Journal of Alzheimer's Disease - Volume 59, issue 4

Authors: Ding, Junhua | Chen, Keliang | Zhang, Weibin | Li, Ming | Chen, Yan | Yang, Qing | Lv, Yingru | Guo, Qihao | Han, Zaizhu

Article Type: Research Article

Abstract: Background: Semantic dementia (SD) is characterized by a selective decline in semantic processing. Although the neuropsychological pattern of this disease has been identified, its topological global alterations and symptom-relevant modules in the whole-brain anatomical network have not been fully elucidated. Objective: This study aims to explore the topological alteration of anatomical network in SD and reveal the modules associated with semantic deficits in this disease. Methods: We first constructed the whole-brain white-matter networks of 20 healthy controls and 19 patients with SD. Then, the network metrics of graph theory were compared between these two groups. …Finally, we separated the network of SD patients into different modules and correlated the structural integrity of each module with the severity of the semantic deficits across patients. Results: The network of the SD patients presented a significantly reduced global efficiency, indicating that the long-distance connections were damaged. The network was divided into the following four distinctive modules: the left temporal/occipital/parietal, frontal, right temporal/occipital, and frontal/parietal modules. The first two modules were associated with the semantic deficits of SD. Conclusion: These findings illustrate the skeleton of the neuroanatomical network of SD patients and highlight the key role of the left temporal/occipital/parietal module and the left frontal module in semantic processing. Show more

Keywords: Graph theoretical analysis, lesion-symptom mapping, network module, semantic deficit, semantic dementia, topological alteration, white-matter neural network

DOI: 10.3233/JAD-170449

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1283-1297, 2017

Authors: Wong, Adrian | Fong, Ching-hang | Mok, Vincent Chung-tong | Leung, Kam-tat | Tong, Raymond Kai-yu

Article Type: Research Article

Abstract: Background: Computerized cognitive tests may serve as a preliminary, low-cost method to identify individuals with suspected cognitive impairment in the community. Objective: To develop a self-administered computerized test, namely the “Computerized Cognitive Screen (CoCoSc), Hong Kong version”, for screening of individuals with cognitive impairment (CI) in community settings. Methods: The CoCoSc is a 15-min computerized cognitive screen covering memory, executive functions, orientation, attention and working memory, and prospective memory administered on a touchscreen computer. Individuals with CI and cognitively normal controls were administered the CoCoSc and the Montreal Cognitive Assessment (MoCA). Validity of the CoCoSc was …assessed based on the relationship with the MoCA using Pearson correlation. Receiver operating characteristic curve (ROC) was used to examine the ability of the CoCoSc to differentiate CI from controls. Results: Fifty-nine individuals with CI and 101 controls were recruited. Seventy-five (46.9%) participants had ≤6 years of education. Performance on the CoCoSc differed between normal and CI groups in both low and high education subgroups. Total scores of the CoCoSc and MoCA were significantly correlated (r  = 0.71, p  < 0.001). The area under ROC was 0.78, p  < 0.001 for the CoCoSc total score in differentiating the CI group from the cognitively normal group. A cut-off of ≤30 on the CoCoSc was associated with a sensitivity of 0.78 and specificity of 0.69. The CoCoSc was well accepted by attendees of community social centers. Conclusion: The CoCoSc is a promising computerized cognitive screen for self-administration in community social centers. It is feasible for testing individuals with high or low education levels. Show more

Keywords: Cognitive function, mass screening, mild cognitive impairment, neuropsychology, self-assessment

DOI: 10.3233/JAD-170196

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1299-1306, 2017

Authors: Bettcher, Brianne M. | Ard, M. Colin | Reed, Bruce R. | Benitez, Andreana | Simmons, Amanda | Larson, Eric B. | Sonnen, Josh A. | Montine, Thomas J. | Li, Ge | Keene, C. Dirk | Crane, Paul K. | Mungas, Dan

Article Type: Research Article

Abstract: We characterized the relationship between late life cholesterol exposure and neuropathological outcomes in a community-based, older adult cohort. Adult Changes in Thought (ACT) is a cohort study that enrolls consenting, randomly selected, non-demented people aged ≥65 from a healthcare delivery system. We used late life HDL and total cholesterol lab values from Group Health computerized records, and calculated HDL and non-HDL levels. We evaluated neuropathological outcomes of Alzheimer’s disease, cerebral amyloid angiopathy, vascular brain injury, and Lewy body disease. Using linear mixed models with age and antilipemic medication as predictors, we obtained predicted cholesterol values at age 70 and 10 …years prior to death for individuals with available cholesterol data in 10-year exposure windows. We used logistic regression to determine whether predicted late life cholesterol levels were associated with neuropathological outcomes controlling for age at death, APOE genotype, sex, and their interactions with cholesterol levels. 525 decedents came to autopsy by 08/2014. Of these, plasma cholesterol concentration was available for 318 (age 70, model 1) and 396 (10 years prior to death, model 2) participants. We did not find associations between late life cholesterol and Alzheimer’s disease neuropathological changes, and there were no associations between cholesterol levels and amyloid angiopathy or vascular brain injury. We observed an association between predicted non-HDL cholesterol at age 70 and Lewy body disease. Our study suggests an association between late life non-HDL cholesterol exposure and Lewy body disease. We did not observe associations between late life cholesterol levels and Braak stage or CERAD score. Show more

Keywords: Alzheimer’s disease, epidemiology, Lewy body, lipids, neuropathology, vascular

DOI: 10.3233/JAD-161224

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1307-1315, 2017

Authors: Li, Dan | Hu, Nan | Yu, Yueyi | Zhou, Aihong | Li, Fangyu | Jia, Jianping

Article Type: Research Article

Abstract: Background: Despite its popularity, the latent structure of 22-item Zarit Burden Interview (ZBI) remains unclear. There has been no study exploring how caregiver multidimensional burden changed. Objective: The aim of the work was to validate the latent structure of ZBI and to investigate how multidimensional burden evolves with increasing global burden. Methods: We studied 1,132 dyads of dementia patients and their informal caregivers. The caregivers completed the ZBI and a questionnaire regarding caregiving. The total sample was randomly split into two equal subsamples. Exploratory factor analysis (EFA) was performed in the first subsample. In the …second subsample, confirmatory factor analysis (CFA) was conducted to validate models generated from EFA. The mean of weighted factor score was calculated to assess the change of dimension burden against the increasing ZBI total score. Results: The result of EFA and CFA supported that a five-factor structure, including role strain, personal strain, incompetency, dependency, and guilt, had the best goodness-of-fit. The trajectories of multidimensional burden suggested that three different dimensions (guilt, role strain and personal strain) became the main subtype of burden in sequence as the ZBI total score increased from mild to moderate. Factor dependency contributed prominently to the total burden in severe stage. Conclusion: The five-factor ZBI is a psychometrically robust measure for assessing multidimensional burden in Chinese caregivers. The changes of multidimensional burden have deepened our understanding of the psychological characteristics of caregiving beyond a single total score and may be useful for developing interventions to reduce caregiver burden. Show more

Keywords: Caregiver burden, confirmatory factor analysis, dementia, informal caregiver, Zarit Burden Interview

DOI: 10.3233/JAD-170172

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1317-1325, 2017

Authors: Lista, Simone | Toschi, Nicola | Baldacci, Filippo | Zetterberg, Henrik | Blennow, Kaj | Kilimann, Ingo | Teipel, Stefan J. | Cavedo, Enrica | dos Santos, Antonio Melo | Epelbaum, Stéphane | Lamari, Foudil | Dubois, Bruno | Nisticò, Robert | Floris, Roberto | Garaci, Francesco | Hampel, Harald | for the Alzheimer Precision Medicine Initiative (APMI)

Article Type: Research Article

Abstract: We investigated cerebrospinal fluid (CSF) concentrations of the postsynaptic biomarker neurogranin at baseline in cognitively healthy controls (HC) compared to individuals with mild cognitive impairment (MCI), patients with Alzheimer’s disease (AD) dementia, and patients with frontotemporal dementia (FTD). CSF neurogranin was quantified using an in-house immunoassay in a cross-sectional multicenter study of 108 participants [AD dementia (n  = 35), FTD (n  = 9), MCI (n  = 41), cognitively HC (n  = 23)]. CSF neurogranin concentrations were significantly higher in AD patients compared with both HC subjects and FTD patients, suggesting that increased CSF neurogranin concentrations may indicate AD-related pathophysiology. CSF neurogranin was independently associated …with both total tau and hyperphosphorylated tau proteins, whereas a non-significant correlation with the 42-amino acid-long amyloid-β peptide was evident. CSF neurogranin, however, was not superior to core AD biomarkers in differentiating HC from the three diagnostic groups, and it did not improve their diagnostic accuracy. We conclude that further classification and longitudinal studies are required to shed more light into the potential role of neurogranin as a pathophysiological biomarker of neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cognitive aging, frontotemporal dementia, mild cognitive impairment, neurogranin

DOI: 10.3233/JAD-170368

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1327-1334, 2017

Authors: Bilgel, Murat | Koscik, Rebecca L. | An, Yang | Prince, Jerry L. | Resnick, Susan M. | Johnson, Sterling C. | Jedynak, Bruno M.

Article Type: Research Article

Abstract: Investigation of the temporal trajectories of currently used neuropsychological tests is critical to identifying earliest changing measures on the path to dementia due to Alzheimer’s disease (AD). We used the Progression Score (PS) method to characterize the temporal trajectories of measures of verbal memory, executive function, attention, processing speed, language, and mental status using data spanning normal cognition, mild cognitive impairment, and AD from 1,661 participants with a total of 7,839 visits (age at last visit 77.6 SD 9.2) in the Baltimore Longitudinal Study of Aging (BLSA) and 1510 participants with a total of 3,473 visits (age at last visit …59.5 SD 7.4) in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). This method aligns individuals in time based on the similarity of their longitudinal measurements to reveal temporal trajectories. As a validation of our methodology, we explored the associations between the individualized cognitive progression scores (Cog-PS) computed by our method and clinical diagnosis. Digit span tests were the first to show declines in both data sets, and were detected mainly among cognitively normal individuals. These were followed by tests of verbal memory, which were in turn followed by Trail Making Tests, Boston Naming Test, and Mini-Mental State Examination. Differences in Cog-PS across the clinical diagnosis and APOE ɛ 4 groups were statistically significant, highlighting the potential use of Cog-PS as individualized indicators of disease progression. Identifying cognitive measures that are changing in preclinical AD can lead to the development of novel cognitive tests that are finely tuned to detecting earliest changes. Show more

Keywords: Alzheimer’s disease, cognition, longitudinal studies, neuropsychological tests, preclinical

DOI: 10.3233/JAD-170448

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1335-1347, 2017

Authors: Gross, Alden L. | Lu, Haidong | Meoni, Lucy | Gallo, Joseph J. | Schrack, Jennifer A. | Sharrett, A. Richey

Article Type: Research Article

Abstract: Background: Links between physical activity and dementia are based primarily on cross-sectional data or studies with unsatisfactory follow-up. Objective: We leveraged three decades of follow-up from an established cohort to determine whether physical activity in midlife is associated with late-life cognition and dementia. Methods: The Johns Hopkins Precursors study (n  = 646) enrolled participants from 1948–1964 and administered questions about physical activity, from which we calculated metabolic equivalents (MET h/day), and exercise from 1978-present. Cognitive tests were administered in 2008. Dementia was adjudicated through 2011. To characterize associations with midlife physical activity, we used linear regression …for cognitive tests and Cox proportional hazards models for dementia onset. Models adjusted for age, sex, smoking, diabetes, and hypertension. Results: No physical activity measure from 1978 was associated with late-life cognition or onset of dementia. Both MET h/day (β= 0.007, 95% CI: 0.002, 0.013) and regular exercise (β= 0.357, 95% CI: 0.202, 0.513) in 2006, however, were associated with better cognition in 2008. Conclusion: Findings from this 30-year cohort study that physical activity measured recently, but not in mid-life, is associated with late-life cognition fits with null findings from randomized trials and other observational studies with extensive follow-up. Cross-sectional findings may be misleading due to reverse causation. Show more

Keywords: Cognition, dementia, older adults, physical activity

DOI: 10.3233/JAD-170290

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1349-1358, 2017

Authors: Lawrence, Emma | Vegvari, Carolin | Ower, Alison | Hadjichrysanthou, Christoforos | De Wolf, Frank | Anderson, Roy M.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disease, with no effective treatment or cure. A gold standard therapy would be treatment to slow or halt disease progression; however, knowledge of causation in the early stages of AD is very limited. In order to determine effective endpoints for possible therapies, a number of quantitative surrogate markers of disease progression have been suggested, including biochemical and imaging biomarkers. The dynamics of these various surrogate markers over time, particularly in relation to disease development, are, however, not well characterized. We reviewed the literature for studies that measured cerebrospinal fluid or plasma …amyloid-β and tau, or took magnetic resonance image or fluorodeoxyglucose/Pittsburgh compound B-positron electron tomography scans, in longitudinal cohort studies. We summarized the properties of the major cohort studies in various countries, commonly used diagnosis methods and study designs. We have concluded that additional studies with repeat measures over time in a representative population cohort are needed to address the gap in knowledge of AD progression. Based on our analysis, we suggest directions in which research could move in order to advance our understanding of this complex disease, including repeat biomarker measurements, standardization and increased sample sizes. Show more

Keywords: Alzheimer’s disease, biomarker, cross-sectional, dementia, longitudinal

DOI: 10.3233/JAD-170261

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1359-1379, 2017

Authors: Franzmeier, Nicolai | Hartmann, Julia C. | Taylor, Alexander N.W. | Araque Caballero, Miguel Á. | Simon-Vermot, Lee | Buerger, Katharina | Kambeitz-Ilankovic, Lana M. | Ertl-Wagner, Birgit | Mueller, Claudia | Catak, Cihan | Janowitz, Daniel | Stahl, Robert | Dichgans, Martin | Duering, Marco | Ewers, Michael

Article Type: Research Article

Abstract: Reserve in aging and Alzheimer’s disease (AD) is defined as maintaining cognition at a relatively high level in the presence of neurodegeneration, an ability often associated with higher education among other life factors. Recent evidence suggests that higher resting-state functional connectivity within the frontoparietal control network, specifically the left frontal cortex (LFC) hub, contributes to higher reserve. Following up these previous resting-state fMRI findings, we probed memory-task related functional connectivity of the LFC hub as a neural substrate of reserve. In elderly controls (CN, n  = 37) and patients with mild cognitive impairment (MCI, n  = 17), we assessed global connectivity of …the LFC hub during successful face-name association learning, using generalized psychophysiological interaction analyses. Reserve was quantified as residualized memory performance, accounted for gender and proxies of neurodegeneration (age, hippocampus atrophy, and APOE genotype). We found that greater education was associated with higher LFC-connectivity in both CN and MCI during successful memory. Furthermore, higher LFC-connectivity predicted higher residualized memory (i.e., reserve). These results suggest that higher LFC-connectivity contributes to reserve in both healthy and pathological aging. Show more

Keywords: Aging, cognitive reserve, education, functional connectivity, memory, mild cognitive impairment, task-fMRI

DOI: 10.3233/JAD-170360

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1381-1392, 2017

Authors: Villarreal, Stephanie | Zhao, Fuqiang | Hyde, Lynn A. | Holder, Daniel | Forest, Thomas | Sondey, Marie | Chen, Xia | Sur, Cyrille | Parker, Eric M. | Kennedy, Matthew E.

Article Type: Research Article

Abstract: Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer’s disease. Multiple anti-amyloid immunotherapies have been dose-limited by adverse amyloid related imaging abnormalities such as vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H) observed in human trials and mice. Verubecestat was tested in a 12-week nonclinical study for the potential to exacerbate microhemorrhage (ARIA-H) profiles in 18-22-month-old post-plaque Tg2576-AβPPswe mice. Animals were treated with verubecestat or controls including the anti-Aβ antibody analog of bapineuzumab (3D6) as a positive control for ARIA induction. ARIA-H was measured using in-life longitudinal T2*-MRI …and Prussian blue histochemistry at study end. Verubecestat reduced plasma and cerebrospinal fluid Aβ40 and Aβ42 by >90% and 62% to 68%, respectively. The ARIA-H profile of verubecestat-treated mice was not significantly different than controls. Anti-Aβ treatment significantly increased ARIA-H detected by Prussian blue staining; however, anti-Aβ antibody treatment did not impact plaque status. Verubecestat treatment significantly suppressed the accumulation of total levels of brain Aβ40 and Aβ42 and Thioflavin S positive plaque load. Stereological analysis of cortex and hippocampus plaque load similarly revealed significantly reduced area of Aβ immunoreactivity and reduced plaque number in verubecestat-treated animals compared to controls. The absence of elevated ARIA events in verubecestat-treated mice was associated with a significant reduction in the level of accumulated CNS amyloid pathology and brain Aβ peptides; effects consistent with the desired therapeutic mechanism of verubecestat in AD patients. These data will be compared with longitudinal MRI profiles from ongoing clinical trials. Show more

Keywords: Alzheimer’s disease, amyloid-β, ARIA, BACE, beta-secretase, disease modification, inhibitor, microhemorrhage, MRI, prodromal Alzheimer’s disease

DOI: 10.3233/JAD-170056

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1393-1413, 2017