Journal of Alzheimer's Disease - Volume 77, issue 4

Authors: Padala, Prasad R. | Boozer, Eugenia M. | Lensing, Shelly Y. | Parkes, Christopher M. | Hunter, Cassandra R. | Dennis, Richard A. | Caceda, Ricardo | Padala, Kalpana P.

Article Type: Research Article

Abstract: Background: Apathy, a profound loss of motivation, initiation, and goal directed cognition, is a common comorbidity of Alzheimer’s disease (AD). The presence of apathy is associated with rapid progression of AD, long-term impairment, disability, and higher mortality. Pharmacological treatments of apathy are limited. Objective: The primary objective was to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) for apathy in AD. Methods: A randomized, double-blind, parallel-arm, sham-controlled pilot study was conducted in subjects with AD and apathy (N = 20). Subjects were randomized to rTMS or sham treatment (5 days/week) for four weeks. Primary outcome, apathy evaluation …scale-clinician version (AES-C), and secondary outcome measures, modified-Mini Mental State Examination (3MS), instrumental activities of daily living (IADL), and clinical global impression (CGI), were assessed at baseline and four weeks. Follow-up visits were conducted at 8 and 12 weeks to test the durability of effects of intervention. Results: Mean age was 77.3 (±7.2) years, 80% were Caucasians and 10% were females. After adjusting for baseline, there was a significantly greater improvement in the AES-C with rTMS compared to sham treatment (–10.1 (–15.9 to –4.3); t (16)   = –3.69; p  = 0.002) at 4 weeks. There was also significantly greater improvement in 3MS (6.9 (1.7 to 12.0); t (15)   = 2.85; p  = 0.012), IADL (3.4 (1.0 to 5.9); χ 2 1  = 7.72; p  = 0.006), CGI-S (1.4 (0.5 to 2.3), t (16)   = 3.29; p  = 0.005), and CGI-I (–2.56 (–3.5 to –1.6), t (17)   = –5.72; p  < 0.001) for rTMS compared to the sham at 4 weeks. The effects of rTMS were durable at 12 weeks. Conclusion: rTMS may be safely used in subjects with AD and may improve apathy, function, and some aspects of cognition. Show more

Keywords: Alzheimer’s disease, apathy, behavioral problems in dementia, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-200640

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1483-1493, 2020

Authors: Chen, Shanshan | Xu, Wenwen | Xue, Chen | Hu, Guanjie | Ma, Wenying | Qi, Wenzhang | Dong, Lin | Lin, Xingjian | Chen, Jiu

Article Type: Research Article

Abstract: Background: Voxel-based morphometry studies have not yielded consistent results among patients with mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Objective: Therefore, we aimed to conduct a meta-analysis of gray matter (GM) abnormalities acquired from these studies to determine their respective neuroanatomical changes. Methods: We systematically searched for voxel-based whole-brain morphometry studies that compared MCI or SCD subjects with healthy controls in PubMed, Web of Science, and EMBASE databases. We used the coordinate-based method of activation likelihood estimation to determine GM changes in SCD, MCI, and MCI sub-groups (amnestic MCI and non-amnestic MCI). …Results: A total of 45 studies were included in our meta-analysis. In the MCI group, we found structural atrophy of the bilateral hippocampus, parahippocampal gyrus (PHG), amygdala, right lateral globus pallidus, right insula, and left middle temporal gyrus. The aMCI group exhibited GM atrophy in the bilateral hippocampus, PHG, and amygdala. The naMCI group presented with structural atrophy in the right putamen, right insula, right precentral gyrus, left medial/superior frontal gyrus, and left anterior cingulate. The right lingual gyrus, right cuneus, and left medial frontal gyrus were atrophic GM regions in the SCD group. Conclusion: Our meta-analysis identified unique patterns of neuroanatomical alternations in both the MCI and SCD group. Structural changes in SCD patients provide new evidence for the notion that subtle impairment of visual function, perception, and cognition may be related to early signs of cognitive impairment. In addition, our findings provide a foundation for future targeted interventions at different stages of preclinical Alzheimer’s disease. Show more

Keywords: Activation likelihood estimation, meta-analysis, mild cognitive impairment, preclinical Alzheimer’s disease, subjective cognitive decline, voxel-based morphometry

DOI: 10.3233/JAD-200659

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1495-1512, 2020

Authors: Lu, Hui | Jing, Donglai | Chen, Yaojing | Cui, Chunlei | Gao, Ran | Wang, Lin | Liang, Zhigang | Chen, Kewei | Wu, Liyong

Article Type: Research Article

Abstract: Background: Pathologic processes in Creutzfeldt-Jakob disease (CJD) are not fully understood. Familial CJD (fCJD) gives opportunities to discover pathologic changes in the preclinical stage. Objective: To investigate cerebral glucose metabolism in the preclinical stage via 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG PET) in fCJD. Methods: Seven asymptomatic carriers of G114V mutation and six family members without PRNP mutation from the same fCJD kindred were included, and were followed for 2 years. Ten symptomatic CJD patients were also recruited. All subjects underwent standardized clinical examinations and 18 F-FDG PET scans. Results were compared in three …groups: baseline carriers against non-carriers (baseline analysis), changes after 2 years in carriers (follow-up analysis), and differences between symptomatic CJD patients and healthy controls (CJD patients analysis). Results: No carriers developed any neurological symptoms during 2-year follow-up. Baseline analysis: carriers demonstrates decreased metabolism (p  < 0.001) in left and right postcentral, left fusiform, left superior temporal, left lingual, left superior parietal, and left Heschl gyrus. Follow-up analysis shows metabolic decline (p  < 0.001) in right inferior temporal, left supra-marginal and left postcentral lobe, and increased metabolism (p  < 0.001) in left fusiform, left angular, left thalamus, left Heschl’s, right Rolandic operculum, and left superior parietal gyrus. CJD patients demonstrates decreased metabolism in right inferior triangularis frontal gyrus, right middle occipital gyrus, right putamen, right thalamus, and right middle temporal gyrus. Conclusion: Hypo-metabolism of parietal and temporal lobe can be detected by 18 F-FDG PET in the preclinical stage of CJD. Subcortical area might compensate in the preclinical stage and decompensate in the symptomatic stage. Show more

Keywords: Familial Creutzfeldt-Jakob disease, 18F-fluorodeoxyglucose positron emission tomography, metabolism, preclinical stage

DOI: 10.3233/JAD-200576

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1513-1521, 2020

Authors: Pérez-Ros, Pilar | Vila-Candel, Rafael | Martin-Utrilla, Salvador | Martínez-Arnau, Francisco M.

Article Type: Research Article

Abstract: Background: Assessing quality of life (QoL) in older people with cognitive impairment is a challenge. There is no consensus on the best tool, but a short, user-friendly scale is advised. Objective: This study aimed to assess the psychometric properties of the self-reported and generic EQ-5D (including the EQ index and EQ visual analog scale [VAS]) in community-dwelling older adults with cognitive impairment. Methods: Cross-sectional study analyzing the feasibility, acceptability, reliability, and validity of the EQ-5D based on 188 self-administered questionnaires in a sample of community-dwelling older adults with Mini-Mental State Examination (MMSE) scores of 10 to …24 points. Results: The EQ index was 0.69 (±0.27) and the EQ VAS was 63.8 (±28.54). Adequate measurement properties were found in acceptability and feasibility. Cronbach’s alpha was 0.69. Good validity was observed in the correlation of each dimension of the EQ-5D with geriatric assessment scales. Higher validity was observed for the EQ index compared to the EQ VAS. Conclusion: The EQ-5D scale could be a good tool for assessing health-related QoL in community-dwelling older adults with cognitive impairment, though it is necessary to assess the dimensions and the EQ index. Show more

Keywords: Cognitive impairment, community-dwelling, measurement, older people, quality of life

DOI: 10.3233/JAD-200806

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1523-1532, 2020

Authors: Al-Janahi, Eiman | Ponirakis, Georgios | Al Hamad, Hanadi | Vattoth, Surjith | Elsotouhy, Ahmed | Petropoulos, Ioannis N. | Khan, Adnan | Gad, Hoda | Chandran, Mani | Sankaranarayanan, Anoop | Ramadan, Marwan | Elorrabi, Marwa | Gadelseed, Masharig | Tosino, Rhia | Gawhale, Priya V. | Arasn, Anjum | Alobaidi, Maryam | Khan, Shafi | Manikoth, Pravija | Hamdi, Yasmin | Osman, Susan | Nadukkandiyil, Navas | AlSulaiti, Essa | Thodi, Noushad | Almuhannadi, Hamad | Mahfoud, Ziyad R. | Own, Ahmed | Shuaib, Ashfaq | Malik, Rayaz A.

Article Type: Research Article

Abstract: Background: Visual rating of medial temporal lobe atrophy (MTA) is an accepted structural neuroimaging marker of Alzheimer’s disease. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic technique that detects neuronal loss in peripheral and central neurodegenerative disorders. Objective: To determine the diagnostic accuracy of CCM for mild cognitive impairment (MCI) and dementia compared to medial temporal lobe atrophy (MTA) rating on MRI. Methods: Subjects aged 60–85 with no cognitive impairment (NCI), MCI, and dementia based on the ICD-10 criteria were recruited. Subjects underwent cognitive screening, CCM, and MTA rating on MRI. Results: 182 subjects …with NCI (n  = 36), MCI (n  = 80), and dementia (n  = 66), including AD (n  = 19, 28.8%), VaD (n  = 13, 19.7%), and mixed AD (n  = 34, 51.5%) were studied. CCM showed a progressive reduction in corneal nerve fiber density (CNFD, fibers/mm2 ) (32.0±7.5 versus 24.5±9.6 and 20.8±9.3, p  < 0.0001), branch density (CNBD, branches/mm2 ) (90.9±46.5 versus 59.3±35.7 and 53.9±38.7, p  < 0.0001), and fiber length (CNFL, mm/mm2 ) (22.9±6.1 versus 17.2±6.5 and 15.8±7.4, p  < 0.0001) in subjects with MCI and dementia compared to NCI. The area under the ROC curve (95% CI) for the diagnostic accuracy of CNFD, CNBD, CNFL compared to MTA-right and MTA-left for MCI was 78% (67–90%), 82% (72–92%), 86% (77–95%) versus 53% (36–69%) and 40% (25–55%), respectively, and for dementia it was 85% (76–94%), 84% (75–93%), 85% (76–94%) versus 86% (76–96%) and 82% (72–92%), respectively. Conclusion: The diagnostic accuracy of CCM, a non-invasive ophthalmic biomarker of neurodegeneration, was high and comparable with MTA rating for dementia but was superior to MTA rating for MCI. Show more

Keywords: Corneal confocal microscopy, corneal nerve fibers, dementia, medial temporal lobe atrophy, mild cognitive impairment, neuropathology

DOI: 10.3233/JAD-200678

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1533-1543, 2020

Authors: Bergeron, Michael F. | Landset, Sara | Zhou, Xianbo | Ding, Tao | Khoshgoftaar, Taghi M. | Zhao, Feng | Du, Bo | Chen, Xinjie | Wang, Xuan | Zhong, Lianmei | Liu, Xiaolei | Ashford, J. Wesson

Article Type: Research Article

Abstract: Background: The widespread incidence and prevalence of Alzheimer’s disease and mild cognitive impairment (MCI) has prompted an urgent call for research to validate early detection cognitive screening and assessment. Objective: Our primary research aim was to determine if selected MemTrax performance metrics and relevant demographics and health profile characteristics can be effectively utilized in predictive models developed with machine learning to classify cognitive health (normal versus MCI), as would be indicated by the Montreal Cognitive Assessment (MoCA). Methods: We conducted a cross-sectional study on 259 neurology, memory clinic, and internal medicine adult patients recruited from two …hospitals in China. Each patient was given the Chinese-language MoCA and self-administered the continuous recognition MemTrax online episodic memory test on the same day. Predictive classification models were built using machine learning with 10-fold cross validation, and model performance was measured using Area Under the Receiver Operating Characteristic Curve (AUC). Models were built using two MemTrax performance metrics (percent correct, response time), along with the eight common demographic and personal history features. Results: Comparing the learners across selected combinations of MoCA scores and thresholds, Naïve Bayes was generally the top-performing learner with an overall classification performance of 0.9093. Further, among the top three learners, MemTrax-based classification performance overall was superior using just the top-ranked four features (0.9119) compared to using all 10 common features (0.8999). Conclusion: MemTrax performance can be effectively utilized in a machine learning classification predictive model screening application for detecting early stage cognitive impairment. Show more

Keywords: Aging, Alzheimer’s disease, dementia, mass screening

DOI: 10.3233/JAD-191340

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1545-1558, 2020

Authors: Blazel, Madeleine M. | Lazar, Karen K. | Van Hulle, Carol A. | Ma, Yue | Cole, Aleshia | Spalitta, Alice | Davenport-Sis, Nancy | Bendlin, Barbara B. | Wahoske, Michelle | Illingworth, Chuck | Gleason, Carey E. | Edwards, Dorothy F. | Blazel, Hanna | Asthana, Sanjay | Johnson, Sterling C. | Carlsson, Cynthia M.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) provides insight into the spectrum of Alzheimer’s disease (AD) pathology. While lumbar punctures (LPs) for CSF collection are generally considered safe procedures, many participants remain hesitant to participate in research involving LPs. Objective: To explore factors associated with participant willingness to undergo a research LP at baseline and follow-up research study visit. Methods: We analyzed data from 700 participants with varying cognition (unimpaired, mild cognitive impairment, and dementia) in the Wisconsin Alzheimer’s Disease Research Center. We evaluated the relationship of demographic variables (age, sex, race, ethnicity, and years of education) and clinical …variables (waist-to-hip ratio, body mass index, AD parental history, cognitive diagnosis) on decision to undergo baseline LP1. We evaluated the relationship of prior LP1 experience (procedure success and adverse events) with the decision to undergo follow-up LP2. The strongest predictors were incorporated into regression models. Results: Over half of eligible participants opted into both baseline and follow-up LP. Participants who underwent LP1 had higher mean education than those who declined (p  = 0.020). White participants were more likely to choose to undergo LP1 (p  < 0.001); 33% of African American participants opted in compared to 65% of white participants. Controlling for age, education, and AD parental history, race was the only significant predictor for LP1 participation. Controlling for LP1 mild adverse events, successful LP1 predicted LP2 participation. Conclusion: Race was the most important predictor of baseline LP participation, and successful prior LP was the most important predictor of follow-up LP participation. Show more

Keywords: Biomarkers, community participation, lumbar puncture, research subject recruitment

DOI: 10.3233/JAD-200394

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1559-1567, 2020

Authors: Bergeron, David | Beauregard, Jean-Mathieu | Jean-Guimond, | Soucy, Jean-Paul | Verret, Louis | Poulin, Stéphane | Matias-Guiu, Jordi A. | Cabrera-Martín, María Nieves | Bouchard, Rémi W. | Laforce Jr, Robert

Article Type: Research Article

Abstract: Background: Hypometabolism of the posterior cingulate cortex (PCC) is an important diagnostic feature of late-onset, amnestic Alzheimer’s disease (AD) measured with 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). However, it is unclear whether PCC hypometabolism has diagnostic value in young-onset, non-amnestic variants of AD, which exhibit less pathology in the hippocampus and default mode network. Objective: Evaluate the prevalence and diagnostic value of PCC hypometabolism in non-amnestic variants of AD. Methods: We retrospectively identified 60 patients with young-onset, atypical dementia who have undergone a detailed clinical evaluation, FDG-PET, and an amyloid biomarker (amyloid-PET or cerebrospinal fluid analysis). …We quantitatively analyzed regional hypometabolism in 70 regions of interest (ROI) using the MIMneuro® software. Results: Based on a cut-off of z-score < –1.5 for significant PCC hypometabolism, the prevalence of PCC hypometabolism in non-amnestic variants of AD was 65% compared to 28% in clinical variants of frontotemporal dementia (FTD). The ROI with the maximal hypometabolism was the dominant middle temporal gyrus in the language variant of AD (mean z score –2.28), middle occipital gyrus in PCA (–3.24), middle temporal gyrus in frontal AD (–2.70), and angular gyrus in corticobasal syndrome due to AD (–2.31). The PCC was not among the 10 most discriminant regions between non-amnestic variants of AD versus clinical variants of FTD. Conclusion: We conclude that PCC hypometabolism is not a discriminant feature to distinguish non-amnestic variants of AD from clinical variants of FTD—and should be interpreted with caution in patients with young-onset, non-amnestic dementia. Show more

Keywords: Alzheimer’s disease, FDG-PET, non-amnestic variants of AD, primary progressive aphasia, posterior cingulate cortex

DOI: 10.3233/JAD-200567

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1569-1577, 2020

Authors: Dutt, Shubir | Li, Yanrong | Mather, Mara | Nation, Daniel A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Neuropathological studies have suggested the tau pathology observed in Alzheimer’s disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker-confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia. Objective: The present study examined whether MRI-based brainstem volumes differ among cognitively normal older adults and those with MCI or dementia due to AD and whether preclinical brainstem volumes predict future progression to dementia. Methods: Alzheimer’s Disease Neuroimaging Initiative participants (N = 1,629) underwent baseline MRI scanning with …variable clinical follow-up (6–120 months). Region of interest and voxel-based morphometric methods assessed brainstem volume differences among cognitively normal (n  = 814), MCI (n  = 542), and AD (n  = 273) participants, as well as subsets of cerebrospinal fluid biomarker-confirmed MCI (n  = 203) and AD (n  = 160) participants. Results: MCI and AD cases showed smaller midbrain volumes relative to cognitively normal participants when normalizing to whole brainstem volume, and showed smaller midbrain, locus coeruleus, pons, and whole brainstem volumes when normalizing to total intracranial volume. Cognitively normal individuals who later progressed to AD dementia diagnosis exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and voxel-wise analyses revealed specific volumetric reduction of the locus coeruleus. Conclusion: Findings are consistent with neuropathological observations of early AD-related pathology in brainstem nuclei and further suggest the clinical relevance of brainstem substructural volumes in preclinical and prodromal AD. Show more

Keywords: Alzheimer’s disease, biomarkers, brainstem, cognitive aging, locus coeruleus, magnetic resonance imaging, mild cognitive impairment, neuroimaging

DOI: 10.3233/JAD-200187

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1579-1594, 2020

Authors: Ling, Yi | Gu, Qilu | Zhang, Junmei | Gong, Tianyu | Weng, Xiongpeng | Liu, Jiaming | Sun, Jing

Article Type: Research Article

Abstract: Background: Post-stroke comorbid cognitive impairment and depression (PSCCID) is a severe neuropsychiatric complication after acute stroke. Gut microbiota dysbiosis is associated with many psychiatric disorders. Alterations in the composition of gut microbiota may serve as a critical role in patients with PSCCID. Objective: We aimed to characterize the microbial profiles of patients with PSCCID. Method: A total of 175 stroke patients were recruited in the study. The composition of gut bacterial communities of patients was determined by 16S ribosomal RNA Miseq sequencing, and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was used to demonstrate …the functional alterations of gut microbiota. We further identified the characteristic gut microbiota of PSCCID using linear discriminant analysis effect size. Results: Patients with PSCCID exhibited an increased abundance of Proteobacteria , including Gammaproteobacteria , Enterobacteriales , and Enterobacteriaceae , and a decreased abundance of several short-chain fatty acids-producing bacteria compared with non-PSCCID patients. The abundance of Gammaproteobacteria and Enterobacteriaceae showed negative correlations with the MoCA score. Moreover, the Kyoto Encyclopedia of Genes and Genomes results demonstrated the enriched orthologs of glycan biosynthesis and metabolism and decreased orthologs of amino acid metabolism in PSCCID patients. Importantly, the characteristic gut microbiota was identified and achieved an area under the curve of 0.847 between the two groups. Conclusion: In this study, we characterized the gut microbiota of PSCCID patients, and revealed the correlations of the altered gut microbiota with clinical parameters, which took a further step towards non-invasive diagnostic biomarkers for PSCCID from fecal samples. Show more

Keywords: Cognitive impairment, correlation, depression, gut microbiota, ischemic stroke

DOI: 10.3233/JAD-200315

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1595-1608, 2020