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