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

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. 79, no. 3, pp. 1297-1305, 2021

Authors: Yan, Yibing | Wu, Xingqi | Wang, Xiaojing | Geng, Zhi | Wang, Lu | Xiao, Guixian | Wu, Yue | Zhou, Shanshan | Liao, Rongfeng | 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. 79, no. 3, pp. 1307-1316, 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. 79, no. 3, pp. 1317-1325, 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. 79, no. 3, pp. 1327-1344, 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. 79, no. 3, pp. 1345-1367, 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. 79, no. 3, pp. 1369-1380, 2021