Journal of Alzheimer's Disease - Volume 54, issue 4

Authors: Myers, Candice A. | Keller, Jeffrey N. | Allen, H. Raymond | Brouillette, Robert M. | Foil, Heather | Davis, Allison B. | Greenway, Frank L. | Johnson, William D. | Martin, Corby K.

Article Type: Research Article

Abstract: Dementia is a chronic condition in the elderly and depression is often a concurrent symptom. As populations continue to age, accessible and useful tools to screen for cognitive function and its associated symptoms in elderly populations are needed. The aim of this study was to test the reliability and validity of a new internet-based assessment battery for screening mood and cognitive function in an elderly population. Specifically, the Helping Hand Technology (HHT) assessments for depression (HHT-D) and global cognitive function (HHT-G) were evaluated in a sample of 57 elderly participants (22 male, 35 female) aged 59–85 years. The study sample …was categorized into three groups: 1) dementia (n  = 8; Mini-Mental State Exam (MMSE) score 10–24), 2) mild cognitive impairment (n  = 24; MMSE score 25–28), and 3) control (n  = 25; MMSE score 29–30). Test-retest reliability (Pearson correlation coefficient, r) and internal consistency reliability (Cronbach’s alpha, α ) of the HHT-D and HHT-G were assessed. Validity of the HHT-D and HHT-G was tested via comparison (Pearson r) to commonly used pencil-and-paper based assessments: HHT-D versus the Geriatric Depression Scale (GDS) and HHT-G versus the MMSE. Good test-retest (r = 0.80; p  < 0.0001) and acceptable internal consistency reliability (α = 0.73) of the HHT-D were established. Moderate support for the validity of the HHT-D was obtained (r  = 0.60 between the HHT-D and GDS; p  < 0.0001). Results indicated good test-retest (r  = 0.87; p  < 0.0001) and acceptable internal consistency reliability (α = 0.70) of the HHT-G. Validity of the HHT-G was supported (r  = 0.71 between the HHT-G and MMSE; p  < 0.0001). In summary, the HHT-D and HHT-G were found to be reliable and valid computerized assessments to screen for depression and cognitive status, respectively, in an elderly sample. Show more

Keywords: Cognitive function, dementia, depression, elderly, mood

DOI: 10.3233/JAD-160441

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1359-1364, 2016

Authors: Brüggenjürgen, Bernd | Andersohn, Frank | Burkowitz, Jörg | Ezzat, Nadja | Gaudig, Maren | Willich, Stefan N.

Article Type: Research Article

Abstract: Background: The individual and societal burden of Alzheimer’s disease (AD) is substantial. Identifying relevant factors deteriorating AD and inducing need for nursing care would be of high relevance for healthcare planning. Objective: The main objective of this study was the identification of predictors of first assignment of a level of long-term care in AD, used as an approximation for disease progression. Methods: In a retrospective cohort study using data from a large German statutory health and long-term care insurance (SHI) company, co-morbidities and drug exposure were evaluated with respect to their predictive value for disease …progression (first day the amount of daily nursing care exceeded 1.5 hours). Time to disease progression was modeled using COX-proportional hazard regression with stepwise selection of predictor variables. Results: The risk of nursing care need increased substantially with increasing age. Number of hospitalizations and number of different drugs used were significant indicators for progression, whereas outpatient visits were associated with a reduced need for care. Gender did not indicate significant influence on progression. Malignant neoplasms of ill-defined, secondary, and unspecified sites, malnutrition, renal failure, and injuries increased the risk of need for nursing care most significantly. Among prescribed drugs, significant increased risks were associated with drugs used in diabetes, preparations for treatment of wounds and ulcers, antiseptics and disinfectants, and analgesics. Conclusions: Physical comorbidities are relevant contributors to an increase in need for nursing care. Some medical predicting conditions may be linked to cognition, while others may be directly linked to demand for care. AD patients with these comorbidities should be monitored with special attention, as they may be under an increased risk of care dependency. Show more

Keywords: Alzheimer’s disease, comorbidities, deterioration, predictors, retrospective cohort study

DOI: 10.3233/JAD-160137

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1365-1372, 2016

Authors: Mukhamedyarov, Marat A. | Rizvanov, Albert A. | Yakupov, Eduard Z. | Zefirov, Andrey L. | Kiyasov, Andrey P. | Reis, Helton J. | Teixeira, Antônio L. | Vieira, Luciene B. | Lima, Luciana M. | Salafutdinov, Ilnur I. | Petukhova, Elena O. | Khaiboullina, Svetlana F. | Schlauch, Karen A. | Lombardi, Vincent C. | Palotás, András

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a devastating and progressive form of dementia that is typically associated with a build-up of amyloid-β plaques and hyperphosphorylated and misfolded tau protein in the brain. Presently, there is no single test that confirms AD; therefore, a definitive diagnosis is only made after a comprehensive medical evaluation, which includes medical history, cognitive tests, and a neurological examination and/or brain imaging. Additionally, the protracted prodromal phase of the disease makes selection of control subjects for clinical trials challenging. In this study we have utilized a gene-expression array to screen blood and skin punch biopsy (fibroblasts, keratinocytes, and …endothelial cells) for transcriptional differences that may lead to a greater understanding of AD as well as identify potential biomarkers. Our analysis identified 129 differentially expressed genes from blood of dementia cases when compared to healthy individuals, and four differentially expressed punch biopsy genes between AD subjects and controls. Additionally, we identified a set of genes in both tissue compartments that showed transcriptional variation in AD but were largely stable in controls. The translational products of these variable genes are involved in the maintenance of the Golgi structure, regulation of lipid metabolism, DNA repair, and chromatin remodeling. Our analysis potentially identifies specific genes in both tissue compartments that may ultimately lead to useful biomarkers and may provide new insight into the pathophysiology of AD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarker, diagnostics, early diagnosis, endothelial cell, fibroblast, inflammation, keratinocyte, lymphocyte, mild cognitive impairment, neurodegeneration, oxidative stress, skin biopsy

DOI: 10.3233/JAD-160457

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1373-1383, 2016

Authors: Karch, André | Llorens, Franc | Schmitz, Matthias | Arora, Amandeep Singh | Zafar, Saima | Lange, Peter | Schmidt, Christian | Zerr, Inga

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers are routinely used for the differential diagnosis of rapidly progressive dementia, but are also affected by patients’ characteristics. Objective: To assess if stratification by age, sex, and genetic risk factors improves the accuracy of cerebrospinal fluid (CSF) biomarkers in patients with rapidly progressive dementia. Methods: 1,538 individuals with sporadic Creutzfeldt-Jakob disease (CJD), 173 with classic Alzheimer’s disease (cAD), 37 with rapidly progressive Alzheimer’s disease (rpAD), and 589 without signs of dementia were included in this retrospective diagnostic study. The effect of age, sex, PRNP codon 129, and APOE …genotype on CSF levels of tau, p-tau, Aβ1–42 , and Aβ1–40 values measured at time of diagnostic work-up was assessed. Results: Tau was a better marker for the differentiation of CJD and rpAD in older (AUC:0.97; 95% CI:0.96–1.00) than in younger (AUC:0.91; 95% CI:0.87–0.94) patients as tau levels increased with age in CJD patients, but not in rpAD patients. PRNP codon 129 and APOE genotype had complex effects on biomarkers in all diseases, making stratification by genotype a powerful tool. In females (AUC:0.78; 95% CI:0.65–0.91) and patients older than 70 (AUC:0.78; 95% CI:0.62–0.93), tau was able to differentiate with moderate accuracy between cAD and rpAD patients. Conclusion: Implementation of stratum-specific reference ranges improves the diagnostic accuracy of CSF biomarkers for the differential diagnosis of rapidly progressive dementia. Diagnostic criteria developed for this setting have to take this into account. Show more

Keywords: Alzheimer’s disease, amyloid-beta, biomarker, cerebrospinal fluid, Creutzfeldt-Jakob disease, dementia, tau

DOI: 10.3233/JAD-160267

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1385-1393, 2016

Authors: Racine, Annie M. | Clark, Lindsay R. | Berman, Sara E. | Koscik, Rebecca L. | Mueller, Kimberly D. | Norton, Derek | Nicholas, Christopher R. | Blennow, Kaj | Zetterberg, Henrik | Jedynak, Bruno | Bilgel, Murat | Carlsson, Cynthia M. | Christian, Bradley T. | Asthana, Sanjay | Johnson, Sterling C.

Article Type: Research Article

Abstract: It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer’s disease(AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer’s Prevention(mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery(CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status(determined by consensus review), and biomarkers for amyloid and tau(CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury(CSF neurofilament light protein). CSF and …PET-PiB were collected in n  = 71 and n  = 91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42 . These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD. Show more

Keywords: Amyloid, biomarkers, cerebrospinal fluid, cognitive impairment, CogState, computerized cognitive testing, neural injury, preclinical Alzheimer’s disease

DOI: 10.3233/JAD-160528

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1395-1408, 2016

Authors: Yuan, Baoyu | Xie, Chunming | Shu, Hao | Liao, Wenxiang | Wang, Zan | Liu, Duan | Zhang, Zhijun

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE) ɛ4 carriers are at increased risk of developing Alzheimer’s disease (AD) while the ɛ2 carriers appear to be protected against the disease. The default mode network (DMN), based in ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), consists of functionally differentiable anterior and posterior subnetworks. Objective: This study was to investigate whether there are differential effects of APOE polymorphisms on DMN subnetworks in amnestic mild cognitive impairment (aMCI). Methods: Functional connectivity (FC) analyses were performed in DMN subnetworks in 74 aMCI (9 APOE ɛ2ɛ3, 44 ɛ3ɛ3, and 21 ɛ3ɛ4) …and 105 healthy controls (HC; 32 APOE ɛ2ɛ3, 39 ɛ3ɛ3, and 34 ɛ3ɛ4). Logistic regression analysis was performed to obtain a model for classifying aMCI and HC. Results: Significant interactions of APOE by aMCI on FCs were found in right cerebellum posterior lobe, left lingual gyrus, and right middle cingulate cortex in the vmPFC subnetwork, and bilateral fusiform gyrus, left inferior frontal gyrus, and left precuneus in the PCC subnetwork. The impairment of episodic memory for ɛ4-carriers in aMCI negatively correlated with altered FC between vmPFC and right middle cingulate cortex, while positively correlated with altered FC between PCC and left fusiform gyrus. A model composed of episodic memory and FCs dexterity correctly classified 89.4% of aMCI and HC. Conclusions: APOE ɛ4 and ɛ2 alleles differentially mediate anterior and posterior DMN subnetworks. Furthermore, it further suggests that the anterior and posterior DMN subnetworks in aMCI play an opposing role on the impairment of episodic memory. Show more

Keywords: Amnesic mild cognitive impairment, default mode network, episodic memory, functional connectivity, functional MRI, posterior cingulated cortex, ventromedial prefrontal cortex

DOI: 10.3233/JAD-160353

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1409-1423, 2016

Authors: Tan, Edwin C.K. | Bell, J. Simon | Lu, Christine Y. | Toh, Sengwee

Article Type: Research Article

Abstract: Objective: The objectives were to investigate national trends in outpatient antihypertensive prescribing in people with dementia in the United States between 2006 and 2012, and to investigate clinical and demographic factors associated with different antihypertensive prescribing patterns. Methods: This was an analysis of the National Ambulatory Medical Care Survey (NAMCS) and the outpatient department component of the National Hospital Ambulatory Medical Care Survey (NHAMCS). Outpatient visits by people aged ≥65 years with documented dementia were analyzed. Complex samples multivariate logistic regression was conducted to estimate temporal trends and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) …for factors associated with prescribing of antihypertensives, multiple antihypertensives and different antihypertensive classes. Results: There was a statistically significant increase in the proportion of physician visits by older people with dementia with a documented diagnosis of hypertension from 49.3% (95% CI: 41.3% –57.4%) in 2006 to 55.7% (95% CI: 50.2% –61.2%) in 2012. There were non-significant increases in overall antihypertensive use and the use of multiple antihypertensive classes. Male sex was associated with any antihypertensive use (AOR 1.37, 95% CI 1.02–1.84) and multiple antihypertensive class use (AOR 1.52, 95% CI 1.14–2.04). Black race (AOR 2.04, 95% CI 1.12–3.71) and Midwest residence (AOR 2.03, 95% CI 1.46–2.82) were associated with multiple antihypertensive use. Conclusion: There was an increase in documented hypertension in physician visits by older people with dementia from 2006 to 2012, but minimal increases in overall antihypertensive use. Various demographic and clinical factors were associated with the prescribing of antihypertensives in people with dementia. Show more

Keywords: Antihypertensive agents, dementia, hypertension, outpatients, pharmacoepidemiology

DOI: 10.3233/JAD-160470

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1425-1435, 2016

Authors: Chincarini, Andrea | Sensi, Francesco | Rei, Luca | Bossert, Irene | Morbelli, Silvia | Guerra, Ugo Paolo | Frisoni, Giovanni | Padovani, Alessandro | Nobili, Flavio | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The assessment of in vivo 18 F images targeting amyloid deposition is currently carried on by visual rating with an optional quantification based on standardized uptake value ratio (SUVr) measurements. We target the difficulties of image reading and possible shortcomings of the SUVr methods by validating a new semi-quantitative approach named ELBA. ELBA involves a minimal image preprocessing and does not rely on small, specific regions of interest (ROIs). It evaluates the whole brain and delivers a geometrical/intensity score to be used for ranking and dichotomic assessment. The method was applied to adniimages 18 F-florbetapir images from the ADNI …database. Five expert readers provided visual assessment in blind and open sessions. The longitudinal trend and the comparison to SUVr measurements were also evaluated. ELBA performed with area under the roc curve (AUC ) = 0.997 versus the visual assessment. The score was significantly correlated to the SUVr values (r  = 0.86, p  < 10-4 ). The longitudinal analysis estimated a test/retest error of ≃2.3%. Cohort and longitudinal analysis suggests that the ELBA method accurately ranks the brain amyloid burden. The expert readers confirmed its relevance in aiding the visual assessment in a significant number (85) of difficult cases. Despite the good performance, poor and uneven image quality constitutes the major limitation. Show more

Keywords: Alzheimer’s disease, amyloid, image analysis, mild cognitive impairment, PET, standardized uptake value ratio

DOI: 10.3233/JAD-160232

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1437-1457, 2016

Authors: Magnin, Eloi | Démonet, Jean-François | Wallon, David | Dumurgier, Julien | Troussière, Anne-Cécile | Jager, Alain | Duron, Emmanuelle | Gabelle, Audrey | de la Sayette, Vincent | Volpe-Gillot, Lisette | Tio, Gregory | Evain, Sarah | Boutoleau-Bretonnière, Claire | Enderle, Adeline | Mouton-Liger, François | Robert, Philippe | Hannequin, Didier | Pasquier, Florence | Hugon, Jacques | Paquet, Claire | on behalf of ePLM collaborators

Article Type: Research Article

Abstract: Background: Few demographical data about primary progressive aphasia (PPA) are available, and most knowledge regarding PPA is based on tertiary centers’ results. Objective: Our aims were to describe demographical characteristics of the PPA population in a large sample of PPA patients from the network of French Alzheimer plan memory centers (Sample 1), and to describe the stratification of cerebrospinal fluid (CSF) biomarkers in two different samples of PPA patients (Samples 2 and 3). Methods: All registered PPA patients in the French Alzheimer’s disease (AD) databank (Sample 1: n  = 2,035) and a subsample (Sample 2: n … = 65) derived from a multicentric prospective cohort with CSF biomarker analysis were analyzed. A multicentric retrospective cohort from language expert tertiary centers (Sample 3: n  = 97) with CSF biomarker analysis was added. Sample 3 was added to replicate the CSF results of the Sample 2 and to evaluate repartition of AD pathology in the three variant of PPA according to the latest classification. Results: Non-Fluent/Agrammatic, Logopenic, and Unclassifiable PPA patients (NF/A-Logo-Unclass PPA) were older and more frequent than Semantic PPA patients (2.2 versus 0.8/100,000 inhabitants; p  < 0.00001). Male predominance occurred after the age of 80 (p  < 0.00001). A higher level of education was observed in the PPA population compared to a typical amnesic AD group. No demographical significant difference between PPA due to AD and not due to AD was observed. The Logopenic variant was most frequent with 85% of AD CSF biomarker profiles (35% in NF/A PPA; 20% in Semantic PPA). Conclusion: PPA occurs also in an elderly population, especially in male patients over 80. CSF biomarkers are useful to stratify PPA. The epidemiology of PPA should be further investigated to confirm gender and cognitive reserve role in PPA to better understand the factors and mechanisms leading to this language-predominant deficit during neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, epidemiology, frontotemporal dementia, gender, primary progressive aphasia

DOI: 10.3233/JAD-160536

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1459-1471, 2016

Authors: Makizako, Hyuma | Shimada, Hiroyuki | Doi, Takehiko | Tsutsumimoto, Kota | Hotta, Ryo | Nakakubo, Sho | Makino, Keitaro | Suzuki, Takao

Article Type: Research Article

Abstract: Background: Older adults with mild cognitive impairment (MCI) are non-demented, but demonstrate cognitive dysfunction, and have significantly higher risk of progressing to dementia. A better understanding of more sensitive risk factors, such as combination of cognitive and psychological status, for progression of MCI to dementia may be crucial for prevention of development of dementia. Objective: To examine MCI, depressive symptoms, and comorbid MCI and depressive symptoms as risk factors for development of dementia. Methods: A total of 3,663 community-dwelling older people were included in this prospective longitudinal study. MCI was determined by age- and education-adjusted …objective cognitive impairment using computerized comprehensive cognitive measures including memory, attention/executive function, and processing speed. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS) and defined by a GDS score of 6 or more. Results: During the 24-month follow-up period, 72 participants (2.0%) developed dementia. Baseline MCI was significantly associated with an increased risk of incident dementia (hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.8–5.5) but depressive symptoms were not (2.0; 1.0–4.2) after adjusting for age, sex, education, prescribed medications, and walking speed. Participants with comorbid MCI and depressive symptoms at baseline had a higher risk of developing dementia (HR, 4.8; 2.3–10.5). Conclusion: Although MCI and depressive symptoms may be associated with increased risk for incident dementia independently, comorbid MCI and depressive symptoms have a significantly greater impact on dementia development among community-dwelling older adults. Show more

Keywords: Comorbidity, dementia, depressive symptoms, mild cognitive impairment

DOI: 10.3233/JAD-160244

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1473-1482, 2016