Journal of Alzheimer's Disease - Volume 90, issue 3

Authors: Chu, Min | Liu, Li | Nan, Haitian | Jiang, Deming | Wang, Yihao | Rosa-Neto, Pedro | Piao, Yueshan | Wu, Liyong

Article Type: Research Article

Abstract: Background: In most cases, the onset of frontotemporal dementia (FTD) occurs between the ages of 45 and 65 years. However, some patients experience an extremely early disease onset. Objective: To investigate the clinical, genetic, and pathological features of extremely early-onset FTD. Methods: We conducted a comprehensive clinical, genetic, and neuropathological analysis of a 25-year-old patient experiencing the onset of behavioral variant frontotemporal dementia (bvFTD). In addition, we conducted a literature review and summarized the clinical, genetic, and pathological features of patients with FTD with onset age≤25 years. Results: The patient was diagnosed with bvFTD; …however, there was no family history of FTD, no positive genetic test results and no deposition of TDP43, tau, ubiquitin, and synuclein in the brain. Literature screening identified 18 patients with onset age ≤25 years with FTD. The youngest patient was 14 years of age. Most patients (8/14) had a positive family history. The most common clinical phenotype was the behavioral variant (12/14). Genetic results were reported for 11 patients; the most common pathogenic gene was MAPT (10/12), with four cases of G389 R, two cases of P301 S, one case of G335 S, one case of G335A, one case of G335 V, and one case of L315 R. Pathological results were reported for 13 patients; the most common pathological subtype was tau (8/13). Conclusion: FTD can start at an extremely early age. The most common phenotype of extremely early onset FTD was the behavioral variant, the most common pathogenic gene was MAPT, and the most common neuropathological type was tau. Show more

Keywords: Early onset, frontotemporal lobe degeneration, genetics, pathology

DOI: 10.3233/JAD-220679

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1139-1151, 2022

Authors: Wu, Shijing | Hu, Li | Lin, Jiajing | Li, Kanglan | Ye, Shicai | Zhu, Shaoping | Liu, Zhou

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) is important in the etiology of Alzheimer’s disease (AD). Removal of Aβ from the brain is a major strategy for the prevention and treatment of AD. Objective: To clarify whether Aβ42 can be cleared by intestinal excretion and whether the gut microbiota (GM) can affect the excretory clearance of Aβ42 in the peripheral blood and intestines. Methods: Male 8-month-old C57BL6 mice were maintained on either normal chow or received broad-spectrum antibiotics in their drinking water for one week. Sterile saline, fluorescein isothiocyanate (FITC), or FITC-Aβ42 (fluorescein isothiocyanate-labeled amyloid-β42 peptides) …was injected 1 h before sampling. Related changes of Aβ42 before and after injection were evaluated. Results: FITC-Aβ42 was injected into mice through the tail vein and could later be detected in feces. Furthermore, the fecal concentrations of FITC-Aβ42 were higher in mice that had been fed antibiotics to alter their GM than in normal mice. However, the FITC-Aβ42 concentrations in blood showed the opposite pattern. Conclusion: Aβ42 can be excreted into the intestinal lumen and is regulated by the GM. Show more

Keywords: Alzheimer’s disease, amyloid-β , antibiotics, excretion of Aβ , gut microbiota

DOI: 10.3233/JAD-220705

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1153-1162, 2022

Authors: Tian, Yizhu | Li, Deyu | Wang, Daifa | Zhu, Ting | Xia, Meiyun | Jiang, Wenyu

Article Type: Research Article

Abstract: Background: The brain activation patterns of mild cognitive impairment (MCI) are still unclear and they involve multiple brain regions. Most previous studies have focused on abnormal activation in the frontal and temporal lobes, with few investigating the entire brain. Objective: To identify and compare the changes in cerebral hemodynamics and abnormal activation patterns in the entire brain of MCI patients and healthy older adults. Methods: Patients with MCI (n  = 22) and healthy controls (HC, n  = 34) matched by age, education levels, sex, and mental state were enrolled. They performed the same letter and category verbal fluency …test (VFT) tasks while their behavioral performance and global cerebral hemodynamics were analyzed. Results: The performance during the category VFT task was significantly better than that during the letter VFT task across all participants (HC: correct: p  < 0.001; intrusions: p  < 0.001; MCI: correct: p  < 0.001; intrusions: p  < 0.001). The number of correct words during the letter and category VFT tasks was significantly higher in the HC group than in the MCI group (p  < 0.001). The deoxygenated-hemoglobin (HbR) concentrations in the left parietal lobule (p  = 0.022) and left inferior parietal lobule (p  = 0.034) were significantly different during the category VFT task. Conclusion: The differences between HC and MCI groups were greater in the category task. The HbR concentration was more sensitive for the category VFT task and concentration changes in the left parietal lobule and left inferior parietal lobule may be useful for clinical screening and application; thus, they deserve more attention. Show more

Keywords: Deoxyhemoglobin, functional near-infrared imaging, hemoglobin oxygenation, mild cognitive impairment, verbal fluency

DOI: 10.3233/JAD-220691

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1163-1175, 2022

Authors: Fukuda, Haruhisa | Maeda, Megumi | Murata, Fumiko | Murata, Yutaka

Article Type: Research Article

Abstract: Background: Donepezil is frequently used to treat Alzheimer’s disease (AD) symptoms but is associated with early discontinuation. Determining the persistence rates of anti-dementia drug use after donepezil initiation may inform the development and improvement of treatment strategies, but there is little evidence from Japan. Objective: To determine anti-dementia drug persistence following donepezil initiation among AD patients in Japan using insurance claims data. Methods: Insurance claims data for AD patients with newly prescribed donepezil were obtained from 17 municipalities between April 2014 and October 2021. Anti-dementia drug persistence was defined as a gap of ≤60 days between …the last donepezil prescription and a subsequent prescription of donepezil, another cholinesterase inhibitor, or memantine. Cox proportional hazards models were used to analyze the association between care needs levels and discontinuation. Results: We analyzed 20,474 AD patients (mean age±standard deviation: 82.2±6.3 years, women: 65.7%). The persistence rates were 89.1% at 30 days, 79.4% at 90 days, 72.6% at 180 days, 64.5% at 360 days, and 58.3% at 540 days after initiation. Among the care needs levels, the hazard ratio (95% confidence interval) for discontinuation was 1.01 (0.94–1.07) for patients with support needs, 1.12 (1.06–1.18) for patients with low long-term care needs, and 1.31 (1.21–1.40) for patients with moderate-to-high long-term care needs relative to independent patients. Conclusion: Japanese AD patients demonstrated low anti-dementia drug persistence rates that were similar to those of other countries. Higher long-term care needs were associated with discontinuation. Further measures are needed to improve drug persistence in AD patients. Show more

Keywords: Alzheimer’s disease, claims database, dementia, donepezil, persistence

DOI: 10.3233/JAD-220200

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1177-1186, 2022

Authors: Beam, Christopher R. | Luczak, Susan E. | Panizzon, Matthew S. | Reynolds, Chandra A. | Christensen, Kaare | Dahl Aslan, Anna K. | Elman, Jeremy A. | Franz, Carol E. | Kremen, William S. | Lee, Teresa | Nygaard, Marianne | Sachdev, Perminder S. | Whitfield, Keith E. | Pedersen, Nancy L. | Gatz, Margaret

Article Type: Research Article

Abstract: Background: Epidemiological research on dementia is hampered by differences across studies in how dementia is classified, especially where clinical diagnoses of dementia may not be available. Objective: We apply structural equation modeling to estimate dementia likelihood across heterogeneous samples within a multi-study consortium and use the twin design of the sample to validate the results. Methods: Using 10 twin studies, we implement a latent variable approach that aligns different tests available in each study to assess cognitive, memory, and functional ability. The model separates general cognitive ability from components indicative of dementia. We examine the validity …of this continuous latent dementia index (LDI). We then identify cut-off points along the LDI distributions in each study and align them across studies to distinguish individuals with and without probable dementia. Finally, we validate the LDI by determining its heritability and estimating genetic and environmental correlations between the LDI and clinically diagnosed dementia where available. Results: Results indicate that coordinated estimation of LDI across 10 studies has validity against clinically diagnosed dementia. The LDI can be fit to heterogeneous sets of memory, other cognitive, and functional ability variables to extract a score reflective of likelihood of dementia that can be interpreted similarly across studies despite diverse study designs and sampling characteristics. Finally, the same genetic sources of variance strongly contribute to both the LDI and clinical diagnosis. Conclusion: This latent dementia indicator approach may serve as a model for other research consortia confronted with similar data integration challenges. Show more

Keywords: Dementia, genetic correlation, harmonization, latent index, quality of life, twin study

DOI: 10.3233/JAD-220472

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1187-1201, 2022

Authors: Chen, Ting-Hsiang | Yeh, Yi-Chun | Huang, Mei-Feng | Chen, Hui-Mei | Lee, Jia-In | Chen, Cheng-Sheng

Article Type: Research Article

Abstract: Background: The Mild Behavioral Impairment Checklist (MBI-C) has been developed to assess mild behavioral impairment (MBI). However, no study has validated the use of MBI-C using a promising translation method in Taiwan. Thus, consistency and discrepancy between informant-rated and self-rated scores have not been extensively researched. Objective: This study validated and compared the informant- and self-rated versions of the MBI-C among community-dwelling people in Taiwan. Method: We recruited 202 pairs of individuals without dementia aged ≥50 years and their cohabitating informants. The participants completed the MBI-C (MBI-C-self), and the informants completed the MBI-C (MBI-C-informant) and the …Neuropsychiatric Inventory Questionnaire (NPI-Q) independently. Internal consistency, inter-rater reliability, and convergent validity were examined. Results: Both MBI-C-self and MBI-C-informant exhibited satisfactory Cronbach’s α values (0.92 and 0.88, respectively). The MBI-C-informant total scorewas correlated with the NPI-Q total score (r = 0.83, p < 0.001). Inter-rater reliability between the two versions, as represented by the inter-rater correlation coefficient, was 0.57 (p < 0.001). The prevalence of MBI based on the MBI-C-informant scores was 1.5% higher than that based on the MBI-C-self scores according to the suggested cut-off score of 8.5. The affective dysregulation domain score of MBI-C-informant was significantly lower than that of MBI-C-self. Conclusion: MBI-C-informant exhibited both high reliability and validity. Discrepancies between MBI-C-informant and MBI-C-self related to the detection rates and affective dysregulation domain scores were noted. The level of consistency and discrepancy between these two versions provide implications for the use of MBI-C in clinical practice and future research. Show more

Keywords: Mild behavioral impairment, Mild Behavioral Impairment Checklist, prodromal, validation

DOI: 10.3233/JAD-220006

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1203-1213, 2022

Authors: Guo, Yumiao | Kang, Meimei | Hui, Xinjie | Fan, Xiaojun | Zhang, Lianguo | Wang, Yejun | Wang, Rong | Nie, Xiuhong

Article Type: Research Article

Abstract: Background: Obstructive sleep apnea (OSA) is a multi-component disorder, which has many comorbidities, including cognitive impairment. Although its potential risk factors were unknown, they could affect the patient’s quality of life and long-term prognosis. Objective: The purpose of this study was to investigate the application of urinary Alzheimer’s disease-associated neurofilament protein (AD7c-NTP) levels in the assessment of cognitive impairment in OSA patients, and to analyze the predictive value of potential high-risk factors on cognitive impairment in OSA patients. Methods: 138 young and middle-aged adults were recruited and underwent overnight polysomnographic recording, Montreal Cognitive Assessment (MoCA), and …urinary AD7c-NTP test. AD7c-NTP and other factors were further applied as biomarkers to develop a cognition risk prediction model. Results: Compared with the control, OSA patients showed significantly lower MoCA scores and higher urinary AD7c-NTP concentrations, while the severe OSA group appeared more significant. The urinary AD7c-NTP level of the OSA cognitive impairment group was higher than that of the non-cognitive impairment group. The results of regression analysis showed that urinary AD7c-NTP level was an independent predictor of cognitive impairment in OSA patients. Based on urinary AD7c-NTP levels and other selected factors, a multimodal prediction model for assessing the risk of cognitive impairment in OSA patients was initially established. Conclusion: The increased urinary AD7c-NTP level could be used as a relevant peripheral biomarker of cognitive impairment in OSA patients. A model using urinary AD7c-NTP combined with other factors was developed and could accurately assess the cognition risk of OSA patients. Show more

Keywords: Alzheimer’s disease-associated neurofilament protein (AD7c-NTP), mild cognitive impairment, obstructive sleep apnea, risk prediction model, PredCI_OSA

DOI: 10.3233/JAD-220451

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1215-1231, 2022

Authors: Weller, Andrew E. | Ferraro, Thomas N. | Doyle, Glenn A. | Reiner, Benjamin C. | Crist, Richard C. | Berrettini, Wade H.

Article Type: Research Article

Abstract: Background: 5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer’s disease (AD)-related pathology. Objective: To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice. Methods: Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models. We analyzed cell type-specific DEGs further using Ingenuity Pathway Analysis (IPA). …Results: We identified several DEGs in both neuronal and glial cell subtypes in comparisons of wild type (WT) versus 5XFAD and WT versus T2KO mice, including Ttr , Fth1 , Pcsk1n , Malat1 , Rpl37 , Rtn1 , Sepw1 , Uba52 , Mbp , Arl6ip5 , Gm26917 , Vwa1 , and Pgrmc1 . We also observed DTU in common between the two comparisons in neuronal and glial subtypes, specifically in the genes Prnp , Rbm4b , Pnisr , Opcml , Cpne7 , Adgrb1 , Gabarapl2 , Ubb , Ndfip1 , Car11 , and Stmn4. IPA identified three statistically significant canonical pathways that appeared in multiple cell types and that overlapped between 5XFAD and T2KO comparisons to WT, including ‘FXR/RXR Activation’, ‘LXR/RXR Activation’, and ‘Acute Phase Response Signaling’. Conclusion: DEG, DTU, and IPA findings, derived from two different mouse models of AD, highlight the importance of energy imbalance and inflammatory processes in specific hippocampal cell types, including subtypes of neurons and glial cells, in the development of AD-related pathology. Additional studies are needed to further characterize these findings. Show more

Keywords: Alzheimer’s disease, animal disease models, gene expression profiling, knockout mice, mice, polyadenylation, RNA-seq

DOI: 10.3233/JAD-220391

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1233-1247, 2022

Authors: Wu, Xin-Rui | Wu, Kai-Min | Deng, Yue-Ting | Huang, Shu-Yi | Yang, Liu | Dong, Qiang | Feng, Jian-Feng | Cheng, Wei | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Previous studies have reported inconsistent associations between chronic kidney disease (CKD) and dementia. Objective: To evaluate whether CKD is a risk factor for dementia and compare the performance of different measures of calculating estimated glomerular filtration rate (eGFR). Methods: 275,167 participants from UK Biobank were included and eGFR at baseline was calculated using serum creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C equations (eGFRcr-cys). Restricted cubic splines and Cox regression models were performed to assess the relationship of eGFR with all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD). Results: We observed a …U-shaped relationship between each eGFR and risk of all-cause dementia and VaD, with eGFRcys and eGFRcr-cys showing a closer linkage (peGFRcys <0.0001, peGFRcrhboxcys <0.0001 and peGFRcr  = 0.0001). Lower and supranormal eGFR were related to increased risk of all-cause dementia. Compared to the reference category of 90–104 ml/min/1.73 m2 , adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause dementia for eGFRcr-cys 30–59, <30, and ≥105 ml/min/1.73 m2 were 1.26 (95% CI [1.05–1.50], p  = 0.012), 2.62 (95% CI [1.54–4.47], p  < 0.001), and 1.41 (95% CI [1.17–1.70], p  < 0.001). No statistically significant association was observed between eGFR with risk of AD. Conclusion: This prospective study identified impaired kidney function as a critical risk factor for dementia and noted the application of cystatin C strengthened the relationship between CKD and dementia, underlining the significant value of preserving kidney function to reduce the risk of dementia and considering cystatin C measurement as part of clinical practice. Show more

Keywords: Creatinine, cystatin C, dementia, glomerular filtration rate, kidney function

DOI: 10.3233/JAD-220609

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1249-1261, 2022

Authors: Gan, Jinghuan | Chen, Zhichao | Shi, Zhihong | Li, Xudong | Liu, Shuai | Liu, Yiming | Zhu, Hongcan | Shen, Lu | Zhang, Guili | You, Yong | Guo, Qihao | Zhang, Nan | Lv, Yang | Gang, Baozhi | Yuan, Junliang | Ji, Yong

Article Type: Research Article

Abstract: Background: Lewy body dementia is the second most common neurodegenerative dementia, but data concerning the onset age and clinical features in the prodromal stage remain limited in China. Objective: To investigate the associations between onset age and clinical manifestations of cognitive impairment with Lewy bodies in a large-sample cohort. Methods: We included 74 patients with mild cognitive impairment with Lewy bodies (MCI-LB), 533 patients with dementia with Lewy bodies (DLB), 118 patients with Parkinson’s disease with MCI (PD-MCI), and 313 patients with Parkinson’s disease dementia (PDD) in this multicenter cohort from 22 memory …clinics of China from 1 January 2018 to 31 March 2022. The onset age, clinical manifestations, and neuropsychological assessments were recorded and analyzed after reviewing the medical records. Results: The average onset age of memory loss was 68.28 (±7.00) years, and parkinsonism happened 2.00 (±1.24) years later for patients with MCI-LB. The average onset age of parkinsonism was 60.56 (±8.96) years, and the memory loss happened 3.49 (±3.02) years later for patients with PD-MCI. Rapid eye movement sleep behavior disorder and visual hallucinations were frequently reported in MCI-LB, DLB, and PDD, while visual hallucinations were least frequently reported in PD-MCI. Lower scores of MMSE and depression, and higher scores of activities of daily living and delusions, were independently associated with older onset age in DLB. Conclusion: The onset of PD-MCI precedes MCI-LB, and memory loss occurs 3 years after parkinsonism. The onset age is associated with cognition and neuropsychiatric symptoms in process. Show more

Keywords: Age, sep Lewy body, sep mild cognitive impairment, sep multicenter, sep Parkinson’s disease

DOI: 10.3233/JAD-220657

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1263-1275, 2022