Journal of Alzheimer's Disease - Volume 22, issue 1

Authors: Bennet, Anna M. | Reynolds, Chandra A. | Gatz, Margaret | Blennow, Kaj | Pedersen, Nancy L. | Prince, Jonathan A.

Article Type: Research Article

Abstract: The two genetic polymorphisms, rs7412 and rs429358, that collectively form the ε2, ε3, and ε4 alleles of apolipoprotein E (APOE) are among the most widely studied sequence variants in the genome. The predominant model for testing APOE involves the haplotype combinations of ε2, ε3, and ε4 and has been basis of associations with dementia, atherosclerosis, and serum lipid levels. Here, we demonstrate the functional independence of these two component sites, with rs7412 contributing to the majority of variance in serum LDL (p=10-20 ), whereas rs429358 alone influences variance in CSF amyloid-β42 (Aβ42 ) (p=10-17 ). This latter relationship is …also reflected in the association of APOE with dementia, where rs429358 strongly influences disease (p=10-67 ), but rs7412 does not. Models based upon ε2, ε3, and ε4 explained less variance for both dementia risk and CSF Aβ42 than did rs429358 alone. When adjusted for CSF Aβ42 , the association of rs429358 with dementia is greatly reduced but remains significant indicating that APOE polymorphism influences disease by additional mechanisms distinct from Aβ42 metabolism. We reach four principal conclusion from this study: 1) rs429358 alone is responsible for the association of APOE with dementia; 2) The association of APOE with dementia is substantially mediated by its effect on CNS Aβ42 levels; 3) The association of APOE with dementia is not mediated by its impact on peripheral lipid metabolism; and 4) The dichotomy of effects of rs429358 and rs7412 represents one of the best examples of genetic pleiotropy for complex traits known and illustrates the importance of allelic heterogeneity in APOE. Show more

Keywords: Alzheimer's disease, amyloid, association, CSF, LDL

DOI: 10.3233/JAD-2010-100864

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 129-134, 2010

Authors: Murphy, M. Paul | Morales, Jacqueline | Beckett, Tina L. | Astarita, Giuseppe | Piomelli, Daniele | Weidner, Adam | Studzinski, Christa M. | Dowling, Amy L.S. | Wang, Xiaohong | LeVine, III, Harry | Kryscio, Richard J. | Lin, Yushun | Barrett, Edward | Head, Elizabeth

Article Type: Research Article

Abstract: Human studies suggest either a protective role or no benefit of statins against the development of Alzheimer's disease (AD). We tested the hypothesis that statin-mediated cholesterol reduction in aged dogs, which have cognitive impairments and amyloid-β (Aβ) pathology, would improve cognition and reduce neuropathology. In a study of 12 animals, we treated dogs with 80 mg/day of atorvastatin for 14.5 months. We did not observe improvements in discrimination learning; however, there were transient impairments in reversal learning, suggesting frontal dysfunction. Spatial memory function did not change with treatment. Peripheral levels of cholesterol, LDLs, triglycerides, and HDL were significantly reduced in …treated dogs. Aβ in cerebrospinal fluid and brain remained unaffected. However, β-secretase-1 (BACE1) protein levels and activity decreased and correlated with reduced brain cholesterol. Finally, lipidomic analysis revealed a significant decrease in the ratio of omega-6 to omega-3 essential fatty in temporal cortex of treated aged dogs. Aged beagles are a unique model that may provide novel insights and translational data that can predict outcomes of statin use in human clinical trials. Treatment with atorvastatin may be beneficial for brain aging by reducing BACE1 protein and omega6:omega3 ratio, however, the potential adverse cognitive outcomes reported here should be more carefully explored given their relevance to human clinical outcomes. Show more

Keywords: Amyloid-β protein precursor (AβPP), β-secretase (BACE1), canine, cholesterol, dog, LRP-1, statin

DOI: 10.3233/JAD-2010-100639

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 135-150, 2010

Authors: Na, Hae-Ri | Kim, Sang-Yun | Chang, Young-Hee | Park, Moon-Ho | Cho, Sung-Tae | Han, Il-Woo | Kim, Tae-You | Hwang, Sul-A.

Article Type: Research Article

Abstract: Functional Assessment Staging (FAST) was devised to meet the need for a more brief patient-derived rating scale for evaluating changes in functional performance and activities of daily living skills in all the stages of Alzheimer's disease (AD). FAST was administered to 464 patients with probable AD according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The patients were also evaluated using the Korean version of the Mini-Mental Status Examination (K-MMSE), the Clinical Dementia Rating (CDR), the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Global Deterioration Scale (GDS), the Barthel Activities …of Daily Living (B-ADL), and the Seoul-Instrumental Activities of Daily Living (S-IADL). For patients with moderate to severe dementia, the Korean versions of the Severe Impairment Battery (SIB-Ko) and Baylor profound mental status examination (BPMSE-Ko) were also administered. There were significant correlations between the FAST and the K-MMSE scores (r= − 0.71, p< 0.001), between the FAST and the SIB-Ko scores (r= − 0.54, p< 0.001) and between the FAST and the BPMSE-Ko scores (r=− 0.46, p< 0.001). The FAST was also correlated with the CDR, the CDR-SB, the B-ADL, and the S-IADL (p< 0.001). Ultimately, FAST is a reliable and valid assessment technique for evaluating functional deterioration in AD patients throughout the disease course. Moreover, the findings of the present study suggest that the FAST elucidates a characteristic pattern of progressive, ordinal, and functional decline in AD in Korean AD patients with dementia. Show more

Keywords: AD, FAST, severe dementia, staging

DOI: 10.3233/JAD-2010-100072

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 151-158, 2010

Authors: Benito-León, Julián | Mitchell, Alex J. | Vega, Saturio | Bermejo-Pareja, Félix

Article Type: Research Article

Abstract: Given the uncertain relationship between objective and subjective memory complaints (SMC), we conducted a study of cognitive function in older people with memory complaints in a large population-based elderly Spanish cohort (NEDICES). A total of 1,073 subjects with SMC and 1,073 matched controls free from dementia underwent a neuropsychological assessment, including tests of global cognitive performance, frontal executive function, verbal fluency, and memory. SMC were associated with a number of specific objective cognitive deficits including poor verbal fluency, and poor immediate and delayed recall. However, there was a limited association with global cognitive impairment despite a strong influence upon Pfeffer …Functional Activities Questionnaire based daily function. In the full sample the strongest predictors of SMC were poor psychological well-being, depressive symptoms (including those taking antidepressants) and hearing impairment. Moderate predictors were age and gender. If individuals with mild cognitive impairment (MCI) were removed, then the strongest predictors were poor psychological well-being, depressive symptoms, hearing impairment, illiteracy, age, and gender. For those with MCI alone, the only significant predictor of memory complaints was poor psychological well-being. Predictors of SMC in those with depressive symptoms included poor psychological well-being and hearing impairment. With depressive symptoms excluded the strongest predictors were poor psychological well-being, hearing impairment, illiteracy, and gender. In this population-based sample, individuals with SMC had evidence of impairments on specific neuropsychological testing which might not be apparent on global measures. Predictors of SMC may differ in those with versus without MCI and those with versus without depressive symptoms. Show more

Keywords: Cognitive function, elderly, epidemiology, subjective memory complaints

DOI: 10.3233/JAD-2010-100972

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 159-170, 2010

Authors: Westman, Eric | Wahlund, Lars-Olof | Foy, Catherine | Poppe, Michaella | Cooper, Allison | Murphy, Declan | Spenger, Christian | Lovestone, Simon | Simmons, Andrew

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly, and early detection is of great importance if new therapies are to be effectively administered. We have used multivariate data analysis (orthogonal partial least squares to latent structures (OPLS) analysis) to investigate whether the discrimination between AD and elderly healthy control subjects can be improved by adding magnetic resonance spectroscopy (MRS) measures to magnetic resonance imaging (MRI). In this study, 30 AD patients and 36 control subjects were included (mean (SD) age=77(5) and 77(5) years, MMSE=23(4) and 29(1) respectively). High resolution T1-weighted axial magnetic resonance images were obtained …from each subject. Automated regional volume segmentation and cortical thickness measures were determined for the images. 1 H MRS was acquired from the hippocampus and LCModel was used for metabolite quantification. Altogether, this yielded 54 different volumetric, cortical thickness and metabolite ratio variables which were used for multivariate analysis. All analyses were performed using seven-fold-cross-validation. Combining MRI and MRS measures resulted in a sensitivity of 97% and a specificity of 94% compared to using MRI or MRS measures alone (sensitivity: 93%, 76%, specificity: 86%, 83% respectively). Adding the MRS measures to the MRI measures more than doubled the positive likelihood ratio from 7 to 17. Adding MRS measures to a multivariate analysis of MRI measures resulted in significantly better classification than using MRI measures alone. The OPLS method shows strong potential for discriminating between Alzheimer's disease and controls. Show more

Keywords: AD, MRI, MRS, multivariate analysis, OPLS

DOI: 10.3233/JAD-2010-100168

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 171-181, 2010

Authors: Bajo, Ricardo | Maestú, Fernando | Nevado, Angel | Sancho, Miguel | Gutiérrez, Ricardo | Campo, Pablo | Castellanos, Nazareth P. | Gil, Pedro | Moratti, Stephan | Pereda, Ernesto | del-Pozo, Francisco

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) has been considered an intermediate state between healthy aging and dementia. The early damage in anatomical connectivity and progressive loss of synapses that characterize early Alzheimer's disease suggest that MCI could also be a disconnection syndrome. Here, we compare the degree of synchronization of brain signals recorded with magnetoencephalography from patients (22) with MCI with that of healthy controls (19) during a memory task. Synchronization Likelihood, an index based on the theory of nonlinear dynamical systems, was used to measure functional connectivity. During the memory task patients showed higher interhemispheric synchronization than healthy controls between left …and right -anterior temporo-frontal regions (in all studied frequency bands) and in posterior regions in the γ band. On the other hand, the connectivity pattern from healthy controls indicated two clusters of higher synchronization, one among left temporal sensors and another one among central channels. Both of them were found in all frequency bands. In the γ band, controls showed higher Synchronization Likelihood values than MCI patients between central-posterior and frontal-posterior channels and a high synchronization in posterior regions. The inter-hemispheric increased synchronization values could reflect a compensatory mechanism for the lack of efficiency of the memory networks in MCI patients. Therefore, these connectivity profiles support only partially the idea of MCI as a disconnection syndrome, as patients showed increased long distance inter-hemispheric connections but a decrease in antero-posterior functional connectivity. Show more

Keywords: Disconnection syndrome, functional connectivity, magnetoencephalography, memory, mild cognitive impairment, synchronization likelihood

DOI: 10.3233/JAD-2010-100177

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 183-193, 2010

Authors: Borroni, Barbara | Malinverno, Matteo | Gardoni, Fabrizio | Grassi, Mario | Parnetti, Lucilla | Agosti, Chiara | Alberici, Antonella | Premi, Enrico | Bonuccelli, Ubaldo | Gasparotti, Roberto | Calabresi, Paolo | Di Luca, Monica | Padovani, Alessandro

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) tau ratio decrease (33kDa/55kDa forms) and mid-saggital midbrain-to-pons (MP) atrophy have been suggested as diagnostic markers for progressive supranuclear palsy (PSP). The usefulness of their combined evaluation has never been tested. We evaluated the CSF tau ratio and the MP atrophy as a combined marker for early identification of PSP. A total of 87 subjects, namely 18 PSP, 25 controls (CON), 16 corticobasal syndrome (CBS), and 28 frontotemporal dementia (FTD), were included. Each subject underwent a lumbar puncture and a conventional MRI scan to assess CSF tau 33 kDa/55 kDa ratio and mid-saggital MP measure, respectively. CSF …tau ratio and MP ratio were significantly reduced in PSP patients when compared to CON, CBS, and FTD (p< 0.001). Data-based “optimal” combination of CSF tau ratio and MP measure was defined, and the combined marker TrMp = CSF Tau ratio 3 × MP ratio was considered. Considering the combined marker, the difference between the area under the curve (dAUC) of the receiver operating characteristic analysis in PSP versus the various subgroups was higher by about 10% than that obtained by each marker individually. In PSP versus others, a proposed “best” cut-off of TrMP = 0.182 resulted in 94.2% sensitivity and 84.0% specificity. When patients with onset of symptoms ⩽ 2 years were included, TrMP resulted significantly decreased in PSP compared to CBS (p< 0.001) and FTD (p< 0.001). The combined marker increases the discriminative power in identifying PSP and suggests that the interplay of different markers should be considered in future trials to enhance diagnostic accuracy from the early stages. Show more

Keywords: Biological marker, cerebrospinal fluid, corticobasal syndrome, frontotemporal dementia, MRI, progressive supranuclear palsy, tau

DOI: 10.3233/JAD-2010-100333

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 195-203, 2010

Authors: Dangour, Alan D. | Whitehouse, Peter J. | Rafferty, Kevin | Mitchell, Stephen A. | Smith, Lesley | Hawkesworth, Sophie | Vellas, Bruno

Article Type: Research Article

Abstract: The increasing worldwide prevalence of dementia is a major public health concern. Findings from some epidemiological studies suggest that diet and nutrition may be important modifiable risk factors for development of dementia. In order to evaluate the strength of the available evidence of an association of dietary factors with dementia including Alzheimer's disease (AD), we systematically searched relevant publication databases and hand-searched bibliographies up to end July 2007. We included prospective cohort studies which evaluated the association of nutrient levels with the risk of developing dementia and randomized intervention studies examining the treatment effect of nutrient supplementation on cognitive function. …One hundred and sixty studies, comprising ninety one prospective cohort studies and sixty nine intervention studies, met the pre-specified inclusion criteria. Of these, thirty-three studies (19 cohort and 14 randomized controlled trials) investigated the effects of folate, B-vitamins, and levels of homocysteine (a biomarker modifiable through B-vitamin supplementation) or fish/fatty acids and are the focus of the present report. Some observational cohort studies indicated that higher dietary intake or elevated serum levels of folate and fish/fatty acids and low serum levels of homocysteine were associated with a reduced risk of incident AD and dementia, while other studies reported no association. The results of intervention studies examining the effects of folic acid or fatty acid supplementation on cognitive function are inconsistent. In summary, the available evidence is insufficient to draw definitive conclusions on the association of B vitamins and fatty acids with cognitive decline or dementia, and further long-term trials are required. Show more

Keywords: Alzheimer's disease, dementia, fatty acids, folate, nutrition, B-group vitamins

DOI: 10.3233/JAD-2010-090940

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 205-224, 2010

Authors: Yang, Jiajia | Ogasa, Takashi | Ohta, Yasuyuki | Abe, Koji | Wu, Jinglong

Article Type: Research Article

Abstract: There is a need to differentiate between patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) from normal-aged controls (NC) in the field of clinical drug discovery. In this study, we developed a tactile angle discrimination system and examined whether the ability to discriminate tactile angle differed between patients with MCI and AD and the NC group. Thirty-seven subjects were divided into three groups: NC individuals (n=14); MCI patients (n=10); and probable AD patients (n=13). All subjects were asked to differentiate the relative sizes of the reference angle (60°) and one of eight comparison angles by passive touch. The …accuracy of angle discrimination was measured and the discrimination threshold was calculated. We discovered that there were significant differences in the angle discrimination thresholds of AD patients compared to the NC group. Interestingly, we also found that ability to discriminate tactile angle of MCI patients were significantly lower than that of the NC group. This is the first study to report that patients with MCI and AD have substantial performance deficits in tactile angle discrimination compared to the NC individuals. This finding may provide a monitor and therapeutic approach in AD diagnosis and treatment. Show more

Keywords: Alzheimer's disease, cognitive function deficit, mild cognitive impairment, tactile angle discrimination, working memory

DOI: 10.3233/JAD-2010-100723

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 225-234, 2010

Authors: Lu, Qun | Ding, Kai | Frosch, Matthew P. | Jones, Shiloh | Wolfe, Michael | Xia, Weiming | Lanford, George W.

Article Type: Research Article

Abstract: Presenilin mutations are linked to the early onset familial Alzheimer's disease (FAD) and lead to a range of neuronal changes, indicating that presenilins interact with multiple cellular pathways to regulate neuronal functions. In this report, we demonstrate the effects of FAD-linked presenilin 1 mutation (PS1M146L) on the expression and distribution of filamin, an actin cross-linking protein that interacts with PS1 both physically and genetically. By using immunohistochemical methods, we evaluated hippocampal dentate gyrus for alterations of proteins involved in synaptic plasticity. Among many proteins expressed in the hippocampus, calretinin, glutamic acid decarboxylase (GAD67), parvalbumin, and filamin displayed distinct changes in …their expression and/or distribution patterns. Striking anti-filamin immunoreactivity was associated with the polymorphic cells of hilar region only in transgenic mice expressing PS1M146L. In over 20% of the PS1M146L mice, the hippocampus of the left hemisphere displayed more pronounced upregulation of filamin than that of the right hemisphere. Anti-filamin labeled the hilar neurons only after the PS1M146L mice reached after four months of age. Double labeling immunohistochemical analyses showed that anti-filamin labeled neurons partially overlapped with cholecystokinin (CCK), somatostatin, GAD67, parvalbumin, and calretinin immunoreactive neurons. In cultured HEK293 cells, PS1 overexpression resulted in filamin redistribution from near cell peripheries to cytoplasm. Treatment of CHO cells stably expressing PS1 with WPE-III-31C or DAPT, selective γ-secretase inhibitors, did not suppress the effects of PS1 overexpression on filamin. These studies support a γ-secretase-independent role of PS1 in modulation of filamin-mediated actin cytoskeleton. Show more

Keywords: Actin, dentate gyrus, filamin, hilar neurons, presenilin mutation, γ-secretase

DOI: 10.3233/JAD-2010-100585

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 235-245, 2010