Journal of Alzheimer's Disease - Volume 44, issue 1

Authors: Molitor, Robert J. | Ko, Philip C. | Ally, Brandon A.

Article Type: Review Article

Abstract: A growing body of literature has investigated changes in eye movements as a result of Alzheimer's disease (AD). When compared to healthy, age-matched controls, patients display a number of remarkable alterations to oculomotor function and viewing behavior. In this article, we review AD-related changes to fundamental eye movements, such as saccades and smooth pursuit motion, in addition to changes to eye movement patterns during more complex tasks like visual search and scene exploration. We discuss the cognitive mechanisms that underlie these changes and consider the clinical significance of eye movement behavior, with a focus on eye movements in mild cognitive …impairment. We conclude with directions for future research. Show more

Keywords: Attention, mild cognitive impairment, saccade, smooth pursuit

DOI: 10.3233/JAD-141173

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 1-12, 2015

Authors: Ji, Lina | Zhao, Xi | Hua, Zichun

Article Type: Review Article

Abstract: The presence of amyloid plaques and vascular amyloid deposits is one of the pathological features of Alzheimer's disease (AD). Amyloid plaques and vascular deposits mainly consist of amyloid-β (Aβ), which is a metabolic product of amyloid-β protein precursor cleaved by β- and γ-secretase. Soluble Aβ monomers readily aggregate into oligomers preceding the formation of insoluble fibrils, and Aβ oligomers are more toxic than fibrils. Intensive therapeutic efforts have been attempted in the treatment of AD targeting Aβ, including preventing Aβ generation, inhibiting Aβ aggregation, and promoting Aβ clearance. The results show that amyloid plaque burden is reduced together with improved …cognition performance in AD. Gelsolin, a multifunctional actin-binding protein, exists intracellularly as a cytoplasmic form and extracellularly as a secreted form in blood/cerebrospinal fluid. Gelsolin is suggested to be implicated in AD, based on the findings that some changes of gelsolin are correlated with disease progression rate in AD patients. Gelsolin binds Aβ, inhibits its aggregation into fibrils, and protects cells from apoptosis induced by Aβ. More importantly, administration or overexpression of gelsolin results in significant reduction of amyloid load and decrease of Aβ level in AD transgenic mice. In this article, we review the most recent progress of gelsolin as a potential therapeutic strategy for treatment of AD, and discuss the possible mechanism involved in the clearance of amyloid plaques in AD. Show more

Keywords: Alzheimer's disease, amyloid plaque, amyloid-β, gelsolin, neurotoxicity

DOI: 10.3233/JAD-141548

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 13-25, 2015

Authors: Khundakar, Ahmad A. | Thomas, Alan J.

Article Type: Review Article

Abstract: Depression is among the most common behavioral and psychological symptoms of dementia, and leads to more rapid decline and higher mortality. Treatment for depression in dementia has centered on conventional antidepressant drug treatment based around the monoamine hypothesis of depression. However, recent major studies have suggested that conventional antidepressant treatments that aim to correct underlying deficits in monoamine neurotransmitters are not effective for depression in dementia. Postmortem studies have also suggested that depression in dementia does not arise from serotonergic or noradrenergic abnormalities, or indeed from the degenerative pathology associated with Alzheimer's disease. In contrast, considerable recent evidence has suggested …that alterations in glutamatergic transmission may contribute to the pathophysiology of depression. This supports the view that treatment-resistant depressed patients, such as many dementia patients, may benefit from agents affecting glutamate transmission. This review will thus draw together the wealth of pathological data examining the basis of depression in Alzheimer's disease and relate this to current thinking on treatment, with the aim of generating discussion on potential novel therapeutic strategies. Show more

Keywords: Alzheimer's disease, antidepressants, cognitive impairment, dementia, depression, late-life

DOI: 10.3233/JAD-148003

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 27-41, 2015

Authors: DiTacchio, Kacee A. | Heinemann, Stephen F. | Dziewczapolski, Gustavo

Article Type: Short Communication

Abstract: Metabolic dysfunction exacerbates Alzheimer's disease (AD) incidence and progression. Here we report that activation of the AMPK pathway, a common target in the management of diabetes, results in gender-divergent cognitive effects in a murine model of the disease. Specifically, our results show that activation of AMPK increases memory dysfunction in males but is protective in females, suggesting that gender considerations may constitute an important factor in medical intervention of diabetes as well as AD.

Keywords: Alzheimer's disease, AMPK, metformin, type 2 diabetes mellitus

DOI: 10.3233/JAD-141332

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 43-48, 2015

Authors: Testi, Silvia | Tamburin, Stefano | Zanette, Giampietro | Fabrizi, Gian Maria

Article Type: Short Communication

Abstract: The C9ORF72 repeat expansion is the major cause of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. In the reported pedigree, the 47-year old proband, presenting a four-year history of frontotemporal dementia, carried the C9ORF72 expansion plus a novel GRN p.Cys246X mutation. The father and a paternal uncle, harboring the C9ORF72 expansion only, had died by pure ALS with onset at 63 and 76 years, respectively. The case report and a review of the literature emphasize that phenotypical variations of the FTLD-ALS spectrum could be due to digenic inheritance.

Keywords: Amyotrophic lateral sclerosis (ALS), C9ORF72, frontotemporal lobar degeneration (FTLD), FTLD-ALS, GRN

DOI: 10.3233/JAD-141794

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 49-56, 2015

Authors: Goh, Liang Kee | Lim, Wee Shiong | Teo, Stephanie | Vijayaraghavan, Aadhitthya | Chan, Mark | Tay, Laura | Ng, Tze Pin | Tan, Chay Hoon | Lee, Tih Shih | Chong, Mei Sian

Article Type: Short Communication

Abstract: We previously reported TOMM40 to be significantly down-regulated in whole blood of Alzheimer's disease (AD) subjects at baseline and after one-year. In this longitudinal follow-up study of TOMM40 expression up to 2 years, we performed 6-monthly assessments for the first year and 2nd year blood sampling on 27 probable AD subjects compared with age- and gender-matched controls. TOMM40 gene expression remained significantly lower in AD patients at all time-points compared to controls, supported by confirmatory RT-PCR results. Our findings of consistently lower TOMM40 expression on longitudinal 2-year sampling support its potential role as a diagnostic blood AD biomarker.

Keywords: Alzheimer's disease, gene expression, progression, TOMM40

DOI: 10.3233/JAD-141590

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 57-61, 2015

Authors: Costa, Alberto | Fadda, Lucia | Perri, Roberta | Brisindi, Marialuisa | Lombardi, Maria Giovanna | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Short Communication

Abstract: This study was aimed at evaluating whether prospective memory (PM) assessment is able to assist the discrimination between amnestic mild cognitive impairment (aMCI) and healthy subjects (HCs) and between aMCI with single versus multiple domains impairment. Individuals with aMCI and HCs were administered an extensive neuropsychological tests battery and a time-based PM task. PM scores significantly improved the accuracy of the regression model in discriminating between aMCI multiple domains, but not aMCI single domain, and HCs. Moreover, the prospective score significantly contributed to the discrimination between the two aMCI subgroups. These findings indicate the usefulness of including the PM procedure …in evaluations of aMCI. Show more

Keywords: Dementia, mild cognitive impairment, neuropsychological assessment, prospective memory

DOI: 10.3233/JAD-142070

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 63-67, 2015

Authors: Robb, Elysia | Perez, Keyla | Hung, Lin W. | Masters, Colin L. | Barnham, Kevin J. | Cherny, Robert A. | Bush, Ashley I. | Adlard, Paul A. | Finkelstein, David I.

Article Type: Research Article

Abstract: Oligomeric forms of amyloid-β (Aβ) are thought to be responsible for the pathogenesis of Alzheimer's disease. While many oligomers of Aβ are thought to be naturally occurring in the brain of humans and/or transgenic animals, it is well known that Aβ oligomers are also readily produced in vitro in the laboratory. In recent studies, we discovered that synthetic monomeric Aβ (4.7 kDa) could be transformed by microdialysis to higher molecular weight species (approximately 56 kDa, by western blot). Surface-enhanced laser desorption/ionization mass spectrometry and electron microscopy further identified these species' as potential Aβ oligomers. The production of similar species could …also be produced by centrifugal filtration and this formation was concentration and pore-size dependent. These higher order species of Aβ were resistant to dissolution in NaOH, HFIP, formic acid, urea, and guanidine. We postulate that we have identified a novel way of producing a high order species of oligomeric Aβ and we provide evidence to suggest that Aβ oligomers can quite easily be a product of normal laboratory practices. These data suggest that the experimental detection of higher order oligomers in tissues derived from Alzheimer's disease brains or from animal models of disease could, in some cases, be a product the method of analysis. Show more

Keywords: Aggregation factors, Alzheimer's disease, amyloid-beta peptide, amyloid aggregation, filtration, microdialysis, oligomer, resistant, W02-reactive

DOI: 10.3233/JAD-132024

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 69-78, 2015

Authors: Hall, Anette | Muñoz-Ruiz, Miguel | Mattila, Jussi | Koikkalainen, Juha | Tsolaki, Magda | Mecocci, Patrizia | Kloszewska, Iwona | Vellas, Bruno | Lovestone, Simon | Visser, Pieter Jelle | Lötjonen, Jyrki | Soininen, Hilkka | for the Alzheimer Disease Neuroimaging Initiative | the AddNeuroMed consortium, DESCRIPA and Kuopio L-MCI

Article Type: Research Article

Abstract: Background: The Disease State Index (DSI) prediction model measures the similarity of patient data to diagnosed stable and progressive mild cognitive impairment (MCI) cases to identify patients who are progressing to Alzheimer's disease. Objectives: We evaluated how well the DSI generalizes across four different cohorts: DESCRIPA, ADNI, AddNeuroMed, and the Kuopio MCI study. Methods: The accuracy of the DSI in predicting progression was examined for each cohort separately using 10 × 10-fold cross-validation and for inter-cohort validation using each cohort as a test set for the model built from the other independent cohorts using bootstrapping with …10 repetitions. Altogether 875 subjects were included in the analysis. The analyzed data included a comprehensive set of age and gender corrected magnetic resonance imaging (MRI) features from hippocampal volumetry, multi-template tensor-based morphometry, and voxel-based morphometry as well as Mini-Mental State Examination (MMSE), APOE genotype, and additional cohort specific data from neuropsychological tests and cerebrospinal fluid measurements (CSF). Results: The DSI model was used to classify the patients into stable and progressive MCI cases. AddNeuroMed had the highest classification results of the cohorts, while ADNI and Kuopio MCI exhibited the lowest values. The MRI features alone achieved a good classification performance for all cohorts. For ADNI and DESCRIPA, adding MMSE, APOE genotype, CSF, and neuropsychological data improved the results. Conclusions: The results reveal that the prediction performance of the combined cohort is close to the average of the individual cohorts. It is feasible to use different cohorts as training sets for the DSI, if they are sufficiently similar. Show more

Keywords: Alzheimer's disease, computer-assisted diagnosis, dementia, magnetic resonance imaging (MRI), mild cognitive impairment

DOI: 10.3233/JAD-140942

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 79-92, 2015

Authors: Vuorinen, Miika | Spulber, Gabriela | Damangir, Soheil | Niskanen, Eini | Ngandu, Tiia | Soininen, Hilkka | Kivipelto, Miia | Solomon, Alina

Article Type: Research Article

Abstract: Background: CAIDE Dementia Risk Score is a validated tool for estimating 20-year dementia risk in the general population based on a midlife risk profile. Objective: To investigate the associations between CAIDE score and dementia-related brain changes up to 30 years later on magnetic resonance imaging (MRI). Methods: Participants in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were derived from random, population-based samples surveyed in 1972, 1977, 1982, or 1987. A first re-examination was conducted in 1998, and a second re-examination in 2005–2008 (total follow-up time up to 30 years). The MRI study population included …112 individuals with MRIs from the first re-examination, and a different group of 69 individuals with MRIs from the second re-examination. MRIs from 1998 were used to determine gray matter volume, and to visually rate white matter hyperintensities (WMH) of presumed vascular origin and medial temporal lobe atrophy (MTA). MRIs from 2005–2008 were used to assess cortical thickness, gray matter and WMH volume, and to visually rate MTA. CAIDE scores were calculated for participants in both re-examinations based on midlife sociodemographic and vascular factors and additionally apolipoprotein E status. Results: Higher midlife CAIDE score was associated with more severe WMH 20 years later: RR (95% CI) was 1.69 (1.15–2.08); and with higher WMH volume (β 0.27, p = 0.036) and higher MTA score (RR 1.91, 95% CI 1.16–2.34) up to 30 years later. Conclusion: CAIDE Dementia Risk Score in midlife was most consistently associated with WMH later in life. A relation with MTA was observed in individuals with longer follow-up time. Show more

Keywords: Brain, dementia, epidemiology, magnetic resonance imaging, risk factor

DOI: 10.3233/JAD-140924

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 93-101, 2015