neurocognitive trajectory of each patient in order to develop personalized precision cognitive medicine.

Keywords: Atypical dementia, neurodegenerative disorders, neurodevelopmental disorders

DOI: 10.3233/JAD-201207

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Wu, Ruozhen | Gu, Jianlan | Zhou, Dingwei | Tung, Yunn Chyn | Jin, Nana | Chu, Dandan | Hu, Wen | Wegiel, Jerzy | Gong, Cheng-Xin | Iqbal, Khalid | Liu, Fei

Article Type: Research Article

Abstract: Background: Neurofibrillary pathology of abnormally hyperphosphorylated tau spreads along neuroanatomical connections, underlying the progression of Alzheimer’s disease (AD). The propagation of tau pathology to axonally connected brain regions inevitably involves trafficking of seeding-competent tau within the axonal compartment of the neuron. Objective: To determine the seeding activity of tau in cerebral gray and white matters of AD. Methods: Levels of total tau, hyperphosphorylation of tau, and SDS- and β-mercaptoethanol–resistant high molecular weight tau (HMW-tau) in crude extracts from gray and white matters of AD frontal lobes were analyzed by immuno-blots. Tau seeding activity …was quantitatively assessed by measuring RIPA-buffer–insoluble tau in HEK-293FT/Tau151 - 391 cells treated with brain extracts. Results: We found a comparable level of soluble tau in gray matter versus white matter of control brains, but a higher level of soluble tau in gray matter than white matter of AD brains. In AD brains, tau is hyperphosphorylated in both gray and white matters, with a higher level in the former. The extracts of both gray and white matters of AD brains seeded tau aggregation in HEK-293FT/tau151–391 cells but the white matter showed less potency. Seeding activity of tau in brain extracts was positively correlated with the levels of tau hyperphosphorylation and HMW-tau. RIPA-insoluble tau, but not RIPA-soluble tau, was hyperphosphorylated tau at multiple sites. Conclusion: Both gray and white matters of AD brain contain seeding-competent tau that can template aggregation of hyperphosphorylated tau, but the seeding potency is markedly higher in gray matter than in white matter. Show more

Keywords: Alzheimer’s disease, gray matter, propagation of tau pathology, seeding-competent tau, white matter

DOI: 10.3233/JAD-201290

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Erkoyun, Hulya Ulugut | van der Lee, Sven J. | Nijmeijer, Bas | Spaendonk, Rosalina van | Nelissen, Anne | Scarioni, Marta | Dijkstra, Anke | Samancı, Bedia | Gürvit, Hakan | Yıldırım, Zerrin | Tepgeç, Fatih | Bilgic, Basar | Barkhof, Frederik | Rozemuller, Annemieke | van der Flier, Wiesje M. | Scheltens, Philip | Cohn-Hokke, Petra | Pijnenburg, Yolande

Article Type: Research Article

Abstract: Background: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia. Objective: We challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD. Methods: We collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n  = 284) and subsequently …who had a genetic variant (n  = 48) with a diagnosis of rtvFTD (n  = 6) in 2 specialized memory clinics. Results: Genetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n  = 4), GRN (n  = 1), and TARDBP (n  = 1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia. Conclusion: Our results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD. Show more

Keywords: Dementia, frontotemporal dementia, frontotemporal lobar degeneration, genetic, GRN, MAPT, right temporallobe, TARDBP

DOI: 10.3233/JAD-201191

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Innis, Ashley D. | Tolea, Magdalena I. | Galvin, James E.

Article Type: Research Article

Abstract: Background: Mindfulness is the practice of awareness and living in the present moment without judgment. Mindfulness-based interventions may improve dementia-related outcomes. Before initiating interventions, it would be beneficial to measure baseline mindfulness to understand targets for therapy and its influence on dementia outcomes. Objective: This cross-sectional study examined patient and caregiver mindfulness with patient and caregiver rating scales and patient cognitive performance and determined whether dyadic pairing of mindfulness influences patient outcomes. Methods: Individuals (N = 291) underwent comprehensive evaluations, with baseline mindfulness assessed using the 15-item Applied Mindfulness Process Scale (AMPS). Correlation, regression, and …mediation models tested relationships between patient and caregiver mindfulness and outcomes. Results: Patients had a mean AMPS score of 38.0±11.9 and caregivers had a mean AMPS score of 38.9±11.5. Patient mindfulness correlated with activities of daily living, behavior and mood, health-related quality of life, subjective cognitive complaints, and performance on episodic memory and attention tasks. Caregiver mindfulness correlated with preparedness, care confidence, depression, and better patient cognitive performance. Patients in dyads with higher mindfulness had better cognitive performance, less subjective complaints, and higher health-related quality of life (all p -values<0.001). Mindfulness effects on cognition were mediated by physical activity, social engagement, frailty, and vascular risk factors. Conclusion: Higher baseline mindfulness was associated with better patient and caregiver outcomes, particularly when both patients and caregivers had high baseline mindfulness. Understanding the baseline influence of mindfulness on the completion of rating scales and neuropsychological test performance can help develop targeted interventions to improve well-being in patients and their caregivers. Show more

Keywords: Alzheimer’s disease, dementia, inflammation, mild cognitive impairment, mindfulness

DOI: 10.3233/JAD-201292

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2021

Authors: Khan, Mostafa J. | Desaire, Heather | Lopez, Oscar L. | Kamboh, M. Ilyas | Robinson, Renã A.S.

Article Type: Research Article

Abstract: Background: African American/Black adults have a disproportionate incidence of Alzheimer’s disease (AD) and are underrepresented in biomarker discovery efforts. Objective: This study aimed to identify potential diagnostic biomarkers for AD using a combination of proteomics and machine learning approaches in a cohort that included African American/Black adults. Methods: We conducted a discovery-based plasma proteomics study on plasma samples (N  = 113) obtained from clinically diagnosed AD and cognitively normal adults that were self-reported African American/Black or non-Hispanic White. Sets of differentially-expressed proteins were then classified using a support vector machine (SVM) to identify biomarker candidates. …Results: In total, 740 proteins were identified of which, 25 differentially-expressed proteins in AD came from comparisons within a single racial and ethnic background group. Six proteins were differentially-expressed in AD regardless of racial and ethnic background. Supervised classification by SVM yielded an area under the curve (AUC) of 0.91 and accuracy of 86%for differentiating AD in samples from non-Hispanic White adults when trained with differentially-expressed proteins unique to that group. However, the same model yielded an AUC of 0.49 and accuracy of 47%for differentiating AD in samples from African American/Black adults. Other covariates such as age, APOE4 status, sex, and years of education were found to improve the model mostly in the samples from non-Hispanic White adults for classifying AD. Conclusion: These results demonstrate the importance of study designs in AD biomarker discovery, which must include diverse racial and ethnic groups such as African American/Black adults to develop effective biomarkers. Show more

Keywords: African American, Alzheimer’s disease, biomarker, black, discovery, disparities, machine learning, plasma, proteomics, race

DOI: 10.3233/JAD-201318

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Hilal, Saima | Mutsaerts, Henri J.M.M | Ferro, Doeschka A. | Petr, Jan | Kuijf, Hugo J. | Biessels, Geert Jan | Chen, Christopher

Article Type: Research Article

Abstract: Background: Intracranial stenosis (ICS) may contribute to cognitive dysfunction by decreased cerebral blood flow (CBF) which can be measured quantitatively by arterial spin labelling (ASL). Interpretation of CBF measurements with ASL, however, becomes difficult in patients with vascular disease due to prolonged arterial transit time (ATT). Recently, spatial coefficient of variation (sCoV) of ASL signal has been proposed that approximates ATT and utilized as a proxy marker for assessment of hemodynamic status of cerebral circulation. Objective: We investigate the association of ICS with CBF and sCoV parameters and its eventual effects on cognition in a memory clinic population. …Methods: We included 381 patients (mean age = 72.3±7.9 years, women = 53.7%) who underwent 3T MRI and detailed neuropsychological assessment. ICS was defined as≥50% stenosis in any intracranial vessel on 3D Time-of-Flight MR Angiography. Gray matter sCoV and CBF were obtained from 2D EPI pseudo-continuous ASL images. Results: ICS was present in 58 (15.2%) patients. Patients with ICS had higher gray matter sCoV and lower CBF. The association with sCoV remained statistically significant after correction for cardiovascular risk factors. Moreover, ICS was associated with worse performance on visuoconstruction, which attenuated with higher sCoV. Mediation analysis showed that there was an indirect effect of ICS on visuoconstruction via sCoV. Conclusion: These findings suggest that compromised CBF as detected by higher sCoV is related to cognitive impairment among individuals diagnosed with ICS. We also showed that sCoV partially mediates the link between ICS and cognition. Therefore, sCoV may provide valuable hemodynamic information in patients with vascular disease. Show more

Keywords: Arterial spin labeling, cerebral perfusion, coefficient of variation, cognition, intracranial stenosis

DOI: 10.3233/JAD-201131

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Ahmed, Mehnaz | Herrmann, Nathan | Chen, Jinghan Jenny | Saleem, Mahwesh | Oh, Paul I. | Andreazza, Ana C. | Kiss, Alexander | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress. Objective: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory. Methods: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2 peak ) assessments and plasma were …collected at baseline and 24-weeks. Results: GPX was higher in VCIND compared to CN (F1,119  = 3.996, p  = 0.048). Higher GPX was associated with poorer baseline VM (β= –0.182, p  = 0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2 peak , and education (b[SE] = –0.02[0.01], p  = 0.004). Only CN participants showed improved VM performance with increased fitness (b[SE] = 1.30[0.15], p  <  0.005). Conclusion: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness. Show more

Keywords: Alzheimer’s disease, coronary artery disease, dementia, glutathione peroxidase, cognition, vascular cognitive impairment

DOI: 10.3233/JAD-200754

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Yan, Yibing | Wu, Xingqi | Wang, Xiaojing | Geng, Zhi | Wang, Lu | Xiao, Guixian | Wu, Yue | Zhou, Shanshan | Wei, Ling | Tian, Yanghua | Wang, Kai

Article Type: Research Article

Abstract: Background: There is increasing evidence that Alzheimer’s disease (AD) patients may present decreased cerebral blood perfusion before pathological brain changes. Using the retina as a window to the brain, we can study disorders of the central nervous system through the eyes. Objective: This study aimed to investigate differences in retinal structure and vessel density (VD) between patients with mild AD and healthy controls (HCs). Furthermore, we explored the relationship between retinal VD and cognitive function. Methods: We enrolled 37 patients with AD and 29 age-matched HCs who underwent standard ophthalmic optical coherence tomography angiography (OCTA) for …evaluation of the retinal layer thickness and VD parameters. Cognitive function was evaluated using a battery of neuropsychological assessments. Finally, the correlations among retinal layer thickness, VD parameters, and cognitive function were evaluated. Results: The retinal fiber layer thickness and retinal VD of patients with AD were significantly reduced compared with HCs. The retinal VD was significantly correlated with overall cognition, memory, executive, and visual-spatial perception functions. However, there was no significant between-group difference in the macular thickness. Conclusion: Our findings indicate a positive correlation between retinal VD and some, but not all, cognitive function domains. Most importantly, we demonstrated the role of OCTA in detecting early capillary changes, which could be a noninvasive biomarker for early AD. Show more

Keywords: Alzheimer’s disease, biomarker, cognitive function, optical coherence tomography angiography, vessel density

DOI: 10.3233/JAD-200971

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Jing, Jiaojiao | Zhang, Feng | Zhao, Li | Xie, Jinghui | Chen, Jianwen | Zhong, Rujia | Zhang, Yanjun | Dong, Chunbo

Article Type: Research Article

Abstract: Background: Florbetapir (AV45) and fluorodeoxyglucose (FDG) PET imaging are valuable techniques to detect the amyloid-β (Aβ) load and brain glucose metabolism in patients with Alzheimer’s disease (AD). Objective: The purpose of this study is to access the characteristics of Aβ load and FDG metabolism in brain for further investigating their relationships with cognitive impairment in AD patients. Methods: Twenty-seven patients with AD (average 70.6 years old, N = 13 male, N = 14 female) were enrolled in this study. These AD patients underwent the standard clinical assessment and received detailed imaging examinations of the nervous system by using Mini-Mental State …Examination (MMSE), Montreal Cognitive Assessment (MOCA), 18 F-AV45, and 18 F-FDG PET scans. Results: Of 27 AD patients, 22 patients (81.5%) showed significantly increases in Aβ load and 26 patients (96.3%) had significantly reductions in FDG metabolism. The moderate AD patients had more brain areas of reduced FDG metabolism and more severe reductions in some regions compared to mild AD patients, with no differences in Aβ load observed. Moreover, the range and degree of reduced FDG metabolism in several regions were positively correlated with the total score of MMSE or MOCA, whereas the range of Aβ load did not. No correlation was found between the range of Aβ load and the range of reduced FDG metabolism in this study. Conclusion: The reduction in FDG metabolisms captured by 18 F-FDG imaging can be used as a potential biomarker for AD diagnosis in the future. 18 F-AV45 imaging did not present valuable evidence for evaluating AD patient in this study. Show more

Keywords: Alzheimer’s disease, amyloid-β load, AV45, glucose metabolism, PET

DOI: 10.3233/JAD-201335

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Sharma, Manu J. | Callahan, Brandy L.

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is considered by some to be a prodromal phase of a progressive disease (i.e., neurodegeneration) resulting in dementia; however, a substantial portion of individuals (ranging from 5–30%) remain cognitively stable over the long term (sMCI). The etiology of sMCI is unclear but may be linked to cerebrovascular disease (CVD), as evidence from longitudinal studies suggest a significant proportion of individuals with vasculopathy remain stable over time. Objective: To quantify the presence of neurodegenerative and vascular pathologies in individuals with long-term (>5-year) sMCI, in a preliminary test of the hypothesis that CVD may be …a contributor to non-degenerative cognitive impairment. We expect frequent vasculopathy at autopsy in sMCI relative to neurodegenerative disease, and relative to individuals who convert to dementia. Methods: In this retrospective study, using data from the National Alzheimer’s Coordinating Center, individuals with sMCI (n  = 28) were compared to those with MCI who declined over a 5 to 9-year period (dMCI; n  = 139) on measures of neurodegenerative pathology (i.e., Aβ plaques, neurofibrillary tangles, TDP-43, and cerebral amyloid angiopathy) and CVD (infarcts, lacunes, microinfarcts, hemorrhages, and microbleeds). Results: Alzheimer’s disease pathology (Aβ plaques, neurofibrillary tangles, and cerebral amyloid angiopathy) was significantly higher in the dMCI group than the sMCI group. Microinfarcts were the only vasculopathy associated with group membership; these were more frequent in sMCI. Conclusion: The most frequent neuropathology in this sample of long-term sMCI was microinfarcts, tentatively suggesting that silent small vessel disease may characterize non-worsening cognitive impairment. Show more

Keywords: Autopsy, cerebrovascular, cognition, dementia, longitudinal, neuropathology

DOI: 10.3233/JAD-200829

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Driscoll, Ira | Ma, Yue | Gallagher, Catherine L. | Johnson, Sterling C. | Asthana, Sanjay | Hermann, Bruce P. | Sager, Mark A. | Blennow, Kaj | Zetterberg, Henrik | Carlsson, Cynthia M. | Engelman, Corinne D. | Dubal, Dena B. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: Background: Identification of new genetic variants that modify Alzheimer’s disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset. Objective: To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk. Methods: Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal …to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC ) and heterozygote (KL-VSHET ). Results: In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps ≥0.14). Conclusion: Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, executive function, memory

DOI: 10.3233/JAD-200944

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Atkins, Janice L. | Pilling, Luke C. | Heales, Christine J. | Savage, Sharon | Kuo, Chia-Ling | Kuchel, George A. | Steffens, David C. | Melzer, David

Article Type: Research Article

Abstract: Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: To estimated p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2 * measures (lower values indicating more iron). Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2 * measures in areas including …the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p  = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes. Show more

Keywords: Cohort, dementia, delirium, gene, hemochromatosis, iron, mutation

DOI: 10.3233/JAD-201080

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Sohrabi, Mona | Pecoraro, Heidi L. | Combs, Colin K.

Article Type: Research Article

Abstract: Background: Although it is known that the brain communicates with the gastrointestinal (GI) tract via the well-established gut-brain axis, the influence exerted by chronic intestinal inflammation on brain changes in Alzheimer’s disease (AD) is not fully understood. We hypothesized that increased gut inflammation would alter brain pathology of a mouse model of AD. Objective: Determine whether colitis exacerbates AD-related brain changes. Methods: To test this idea, 2% dextran sulfate sodium (DSS) was dissolved in the drinking water and fed ad libitum to male C57BL/6 wild type and App NL  - G  - F …mice at 6–10 months of age for two cycles of three days each. DSS is a negatively charged sulfated polysaccharide which results in bloody diarrhea and weight loss, changes similar to human inflammatory bowel disease (IBD). Results: Both wild type and App NL  - G  - F mice developed an IBD-like condition. Brain histologic and biochemical assessments demonstrated increased insoluble Aβ 1–40/42 levels along with the decreased microglial CD68 immunoreactivity in DSS treated App NL  - G  - F mice compared to vehicle treated App NL  - G  - F mice. Conclusion: These data demonstrate that intestinal dysfunction is capable of altering plaque deposition and glial immunoreactivity in the brain. This study increases our knowledge of the impact of peripheral inflammation on Aβ deposition via an IBD-like model system. Show more

Keywords: Alzheimer’s disease, Aβ deposition, dextran sulfate sodium, inflammatory bowel disease, neuroinflammation

DOI: 10.3233/JAD-201099

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: GjØra, Linda | Heine Strand, BjØrn | Bergh, Sverre | Borza, Tom | Brækhus, Anne | Engedal, Knut | Johannessen, Aud | Kvello-Alme, Marte | Krokstad, Steinar | Livingston, Gill | Matthews, Fiona E. | Myrstad, Christian | Skjellegrind, Håvard | Thingstad, Pernille | Aakhus, Eivind | Aam, Stina | Selbæk, Geir

Article Type: Research Article

Abstract: Background: Having accurate, up-to-date information on the epidemiology of mild cognitive impairment (MCI) and dementia is imperative. Objective: To determine the prevalence of MCI and dementia in Norway using data from a large population-based study. Methods: All people 70 + years of age, n  = 19,403, in the fourth wave of the Trøndelag Health Study (HUNT4) were invited to participate in the study HUNT4 70 + . Trained health personnel assessed participants using cognitive tests at a field station, at homes, or at their nursing home. Interviewers also completed a structured carer questionnaire in regard to participants suspected of having dementia. …Clinical experts made diagnoses according to DSM-5 criteria. We calculated prevalence weighing the data to ensure population representativeness. Results: A total of 9,930 (51.1%) of the possible 19,403 people participated, and 9,663 of these had sufficient information for analysis. Standardized prevalence of dementia and MCI was 14.6% (95% confidence interval (CI) 13.9–15.4) and 35.3% (95% CI 34.3–36.4), respectively. Dementia was more prevalent in women and MCI more prevalent in men. The most prevalent dementia subtype was Alzheimer’s disease (57%). By adding data collected from a study of persons ≤70 years in the same region, we estimate that there are 101,118 persons with dementia in Norway in 2020, and this is projected to increase to 236,789 and 380,134 in 2050 and 2100, respectively. Conclusion: We found a higher prevalence of dementia and MCI than most previous studies. The present prevalence and future projections are vital for preparing for future challenges to the healthcare system and the entire society. Show more

Keywords: Alzheimer’s disease, dementia, epidemiology, population study, prevalence

DOI: 10.3233/JAD-201275

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Themistocleous, Charalambos | Ficek, Bronte | Webster, Kimberly | den Ouden, Dirk-Bart | Hillis, Argye E. | Tsapkini, Kyrana

Article Type: Research Article

Abstract: Background: The classification of patients with primary progressive aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists. Objective: The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA. Methods: In this paper, we present a machine learning model based on deep neural networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via …acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as to expert clinicians’ classifications. Results: The DNN model outperformed the other machine learning models as well as expert clinicians’ classifications with 80% classification accuracy. Importantly, 90% of patients with nfvPPA and 95% of patients with lvPPA was identified correctly, providing reliable subtyping of these patients into their corresponding PPA variants. Conclusion: We show that the combined speech and language markers from connected speech productions can inform variant subtyping in patients with PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick, and inexpensive classification of patients with PPA. Show more

Keywords: Classification, machine learning, natural language processing, primary progressive aphasia

DOI: 10.3233/JAD-201101

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Fernández-Matarrubia, Marta | Goni, Leticia | Rognoni, Teresa | Razquin, Cristina | Fernández-Lázaro, César Ignacio | Bes-Rastrollo, Maira | Martínez-González, Miguel Ángel | Toledo, Estefanía

Article Type: Research Article

Abstract: Background: Available evidence on the association of physical activity (PA) or sedentary behavior with cognitive decline is inconclusive. Objective: To assess the association between an active lifestyle score and leisure-time physical activity (LTPA) and changes in cognitive function in the Seguimiento Universidad de Navarra (SUN) prospective cohort. Methods: Cognitive function was evaluated in a subsample of 806 participants of the SUN cohort study using the validated Telephone Interview for Cognitive Status-modified (STICS-m) questionnaire at baseline and after 6 years. LTPA was evaluated with a previously validated 17-item self-administered questionnaire and with information on sedentary lifestyles. We …also calculated a multidimensional 8-item PA score. Multivariable linear regression analysis evaluated the association between PA and changes in cognitive function and its interaction by APOE genotype. Results: Mean age of participants was 66 (SD 5.3) years and 69.7% were male. When stratifying by APOE variants, no significant associations between the active lifestyle score or LTPA and changes in cognitive performance over time were found among APOE ɛ4 carriers. However, we observed that a higher adherence to an active lifestyle (high versus low PA score β= 0.76 95% CI 0.15,1.36; p trend = 0.011) and a high LTPA (Q4 versus Q1 β= 0.63; 95% CI –0.01,1.26; p trend = 0.030) were associated with more favorable changes in cognitive function over time among APOE ɛ4 non-carriers with statistically significant interactions in both cases (p for interaction = 0.042 for PA score, and p  = 0.039 for LTPA). Conclusion: The results of the present study suggest that an active lifestyle is associated with a better status of cognitive function over time only among APOE ɛ4 non-carriers. Show more

Keywords: APOE , cognition, cognitive function, exercise, physical activity, prospective study, sedentarism

DOI: 10.3233/JAD-201090

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Soldevila-Domenech, Natalia | Forcano, Laura | Boronat, Anna | Lorenzo, Thais | Piera, Iris | Puig-Pijoan, Albert | Mateus, Julian | González de Echevarri Gómez, José María | Knezevic, Iva | Soteras, Anna | Fauria, Karine | Pizarro, Nieves | Molinuevo, Jose Luis | de la Torre, Rafael | PENSA Study Group. From IMIM: | From BBRC:

Collaborators: de la Torre, Rafael | Forcano, Laura | Pizarro, Neus | Puig-Pijoan, Albert | Soldevila-Domenech, Natalia | Boronat, Anna | Lorenzo, Thais | Cuenca, Aida | Mateus, Julian | Piera, Iris | Aldea, Ana | Diaz-Pellicer, Patricia | Dierssen, Mara | Gomis, Maria | Molinuevo, Jose Luis | Knezevic, Iva | Menezes-Cabral, Sofia | Soteras, Anna | González-de-Echávarri, José Maria | Sánchez-Benavides, Gonzalo | Gispert, Juan Domingo | Fauria, Karine | Minguillón, Carolina

Article Type: Short Communication

Abstract: We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60–80 years) diagnosed with subjective cognitive decline and APOE ɛ 3/ɛ 4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages …of Alzheimer’s disease should be further evaluated. Show more

Keywords: Alzheimer’s disease, confinement, COVID-19, mental health, subjective cognitive decline

DOI: 10.3233/JAD-201408

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

Authors: Zhu, Lihong | Yuan, Qiongru | Zeng, Zhaohao | Zhou, Ruiyi | Luo, Rixin | Zhang, Jiawei | Tsang, Chi Kwan | Bi, Wei

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) deposition. The metabolism of Aβ is critically affected by autophagy. Although rifampicin is known to mediate neuroinflammation, the underlying mechanism by which rifampicin regulates the cognitive sequelae remains unknown. Objective: Based on our previous findings that rifampicin possesses neuroprotective effects on improving cognitive function after neuroinflammation, we aimed to examine in this study whether rifampicin can inhibit Aβ accumulation by enhancing autophagy in a mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. Methods: Adult C57BL/6 mice were intraperitoneally injected with rifampicin, chloroquine, and/or LPS every day for 7 …days. Pathological and biochemical assays and behavioral tests were performed to determine the therapeutic effect and mechanism of rifampicin on the hippocampus of LPS-induced mice. Results: We found that rifampicin ameliorated cognitive impairments in the LPS-induced mice. In addition, rifampicin attenuated the inhibition of autophagosome formation, suppressed the accumulation of Aβ1–42 , and protected the hippocampal neurons against LPS-induced damage. Our results further demonstrated that rifampicin improved the neurological function by promoting autophagy through the inhibition of Akt/mTOR/p70S6K signaling pathway in the hippocampus of LPS-induced mice. Conclusion: Rifampicin ameliorates cognitive impairment by suppression of Aβ1–42 accumulation through inhibition of Akt/mTOR/p70S6K signaling and enhancement of autophagy in the hippocampus of LPS-induced mice. Show more

Keywords: Alzheimer’s disease, amyloid-β, autophagy, cognitive impairment, neuroinflammation, rifampicin

DOI: 10.3233/JAD-200690

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

Authors: Fu, Zhenrong | Zhao, Mingyan | Wang, Xuetong | He, Yirong | Tian, Yuan | Yang, Yujing | Han, Ying | Li, Shuyu

Article Type: Research Article

Keywords: Brainprint, brain asymmetry, early diagnosis, subjective cognitive decline

DOI: 10.3233/JAD-201116

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

Authors: Benítez, María J. | Cuadros, Raquel | Jiménez, Juan S.

Article Type: Research Article

Abstract: Background: Tau is a microtubule associated protein that regulates the stability of microtubules and the microtubule-dependent axonal transport. Its hyperphosphorylated form is one of the hallmarks of Alzheimer’s disease and other tauopathies and the major component of the paired helical filaments that form the abnormal proteinaceous tangles found in these neurodegenerative diseases. It is generally accepted that the phosphorylation extent of tau is the result of an equilibrium in the activity of protein kinases and phosphatases. Disruption of the balance between both types of enzyme activities has been assumed to be at the origin of tau hyperphosphorylation and the subsequent …toxicity and progress of the disease. Objective: We explore the possibility that, beside the phosphatase action on phosphorylated tau, the catalytic subunit of PKA catalyzes both tau phosphorylation and also tau dephosphorylation, depending on the ATP/ADP ratio. Methods: We use the shift in the relative electrophoretic mobility suffered by different phosphorylated forms of tau, as a sensor of the catalytic action of the enzyme. Results: The results are in agreement with the long-known thermodynamic reversibility of the phosphorylation reaction (ATP + Protein = ADP+Phospho-Protein) catalyzed by PKA and many other protein kinases. Conclusion: The results contribute to put the compartmentalized energy state of the neuron and the mitochondrial-functions disruption upstream of tau-related pathologies. Show more

Keywords: Dephosphorylation, electrophoretic mobility, phosphorylation, PKA, tau protein, thermodynamic reversibility

DOI: 10.3233/JAD-201077

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

Authors: Gonzalez, Christopher | Tommasi, Nicole S. | Briggs, Danielle | Properzi, Michael J. | Amariglio, Rebecca E. | Marshall, Gad A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument –Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models …with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p  <  0.001; inferior temporal: p  <  0.001; dorsolateral prefrontal: p  = 0.01; posterior cingulate: p  = 0.03; precuneus: p  <  0.001; and supramarginal gyrus: p  = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p  = 0.005; amyloid and posterior cingulate tau interaction: p  = 0.005; amyloid and precuneus tau interaction: p  <  0.001; and amyloid and supramarginal tau interaction: p  = 0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD. Show more

Keywords: Alzheimer’s disease, amyloid, financial capacity, instrumental activities of daily living, mild cognitive impairment, positron emission tomography, tau

DOI: 10.3233/JAD-201122

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

Authors: Gruters, Angélique A. | Ramakers, Inez H.G.B. | Stiekema, Annemarie P.M. | Verhey, Frans R.J. | Kessels, Roy P.C. | de Vugt, Marjolein E.

Article Type: Research Article

Abstract: Background: Neuropsychological feedback is an important part of the neuropsychological assessment process. However, patients have difficulties remembering this information. Objective: The aim of this study was to develop a web-based visual tool to improve the understanding of neuropsychological results, information retention, and psychologist-patient communication. Methods: The visual tool was developed and optimized using an iterative three-phase stepwise approach to determine its usability, technology acceptance, and feasibility in a memory clinic population. Feedback from different user perspectives (patients, family members, and psychologists) was obtained in each phase using a multimethod approach (e.g., a multidisciplinary brainstorm session, think-aloud …sessions, focus groups). The prototype was subsequently tested in a pilot study. Results: The first phases offered insights that led to optimization of the prototype. On a scale ranging from 0 to 100, psychologists evaluated the usability as high [88.1±7.6,70–87]. During the pilot study, both patients and significant others gave positive feedback, but information retention in patients remained low. All participants thought the benefits of the visual tool included seeing cognitive strengths and weaknesses with a translation to daily life all at one glance and receiving feedback on paper to take home. Important barriers were mentioned by psychologists, such as a limited set of tests included and no integration with hospital systems. Conclusion: Overall, patients, family members, and psychologists reported that a visual display of the cognitive profile with insights into daily life had added value to clinical practice. Feedback from the pilot study was adopted in the tool for future implementation purposes. Show more

Keywords: Communication, dementia, neuropsychological tests, neuropsychology, visual aids

DOI: 10.3233/JAD-201128

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

Authors: Nozaki, Shoko | Sawada, Norie | Matsuoka, Yutaka J. | Shikimoto, Ryo | Mimura, Masaru | Tsugane, Shoichiro

Article Type: Research Article

Abstract: Background: The relationship between midlife dietary habits and risk of dementia remains unclear. Objective: To investigate the association between dietary fish and n-3 polyunsaturated fatty acid (PUFA) consumption in midlife and risk of dementia in later life. Methods: This population-based cohort study assessed food frequency (average intake in 1995 and 2000) and cognition (2014-2015) in 1,127 participants (aged 45–64 in 1995). We used logistic regression analyses to calculate odds ratios (ORs) for dementia and mild cognitive impairment (MCI) diagnoses for consumption quartiles of fish, PUFA-rich fish, total n-3 PUFAs, total n-6 PUFAs, types of PUFAs, and …n-3/n-6 PUFA ratio. Estimated ORs were adjusted for age; sex; education; smoking status; alcohol consumption frequency; physical activity; histories of cancer, myocardial infarction, and diabetes mellitus; and depression. Results: Significantly reduced risks of dementia over non-dementia (MCI plus cognitively normal) were observed in the second (OR = 0.43 (95%CI = 0.20–0.93)), third (OR = 0.22 (95%CI = 0.09–0.54)), and highest quartiles (OR = 0.39 (95%CI = 0.18–0.86)) for fish; the third (OR = 0.39(95%CI = 0.16–0.92)) and highest quartiles (OR = 0.44(95%CI = 0.19–0.98)) for eicosapentaenoic acid (EPA); the second (OR = 0.39(95%CI = 0.18–0.84)), third (OR = 0.30(95%CI = 0.13–0.70)), and highest quartiles (OR = 0.28(95%CI = 0.12–0.66)) for docosahexaenoic acid (DHA); and the third (OR = 0.36 (95%CI = 0.16–0.85)) and highest quartiles (OR = 0.42 (95%CI = 0.19–0.95)) for docosapentaenoic acid (DPA). Conclusion: High intake of fish in midlife might aid in preventing dementia. Show more

Keywords: Cognitive dysfunction, dementia, diet, epidemiology, habits, longitudinal studies, observational study, risk factors, unsaturated fatty acids

DOI: 10.3233/JAD-191313

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

Authors: Ryan, Margaret | Tan, Valerie T.Y. | Thompson, Nasya | Guévremont, Diane | Mockett, Bruce G. | Tate, Warren P. | Abraham, Wickliffe C. | Hughes, Stephanie M. | Williams, Joanna

Article Type: Research Article

Abstract: Background: Secreted amyloid precursor protein-alpha (sAPPα) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-β toxicity. In a significant step toward validating sAPPα as a therapeutic for Alzheimer’s disease (AD), we demonstrated that long-term overexpression of human sAPPα (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. Objective: To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPPα-treated APP/PS1 mice. Methods: We assessed the long-term effects on the hippocampal …transcriptome following continuous lentiviral delivery of sAPPα or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). Results: Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPPα-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter, and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival, and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPPα activation of Interleukin-4, which can counteract inflammatory changes in AD. Conclusion: This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPPα levels in vivo Show more

Keywords: Alzheimer’s disease, drug development, oligonucleotide array, real-time polymerase chain reaction, transcriptome, transgenic mouse

DOI: 10.3233/JAD-200757

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

Authors: Barthelson, Karissa | Pederson, Stephen Martin | Newman, Morgan | Lardelli, Michael

Article Type: Research Article

Abstract: Background: The early cellular stresses leading to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1 ) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic, late-onset AD (LOAD). SORL1 protein has been shown to act in the trafficking of the amyloid β A4 precursor protein (AβPP) that is proteolysed to form one of the pathological hallmarks of AD, amyloid-β (Aβ) peptide. However, other functions of SORL1 in AD are less well understood. Objective: To investigate …the effects of heterozygosity for an EOfAD-like mutation in SORL1 on the brain transcriptome of young-adult mutation carriers using zebrafish as a model organism. Methods: We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1 and performed RNA-sequencing on mRNA isolated from the young adult brains of siblings in a family of fish either wild type (non-mutant) or heterozygous for the EOfAD-like mutation. Results: We identified subtle differences in gene expression indicating changes in mitochondrial and ribosomal function in the mutant fish. These changes appear to be independent of changes in mitochondrial content or the expression of AβPP-related proteins in zebrafish. Conclusion: These findings provided evidence supporting that EOfAD mutations in SORL1 affect mitochondrial and ribosomal function and provide the basis for future investigation elucidating the nature of these effects. Show more

Keywords: Alzheimer’s disease, mitochondria, ribosome, RNA-seq, sorl1, zebrafish

DOI: 10.3233/JAD-201383

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

Authors: Kumon, Hiroshi | Yoshino, Yuta | Funahashi, Yu | Mori, Hiroaki | Ueno, Mariko | Ozaki, Yuki | Yamazaki, Kiyohiro | Ochi, Shinichiro | Mori, Takaaki | Iga, Jun-ichi | Nagai, Masahiro | Nomoto, Masahiro | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background: Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a validated genetic risk factor for late-onset Alzheimer’s disease (AD) and is associated with other neurodegenerative diseases. However, PICALM expression in the blood of neurodegenerative diseases remains elusive. Objective: This study aimed to assess the usefulness of PICALM expression levels in the blood of patients with AD, Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and geriatric major depressive disorder (MDD) as a diagnostic biomarker. Methods: In total, 45, 20, 21, and 19 patients with AD, PD, DLB, and geriatric MDD, respectively, and 54 healthy controls (HCs) were …enrolled in the study. Expression data from Gene Expression Omnibus database (GSE97760), (GSE133347) and (GSE98793), (GSE48350), and (GSE144459) were used to validate the ability of biomarkers in the blood of patients with AD, PD, geriatric MDD, and a postmortem human AD brain and animal model of AD (3xTg-AD mouse), respectively. Results: PICALM mRNA expression in human blood was significantly increased in patients with AD compared with that in HCs. PICALM mRNA expression and age were negatively correlated only in patients with AD. PICALM mRNA expression in human blood was significantly lower in patients with PD than in HCs. No changes in PICALM mRNA expression were found in patients with DLB and geriatric MDD. Conclusion: PICALM mRNA expression in blood was higher in patients with AD, but lower in patients with PD, which suggests that PICALM mRNA expression in human blood may be a useful biomarker for differentiating neurodegenerative diseases and geriatric MDD. Show more

Keywords: Alzheimer’s disease, blood, gene expression, major depressive disorder, phosphatidylinositol-binding clathrin assembly protein

DOI: 10.3233/JAD-201046

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

Authors: Trumbore, Conrad N.

Article Type: Other

Abstract: Amyloid-β (Aβ) and tau oligomers have been identified as neurotoxic agents responsible for causing Alzheimer’s disease (AD). Clinical trials using Aβ and tau as targets have failed, giving rise to calls for new research approaches to combat AD. This paper provides such an approach. Most basic AD research has involved quiescent Aβ and tau solutions. However, studies involving laminar and extensional flow of proteins have demonstrated that mechanical agitation of proteins induces or accelerates protein aggregation. Recent MRI brain studies have revealed high energy, chaotic motion of cerebrospinal fluid (CSF) in lower brain and brainstem regions. These and studies showing …CSF flow within the brain have shown that there are two energetic hot spots. These are within the third and fourth brain ventricles and in the neighborhood of the circle of Willis blood vessel region. These two regions are also the same locations as those of the earliest Aβ and tau AD pathology. In this paper, it is proposed that cardiac systolic pulse waves that emanate from the major brain arteries in the lower brain and brainstem regions and whose pulse waves drive CSF flows within the brain are responsible for initiating AD and possibly other amyloid diseases. It is further proposed that the triggering of these diseases comes about because of the strengthening of systolic pulses due to major artery hardening that generates intense CSF extensional flow stress. Such stress provides the activation energy needed to induce conformational changes of both Aβ and tau within the lower brain and brainstem region, producing unique neurotoxic oligomer molecule conformations that induce AD. Show more

Keywords: Amyloid-β, arteries, atherosclerosis, cerebrospinal fluid, extensional flow, fluid flow stress, heart failure, oligomer, shear, strain, systolic pulse, tau, ventricles

DOI: 10.3233/JAD-201025

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2020

Authors: Chatterjee, Pratishtha | Fagan, Anne M. | Xiong, Chengjie | McKay, Matthew | Bhatnagar, Atul | Wu, Yunqi | Singh, Abhay K. | Taddei, Kevin | Martins, Ian | Gardener, Samantha L. | Molloy, Mark P. | Multhaup, Gerhard | Masters, Colin L. | Schofield, Peter R. | Benzinger, Tammie L.S. | Morris, John C. | Bateman, Randall J. | Greenberg, Steven M. | Wermer, Marieke J.H. | van Buchem, Mark A. | Sohrabi, Hamid R. | Martins, Ralph N. | Dominantly Inherited Alzheimer Network

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. Objective: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). Methods: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple …comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). Results: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p  < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aβ40 (rs = 0.621, p = 0.024), CSF Aβ42 (rs = 0.714, p = 0.006), and brain Aβ load (rs = –0.527, p = 0.030). Conclusion: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia. Show more

Keywords: Blood biomarkers, cerebral amyloid angiopathy, early diagnosis, hereditary cerebral hemorrhage with amyloidosis - dutch type, intracerebral hemorrhage, metabolomics, vascular dementia

DOI: 10.3233/JAD-201267

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

Authors: Bao, Yi-Wen | Chau, Anson C.M. | Chiu, Patrick Ka-Chun | Shea, Yat Fung | Kwan, Joseph S.K. | Chan, Felix Hon Wai | Mak, Henry Ka-Fung

Article Type: Research Article

Abstract: Background: With the more widespread use of 18F-radioligand-based amyloid-β (Aβ) PET-CT imaging, we evaluated Aβ binding and the utility of neocortical 18 F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. Objective: 18 F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer’s disease (AD), and 2) MCI from other non-AD dementias (OD). Methods: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18 F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included …13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). Results: The global mean 18 F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aβ binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. Conclusion: 18 F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, early-onset Alzheimer’s disease, 18F-Flutemetamol, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-200890

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

Authors: Streit, Wolfgang J. | Khoshbouei, Habibeh | Bechmann, Ingo

Article Type: Review Article

Abstract: Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade …theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea. Show more

Keywords: Aging, dystrophy, late-onset Alzheimer’s disease, neurodegeneration, neuroinflammation, senescence

DOI: 10.3233/JAD-201248

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

Authors: Futamura, Akinori | Hieda, Sotaro | Mori, Yukiko | Sugimoto, Azusa | Kasai, Hideyo | Kuroda, Takeshi | Yano, Satoshi | Kasuga, Kensaku | Murakami, Hidetomo | Ikeuchi, Takeshi | Ono, Kenjiro

Article Type: Short Communication

Abstract: We compared ‘CIScore’ determined by quantitative single photon emission computed tomography studies of the cingulate island sign to cerebrospinal fluid (CSF) biomarkers in Lewy body disease (LBD) and Alzheimer’s disease (AD) to assess its usefulness and pathological background. Among the 16 each age-matched LBD and AD patients, the CIScore differed significantly but was not correlated with CSF biomarkers. In LBD, hippocampal atrophy significantly correlated with Clinical Dementia Rating and CSF p-tau and t-tau levels. Our results showed CIS was not related to CSF biomarkers in LBD and high CSF tau levels were related to clinical disease severity and hippocampal atrophy.

Keywords: Alzheimer’s disease, amyloid β-protein 42, cingulate island sign, Lewy body disease, medial temporal atrophy, phosphorylated tau protein

DOI: 10.3233/JAD-201145

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

Authors: McGrattan, Andrea M. | Zhu, Yueping | Richardson, Connor D. | Mohan, Devi | Soh, Yee Chang | Sajjad, Ayesha | Aller, Carla van | Chen, Shulin | Paddick, Stella-Maria | Prina, Matthew | Siervo, Mario | Robinson, Louise A. | Stephan, Blossom C.M.

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a cognitive state associated with increased risk of dementia. Little research on MCI exists from low-and middle-income countries (LMICs), despite high prevalence of dementia in these settings. Objective: This systematic review aimed to review epidemiological reports to determine the prevalence of MCI and its associated risk factors in LMICs. Methods: Medline, Embase, and PsycINFO were searched from inception until November 2019. Eligible articles reported on MCI in population or community-based studies from LMICs. No restrictions on the definition of MCI used as long as it was clearly defined. …Results: 4,621 articles were screened, and 78 retained. In total, n  = 23 different LMICs were represented; mostly from China (n  = 55 studies). Few studies from countries defined as lower-middle income (n  = 14), low income (n  = 4), or from population representative samples (n  = 4). There was large heterogeneity in how MCI was diagnosed; with Petersen criteria the most commonly applied (n  = 26). Prevalence of aMCI (Petersen criteria) ranged from 0.6%to 22.3%. Similar variability existed across studies using the International Working Group Criteria for aMCI (range 4.5%to 18.3%) and all-MCI (range 6.1%to 30.4%). Risk of MCI was associated with demographic (e.g., age), health (e.g., cardio-metabolic disease), and lifestyle (e.g., social isolation, smoking, diet and physical activity) factors. Conclusion: Outside of China, few MCI studies have been conducted in LMIC settings. There is an urgent need for population representative epidemiological studies to determine MCI prevalence in LMICs. MCI diagnostic methodology also needs to be standardized. This will allow for cross-study comparison and future resource planning. Show more

Keywords: Epidemiology, low-and middle-income country,, mild cognitive impairment, prevalence, risk factors, systematic review

DOI: 10.3233/JAD-201043

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

Authors: Hoang, Minh Tuan | Kåreholt, Ingemar | von Euler, Mia | von Koch, Lena | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Patient dissatisfaction with stroke care is associated with poor self-rated health and unmet care needs. Dementia patients’ satisfaction with stroke care is understudied. Objective: To compare satisfaction with stroke care in patients with and without dementia. Methods: This longitudinal cohort study included 5,932 dementia patients (2007–2017) who suffered a first stroke after dementia diagnosis and 39,457 non-dementia stroke patients (2007–2017). Data were retrieved by linking the Swedish Stroke Register, the Swedish Dementia Register, the Swedish National Patient Register, and the Swedish Prescribed Drug Register. The association between dementia and satisfaction was analyzed with ordinal logistic …regression. Results: When dementia patients answered themselves, they reported significantly lower odds of satisfaction with acute stroke care (OR: 0.71; 95% CI: 0.60–0.85), healthcare staff’s attitude (OR: 0.79; 95% CI: 0.66–0.96), communication with doctors (OR: 0.78; 95% CI: 0.66–0.92), stroke information (OR: 0.62; 95% CI: 0.52–0.74); but not regarding inpatient rehabilitation (OR: 0.93; 95% CI: 0.75–1.16), or outpatient rehabilitation (OR: 0.93; 95% CI: 0.73–1.18). When patients answered with caregivers’ help, the association between dementia status and satisfaction remained significant in all items. Subgroup analyses showed that patients with Alzheimer’s disease and mixed dementia reported lower odds of satisfaction with acute care and healthcare staff’s attitude when they answered themselves. Conclusion: Patients with dementia reported lower satisfaction with stroke care, revealing unfulfilled care needs among dementia patients, which are possibly due to different (or less) care, or because dementia patients require adaptations to standard care. Show more

Keywords: Care, dementia, patient-reported, rehabilitation, satisfaction, stroke

DOI: 10.3233/JAD-200976

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

Authors: Balea-Fernandez, Francisco Javier | Martinez-Vega, Beatriz | Ortega, Samuel | Fabelo, Himar | Leon, Raquel | Callico, Gustavo M. | Bibao-Sieyro, Cristina

Article Type: Research Article

Abstract: Background: Sociodemographic data indicate the progressive increase in life expectancy and the prevalence of Alzheimer’s disease (AD). AD is raised as one of the greatest public health problems. Its etiology is twofold: on the one hand, non-modifiable factors and on the other, modifiable. Objective: This study aims to develop a processing framework based on machine learning (ML) and optimization algorithms to study sociodemographic, clinical, and analytical variables, selecting the best combination among them for an accurate discrimination between controls and subjects with major neurocognitive disorder (MNCD). Methods: This research is based on an observational-analytical design. Two …research groups were established: MNCD group (n  = 46) and control group (n  = 38). ML and optimization algorithms were employed to automatically diagnose MNCD. Results: Twelve out of 37 variables were identified in the validation set as the most relevant for MNCD diagnosis. Sensitivity of 100%and specificity of 71%were achieved using a Random Forest classifier. Conclusion: ML is a potential tool for automatic prediction of MNCD which can be applied to relatively small preclinical and clinical data sets. These results can be interpreted to support the influence of the environment on the development of AD. Show more

Keywords: Alzheimer’s disease, machine learning, neurocognitive disorders, risk factors

DOI: 10.3233/JAD-200955

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Babulal, Ganesh M. | Johnson, Ann | Fagan, Anne M. | Morris, John C. | Roe, Catherine M.

Article Type: Research Article

Abstract: We examined whether driving behavior can predict preclinical Alzheimer’s disease (AD). Data from 131 cognitively normal older adults with cerebrospinal fluid (CSF) and/or positron emission tomography (PET) biomarkers were examined with naturalistic driving behavior. Receiver operating characteristic curves were used to predict the highest 10%, 25%, and 50% of values for CSF tau/Aβ42 , ptau181 /Aβ42 , or amyloid PET. Six in vivo driving variables alone yielded area under the curves (AUC) from 0.64–0.82. Addition of age, Apolipoprotein ɛ 4, and neuropsychological measures to the models improved the AUC (0.81 to 0.90). Driving can be used as novel neurobehavioral …marker to identify presence of preclinical AD. Show more

Keywords: Aging drivers, Alzheimer’s disease, biomarkers, driving decline, preclinical

DOI: 10.3233/JAD-201294

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

Authors: Gabrielyan, Lilit | Liang, Honghui | Minalyan, Artem | Hatami, Asa | John, Varghese | Wang, Lixin

Article Type: Research Article

Abstract: Background: Alpha-synuclein (α-syn) is a molecule involved in pathology of Parkinson’s disease, and 90%of α-syn in Lewy bodies is phosphorylated at serine 129 (pS129 α-syn). Objective: To assess motor and non-motor behaviors in male and female mice overexpressing human α-syn under Thy1 promoter (Thy1-α-syn) and wild type (wt) littermates. Methods: Motor and non-motor behaviors brain human α-syn levels by ELISA, and mapped α-syn and pS129 α-syn in the brain by immunohistochemistry. Results: Male and female wt littermates did not show differences in the behavioral tests. Male Thy1-α-syn mice displayed more severe impairments than female …counterparts in cotton nesting, pole tests, adhesive removal, finding buried food, and marble burying. Concentrations of human α-syn in the olfactory regions, cortex, nigrostriatal system, and dorsal medulla were significantly increased in Thy1-α-syn mice, higher in males than females. Immunoreactivity of α-syn was not simply increased in Thy1-α-syn mice but had altered localization in somas and fibers in a few brain areas. Abundant pS129 α-syn existed in many brain areas of Thy1-α-syn mice, while there was none or only a small amount in a few brain regions of wt mice. The substantia nigra, olfactory regions, amygdala, lateral parabrachial nucleus, and dorsal vagal complex displayed different distribution patterns between wt and transgenic mice, but not between sexes. Conclusion: The severer abnormal behaviors in male than female Thy1-α-syn mice may be related to higher brain levels of human α-syn, in the absence of sex differences in the altered brain immunoreactivity patterns of α-syn and pS129 α-syn. Show more

Keywords: α-synuclein, behavior, brain, mouse, phosphorylated serine-129 α-synuclein, synucleinopathy

DOI: 10.3233/JAD-200983

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

Authors: Tham, Rachel | Schikowski, Tamara

Article Type: Review Article

Abstract: Traffic-related air pollution is ubiquitous and almost impossible to avoid. It is important to understand the role that traffic-related air pollution may play in neurodegenerative diseases, such as dementia, Alzheimer’s disease, and Parkinson’s disease, particularly among older populations and at-risk groups. There is a growing interest in this area among the environmental epidemiology literature and the body of evidence identifying this role is emerging and strengthening. This review focuses on the principal components of traffic-related air pollutants (particulate matter and nitrogen oxides) and the epidemiological evidence of their contribution to common neurodegenerative diseases. All studies reported are currently observational in …nature and there are mixed findings depending on the study design, assessment of traffic-related air pollutant levels, assessment of the neurodegenerative disease outcome, time period of assessment, and the role of confounding environmental factors and at-risk genetic characteristics. All current studies have been conducted in income-rich countries where traffic-related air pollution levels are relatively low. Additional longer-term studies are needed to confirm the levels of risk, consider other contributing environmental factors and to be conducted in settings where air pollution exposures are higher and at-risk populations reside and work. Better understanding of these relationships will help inform the development of preventive measures and reduce chronic cognitive and physical health burdens (cost, quality of life) at personal and societal levels. Show more

Keywords: Air pollution, Alzheimer’s disease, dementia, mild cognitive impairment, Parkinson’s disease

DOI: 10.3233/JAD-200813

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

Authors: Tromp, Krista | Smedinga, Marthe | Richard, Edo | Perry, Marieke | Schermer, Maartje H.N.

Article Type: Research Article

Abstract: Background: Hope for future treatments to prevent or slow down dementia motivates researchers to strive for ever-earlier diagnoses of Alzheimer’s disease (AD) based on biomarkers, even before symptoms occur. But is a biomarker-based early diagnosis desirable in clinical practice? Objective: This study explores the ethical considerations that shape current clinical practice regarding early AD diagnostics and the use of biomarkers. Methods: In this qualitative study, Dutch physicians were interviewed. Topics included physicians’ views concerning early AD diagnosis in persons with no or mild cognitive impairment, physicians’ considerations regarding current and expected future practices of early AD …diagnosis, the use of biomarkers, and the use of the concepts preclinical and prodromal AD. We analyzed the transcripts using directed content analysis. Results: 15 general practitioners, neurologists, and geriatricians in the Netherlands were interviewed. Most of them interpreted an early AD diagnosis with an early diagnosis of dementia. We identified six clusters of considerations sometimes in favor but most often against pursuing an early AD diagnosis in people with no or mild cognitive impairment that influence physicians’ diagnostic decision-making: preferences and characteristics of persons, test characteristics, impact on care, type of setting, disease concepts, and issues on a societal level. Conclusion: The discussion concerning an early AD diagnosis based on biomarkers which is widely held in the scientific field, has not entered clinical practice structurally. A biomarker-based early diagnosis does not fit within Dutch physicians’ views on what good care for people with no, subjective, or mild cognitive impairment should entail. Show more

Keywords: Alzheimer’s disease, biomarkers, decision-making, early diagnosis, ethics

DOI: 10.3233/JAD-200884

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

Authors: Wang, Yang-Yang | Yan, Qian | Huang, Zhen-Ting | Zou, Qian | Li, Jing | Yuan, Ming-Hao | Wu, Liang-Qi | Cai, Zhi-You

Article Type: Research Article

Abstract: Background: Berberine (BBR) plays a neuroprotective role in the pathogenesis of Alzheimer’s disease (AD), inhibiting amyloid-β (Aβ) production and promoting Aβ clearance. Advanced glycation end products (AGEs) promote Aβ aggregation and tau hyperphosphorylation. The activation of mTOR signaling occurring at the early stage of AD has a prominent impact on the Aβ production. This work focused on whether BBR regulates the production and clearance of ribosylation-induced Aβ pathology via inhibiting mTOR signaling. Objective: To explore whether BBR ameliorates ribosylation-induced Aβ pathology in APP/PS1 mice. Methods: Western blot and immunofluorescence staining were used to detect the related …proteins of the mammalian target of Rapamycin (mTOR) signaling pathway and autophagy, as well as the related kinases of Aβ generation and clearance. Tissue sections and Immunofluorescence staining were used to observe Aβ42 in APP/PS1 mice hippocampal. Morris water maze test was used to measure the spatial learning and memory of APP/PS1 mice. Results: BBR improves spatial learning and memory of APP/PS1 mice. BBR limits the activation of mTOR/p70S6K signaling pathway and enhances autophagy process. BBR reduces the activity of BACE1 and γ-secretase induced by D-ribose, and enhances Aβ-degrading enzymes and Neprilysin, and inhibits the expression of Aβ in APP/PS1 mice. Conclusion: BBR ameliorates ribosylation-induced Aβ pathology via inhibiting mTOR/p70S6K signaling and improves spatial learning and memory of the APP/PS1 mice. Show more

Keywords: AGEs, Alzheimer’s disease, amyloid-β, autophagy, berberine, mTOR

DOI: 10.3233/JAD-200995

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

Authors: Hirt, Julian | Ballhausen, Nicola | Hering, Alexandra | Kliegel, Matthias | Beer, Thomas | Meyer, Gabriele

Article Type: Research Article

Abstract: Background: Using non-pharmacological interventions is a current approach in dementia care to manage responsive behaviors, to maintain functional capacity, and to reduce emotional stress. Novel technologies such as social robot interventions might be useful to engage people with dementia in activities and interactions as well as to improve their cognitive, emotional, and physical status. Objective: Assessing the effects and the quality of reporting of social robot interventions for people with dementia. Methods: In our systematic review, we included quasi-experimental and experimental studies published in English, French, or German, irrespective of publication year. Searching CINAHL, Cochrane …Library, MEDLINE, PsycINFO, and Web of Science Core Collection was supplemented by citation tracking and free web searching. To assess the methodological quality of included studies, we used tools provided by the Joanna Briggs Institute. To assess the reporting of the interventions, we applied CReDECI 2 and TIDieR. Results: We identified sixteen studies published between 2012 and 2018, including two to 415 participants with mostly non-defined type of dementia. Eight studies had an experimental design. The predominant robot types were pet robots (i.e., PARO). Most studies addressed behavioral, emotion-related, and functional outcomes with beneficial, non-beneficial, and mixed results. Predominantly, cognitive outcomes were not improved. Overall, studies were of moderate methodological quality. Conclusion: Heterogeneous populations, intervention characteristics, and measured outcomes make it difficult to generalize the results with regard to clinical practice. The impact of social robot interventions on behavioral, emotion-related, and functional outcomes should therefore be assessed considering the severity of dementia and intervention characteristics. Show more

Keywords: Dementia, robotics, systematic review, technology

DOI: 10.3233/JAD-200347

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

Authors: Keenan, Ryan J. | Oberrauch, Sara | Bron, Romke | Nowell, Cameron J. | Challis, Leesa M. | Hoyer, Daniel | Jacobson, Laura H.

Article Type: Research Article

Abstract: Background: Sleep/wake disturbances (e.g., insomnia and sleep fragmentation) are common in neurodegenerative disorders, especially Alzheimer’s disease (AD) and frontotemporal dementia (FTD). These symptoms are somewhat reminiscent of narcolepsy with cataplexy, caused by the loss of orexin-producing neurons. A bidirectional relationship between sleep disturbance and disease pathology suggests a detrimental cycle that accelerates disease progression and cognitive decline. The accumulation of brain tau fibrils is a core pathology of AD and FTD-tau and clinical evidence supports that tau may impair the orexin system in AD/FTD. This hypothesis was investigated using tau mutant mice. Objective: To characterize orexin receptor mRNA …expression in sleep/wake regulatory brain centers and quantify noradrenergic locus coeruleus (LC) and orexinergic lateral hypothalamus (LH) neurons, in tau transgenic rTg4510 and tau–/– mice. Methods: We used i n situ hybridization and immunohistochemistry (IHC) in rTg4510 and tau–/– mice. Results: rTg4510 and tau–/– mice exhibited a similar decrease in orexin receptor 1 (OX1 R) mRNA expression in the LC compared with wildtype controls. IHC data indicated this was not due to decreased numbers of LC tyrosine hydroxylase-positive (TH) or orexin neurons and demonstrated that tau invades TH LC and orexinergic LH neurons in rTg4510 mice. In contrast, orexin receptor 2 (OX2 R) mRNA levels were unaffected in either model. Conclusion: The LC is strongly implicated in the regulation of sleep/wakefulness and expresses high levels of OX1 R. These findings raise interesting questions regarding the effects of altered tau on the orexin system, specifically LC OX1 Rs, and emphasize a potential mechanism which may help explain sleep/wake disturbances in AD and FTD. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, in situ hybridization, locus coeruleus, orexin, orexin receptor, rTg4510, sleep, tau

DOI: 10.3233/JAD-201177

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

Authors: Yuan, Jing | Maserejian, Nancy | Liu, Yulin | Devine, Sherral | Gillis, Cai | Massaro, Joseph | Au, Rhoda

Article Type: Research Article

Abstract: Background: Studies providing Alzheimer’s disease (AD) prevalence data have largely neglected to characterize the proportion of AD that is mild, moderate, or severe. Estimates of the severity distribution along the AD continuum, including the mild cognitive impairment (MCI) stage, are important to plan research and allocate future resources, particularly resources targeted at particular stages of disease. Objective: To characterize the distribution of severity of AD dementia and MCI among prevalent cases in the population-based Framingham Heart Study. Methods: Participants (aged 50–94) with prevalent MCI or AD dementia clinical syndrome were cross-sectionally selected from three time-windows of …the population-based Framingham Heart Study in 2004-2005 (n  = 381), 2006-2007 (n  = 422), and 2008-2009 (n  = 389). Summary estimates of the severity distribution were achieved by pooling results across time-windows. Diagnosis and severity were assessed by consensus dementia review. MCI-progressive was determined if the participant had documented progression to AD dementia clinical syndrome using longitudinal data. Results: Among AD dementia participants, the pooled percentages were 50.4%for mild, 30.3%for moderate, and 19.3%for severe. Among all MCI and AD participants, the pooled percentages were 29.5%, 19.6%, 25.7%, and 45.2%for MCI-not-progressive, MCI-progressive, mild AD dementia, and the combined group of MCI-progressive and mild AD dementia, respectively. Distributions by age and sex were presented. Conclusion: The finding that half of the people living with AD have mild disease underscores the need for research and interventions to slow decline or prevent progression of this burdensome disease. Show more

Keywords: Alzheimer’s disease, dementia, epidemiological study, epidemiology, Framingham Heart Study, mild cognitive impairment, prevalence

DOI: 10.3233/JAD-200786

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

Authors: Lage, Carmen | González-Suárez, Andrea | Puerto Alcalde-Hierro, María | Isabel Sampedro-González, María | Ángeles Villanueva-Eguaras, María | Rubén Sánchez-Crespo, Manuel | Widmann, Catherine | Brosseron, Frederic | Pozueta, Ana | López-García, Sara | García-Martínez, María | Kazimierczak, Martha | Bravo-González, María | Fernández-Rodríguez, Andrea | Drake-Pérez, Marta | Irure-Ventura, Juan | López-Hoyos, Marcos | Rodríguez-Rodríguez, Eloy | Heneka, Michael T | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: Background: Major surgery has been associated with perioperative neurocognitive disorders (PND), but the contributing factors and long-term prognosis are uncertain. We hypothesize that preclinical Alzheimer’s disease (AD) might predispose to cognitive deterioration after surgery. Objective: To analyze the effect of amyloid-β on the cognitive trajectory after orthopedic surgery in a sample of non-demented subjects. Methods: Non-demented individuals older than 65 years that were on the waiting list for orthopedic surgery with spinal anesthesia underwent a neuropsychological assessment before and after surgery. During surgery, cerebrospinal fluid samples were obtained to determine AD biomarkers. Results: Cumulative …incidence of PND was 55.2%during a mean follow-up of nine months. The most affected cognitive domains were executive function and constructional praxis. The presence of abnormal levels of amyloid-β was associated to a postoperative impairment in verbal and visual memory tests. According to their AD biomarker profile, participants were categorized as either Amyloid Positive (A +) or Amyloid Negative (A-). The incidence of PND did not differ between both groups. The A- group showed a tendency similar to the global sample, worsening in executive function tests and improving on memory scales due to practice effects. In contrast, the A  + group showed a notable worsening on memory performance. Conclusion: Our findings support the hypothesis that surgery may promote or accelerate memory decline in cognitively asymptomatic subjects with brain amyloid-β deposits. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, biomarkers, dementia, surgery

DOI: 10.3233/JAD-191229

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

Authors: Basta, Maria | Zaganas, Ioannis | Simos, Panagiotis | Koutentaki, Eirini | Dimovasili, Christina | Mathioudakis, Lambros | Bourbouli, Mara | Panagiotakis, Symeon | Kapetanaki, Stefania | Vgontzas, Alexandros

Article Type: Research Article

Abstract: Background: Apolipoprotein E gene (APOE ) ɛ4 allele increases the risk for Alzheimer’s disease (AD). Furthermore, among patients with cognitive impairment, longer sleep duration is associated with worse cognitive performance. To date, literature examining the associations between APOE ɛ4 allele and objective sleep duration is limited. Objective: Our aim was to assess the association between APOE ɛ4 and objective sleep duration, among patients with mild cognitive impairment (MCI) and AD. A sub-sample of 89 patients with AD (n  = 49) and MCI (n  = 40) were recruited from a large, population-based cohort of 3,140 elders (>60 years) residing …on Crete, Greece. Methods: All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24 h actigraphy and APOE ɛ4 allele genotyping. Comparisons of sleep duration variables between APOE ɛ4 allele carriers and non-carriers were assessed using ANCOVA, controlling for confounders. Results: The sample included 18 APOE ɛ4 carriers and 71 non-carriers, aged 78.6±6.6 and 78.2±6.5 years, respectively. Comparisons between the APOE ɛ4 carriers and non-carriers revealed no significant differences in terms of demographic and clinical variables. In terms of objective sleep duration across the two groups, APOE ɛ4 carriers compared to non-carriers had significantly longer nighttime Total Sleep Time (nTST) (7.7±1.4 versus 7.2±1.3  h, respectively, p  = 0.011), as well as 24 h TST (8.5±1.6 versus 7.8±1.5  h, respectively, p  = 0.012). Conclusion: Among patients with MCI and AD, APOE ɛ4 carriers have longer objective nighttime and 24 h sleep duration compared to non-carriers. These findings further support that objective long sleep duration is a genetically-driven pre-clinical marker associated with worse prognosis in elderly with cognitive impairment. Show more

Keywords: Actigraphy, Alzheimer’s disease, cognitive disorders, genetic risk factors, mild cognitive impairment, sleep

DOI: 10.3233/JAD-200958

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

Authors: Park, Yae Won | Choi, Dongmin | Park, Mina | Ahn, Sung Jun | Ahn, Sung Soo | Suh, Sang Hyun | Lee, Seung-Koo | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Noninvasive identification of amyloid-β (Aβ) is important for better clinical management of mild cognitive impairment (MCI) patients. Objective: To investigate whether radiomics features in the hippocampus in MCI improve the prediction of cerebrospinal fluid (CSF) Aβ 42 status when integrated with clinical profiles. Methods: A total of 407 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative were allocated to training (n  = 324) and test (n  = 83) sets. Radiomics features (n  = 214) from the bilateral hippocampi were extracted from magnetic resonance imaging (MRI). A cut-off of <192 pg/mL was applied to define CSF Aβ 42 …status. After feature selection, random forest with subsampling methods were utilized to develop three models with which to predict CSF Aβ 42 : 1) a radiomics model; 2) a clinical model based on clinical profiles; and 3) a combined model based on radiomics and clinical profiles. The prediction performances thereof were validated in the test set. A prediction model using hippocampus volume was also developed and validated. Results: The best-performing radiomics model showed an area under the curve (AUC) of 0.674 in the test set. The best-performing clinical model showed an AUC of 0.758 in the test set. The best-performing combined model showed an AUC of 0.823 in the test set. The hippocampal volume model showed a lower performance, with an AUC of 0.543 in the test set. Conclusion: Radiomics models from MRI can help predict CSF Aβ 42 status in MCI patients and potentially triage the patients for invasive and costly Aβ tests. Show more

Keywords: Amyloid, artificial intelligence, machine learning, mild cognitive impairment, radiomics

DOI: 10.3233/JAD-200734

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

Authors: Wu, Wenzhe | Lee, Inhan | Spratt, Heidi | Fang, Xiang | Bao, Xiaoyong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia caused by irreversible neurodegeneration, with the onset mechanisms elusive. tRNA-derived RNA fragments (tRFs), a recently discovered family of small non-coding RNAs (sncRNAs), have been found to associate with many human diseases, including infectious, metabolic, and neurological diseases. However, whether tRFs play a role in human AD development is not known. Objective: This study aimed to explore whether tRFs are involved in human AD. Methods: Thirty-four postmortem human hippocampus samples were used. The expression of Drosha, Dicer, and angiogenin (ANG), three ribonucleases responsible for the biogenesis …of sncRNAs, was determined by qRT-PCR and western blot. The tRFs in the hippocampus was detected by qRT-PCR or northern blot. We also used qRT-PCR to quantify NOP2/Sun RNA methyltransferase 2 (NSun2) and polyadenylation factor I subunit 1 (CLP1), two tRNA modification enzymes. Results: tRFs derived from a subset of tRNAs are significantly altered in the hippocampus of AD patients. The expression change of some tRFs showed age- and disease stage-dependent. ANG is significantly enhanced in AD, suggesting its role in inducing tRFs in AD. The expression of NSun2 in AD patients younger than 65 was significantly decreased. According to a previous report supporting NSun2-mediated tRNA methylation modification making tRNA less susceptible to ANG-mediated cleavage, our results suggested that the decrease in NSun2 may make tRNAs less methylated and subsequently enhanced tRF production from ANG-mediated tRNA cleavage. Conclusion: Our studies demonstrated for the first time the involvement of tRFs in human AD. Show more

Keywords: Alzheimer’s disease, biomarkers, neuropathology, small non-coding RNAs, tRNA-derived RNA fragments

DOI: 10.3233/JAD-200917

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

Authors: Minta, Karolina | Brinkmalm, Gunnar | Portelius, Erik | Johansson, Per | Svensson, Johan | Kettunen, Petronella | Wallin, Anders | Zetterberg, Henrik | Blennow, Kaj | Andreasson, Ulf

Article Type: Research Article

Abstract: Background: Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF). Objective: The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer’s disease (AD) and vascular dementia (VaD) compared with controls. Methods: The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, …and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n = 9) and neurocan (n = 11) were quantified using high-resolution parallel reaction monitoring mass spectrometry. Results: In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased inVaDas compared withADpatients (AUC = 0.83.0.93, p ≤0.05) and as compared with the control group (AUC = 0.79.0.87, p  ≤ 0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC = 0.86.0.91, p  ≤ 0.05) and to controls (AUC = 0.80.0.82, p  ≤ 0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC = 0.64.80, p  > 0.05). No peptides differed between AD and controls. Conclusion: Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD. Show more

Keywords: Alzheimer’s disease, brevican, cerebrospinal fluid, extracellular matrix, neurocan, vascular dementia

DOI: 10.3233/JAD-201039

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

Authors: Chen, Guanqun | Zhao, Mingyan | Yang, Kun | Lin, Hua | Han, Chunlei | Wang, Xiaoni | Han, Ying

Article Type: Research Article

Abstract: Background: Education plays a potential important effect on the prevalence and incidence of dementia. However, most of the evidence based on convenience sampling. Objective: To explore effects of education on cognition in individuals with subjective cognitive decline (SCD) and cognitive impairment (CI) from a population-based study. Methods: We examined the effect of education on cognition among individuals with SCD (n  = 451) and CI (n  = 280) from a population-based study. A series of neuropsychological tests of memory, executive, language, and general cognitive function were used to assess the participants. Results: Multiple regression analyses revealed that …education has a positive effect on cognition in both SCD and CI group in the population-based research. Further stratification study showed that the beneficial effect of education remains in the SCD group regardless of the education level, especially in the SCD participants with a low education level. However, that effect of education exists in the CI group with a low education level and disappears in the high education level. Conclusion: These results from a population-based sample suggest that high educational attainment may delay cognitive decline in the individuals with SCD regardless of high or low educational level, and high education only predicts cognition in those in the low educational level in CI group. Show more

Keywords: Alzheimer’s disease, cognitive reserve, dementia, education, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-201170

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

Authors: Tagliapietra, Matteo | Frasson, Emma | Cardellini, Davide | Mariotto, Sara | Ferrari, Sergio | Zanusso, Gianluigi | Plebani, Mauro | Monaco, Salvatore

Article Type: Research Article

Abstract: Background: Anti-IgLON5 disease is a rare neurodegenerative tauopathy that displays heterogeneity in clinical spectrum, disease course, cerebrospinal fluid (CSF) findings, and variable response to immunotherapy. Sleep disorders, bulbar dysfunction, and gait abnormalities are common presenting symptoms, and conventional brain MRI scanning is often unrevealing. Objective: To provide a comprehensive overview of the literature and to assess the frequency of symptoms, MRI findings, and treatment response in patients with IgLON5 autoimmunity in the serum and CSF or restricted to serum. Methods: We examined a 65-year-old woman with bulbar-onset IgLON5 disease with serum-restricted antibodies, and we also performed …a systematic review of all confirmed cases reported in the English literature. Results: We identified 93 patients, included our case. Clinical data were obtained in 58 subjects, in whom the most frequent symptoms were sleep-disordered breathing, dysphagia, parasomnias, dysarthria, limb or gait ataxia, stridor or vocal cord paresis, movement disorders, and postural instability. Distinct MRI alterations were identified in 12.5% of cases, as opposed to unspecific or unremarkable changes in the remaining patients. T2-hyperintense non-enhancing signal alterations involving the hypothalamus and the brainstem tegmentum were observed only in the present case. Inflammatory CSF was found in half of the cases and serum-restricted antibodies in 4 patients. Treatment with immunosuppressant or immunomodulatory drugs led to sustained clinical response in 19/52 patients. Conclusion: Anti-IgLON5 autoimmunity should be considered in patients with sleep disorders, bulbar syndrome, autonomic involvement, and movement disorders, and high-field brain MRI can be of diagnostic help. Show more

Keywords: Anti-IgLON5 disease, autoimmune encephalitis, biomarkers, brain/diagnostic imaging, cerebrospinal fluid, stridor, tauopathy

DOI: 10.3233/JAD-201105

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

Authors: Orjuela, Adrian | Lakey-Beitia, Johant | Mojica-Flores, Randy | Hegde, Muralidhar L. | Lans, Isaias | Alí-Torres, Jorge | Rao, K.S.

Article Type: Research Article

Abstract: Background: The most important hallmark in the neuropathology of Alzheimer’s disease (AD) is the formation of amyloid-β (Aβ) fibrils due to the misfolding/aggregation of the Aβ peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit Aβ42 peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties. Objective: To computationally assess the interaction between Aβ peptide and a set …of curcumin derivatives previously explored in experimental assays. Methods: The interactions of ten ligands with Aβ monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in-silico evaluation of the interaction between these derivatives and the Aβ42 peptide, both in the monomeric and fibril forms. Results: The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the Aβ42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aβ42 monomers occur in a region critical for peptide aggregation. Conclusion: Results showed that a single substitution in curcumin improved the interaction of the ligands with the Aβ monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD. Show more

Keywords: Alzheimer’s disease, Aβ monomer, Aβ42 fibril, AutoDock Vina, AutoDock 4, curcumin, curcumin derivatives, molecular docking, Smina

DOI: 10.3233/JAD-200941

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

Authors: Petersen, Melissa E. | Rafii, Michael S. | Zhang, Fan | Hall, James | Julovich, David | Ances, Beau M. | Schupf, Nicole | Krinsky-McHale, Sharon J. | Mapstone, Mark | Silverman, Wayne | Lott, Ira | Klunk, William | Head, Elizabeth | Christian, Brad | Foroud, Tatiana | Lai, Florence | Diana Rosas, H. | Zaman, Shahid | Wang, Mei-Cheng | Tycko, Benjamin | Lee, Joseph | Handen, Benjamin | Hartley, Sigan | Fortea, Juan | O’Bryant, Sid | for the Alzheimer’s Biomarker Consortium –Down Syndrome (ABC-DS)

Article Type: Research Article

Abstract: Background: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD); however, the application of such biomarkers has been limited among the DS population. Objective: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. Methods: Plasma samples were analyzed from n  = 305 (n  = 225 cognitively stable (CS); …n  = 44 MCI-DS; n  = 36 DS–AD) participants enrolled in the Alzheimer’s Biomarker Consortium —Down Syndrome. Results: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. Conclusion: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs. Show more

Keywords: Neurofilament light chain, proteomics, sensitivity, specificity, total-tau, trisomy 21

DOI: 10.3233/JAD-201167

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

Authors: Ailshire, Jennifer | Walsemann, Katrina M.

Article Type: Research Article

Abstract: Background: Air pollution is linked to worse cognitive function in older adults, but whether differences in this relationship exist by education, a key risk factor for cognitive decline, remains unknown. Objective: To determine if the association between fine particulate matter air pollution (PM2.5 ) and incident cognitive impairment varies by level of education in two cohorts assessed a decade apart. Methods: We used data on adults ages 60 and older from the nationally representative Health and Retirement Study (HRS) linked with tract-level annual average PM2.5 . We used mixed-effects logistic regression models to examine education differences …in the association between PM2.5 and incident cognitive impairment in two cohorts: 2004 (n  = 9,970) and 2014 (n  = 9,185). Cognitive impairment was determined with tests of memory and processing speed for self-respondents and proxy and interviewer assessments of cognitive functioning in non-self-respondents. Results: PM2.5 was unrelated to incident cognitive impairment among those with 13 or more years of education, but the probability of impairment increased with greater concentrations of PM2.5 among those with 8 or fewer years of education. The interaction between education and PM2.5 was only found in 2004, possibly because PM2.5 concentrations were much lower in 2014. Conclusion: Education is an important risk factor for cognitive decline and impairment, and in higher pollution contexts may serve as a protective factor against the harms of air pollution on the aging brain. Additionally, because air pollution is ubiquitous, and particularly harmful to vulnerable populations, even small improvements in air quality may have large impacts on population health. Show more

Keywords: Aging, air pollution, cognition, dementia, education, modifiable risk factors

DOI: 10.3233/JAD-200765

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

Authors: Seino, Yusuke | Nakamura, Takumi | Harada, Tomoo | Nakahata, Naoko | Kawarabayashi, Takeshi | Ueda, Tetsuya | Takatama, Masamitsu | Shoji, Mikio

Article Type: Research Article

Abstract: Background: High sensitivity liquid chromatography mass spectrometry (LC-MS/MS) was recently introduced to measure amyloid-β (Aβ) species, allowing for a simultaneous assay that is superior to ELISA, which requires more assay steps with multiple antibodies. Objective: We validated the Aβ1-38 , Aβ1-40 , Aβ1-42 , and Aβ1-43 assay by LC-MS/MS and compared it with ELISA using cerebrospinal fluid (CSF) samples to investigate its feasibility for clinical application. Methods: CSF samples from 120 subjects [8 Alzheimer’s disease (AD) with dementia (ADD), 2 mild cognitive dementia due to Alzheimer’s disease (ADMCI), 14 cognitively unimpaired (CU), and 96 neurological …disease subjects] were analyzed. Aβ species were separated using the Shimadzu Nexera X2 system and quantitated using a Qtrap 5500 LC-MS/MS system. Aβ1-40 and Aβ1-42 levels were validated using ELISA. Results: CSF levels in CU were 666±249 pmol/L in Aβ1-38 , 2199±725 pmol/L in Aβ1-40 , 153.7±79.7 pmol/L in Aβ1-42 , and 9.78±4.58 pmol/L in Aβ1-43 . The ratio of the amounts of Aβ1-38 , Aβ1-40 , Aβ1-42 , and Aβ1-43 was approximately 68:225:16:1. Linear regression analyses showed correlations among the respective Aβ species. Both Aβ1-40 and Aβ1-42 values were strongly correlated with ELISA measurements. No significant differences were observed in Aβ1-38 or Aβ1-40 levels between AD and CU. Aβ1-42 and Aβ1-43 levels were significantly lower, whereas the Aβ1-38/1-42 , Aβ1-38/1-43 , and Aβ1-40/ Aβ1-43 ratios were significantly higher in AD than in CU. The basic assay profiles of the respective Aβ species were adequate for clinical usage. Conclusion: A quantitative LC-MS/MS assay of CSF Aβ species is as reliable as specific ELISA for clinical evaluation of CSF biomarkers for AD. Show more

Keywords: Aβ1-38, Aβ1-40, Aβ1-42 Aβ1-43, cerebrospinal fluid, ELISA, liquid chromatography mass spectrometry

DOI: 10.3233/JAD-200987

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

Authors: Mozersky, Jessica | Hartz, Sarah | Linnenbringer, Erin | Levin, Lillie | Streitz, Marissa | Stock, Kristin | Moulder, Krista | Morris, John C.

Article Type: Research Article

Abstract: Background: Cognitively normal (CN) older adults participating in Alzheimer’s disease (AD) research increasingly ask for their research results—including genetic and neuroimaging findings—to understand their risk of developing AD dementia. AD research results are typically not returned for multiple reasons, including possible psychosocial harms of knowing one is at risk of a highly feared and untreatable disease. Objective: We developed materials that convey information about 5-year absolute risk of developing AD dementia based on research results. Methods: 20 CN older adults who received a research brain MRI result were interviewed regarding their wishes for research results to …inform material development (Pilot 1). Following material development, 17 CN older adults evaluated the materials for clarity and acceptability (Pilot 2). All participants were community-dwelling older adults participating in longitudinal studies of aging at a single site. Results: Participants want information on their risk of developing AD dementia to better understand their own health, satisfy curiosity, inform family, and future planning. Some articulated concerns, but the majority wanted to know their risk despite the limitations of information. Participants found the educational materials and results report clear and acceptable, and the majority would want to know their research results after reviewing them. Conclusion: These materials will be used in a clinical study examining the psychosocial and cognitive effects of offering research results to a cohort of CN older adults. Future AD research may incorporate the return of complex risk information to CN older adults, and materials are needed to communicate this information. Show more

Keywords: Alzheimer’s disease dementia, biomarkers, cognitively normal older adults, genetics, health communication, imaging, pre-symptomatic, research ethics, return of research results, risk

DOI: 10.3233/JAD-200993

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

Authors: Fanet, Hortense | Tournissac, Marine | Leclerc, Manon | Caron, Vicky | Tremblay, Cyntia | Vancassel, Sylvie | Calon, Frédéric

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized. Objective: Here, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in triple-transgenic mouse model of AD (3xTg-AD) mice, a model of age-related tau and amyloid-β (Aβ) neuropathologies associated with behavior impairment. …Methods: Non-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat – CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days. Results: This sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on Aβ and tau neuropathologies. Conclusion: Overall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic symptoms accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders. Show more

Keywords: 3xTg-AD mice, Alzheimer’s disease, high-fat diet, tetrahydrobiopterin (BH4)

DOI: 10.3233/JAD-200637

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

Authors: Murchison, Charles F. | Kennedy, Richard E. | McConathy, Jonathan E. | Roberson, Erik D.

Article Type: Research Article

Abstract: Background: African Americans are at increased risk for Alzheimer’s disease (AD) but barriers to optimal clinical care are unclear. Objective: To comprehensively evaluate potential racial differences in the diagnosis and treatment of AD in an academic medical center. Methods: We used the clinical informatics tool, i2b2, to analyze all patient encounters for AD or mild cognitive impairment (MCI) in the University of Alabama at Birmingham Health System over a three-year period, examining neuroimaging rates and dementia-related medication use by race and clinic site using ratio tests on contingency tables of stratified patient counts. Results: …Enterprise-wide, African Americans were not underrepresented among outpatients seen for AD/MCI. However, there were differences in the clinic setting where visits occurred, with African Americans overrepresented in Geriatrics and primary care clinics and underrepresented in Memory Disorders specialty clinics. There were no racial differences in the rates at which any clinic ordered PET neuroimaging tests or dementia-related medications. However, unsurprisingly, specialty clinics ordered both PET neuroimaging and dementia-related medications at a higher rate than primary care clinics, and overall across the medical enterprise, African Americans were statistically less likely to have PET neuroimaging or dementia-related medications ordered. Conclusion: African Americans with AD/MCI were not underrepresented at this academic medical center but were somewhat less likely to have PET neuroimaging or to be on dementia-related medications, potentially in part from underrepresentation in the specialty clinics where these orders are more likely. The reasons for this underrepresentation in specialty clinics are likely multifactorial and important to better understand. Show more

Keywords: African Americans, Alzheimer’s disease, cognition, dementia, geriatrics, mild cognitive impairment, neuroimaging, racial factors, referral and consultation

DOI: 10.3233/JAD-200796

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

Authors: Jiang, Yang | Li, Juan | Schmitt, Frederick A. | Jicha, Gregory A. | Munro, Nancy B. | Zhao, Xiaopeng | Smith, Charles D. | Kryscio, Richard J. | Abner, Erin L.

Article Type: Research Article

Abstract: Background: Early prognosis of high-risk older adults for amnestic mild cognitive impairment (aMCI), using noninvasive and sensitive neuromarkers, is key for early prevention of Alzheimer’s disease. We have developed individualized measures in electrophysiological brain signals during working memory that distinguish patients with aMCI from age-matched cognitively intact older individuals. Objective: Here we test longitudinally the prognosis of the baseline neuromarkers for aMCI risk. We hypothesized that the older individuals diagnosed with incident aMCI already have aMCI-like brain signatures years before diagnosis. Methods: Electroencephalogram (EEG) and memory performance were recorded during a working memory task at baseline. …The individualized baseline neuromarkers, annual cognitive status, and longitudinal changes in memory recall scores up to 10 years were analyzed. Results: Seven of the 19 cognitively normal older adults were diagnosed with incident aMCI for a median 5.2 years later. The seven converters’ frontal brainwaves were statistically identical to those patients with diagnosed aMCI (n  = 14) at baseline. Importantly, the converters’ baseline memory-related brainwaves (reduced mean frontal responses to memory targets) were significantly different from those who remained normal. Furthermore, differentiation pattern of left frontal memory-related responses (targets versus nontargets) was associated with an increased risk hazard of aMCI (HR = 1.47, 95% CI 1.03, 2.08). Conclusion: The memory-related neuromarkers detect MCI-like brain signatures about five years before diagnosis. The individualized frontal neuromarkers index increased MCI risk at baseline. These noninvasive neuromarkers during our Bluegrass memory task have great potential to be used repeatedly for individualized prognosis of MCI risk and progression before clinical diagnosis. Show more

Keywords: Amnestic mild cognitive impairment, cognitive ERP, delayed match-to-sample, dementia risk, EEG, memory-related potentials, working memory

DOI: 10.3233/JAD-200931

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

Authors: Waki, Takashi | Tanaka-Mizuno, Sachiko | Takashima, Naoyuki | Takechi, Hajime | Hayakawa, Takehito | Miura, Katsuyuki | Ueshima, Hirotsugu | Kita, Yoshikuni | Dodge, Hiroko H.

Article Type: Correction

DOI: 10.3233/JAD-209011

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2020

Authors: Teipel, Stefan J. | Marie Temp, Anna Gesine | Levin, Fedor | Dyrba, Martin | Grothe, Michel J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: TAR DNA-binding protein 43 (TDP-43) has been recognized as a frequent co-pathology of Alzheimer’s disease (AD). The effect of the presence of TDP-43 pathology on in vivo measures of AD-related amyloid pathology using amyloid sensitive PET is still unresolved. Objective: To study the association of TDP-43 pathology with antemortem amyloid PET signal. Methods: We studied 30 cases from the ADNI autopsy sample with available ratings of presence of TDP-43 and antemortem amyloid sensitive 18 F-FlorbetapirPET. We used Bayesian regression to determine the effect of TDP-43 on global and regional amyloid PET signal. In a …post-hoc analysis, we assessed the association of TDP-43 pathology with antemortem memory performance. Results: We found substantial to strong evidence for a negative effect of TDP-43 (Bayes factor against the null model (BF10 ) = 9.0) and hippocampal sclerosis (BF10  = 6.4) on partial volume corrected hippocampal 18 F-Florbetapir uptake. This effect was only partly mediated by the negative effect of TDP-43 on hippocampal volume. In contrast, Bayesian regression supported that there is no effect of TDP-43 on global cortical PET-signal (BF10  = 0.65). We found an anecdotal level of evidence for a negative effect of TDP-43 pathology on antemortem memory performance after accounting for global amyloid PET signal (BF10  = 1.6). Conclusion: Presence of TDP-43 pathology does not confound the global amyloid PET-signal but has a selective effect on hippocampal PET-signal that appears only partially dependent on TDP-43 mediated atrophy. Show more

Keywords: Amyloid pathology, florbetapir PET, hippocampal sclerosis, hippocampal volume, memory, TAR DNA-binding protein 43

DOI: 10.3233/JAD-201032

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

Authors: Berger, Miles | Cooter, Mary | Roesler, Alexander S. | Chung, Stacey | Park, John | Modliszewski, Jennifer L. | VanDusen, Keith W. | Thompson, J. Will | Moseley, Arthur | Devinney, Michael J. | Smani, Shayan | Hall, Ashley | Cai, Victor | Browndyke, Jeffrey N. | Lutz, Michael W. | Corcoran, David L. | and Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Results: Increasing APOE4 copy number …was associated with a significant decrease in a CRP peptide level across all five models (q  <  0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q  <  0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies. Show more

Keywords: Alzheimer disease, apolipoprotein E4, biomarker, C-reactive protein, cerebrospinal fluid, complement activation, mass spectrometry, neurogenic inflammation

DOI: 10.3233/JAD-200747

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

Authors: Romano, Raymond R. | Carter, Michael A. | Dietrich, Mary S. | Cowan, Ronald L. | Bruehl, Stephen P. | Monroe, Todd B.

Article Type: Research Article

Abstract: Background: This study evaluated whether the apolipoprotein ɛ 4 (APOE4 ) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer’s disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects. Objective: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ 4 allele. Methods: Forty-nine cognitively healthy subjects aged 30–89 years old with the APOE4 allele …(n  = 12) and without (n  = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli. Results: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p  = 0.040) and the level of unpleasantness associated with each (p  = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level. Conclusion: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted. Show more

Keywords: Alzheimer’s disease, APOE , biomarker, nociception, pain

DOI: 10.3233/JAD-201293

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