Journal of Alzheimer's Disease - Volume 26, issue 4

Authors: Kanyenda, Limbikani J. | Verdile, Giuseppe | Boulos, Sherif | Krishnaswamy, Sudarsan | Taddei, Kevin | Meloni, Bruno P. | Mastaglia, Frank L. | Martins, Ralph N.

Article Type: Review Article

Abstract: CD147, also known as basigin, EMMPRIN, neurothelin, TCSF, M6, HT7, OX47, or gp42, is a transmembrane glycoprotein of the immunoglobulin super-family. It is expressed in many neuronal and non-neuronal tissues including the hippocampus, pre-frontal cortex thyroid, heart, early erythroid, amygdala, and placenta. This protein is involved in various cellular and biological functions, such as lymphocyte migration and maturation, tissue repair cancer progression, T and B lymphocyte activation, and induction of extracellular matrix metalloproteinase. The CD147 protein interacts with other proteins such as cyclophilin A (CyPA), Cyclophilin B (CyPB), sterol carrier protein (SCP), caveolin-1 and integrins, and can influence amyloid-β (Aβ) …peptide levels, a protein that is central to Alzheimer's disease (AD) pathogenesis. Mechanisms by which CD147 regulate Aβ levels remain unclear, thus in this review we discuss its involvement in Aβ production and clearance and potential mechanisms by which controlling CD147 levels could impact on Aβ accumulation and AD pathogenesis. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, CD147, cholesterol, EMMPRIN, γ-secretase, immunoglobulin superfamily, sterol carrier protein-2

DOI: 10.3233/JAD-2011-110584

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 593-605, 2011

Authors: Huang, Han-Chang | Jiang, Zhao-Feng

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disease. Amyloid-β peptide (Aβ) is the most crucial molecule related to the pathological development of AD. Amyloid-β protein precursor (AβPP) is one of AβPP family members with conserved type I transmembrane. The genetic mutations of AβPP and the abnormity of its post-transcription and proteolytic processing contribute to the elevation of Aβ. The accumulation of Aβ in senile plaques is believed to be the most important event in AD pathology. Therefore, as a key upstream molecule of Aβ, AβPP is related to the AD pathology, but the biological function …of AβPP is still not fully clear. AβPP-like proteins are widely expressed in multicellular eukaryotes. AβPP-like homologous genes and proteins are highly conserved in various organisms from invertebrates to mammals. AβPP-like genes undergo similarly pathways of transcription and post-transcription processing, and AβPP-like proteins is proteolyzed by the similar α-cleavage and the β-cleavage pathways. Based on the homology and the resemble domains, AβPP may play similar roles in organisms. In this article, we reviewed homology and structures of AβPP family members in organisms and further discussed potential biological function in normal and AD brains. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, biological function, homology, structure

DOI: 10.3233/JAD-2011-110335

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 607-626, 2011

Authors: Bloudek, Lisa M. | Spackman, D. Eldon | Blankenburg, Michael | Sullivan, Sean D.

Article Type: Research Article

Abstract: Mild Alzheimer's disease (AD) is often difficult to differentiate from mild cognitive impairment (MCI) or non-AD dementias. A multitude of diagnostic biomarkers and advanced imaging strategies have been developed to aid in the diagnosis and management of AD. We sought to review and analyze the published evidence on key test characteristics of major diagnostic strategies to formulate best estimates of sensitivity (SN) and specificity (SP). A systematic review was undertaken to locate and abstract all studies of biomarkers or diagnostic imaging for AD published in English from January 1990 to March 2010 that provided estimates of SN and SP. Meta-analysis …was performed using a bivariate mixed-effects binary regression model. We calculated -SN, SP, and area under the receiver operating curves (AUROC), with confidence and prediction contours. Of 1,840 unique studies identified, 119 presented primary data sufficient for analysis. SN and SP were calculated against non-demented controls, non-AD dementias with and without MCI, if available. Compared to non-demented controls, FDG-PET demonstrated the highest AUROC (0.96), with 90% SN (95%CI 84% to 94%), and 89% SP (95% CI 81% to 94%). FDG-PET also was most accurate in discriminating AD from demented controls (including MCI) with AUROC 0.91, and 92% SN (95%CI 84% to 96%) and 78% SP (95% CI 69% to 85%). For discrimination of AD from non-AD dementias (excluding MCI), CSF Ptau, and SPECT produced identical AUROC (0.86). Diagnostic strategies for AD show wide variation in test characteristics and some show promise for use in clinical practice. Show more

Keywords: Alzheimer's disease, amyloid-β protein, biomarkers, diagnosis, emission-computed, magnetic resonance imaging, sensitivity and specificity, single-photon, tau proteins, tomography

DOI: 10.3233/JAD-2011-110458

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 627-645, 2011

Authors: So, Pauline P.L. | Chen, Ci-Di | Abraham, Carmela R.

Article Type: Research Article

Abstract: Amyloidogenic processing of the amyloid-β protein precursor (AβPP) produces amyloid-β peptides (Aβ), the major constituent of amyloid plaques in the brains of Alzheimer's disease (AD) patients. Experimental evidence suggests that increased dimerization of AβPP increases Aβ while decreased dimerization of AβPP decreases Aβ production. If true, developing tools for detecting AβPP-AβPP interactions to understand AβPP processing leading to Aβ production would be important. Here, we developed the method of β-galactosidase (β-gal) enzyme fragment complementation as a means to detect AβPP-AβPP interactions. Inactive β-gal fragments are independently tagged to the C-terminal ends of monomeric AβPPs, and will come together to form …a functional enzyme upon AβPP-AβPP interactions. Successful detection of β-gal activity has been used to qualitatively visualize and quantify the amount of AβPP dimers or higher oligomers. This method can be used to enhance our understanding of the biological processes dependent upon AβPP-AβPP interactions. Show more

Keywords: Alzheimer disease, amyloid-β peptides, β-galactosidase, enzyme fragment complementation, protein-protein interactions

DOI: 10.3233/JAD-2011-110323

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 647-655, 2011

Authors: Liu, Peng | Kemper, Lisa J. | Wang, Jun | Zahs, Kathleen R. | Ashe, Karen H. | Pasinetti, Giulio M.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) oligomers, found in the brains of Alzheimer's disease (AD) patients and transgenic mouse models of AD, cause synaptotoxicity and memory impairment. Grape seed polyphenolic extract (GSPE) inhibits Aβ oligomerization in vitro and attenuates cognitive impairment and AD-related neuropathology in the brains of transgenic mice. In the current study, GSPE was administered to Tg2576 mice for a period of five months. Treatment significantly decreased brain levels of Aβ*56, a 56-kDa Aβ oligomer previously shown to induce memory dysfunction in rodents, without changing the levels of transgenic amyloid-β protein precursor, monomeric Aβ, or other Aβ oligomers. These results thus provide …the first demonstration that a safe and affordable intervention can lower the levels of a memory-impairing Aβ oligomer in vivo and strongly suggest that GSPE should be further tested as a potential prevention and/or therapy for AD. Show more

Keywords: Alzheimer's disease, amyloid-β, grape seed polyphenolic extract, oligomer, transgenic mice

DOI: 10.3233/JAD-2011-110383

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 657-666, 2011

Authors: O'Dwyer, Laurence | Lamberton, Franck | Bokde, Arun L.W. | Ewers, Michael | Faluyi, Yetunde O. | Tanner, Colby | Mazoyer, Bernard | O'Neill, Des | Bartley, Máiréad | Collins, D. Rónán | Coughlan, Tara | Prvulovic, David | Hampel, Harald

Article Type: Research Article

Abstract: White matter (WM) degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI) may be a key indicator of early damage in AD. Here, we analyzed WM diffusion tensor data using Tract-Based Spatial Statistics in conjunction with mixed-effects models. Four indices of diffusion were assessed in 61 healthy control, 19 non-amnestic MCIs, 14 amnestic MCIs, and 9 AD patients. The aim of the study was to use advanced mixed-effects models to investigate the retrogenesis hypothesis of AD, which suggests that tracts that are late to myelinate in ontogenetic development are the earliest to be affected in AD. Our results show …that a number of late-myelinating pathways, including the parahippocampal region and the inferior longitudinal fasciculus, were predominantly affected by changes in WM volume. Conversely, early-myelinating pathways were found to be affected by a combination of both WM and gray matter (GM) atrophy. A model of the entire WM structure of the brain returned GM models for two indices of diffusion, suggesting that more complex regional landscapes of diffusion lie hidden beneath a global analysis of the entire brain. Our results warn against an explanation of white matter damage that points simply to one of two mechanisms: secondary degeneration or direct damage of myelin. We suggest that tracts may be affected by both mechanisms, with the balance depending on whether tracts are early or late-myelinating. A greater understanding of the pattern of WM changes in AD may prove useful for the early detection of AD. Show more

Keywords: Alzheimer's disease, diffusion tensor imaging, mild cognitive impairment, mixed models, statistical models, tract based spatial statistics

DOI: 10.3233/JAD-2011-110137

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 667-682, 2011

Authors: Blazquez-Llorca, Lidia | Garcia-Marin, Virginia | Merino-Serrais, Paula | Ávila, Jesús | DeFelipe, Javier

Article Type: Research Article

Abstract: A key symptom in the early stages of Alzheimer's disease (AD) is the loss of declarative memory. The anatomical substrate that supports this kind of memory involves the neural circuits of the medial temporal lobe, and in particular, of the hippocampal formation and adjacent cortex. A main feature of AD is the abnormal phosphorylation of the tau protein and the presence of tangles. The sequence of cellular changes related to tau phosphorylation and tangle formation has been studied with an antibody that binds to diffuse phosphotau (AT8). Moreover, another tau antibody (PHF-1) has been used to follow the pathway of …neurofibrillary (tau aggregation) degeneration in AD. We have used a variety of quantitative immunocytochemical techniques and confocal microscopy to visualize and characterize neurons labeled with AT8 and PHF-1 antibodies. We present here the rather unexpected discovery that in AD, there is conspicuous abnormal phosphorylation of the tau protein in a selective subset of dendritic spines. We identified these spines as the typical thorny excrescences of hippocampal CA3 neurons in a pre-tangle state. Since thorny excrescences represent a major synaptic target of granule cell axons (mossy fibers), such aberrant phosphorylation may play an essential role in the memory impairment typical of AD patients. Show more

Keywords: Alzheimer's disease, glutamatergic terminals, hippocampal formation, tau protein, thorny excrescences

DOI: 10.3233/JAD-2011-110659

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 683-698, 2011

Authors: Davies, Neil M. | Kehoe, Patrick G | Ben-Shlomo, Yoav | Martin, Richard M.

Article Type: Research Article

Abstract: We investigated whether angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACE-Is) are more strongly associated with Alzheimer's disease (AD), vascular dementia (VaD), and other dementias, than other anti-hypertensive drugs. We conducted a nested case-control analysis within the UK general practice research database, with prospectively recorded anti-hypertensive prescribing data. We sampled cases aged ≥60 years and diagnosed between 1997–2008 (5,797 with AD, 2,186 with VaD, 1,214 with unspecified/other dementia) which were matched to up to four controls by age, general practice and gender. We computed odds-ratios and dose response effects for AD, vascular and unspecified/other dementia, comparing those …prescribed ARBs or ACE-Is for at least six months with patients prescribed other anti-hypertensives. We controlled for matching factors, co-morbidities, smoking status, an area measure of socioeconomic status, consultation rate and blood pressure and accounted for reverse causality by introducing time-lags of up to eight years prior to diagnosis/index date. Patients diagnosed with AD, vascular and unspecified/other dementia had fewer prescriptions for ARBs and ACE-Is. Inverse associations with AD were strongest for ARBs (odds-ratio; 0.47, 95%CI, 0.37–0.58) compared with ACE-Is (odds-ratio; 0.76, 95%CI, 0.69–0.84) (pdifference < 0.001). Associations of ARBs with AD were stronger than for vascular dementia (pdifference = 0.01) and unspecified/other dementia (pdifference = 0.23). There were inverse dose-response relationships between ARBs and ACE-Is with AD (both ptrend < 0.01). The inverse association of ACE-Is with AD diminished when using longer time lags but the ARB-AD association persisted. Patients with AD were around half as likely to be prescribed ARBs. Further randomized controlled trial evidence is required to rigorously test these findings. Show more

Keywords: All cognitive disorders/dementia, Alzheimer's disease, case control studies, risk factors in epidemiology, vascular dementia

DOI: 10.3233/JAD-2011-110347

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 699-708, 2011

Authors: Sattler, Christine | Erickson, Kirk I. | Toro, Pablo | Schröder, Johannes

Article Type: Research Article

Abstract: To evaluate the predictive effects of subjective measures of physical activity (PA) and objective measures of physical fitness (PF) on dementia risk, Participants of the prospective population-based ILSE-study (*1930-1932; 12-year follow-up) were examined at three examination waves (t1 : 1993/94; t2 : 1997/98; t3 : 2005/07). 381 subjects of the original cohort (n = 500) were re-examined at t3. 29% of the subjects who were cognitively healthy at baseline received the diagnosis of mild cognitive impairment (MCI) and 7% of Alzheimer's disease (AD). Subjects were screened for physical and mental health using medical interviews, physical, and neuropsychological examinations. Participants completed …a questionnaire on their current and past PA at t1. Subjects were classified as physically active if they reported a regular sport activity for at least 2 hours per week in the past year. Muscular strength (handgrip) and motor coordination (balance) served as objective indicators of PF. Subjects who passed the balance-test at t1 had a reduced risk of developing MCI/AD at t3 (OR = 0.35, 95%CI 0.19–0.66, p < 0.01) and performed significantly better on various neuropsychological measures. Muscular strength or subjective reports of PA did not predict MCI/AD development. Our results confirm the hypothesis that PF acts as a protective factor for the development of cognitive disorders. In our study, context, motor coordination served as a better predictor than muscular strength or self-rated PA. Since subjects with cognitive disorders due to cerebral and/or systemic disorders were excluded from the analyses, our findings suggest that the effect of skill-related PF extends beyond the reduction of cardiovascular risk factors. Show more

Keywords: Aging, Alzheimer's disease, cognition, cohort studies, physical activity, prevention

DOI: 10.3233/JAD-2011-110548

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 709-718, 2011

Authors: Hänggi, Jürgen | Streffer, Johannes | Jäncke, Lutz | Hock, Christoph

Article Type: Research Article

Abstract: Distinguishing amnestic mild cognitive impairment (MCI) from Alzheimer's disease (AD) and healthy aging depends mainly on clinical evaluation, and, ultimately, on investigator's judgment. Clinical evaluation in vivo is based primarily on cognitive assessments. The present study explores the potential of volumetric magnetic resonance imaging of parietal and lateral temporal brain structures to support the diagnosis of AD and to distinguish AD patients from patients with MCI and healthy control subjects (HCS). 52 age-matched HCS, 18 patients with MCI, and 59 patients with probable late onset AD were investigated. Using computational, neuromorphometric procedures gray matter (GM) was automatically parcellated into 28 …local regions of interest, the volumes of which were computed. The left hippocampus (sensitivity/specificity: 80.8–90.4%/55.6–86.4%) and the right hippocampus (73.1–90.4%/66.7–84.7%) provided highest diagnostic accuracy in separating all three diagnostic groups. Promising diagnostic values for distinguishing MCI from HCS were found for the left superior parietal gyrus (61.5%/55.6%) and left supramarginal gyrus (65.4%/66.7%), and for distinguishing subjects with MCI from AD patients for the right middle temporal gyrus (77.8%/79.7%), left inferior temporal gyrus (83.3%/72.9%), and right superior temporal gyrus (77.8%/71.2%). The left superior temporal pole (92.3%/84.7%), left parahippocampal gyrus (86.5%/81.4%), left Heschl's gyrus (86.5%/79.7%), and the right superior temporal pole (82.7%/78.0%) revealed most promising diagnostic values for distinguishing AD patients from HCS. Data revealed that lateral temporal and parietal GM volumes distinguish between HCS, MCI, and AD as accurate as hippocampal volumes do; hence, these volumes can be used in the diagnostic procedure. Results also suggest that cognitive functions associated with these brain regions, e.g., language and visuospatial abilities, may be tested more extensively to obtain additional information that might enhance the diagnostic accuracy further. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, cerebral structures, dementia diagnostics, language, lateral temporal lobe, parietal lobe, sensitivity and specificity, structural magnetic resonance imaging, visuospatial abilities, working memory

DOI: 10.3233/JAD-2011-101260

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 719-734, 2011