Journal of Alzheimer's Disease - Volume 42, issue 4

Authors: Holler, Christopher J. | Davis, Paulina R. | Beckett, Tina L. | Platt, Thomas L. | Webb, Robin L. | Head, Elizabeth | Murphy, M. Paul

Article Type: Research Article

Abstract: Recent genome wide association studies have implicated bridging integrator 1 (BIN1) as a late-onset Alzheimer's disease (AD) susceptibility gene. There are at least 15 different known isoforms of BIN1, with many being expressed in the brain including the longest isoform (iso1), which is brain-specific and localizes to axon initial segments and nodes of Ranvier. It is currently unknown what role BIN1 plays in AD. We analyzed BIN1 protein expression from a large number (n = 71) of AD cases and controls from five different brain regions (hippocampus, inferior parietal cortex, inferior temporal cortex, frontal cortex (BA9), and superior and middle …temporal gyri). We found that the amount of the largest isoform of BIN1 was significantly reduced in the AD brain compared to age-matched controls, and smaller BIN1 isoforms were significantly increased. Further, BIN1 was significantly correlated with the amount of neurofibrillary tangle (NFT) pathology but not with either diffuse or neuritic plaques, or with the amount of amyloid-β peptide. BIN1 is known to be abnormally expressed in another human disease, myotonic dystrophy, which also features prominent NFT pathology. These data suggest that BIN1 is likely involved in AD as a modulator of NFT pathology, and that this role may extend to other human diseases that feature tau pathology. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, cellular nucleic acid binding protein, myotonic dystrophy, tau, ZNF9

DOI: 10.3233/JAD-132450

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1221-1227, 2014

Authors: Rodriguez-Ortiz, Carlos J. | Baglietto-Vargas, David | Martinez-Coria, Hilda | LaFerla, Frank M. | Kitazawa, Masashi

Article Type: Research Article

Abstract: MicroRNAs are a group of small RNAs that regulate diverse cellular processes including neuronal function. Recent studies have shown that dysregulation of specific microRNAs is critically involved in the development of Alzheimer's disease (AD). Most of these reports have focused on microRNAs implicated in alterations of amyloid-β and tau. However, studies exploring the relation between microRNAs dysregulation in AD and synaptic plasticity are scarce despite the well-known involvement of microRNAs in synaptic plasticity. Since impairments in synaptic plasticity and neuronal loss are two important features displayed in AD patients, it is feasible to hypothesize that alterations in plasticity-related microRNAs underlie …AD progression. Here, levels of a small number of microRNAs implicated in normal neuronal function and/or plasticity were examined in an AD model. Twelve-month old 3xTg-AD mice with plaques and tangles presented a significant upregulation of miR-181 in the hippocampus compared to age-matched wild type mice. Increased miR-181 was not detected in pre-pathological 3xTg-AD mice. Analysis of predicted targets of miR-181 identified c-Fos and SIRT-1, proteins critically involved in memory formation. Both c-Fos and SIRT-1 levels were significantly decreased in the ventral hippocampus of twelve-month old 3xTg-AD mice. Overexpression of miR-181 in SH-SY5Y cells significantly decreased c-Fos and SIRT-1, strongly suggesting that miR-181 directly regulates the expression of these two proteins. These findings indicate a connection between miR-181 and proteins involve in synaptic plasticity and memory processing in a transgenic mouse model of AD. Our results suggest that microRNAs involved in synaptic plasticity might be an important factor that contributes to AD neuropathology. Show more

Keywords: Alzheimer's disease, miRNA, sirtuin-1, synaptic plasticity, translational regulation

DOI: 10.3233/JAD-140204

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1229-1238, 2014

Authors: Van der Mussele, Stefan | Fransen, Erik | Struyfs, Hanne | Luyckx, Jill | Mariën, Peter | Saerens, Jos | Somers, Nore | Goeman, Johan | De Deyn, Peter P. | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Behavioral and psychological signs and symptoms of dementia (BPSD) belong to the core symptoms of dementia and are also common in mild cognitive impairment (MCI). Objective: This study would like to contribute to the understanding of the prognostic role of BPSD in MCI for the progression to dementia due to Alzheimer’s disease (AD). Methods: Data were generated through an ongoing prospective longitudinal study on BPSD. Assessment was performed by means of the Middelheim Frontality Score, Behave-AD, Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia (CSDD), and Geriatric Depression Scale 30-questions (GDS-30). Cox proportional hazard …models were used to test the hypothesis that certain BPSD in MCI are predictors of developing AD. Results: The study population consisted of 183 MCI patients at baseline. At follow-up, 74 patients were stable and 109 patients progressed to AD. The presence of significant depressive symptoms in MCI as measured by the CSDD (HR: 2.06; 95% CI: 1.23–3.44; p = 0.011) and the GDS-30 (HR: 1.77; 95% CI: 1.10–2.85; p = 0.025) were associated with progression to AD. The severity of depressive symptoms as measured by the GDS-30 was a predictor for progression too (HR: 1.06; 95% CI: 1.01–1.11; p = 0.020). Furthermore, the severity of agitated behavior, especially verbal agitation and the presence of purposeless activity, was also associated with progression, whereas diurnal rhythm disturbances were associated with no progression to AD. Conclusion: Depressive symptoms in MCI appear to be predictors for progression to AD. Show more

Keywords: Alzheimer's disease, association, BPSD, Cox proportional hazard, dementia, depression, depressive symptoms, mild cognitive impairment, predictor, prognostic value

DOI: 10.3233/JAD-140405

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1239-1250, 2014

Authors: Ford, Andrew H. | Almeida, Osvaldo P. | Flicker, Leon | Garrido, Griselda J. | Greenop, Kathryn R. | Foster, Jonathan K. | Etherton-Beer, Christopher | van Bockxmeer, Frank M. | Lautenschlager, Nicola T.

Article Type: Research Article

Abstract: Reduced awareness of cognitive deficits in mild cognitive impairment (MCI) is associated with poorer outcomes although little is known about the anatomical correlates of this. We examined the association of insight and grey matter volume using a voxel-based morphometry approach in 65 volunteers with MCI and 55 healthy age-matched controls. Participants with MCI had multiple areas of subtle grey matter volume loss compared with controls, although these did not survive correction for multiple comparisons. These were predominantly in the temporal and anterior portions of the brain. Individuals with MCI did not differ from each other on a number of demographic …and cognitive variables according to level of insight. Reduced awareness of cognitive deficits was associated with few differences in grey matter volume apart from a subtle loss of grey matter in the medial frontal gyri. Given the modest nature of these findings, the routine assessment of insight in non-clinical populations of individuals with MCI is therefore not supported. Prospective data in larger samples, however, would be helpful to clarify this further and determine if impaired insight predicts brain atrophy and cognitive decline. Show more

Keywords: Awareness, grey matter, insight, mild cognitive impairment

DOI: 10.3233/JAD-132678

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1251-1259, 2014

Authors: Galimberti, Daniela | Villa, Chiara | Fenoglio, Chiara | Serpente, Maria | Ghezzi, Laura | Cioffi, Sara M.G. | Arighi, Andrea | Fumagalli, Giorgio | Scarpini, Elio

Article Type: Research Article

Abstract: Several micro(mi)RNA are deregulated in brain, cerebrospinal fluid (CSF), and serum/plasma from patients with Alzheimer's disease (AD). The aim of the study was to profile circulating miRNAs in serum as non-invasive biomarkers for AD, correlating them with those identified in CSF, the biological fluid which better reflects biochemical changes occurring during pathological processes in the brain and may provide a robust indicator of AD-related disease pathogenesis thanks to the evidence of low amyloid and high levels of tau and hyperphosphorylated tau. Using a two-step analysis (array and validation through real-time PCR), a down-regulation (mean fold change ± SEM) of miR-125b …(0.415 ± 0.11 versus 1.381 ± 0.36, p = 0.009), miR-23a (0.111 ± 0.03 versus 0.732 ± 0.14, p < 0.001), and miR-26b (0.414 ± 0.11 versus 1.353 ± 0.39, p < 0.01), out of 84 tested, was shown in serum from 22 AD patients compared with 18 non-inflammatory and 8 inflammatory neurological controls (NINDCs and INDCs) and 10 patients with frontotemporal dementia. Significant down-regulation of miR-125b and miR-26b was also confirmed in CSF from AD patients versus NINDCs (miR-125b: 0.089 ± 0.03 versus 0.230 ± 0.08, p < 0.001; miR-26b: 0.217 ± 0.06 versus 1.255 ± 0.29, p < 0.001, mean fold change ± SEM, respectively), whereas data were not replicated for miR-23a. In serum, miR-125b had an AUC of 0.82 to distinguish AD from NINDCs (95% CI: 0.65–0.98, p = 0.005). In conclusion, we demonstrated that cell-free miR-125b serum levels are decreased in serum from patients with AD as compared with NINDC and distinguish between AD and NINDCs with an accuracy of 82%. Show more

Keywords: Alzheimer's disease, biomarker, miRNA, serum

DOI: 10.3233/JAD-140756

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1261-1267, 2014

Authors: Winkler, Angela | Dlugaj, Martha | Weimar, Christian | Jöckel, Karl-Heinz | Erbel, Raimund | Dragano, Nico | Moebus, Susanne | on behalf of the Heinz Nixdorf Recall Study Investigative Group

Article Type: Research Article

Abstract: Background: Several studies reported on the association of type 2 diabetes (T2DM) with dementia. Studies on the association of T2DM and mild cognitive impairment (MCI) are rare. Objective: To evaluate the gender-specific association of T2DM with MCI and MCI subtypes (amnestic MCI (aMCI) and non-amnestic MCI (naMCI)) in a middle-aged (50–65 years) and old-aged (66–80 years) population-based study sample. Methods: We compared 560 participants with MCI (aMCI n = 289, naMCI n = 271) with 1,376 cognitively normal participants from the Heinz Nixdorf Recall study. Diabetic status was based on self-reported physician’s diagnosis or treatment with …anti-diabetic medication. We performed group comparisons regarding all cognitive subtests for participants with and without T2DM. Logistic regression models (adjusted for age, education, cardiovascular risk factors, and depression) were used to determine the association of T2DM with MCI and MCI subtypes. Results: In the middle-aged group, fully adjusted models showed an association (odds ratio, 95% CI) of T2DM with MCI that was more pronounced in men (total: 2.03, 1.23–3.36, men: 2.16, 1.12–4.14, women 1.69, 0.73–3.89). T2DM was associated with MCI subtypes (aMCI: 2.01, 1.08–3.73; naMCI: 2.06, 1.06–3.98), whereas, the association was stronger with naMCI in men (2.61, 1.14–5.98) and with aMCI in women (3.02, 1.27–7.17). We found no total or gender-specific association of T2DM with MCI or MCI subtypes in the old-aged group. Conclusions: Our data show that T2DM is associated with MCI and MCI subtypes in middle-aged, but not in old-aged participants. Furthermore, the results indicate a gender-specific vulnerability of T2DM on cognition, especially in MCI subtypes. Show more

Keywords: Aging, gender, mild cognitive impairment, population-based studies, type 2 diabetes mellitus

DOI: 10.3233/JAD-140696

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1269-1277, 2014

Authors: Chirila, Florin V. | Khan, Tapan K. | Alkon, Daniel L.

Article Type: Research Article

Abstract: The inaccuracy of the diagnosis for Alzheimer's disease (AD) has made its therapeutic intervention difficult, particularly early enough to prevent significant neurodegeneration and cognitive dysfunction. Here, we describe a novel, highly accurate peripheral diagnostic for AD patients based on quantitatively measured aggregation rate of human skin fibroblasts. The elevated aggregation rate with increasing cell density in AD cases is the basis of this new biomarker. The new biomarker was successfully cross-validated with two more mature assays, AD-Index, based on the imbalances of ERK1/2, and Morphology, based on network dynamics, and showed 92% overlap. A significant number of cases tested with …this new biomarker were freshly obtained (n = 29), and 82% of the cases are hyper-validated cases, i.e., autopsy and/or genetically confirmed AD or non-Alzheimer's disease demented patients (Non-ADD) and non-demented age-matched controls. Furthermore, we show that by using a simple majority rule, i.e., two out of the three assays have the same outcome, we significantly increase the agreement with clinical AD diagnosis (100%). Based on the high accuracy of this strategy, the biomarker profile appears to accurately identify AD patients for therapeutic intervention. Show more

Keywords: Aggregation rate, Alzheimer's disease, cross-validation, majority rule, skin fibroblasts

DOI: 10.3233/JAD-140672

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1279-1294, 2014

Authors: Meng, Xiang-Fei | Yu, Jin-Tai | Wang, Hui-Fu | Tan, Meng-Shan | Wang, Chong | Tan, Chen-Chen | Tan, Lan

Article Type: Research Article

Abstract: Background/Objective: We examine whether midlife vascular risk factors (VRFs) are associated with increased risk of incident Alzheimer’s disease (AD) in a systematic review and meta-analysis of published cohort studies. Methods: Original cohort studies were included if they reported adjusted combined odds ratio (COR) and corresponding 95% confidence intervals (CIs) or enough information to quantify the association between risk for AD in late-life and baseline VRFs of midlife. Results: There were positive and significant associations between high blood pressure (COR 1.31; 95% CI: 1.01–1.70), hypercholesterolemia (COR 1.72; 95% CI: 1.32–2.24), obesity (COR 1.88; 95% CI: 1.32–2.69), and …diabetes mellitus in midlife (COR 1.4; 95% CI: 1.25–1.57). Smoking and hyperhomocysteinemia (although only one high-quality paper) were also associated with an increased risk of AD generally. Conclusions: These results strengthen the epidemiological evidence that VRFs of midlife significantly increase risk for AD. Show more

Keywords: Alzheimer's disease, diabetes mellitus, high blood pressure, hypercholesterolemia, hyperhomocysteinemia, meta-analysis, midlife vascular risk factors, obesity, smoking, systematic review

DOI: 10.3233/JAD-140954

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1295-1310, 2014

Authors: Colucci, Luisa | Bosco, Massimiliano | Fasanaro, Angiola Maria | Gaeta, Giuseppe Lucio | Ricci, Giovanna | Amenta, Francesco

Article Type: Research Article

Abstract: Background/Objective: Alzheimer’s disease (AD) is a very costly pathology. Total costs of AD result from the sum of direct and indirect costs. Intangible costs represent an additional burden that is difficult to quantify. This paper has reviewed the evaluation of the costs of AD and the methodologies to estimate them, and proposes the use of some tools which may be useful in establishing the financial weight of the disease. Method: A systematic literature search was conducted using the Pubmed and Medline databases as a source of published papers. Results: In AD, direct and indirect costs and …their sum (total costs) are very high and tend to increase parallel with the evolution of the pathology. The evolution of AD is characterized by the loss of functional autonomy, the onset of behavioral and sleep disorders, and the development of delusions and hallucinations. This requires more frequent medical examinations and hospitalizations resulting in higher direct costs, which become the relevant weight. None of the papers reviewed investigated intangible cost. Conclusion: The calculation of costs of AD is frequently based on cognitive decline and the degree of dependence of patients. The evaluation of intangible costs (psychological pain of the patient and of the unpaid caregivers’ and their impaired quality of life) is a missing aspect in all reviewed studies. Due to the complexity of AD, it will be necessary to adopt cost evaluation systems including the different dimensions of the problem and its various aspects. Show more

Keywords: Costs of Alzheimer's disease, direct costs, evaluation costs, indirect costs, intangible costs, total costs

DOI: 10.3233/JAD-131556

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1311-1324, 2014

Authors: O'Bryant, Sid E. | Xiao, Guanghua | Zhang, Fan | Edwards, Melissa | German, Dwight C. | Yin, Xiangling | Como, Tori | Reisch, Joan | Huebinger, Ryan M. | Graff-Radford, Neill | Dickson, Dennis | Barber, Robert | Hall, James | O'Suilleabhain, Padraig | Grammas, Paula

Article Type: Research Article

Abstract: Background: There is a significant need for rapid and cost-effective biomarkers of Alzheimer’s disease (AD) for advancement of clinical practice and therapeutic trials. Objective: The aim of the current study was to cross-validate our previously published serum-based algorithm on an independent assay platform as well as validate across tissues and species. Preliminary analyses were conducted to examine the utility in distinguishing AD from non-AD neurological disease (Parkinson’s disease, PD). Methods: Serum proteins from our previously published algorithm were quantified from 150 AD cases and 150 controls on the Meso Scale Discovery (MSD) platform. Serum samples were …analyzed from 49 PD cases and compared to a random sample of 51 AD cases and 62 controls. Support vector machines (SVM) were used to discriminate PD versus AD versus controls. Human and AD mouse model microvessel images were quantified with HAMAMATSU imaging software. Mouse serum biomarkers were assayed via MSD. Results: Analysis of 21 serum proteins from 150 AD cases and 150 controls yielded an algorithm with sensitivity and specificity of 0.90 for correctly classifying AD. This multi-marker approach was then validated across species and tissue. Assay of the top proteins in human and AD mouse model brain microvessels correctly classified 90–100% of the samples. SVM analyses were highly accurate at distinguishing PD versus AD versus controls. Conclusions: This serum-based biomarker panel should be tested in a community-based setting to determine its utility as a first-line screen for AD and non-AD neurological diseases for primary care providers. Show more

Keywords: Alzheimer's disease, blood-based biomarkers, serum, species, tissue

DOI: 10.3233/JAD-141041

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1325-1335, 2014