Journal of Alzheimer's Disease - Volume 93, issue 2

Authors: Heikkinen, Sami | Huber, Nadine | Katisko, Kasper | Kokkola, Tarja | Hartikainen, Päivi | Krüger, Johanna | Leinonen, Ville | Korhonen, Ville E. | Herukka, Sanna-Kaisa | Remes, Anne M. | Borroni, Barbara | Alberici, Antonella | Libri, Ilenia | Solje, Eino | Haapasalo, Annakaisa

Article Type: Short Communication

Abstract: Frontotemporal dementia (FTD) can manifest as diverse clinical phenotypes and is frequently caused by mutations in different genes, complicating differential diagnosis. This underlines the urgent need for valid biomarkers. Altered lysosomal and immune functions proposedly contribute to FTD pathogenesis. Cathepsins, including cathepsin S, are enzymes preferentially expressed in brain in microglia, which influence lysosomal and immune function. Here, we examined whether alterations in serum cathepsin S levels associate with specific clinical, genetic, or neuropathological FTD subgroups, but no such alterations were observed. However, further research on other lysosomal proteins may reveal new biologically relevant biomarkers in FTD.

Keywords: Biomarker, cathepsin S, C9orf72, diagnostics, frontotemporal dementia, GRN, MAPT, proteinopathy, tau, TDP-43

DOI: 10.3233/JAD-221060

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 395-401, 2023

Authors: Rhyu, Jee-Min | Park, Joonhong | Shin, Byoung-Soo | Kim, Young-Eun | Kim, Eun-Joo | Kim, Ko Woon | Cho, Yong Gon

Article Type: Short Communication

Abstract: Mutations in ITM2B have been reported to be associated with several familial dementias, such as Familial British dementia and familial Danish dementia. These are autosomal dominant disorders characterized by progressive dementia with an onset at around the fifth decade of life. We describe a family with cognitive impairment caused by a novel ITM2B p.*267Serext*11 mutation. The probands presented with cognitive impairment and cerebral infarction. MRI revealed diffuse white matter hyperintensity and microbleeds. Amyloid deposition was not observed on amyloid positron emission tomography. Our case suggests that the BRI2 mutation impacts cognition regardless of amyloid-β accumulation.

Keywords: Alzheimer’s disease, c.800G>C, cerebral amyloid angiopathy, dementia, ITM2B gene, white matter hyperintensity

DOI: 10.3233/JAD-230051

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 403-409, 2023

Authors: Sulheim, Einar | WiderØe, Marius | Bäck, Marcus | Nilsson, K. Peter R. | Hammarström, Per | Nilsson, Lars N.G. | Davies, Catharina de Lange | Åslund, Andreas K.O.

Article Type: Research Article

Abstract: Background: Early detection of amyloid-β (Aβ) aggregates is a critical step to improve the treatment of Alzheimer’s disease (AD) because neuronal damage by the Aβ aggregates occurs before clinical symptoms are apparent. We have previously shown that luminescent conjugated oligothiophenes (LCOs), which are highly specific towards protein aggregates of Aβ, can be used to fluorescently label amyloid plaque in living rodents. Objective: We hypothesize that the LCO can be used to target gadolinium to the amyloid plaque and hence make the plaque detectable by T1 -weighted magnetic resonance imaging (MRI). Methods: A novel LCO-gadolinium construct was …synthesized to selectively bind to Aβ plaques and give contrast in conventional T1 -weighted MR images after intravenous injection in Tg-APPSwe mice. Results: We found that mice with high plaque-burden could be identified using the LCO-Gd constructs by conventional MRI. Conclusion: Our study shows that MR imaging of amyloid plaques is challenging but feasible, and hence contrast-mediated MR imaging could be a valuable tool for early AD detection. Show more

Keywords: Alzheimer’s disease, amyloid-β (Aβ), fluorescence, magnetic resonance imaging, multimodal imaging

DOI: 10.3233/JAD-220198

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 411-419, 2023

Authors: Eithz, Nanna | Sørensen, Jan | Sopina, Liza

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) carries a significant economic burden, with costs peaking around the time of diagnosis. However, the cost of diagnosis, including the time leading up to it, has not been studied thoroughly. Furthermore, regionalized healthcare structure could result in differences in the pre-diagnostic costs for people with suspected AD. Objective: This study set out to estimate the excess healthcare costs before and after AD diagnosis compared to a matched non-AD population and to investigate regional variation in AD healthcare costs in Denmark. Methods: We used a register-based cohort of 25,523 matched pairs of new …cases of AD and non-AD controls. The healthcare costs included costs on medication, and inpatient-, outpatient-, and primary care visits. Generalized estimating equations were employed to estimate the excess healthcare cost attributable to diagnosing AD, and the variation in costs across regions. Results: Mean excess costs attributable to AD were € 3,284 and € 6,173 in the year before and after diagnosis, respectively. Regional differences in healthcare costs were identified in both the AD and control groups and were more pronounced in patients with AD (PwAD). Conclusion: PwAD incur higher healthcare costs across all cost categories in the year before and after diagnosis. Regional differences in healthcare utilization by PwAD may reveal potential variation in access to healthcare. These findings suggest that a more standardized and targeted diagnostic process may help reduce costs and variation in access to healthcare. Show more

Keywords: Alzheimer’s disease, cohort study, cost, diagnosis

DOI: 10.3233/JAD-220821

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 421-433, 2023

Authors: Qian, Lin | Bian, Wenjuan | Wang, Diqi | Ming, Zhuoqun | Zhang, Yu | Zhang, Linbo | Fu, Lu

Article Type: Research Article

Abstract: Background: Patients with Alzheimer’s disease (AD) have considerably increased globally as a result of population aging, placing a significant burden on the global economy and the medical system. The outcome of clinical trials for AD immunotherapy that solely targeted amyloid-β (Aβ) or phosphorylated tau protein (p-Tau) was unsatisfactory. Therefore, blocking both Aβ and p-Tau’s pathological processes simultaneously while also preventing their interaction may be the key to developing an effective AD therapy. Objective: To develop a novel immunotherapy based on bispecific tandem scFv (TaFv) against AD. Methods: Bispecific single-chain antibody that targets both Aβ and p-Tau …were obtained using E. coli expression system. Biological ability of TaFvs were determined by ELISA, SDS-PAGE, and immunohistochemical assay. Recombinant adeno-associated virus 9 (rAAV9) were packaged to create TaFv. The in vivo activity of rAAV9 were detected in mouse, using biophotonic imaging and frozen section methods. Results: The outcomes demonstrated that both Aβ and p-Tau had a high affinity for the bispecific TaFv. Additionally, it can bind to the amyloid plaques and neuronal tangles in the brain slices of an AD mouse model. Moreover, the rAAV9 could infect neuronal cells, transverse the blood-brain barrier, and express TaFv in the mouse brain. Conclusion: This novel immunotherapy offers a fresh concept for the immunotherapy of AD and successfully delivers the double target antibody into the brain, acting on both pathogenic substances Aβ and p-Tau. Show more

Keywords: AAV9, Alzheimer’s disease, amyloid-β, bispecific Tandem scFv (TaFv), tau

DOI: 10.3233/JAD-221088

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 435-448, 2023

Authors: Duff, Kevin | Wan, Laura | Embree, Lindsay | Hoffman, John M.

Article Type: Research Article

Abstract: Background: The Quick Dementia Rating System (QDRS) is a brief, informant-reported dementia staging tool that approximates scores on the Clinical Dementia Rating Scale in patients with Alzheimer’s disease (AD). Objective: The current study sought to examine change in the QDRS across time, which is necessary for clinical and research efforts. Methods: One-hundred ten older adults (intact, mild cognitive impairment [MCI], mild AD, classified with Alzheimer’s Disease Neuroimaging Initiative criteria) were rated on the QDRS by an informant and had an amyloid positron emission tomography scan at baseline. The informant re-rated each participant on the QDRS after …one year. Dependent t-tests compared the entire sample and various subgroups (e.g., cognitive status, amyloid status) on baseline and follow-up QDRS scores. Results: In the entire sample, the Total score on the QDRS significantly increased (i.e., worsened) on follow-up (p  < 0.001). When subgroups were analyzed, the MCI and mild AD subjects showed increasing (i.e., worsening) QDRS Total scores (both p  < 0.001), but the intact subjects remained stable over time (p  = 0.28). Additionally, those classified as being amyloid positive at baseline showed significantly increased QDRS Total scores at follow-up (p  < 0.001) compared to those who were amyloid negative at baseline, whose QDRS Total scores remained stable over time (p  = 0.63). Conclusion: The QDRS can potentially demonstrate worsening functioning status across one year, especially in those who have MCI or mild AD and those who are amyloid positive. Therefore, the current results preliminarily suggest that the QDRS may provide an efficient tool for tracking progression in clinical trials in AD. Show more

Keywords: Alzheimer’s disease, cognitive decline, longitudinal studies, mild cognitive impairment

DOI: 10.3233/JAD-221252

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 449-457, 2023

Authors: Ma, Yanjun | Li, Chenglong | Hua, Rong | Yang, Chao | Xie, Wuxiang | Zhang, Luxia

Article Type: Research Article

Abstract: Background: Studies on the association between cystatin C based estimated glomerular filtration rate (eGFRcys) and cognitive outcomes yielded inconsistent results. Objective: The present study aimed to examine the potential association of eGFRcys with subsequent cognitive decline rate. Methods: A total of 11,503 community-based participants were involved in our analyses, including 5,837 (aged 72.9±6.3; 58.6% women) in the Health and Retirement Study (HRS) from the US and 5,666 (aged 58.1±9.2; 49.0% women) in the China Health and Retirement Longitudinal Study (CHARLS). The association of eGFRcys with subsequent cognitive decline rate was evaluated by linear mixed models. …Results: During 85,266 person-years of follow-up, both baseline elevated serum cystatin C (–0.048 standard deviation [SD]/year per mg/L; 95% confidence interval [CI], –0.060 to –0.036; p  < 0.001) and decreased eGFRcys (0.026 SD/year per 30 mL/min/1.73m2 ; 95% CI, 0.020 to 0.032; p  < 0.001) were associated with faster cognitive decline rate after full adjustment. Compared with those had eGFRcys ≥90 mL/min/1.73m2 , participants with eGFRcys between 60 to 90 mL/min/1.73m2 (–0.012 SD/year; 95% CI, –0.020 to –0.004; p  = 0.004) and those with eGFRcys <60 mL/min/1.73m2 (–0.048 SD/year; 95% CI, –0.058 to –0.039; p  < 0.001) experienced statistically significantly faster cognitive decline after adjustment. The associations were independent from serum creatinine/eGFRcre (eGFR that was calculated from serum creatinine). Conclusion: Decreased eGFRcys are significantly associated with faster cognitive decline after full adjustment, independently from serum creatinine/eGFRcre. Serum cystatin C might be a risk factor or a prodromal biomarker of cognitive decline. Show more

Keywords: Alzheimer’s disease, Cognitive decline, creatinine, cystatin, glomerular filtration rate

DOI: 10.3233/JAD-221162

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 459-469, 2023

Authors: Bae-Shaaw, Yuna H. | Shier, Victoria | Sood, Neeraj | Seabury, Seth A. | Joyce, Geoffrey

Article Type: Research Article

Abstract: Background: The Beers Criteria identifies potentially inappropriate medications (PIMs) that should be avoided in older adults living with dementia. Objective: The aim of this study was to provide estimates of the prevalence and persistence of PIM use among community-dwelling older adults living with dementia in 2011-2017. Methods: Medicare claims data were used to create an analytic dataset spanning from 2011 to 2017. The analysis included community-dwelling Medicare fee-for-service beneficiaries aged 65 and older who were enrolled in Medicare Part D plans, had diagnosis for dementia, and were alive for at least one calendar year. Dementia status …was determined using Medicare Chronic Conditions Date Warehouse (CCW) Chronic Condition categories and Charlson Comorbidity Index. PIM use was defined as 2 or more prescription fills with at least 90 days of total days-supply in a calendar year. Descriptive statistics were used to report the prevalence and persistence of PIM use. Results: Of 1.6 million person-year observations included in the sample, 32.7% used one or more PIMs during a calendar year in 2011-2017. Breakdown by drug classes showed that 14.9% of the sample used anticholinergics, 14.0% used benzodiazepines, and 11.0% used antipsychotics. Conditional on any use, mean annual days-supply for all PIMs was 270.6 days (SD = 102.7). The mean annual days-supply for antipsychotic use was 302.7 days (SD = 131.2). Conclusion: Significant proportion of community-dwelling older adults with dementia used one or more PIMs, often for extended periods of time. The antipsychotic use in the community-dwelling older adults with dementia remains as a significant problem. Show more

Keywords: Alzheimer’s disease, anticholinergics, antipsychotics, benzodiazepines, community-dwelling, dementia, potentially inappropriate medication

DOI: 10.3233/JAD-221168

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 471-481, 2023

Authors: Zheng, Yong-Bo | Sun, Jie | Shi, Le | Su, Si-Zhen | Chen, Xuan | Wang, Qian-Wen | Huang, Yue-Tong | Wang, Yi-Jie | Zhu, Xi-Mei | Que, Jian-Yu | Zeng, Na | Lin, Xiao | Yuan, Kai | Yan, Wei | Deng, Jia-Hui | Shi, Jie | Bao, Yan-Ping | Lu, Lin

Article Type: Research Article

Abstract: Background: Several epidemiological studies have reported the protective role of caffeine on health outcomes; however, it remained debatable on caffeine consumption and brain amyloid positivity. Objective: We aimed to determine the relationship between caffeine consumption and brain amyloid pathology in cognitively normal older adults. Methods: The dataset used for analysis in this cross-sectional study was selected from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study. Multivariable logistic regression analyses were performed to explore the association between caffeine consumption and amyloid positivity using odds ratios (ORs) and 95% confidence intervals (CIs). Results: In total, 4,394 …participants were included in the final analysis. No significant association between caffeine consumption and amyloid positivity was observed in the whole participants (OR, 0.95; 95% CI, 0.78–1.14; p  = 0.558). Subgroup analysis showed that caffeine intake was significantly associated with decreased amyloid positivity in males (OR, 0.72; 95% CI, 0.54–0.97; p  = 0.032) but not in females (OR, 1.14; 95% CI, 0.90–1.46; p  = 0.280), and the association between caffeine and amyloid positivity was not affected by age or APOE genotypes. In addition, different levels of caffeine were not associated with amyloid positivity. Conclusion: The findings suggest that caffeine consumption was not significantly associated with amyloid positivity in the whole sample. However, caffeine consumption may be inversely associated with amyloid positivity among males but not females. More studies are needed to explore the mechanisms underlying caffeine consumption and brain amyloid positivity. Show more

Keywords: Amyloid positivity, caffeine, dementia, sex-specific

DOI: 10.3233/JAD-220591

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 483-493, 2023

Authors: Nagaraja, Nandakumar | Wang, Wei-en | Duara, Ranjan | DeKosky, Steven T. | Vaillancourt, David

Article Type: Research Article

Abstract: Background: Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer’s disease (AD). Objective: To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. Methods: Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer’s Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in …four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. Results: The study included 231 patients with no (n  = 45), mild (n  = 70), moderate (n  = 67), and severe (n  = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p  = 0.023) but this was not significant when adjusted for APOE ɛ4 (p  = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p  = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p  = 0.04); but (b) had no evidence of correlation with CDRsb score (p  = 0.57). Conclusion: Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype. Show more

Keywords: Alzheimer’s disease, trophy, cerebral amyloid angiopathy, hippocampus

DOI: 10.3233/JAD-220624

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 495-507, 2023