Journal of Alzheimer's Disease - Volume 47, issue 1

Authors: Liu-Seifert, Hong | Siemers, Eric | Price, Karen | Han, Baoguang | Selzler, Katherine J. | Henley, David | Sundell, Karen | Aisen, Paul | Cummings, Jeffrey | Raskin, Joel | Mohs, Richard | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The temporal relationship of cognitive deficit and functional impairment in Alzheimer’s disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression. Objective: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials. Methods: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were …assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time. Results: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa. Conclusions: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cognition, correlation of data, dementia, function, Phase 3 clinical trials, solanezumab

DOI: 10.3233/JAD-142508

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 205-214, 2015

Authors: Tiwari, Manish K. | Kepp, Kasper P.

Article Type: Research Article

Abstract: Protein aggregation is a hallmark of many neurodegenerative disorders. Alzheimer’s disease (AD) is directly linked to deposits of amyloid-β (Aβ) derived from the amyloid-β protein precursor (AβPP), and multiple experimental studies have investigated the aggregation behavior of these amyloids. The present paper reports modeling of the aggregation propensities and cell toxicities of genetic variants of Aβ known to increase disease risk. From correlation to experimental data, and using four distinct experimental structures to test structural sensitivity, we find that the Spatial Aggregation Propensity (SAP) formalism can describe the relative experimental aggregation propensities of Aβ 42 variants (R 2  = 0.49 …and 0.70, p ∼0.02 and 0.002, for 1IYT and 1Z0Q conformations using a probe radius of 10 Å). Our analysis finds correlation between the reduction in hydrophilic surface and experimental aggregation propensities. Finally, we show that experimental cell toxicities of Aβ variants are well described by computed SAP values, suggesting direct interplay between aggregation propensity and cell toxicity and providing a step toward a first computational estimator of Aβ toxicity. The present study contributes to our understanding of amyloid aggregation and suggests a method to predict aggregation propensity and toxicity of Aβ variants, and potentially to reduce aggregation propensities of amyloids by molecular intervention directed toward specific conformations of the peptides. Show more

Keywords: Alzheimer’s disease, amyloid-β, hydrophilic surface, protein aggregation, structure-activity relations

DOI: 10.3233/JAD-150046

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 215-229, 2015

Authors: Edmonds, Emily C. | Delano-Wood, Lisa | Galasko, Douglas R. | Salmon, David P. | Bondi, Mark W. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The NIA-AA criteria for “preclinical” Alzheimer’s disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and “subtle cognitive decline,” which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define “subtle cognitive decline” using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately …based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, amyloid, biomarkers, cerebrospinal fluid, dementia, neurodegeneration, neuropsychology, preclinical Alzheimer’s disease, subtle cognitive decline

DOI: 10.3233/JAD-150128

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 231-242, 2015

Authors: van Harten, Argonde C. | Mulders, Joyce | Scheltens, Philip | van der Flier, Wiesje M. | Oudejans, Cees B.M.

Article Type: Research Article

Abstract: Background and Objective: The need to find a better reflection of Alzheimer’s disease (AD) pathophysiology led us to investigate differential expression of microRNA (miRNA) in cerebrospinal fluid (CSF) of AD patients compared to matched controls, using a genome-wide data-driven approach. Methods: From the Amsterdam Dementia Cohort, we selected 19 AD patients with CSF indicative of AD pathophysiology and 19 age and gender-matched controls without CSF evidence of AD (67 ± 6 years old, 20 [53%] female). We measured 754 miRNA in CSF using qRT-PCR (Taqman Array MicroRNA cards A and B, v3.0) according to the …Megaplex Taqman protocol. Hierarchical cluster analysis was performed and groups were compared using Linear Models for Microarray Data, a modified t -test. We performed validation analysis using qRT-PCR single assays. Results: 144 ± 66 miRNA could be detected using Megaplex array analysis (19% ). Mean Ct (average 32.4 ± 0.5) was correlated to age (r  = 0.52, p  = 0.001). Five miRNA were differentially expressed in CSF of AD patients. None of these could be replicated. After stratification by age, seven miRNA showed differential expression in late-onset AD, of which lower abundance of let-7a was replicated (log10RQ −1.46, p  <  0.05). In early-onset AD, twelve miRNA were differentially expressed of which lower abundance of miRNA-532-3p remained borderline significant (log10RQ −1.27, p  = 0.05). Conclusion: Although we could not consistently separate AD patients and controls in the whole group, we have found indications miRNA in CSF are able to reflect aging and perhaps also heterogeneity in AD. Further investigation requires optimizing RNA input, while maintaining strict age matching. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, microRNAs

DOI: 10.3233/JAD-140075

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 243-252, 2015

Authors: Huart, Caroline | Rombaux, Philippe | Gérard, Thomas | Hanseeuw, Bernard | Lhommel, Renaud | Quenon, Lisa | Ivanoiu, Adrian | Mouraux, André

Article Type: Research Article

Abstract: Background: Olfactory dysfunction is associated with Alzheimer’s disease (AD), and already present at pre-dementia stage. Objectives: Based on the assumption that early neurodegeneration in AD is asymmetrical and that olfactory input is primarily processed in the ipsilateral hemisphere, we assessed whether unirhinal psychophysical and electrophysiological assessment of olfactory function can contribute to the diagnostic workup of mild cognitive impairment (MCI). Methods: Olfactory function of 13 MCI patients with positive amyloid PET, 13 aged-matched controls (AC) with negative amyloid PET and 13 patients with post-infectious olfactory loss (OD) was assessed unirhinally using (1) …psychophysical testing of olfactory detection, discrimination and identification performance and (2) the recording of olfactory event-related brain potentials. Time-frequency analysis was used to enhance the signal-to-noise ratio of the electrophysiological responses. Psychophysical and electrophysiological assessment of auditory and trigeminal chemosensory function served as controls. Results: As compared to AC and OD, MCI patients exhibited a significant asymmetry of olfactory performance. This asymmetry efficiently discriminated between MCI and AC (sensitivity: 85% , specificity: 77% ), as well as MCI and OD (sensitivity: 85% , specificity: 70% ). There was also an asymmetry of the electrophysiological responses, but not specific for MCI. In both MCI and OD, olfactory stimulation of the best nostril elicited significantly more activity than stimulation of the worse nostril, between 3–7.5 Hz and 1.2–2.0 s after stimulus onset. Trigeminal and auditory psychophysical testing did not show any difference between groups. Conclusion: MCI patients exhibit a marked asymmetry of behavioral olfactory function, which could be useful for the diagnostic workup of MCI. Show more

Keywords: Alzheimer’s disease, EEG, evoked potentials, mild cognitive impairment, olfaction, smell

DOI: 10.3233/JAD-141494

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 253-270, 2015

Article Type: Correction

DOI: 10.3233/JAD-159901

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 271-271, 2015

Article Type: Meeting Report

DOI: 10.3233/JAD-150392

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 273-276, 2015