Journal of Alzheimer's Disease - Volume 49, issue 4

Authors: Gabelle, Audrey | Gutierrez, Laure-Anne | Dartigues, Jean-François | Ritchie, Karen | Touchon, Jacques | Berr, Claudine

Article Type: Research Article

Abstract: Background: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer’s disease (AD). The amyloid process seems to be early in AD, and brain amyloid load affects the frontal lobe. Objective: To determine if certain simple clinical signs, especially frontal-related signs, could help reach an earlier and better diagnosis. Methods: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of AD to controls matched for age, gender, and education. The standardized neurological exam included extrapyramidal signs (akinesia, rigidity, rest tremor), pyramidal symptoms (spastic rigidity, Babinski reflex), primitive reflexes …(snout, palmomental reflex grasping), and tremor (essential, intentional, head) at the time of diagnosis and two years before. Results: We compared 106 incident AD subjects (mean age at diagnosis 82.2 (SD = 5.9); median MMSE at diagnosis = 23) to 208 matched controls. In patients younger than 80, palmomental reflexes were more frequent in AD than controls, two years before diagnosis (25.0 versus 7.0% , p  = 0.03) and at time of diagnosis (30.3 versus 12.3% , p  = 0.02). No difference was observed for other signs two years before diagnosis or for patients older than 80. Conclusion: Before diagnosis, the clinical examination of AD patients is not strictly normal; the primitive reflexes appear to be pathological. It might be in connection with the frontal amyloid load at an early stage of the disease. Clinical examination can reveal simple and interesting signs that deserve consideration as well as the other more invasive and expensive biomarkers. Show more

Keywords: Alzheimer’s disease, biomarkers, clinical examination, frontal signs, palmomentonal reflex

DOI: 10.3233/JAD-150436

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1135-1141, 2016

Authors: Dukart, Juergen | Sambataro, Fabio | Bertolino, Alessandro

Article Type: Research Article

Abstract: A variety of imaging, neuropsychological, and genetic biomarkers have been suggested as potential biomarkers for the identification of mild cognitive impairment (MCI) in patients who later develop Alzheimer’s disease (AD). Here, we systematically evaluated the most promising combinations of these biomarkers regarding discrimination between stable and converter MCI and reflection of disease staging. Alzheimer’s Disease Neuroimaging Initiative data of AD (n  = 144), controls (n  = 112), stable (n  = 265) and converter (n  = 177) MCI, for which apolipoprotein E status, neuropsychological evaluation, and structural, glucose, and amyloid imaging were available, were included in this study. Naïve Bayes classifiers were built on AD …and controls data for all possible combinations of these biomarkers, with and without stratification by amyloid status. All classifiers were then applied to the MCI cohorts. We obtained an accuracy of 76% for discrimination between converter and stable MCI with glucose positron emission tomography as a single biomarker. This accuracy increased to about 87% when including further imaging modalities and genetic information. We also identified several biomarker combinations as strong predictors of time to conversion. Use of amyloid validated training data resulted in increased sensitivities and decreased specificities for differentiation between stable and converter MCI when amyloid was included as a biomarker but not for other classifier combinations. Our results indicate that fully independent classifiers built only on AD and controls data and combining imaging, genetic, and/or neuropsychological biomarkers can more reliably discriminate between stable and converter MCI than single modality classifiers. Several biomarker combinations are identified as strongly predictive for the time to conversion to AD. Show more

Keywords: Florbetapir, [18F]fluorodeoxyglucose positron emission tomography, mild cognitive impairment, structural magnetic resonance imaging

DOI: 10.3233/JAD-150570

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1143-1159, 2016

Authors: Geng, Junhua | Xia, Lu | Li, Wanjie | Zhao, Changqi | Dou, Fei

Article Type: Research Article

Abstract: Neurofibrillary tangles are the main pathological feature of Alzheimer’s disease. Insoluble tau protein is the major component of neurofibrillary tangles. Defects in the tau protein degradation pathway in neurons can lead to the accumulation of tau and its subsequent aggregation. Currently, contradictory results on the tau degradation pathway have been reported by different groups. This discrepancy is most likely due to different cell lines and methods used in those studies. In this study, we found that cycloheximide treatment induced mild activation of a ZVAD-sensitive protease in Drosophila Kc cells, resulting in cleavage of tau at its C-terminus; this cleavage …could generate misleading tau protein degradation pattern results depending on the antibodies used in the assay. Because cycloheximide is a broadly used chemical reagent for the study of protein degradation, the unexpected artificial effect we observed here indicates that cycloheximide is not suitable for the study of tau degradation. Other methods, such as inducible expression systems and pulse-chase assays, may be more appropriate for studying tau degradation under physiological conditions. Show more

Keywords: Caspase, cycloheximide, degradation, Drosophila Kc cells, human tau, truncation, ZVAD-sensitive protease

DOI: 10.3233/JAD-150423

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1161-1168, 2016

Authors: Kandiah, Nagaendran | Chander, Russell Jude | Lin, Xuling | Ng, Aloysius | Poh, Yen Yeong | Cheong, Chin Yee | Cenina, Alvin Rae | Assam, Pryseley Nkouibert

Article Type: Research Article

Abstract: Background: Post stroke cognitive impairment (PSCI), an important complication of strokes, has numerous risk factors. A scale adequately classifying risk of cognitive impairment 3–6 months after mild stroke will be useful for clinicians. Objective: To develop a risk score based on clinical and neuroimaging variables that will be useful in identifying mild ischemic stroke patients at high risk for PSCI. Methods: The risk score development cohort comprised of a retrospective dataset of 209 mild stroke patients with MRI confirmed infarcts, without pre-stroke cognitive impairment, and evaluated within 6 months post-stroke for PSCI. Logistic regression identified factors …predictive of PSCI and a risk score was developed based on regression coefficients. The risk score was checked for stability using 10-fold cross-validation and validated in an independent prospective cohort of 185 ischemic mild stroke patients. Results: Within 6 months post-stroke, 37.32% developed PSCI in the retrospective dataset. A 15-point risk score based on age, education, acute cortical infarcts, white matter hyperintensity, chronic lacunes, global cortical atrophy, and intracranial large vessel stenosis was highly predictive of PSCI with an AUC of 0.829. 10.11% with low scores, 52.69% with moderate scores, and 74.07% with high scores developed PSCI. In the prospective validation cohort, the model had an AUC of 0.776, and exhibited similar accuracy and stability statistics at both 6 and 12 months. Conclusion: The seven item risk score adequately identified mild stroke patients who are at an increased risk of developing PSCI. Show more

Keywords: Cognitive impairment, ischemic stroke, magnetic resonance imaging, prognosis, risk score

DOI: 10.3233/JAD-150736

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1169-1177, 2016

Authors: Bennett, James | Burns, Jeffrey | Welch, Paul | Bothwell, Rebecca

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is an aging-related, degenerative brain disease of adults. Most (∼95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid (CSF) AD-related proteins, regional brain atrophy, and oxidative stress damage. We treated mild-moderate AD individuals with R(+)-pramipexole-dihydrochloride (R(+)PPX), a neuroprotective, lipophilic-cation, free-radical scavenger that accumulates into brain and mitochondria. 19 subjects took R(+)PPX twice a day in increasing daily doses up to 300 mg/day under a physician-sponsor IND (60,948, JPB), IRB-approved protocol and quarterly external safety committee monitoring. 15 persons finished and contributed baseline and post-treatment serum, lumbar spinal …fluid, brain 18 F-2DG PET scans, and ADAS-Cog scores. ADAS-Cog scores did not change (n  = 1), improved (n  = 2), declined 1–3 points (n  = 5), or declined 4–13 points (n  = 8) over 6 months of R(+)PPX treatment. Serum PPX levels were not related to changes in ADAS-Cog scores. Fasting AM serum PPX levels at 6 months varied considerably across subjects and correlated strongly with CSF [PPX] (r  = 0.97, p  <  0.0001). CSF [PPX] was not related to CSF [Aβ (42)], [Tau], or [P-Tau]. Regional 18 F-2DG measures of brain glucose uptake demonstrated a 3–6% decline during R(+)PPX treatment. 56 mild-moderate adverse events occurred, 26 probably/definitely related to R(+)PPX use, with 4 withdrawals. R(+)PPX was generally well-tolerated and entered brain extracellular space linearly. Further studies of R(+)PPX in AD should include a detailed pharmacokinetic study of peak and trough serum [PPX] variations among subjects prior to planning any larger studies that would be needed to determine efficacy in altering disease progression. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive disorder, investigational treatment, oxidative stress, PET scan

DOI: 10.3233/JAD-150788

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1179-1187, 2016

Authors: Chung, Jun Ku | Plitman, Eric | Nakajima, Shinichiro | Chow, Tiffany W. | Chakravarty, M. Mallar | Caravaggio, Fernando | Gerretsen, Philip | Brown, Eric E. | Iwata, Yusuke | Mulsant, Benoit H. | Graff-Guerrero, Ariel

Article Type: Correction

DOI: 10.3233/JAD-159007

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1189-1190, 2016

Authors: Fiala, Milan | Terrando, Niccolo | Dalli, Jesmond

Article Type: Correction

DOI: 10.3233/JAD-159008

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1191-1191, 2016

Article Type: Other

DOI: 10.3233/JAD-150959

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1193-1196, 2016

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1197-1210, 2016