Journal of Alzheimer's Disease - Volume 39, issue 4

Authors: Nicolas, Gaël | Beherec, Laurène | Hannequin, Didier | Opolczynski, Gaëlle | Rothärmel, Maud | Wallon, David | Véra, Pierre | Martinaud, Olivier | Guillin, Olivier | Campion, Dominique

Article Type: Research Article

Abstract: Background: Although numerous studies have assessed cognitive dysfunction in patients with schizophrenia, very few have focused on the diagnosis of dementia. Objective: Our objectives were to accurately diagnose dementia in a cohort of middle-aged patients with schizophrenia and to assess the type of dementia. Methods: 96 patients with schizophrenia (46 inpatients and 50 outpatients), aged 50 to 70 years, underwent a psychiatric, neurological, and neuropsychological evaluation at baseline and after a 20-month follow-up. We established a 3-step procedure: 1) diagnose dementia according to the DSM-IV criteria, using the Mattis Dementia Rating and Activities of Daily Living …scales; 2) characterize dementia using brain imaging, perfusion by 99m Tc-ECD-SPECT and laboratory tests including Alzheimer’s disease cerebrospinal fluid biomarkers; and 3) search for genetic determinants. Results: Fourteen patients fulfilled the diagnostic criteria of dementia. Four were diagnosed with possible or probable behavioral-variant frontotemporal dementia (bvFTD), two with probable Alzheimer’s disease, two with probable vascular dementia (including one due to CADASIL), one with CNS inflammatory disease, and six could not be fully characterized. Conclusions: The diagnosis of dementia in middle-aged patients with schizophrenia is challenging but possible, using a multistep procedure. The most frequent condition, bvFTD, could reflect the presence of an evolutive neurodegenerative process in some patients. Show more

Keywords: Alzheimer's disease, dementia, frontotemporal lobar degeneration, Mattis Dementia Rating Scale, schizophrenia, vascular dementia

DOI: 10.3233/JAD-131688

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 809-822, 2014

Authors: Mitolo, Micaela | Salmon, David P. | Gardini, Simona | Galasko, Douglas | Grossi, Enzo | Caffarra, Paolo

Article Type: Research Article

Abstract: Visual-constructional apraxia is a prominent feature of dementia with Lewy bodies (DLB) that might help to clinically distinguish it from Alzheimer's disease (AD). The main goal of this study was to assess performance on the copy intersecting-pentagon item of the Mini-Mental State Examination with the new Qualitative Scoring method for the Pentagon copy Test (QSPT). In order to determine which aspects of the drawings might differentiate DLB from AD, pentagon drawings of autopsy-verified DLB (n = 16) and AD (n = 15) patients were assessed using the QSPT. The qualitative scoring encompasses the assessment of different parameters of the drawing, …such as number of angles, distance/intersection, closure/opening, rotation, and closing-in. The QSPT scores were compared between groups using linear analyses and artificial neural network analyses at four different time points. Linear analyses showed that during the first evaluation, number of angles was the only parameter that showed a significant difference between DLB and AD patients. A gradual decline in other parameters and total pentagon score occurred in both groups during subsequent years, with greater decline for the DLB group. The artificial neural network analyses using auto-contractive maps showed that, with disease progression, DLB became related to relatively lower qualitative pentagon scores, whereas AD became related to relatively higher qualitative scores. These findings suggest that the QSPT might be a sensitive measure of visuo-constructive abilities able to differentiate DLB from AD at disease onset and as the diseases progress, but further studies on larger population are necessary in order to establish its clinical relevance. Show more

Keywords: Alzheimer's disease, autopsy-confirmed, copy of pentagons, dementia with Lewy bodies

DOI: 10.3233/JAD-131403

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 823-832, 2014

Authors: Grande, Giulia | Vanacore, Nicola | Maggiore, Laura | Cucumo, Valentina | Ghiretti, Roberta | Galimberti, Daniela | Scarpini, Elio | Mariani, Claudio | Clerici, Francesca

Article Type: Research Article

Abstract: Background: Leisure activities, particularly exercise, play a protective role against dementia in healthy people, but it is unknown if this protective effect could be generalized to subjects with mild cognitive impairment (MCI). Objective: To investigate the influence of leisure activities on the risk of progression of MCI to dementia. Methods: 176 MCI subjects attending a memory clinic underwent a standardized lifestyle questionnaire between October 2007 and May 2010. Social, cognitive, and physical scores were derived based on the assiduity of interpersonal contacts and on the frequency of participation in individual leisure activities. Subjects were requested to …return every 12 months for dementia surveillance. The outcome measure was the risk of dementia associated with social, cognitive, and physical scores. Results: Over a median follow-up time of 2.59 year, 92 (52.2%) MCI subjects developed dementia. Subjects with physical scores in the highest third had a lower risk (HR 0.44; 95% CI 0.23–0.85) of dementia compared with those in the lowest third. No association was found between cognitive or social scores and the risk of dementia. Conclusion: To our knowledge, this is the first prospective clinical study which demonstrates that high levels of participation in physical leisure activities are associated with reduced risk of dementia in subjects with MCI. In line with findings coming from community-based studies on healthy elderly, our finding suggests that the protective role of exercise against the development of dementia can be generalized to MCI subjects seen in clinical practice. Clinicians should encourage MCI subjects to participate in physical leisure activities. Show more

Keywords: Dementia, exercise, leisure activities, lifestyle, mild cognitive impairment

DOI: 10.3233/JAD-131808

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 833-839, 2014

Authors: Wang, Hualong | Lian, Kaoqi | Han, Bing | Wang, Yanyong | Kuo, Sheng-Han | Geng, Yuan | Qiang, Jing | Sun, Meiyu | Wang, Mingwei

Article Type: Research Article

Abstract: Alzheimer's disease (AD), the most common age-dependent neurodegenerative disorder, produces a progressive decline in cognitive function. The metabolic mechanism of AD has emerged in recent years. In this study, we used multivariate analyses of gas chromatography-mass spectrometry measurements to determine that learning and retention-related metabolic profiles are altered during aging in the hippocampus of the senescence-accelerated mouse prone 8 (SAMP8). Alterations in 17 metabolites were detected in mature and aged mice compared to young mice (13 decreased and 4 increased metabolites), including metabolites related to dysfunctional lipid metabolism (significantly increased cholesterol, oleic acid, and phosphoglyceride levels), decreased amino acid (alanine, …serine, glycine, aspartic acid, glutamate, and gamma-aminobutyric acid), and energy-related metabolite levels (malic acid, butanedioic acid, fumaric acid, and citric acid), and other altered metabolites (increased N-acetyl-aspartic acid and decreased pyroglutamic acid, urea, and lactic acid) in the hippocampus. All of these alterations indicated that the metabolic mechanisms of age-related cognitive impairment in SAMP8 mice were related to multiple pathways and networks. Lipid metabolism, especially cholesterol metabolism, appears to play a distinct role in the hippocampus in AD. Show more

Keywords: Aging, Alzheimer's disease, cholesterol, gas chromatography-mass spectrometry, hippocampus, metabolic profiles

DOI: 10.3233/JAD-131463

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 841-848, 2014

Authors: Martin, Carolina | Aguila, Blanca | Araya, Paulina | Vio, Karin | Valdivia, Sharin | Zambrano, Angara | Concha, Margarita I. | Otth, Carola

Article Type: Research Article

Abstract: Background: Currently, it is unclear whether asymptomatic recurrent reactivations of herpes simplex virus type 1 (HSV-1) occur in the central nervous systems of infected people, and if these events could lead to a progressive deterioration of neuronal function. In this context, HSV-1 constitutes an important candidate to be included among the risk factors for the development of neuropathies associated with chronic neuroinflammation. Objective: The aim of this study was to assess in vivo inflammatory and neurodegenerative markers in the brain during productive and latent HSV-1 infection using a mouse model of herpes simplex encephalitis. Methods: Neuroinflammation …and neurodegeneration markers were evaluated in mice trigeminal ganglia and cerebral cortex during HSV-1 infection, by immunohistochemistry, western blot, and RT-PCR. Results: Neuronal ICP4 viral antigen expression indicative of a reactivation episode during asymptomatic latency of HSV-1 infection in mice was accompanied by upregulation of neuroinflammatory (toll-like receptor-4, interferon α/β, and p-IRF3) and early neurodegenerative markers (phospho-tau and TauC3). Conclusions: HSV-1 reactivation from latency induced neuroinflammatory and neurodegenerative markers in the brain of asymptomatic mice suggesting that recurrent reactivations could be associated with cumulative neuronal dysfunctions. Show more

Keywords: Herpes simplex encephalitis, herpes simplex virus type 1, neurodegeneration, neuroinflammation, TauC3, toll-like receptor 4, trigeminal ganglion

DOI: 10.3233/JAD-131706

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 849-859, 2014

Authors: Omori, Chiori | Kaneko, Madoka | Nakajima, Etsuko | Akatsu, Hiroyasu | Waragai, Masaaki | Maeda, Masahiro | Morishima-Kawashima, Maho | Saito, Yuhki | Nakaya, Tadashi | Taru, Hidenori | Yamamoto, Tohru | Asada, Takashi | Hata, Saori | Suzuki, Toshiharu | for the Japanese Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: p3-Alcα is a metabolic fragment of Alcadeinα (Alcα). Similar to the generation of the p3 fragment from amyloid-β protein precursor (AβPP) processing, Alcα is cleaved by α- and γ-secretases, leading to the secretion of p3-Alcα peptides into cerebrospinal fluid (CSF). p3-Alcα is also detected in the plasma, similar to amyloid-β (Aβ), which is a metabolic fragment of AβPP cleaved by amyloidogenic β- and γ-secretases. Because p3-Alcα is a non-aggregatable and stable peptide, unlike aggregatable Aβ and metabolically labile p3 of AβPP, the changes of p3-Alcα in quality and/or quantity in CSF and plasma are expected to be a marker for …assessing alteration of substrate cleavage by γ-secretase, such as Aβ generation from AβPP. The present study describes a sandwich enzyme-linked immunosorbent assay for quantifying levels of p3-Alcα35, the major form of the p3-Alcα species, and examines levels of p3-Alcα35 in the plasma of three independent Japanese cohorts. In two of the three cohorts, the p3-Alcα35 levels were significantly increased with a concomitant decrease in the Mini-Mental State Examination score, or in clinically diagnosed Alzheimer's disease (AD) patients, when compared with age-matched non-demented subjects. The values were significantly lower in AD subjects who were administered donepezil, when compared to AD subjects without donepezil treatment. The increase in plasma p3-Alcα35 levels may indicate an endophenotype in subjects in whom AD is due to a progressing cognitive impairment in subjects with a γ-secretase malfunction, or a disorder of the clearance of peptides. Show more

Keywords: Alzheimer's disease, alcadein, diagnosis, donepezil, γ-secretase, p3-Alc, plasma biomarker

DOI: 10.3233/JAD-131610

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 861-870, 2014

Authors: Reinert, Jochim | Martens, Henrik | Huettenrauch, Melanie | Kolbow, Tekla | Lannfelt, Lars | Ingelsson, Martin | Paetau, Anders | Verkkoniemi-Ahola, Auli | Bayer, Thomas A. | Wirths, Oliver

Article Type: Research Article

Abstract: The pathogenesis of Alzheimer's disease (AD) is believed to be closely dependent on deposits of neurotoxic amyloid-β peptides (Aβ), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different Aβ peptides existing are generated by subsequent cleavage of the amyloid-β protein precursor (AβPP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species Aβ40 and Aβ42 , Aβ peptides with other C-termini such as Aβ38 have not received much attention. In the present study, we used a highly specific and sensitive antibody against …Aβ38 to analyze the distribution of this Aβ species in cases of sporadic and familial AD, as well as in the brains of a series of established transgenic AD mouse models. We found Aβ38 to be present as vascular deposits in the brains of the majority of sporadic AD cases, whereas it is largely absent in non-demented control cases. Aβ38 -positive extracellular plaques were virtually limited to familial cases. Interestingly we observed Aβ38 -positive plaques not only among familial cases due to AβPP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that Aβ38 deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only AβPP, or combinations of AβPP, PSEN1, and tau transgenes. Show more

Keywords: Aβ38, AβPP, amyloid, mutations, presenilin, transgenic mice, vasculature, vessels

DOI: 10.3233/JAD-131373

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 871-881, 2014

Authors: Cheng, Qi | Sun, Hong-Xian | Ye, Fu-Lin | Wang, Gang | Ling, Hua-Wei | Chen, Sheng-Di | Jiang, Guo-Xin

Article Type: Research Article

Abstract: The number of elderly in the world is increasing rapidly, especially in China. The prevalence of dementia among elderly was investigated in a community of Sheshan town, located in the Southwest suburb of Shanghai, China. Face-to-face interviews were conducted to collect relevant information with prepared questionnaires. The Chinese version of the Mini-Mental Status Examination was used to screen subjects with cognitive impairment (CI). Physical examinations and neuropsychological assessments were carried out. Dementia and its major subtypes, Alzheimer's disease (AD) and vascular dementia (VaD), were diagnosed by senior neurologists according to relevant diagnostic criteria. In addition, magnetic resonance imaging and EEG …(with P300) were performed for a number of cases with AD or VaD. There were 1,472 participants (666 males and 806 females) aged 60 years and over in the study. A total of 167 subjects with CI were screened. Among them, dementia was recognized in 79 cases with a prevalence of 5.37% (95% confidence intervals: 4.22%–6.52%). The diagnosis of AD was made for 53 cases (16 males and 37 females) with a prevalence of 3.60% (95% confidence intervals: 2.65%–4.55%), and VaD for 21 cases (5 males and 16 females) with a prevalence of 1.43% (95% confidence intervals: 0.82%–2.03%); while the ratio of AD to VaD was 2.52. The prevalence rates of dementia among elderly from our study are higher than that previously reported from China, but in line with that reported from most world regions. A nationwide survey and surveillance system on the prevalence of dementia is recommended. Show more

Keywords: Alzheimer's disease, dementia, prevalence, vascular dementia

DOI: 10.3233/JAD-131601

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 883-889, 2014

Authors: Wang, Gang | Tang, Hui-Dong | Zhuang, Jun-Peng | Xu, Xu-Hua | Liu, Li-Hua | Li, Bo | Wang, Li-Ling | Xu, Zhi-Min | Cheng, Qi | Chen, Sheng-Di

Article Type: Research Article

Abstract: Background: The prevalence of cognitive impairment (CI) and its associated risk factors among elderly peoples in China has been investigated. However, dynamic studies revealing the risk factors associated with cognitive decline from follow-up observations in China are rarely performed. Objective: The present study aimed to identify factors predicting late-life cognitive decline in China. Methods: Participants were 223 community-dwelling residents (⩾65 years old) from the urban community of Shanghai with no CI upon comprehensive assessments at baseline. Cognitive decline at 2-year follow-up was defined as a drop of two or more points from baseline score in the …Mini-Mental State Examination (MMSE). Associations with baseline demographic, lifestyle, health, and medical factors were then determined within the population. Results: After 2 years, cognitive decline and incident CI developed in 75 (33.6%) and 25 (11.2%) participants, respectively. Across all participants, risk factors for cognitive decline included low education, high body mass index, and diabetes mellitus. Among participants with cognitive decline, points were predominantly lost in items relating to time orientation and complex commands in the MMSE. Conclusion: This study confirms the differences in risk factors between cross-sectional and longitudinal studies for cognitive decline among the elderly population in urban Shanghai. Interventions tailored to potential risk factors associated with cognitive decline may offer further benefits. Show more

Keywords: Alzheimer's disease, body mass index, cognitive impairment, diabetes mellitus

DOI: 10.3233/JAD-131514

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 891-897, 2014

Authors: BK, Binukumar | Zheng, Ya-Li | Shukla, Varsha | Amin, Niranjana D. | Grant, Philip | Pant, Harish C.

Article Type: Research Article

Abstract: Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer's disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. Cyclin dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39, found principally in neurons and in pancreatic β cells. Recent studies suggest that Cdk5 hyperactivity is a possible link between neuropathology seen in AD and diabetes. Previously, we identified P5, a truncated 24-aa peptide derived from the Cdk5 activator p35, later modified as TFP5, so as to penetrate the blood-brain barrier after intraperitoneal …injections in AD model mice. This treatment inhibited abnormal Cdk5 hyperactivity and significantly rescued AD pathology in these mice. The present study explores the potential of TFP5 peptide to rescue high glucose (HG)-mediated toxicity in rat embryonic cortical neurons. HG exposure leads to Cdk5-p25 hyperactivity and oxidative stress marked by increased reactive oxygen species production, and decreased glutathione levels and superoxide dismutase activity. It also induces hyperphosphorylation of tau, neuroinflammation as evident from the increased expression of inflammatory cytokines like TNF-α, IL-1β, and IL-6, and apoptosis. Pretreatment of cortical neurons with TFP5 before HG exposure inhibited Cdk5-p25 hyperactivity and significantly attenuated oxidative stress by decreasing reactive oxygen species levels, while increasing superoxide dismutase activity and glutathione. Tau hyperphosphorylation, inflammation, and apoptosis induced by HG were also considerably reduced by pretreatment with TFP5. These results suggest that TFP5 peptide may be a novel candidate for type 2 diabetes therapy. Show more

Keywords: Alzheimer's disease, cyclin dependent kinase 5, diabetes, neuroinflammation, oxidative stress

DOI: 10.3233/JAD-131784

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 899-909, 2014