Journal of Alzheimer's Disease - Volume 51, issue 2

Authors: Manousopoulou, Antigoni | Saito, Satoshi | Yamamoto, Yumi | Al-Daghri, Nasser M. | Ihara, Masafumi | Carare, Roxana O. | Garbis, Spiros D.

Article Type: Short Communication

Abstract: The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer’s disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel …hemisphere-specific therapeutic targets. Show more

Keywords: Alzheimer’s disease, cilostazol, hemisphere asymmetry, mass spectrometry pharmacology, pharmacodynamics, pharmacoproteomics

DOI: 10.3233/JAD-151078

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 333-338, 2016

Authors: Smith, Ruben | Wibom, Moa | Olsson, Tomas | Hägerström, Douglas | Jögi, Jonas | Rabinovici, Gil D. | Hansson, Oskar

Article Type: Short Communication

Abstract: It is unclear whether the distribution of tau pathology differs between cases with early-onset familial Alzheimer’s disease (AD) and sporadic AD. We present positron emission tomography (PET) data from a young patient with a presenilin-1 mutation (Thr116Asn). 18 F-flutemetamol PET showed a distribution of amyloid-β fibrils similar to sporadic AD. However, the pattern of tau pathology, revealed using 18 F-AV1451 PET, showed higher uptake in posterior cingulate, precuneus, parietal and occipital cortices compared to late-onset sporadic AD. Further, the tau pathology, but not amyloid pathology, exhibited a very clear inverse relationship with 18 F-fluorodeoxyglucose-metabolism, indicating neuronal hypometabolism in …regions affected by tau aggregates. Show more

Keywords: Alzheimer’s disease, positron-emission tomography, presenilins, tau proteins

DOI: 10.3233/JAD-151004

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 339-343, 2016

Authors: Dugger, Brittany N. | Whiteside, Charisse M. | Maarouf, Chera L. | Walker, Douglas G. | Beach, Thomas G. | Sue, Lucia I. | Garcia, Angelica | Dunckley, Travis | Meechoovet, Bessie | Reiman, Eric M. | Roher, Alex E.

Article Type: Research Article

Abstract: Tau becomes excessively phosphorylated in Alzheimer’s disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n  = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, …followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n  = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p  = 0.009) and pT231 (p  = 0.005) in AD cases but not total tau (p  = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p  = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage. Show more

Keywords: Braak NFT stage, colon, HT7, liver, PHF-1, propagation, skin, spread, submandibular gland, T231

DOI: 10.3233/JAD-150859

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 345-356, 2016

Authors: Turró-Garriga, Oriol | Garre-Olmo, Josep | Calvó-Perxas, Laia | Reñé-Ramírez, Ramón | Gascón-Bayarri, Jordi | Conde-Sala, Josep Lluís

Article Type: Research Article

Abstract: Anosognosia in Alzheimer’s disease (AD) has been associated with greater cognitive impairment and more behavioural and psychological symptoms of dementia (BPSD). This study examines the incidence, persistence, and remission rates of anosognosia over a 12-month period, as well as the related risk factors. This was an observational 12-month prospective study. The longitudinal sample comprised 177 patients with mild or moderate AD, and their respective caregivers. Anosognosia was assessed using the Anosognosia Questionnaire in Dementia, and we also evaluated cognitive status (Mini-Mental State Examination), functional disability (Disability Assessment in Dementia), and the presence of BPSD (Neuropsychiatric Inventory). Multinomial logistic regression was …used to determine the variables associated with the incidence, persistence and remission of anosognosia. The prevalence of anosognosia was 39.5% (95% CI = 32.1–47.1) at baseline. At 12 months, incidence was 38.3% (95% CI = 28.6–48.0), persistence was 80.0% (95% CI = 69.9–90.1) and remission was 20.0% (95% CI = 9.9–30.1). The regression model identified lower age, more education, and the presence of delusions as variables associated with incidence, and more education, lower instrumental DAD score, and disinhibition as variables associated with persistence. No variables were associated with remission (n  = 14). The presence of anosognosia in AD patients is high. Education and certain neuropsychiatric symptoms may explain a greater and earlier incidence of anosognosia. However, anosognosia also increases with greater cognitive impairment and disease severity. Show more

Keywords: Alzheimer’s disease, anosognosia, caregivers, epidemiological dementia study, incidence, insight, dementia, longitudinal studies, neuropsychiatric disorders

DOI: 10.3233/JAD-150706

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 357-366, 2016

Authors: Ramanan, Siddharth | Flanagan, Emma | Leyton, Cristian E. | Villemagne, Victor L. | Rowe, Christopher C. | Hodges, John R. | Hornberger, Michael

Article Type: Research Article

Abstract: Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer’s disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on …a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n  = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases. Show more

Keywords: Logopenic progressive aphasia, memory, Pittsburgh Compound B, primary progressive aphasia, progressive nonfluent aphasia

DOI: 10.3233/JAD-150752

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 367-376, 2016

Authors: Serra, Laura | Cercignani, Mara | Mastropasqua, Chiara | Torso, Mario | Spanò, Barbara | Makovac, Elena | Viola, Vanda | Giulietti, Giovanni | Marra, Camillo | Caltagirone, Carlo | Bozzali, Marco

Article Type: Research Article

Abstract: This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer’s disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. …Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy. Show more

Keywords: Alzheimer’s disease, functional disconnection, grey matter atrophy, longitudinal study, mild cognitive impairment

DOI: 10.3233/JAD-150961

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 377-389, 2016

Authors: Gray, Nora E. | Zweig, Jonathan A. | Kawamoto, Colleen | Quinn, Joseph F. | Copenhaver, Philip F.

Article Type: Research Article

Abstract: Because STX is a selective ligand for membrane estrogen receptors, it may be able to confer the beneficial effects of estrogen without eliciting the deleterious side effects associated with activation of the nuclear estrogen receptors. This study evaluates the neuroprotective properties of STX in the context of amyloid-β (Aβ) exposure. MC65 and SH-SY5Y neuroblastoma cell lines, as well as primary hippocampal neurons from wild type (WT) and Tg2576 mice, were used to investigate the ability of STX to attenuate cell death, mitochondrial dysfunction, dendritic simplification, and synaptic loss induced by Aβ. STX prevented Aβ-induced cell death in both neuroblastoma cell …lines; it also normalized the decrease in ATP and mitochondrial gene expression caused by Aβ in these cells. Notably, STX also increased ATP content and mitochondrial gene expression in control neuroblastoma cells (in the absence of Aβ). Likewise in primary neurons, STX increased ATP levels and mitochondrial gene expression in both genotypes. In addition, STX treatment enhanced dendritic arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites caused by Aβ exposure in Tg2576 neurons. These data suggest that STX can act as an effective neuroprotective agent in the context of Aβ toxicity, improving mitochondrial function as well as dendritic growth and synaptic differentiation. In addition, since STX also improved these endpoints in the absence of Aβ, this compound may have broader therapeutic value beyond Alzheimer’s disease. Show more

Keywords: Amyloid-β toxicity, mitochondrial dysfunction, neuroprotection, selective estrogen receptor modulator

DOI: 10.3233/JAD-150756

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 391-403, 2016

Authors: Kida, Jiro | Nemoto, Kiyotaka | Ikejima, Chiaki | Bun, Shogyoku | Kakuma, Tatsuyuki | Mizukami, Katsuyoshi | Asada, Takashi

Article Type: Research Article

Abstract: Background: While longitudinal studies have investigated the relationships between mild cognitive impairment (MCI) subtypes and dementia subtypes, the results have been contradictory. In addition, some research shows that depression accompanied by MCI might increase the risk of Alzheimer’s disease (AD). Objective: The aim of this study is to longitudinally investigate the relationships between MCI subtypes and dementia subtypes, with special attention to the effect of comorbid depressive symptoms in a Japanese rural community. Methods: Non-demented participants (n  = 802) completed a baseline and follow-up study. Outcomes were conversion to dementia especially AD, MCI, or no conversion. A …complementary log-log analysis was conducted to investigate the risk of dementia and AD in amnestic MCI (aMCI) compared to nonamnestic MCI (naMCI) groups. The impact of depressive symptoms on the transition from MCI to AD and from cognitively normal to MCI or AD was also analyzed. Results: The risk of developing dementia, in particular AD, for the aMCI group was significantly higher than that for the naMCI group. In the aMCI group, the presence of depressive symptoms increased the risk of developing AD, but depressive symptoms in the naMCI group did not. In the cognitively normal group, the presence of depressive symptoms increased the risk of aMCI but not naMCI or AD. Conclusion: MCI subtyping could be useful in finding a prodrome for dementia and in particular for AD. The differing impacts of depressive symptoms on the development of AD suggest that the relationship between depressive symptoms and cognitive impairment could differ in aMCI and naMCI patients. Show more

Keywords: Alzheimer’s disease, community, conversion, depressive symptoms, mild cognitive impairment

DOI: 10.3233/JAD-150603

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 405-415, 2016

Authors: Li, Wen-Xing | Dai, Shao-Xing | Liu, Jia-Qian | Wang, Qian | Li, Gong-Hua | Huang, Jing-Fei

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and schizophrenia (SZ) are both accompanied by impaired learning and memory functions. This study aims to explore the expression profiles of learning or memory genes between AD and SZ. We downloaded 10 AD and 10 SZ datasets from GEO-NCBI for integrated analysis. These datasets were processed using RMA algorithm and a global renormalization for all studies. Then Empirical Bayes algorithm was used to find the differentially expressed genes between patients and controls. The results showed that most of the differentially expressed genes were related to AD whereas the gene expression profile was little affected in the SZ. …Furthermore, in the aspects of the number of differentially expressed genes, the fold change and the brain region, there was a great difference in the expression of learning or memory related genes between AD and SZ. In AD, the CALB1, GABRA5, and TAC1 were significantly downregulated in whole brain, frontal lobe, temporal lobe, and hippocampus. However, in SZ, only two genes CRHBP and CX3CR1 were downregulated in hippocampus, and other brain regions were not affected. The effect of these genes on learning or memory impairment has been widely studied. It was suggested that these genes may play a crucial role in AD or SZ pathogenesis. The different gene expression patterns between AD and SZ on learning and memory functions in different brain regions revealed in our study may help to understand the different mechanism between two diseases. Show more

Keywords: Alzheimer’s disease, gene expression, learning or memory, schizophrenia

DOI: 10.3233/JAD-150807

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 417-425, 2016

Authors: D’Onofrio, Grazia | Panza, Francesco | Sancarlo, Daniele | Paris, Francesco F. | Cascavilla, Leandro | Mangiacotti, Antonio | Lauriola, Michele | Paroni, Giulia H. | Seripa, Davide | Greco, Antonio

Article Type: Research Article

Abstract: In Alzheimer’s disease (AD) patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. We determined the effect of delusions on mortality risk, clinical outcomes linked to comprehensive geriatric assessment (CGA), cognitive, depressive, and neuropsychiatric symptoms (NPS) in 380 consecutive AD patients with Mini-Mental State Examination, Clinical Dementia Rating scale, 15-item Geriatric Depression Scale, and Neuropsychiatric Inventory (NPI), assessing one-year mortality risk using the Multidimensional Prognostic Index (MPI). We included 121 AD patients with delusions (AD-D) and 259 AD patients without delusions (AD-noD). AD-D patients were significantly older, with higher age at …onset and cognitive impairment, a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant. At CGA, AD-D patients showed a higher grade of disability in basic and instrumental activities of daily living, and an increased risk of malnutrition and bedsores. The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p  <  0.0001) and MPI grade. AD-D patients showed also a significant higher score in NPI of the following NPS than AD-noD patients: hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Therefore, AD-D patients showed higher dementia severity, and higher impairment in cognitive and depressive symptoms, and several neuropsychiatric domains than AD-noD patients, and this appeared to be associated with higher multidimensional impairment and increased risk of mortality. Show more

Keywords: Alzheimer’s disease, comprehensive geriatric assessment, delusions, depressive symptoms, functional status, mortality, Multidimensional Prognostic Index, neuropsychiatric symptoms

DOI: 10.3233/JAD-150944

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 427-437, 2016