Journal of Alzheimer's Disease - Volume 35, issue 4

Authors: Ong, Wei-Yi | Tanaka, Kazuhiro | Dawe, Gavin S. | Ittner, Lars M. | Farooqui, Akhlaq A.

Article Type: Review Article

Abstract: Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to ‘slow excitotoxicity’, defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations the N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an …increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as AβPP/Aβ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, tau, excitotoxicity, insulin resistance, phospholipase A2, cholesterd oxidation products, iron, memantine

DOI: 10.3233/JAD-121990

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 643-668, 2013

Authors: Arosio, Beatrice | Abbate, Carlo | Galimberti, Daniela | Rossi, Paolo Dionigi | Inglese, Silvia | Fenoglio, Chiara | Ridolfi, Elisa | Gussago, Cristina | Casati, Martina | Tedone, Enzo | Ferri, Evelyn | Serpente, Maria | Scarpini, Elio | Mari, Daniela

Article Type: Short Communication

Abstract: We describe a case of late onset frontotemporal dementia carrying the g.1977_1980 delCACT (Thr272fs) mutation in progranulin (GRN) gene, characterized by a positive family history for dementia and a clinical phenotype resembling dementia with Lewy bodies. Symptoms included prominent visuospatial impairment, complex misidentification syndrome, visual zooptic hallucinations, hypersomnia, mental fluctuations, and signs of parkinsonism. The patient showed normal cerebrospinal fluid levels of amyloid-β, tau, and Ptau biomarkers, an asymmetric pattern of cerebral atrophy and hypoperfusion, and parietal hypometabolism. A major contributing factor to the diagnosis was the testing of plasmatic progranulin levels (extremely low), which prompted us to sequence GRN.

Keywords: GRN Thr272fs, frontotemporal dementia, phenotype, progranulin

DOI: 10.3233/JAD-130053

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 669-674, 2013

Authors: Yuan, Qiuju | Su, Huanxing | Zhang, Yalun | Chau, Wing Hin | Ng, Cheung Toa | Song, You-Qiang | Huang, Jian-Dong | Wu, Wutian | Lin, Zhi-Xiu

Article Type: Research Article

Abstract: The transgenic TgCRND8 mouse is widely used as an animal model of Alzheimer's disease (AD) and exhibits an early onset of senile plaque pathogenesis in the brain. Here we report that TgCRND8 mice also have amyloid-β (Aβ) neuropathology in spinal cord. TgCRND8 mice began to show obvious Aβ deposition in both gray matter of dorsal horn and white matter in the central part of dorsal column of the spinal cord at 10 months of age onward. Further experiments showed that the distribution of Aβ deposition in the spinal cord corresponds to the corticospinal tract pathway and its projection regions in …TgCRND8 mice. We hypothesized that neurons in the sensorimotor cortex is the source of the Aβ peptide deposited in the spinal cord of these mice. To test the hypothesis, we ablated the sensorimotor cortex to interrupt connections between the sensorimotor cortex and spinal cord. We found that Aβ burden was significantly reduced in the denervated side compared to the contralateral side. Our results suggest that the sensorimotor cortex might be the primary source of Aβ in spinal cord of TgCRND8 mice. This is consistent with the observation that the sensorimotor cortex is one region particularly vulnerable during the progression of AD. The characteristics of Aβ distribution in TgCRND8 mice suggest that there are other ways related to the formation of Aβ plaques in addition to the terminal and synaptic release of Aβ. Show more

Keywords: Amyloid-β formation, axonal transport, spinal cord, TgCRND8 mice

DOI: 10.3233/JAD-122323

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 675-685, 2013

Authors: Lee, Allen Ting Chun | Chan, Wai Chi | Chiu, Helen Fung Kum | Richards, Marcus | Ng, Sammy Ping Sum | Hui, Linda Yin Fun | Chan, Wai Man | Lam, Linda Chiu Wa

Article Type: Research Article

Abstract: Hypertension is a risk factor for dementia, but its exact role in contributing to dementia remains unknown. We conducted a community-based retrospective cohort study to examine the association of hypertension and widened pulse pressure (PP) with incident significant cognitive impairment (SCI) in Chinese older people in Hong Kong. A total of 1,925 subjects who were 65 years and older, ethnic Chinese, and community-living, with no history of cerebrovascular accidents or dementia, were recruited. Demographics, medical history, and physical parameters recorded at baseline were retrieved for analysis. Primary outcome was SCI developed in 6 years, which was defined by the presence …of clinical dementia, scoring below the cutoff point on the Cantonese version of the Mini-Mental State Examination, and/or a global Clinical Dementia Rating of 1 to 3. Our data showed no difference in the point prevalence of pre-existing hypertension between subjects who remained cognitively stable and those who developed SCI (64.2% versus 65.8%; χ2 test, p = 0.68). However, subjects with incident SCI had a higher baseline PP (70 mmHg versus 66 mmHg; Mann-Whitney U-test, p = 0.03) and a decreasing trend in PP with time. Multiple logistic regression analysis showed that PP had a small but significant effect on the risk of SCI among the younger old subjects (OR = 1.02, p = 0.03). Our findings suggested that widened PP might be a risk factor for SCI among the younger old people. Further studies are needed to ascertain the association between hypertension and SCI in the Chinese older population and how widened PP contributes to SCI. Show more

Keywords: Cognitive impairment, hypertension, older people, pulse pressure

DOI: 10.3233/JAD-122116

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 687-696, 2013

Authors: Hjorth, Erik | Zhu, Mingqin | Toro, Veronica Cortés | Vedin, Inger | Palmblad, Jan | Cederholm, Tommy | Freund-Levi, Yvonne | Faxen-Irving, Gerd | Wahlund, Lars-Olof | Basun, Hans | Eriksdotter, Maria | Schultzberg, Marianne

Article Type: Research Article

Abstract: The use of supplements with omega-3 (ω3) fatty acids (FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is widespread due to proposed beneficial effects on the nervous and cardiovascular systems. Many effects of ω3 FAs are believed to be caused by down-regulation and resolution of inflammation. Alzheimer's disease (AD) is associated with inflammation mediated by microglia and astrocytes, and ω3 FAs have been proposed as potential treatments for AD. The focus of the present study is on the effects of DHA and EPA on microglial phagocytosis of the AD pathogen amyloid-β (Aβ), on secreted and cellular markers of …immune activity, and on production of brain-derived neurotrophic factor (BDNF). Human CHME3 microglial cells were exposed to DHA or EPA, with or without the presence of Aβ42 . Phagocytosis of Aβ42 was analyzed by flow cytometry in conjunction with immunocytochemistry using antibodies to cellular proteins. Secreted proteins were analyzed by ELISA. Both DHA and EPA were found to stimulate microglial phagocytosis of Aβ42 . Phagocytosis of Aβ42 was performed by microglia with a predominance of M2 markers. EPA increased the levels of BDNF in the culture medium. The levels of TNF-α were decreased by DHA. Both DHA and EPA decreased the pro-inflammatory M1 markers CD40 and CD86, and DHA had a stimulatory effect on the anti-inflammatory M2 marker CD206. DHA and EPA can be beneficial in AD by enhancing removal of Aβ42 , increasing neurotrophin production, decreasing pro-inflammatory cytokine production, and by inducing a shift in phenotype away from pro-inflammatory M1 activation. Show more

Keywords: Amyloid, brain-derived neurotrophic factor, cytokine, DHA, EPA, interleukin, M1, M2, resolution

DOI: 10.3233/JAD-130131

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 697-713, 2013

Authors: Arenaza-Urquijo, Eider M. | Molinuevo, José-Luis | Sala-Llonch, Roser | Solé-Padullés, Cristina | Balasa, Mircea | Bosch, Beatriz | Olives, Jaume | Antonell, Anna | Lladó, Albert | Sánchez-Valle, Raquel | Rami, Lorena | Bartrés-Faz, David

Article Type: Research Article

Abstract: Cognitive reserve capacity may increase tolerance of neurodegenerative processes. However, its role regarding amyloid-β (Aβ42 ) deposition in cognitively normal subjects is not well understood. We aimed to investigate the association between areas showing Aβ42 -related structural changes and cognitive reserve proxies in cognitively intact subjects showing normal or abnormal Aβ42 cerebrospinal fluid (CSF) concentrations. Thirty-three subjects (aged 55–85) underwent lumbar puncture and high resolution anatomical magnetic resonance imaging analyzed by voxel-based morphometry and cortical thickness procedures. Subjects with abnormal Aβ42 CSF levels showed significant left hippocampal atrophy and greater cortical thinning in parietal, temporal, and frontal regions …(including the supramarginal and the anterior cingulate gyrus) compared to subjects with normal Aβ42 CSF levels. Using a multivariate general linear model, we investigated the relationship between these areas and cognitive reserve proxies. We found a significant relationship between decreased volume of the left hippocampus or decreased cortical thickness of the right supramarginal gyrus and higher cognitive reserve proxies only in the group with abnormal Aβ42 CSF levels. Thus, subjects with abnormal Aβ42 CSF levels (which may be at a higher risk of developing Alzheimer's disease) and with high scores on cognitive reserve proxies may be tolerating a more advanced neurodegenerative process in critical cortical and subcortical regions. The present results emphasize the relevance of evaluating cognitive reserve proxies, as well as the importance of using neuroimaging techniques for early diagnosis in individuals with higher reserve. Show more

Keywords: Aging, amyloid, cognitive reserve, hippocampus, structural MRI

DOI: 10.3233/JAD-121906

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 715-726, 2013

Authors: Muñoz-Ruiz, Miguel Ángel | Hartikainen, Päivi | Hall, Anette | Mattila, Jussi | Koikkalainen, Juha | Herukka, Sanna-Kaisa | Julkunen, Valtteri | Vanninen, Ritva | Liu, Yawu | Lötjönen, Jyrki | Soininen, Hilkka

Article Type: Research Article

Abstract: Background: Disease State Index and Disease State Fingerprint represent a novel tool which collates data information from different sources, helping the clinician in the diagnosis and follow-up of dementia diseases. It has been demonstrated that it is applicable in the diagnosis of Alzheimer’s disease (AD). Objective: We applied this novel tool to classify frontotemporal dementia (FTD) cases in comparison with controls, AD, and mild cognitive impairment (MCI) subjects. Methods: Thirty seven patients with FTD, 35 patients with AD, 26 control subjects, and 64 subjects with MCI were included in the study. The Disease State Index encompassed …data from cognitive performance assessed by Mini-Mental State Examination, cerebrospinal fluid biomarkers, MRI volumetric and morphometric parameters as well as APOE genotype. Results: We applied the Disease State Index for comparisons at the group level. The data showed that FTD patients could be differentiated with a high accuracy, sensitivity, and specificity from controls (0.84, 0.84, 0.83) and from MCI (0.79, 0.78, 0.80). However, the correct accuracy was lower in the FTD versus AD comparison (0.69, 0.70, 0.71). In addition, we demonstrated the use of Disease State Fingerprint by comparing one particular FTD case with control, AD, and MCI population data. Conclusion: The results suggest that the Disease State Fingerprint and the underlying Disease State Index are particularly useful in differentiating between normal status and disease in patients with dementia, but it may also help to distinguish between the two dementia diseases, FTD and AD. Show more

Keywords: Alzheimer's disease, cognition, frontotemporal dementia, memory, mild cognitive impairment

DOI: 10.3233/JAD-122260

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 727-739, 2013

Authors: Wirths, Oliver | Hillmann, Antje | Pradier, Laurent | Härtig, Wolfgang | Bayer, Thomas A.

Article Type: Research Article

Abstract: N-terminally truncated pyroglutamate amyloid-β (Aβ) starting at position 3 (AβpE3 ) represents a major fraction of Aβ peptides in Alzheimer's disease (AD). Recently, we have identified low molecular weight AβpE3 oligomers, which can be detected by 9D5, a novel mouse monoclonal antibody. In the present study, we analyzed the immunohistochemical staining profile in the brain of patients with AD and in the APP/PS1KI mouse model, as well as in aged rhesus monkeys. 9D5-positive microglia and blood vessels were found in many AD cases, in the transgenic mouse model, and in an aged macaque. The presence of 9D5-immunoreactivity in microglia …indicates that low molecular weight AβpE3 oligomers may be phagocytosed, since in the APP/PS1KI model, Aβ is exclusively produced in neurons due to neuronal expression of transgenic AβPP. Show more

Keywords: 9D5, Alzheimer's disease, amyloid, APP/PS1KI transgenic mouse model, gliosis, microglia, pyroglutamate Aβ, rhesus monkey

DOI: 10.3233/JAD-121945

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 741-749, 2013

Authors: Wang, Yang | Risacher, Shannon L. | West, John D. | McDonald, Brenna C. | MaGee, Tamiko R. | Farlow, Martin R. | Gao, Sujuan | O'Neill, Darren P. | Saykin, Andrew J.

Article Type: Research Article

Abstract: Default mode network (DMN) disruption has been reported in Alzheimer's disease (AD), yet the specific pattern of altered connectivity over the course of prodromal AD remains to be characterized. The aim of this study was to assess DMN connectivity in older adults with informant-verified cognitive complaints (CC) but normal neuropsychological performance compared to individuals with mild cognitive impairment (MCI) and healthy controls (HC). DMN maps were derived from resting-state fMRI using independent component analysis. Group comparisons of DMN connectivity were performed between older adults with MCI (n = 18), CC (n = 23), and HC (n = 16). Both CC …and MCI showed decreased DMN connectivity in the right hippocampus compared to HC, with the CC group showing greater connectivity than MCI. These differences survived atrophy correction and correlated with cognitive performance. DMN connectivity appears sensitive to early prodromal neurodegenerative changes associated with AD, notably including pre-MCI individuals with cognitive complaints. Show more

Keywords: Alzheimer's disease, cognitive complaints, default mode network, functional connectivity, hippocampus, memory, mild cognitive impairment

DOI: 10.3233/JAD-130080

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 751-760, 2013

Authors: Rebelo, Sandra | Domingues, Sara C. | Santos, Mariana | Fardilha, Margarida | Esteves, Sara L. C. | Vieira, Sandra Isabel | Vintém, Ana Paula B. | Wu, Wenjuan | da Cruz e Silva, Edgar F. | da Cruz e Silva, Odete A. B.

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) binds several proteins determining metabolism, processing, and the physiological fate of the former. Among these is Fe65, a protein with specific functional significance for AβPP, in particular conferring stability when the latter is dephosphorylated on Thr668 . Thus, it follows that phosphatases like protein phosphatase 1 (PP1) are relevant to AβPP processing. Consequently, the identification of AβPP binding proteins, which can be modulated directly or indirectly by PP1, take on added relevance in terms of biological significance. Using the yeast tri-hybrid system and co-immunoprecipitation assays, we describe a novel tri-complex comprising AβPP, Fe65 and PP1. …We show that the trimeric complex (AβPP:Fe65:PP1γ) occurs in COS-7 cells, rat hippocampal and cortical primary neurons, and in adult rat hippocampus and cortex. Using overlay assays, we demonstrate that Fe65 is in fact the bridging protein in the complex formed and thus we simultaneously describe another PP1 binding protein. This is singularly important given that PP1 binding proteins determine and confer subcellular localization, as well as substrate specificity, thus regulating the phosphatase activity and subsequent intracellular events. Additionally, we show that this interaction correlates with AβPP Thr668 phosphorylation state, consistent with the role of protein (de)phosphorylation as a key mechanism in regulating cellular events. Show more

Keywords: Primary cultures, PP1 binding protein, protein phosphatases, protein phosphorylation, subcellular localization, yeast tri-hybrid

DOI: 10.3233/JAD-130095

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 761-775, 2013