Journal of Alzheimer's Disease - Volume 69, issue 4

Authors: Wang, Xiwu | Zhou, Wenjun | Ye, Teng | Lin, Xiaodong | Zhang, Jie | for Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Our aim was to examine whether the influence of apolipoprotein E4 (APOE4) genotype on cognitive decline differs in male and female across the Alzheimer’s disease (AD) continuum. Among individuals with normal cognition (NC; n  = 415), mild cognitive impairment (MCI; n  = 870), and AD (n  = 334), we investigated the longitudinal associations of APOE4 genotype and sex with cognitive decline over 13 years. Our cognitive outcomes were Rey Auditory Verbal Learning Test (RAVLT) total learning score and delayed recall and Mini-Mental State Examination (MMSE) score. There were significant effects of the APOE4×sex interaction on change in verbal memory in the MCI group, …but not the NC or AD group. Specifically, among individuals with MCI, female APOE4 carriers had a steeper decline in RAVLT total learning score, but not delayed recall or MMSE score compared to all other groups (APOE4 + /Male, APOE4-/Female, APOE4-/Male). In conclusion, female APOE4 carriers have faster rates of memory decline than their male counterparts among MCI individuals. Show more

Keywords: Alzheimer’s disease, APOE, memory decline, sex differences

DOI: 10.3233/JAD-181234

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1161-1169, 2019

Authors: Nation, Daniel A. | Ho, Jean K. | Dutt, Shubir | Han, S. Duke | Lai, Mark H.C. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: A clinical diagnosis of cognitive impairment is traditionally based on a single cognitive exam, but serial cognitive testing can be sensitive to subtle cognitive changes in asymptomatic individuals and inform cognitive trajectory. Objective: We evaluated the prognostic utility of identifying longitudinal neuropsychological decline along with single cognitive exam and Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers in predicting dementia. We also examined brain volumetric differences based on decline trajectories. Method: Regression models quantified 12-month neuropsychological decline relative to normative expectations among non-demented older adults (N  = 1,074). Progression to dementia over follow-up (18-120 months) was diagnosed …using independent modes of assessment. Results: In Cox regression models controlling for age, sex, education, apolipoprotein E4, and baseline cognitive diagnosis, neuropsychological decline predicted increased dementia risk, χ 2  = 69.861, p  < 0.001, odds ratio = 2.841, even after correction for CSF biomarkers (amyloid-β , phosphorylated tau, total tau), χ 2  = 26.365, p  < 0.001, odds ratio = 2.283. Voxel-based morphometry analysis indicated smaller hippocampal and medial temporal volume in participants with neuropsychological decline. Conclusions: Longitudinal diagnosis of neuropsychological decline improved prognostic accuracy beyond single cognitive exam diagnoses and AD CSF biomarkers, even in asymptomatic older adults. Older adults with a trajectory of neuropsychological decline exhibit smaller medial temporal and hippocampal brain volume. Longitudinal diagnostic approaches may benefit selection and randomization procedures for AD clinical trials in asymptomatic individuals. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive decline, dementia

DOI: 10.3233/JAD-180525

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1171-1182, 2019

Authors: König, Alexandra | Linz, Nicklas | Zeghari, Radia | Klinge, Xenia | Tröger, Johannes | Alexandersson, Jan | Robert, Philippe

Article Type: Research Article

Abstract: Background: Apathy is present in several psychiatric and neurological conditions and has been found to have a severe negative effect on disease progression. In older people, it can be a predictor of increased dementia risk. Current assessment methods lack objectivity and sensitivity, thus new diagnostic tools and broad-scale screening technologies are needed. Objective: This study is the first of its kind aiming to investigate whether automatic speech analysis could be used for characterization and detection of apathy. Methods: A group of apathetic and non-apathetic patients (n  = 60) with mild to moderate neurocognitive disorder were recorded while …performing two short narrative speech tasks. Paralinguistic markers relating to prosodic, formant, source, and temporal qualities of speech were automatically extracted, examined between the groups and compared to baseline assessments. Machine learning experiments were carried out to validate the diagnostic power of extracted markers. Results: Correlations between apathy sub-scales and features revealed a relation between temporal aspects of speech and the subdomains of reduction in interest and initiative, as well as between prosody features and the affective domain. Group differences were found to vary for males and females, depending on the task. Differences in temporal aspects of speech were found to be the most consistent difference between apathetic and non-apathetic patients. Machine learning models trained on speech features achieved top performances of AUC = 0.88 for males and AUC = 0.77 for females. Conclusions: These findings reinforce the usability of speech as a reliable biomarker in the detection and assessment of apathy. Show more

Keywords: Apathy, assessment, machine learning, neuropsychiatric symptoms, speech analysis, voice analysis

DOI: 10.3233/JAD-181033

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1183-1193, 2019

Authors: Kwon, Oh Hoon | Cho, Yoon Young | Kim, Tae-Wan | Chung, Sungkwon

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is caused by the accumulation of neurotoxic amyloid-β (Aβ) peptides. Aβ is derived from amyloid-β protein precursor (AβPP). In the non-amyloidogenic pathway, AβPP is cleaved by α -secretase and γ -secretase at the plasma membrane, excluding Aβ production. Alternatively, AβPP in the plasma membrane is internalized via endocytosis, and delivered to early endosomes and lysosomes, where it is cleaved by β-secretase and γ -secretase. Recent studies have shown that insulin in the periphery crosses the blood-brain barrier, and plays important roles in the brain. Furthermore, impaired insulin signaling has been linked to the progression of AD, and …intranasal insulin administration improves memory impairments and cognition. However, the underlying molecular mechanisms of insulin treatment remain largely unknown. To investigate the effects of insulin on AβPP processing, we tested the effects of insulin on neuroblastoma SH-SY5Y cells overexpressing AβPP, and cultured rat cortical neurons. We found that insulin increased the level of cell surface AβPP, decreasing the endocytosis rate of AβPP. Insulin reduced Aβ generation through upregulation of AβPP O-GlcNAcylation via Akt insulin signaling. Our present data suggest that insulin affects Aβ production by regulating AβPP processing through AβPP O-GlcNAcylation. These results provide mechanistic insight into the beneficial effects of insulin, and a possible link between insulin deficient diabetes and cerebral amyloidosis in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , amyloid-β protein precursor, insulin, O-GlcNAcylation

DOI: 10.3233/JAD-190060

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1195-1211, 2019

Authors: Minta, Karolina | Portelius, Erik | Janelidze, Shorena | Hansson, Oskar | Zetterberg, Henrik | Blennow, Kaj | Andreasson, Ulf

Article Type: Research Article

Abstract: Background: Brevican, neurocan, tenascin-C, and tenascin-R are extracellular matrix (ECM) proteins that are mainly expressed in the brain. They play important roles in proliferation and migration of neurons and other cell types in the brain. These ECM proteins may also be involved in various pathologies, including reactive gliosis. Objective: The aim of the study was to investigate if ECM protein concentrations in cerebrospinal fluid (CSF) are linked to the neurodegenerative process in Alzheimer’s disease (AD). Methods: Lumbar CSF samples from a non-AD control group (n  = 50) and a clinically diagnosed AD group (n  = 42), matched for …age and gender, were analyzed using commercially available ELISAs detecting ECM proteins. Mann-Whitney U test was used to examine group differences, while Spearman’s rho test was used for correlations. Results: Brevican, neurocan, tenascin-R, and tenascin-C concentrations in AD patients did not differ compared to healthy controls or when the groups were dichotomized based on the Aβ42/40 cut-off. CSF tenascin-C and tenascin-R concentrations were significantly higher in women than in men in the AD group (p  = 0.02). Conclusion: ECM proteins do not reflect AD-pathology in CSF. CSF tenascin-C and tenascin-R upregulation in women possibly reveal sexual dimorphism in the central nervous system immunity during AD. Show more

Keywords: Alzheimer’s disease, brevican, neurocan, tenascin-C, tenascin-R

DOI: 10.3233/JAD-190187

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1213-1220, 2019