Journal of Alzheimer's Disease - Volume 68, issue 4

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. 68, no. 4, pp. 1439-1451, 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. 68, no. 4, pp. 1453-1468, 2019

Authors: Heser, Kathrin | Kleineidam, Luca | Wiese, Birgitt | Oey, Anke | Roehr, Susanne | Pabst, Alexander | Kaduszkiewicz, Hanna | van den Bussche, Hendrik | Brettschneider, Christian | König, Hans-Helmut | Weyerer, Siegfried | Werle, Jochen | Fuchs, Angela | Pentzek, Michael | Mösch, Edelgard | Bickel, Horst | Maier, Wolfgang | Scherer, Martin | Riedel-Heller, Steffi G. | Wagner, Michael

Article Type: Research Article

Abstract: Background/Objective: Subjective cognitive decline (SCD) has often been associated with an increased risk for subsequent dementia. However, sex-specific associations are understudied until now. Methods: Cross-sectional and longitudinal associations over a follow-up period of up to 13 years were investigated in a sample of participants without objective cognitive impairment at baseline (n  = 2,422, mean age = 79.63 years). Logistic regression and Cox proportional hazards models were conducted. Results: Women less frequently reported SCD without worries (p  < 0.001), but tended to report more often SCD with worries (p  = 0.082) at baseline compared to men. In models adjusted for age, education, …cognitive status, and depressive symptoms, SCD at baseline increased the risk for subsequent dementia (p  < 0.001), and this effect was less pronounced in males (interaction sex×SCD: p  = 0.022). Stratified analyses showed that SCD increased the risk for subsequent dementia in women (HR = 1.77, p  < 0.001), but not in men (HR = 1.07, p  = 0.682). Similar results were found in analyses with SCD without and with worries, except that SCD with worries also predicted subsequent Alzheimer’s disease (AD) in men (p  = 0.037). Conclusion: At baseline, men reported more SCD without worries and women tended to report more SCD with worries. SCD in women was more strongly associated with subsequent dementia. SCD without and with worries was related to incident dementia and AD in women, whereas in men only SCD with worries increased the risk for AD, but not for all-cause dementia. Show more

Keywords: Alzheimer’s disease, dementia, gender, sex, subjective cognitive decline, subjective memory decline, subjective memory impairment

DOI: 10.3233/JAD-180981

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1469-1478, 2019

Authors: Moran, Chris | Xie, Kenneth | Poh, Su | Chew, Sarah | Beare, Richard | Wang, Wei | Callisaya, Michele | Srikanth, Velandai

Article Type: Research Article

Abstract: Background: Hypertension is an established risk factor for dementia. However, it is unclear whether there are differential effects of angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) on brain health. In human observational studies, the evidence for superiority of either agent remains unclear. Objective: To compare brain atrophy and cognitive decline between people treated with ACEi or ARB. Methods: Participants aged 55–90 years without dementia had brain magnetic resonance imaging and neuropsychological assessments performed at 3 time points. The sample was enriched with people with type 2 diabetes (T2D). Multivariable mixed models were used …to examine longitudinal associations of antihypertensive medication class with change in cognition and total brain volume. Results: Of 565 people with longitudinal data, there were 163 on ACEi (mean age 69.9 years, T2D:64% with) and 125 on ARB (mean age 69.6 years, T2D:62%) at baseline. The baseline characteristics of those taking either an ACEi or ARB were similar with regards to age, sex, blood pressure control, and vascular risk factors. The mean duration of follow up was 3.2 years. The baseline association of ACEi and ARB use with total brain volume was similar in both groups. However, those taking an ARB had a slower rate of brain atrophy than those taking an ACEi (p  = 0.031). Neither ACEi nor ARB use was associated with baseline cognitive function or cognitive decline. Conclusions: These results support the theory that ARB may be preferable to ACEi to reduce brain atrophy. The mechanisms underlying this differential association warrant further investigation. Show more

Keywords: Angiotensin-converting enzyme inhibitors, antihypertensive agents, blood pressure, cognition, dementia

DOI: 10.3233/JAD-180943

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1479-1488, 2019

Authors: Sheikh-Bahaei, Nasim | Manavaki, Roido | Sajjadi, S. Ahmad | Priest, Andrew N. | O’Brien, John T. | Gillard, Jonathan H.

Article Type: Research Article

Abstract: Background: Despite the well-documented relationship between lobar cerebral microbleeds (lCMB) and Alzheimer’s disease (AD), there is limited knowledge about the role of lCMB in AD pathology. Objective: To understand the nature of this relationship, we investigated the association between lCMB, amyloid load, perfusion, and metabolism. Methods: Participants with AD, mild cognitive impairment (MCI), and healthy controls were recruited and scanned with 11 C-Pittsburg-Compound B (PiB), Fluorodeoxyglucose (FDG) PET, and susceptibility-weighted MRI. Early PiB-PET frames were used to estimate perfusion. The association between lCMB and PET uptake in each anatomical lobe was measured using multiple regression models. …Results: The presence of lCMB predicted increased total (p  < 0.001) and regional (p  = 0.0002) PiB uptake, as well as decreased cerebral perfusion (p  = 0.03). Cases with lCMB had hypometabolism in their temporal lobe (p  = 0.04). Conclusion: There are significant relationships between lCMBs and various markers of AD pathology. lCMB has a spatial association with Aβ load and a complex effect on perfusion and metabolism. Show more

Keywords: Alzheimer’s disease, cerebral metabolism, cerebral perfusion, FDG-PET, lobar cerebral microbleeds, PiB-PET, susceptibility weighted imaging

DOI: 10.3233/JAD-180443

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1489-1497, 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. 68, no. 4, pp. 1499-1510, 2019

Authors: Langer, Kailey | O’Shea, Deirdre M. | De Wit, Liselotte | DeFeis, Brittany | Mejia, Andrea | Amofa, Priscilla | Chandler, Melanie | Locke, Dona E.C. | Fields, Julie | Phatak, Vaishali | Dean, Pamela M. | 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. 68, no. 4, pp. 1511-1519, 2019

Authors: Rofes, Adrià | de Aguiar, Vânia | Ficek, Bronte | Wendt, Haley | Webster, Kimberly | Tsapkini, Kyrana

Article Type: Research Article

Abstract: People with primary progressive aphasia (PPA) present language difficulties that require lengthy assessments and follow-ups. Despite individual differences, people with PPA are often classified into three variants that present some distinctive language difficulties. We analyzed the data of 6 fluency tasks (i.e., “F”, “A”, “S”, “Fruits”, “Animals”, “Vegetables”). We used random forests to pinpoint relevant word properties and error types in the classification of the three PPA variants, conditional inference trees to indicate how relevant variables may interact with one another and ANOVAs to cross-validate the results. Results indicate that total word count helps distinguish healthy individuals (N = 10) from people …with PPA (N = 29). Furthermore, mean familiarity differentiates people with svPPA (N = 8) from people with lvPPA (N = 10) and nfvPPA (N = 11). No other word property or error type was relevant in the classification. These results relate to previous literature, as familiarity effects have been reported in people with svPPA in naming and spontaneous speech. Also, they strengthen the relevance of using familiarity to identify a specific group of people with PPA. This paper enhances our understanding of what determines word retrieval in people with PPA, complementing and extending data from naming studies. Show more

Keywords: Category, familiarity, fluency, letter, primary progressive aphasia

DOI: 10.3233/JAD-180990

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1521-1534, 2019

Authors: Belbin, Olivia | Morgan, Kevin | Medway, Chris | Warden, Donald | Cortina-Borja, Mario | van Duijn, Cornelia M. | Adams, Hieab H.H. | Frank-Garcia, Ana | Brookes, Keeley | Sánchez-Juan, Pascual | Alvarez, Victoria | Heun, Reinhard | Kölsch, Heike | Coto, Eliecer | Kehoe, Patrick G. | Rodriguez-Rodriguez, Eloy | Bullido, Maria J | Ikram, M. Arfan | Smith, A. David | Lehmann, Donald J.

Article Type: Research Article

Abstract: Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer’s disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF , DBH , and SORT1 loci comprising 5,682 controls and 2,454 …AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1–1.2, p  = 0.005–0.3), an effect size that was consistent in the Northern European (OR = 1.1–1.2, p  = 0.002–0.8) but not the smaller Spanish (OR = 0.8–1.6, p  = 0.4–1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3–1.5 p  = 0.002–0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2–1.3, p  = 0.007–0.00008) than men (OR = 0.9–1.0, p  = 0.3–0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p  = 0.04) the synergistic interaction (SF = 2.2, p  = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p  = 0.04) than men (SF = 2.0, p  = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, dopamine beta-hydroxylase, epistasis, genetics, neurotrophins, Sortilin

DOI: 10.3233/JAD-181116

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1535-1547, 2019

Authors: Spencer, Barbara E. | Jennings, Robin G. | Brewer, James B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Biomarkers may soon be used to predict decline in older individuals. Extended follow-up studies are needed to determine the stability of such biomarker-based predictions. Objective: To examine the long-term performance of baseline cognitive, neuroimaging, and cerebrospinal fluid (CSF) biomarker-assisted prognoses in patients with mild cognitive impairment. Methods: Established, biomarker-defined cohorts of subjects with mild cognitive impairment were examined for progression to dementia. Subjects with a baseline volumetric magnetic resonance imaging, lumbar puncture, and Rey Auditory Verbal Learning Test were included. Dementia-free survival time in each biomarker-defined risk group was determined with Kaplan-Meier survival curves. The …influence of each risk factor or combination of factors on dementia-free survival was examined with Cox proportional hazard analyses. Results: 185 subjects were followed longitudinally for a mean (SD) 4.3 (2.8) years. 59% of participants converted within the follow-up period and the median dementia-free survival time was 2.8 years. Each individual risk factor predicted conversion to dementia (HR 1.9–3.7). The joint presence of any two risk factors increased risk for conversion (HR 7.1–11.0), with the presence of medial temporal atrophy and memory impairment showing the greatest risk for decline. Concordant atrophy, memory impairment, and abnormal CSF amyloid and tau was associated with the highest risk for conversion (HR 15.1). The presence of medial temporal atrophy was associated with the shortest dementia-free survival time, both alone and in combination with memory impairment, abnormal CSF amyloid and tau, or both. Conclusion: These results suggest that baseline biomarker-assisted predictions of decline to dementia are stable over the long term, and that combinations of complementary biomarkers can improve the accuracy of these predictions. Show more

Keywords: Biomarkers, cerebrospinal fluid, dementia, magnetic resonance imaging, mild cognitive impairment, prognosis, rey auditory verbal learning test

DOI: 10.3233/JAD-181243

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1549-1559, 2019