Journal of Alzheimer's Disease - Volume 67, issue 2

Authors: Hessen, Erik | Kirsebom, Bjørn-Eivind | Eriksson, Cecilia Magdalena | Eliassen, Carl Fredrik | Nakling, Arne Exner | Bråthen, Geir | Waterloo, Knut K. | Aarsland, Dag | Fladby, Tormod

Article Type: Research Article

Abstract: Background: In the care of persons with cognitive problems, it is important to use a valid mild cognitive impairment (MCI) criterion that discriminates well between normal and pathological aging. Objective: To find the brief neuropsychological screening criterion that best correlates with cerebrospinal fluid (CSF) biomarkers for cognitive decline and dementia in persons seeking help for cognitive problems. Methods: 452 consecutively recruited patients (age 40–80 years) from memory-clinics in the Norwegian national multicentre longitudinal study Dementia Disease Initiation were included. CSF data as well as full data from brief neuropsychological screening were available for …all patients. Results: Amnestic MCI, including at least one memory test below T-score 40, outperformed the conventional US National Institute on Aging-Alzheimer’s Association (NIA-AA) MCI criterion. Only amnestic MCI was significantly associated with biomarker pattern of NIA-AA stage 2 (low CSF Aβ 42 concentrations and elevated tau) in multivariate regression analysis. Conclusions: The finding that amnestic MCI based on brief neuropsychological assessment is significantly associated with CSF biomarkers for cognitive decline and Alzheimer’s disease is in accordance with longitudinal studies that find memory impairment; both in itself and especially in combination with other cognitive deficit to constitute a risk factor for subsequent cognitive decline and dementia. The prevalence of pathological biomarkers for Alzheimer’s disease is common in the elderly and the clinical significance of present findings depend on longitudinal validation. Show more

Keywords: Alzheimer’s disease, amnestic MCI, brief neuropsychological assessment, cerebrospinal fluid biomarkers, mild cognitive impairment, NIA-AA MCI criterion, NIA-AA stage 2

DOI: 10.3233/JAD-180964

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 715-723, 2019

Authors: Letra, Liliana | Matafome, Paulo | Rodrigues, Tiago | Duro, Diana | Lemos, Raquel | Baldeiras, Inês | Patrício, Miguel | Castelo-Branco, Miguel | Caetano, Gina | Seiça, Raquel | Santana, Isabel

Article Type: Research Article

Abstract: Background: Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer’s disease. However, the involvement of adipokines, particularly adiponectin, remains unclear. Objective: To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer’s disease and evaluate their relationship with classical biomarkers and their value as markers of progression. Methods: Amnestic mild cognitive impairment (MCI, n  = 71) and Alzheimer’s dementia (AD, n  = 53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were …explored using adjusted Spearman’s correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines. Results: Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ 42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95% CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85μ g/ml maximized the sum of specificity (87%) and sensitivity (44%). Conclusion: Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer’s disease. Show more

Keywords: Adipokines, adiponectin, adipose tissue, Alzheimer’s disease, biomarkers, cerebrospinal fluid, leptin

DOI: 10.3233/JAD-180669

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 725-735, 2019

Authors: Chen, Yi-Chun | Chiu, Ya-Jen | Lin, Chih-Hsin | Hsu, Wen-Chuin | Wu, Jia-Lu | Huang, Chen-Hsiang | Lin, Chia-Wei | Yao, Ching-Fa | Huang, Hei-Jen | Lo, Yen-Shi | Chen, Chiung-Mei | Wu, Yih-Ru | Chang, Kuo-Hsuan | Lee-Chen, Guey-Jen | Mei Hsieh-Li, Hsiu

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), associated with abnormal accumulation of amyloid-β (Aβ), is the most common cause of dementia among older people. A few studies have identified substantial AD biomarkers in blood but their results were inconsistent. Here we screened gene expression alterations on Aβ-GFP SH-SY5Y neuronal model for AD, and evaluated the findings on peripheral leukocytes from 78 patients with AD and 56 healthy controls. The therapeutic responses of identified biomarker candidates were further examined in Aβ-GFP SH-SY5Y neuronal and APP/PS1/Tau triple transgenic (3×Tg-AD) mouse models. Downregulation of apolipoprotein E (APOE) and tropomyosin receptor kinase A (TRKA) were detected in Aβ-GFP …SH-SY5Y cells and validated by peripheral leukocytes from AD patients. Treatment with an in-house indole compound NC009-1 upregulated the expression of APOE and TRKA accompanied with improvement of neurite outgrowth in Aβ-GFP SH-SY5Y cells. NC009-1 further rescued the downregulated APOE and TRKA and reduced Aβ and tau levels in hippocampus and cortex, and ameliorated cognitive deficits in streptozocin-induced hyperglycemic 3×Tg-AD mice. These results suggest the role of APOE and TRKA as potential peripheral biomarkers in AD, and offer a new drug development target of AD treatment. Further studies of a large series of AD patients will be warranted to verify the findings and confirm the correlation between these markers and therapeutic efficacy. Show more

Keywords: Alzheimer’s disease, amyloid-β, APOE, biomarker, indole compound, TRKA

DOI: 10.3233/JAD-180643

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 737-756, 2019

Authors: Marshall, Gad A. | Gatchel, Jennifer R. | Donovan, Nancy J. | Muniz, Martha C. | Schultz, Aaron P. | Becker, J. Alex | Chhatwal, Jasmeer P. | Hanseeuw, Bernard J. | Papp, Kathryn V. | Amariglio, Rebecca E. | Rentz, Dorene M. | Sperling, Reisa A. | Johnson, Keith A.

Article Type: Research Article

Abstract: Background: Instrumental activities of daily living (IADL) impairment and apathy occur in early-stage Alzheimer’s disease (AD) and are associated with regional atrophy and hypometabolism in vivo and greater tau burden at autopsy. Objective: To explore the association between IADL impairment, apathy, and in vivo regional tau in mild cognitive impairment (MCI) and AD dementia. Methods: Forty participants (24 MCI, 16 AD dementia) underwent assessments of IADL (Functional Activities Questionnaire, FAQ) and apathy (Apathy Evaluation Scale Informant report, AES-I). Regional tau was assessed using flortaucipir positron emission tomography (PET) and amyloid using Pittsburgh Compound B …PET. Regions with unadjusted associations of p ≤0.01 were entered into regression models assessing the relationship between tau and FAQ or AES-I, adjusting for age, sex, and cognition, with/without a tau by amyloid interaction. Results: Unadjusted IADL impairment but not apathy was associated with greater tau in multiple regions. After adjusting for covariates, for medial orbitofrontal and entorhinal cortex the interaction between tau and amyloid was associated with IADL impairment and for anterior cingulate it was not but independent associations with both tau and amyloid were retained. With whole brain analyses, similar results were seen for IADL, while for apathy tau in small clusters within the right anterior cingulate and dorsolateral prefrontal cortices were seen, which were more pronounced in individuals with greater amyloid. Conclusions: This exploratory study suggests that IADL impairment in AD is associated with medial temporal and frontal tau, especially in individuals with elevated amyloid, while apathy may be associated with right frontal tau. Show more

Keywords: Alzheimer’s disease, amyloid, apathy, instrumental activities of daily living, mild cognitive impairment, positron emission tomography, tau.

DOI: 10.3233/JAD-170578

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 757-768, 2019

Authors: Lee, Eunjung | Gatz, Margaret | Tseng, Chiuchen | Schneider, Lon S. | Pawluczyk, Sonia | Wu, Anna H. | Deapen, Dennis

Article Type: Research Article

Abstract: Background: Medicare claims record linkage has been used to identify diagnosed dementia cases in order to estimate dementia prevalence and cost of care. Claims records in the 1990 s and early 2000 s have been found to provide 85% – ∼90% sensitivity and specificity. Objective: Considering that dementia awareness has improved over time, we sought to examine sensitivity and specificity of more recent Medicare claims records against a standard criterion, clinical diagnosis of dementia. Methods: For a sample of patients evaluated at the University of Southern California Alzheimer Disease Research Center (ADRC), we performed database linkage with Medicare …claims files for a six-year period, 2007–2012. We used clinical diagnosis at the ADRC as the criterion diagnosis in order to calculate sensitivity and specificity. Results: Medicare claims correctly identified 85% of dementia patients and 77% of individuals with normal cognition. About half of patients clinically diagnosed with mild cognitive impairment had dementia diagnoses in Medicare claims. Misclassified dementia patients (i.e., missed diagnosis by Medicare claims) had more favorable Mini-Mental State Examination and Clinical Dementia Rating scores and were less likely to present behavioral symptoms than correctly-classified dementia patients. Conclusions: Database linkage to Medicare claims records is an efficient and reasonably accurate tool to identify dementia cases in a population-based cohort. However, possibilities of obtaining biased results due to misclassification of dementia status need to be carefully considered to use Medicare claims diagnosis for etiologic research studies. Additional confirmation of dementia diagnosis may also be considered. A larger study is warranted to confirm our findings. Show more

Keywords: Data linkage, dementia, Medicare, sensitivity and specificity

DOI: 10.3233/JAD-181005

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 769-778, 2019