Journal of Alzheimer's Disease - Volume 79, issue 3

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. 79, no. 3, pp. 1171-1184, 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. 79, no. 3, pp. 1185-1194, 2021

Authors: Ulugut Erkoyun, Hulya | van der Lee, Sven J. | Nijmeijer, Bas | van Spaendonk, Rosalina | 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. 79, no. 3, pp. 1195-1201, 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 estimate 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. 79, no. 3, pp. 1203-1211, 2021

Authors: GjØra, Linda | Strand, BjØrn Heine | 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 (51.2%) 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. 79, no. 3, pp. 1213-1226, 2021

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. 79, no. 3, pp. 1227-1233, 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 AppNL -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 AppNL -G -F mice developed an IBD-like condition. Brain histologic and biochemical assessments demonstrated increased insoluble Aβ1–40/42 levels along with the decreased microglial CD68 immunoreactivity in DSS treated AppNL -G -F mice compared to vehicle treated AppNL -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. 79, no. 3, pp. 1235-1255, 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. 79, no. 3, pp. 1257-1268, 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. 79, no. 3, pp. 1269-1283, 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. 79, no. 3, pp. 1285-1296, 2021