Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Robertson, Kayela | Larson, Eric B. | Crane, Paul K. | Cholerton, Brenna | Craft, Suzanne | McCormick, Wayne C. | McCurry, Susan M. | Bowen, James D. | Baker, Laura D. | Trittschuh, Emily H.

Article Type: Research Article

Abstract: Lack of a unitary operational definition of mild cognitive impairment (MCI) has resulted in mixed prevalence rates and unclear predictive validity regarding conversion to dementia and likelihood of reversion. We examined 1,721 nondemented participants aged 65 and older from the Adult Changes in Thought (ACT) community-based cohort. Participants were followed longitudinally through biennial visits (average years assessed = 5.38). Categorization of MCI was based on: 1) deviation of neuropsychological test scores from a benchmark based on either standard or individualized expectations of a participant’s mean premorbid cognitive ability, and 2) cutoff for impairment (1.0 versus 1.5 standard deviations [sd] below benchmark). MCI …prevalence ranged from 56–92%; using individualized benchmarks and less stringent cutoffs produced higher rates. During follow-up, 17% of the cohort developed dementia. Examination of sensitivity, specificity, and predictive validity revealed that the criterion of 1.5 sd from the standardized benchmark was optimal, but still had limited predictive validity. Participants meeting this criterion at their first visit were three times more likely to develop dementia and this increased to seven times if participants had this diagnosis at the second timepoint as well. Those who did not have an MCI diagnosis at their first visit, but did at their second, had a significant increase of risk (but to a lesser extent than those diagnosed at both visits), while those who had an MCI diagnosis at their first visit, but not their second, did not have a significantly increased risk. These results highlight how assessing MCI stability greatly improves prediction of risk. Show more

Keywords: Cognitive dysfunction, dementia, epidemiology, incidence, prevalence

DOI: 10.3233/JAD-180746

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Liedes, Hilkka | Lötjönen, Jyrki | Kortelainen, Juha M. | Novak, Gerald | van Gils, Mark | Gordon, Mark Forrest | for the Alzheimer’s Disease Neuroimaging Initiative | and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing

Article Type: Research Article

Abstract: Background: Hippocampal atrophy (HA) is one of the biomarkers for Alzheimer’s disease (AD). Objective: To identify the best biomarkers and develop models for prediction of HA over 24 months using baseline data. Methods: The study included healthy elderly controls, subjects with mild cognitive impairment, and subjects with AD, obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI 1) and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) databases. Predictor variables included cognitive and neuropsychological tests, amyloid-β, tau, and p-tau from cerebrospinal fluid samples, apolipoprotein E, and features extracted from magnetic resonance images (MRI). Least-mean-squares …regression with elastic net regularization and least absolute deviation regression models were tested using cross-validation in ADNI 1. The generalizability of the models including only MRI features was evaluated by training the models with ADNI 1 and testing them with AIBL. The models including the full set of variables were not evaluated with AIBL because not all needed variables were available in it. Results: The models including the full set of variables performed better than the models including only MRI features (root-mean-square error (RMSE) 1.76–1.82 versus 1.93–2.08). The MRI-only models performed well when applied to the independent validation cohort (RMSE 1.66–1.71). In the prediction of dichotomized HA (fast versus slow), the models achieved a reasonable prediction accuracy (0.79–0.87). Conclusions: These models can potentially help identifying subjects predicted to have a faster HA rate. This can help in selection of suitable patients into clinical trials testing disease-modifying drugs for AD. Show more

Keywords: Alzheimer’s disease, atrophy, decision support techniques, disease progression, hippocampus, magnetic resonance imaging, regression analysis, statistical models

DOI: 10.3233/JAD-180484

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Boscher, Emmanuelle | Husson, Thomas | Quenez, Olivier | Laquerrière, Annie | Marguet, Florent | Cassinari, Kevin | Wallon, David | Martinaud, Olivier | Charbonnier, Camille | Nicolas, Gaël | Deleuze, Jean-François | Boland, Anne | Lathrop, Mark | Frébourg, Thierry | FREX Consortium | Campion, Dominique | Hébert, Sébastien S. | Rovelet-Lecrux, Anne

Article Type: Research Article

Abstract: Early-onset Alzheimer’s disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100% . With the exception of rare mutations in APP , PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative …for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1 . This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD. Show more

Keywords: Copy number variants, early-onset Alzheimer’s disease, microRNA, miR-138

DOI: 10.3233/JAD-180940

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Baschi, Roberta | Restivo, Vincenzo | Nicoletti, Alessandra | Cicero, Edoardo Calogero | Luca, Antonina | Recca, Deborah | Zappia, Mario | Monastero, Roberto

Article Type: Research Article

Abstract: Neuropsychiatric symptoms (NPS) have been frequently described in Parkinson’s disease (PD), even in the earliest stages of the disease. Recently the construct of mild behavioral impairment (MBI) has been proposed as an at-risk state for incident cognitive decline and dementia. The aim of the present study is to evaluate the prevalence and associated factors of MBI in PD. Cross-sectional data from 429 consecutive PD patients enrolled in the PArkinson’s disease COgnitive impairment Study (PACOS) were included in the study. All subjects underwent neuropsychological assessment, according to the MDS Level II criteria. NPS were evaluated with the Neuropsychiatric Inventory. Multivariate logistic …regression models were used to evaluate clinical and behavioral characteristics, which are associated with PD-MBI. PD-MBI was ascertained in 361 (84.1%) subjects of whom 155 (36.1%) were newly diagnosed patients (disease duration ≤1 year) and 206 (48.0%) had a disease duration >1 year. Furthermore, 68 (15.9%) out of 429 subjects were PDw (without MBI). Across the MBI domains, Impulse Dyscontrol was significantly more prevalent among PD-MBI with disease duration >1 year than newly diagnosed patients. The frequency of Social Inappropriateness and Abnormal Perception significantly increased throughout the entire PD-MBI sample with increasing Hoehn and Yahr (H&Y) stages. PD-MBI in newly diagnosed PD was significantly associated with H&Y stage (OR 2.35, 95% CI 1.05–5.24) and antidepressant drug use (OR 2.94, 95% CI 0.91–9.47), while in patients with a disease duration >1 year was associated with UPDRS-ME (OR 3.37, 95% CI 1.41–8.00). The overall MBI frequency in the PACOS sample was 84% and 36% among newly diagnosed patients. The presence of MBI mainly related to motor impairment and disability. Show more

Keywords: Cognitive impairment, mild behavioral impairment, neuropsychiatric symptoms, Parkinson’s disease, prevalence

DOI: 10.3233/JAD-181117

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Alexopoulos, Panagiotis | Thierjung, Nathalie | Economou, Polychronis | Werle, Lukas | Buhl, Felix | Kagerbauer, Simone | Papanastasiou, Anastasios D. | Grimmer, Timo | Gourzis, Philippos | Berthele, Achim | Hemmer, Bernhard | Kübler, Hubert | Martin, Jan | Politis, Antonios | Perneczky, Robert

Article Type: Short Communication

Abstract: Cost- and time-effective markers of Alzheimer’s disease (AD), reliable and feasible at the population level are urgently needed. Soluble amyloid-β protein precursor β (sAβPPβ) in plasma has attracted scientific attention as a potential AD biomarker candidate. Here we report that plasma sAβPPβ levels in patients with AD dementia and typical for AD cerebrospinal fluid (CSF) biomarker profiles (N = 33) are significantly lower (p  < 0.01) than those of cognitively healthy elderly individuals without AD (N = 39), while CSF sAβPPβ levels did not differ between the studied groups. This provides further evidence for the potential of sAβPPβ in plasma as an AD biomarker candidate.

Keywords: Biomarker candidate, NIA-AA research framework diagnostic criteria, soluble amyloid-β protein precursor β

DOI: 10.3233/JAD-181088

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Langer, Kailey | O’Shea, Deirdre | De Wit, Liselotte | DeFeis, Brittany | Mejia, Andrea | Amofa, Priscilla | Chandler, Melanie | Locke, Dona | Fields, Julie | Phatak, Vaishali | Dean, Pamela | Smith, Glenn

Article Type: Research Article

Abstract: Background: Research has shown that individuals with mild cognitive impairment (MCI) value quality of life (QoL) above and beyond cognitive function or other potential outcomes in MCI. There is evidence supporting the negative impact of poor physical function on QoL ratings. Objective: The study explored whether a modified measure of self-efficacy for managing MCI and education mediated and/or moderated the relationship between physical function and QoL in persons with MCI. Methods: Baseline data from 200 participants with MCI were obtained from a larger study assessing the effectiveness of a behavioral intervention. Physical function was assessed by …the Short Physical Performance Battery. QoL was assessed with the Quality of Life in Alzheimer’s Disease scale. Memory-related self-efficacy was assessed using a modified 9-item version of the Chronic Disease Self-Efficacy Scales. Mediation and moderation analyses tested the hypotheses that self-efficacy and education alter the association between physical function and QoL in individuals with MCI. All analyses were adjusted for age, cognitive severity, and sex. Results: Self-efficacy for managing MCI was a significant mediator of the association between physical function and perceived QoL. Individuals with better physical function reported higher self-efficacy which was associated with higher QoL ratings. Conclusions: Greater self-efficacy for managing MCI mediated the negative association between physical function and quality of life in this exploratory study. Interventions aimed at enhancing memory self-efficacy in MCI may improve perceived QoL, even in the presence of poor physical function. Future research is needed to investigate this further. Show more

Keywords: Activities of daily living, cognitive reserve, life quality, mild cognitive impairment, self-efficacy

DOI: 10.3233/JAD-181020

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: O’Caoimh, Rónán | Gao, Yang | Svendrovski, Anton | Illario, Maddalena | Iaccarino, Guido | Yavuz, Burcu Balam | Kehoe, Patrick Gavin | Molloy, D. William

Article Type: Research Article

Abstract: Background: Visit-to-visit blood pressure (BP) variability (VVV) is increasingly recognized as a marker of cardiovascular risk. Although implicated in cognitive decline, few studies are currently available assessing its effects on established dementia. Objective: To investigate if VVV is associated with one-year rate of decline in measures of cognition and function in patients with mild to moderate Alzheimer’s disease (AD) in the Doxycycline And Rifampicin for Alzheimer’s Disease study. Methods: Patients were included if ≥3 BP readings were available (n  = 392). VVV was defined using different approaches including the coefficient of variation (CV) in BP readings between …visits. Outcomes included rates of decline in the Standardized Alzheimer’s Disease Assessment Scale–Cognitive Subscale (SADAS-cog), Standardized MMSE, Clinical Dementia Rating Scale, the Quick Mild Cognitive Impairment screen and the Lawton-Brody activities of daily living (ADL) scale. Results: Half of the patients (196/392) had a ≥4-point decline in the SADAS-cog over one-year. Using this cut-off, there were no statistically significant associations between any measures of VVV, for systolic or diastolic BP, with and without adjustment for potential confounders including treatment allocation, history of hypertension and use of anti-hypertensive and cognitive enhancing medications. Multiple regression models examining the association between systolic BP CV by quartile and decline over one-year likewise showed no clinically significant effects, apart from a U -shaped pattern of ADL decline of borderline clinical significance.∥Conclusions: This observational study does not support recent research showing that VVV predicts cognitive decline in AD. Further studies are needed to clarify its effects on ADL in AD. Show more

Keywords: Visit-visit-variability, blood pressure variability, blood pressure, cognition, Alzheimer’s disease

DOI: 10.3233/JAD-180774

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Aiello Bowles, Erin J. | Crane, Paul K. | Walker, Rod L. | Chubak, Jessica | LaCroix, Andrea Z. | Anderson, Melissa L. | Rosenberg, Dori | Keene, C. Dirk | Larson, Eric B.

Article Type: Research Article

Abstract: Background: Past research has focused on risk factors for developing dementia, with increasing recognition of “resilient” people who live to old age with intact cognitive function despite pathological features of Alzheimer’s disease (AD). Objective: To evaluate demographic factors, mid-life characteristics, and non-AD neuropathology findings that may be associated with cognitive resilience to AD pathology. Methods: We analyzed data from 276 autopsy cases with intermediate or high levels of AD pathology from the Adult Changes in Thought study. We defined cognitive resilience as having Cognitive Abilities Screening Instrument scores >86 within two years of death and no …clinical dementia diagnosis; non-resilient people had dementia diagnoses from AD or other causes before death. We compared mid-life characteristics, demographics, and additional neuropathology findings between resilient and non-resilient people. We used multivariable logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for being resilient compared to not being resilient adjusting for demographic and neuropathology factors. Results: We classified 68 (25%) people as resilient and 208 (75%) as not resilient. A greater proportion of resilient people had a college degree (50%) compared with non-resilient (32%, p  = 0.01). The odds of being resilient were significantly increased among people with a college education (OR = 2.01, 95% CI = 1.01–3.99) and significantly reduced among people with additional non-AD neuropathology findings such as hippocampal sclerosis (OR = 0.28, 95% CI = 0.09–0.89) and microinfarcts (OR = 0.34, 95% CI = 0.15–0.78). Discussion: Increased education and absence of non-AD pathology may be independently associated with cognitive resilience, highlighting the importance of evaluating co-morbid factors in future research on mechanisms of cognitive resilience. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, education, neuropathology

DOI: 10.3233/JAD-180942

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Black, Christopher | Lipton, Richard B. | Thiel, Ellen | Brouillette, Matthew | Khandker, Rezaul

Article Type: Research Article

Abstract: The relationship between Alzheimer’s disease (AD) treatment patterns and healthcare costs is unknown. Administrative claims data from the MarketScan Commercial and Medicare databases covering 2010 through 2016 were used to identify the comorbidities, treatment patterns, and healthcare costs in the three years prior to and one year post medical diagnosis of AD in 21,448 patients with no treatment and 57,970 patients with treatment. Pre-index mean annual costs ranged from $14,228 to $26,876, and post-index mean annual costs ranged from $21,052 to $45,685 depending on age and treatment timing. After adjusting for baseline characteristics, patients 50–100 years old who initiated treatment …with an FDA approved drug prior to or concurrent with diagnosis had healthcare costs 9%–19% lower in the year following diagnosis than those who did not receive treatment. Early or concurrent treatment is associated with lower overall healthcare costs in the year following AD diagnosis. Show more

Keywords: Administrative claims, Alzheimer’s disease, delayed diagnosis, health care costs, time-to-treatment

DOI: 10.3233/JAD-180983

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Mis, Rachel | Devlin, Kathryn | Drabick, Deborah | Giovannetti, Tania

Article Type: Research Article

Abstract: Heterogeneity of subtle functional difficulties in mild cognitive impairment (MCI) remains poorly understood. We characterized patterns of informant reports of functional abilities among participants with MCI and the relation between functional ability pattern and cognitive abilities and subsequent decline. Data from 4,273 MCI participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) were included in latent profile analyses (LPA) of informant responses on the Functional Activities Questionnaire (FAQ). Profiles from the best fitting model were compared on demographic, clinical, and cognitive variables. The best fitting model supported three profiles varying by level and type of difficulty: intact …function (n  = 3,299), intermediate (n  = 769), and high ratings of difficulty (n  = 205). For the Intermediate profile, items related to finances, remembering dates, and travel were rated as most difficult. The High Ratings profile also had elevated ratings on the meal preparation item. Participants with either the Intermediate or High Ratings profile demonstrated a three-fold increase in conversion to dementia as compared to participants with the Intact profile. Demographically, the Intact profile was younger and consisted of a higher proportion of minorities. On cognitive tests, the Intact profile showed the best performance, and the Intermediate profile performed comparably to or better than the High Ratings profile. There is meaningful heterogeneity in informant ratings of function in MCI, though individuals with MCI whose informants report even intermediate-level functional difficulties are more likely to progress to dementia, suggesting that even subtle functional difficulties place individuals at higher risk for future decline. Show more

Keywords: Activities of daily living, alzheimer’s disease, episodic memory, executive function, mild cognitive impairment

DOI: 10.3233/JAD-180975

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019