Journal of Alzheimer's Disease - Volume 77, issue 3

Authors: van Engelen, Marie-Paule E. | Gossink, Flora T. | de Vijlder, Lieke S. | Meursing, Jan R.A. | Scheltens, Philip | Dols, Annemiek | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: Background: Limited literature exists regarding the clinical features of end stage behavioral variant frontotemporal dementia (bvFTD). This data is indispensable to inform and prepare family members as well as professional caregivers for the expected disease course and to anticipate with drug-based and non-pharmacological treatment strategies. Objective: The aim of the present study was to describe end stage bvFTD in a broad explorative manner and to subsequently evaluate similarities and dissimilarities with the end stage of the most prevalent form of young-onset dementia, Alzheimer’s disease (yoAD). Methods: We analyzed medical files on patients, using a mixed model …of qualitative and quantitative approaches. Included were previously deceased patients with probable bvFTD and probable yoAD. End stage was defined as the last 6 months prior to death. Primary outcome measures comprised somatic, neurological, and psychiatric symptoms and the secondary outcome measure was cause of death. Results: Out of 89 patients, a total of 30 patients were included (bvFTD; n  = 12, yoAD; n  = 18). Overall, the end stages of bvFTD and yoAD were characterized by a broad spectrum of clinical symptoms including severe autonomic dysfunction and an increased muscle tone. Patients with bvFTD displayed more mutism compared with yoAD while compulsiveness was only present in bvFTD. Conclusion: Our study describes the full clinical spectrum of end stage bvFTD and yoAD. In this study, symptoms extend far beyond the initial behavioral and cognitive features. By taking both somatic, psychiatric, and neurological features into account, family members and professional caregivers may anticipate (non) pharmacological treatment. Show more

Keywords: Alzheimer’s disease, disorders of the autonomic nervous system, frontotemporal dementia, nursing homes, palliative care

DOI: 10.3233/JAD-200337

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1169-1180, 2020

Authors: Aigbogun, Myrlene Sanon | Cloutier, Martin | Gauthier-Loiselle, Marjolaine | Guerin, Annie | Ladouceur, Martin | Baker, Ross A. | Grundman, Michael | Duffy, Ruth A. | Hartry, Ann | Gwin, Keva | Fillit, Howard

Article Type: Research Article

Abstract: Background: Few studies have examined patient characteristics and treatment patterns among patients with dementia and agitation in the United States (US). Objective: To examine real-world treatment patterns and characteristics of patients with agitation related to dementia who were treated with antipsychotics in US residential care and community-based settings. Methods: This retrospective chart review collected US physician-level data from patients 55 to 90 years old initiated on an antipsychotic medication for the treatment of agitation related to dementia from January 2018 to May 2018. Clinical characteristics and treatment patterns were assessed overall and stratified by residential care …and community-based settings. Results: A total of 313 participating physicians, 59.5% of whom were primary care physicians, abstracted 801 patient charts (residential care: n  = 312; community-based: n  = 489). Of patients with agitation who were initiated on an antipsychotic, most patients (74.5%) were initiated within 3 months of the onset of their studied agitation episode, and 62.8% experienced multiple agitation episodes before initiation. While non-pharmacological therapies are recommended first-line approach for agitation in dementia, use of non-pharmacological therapy before initiation of antipsychotics was reported for only 37.8% of patients in residential care and 21.3% in community-based settings. Conclusion: Most patients were initiated on an antipsychotic treatment after multiple episodes of agitation and largely without initial non-pharmacological therapy, suggesting that current treatment guideline recommendations for first-line non-pharmacological intervention may not be adequately followed in clinical practice. Understanding the clinical burden and treatment patterns among dementia patients with agitation is imperative for effective disease management. Show more

DOI: 10.3233/JAD-200127

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1181-1194, 2020

Authors: Jang, Jung Yun | Ho, Jean K. | Blanken, Anna E. | Dutt, Shubir | Nation, Daniel A. | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Affective neuropsychiatric symptoms (aNPS: depression, anxiety, apathy, irritability) have been linked to increased dementia risk. However, less is known whether this association is independent of Alzheimer’s disease (AD) pathophysiology. Objective: To investigate the contribution of early aNPS to dementia risk in cognitively normal (CN) older adults and mild cognitive impairment (MCI) patients, with and without AD biomarker abnormality. Methods: Participants included 763 community-dwelling, stroke-free older adults identified as CN and 617 with MCI at baseline, drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Baseline assessments included a neuropsychological battery, the Neuropsychiatric Inventory (NPI), and …apolipoprotein E ɛ 4 (ApoE4) genotyping. A participant subset completed cerebrospinal fluid (CSF) AD biomarker assessment. Time to progression to dementia was measured based on months at follow-up when an individual was diagnosed with dementia, over the follow-up period of 48 months. Results: Latent class analysis identified 3 subgroups of older adults in CN and MCI, indicated by the baseline profiles of neuropsychiatric symptoms (NPS). Subgroups with higher aNPS were at increased risk of progression to dementia in both CN (HR = 3.65, 95% CI [1.80, 7.40]) and MCI (HR = 1.52, 95% CI [1.16, 2.00]; HR = 1.86 [1.05, 3.30]) groups, adjusting for age, sex, global cognition, and ApoE4, compared with their counterparts with minimal NPS. There was no difference between higher aNPS and minimal NPS subgroups in their CSF AD biomarker profiles. Conclusion: Findings suggest that aNPS may represent a neurobiological vulnerability that uniquely contribute to the dementia risk, independent of AD biomarker profiles. Show more

Keywords: Alzheimer’s disease, CSF biomarkers, dementia, neuropsychiatric symptoms

DOI: 10.3233/JAD-200190

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1195-1207, 2020

Authors: Rai, Surya Prakash | Bascuñana, Pablo | Brackhan, Mirjam | Krohn, Markus | Möhle, Luisa | Paarmann, Kristin | Pahnke, Jens

Article Type: Research Article

Abstract: Background: The recent failure of clinical trials to treat Alzheimer’s disease (AD) indicates that the current approach of modifying disease is either wrong or is too late to be efficient. Mild cognitive impairment (MCI) denotes the phase between the preclinical phase and clinical overt dementia. AD mouse models that overexpress human amyloid-β (Aβ) are used to study disease pathogenesis and to conduct drug development/testing. However, there is no direct correlation between the Aβ deposition, the age of onset, and the severity of cognitive dysfunction. Objective: To detect and predict MCI when Aβ plaques start to appear in the …hippocampus of an AD mouse. Methods: We trained wild-type and AD mice in a Morris water maze (WM) task with different inter-trial intervals (ITI) at 3 months of age and assessed their WM performance. Additionally, we used a classification algorithm to predict the genotype (APPtg versus wild-type) of an individual mouse from their respective WM data. Results: MCI can be empirically detected using a short-ITI protocol. We show that the ITI modulates the spatial learning of AD mice without affecting the formation of spatial memory. Finally, a simple classification algorithm such as logistic regression on WM data can give an accurate prediction of the cognitive dysfunction of a specific mouse. Conclusion: MCI can be detected as well as predicted simultaneously with the onset of Aβ deposition in the hippocampus in AD mouse model. The mild cognitive impairment prediction can be used for assessing the efficacy of a treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β , genotype detection, logistic regression, MCI detection, MCI prediction, mild cognitive impairment, water maze

DOI: 10.3233/JAD-200675

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1209-1221, 2020

Authors: Blom, Kim | Koek, Huiberdina L. | Zwartbol, Maarten H.T. | Ghaznawi, Rashid | Kuijf, Hugo J. | Witkamp, Theo D. | Hendrikse, Jeroen | Biessels, Geert Jan | Geerlings, Mirjam I. | on behalf of the UCC-SMART Study Group

Article Type: Research Article

Abstract: Background: Vascular risk factors have been associated with risk of Alzheimer’s disease (AD) and volume loss of the hippocampus, but the associations with subfields of the hippocampus are understudied. Knowing if vascular risk factors contribute to hippocampal subfield atrophy may improve our understanding of vascular contributions to neurodegenerative diseases. Objective: To investigate the associations between age, sex, and vascular risk factors with hippocampal subfields volumes on 7T MRI in older persons without dementia. Methods: From the Medea 7T study, 283 participants (67±9 years, 68% men) without dementia had 7T brain MRI and hippocampal subfield segmentation. Subfields …were automatically segmented on the 3D T2-weighted 7T images with ASHS software. Using linear mixed models, we estimated adjusted associations of age, sex, and vascular risk factors with z-scores of volumes of the entorhinal cortex (ERC), subiculum (SUB), Cornu Ammonis (CA)1, CA2, CA3, CA4, and dentate gyrus (DG), and tail as multivariate correlated outcomes. Results: Increasing age was associated with smaller volumes in all subfields, except CA4/DG. Current smoking was associated with smaller ERC and SUB volumes; moderate alcohol use with smaller CA1 and CA4/DG, obesity with smaller volumes of ERC, SUB, CA2, CA3, and tail; and diabetes mellitus with smaller SUB volume. Sex, former smoking, and hypertension were not associated with subfield volumes. When formally tested, no risk factor affected the subfield volumes differentially. Conclusion: Several vascular risk factors were associated with smaller volumes of specific hippocampal subfields. However, no statistical evidence was found that subfields were differentially affected by these risk factors. Show more

Keywords: Cornu ammonis, dentate gyrus, entorhinal cortex, hippocampal region, hippocampus, magnetic resonance imaging, risk factors

DOI: 10.3233/JAD-200159

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1223-1239, 2020

Authors: Wang, Jing | Xiao, Lily Dongxia | Wang, Kai | Luo, Yan | Li, Xiaomei

Article Type: Research Article

Abstract: Background: China has the largest population living with dementia globally and urban-rural differences are significant in prevalence, risk factors, and health resources. Epidemiologic studies on cognitive impairment in rural areas are limited in China and other low- and middle-income countries. Objective: This study investigated cognitive impairment and associated factors in rural elderly aged 65 years and over in China. Methods: In total, 1,250 participants from ten villages in North China were recruited from June to September, 2017. Face-to-face structured interviews were conducted for data collection. The interviews included socio-demographic information, health status, and psychological assessments. Cognitive …function was assessed using the Chinese version of the Mini-Mental State Examination. A multivariate logistic regression model with backward method was employed to identify factors associated with cognitive impairment. Results: The positive rate of cognitive impairment among rural Chinese elderly aged 65 years and older was 42.9% (95% CI, 40.1–45.6). No significant differences were found in cognitive impairment by age or gender before the age of 75 years. Older age, lack of formal school education, reliance on the basic living allowance as the only income source, poor hearing and vision function, diabetes, and activities of daily living dependence were associated with higher rate of cognitive impairment, while tea consumption and fatty liver disease were associated with lower cognitive impairment rate. Conclusion: A very high percentage of rural elderly in China had cognitive impairment. Education programs and prevention interventions targeting modifiable risk factors among high-risk populations should be developed through collective efforts involving all stakeholders. Show more

Keywords: China, cognitive dysfunction, correlates, older adults

DOI: 10.3233/JAD-200404

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1241-1253, 2020

Authors: Xu, Hui | Jia, Jianping

Article Type: Research Article

Abstract: Background: The pathogenesis of Alzheimer’s disease (AD) involves various immune-related phenomena; however, the mechanisms underlying these immune phenomena and the potential hub genes involved therein are unclear. An understanding of AD-related immune hub genes and regulatory mechanisms would help develop new immunotherapeutic targets. Objective: The aim of this study was to explore the hub genes and the mechanisms underlying the regulation of competitive endogenous RNA (ceRNA) in immune-related phenomena in AD pathogenesis. Methods: We used the GSE48350 data set from the Gene Expression Omnibus database and identified AD immune-related differentially expressed RNAs (DERNAs). We constructed protein–protein …interaction (PPI) networks for differentially expressed mRNAs and determined the degree for screening hub genes. By determining Pearson’s correlation coefficient and using StarBase, DIANA-LncBase, and Human MicroRNA Disease Database (HMDD), the AD immune-related ceRNA network was generated. Furthermore, we assessed the upregulated and downregulated ceRNA subnetworks to identify key lncRNAs. Results: In total, 552 AD immune-related DERNAs were obtained. Twenty hub genes, including PIK3R1 , B2M , HLA-DPB1 , HLA-DQB1 , PIK3CA , APP , CDC42 , PPBP , C3AR1 , HRAS , PTAFR , RAB37 , FYN , PSMD1 , ACTR10 , HLA-E , ARRB2 , GGH , ALDOA , and VAMP2 were identified on PPI network analysis. Furthermore, upon microRNAs (miRNAs) inhibition, we identified LINC00836 and DCTN1-AS1 as key lncRNAs regulating the aforementioned hub genes. Conclusion: AD-related immune hub genes include B2M , FYN , PIK3R1 , and PIK3CA , and lncRNAs LINC00836 and DCTN1-AS1 potentially contribute to AD immune-related phenomena by regulating AD-related hub genes. Show more

Keywords: Alzheimer’s disease, competitive endogenous RNA, hub genes, immune system

DOI: 10.3233/JAD-200081

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1255-1265, 2020

Authors: Stickel, Ariana M. | Tarraf, Wassim | Wu, Benson | Marquine, Maria J. | Vásquez, Priscilla M. | Daviglus, Martha | Estrella, Mayra L. | Perreira, Krista M. | Gallo, Linda C. | Lipton, Richard B. | Isasi, Carmen R. | Kaplan, Robert | Zeng, Donglin | Schneiderman, Neil | González, Hector M.

Article Type: Research Article

Abstract: Background: Among older adults, poorer cognitive functioning has been associated with impairments in instrumental activities of daily living (IADLs). However, IADL impairments among older Hispanics/Latinos is poorly understood. Objective: To characterize the relationships between cognition and risk for IADL impairment among diverse Hispanics/Latinos. Methods: Participants included 6,292 community-dwelling adults from the Study of Latinos - Investigation of Neurocognitive Aging, an ancillary study of 45+ year-olds in the Hispanic Community Health Study/Study of Latinos. Cognitive data (learning, memory, executive functioning, processing speed, and a Global cognitive composite) were collected at Visit 1. IADL functioning was self-reported 7 …years later, and treated as a categorical (i.e., risk) and continuous (i.e., degree) measures of impairment. Survey two-part models (mixture of logit and generalized linear model with Gaussian distribution) and ordered logistic regression tested the associations of cognitive performance (individual tests and composite z-score) with IADL impairment. Additionally, we investigated the moderating role of age, sex, and Hispanic/Latino background on the association between cognition and IADL impairment. Results: Across all cognitive measures, poorer performance was associated with higher odds of IADL impairment 7 years later. Associations were generally stronger for the oldest group (70+ years) relative to the youngest group (50–59 years). Sex and Hispanic/Latino background did not modify the associations. Across the full sample, lower scores on learning, memory, and the Global cognitive composite were also associated with higher degree of IADL impairment. Conclusion: Across diverse Hispanics/Latinos, cognitive health is an important predictor of everyday functioning 7 years later, especially in older adulthood. Show more

Keywords: Activities of daily living, aging, cognition, hispanics, latinos, sex

DOI: 10.3233/JAD-200502

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1267-1278, 2020

Authors: Sanborn, Victoria | Preis, Sarah R. | Ang, Alvin | Devine, Sherral | Mez, Jesse | DeCarli, Charles | Au, Rhoda | Alosco, Michael L. | Gunstad, John

Article Type: Research Article

Abstract: Background: There is growing interest in the pathophysiological processes of preclinical Alzheimer’s disease (AD), including the potential role of leptin. Human studies have shown that both low and high levels of leptin can be associated with worse neurocognitive outcomes, suggesting this relationship may be moderated by another risk factor. Objective: We examined the association between plasma leptin levels and both neuropsychological test performance and structural neuroimaging and assessed whether body mass index (BMI) is an effect modifier of these associations. Methods: Our study sample consisted of 2,223 adults from the Framingham Heart Study Third Generation Cohort …(average age = 40 years, 53% women). Results: Among the entire sample, there was no association between leptin and any of the neuropsychological domain measures or any of the MRI brain volume measures, after adjustment for BMI, APOE4 , and other clinical factors. However, we did observe that BMI category was an effect modifier for the association between leptin and verbal memory (p for interaction = 0.03), where higher levels of leptin were associated with better performance among normal weight participants (BMI 18.5–24.9) kg/m2 (beta = 0.12, p  = 0.02). No association was observed between leptin level and verbal memory test performance among participants who were overweight or obese. Conclusion: These findings suggest that the association between leptin and cognitive function is moderated by BMI category. Prospective examination of individuals transitioning from middle age to older adulthood will help to clarify the contribution of leptin to AD and other neurodegenerative conditions. Show more

Keywords: Aging, Alzheimer’s disease, cognition, leptin, neuroimaging, obesity

DOI: 10.3233/JAD-191247

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1279-1289, 2020

Authors: Sanchez, Danielle L. | Thomas, Kelsey R. | Edmonds, Emily C. | Bondi, Mark W. | Bangen, Katherine J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Increasing evidence indicates that cerebrovascular dysfunction may precede cognitive decline in aging and Alzheimer’s disease (AD). Reduced cerebral blood flow (CBF) is associated with cognitive impairment in older adults. However, less is known regarding the association between CBF and functional decline, and whether CBF predicts functional decline beyond cerebrovascular and metabolic risk factors. Objective: To examine the association between regional CBF and functional decline in nondemented older adults. Method: One hundred sixty-six (N = 166) participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent neuropsychological testing and neuroimaging. Pulsed arterial spin labeling magnetic resonance imaging was …acquired to quantify resting CBF. Everyday functioning was measured using the Functional Assessment Questionnaire at baseline and annual follow-up visit across three years. Results: Adjusting for age, education, sex, cognitive status, depression, white matter hyperintensity volume, cerebral metabolism, and reference (precentral) CBF, linear mixed effects models showed that lower resting CBF at baseline in the medial temporal, inferior temporal, and inferior parietal lobe was significantly associated with accelerated decline in everyday functioning. Results were similar after adjusting for conventional AD biomarkers, including cerebrospinal fluid (CSF) amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) and apolipoprotein E (APOE ) ɛ 4 positivity. Individuals who later converted to dementia had lower resting CBF in the inferior temporal and parietal regions compared to those who did not. Conclusion: Lower resting CBF in AD vulnerable regions including medial temporal, inferior temporal, and inferior parietal lobes predicted faster rates of decline in everyday functioning. CBF has utility as a biomarker in predicting functional declines in everyday life and conversion to dementia. Show more

Keywords: Activities of daily living, aging, Alzheimer’s disease, biomarkers, cerebrovascular circulation, dementia, magnetic resonance imaging, neuropsychology, perfusion, regional blood flow

DOI: 10.3233/JAD-200490

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1291-1304, 2020