Journal of Alzheimer's Disease - Volume 86, issue 1

Authors: Henderson, Catherine | Knapp, Martin | Martyr, Anthony | Gamble, Laura D. | Nelis, Sharon M. | Quinn, Catherine | Pentecost, Claire | Collins, Rachel | Wu, Yu-Tzu | Jones, Ian R. | Victor, Christina R. | Pickett, James A. | Jones, Roy W. | Matthews, Fiona E. | Morris, Robin G. | Rusted, Jennifer | Thom, Jeanette M. | Clare, Linda | on behalf of the IDEAL programme team

Article Type: Research Article

Abstract: Background: The drivers of costs of care for people with dementia are not well understood and little is known on the costs of care for those with rarer dementias. Objective: To characterize use and costs of paid and unpaid care over time in a cohort of people with dementia living in Britain. To explore the relationship between cohort members’ demographic and clinical characteristics and service costs. Methods: We calculated costs of health and social services, unpaid care, and out-of-pocket expenditure for people with mild-to-moderate dementia participating in three waves of the IDEAL cohort (2014–2018). Latent growth …curve modelling investigated associations between participants’ baseline sociodemographic and diagnostic characteristics and mean weekly service costs. Results: Data were available on use of paid and unpaid care by 1,537 community-dwelling participants with dementia at Wave 1, 1,199 at Wave 2, and 910 at Wave 3. In models of paid service costs, being female was associated with lower baseline costs and living alone was associated with higher baseline costs. Dementia subtype and caregiver status were associated with variations in baseline costs and the rate of change in costs, which was additionally influenced by age. Conclusion: Lewy body and Parkinson’s disease dementias were associated with higher service costs at the outset, and Lewy body and frontotemporal dementias with more steeply increasing costs overall, than Alzheimer’s disease. Planners of dementia services should consider the needs of people with these relatively rare dementia subtypes as they may require more resources than people with more prevalent subtypes. Show more

Keywords: Dementia, dementia with Lewy bodies, frontotemporal dementia, health services, Parkinson’s disease dementia, social services, unpaid caregivers

DOI: 10.3233/JAD-215117

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 135-153, 2022

Authors: Lerch, Ondřej | Laczó, Martina | Vyhnálek, Martin | Nedelská, Zuzana | Hort, Jakub | Laczó, Jan

Article Type: Research Article

Abstract: Background: Cholinergic deficit and medial temporal lobe (MTL) atrophy are hallmarks of Alzheimer’s disease (AD) leading to early allocentric spatial navigation (aSN) impairment. APOE ɛ 4 allele (E4) is a major genetic risk factor for late-onset AD and contributes to cholinergic dysfunction. Basal forebrain (BF) nuclei, the major source of acetylcholine, project into multiple brain regions and, along with MTL and prefrontal cortex (PFC), are involved in aSN processing. Objective: We aimed to determine different contributions of individual BF nuclei atrophy to aSN in E4 positive and E4 negative older adults without dementia and assess whether they …operate on aSN through MTL and PFC or independently from these structures. Methods: 120 participants (60 E4 positive, 60 E4 negative) from the Czech Brain Aging Study underwent structural MRI and aSN testing in real-space arena setting. Hippocampal and BF nuclei volumes and entorhinal cortex and PFC thickness were obtained. Associations between brain regions involved in aSN were assessed using MANOVA and complex model of mutual relationships was built using structural equation modelling (SEM). Results: Path analysis based on SEM modeling revealed that BF Ch1-2, Ch4p, and Ch4ai nuclei volumes were indirectly associated with aSN performance through MTL (pch1 - 2  = 0.039; pch4p  = 0.042) and PFC (pch4ai  = 0.044). In the E4 negative group, aSN was indirectly associated with Ch1-2 nuclei volumes (p  = 0.015), while in the E4 positive group, there was indirect effect of Ch4p nucleus (p  = 0.035). Conclusion: Our findings suggest that in older adults without dementia, BF nuclei affect aSN processing indirectly, through MTL and PFC, and that APOE E4 moderates these associations. Show more

Keywords: Allocentric spatial navigation, apolipoprotein E, basal forebrain, entorhinal cortex, hippocampus, magnetic resonance imaging, prefrontal cortex

DOI: 10.3233/JAD-215034

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 155-171, 2022

Authors: Dennison, Jessica L. | Volmar, Claude-Henry | Modarresi, Farzaneh | Ke, Danbing | Wang, James | Gravel, Emilie | Hammond-Vignini, Sabrina | Li, Zuomei | Timmons, James A. | Lohse, Ines | Hayward, Marshall A. | Brothers, Shaun P. | Wahlestedt, Claes

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROL™, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. Objective: We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. Methods: For sub-chronic reversal studies, 15-month-old male triple transgenic …(APPSW /PS1M146V /TauP301L ; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. Results: JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1 ) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. Conclusion: JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels. Show more

Keywords: Alzheimer’s disease, inflammation, neuroprotection, resveratrol, sex differences

DOI: 10.3233/JAD-215370

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 173-190, 2022

Authors: Zhang, Li-Na | Li, Meng-Jie | Shang, Ying-Hui | Liu, Yun-Ru | Han-Chang, Huang | Lao, Feng-Xue

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) characterized by neurofibrillary tangles caused by hyperphosphorylated tau is the most common cause of dementia. Zeaxanthin (Zea), derived from fruits and vegetables, may reduce the risk of AD. Endoplasmic reticulum stress (ERS) might cause memory impairment in AD. Objective: Here, we studied protective role of Zea on the relationship among ERS, activity of glycogen synthase kinase 3β (GSK-3β, tau phosphorylated kinase), and p-Tau (Ser 396 and Thr 231). Methods: The results were obtained in non-RA and RA group by using different treatment, such as 9-cis-retinoic acid (RA), TM (ERS inducer), Zea, 4-PBA …(ERS inhibitor), and SB216763 (GSK-3β inhibitor). The methods included flow cytometry and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] for the detections of cell cycle and cell viability and western blot as a third measure of proteins in relation to ERS and tau phosphorylation. We have collected and analyzed all the data that suggested application of drugs for the treatment in non-RA and RA group. Results: Zea displays its protection on TM-induced cell injury, upregulation of GRP78 expression, and change of GSK-3β activity and tau phosphorylation when 4-PBA and SB216763 interfere with the process. Conclusion: These studies indicated that Zea is in vicious circle in ERS, GSK-3β, and tau phosphorylation, and further reflect its potential value in AD. Show more

Keywords: Alzheimer’s disease, glycogen synthase kinase 3β, SB216763, tau, Zeaxanthin

DOI: 10.3233/JAD-215408

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 191-204, 2022

Authors: Premi, Enrico | Costa, Tommaso | Gazzina, Stefano | Benussi, Alberto | Cauda, Franco | Gasparotti, Roberto | Archetti, Silvana | Alberici, Antonella | van Swieten, John C. | Sanchez-Valle, Raquel | Moreno, Fermin | Santana, Isabel | Laforce, Robert | Ducharme, Simon | Graff, Caroline | Galimberti, Daniela | Masellis, Mario | Tartaglia, Carmela | Rowe, James B. | Finger, Elizabeth | Tagliavini, Fabrizio | de Mendonça, Alexandre | Vandenberghe, Rik | Gerhard, Alexander | Butler, Chris R. | Danek, Adrian | Synofzik, Matthis | Levin, Johannes | Otto, Markus | Ghidoni, Roberta | Frisoni, Giovanni | Sorbi, Sandro | Peakman, Georgia | Todd, Emily | Bocchetta, Martina | Rohrer, Johnathan D. | Borroni, Barbara | GENFI Consortium Members

Collaborators: Afonso, Sónia | Rosario Almeida, Maria | Anderl-Straub, Sarah | Andersson, Christin | Antonell, Anna | Arighi, Andrea | Balasa, Mircea | Barandiaran, Myriam | Bargalló, Nuria | Bartha, Robart | Bender, Benjamin | Benussi, Luisa | Bessi, Valentina | Binetti, Giuliano | Black, Sandra | Borrego-Ecija, Sergi | Bras, Jose | Bruffaerts, Rose | Caroppo, Paola | Cash, David | Castelo-Branco, Miguel | Convery, Rhian | Cope, Thomas | de Arriba, María | Di Fede, Giuseppe | Díaz, Zigor | Duro, Diana | Fenoglio, Chiara | Ferrari, Camilla | B. Ferreira, Catarina | Fox, Nick | Freedman, Morris | Fumagalli, Giorgio | Gabilondo, Alazne | Gauthier, Serge | Giaccone, Giorgio | Gorostidi, Ana | Greaves, Caroline | Guerreiro, Rita | Heller, Carolin | Hoegen, Tobias | Indakoetxea, Begoña | Jelic, Vesna | Jiskoot, Lize | Karnath, Hans-Otto | Keren, Ron | Langheinrich, Tobias | João Leitão, Maria | Lladó, Albert | Lombardi, Gemma | Loosli, Sandra | Maruta, Carolina | Mead, Simon | Meeter, Lieke | Miltenberger, Gabriel | van Minkelen, Rick | Mitchell, Sara | Moore, Katrina | Nacmias, Benedetta | Nicholas, Jennifer | Öijerstedt, Linn | Olives, Jaume | Panman, Jessica | Papma, Janne | Pievani, Michela | Pijnenburg, Yolande | Polito, Cristina | Prioni, Sara | Prix, Catharina | Rademakers [as London Ontario geneticist], Rosa | Redaelli, Veronica | Rittman, Tim | Rogaeva, Ekaterina | Rosa-Neto, Pedro | Rossi, Giacomina | Rossor, Martin | Santiago, Beatriz | Scarpini, Elio | Schönecker, Sonja | Semler, Elisa | Shafei, Rachelle | Shoesmith, Christen | Tábuas-Pereira, Miguel | Tainta, Mikel | Taipa, Ricardo | Tang-Wai, David | L Thomas, David | Thompson, Paul | Thonberg, Hakan | Timberlake, Carolyn | Tiraboschi, Pietro | Van Damme, Philip | Vandenbulcke, Mathieu | Veldsman, Michele | Verdelho, Ana | Villanua, Jorge | Warren, Jason | Wilke, Carlo | Woollacott, Ione | Wlasich, Elisabeth | Zetterberg, Henrik | Zulaica, Miren

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD). Objectives: To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD. Methods: 84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.2±16.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded. Results: Prediction accuracy was high for each considered brain region (i.e., prefrontal region, …real CT at follow-up versus predicted CT at follow-up, mean error ≤1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power = 0.80, alpha = 0.05). Conclusion: The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself. Show more

Keywords: Frontotemporal dementia, granulin, magnetic resonance imaging, mutation, preclinical, presymptomatic

DOI: 10.3233/JAD-215447

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 205-218, 2022

Authors: Manivannan, Madhumitha | Heunis, Julia | Hooper, Sarah M. | Bernstein Sideman, Alissa | Lui, Kristi P. | Braley, Tamara L. | Possin, Katherine L. | Chiong, Winston

Article Type: Research Article

Abstract: Background: Financial mismanagement and abuse in dementia have serious consequences for patients and their families. Vulnerability to these outcomes reflects both patient and contextual factors. Objective: Our study aimed to assess how multidisciplinary care coordination programs assist families in addressing psychosocial vulnerabilities and accessing needed resources. Methods: Our study was embedded in a clinical trial of the Care Ecosystem, a telephone- and internet-based supportive care intervention for patients with dementia and caregivers. This program is built around the role of the Care Team Navigator (CTN), an unlicensed dementia care guide who serves as the patient and …caregiver’s primary point of contact, screening for common problems and providing support. We conducted a qualitative analysis of case summaries from a subset of 19 patient/caregiver dyads identified as having increased risk for financial mismanagement and abuse, to examine how Care Ecosystem staff identified vulnerabilities and provided support to patients and families. Results: CTNs elicited patient and caregiver needs using templated conversations to address common financial and legal planning issues in dementia. Sources of financial vulnerability included changes in patients’ behavior, caregiver burden, intrafamily tension, and confusion about resources to facilitate end-of-life planning. The Care Ecosystem staff’s rapport with their dyads helped them address these issues by providing emotional support, information on how to access financial, medical, and legal resources, and improving intra-familial communication. Conclusion: The Care Ecosystem offers a scalable way to address vulnerabilities to financial mismanagement and abuse in patients and caregivers through coordinated care by unlicensed care guides supported by a multidisciplinary team. Show more

Keywords: Care navigation, caregivers, dementia, financial management

DOI: 10.3233/JAD-215284

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 219-229, 2022

Authors: Siddiqui, Fatima | Nistala, Kameswara Rishi Yeshayahu | Quek, Chrystie Wan Ning | Leong, Victoria Shi Ying | Tan, Amarinda Ying Shan | Tan, Christopher Yu En | Hilal, Saima

Article Type: Research Article

Abstract: Background: Dementia is the decline in cognitive function sufficient to impair one’s accustomed functioning. Countries with aging populations, such as Singapore, face rising rates of dementia. Dementia patients and their caregivers endure great financial and emotional stress. With the broad aim of minimizing these stresses, this study provides a cross-sectional view of the knowledge, attitudes, and perceptions (KAP) towards dementia in middle-aged Singaporean residents. Objective: We aim to examine 1) the associations between demographic correlates and KAP; and 2) the effect of dementia knowledge on attitudes and perceptions towards dementia. Methods: An online anonymous cross-sectional questionnaire …was administered to Singaporeans and Permanent Residents aged 45 to 65 years old in English, Mandarin, and Malay. Knowledge was evaluated across three domains: symptoms, risk factors, and management. Total and domain scores were dichotomized as good or poor knowledge using median cut-offs. Attitudes/perceptions across six domains were evaluated on Likert scales, and responses to each question were dichotomized into positive or negative attitudes/perceptions. Results: From 1,733 responses, 1,209 valid complete responses were accepted (mean age±SD 54.8±5.12 years old, females = 69.6%). Lower socioeconomic status was associated with poorer knowledge and greater barriers to risk-mitigating lifestyle modifications. Lack of personal experience with dementia and poor knowledge were also associated with erroneous attitudes/perceptions. Conclusion: Socioeconomic status and personal experience affect KAP towards dementia. Policy and education campaigns to address KAP towards dementia should account for baseline differences across demographics, for greater improvements in dementia incidence and support. Show more

Keywords: Attitudes, dementia, knowledge, middle age, practices

DOI: 10.3233/JAD-215262

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 231-244, 2022

Authors: Secnik, Juraj | Xu, Hong | Schwertner, Emilia | Hammar, Niklas | Alvarsson, Michael | Winblad, Bengt | Eriksdotter, Maria | Garcia-Ptacek, Sara | Religa, Dorota

Article Type: Research Article

Abstract: Background: The effectiveness of glucose-lowering drugs (GLDs) is unknown among patients with dementia. Objective: To analyze all-cause mortality among users of six GLDs in dementia and dementia-free subjects, respectively. Methods: This was a longitudinal open-cohort registry-based study using data from the Swedish Dementia Registry, Total Population Register, and four supplemental registers providing data on dementia status, drug usage, confounders, and mortality. The cohort comprised 132,402 subjects with diabetes at baseline, of which 11,401 (8.6%) had dementia and 121,001 (91.4%) were dementia-free. Subsequently, comparable dementia – dementia-free pairs were sampled. Then, as-treated and intention-to-treat exposures to metformin, …insulin, sulfonylurea, dipeptidyl-peptidase-4 inhibitors, glucagon-like peptide-1 analogues (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) were analyzed in the parallel dementia and dementia-free cohorts. Confounding was addressed using inverse-probability weighting and propensity-score matching, and flexible parametric survival models were used to produce hazard ratios (HR) and 95% confidence intervals (CI) of the association between GLDs and all-cause mortality. Results: In the as-treated models, increased mortality was observed among insulin users with dementia (HR 1.34 [95%CI 1.24–1.45]) as well as in dementia-free subjects (1.54 [1.10–1.55]). Conversely, sulfonylurea was associated with higher mortality only in dementia subjects (1.19 [1.01–1.42]). GLP-1a (0.44 [0.25–0.78]) and SGLT-2i users with dementia (0.43 [0.23–0.80]) experienced lower mortality compared to non-users. Conclusion: Insulin and sulfonylurea carried higher mortality risk among dementia patients, while GLP-1a and SGLT-2i were associated with lower risk. GLD-associated mortality varied between dementia and comparable dementia-free subjects. Further studies are needed to optimize GLD use in dementia patients. Show more

Keywords: Antidiabetics, dementia, diabetes, hyperglycemia, mortality, propensity-score

DOI: 10.3233/JAD-215337

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 245-257, 2022

Authors: Che, Bizhong | Chen, Haichang | Wang, Aili | Peng, Hao | Bu, Xiaoqing | Zhang, Jintao | Ju, Zhong | Xu, Tan | He, Jiang | Zhong, Chongke | Zhang, Yonghong

Article Type: Research Article

Abstract: Background: L-carnitine has been shown to exert neuroprotective effects on cerebral ischemia, mainly by improving mitochondrial function and reducing inflammation. L-carnitine supplementation has also been promoted to enhance cognitive function. However, the relationship between L-carnitine and cognitive impairment after ischemic stroke has seldom been studied. Objective: We aimed to evaluate the association between plasma L-carnitine and poststroke cognitive impairment. Methods: The study sample population was drawn from the China Antihypertensive Trial in Acute Ischemic Stroke. Plasma L-carnitine were measured at baseline in 617 patients with ischemic stroke using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Cognitive function was …evaluated using the Montreal Cognitive Assessment at 3-month follow-up after ischemic stroke. Results: Plasma L-carnitine were inversely associated with cognitive impairment at 3 months after ischemic stroke, and the adjusted odds ratio (95% CI) for the highest versus lowest quartiles of L-carnitine was 0.60 (0.37, 0.98; p for trend = 0.04). Each 1-SD increase in log-transformed L-carnitine concentration was significantly associated with a 15% (95% CI: 1%, 29%) reduction in the risk of cognitive impairment after stroke. The addition of L-carnitine to the model including conventional risk factors significantly improved the risk reclassification for cognitive impairment (net reclassification improvement: 17.9%, integrated discrimination improvement: 0.8%; both p  < 0.05). Furthermore, joint effects of L-carnitine and inflammation markers were observed, and patients with higher L-carnitine and a lower inflammatory status simultaneously had the lowest risk of poststroke cognitive impairment. Conclusion: The present study provided prospective evidence on the inverse association between plasma L-carnitine and cognitive impairment after ischemic stroke. Show more

Keywords: Acute ischemic stroke, cognitive impairment, inflammation, L-carnitine

DOI: 10.3233/JAD-215376

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 259-270, 2022

Authors: Schaffert, Jeff | LoBue, Christian | Hynan, Linda S. | Hart Jr., John | Rossetti, Heidi | Carlew, Anne R. | Lacritz, Laura | White III, Charles L. | Cullum, C. Munro

Article Type: Research Article

Abstract: Background: Life expectancy (LE) following Alzheimer’s disease (AD) is highly variable. The literature to date is limited by smaller sample sizes and clinical diagnoses. Objective: No study to date has evaluated predictors of AD LE in a retrospective large autopsy-confirmed sample, which was the primary objective of this study. Methods: Participants (≥50 years old) clinically and neuropathologically diagnosed with AD were evaluated using National Alzheimer’s Coordinating Center (N = 1,401) data. Analyses focused on 21 demographic, medical, neuropsychiatric, neurological, functional, and global cognitive predictors of LE at AD dementia diagnosis. These 21 predictors were evaluated in univariate analyses. …Variables found to be significant were then entered into a forward multiple regression. LE was defined as months between AD diagnosis and death. Results: Fourteen predictors were significant in univariate analyses and entered into the regression. Seven predictors explained 27% of LE variance in 764 total participants. Mini-Mental State Examination (MMSE) score was the strongest predictor of LE, followed by sex, age, race/ethnicity, neuropsychiatric symptoms, abnormal neurological exam results, and functional impairment ratings. Post-hoc analyses revealed correlations of LE were strongest with MMSE ≤12. Conclusion: Global cognitive functioning was the strongest predictor of LE following diagnosis, and AD patients with severe impairment had the shortest LE. AD patients who are older, male, white, and have more motor symptoms, functional impairment, and neuropsychiatric symptoms were also more likely have shorter LE. While this model cannot provide individual prognoses, additional studies may focus on these variables to enhance predictions of LE in patients with AD. Show more

Keywords: Alzheimer’s disease, autopsy-confirmed, dementia, life expectancy, mortality

DOI: 10.3233/JAD-215200

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 271-281, 2022