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

Authors: Frost, Shaun | Martins, Ralph N. | Kanagasingam, Yogesan

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia and is clinically characterized by a progressive decline in memory, learning, and executive functions, and neuropathologically characterized by the presence of cerebral amyloid deposits. Despite a century of research, there is still no cure or conclusive premortem diagnosis for the disease. A number of symptom-modifying drugs for AD have been developed, but their efficacy is minimal and short-lived. AD cognitive symptoms arise only after significant, irreversible neural deterioration has occurred; hence there is an urgent need to detect AD early, before the onset of cognitive symptoms. An accurate, early diagnostic …test for AD would enable current and future treatments to be more effective, as well as contribute to the development of new treatments. While most AD related pathology occurs in the brain, the disease has also been reported to affect the eye, which is more accessible for imaging than the brain. AD-related proteins exist in the normal human eye and may produce ocular pathology in AD. There is some homology between the retinal and cerebral vasculatures and the retina also contains nerve cells and fibers that form a sensory extension of the brain. The eye is the only place in the body where vasculature or neural tissue is available for non-invasive optical imaging. This article presents a review of current literature on ocular morphology in AD and discusses the potential for an ocular-based screening test for AD. Show more

Keywords: Aging, amyloid-β protein, cataract, diagnosis, lens, retinal, vision disorders

DOI: 10.3233/JAD-2010-100819

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 1-16, 2010

Authors: Salmina, Alla B. | Inzhutova, Alyona I. | Malinovskaya, Natalia A. | Petrova, Marina M.

Article Type: Review Article

Abstract: Current theories state that Alzheimer's disease (AD) is a vascular disorder that initiates its pathology through cerebral microvascular abnormalities. Endothelial dysfunction caused by the injury or death of endothelial cells contributes to progression of AD. Also, functional relationships between neurons, glial cells, and vascular cells within so-called neurovascular unit are dramatically compromised in AD. Several recent studies have highlighted that endothelial cells might be the target for the toxic action of heavily aggregated proteins, glia-derived cytokines, and stimuli inducing oxidative and metabolic stress in AD brains. Here, we describe the properties of the brain endothelium that contribute to its specific …functions in the central nervous system, and how endothelial-neuronal-glial cell interactions are compromised in the pathogenesis of AD. We also discuss the ways in which functioning of endothelial cells can be modulated in cerebral microvessels. Understanding of molecular mechanisms of endothelial injury and repair in AD would give us novel diagnostic biomarkers and pharmacological targets. Show more

Keywords: Alzheimer's disease, blood-brain barrier, endothelial dysfunction, endothelial-glial interactions

DOI: 10.3233/JAD-2010-091690

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 17-36, 2010

Authors: van der Steen, Jenny T.

Article Type: Review Article

Abstract: Death with dementia is increasingly common. Although prognostication is difficult, it is an incurable life-limiting illness for which palliative care for the patient is often appropriate. Dementia patients are otherwise at risk of overtreatment with burdensome and possibly non-beneficial interventions and undertreatment of symptoms. Although recent studies indicate encouraging trends of improved palliative care, little evidence supports effectiveness of specific treatments. As of January 2010, at least 45 studies, almost all performed after 2000, have reported on treatment, comfort, symptom burden, and families' satisfaction with care. Over half (25; 56%) of these studies were in US settings, and most were …small or retrospective. Few randomized trials and prospective observational studies have been performed so far, but several promising studies have been completed recently or are underway in various countries. Guidelines for care and treatment, still mostly consensus-based, support the benefits of advance care planning, continuity of care, and family and practitioner education. Assessment tools for pain, prognosis, and family evaluations of care have been developed and some have been shown to be effective in clinical practice. With increasing numbers of well-designed, large-scale studies, research in the next decade may result in better evidence-based guidelines and practice. Show more

Keywords: Dementia, hospice care, intervention studies, palliative care, prospective studies, retrospective studies, terminal care

DOI: 10.3233/JAD-2010-100744

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 37-55, 2010

Authors: Bredesen, Dale E. | John, Varghese | Galvan, Veronica

Article Type: Review Article

Abstract: Reports from multiple laboratories have now been published analyzing the critical nature of the caspase cleavage site of amyloid-β protein precursor (AβPP) for cell death induction, synaptic loss, hippocampal atrophy, long-term potentiation, memory loss, neophobia, and other aspects of the Alzheimer's phenotype. Here we review the results and implications of these studies for the understanding of Alzheimer's disease pathophysiology and the potential development of therapeutics that target this site in AβPP.

Keywords: Alzheimer's disease, amyloid-β peptide caspases, transgenic mouse

DOI: 10.3233/JAD-2010-100537

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 57-63, 2010

Authors: Walton, J.R.

Article Type: Short Communication

Abstract: This study examines hippocampal CA1 cells from brains of aged humans, with and without Alzheimer's disease, for hyperphosphorylated tau and aluminum during early neurofibrillary tangle (NFT) formation and growth. A very small proportion of hippocampal pyramidal cells contain cytoplasmic pools within their soma that either appear homogeneous or contain short filaments (i.e., early NFTs). The cytoplasmic pools are aggregates of an aluminum/hyperphosphorylated tau complex similar to that found in mature NFTs. The photographic evidence presented combines with existing evidence to support a role for aluminum in the formation and growth of NFTs in neurons of humans with Alzheimer's disease.

Keywords: aluminium, Alzheimer's disease, hyperphosphorylated tau, neurofibrillary tangles

DOI: 10.3233/JAD-2010-100486

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 65-72, 2010

Authors: Kim, Hye Yun | Kim, YoungSoo | Han, Gyoonhee | Kim, Dong Jin

Article Type: Research Article

Abstract: It is well known that the transient and prolonged misfolding nature of amyloid-β (Aβ) makes it difficult to perform proper in vitro studies and obtain consistent results. From monomers to fibrils, the aggregated forms of Aβ are significant hallmarks in the Alzheimer's disease (AD) cascade and become the valuable targets for early diagnosis and therapy for AD. Thus, development of optimized in vitro fibrillogenic conditions to induce the desired Aβ states is essential to AD research. In this study, fifteen organic amino acid compounds (glycine, taurine, tramiprosate, and their derivatives) were employed to induce different fibrillogenic conditions for Aβ. The …fibrillogenic patterns of Aβ peptides in these compounds were analyzed by thioflavin T assay and SDS-PAGE with photoinduced cross-linking of unmodified proteins protocols, then were analyzed and compared to those obtained via transmission electron microscopy and neuronal cell viability assays. Our study suggests various compounds capable of inducing different levels of in vitro Aβ1-40 fibrillogenesis, potentially useful tools in the study of Aβ for AD. Show more

Keywords: Alzheimer's disease, amyloid-β, fibril, fibrillogenesis, monomer, oligomer, protofibril

DOI: 10.3233/JAD-2010-100183

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 73-85, 2010

Authors: Reesink, Fransje E. | Lemstra, Afina W. | van Dijk, Karin D. | Berendse, Henk W. | van de Berg, Wilma D.J. | Klein, Martin | Blankenstein, Marinus A. | Scheltens, Philip | Verbeek, Marcel M. | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: In this study, we assessed whether cerebrospinal fluid (CSF) levels of the biomarker α-synuclein have a diagnostic value in differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We also analyzed associations between CSF biomarkers and cognitive performance in DLB and in AD. We included 35 DLB patients, 63 AD patients, 18 patients with Parkinson's disease (PD), and 34 patients with subjective complaints (SC). Neuropsychological performance was measured by means of the Mini-Mental Status Examination (MMSE), Visual Association Test (VAT), VAT object-naming, Trail Making Test, and category fluency. In CSF, levels of α-synuclein, amyloid-β 1-42 (Aβ1-42 ), …total tau (tau), and tau phosphorylated at threonine 181 (ptau-181) were measured. CSF α-synuclein levels did not differentiate between diagnostic groups (p=0.16). Higher ptau-181 and higher tau levels differentiated AD from DLB patients (p< 0.05). In DLB patients, lower Aβ1-42 and higher total tau levels were found than in SC and PD patients (p< 0.05). In DLB patients, linear regression analyses of CSF biomarkers showed that lower α-synuclein was related to lower MMSE-scores (β (SE) = 6(2) and p< 0.05) and fluency (β (SE) = 4(2), p< 0.05). Ultimately, CSF α-synuclein was not a useful diagnostic biomarker to differentiate DLB and/or PD (α-synucleinopathies) from AD or SC. In DLB patients maybe lower CSF α-synuclein levels are related to worse cognitive performance. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, dementia with Lewy bodies, diagnosis, α-synuclein

DOI: 10.3233/JAD-2010-100186

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 87-95, 2010

Authors: Hong, Hyun-Seok | Hwang, Ji-Yeon | Son, Sung-Min | Kim, Yoon-Hee | Moon, Minho | Mook-Jung, Inhee

Article Type: Research Article

Abstract: Deposition of amyloid-β peptide (Aβ) and neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD), a neurodegenerative disease characterized by cognitive deficits and neuronal loss. Recently, calcineurin (CaN) has been reported as a potential modulator of memory function, synaptic plasticity, and neural degeneration in brains of AD animal models. In the present study, we examined the relationship between Aβ accumulations and CaN activity in brains of the AβPP/PS1 double transgenic mice. Treatment with FK506, a CaN inhibitor, significantly reduces Aβ burden and restores synaptic proteins (synaptophysin and postsynaptic density protein-95; PSD-95) while inducing matrix metallopeptidase-9 (MMP-9) expression in GFAP-positive astrocytes …in the brain. These results suggest a role of FK506 and control of CaN activity in neuroprotection associated with Aβ deposition in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, AβPP/PS1 double transgenic mouse, calcineurin, FK506, MMP-9

DOI: 10.3233/JAD-2010-100261

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 97-105, 2010

Authors: Yang, Shi-Gao | Zhang, Xi | Sun, Xiao-Sia | Ling, Tie-Jun | Feng, Ying | Du, Xue-Ying | Zhao, Min | Yang, Yang | Xue, Di | Wang, Li | Liu, Rui-Tian

Article Type: Research Article

Abstract: Amyloid-β (Aβ) plays a pivotal role in Alzheimer's disease (AD) pathogenesis and in toxic mechanisms such as oxidative stress, mitochondrial dysfunction, calcium turbulence, and apoptosis induction. Therefore, interfering with Aβ aggregation has long been one of the most promising strategies for AD treatment. Ecdysterones (ECRs) are steroidal hormones in insects and terrestrial plants that have high structural diversity and multiple beneficial pharmacological activities. Here, we studied the effects of six ECRs on Aβ aggregation and cytotoxicity. Two ECRs with an acetoxyl group at the 2 or 3 position and saturated chains as side groups showed apparent promotion of Aβ42 …fibrilization, resulting in less Aβ42 oligomers in the samples. Another three with unsaturated side chains clearly inhibited Aβ aggregation and disaggregated preformed fibrils, but increased the Aβ42 oligomer levels. Nevertheless, our MTT results showed that all ECRs tested inhibited Aβ42 -induced cytotoxicity. This protective activity may be partly attributable to ECR-mediated amelioration of Aβ42 -induced release of reactive oxygen species. Taken together, our findings suggest that ECRs, a series of natural compounds in many plants and insects, have therapeutic potential in AD and that the deduced structure-activity relationships may be beneficial in drug design for the treatment of AD and other amyloidoses. Show more

Keywords: Aggregation, Alzheimer's disease, amyloid-β, ecdysterone, Klaseopsis chinensis, neurotoxicity

DOI: 10.3233/JAD-2010-100621

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 107-117, 2010

Authors: Steinacker, Petra | Klafki, Hans | Lehnert, Stefan | Jesse, Sarah | v. Arnim, Christine A.F. | Tumani, Hayrettin | Pabst, Alice | Kretzschmar, Hans A. | Wiltfang, Jens | Otto, Markus

Article Type: Research Article

Abstract: The clinical diagnosis of Creutzfeldt-Jakob disease (CJD) can be supported by several biochemical markers in cerebrospinal fluid (CSF) such as 14-3-3 proteins and tau protein. Unfortunately, none of the currently known markers are suited for screening or seems to be directly related to the pathophysiological process. A marker fulfilling these criteria might facilitate the early detection and might also serve in monitoring drug efficacy. Recently, the extracellular signal-regulated kinase ERK1/2 was detected in CSF of patients with neuropsychiatric disorders. Furthermore, ERK1/2 was reported to be activated in brains of animals infected with pathological prion protein. Therefore, we investigated CSF of …19 patients with CJD, 23 patients with other dementias including patients with Alzheimer's disease, and 12 patients with other neurological disorders. The measurement of ERK1/2 in the CSF samples was performed with an electrochemiluminescence assay and Western immunoblot. ERK1/2 and doubly phosphorylated ERK1/2 (pERK1/2) were detected in all patient groups. Significantly elevated mean levels of total ERK1/2 and pERK1/2 were found in the CJD patients. This increase was also observed in a CJD case that was negative for 14-3-3 protein or in CJD cases that had low levels of tau protein. Western immunoblot analysis suggested that ERK2 was the predominant form of ERKs present in our CSF samples. This pilot study suggests that ERK1/2 is a potential CSF biomarker for CJD, directly associated with the pathophysiological processes. Analysis of larger sample cohorts including other diseases with rapid neurodegeneration are required to confirm our findings. Show more

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, Creutzfeldt-Jakob disease, duplex electrochemiluminescence assay, extracellular signal-regulated kinase ERK1/2

DOI: 10.3233/JAD-2010-100030

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 119-128, 2010

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

Authors: Lambert, Jean-Charles | Sleegers, Kristel | González-Pérez, Antonio | Ingelsson, Martin | Beecham, Gary W. | Hiltunen, Mikko | Combarros, Onofre | Bullido, Maria J. | Brouwers, Nathalie | Bettens, Karolien | Berr, Claudine | Pasquier, Florence | Richard, Florence | DeKosky, Steven T. | Hannequin, Didier | Haines, Jonathan L. | Tognoni, Gloria | Fiévet, Nathalie | Dartigues, Jean-François | Tzourio, Christophe | Engelborghs, Sebastiaan | Arosio, Beatrice | Coto, Elicer | De Deyn, Peter | Del Zompo, Maria | Mateo, Ignacio | Boada, Merce | Antunez, Carmen | Lopez-Arrieta, Jesus | Epelbaum, Jacques | Schjeide, Brit-Maren Michaud | Frank-Garcia, Ana | Giedraitis, Vilmentas | Helisalmi, Seppo | Porcellini, Elisa | Pilotto, Alberto | Forti, Paola | Ferri, Raffaele | Delepine, Marc | Zelenika, Diana | Lathrop, Mark | Scarpini, Elio | Siciliano, Gabriele | Solfrizzi, Vincenzo | Sorbi, Sandro | Spalletta, Gianfranco | Ravaglia, Giovanni | Valdivieso, Fernando | Vepsäläinen, Saila | Alvarez, Victoria | Bosco, Paolo | Mancuso, Michelangelo | Panza, Francesco | Nacmias, Benedetta | Bossù, Paola | Hanon, Olivier | Piccardi, Paola | Annoni, Giorgio | Mann, David | Marambaud, Philippe | Seripa, Davide | Galimberti, Daniela | Tanzi, Rudolph E | Bertram, Lars | Lendon, Corinne | Lannfelt, Lars | Licastro, Federico | Campion, Dominique | Pericak-Vance, Margaret A. | Soininen, Hilkka | Van Broeckhoven, Christine | Alpérovitch, Annick | Ruiz, Agustin | Kamboh, M. Ilyas | Amouyel, Philippe

Article Type: Research Article

Abstract: The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant …of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene. Show more

Keywords: Age at onset, Alzheimer's disease, apolipoprotein E, CALHM1, polymorphism

DOI: 10.3233/JAD-2010-100933

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 247-255, 2010

Authors: Yu, Cun-Jing | Zheng, Mao-Fa | Kuang, Chun-Xiang | Huang, Wei-Da | Yang, Qing

Article Type: Research Article

Abstract: A well-known traditional Chinese medicinal prescription, Oren-gedoku-to (OGT), has been used in clinical therapies for many types of dementia in China and Japan. Additionally, it ameliorates the age-related deterioration of learning and memory in an Alzheimer's disease (AD) rat model. Indoleamine 2, 3-dioxygenase (IDO-1) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism, which ultimately leads to the production of the excitotoxin quinolinic acid (QUIN). IDO-1 has recently been established as one of the key players involved in the pathogenesis of AD. OGT is indicated to prevent cholinergic dysfunction and reduce oxidative stress; however, the exact …mechanism underlying its ability to improve cognitive ability remains elusive. Here we present a novel mechanism of OGT's therapeutic potential in AD. We demonstrated that OGT significantly inhibited recombinant human IDO-1 (rhIDO-1) activity in vitro, and its four main constituents (i.e., berberine, palmatine, jatrorrhizine, and baicalein) were potent IDO-1 inhibitors. IC50 values, obtained from a cell-based assay, of HEK 293 cells and an enzymatic assay were much lower than the most commonly used IDO-1 inhibitor, 1-methyl tryptophan (1-MT). Berberine was the best inhibitor and had IC50 values of 7 μM (cell-based assay) and 9.3 μM (enzymatic assay). Jatrorrhizine and palmatine exhibited irreversible inhibition of rhIDO-1, whereas berberine and baicalein behaved as uncompetitive, reversible inhibitors with Ki values of 8 μM and 215 μM, respectively. In conclusion, constituents of OGT show strong IDO-1 inhibitory activity and may have significant therapeutic potential for AD. Show more

Keywords: Alzheimer's disease, constituent, Indoleamine 2, 3-dioxygenase, Indoleamine 2, 3-dioxygenase inhibitor, Oren-gedoku-to

DOI: 10.3233/JAD-2010-100684

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 257-266, 2010

Authors: Saur, Ralf | Milian, Monika | Erb, Michael | Eschweiler, Gerhard W. | Grodd, Wolfgang | Leyhe, Thomas

Article Type: Research Article

Abstract: In patients with Alzheimer's disease (AD), neuroimaging studies have demonstrated decreased brain activation, while increased activation was detected in patients with mild cognitive impairment (MCI). It can be hypothesized that increased cerebral activity seen in patients with MCI reflects neural compensation at the beginning of neurodegenerative processes. Later, as patients develop AD, neural integrity is increasingly impaired. This is accompanied by decreased neural activation. In this study we examined cognitive performance and functional magnetic resonance imaging activation on a Clock Reading task (CRT) and a Spatial Control task (SCT) in healthy controls, patients with MCI, and patients with early AD. …Correlations between neural-functional activation and cognitive state, measured by the Mini Mental Status Examination, were determined using rank, linear and quadratic correlation models. It could be shown that CRT, in comparison to SCT, specifically activates brain regions in the ventral visual stream and precuneus known to be involved in conceptual processing and spatial imagery. The correlation between brain activity and cognitive state followed a quadratic rather than a linear pattern in several brain regions, including the lingual gyrus, cuneus, and precuneus. The strongest brain activity was found in patients with MCI and less severely impaired early AD subjects. These findings support the hypothesis that patients in early stages of dementia compensate for neuronal loss by the recruitment of additional neural resources reflected by increased neural activation, as measured by the blood oxygen level-dependent signal. Show more

Keywords: Alzheimer's disease, clock test, correlation analysis, functional magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2010-091390

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 267-284, 2010

Authors: Sarazin, Marie | Chauviré, Valérie | Gerardin, Emilie | Colliot, Olivier | Kinkingnéhun, Serge | de Souza, Leonardo Cruz | Hugonot-Diener, Laurence | Garnero, Line | Lehéricy, Stéphane | Chupin, Marie | Dubois, Bruno

Article Type: Research Article

Abstract: The Free and Cued Selective Reminding Test (FCSRT) is a verbal episodic memory test used to identify patients with mild Alzheimer's disease (AD). The present study investigates the relationships between performance on FCSRT and grey matter atrophy assessed with structural MRI in patients with AD. Three complementary MRI-based analyses (VBM analysis, ROI-based analysis, and three-dimensional hippocampal surface-based shape analysis) were performed in 35 patients with AD to analyze correlations between regional atrophy and their scores for episodic memory using the FCSRT. With VBM analysis, the total score on the FCSRT was correlated with left medial temporal lobe atrophy including the …left hippocampus but also the thalami. In addition, using ROI-based analysis, the total recall score on the FCSRT was correlated with the left hippocampal volume. With three-dimensional hippocampal surface-based shape analysis, both free recall and total recall scores were correlated with regions corresponding approximately to the CA1 field. No correlation was found with short term memory scores using any of these methods of analysis. In AD, the FCSRT may be considered as a useful clinical marker of memory disorders due to medial temporal damage, specially the CA1 field of the hippocampus. Show more

Keywords: Alzheimer's disease, assessment of cognitive disorders/dementia, cognitive neuropsychology in dementia, memory, MRI

DOI: 10.3233/JAD-2010-091150

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 285-294, 2010

Authors: Yoshiyama, Yasumasa | Kojima, Ayako | Ishikawa, Chieko | Arai, Kimihito

Article Type: Research Article

Abstract: Acetylcholinesterase inhibitors (AChEIs) are widely used to compensate for acetylcholine (ACh) depletion in the Alzheimer's disease (AD) brain. Some clinical and experimental studies, however, have suggested that AChEIs also provide neuroprotection. To assess the effect of AChEIs on neurodegeneration, donepezil (DZ), an AChEI, was administered to FTDP-17 model mice with a P301S tau mutation (line PS19). Eight months of DZ treatment resulted in amelioration of neuroinflammation, tau pathology, synaptic loss, and neuronal loss, as well as decreased tau insolubility and phosphorylation. Tau kinase activity analysis demonstrated significantly suppressed c-Jun N-terminal kinase (JNK) in the brains of DZ-treated PS19 mice. Recently, …ACh has been shown to suppress inflammation, which plays a role in neurodegeneration. To confirm the anti-inflammatory effect of DZ, PS19 mice were injected with lipopolysaccharide, in combination with or without DZ, for one month. Results demonstrated that DZ suppressed IL-1β and COX-2 expression in the brain, as well as the spleen, suggesting that DZ directly prevents systemic inflammation. These data indicated that ACh did not act just as a cognition-linking neurotransmitter, but might suppress pathological mechanisms of neurodegeneration via anti-inflammatory action. Show more

Keywords: Acetylcholine, donepezil, neurodegeneration, neuroinflammation, tau

DOI: 10.3233/JAD-2010-100681

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 295-306, 2010

Authors: Valla, Jon | Yaari, Roy | Wolf, Andrew B. | Kusne, Yael | Beach, Thomas G. | Roher, Alex E. | Corneveaux, Jason J. | Huentelman, Matthew J. | Caselli, Richard J. | Reiman, Eric M.

Article Type: Research Article

Abstract: In vivo PET imaging studies of young-adult carriers of the apolipoprotein E ε4 allele (APOEε4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEε4. At-risk ε4 carriers had …lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old ε4 homozygote, the ε4 carriers did not have increased soluble amyloid-β, histologic amyloid-β, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology. Show more

Keywords: Alzheimer's etiology, bioenergetics, biomarkers, cytochrome c oxidase, differential vulnerability, neocortex

DOI: 10.3233/JAD-2010-100129

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 307-313, 2010

Authors: Haller, Sven | Nguyen, Duy | Rodriguez, Cristelle | Emch, Joan | Gold, Gabriel | Bartsch, Andreas | Lovblad, Karl O. | Giannakopoulos, Panteleimon

Article Type: Research Article

Abstract: Although cross-sectional diffusion tensor imaging (DTI) studies revealed significant white matter changes in mild cognitive impairment (MCI), the utility of this technique in predicting further cognitive decline is debated. Thirty-five healthy controls (HC) and 67 MCI subjects with DTI baseline data were neuropsychologically assessed at one year. Among them, there were 40 stable (sMCI; 9 single domain amnestic, 7 single domain frontal, 24 multiple domain) and 27 were progressive (pMCI; 7 single domain amnestic, 4 single domain frontal, 16 multiple domain). Fractional anisotropy (FA) and longitudinal, radial, and mean diffusivity were measured using Tract-Based Spatial Statistics. Statistics included group comparisons …and individual classification of MCI cases using support vector machines (SVM). FA was significantly higher in HC compared to MCI in a distributed network including the ventral part of the corpus callosum, right temporal and frontal pathways. There were no significant group-level differences between sMCI versus pMCI or between MCI subtypes after correction for multiple comparisons. However, SVM analysis allowed for an individual classification with accuracies up to 91.4% (HC versus MCI) and 98.4% (sMCI versus pMCI). When considering the MCI subgroups separately, the minimum SVM classification accuracy for stable versus progressive cognitive decline was 97.5% in the multiple domain MCI group. SVM analysis of DTI data provided highly accurate individual classification of stable versus progressive MCI regardless of MCI subtype, indicating that this method may become an easily applicable tool for early individual detection of MCI subjects evolving to dementia. Show more

Keywords: Diffusion tensor imaging, fractional anisotrophy, mild cognitive impairment, support vector machines, Tract-Based Spatial Statistics

DOI: 10.3233/JAD-2010-100840

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 315-327, 2010

Authors: Cao, Ying | Xiao, Yan | Ravid, Rivka | Guan, Zhi-Zhong

Article Type: Research Article

Abstract: In the study, the expression of clathrin regulatory proteins dynamin I, AP180, and synaptic vesicle protein synaptophysin in multiple brain regions of the patients with Alzheimer's disease (AD), the transgenic mice carrying the Swedish mutation of amyloid-β protein precursor (AβPP) 670/671 (AβPPSWE ), and the rats injected by bilateral hippocampus with amyloid-β peptide (Aβ)1-42 were examined by immunohistochemistry and Nissl staining, Western blotting, and Real-time PCR, respectively. Spatial learning and memory of the rats were evaluated by Morris Water Maze test, and the ability of endocytosis in the cultured rat hippocampal neurons was detected by FM1-43 fluorescence imaging. Significant …decreases in protein levels of dynamin I, AP180, and synaptophysin were observed in both AD patients and mice with AβPPSWE as compared to controls. Obvious declines of dynamin I and synaptophysin at protein and mRNA levels and impaired learning and spatial memory ability were found in the rats injected with Aβ1-42 as compared to controls. In addition, deposits of Aβ localized in the hippocampus around the sites of Aβ1-42 injection and the decreased numbers of Nissl bodies in neurons were found. Moreover, the disrupted synaptic vesicle endocytosis and decreased dynamin I protein were detected in stimulated hippocampal neurons treated with Aβ1-42 . These findings imply a malfunctioning clathrin-mediated endocytosis during AD pathological processes, which might be relevant to the mechanism underlying the cognitive deficit associated with AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, AP180, clathrin regulatory proteins, dynamin I, synaptophysin

DOI: 10.3233/JAD-2010-100162

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 329-342, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-101468

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 343-344, 2010