American journal of neurodegenerative disease最新文献

To advance disease-modifying therapies, it is critical to understand the relationship between the neuropathological changes of Alzheimer's Disease (AD) and the clinical measures used in therapeutic trials. We reviewed neuropathologically proven cases of AD from the National Alzheimer's Coordinating Center (NACC) and examined correlations between neuropathological changes and clinical-trial related instruments collected as part of the Uniform Dataset (UDS). We explored the relationships between neurofibrillary tangles, neuritic plaques, and total pathology burden with immediate and delayed recall, Clinical Dementia Rating-Sum of Boxes, Functional Activity Questionnaire, Neuropsychiatric Inventory Questionnaire, and Mini-Mental State Examination scores. 169 patients in NACC database had appropriate neuropathological and clinical data. All instruments correlated highly with neuritic plaques, Braak staging, and total pathology. Correlation coefficients for the relationships were relatively modest, suggesting that the pathologic burden examined accounts for between 13 and 40% of the variance of each of the instruments assessed. We conclude that there is a strong correlation between clinical trial-related measures and neuropathology identified at autopsy in AD. The amount of variance explained by the pathology is limited and other factors, both disease- and measurement-related, contribute to the variability observed in clinical measurements.

In a collaboration involving 11 groups with research interests in cerebral amyloid angiopathy (CAA), we used a two-stage process to develop and in turn validate a new consensus protocol and scoring scheme for the assessment of CAA and associated vasculopathic abnormalities in post-mortem brain tissue. Stage one used an iterative Delphi-style survey to develop the consensus protocol. The resultant scoring scheme was tested on a series of digital images and paraffin sections that were circulated blind to a number of scorers. The scoring scheme and choice of staining methods were refined by open-forum discussion. The agreed protocol scored parenchymal and meningeal CAA on a 0-3 scale, capillary CAA as present/absent and vasculopathy on 0-2 scale, in the 4 cortical lobes that were scored separately. A further assessment involving three centres was then undertaken. Neuropathologists in three centres (Bristol, Oxford and Sheffield) independently scored sections from 75 cases (25 from each centre) and high inter-rater reliability was demonstrated. Stage two used the results of the three-centre assessment to validate the protocol by investigating previously described associations between APOE genotype (previously determined), and both CAA and vasculopathy. Association of capillary CAA with or without arteriolar CAA with APOE ε4 was confirmed. However APOE ε2 was also found to be a strong risk factor for the development of CAA, not only in AD but also in elderly non-demented controls. Further validation of this protocol and scoring scheme is encouraged, to aid its wider adoption to facilitate collaborative and replication studies of CAA.

Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia (FTD), a predominantly behavioral disease, and amyotrophic lateral sclerosis (ALS), a disease of motor neurons. The primary objectives of this review are to highlight the clinical heterogeneity associated with C9ORF72 pathogenic expansion and identify potential molecular mechanisms underlying selective vulnerability of distinct neural populations. The proposed mechanisms by which C9ORF72 expansion causes behavioral and motor neuron disease highlight the emerging role of impaired RNA and protein homeostasis in a spectrum of neurodegeneration and strengthen the biological connection between FTD and ALS.

Background: In 2011 the C9ORF72 repeat expansion was identified as the most frequent genetic mutation underlying FTD and ALS. The main aim of this study was to investigate clinical characteristics in a large C9ORF72-positive FTD family, and to compare these with the neuropathological findings.

Methods: The clinical records of 12 related FTD patients were thoroughly evaluated. The five neuropathologically examined cases were revised using additional TDP-43 immuno-stainings. Four cases were screened for the C9ORF72 expansion.

Results: All 12 patients fulfilled the criteria for bvFTD. Restlessness and social neglect were often among the first reported symptoms. Psychotic symptoms were reported in 8 patients. Somatic complaints were seen in 7 cases. All the neuropathologically examined cases were TDP-43 positive.

Conclusions: The phenotype of this C9ORF72 hexanucleotide expansion carrier family was bvFTD. The clinical symptom profile was strikingly homogenous. Psychotic symptoms and somatic complaints were observed in most of the cases.

Parkinson's disease (PD) is a multifactorial movement disorder characterized by progressive neurodegeneration. Genome-wide association studies (GWAS) have nominated over fifteen distinct loci associated with risk of PD, however the biological mechanisms by which these loci influence disease risk are mostly unknown. GWAS are only the first step in the identification of disease genes: the specific causal variants responsible for the risk within the associated loci and the interactions between them must be identified to fully comprehend their impact on the development of PD. In the present study, we first attempted to replicate the association signals of 17 PD GWAS loci in our series of 1381 patients with PD and 1328 controls. BST1, SNCA, HLA-DRA, CCDC62/HIP1R and MAPT all showed a significant association with PD under different models of inheritance and LRRK2 showed a suggestive association. We then examined the role of coding LRRK2 variants in the GWAS association signal for that gene. The previously identified LRRK2 risk mutant p.M1646T and protective haplotype p.N551K-R1398H-K1423K did not explain the association signal of LRRK2 in our series. Finally, we investigated the gene-gene interaction between PARK16 and LRRK2 that has previously been proposed. We observed no interaction between PARK16 and LRRK2 GWAS variants, but did observe a non-significant trend toward interaction between PARK16 and LRRK2 variants within the protective haplotype. Identification of causal variants and the interactions between them is the crucial next step in making biological sense of the massive amount of data generated by GWAS studies. Future studies combining larger sample sizes will undoubtedly shed light on the complex molecular interplay leading to the development of PD.

Previous studies comparing early-onset Alzheimer's disease (EOAD) and late-onset AD (LOAD) have been limited by cross-sectional design and a focus on isolated clinical variables. This study aims to explore differentials in clinical features between EOAD and LOAD and to examine longitudinally trends in cognitive function. Data from 3,747 subjects with AD from C-Path Online Data Repository was used to compare demographics, body mass index (BMI), mean arterial pressure (MAP), biochemistry and cognitive assessments, including mini-mental state examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), between EOAD and LOAD. The baseline differences were examined by binominal proportion test and t-test. The trends of cognitive functions, evaluating by MMSE and ADAS-Cog, were examined by the mixed model, controlling for the effect of repeated measures of the same person. No significant difference was found in BMI and MAP. C-reactive protein, creatinine and blood urea nitrogen (BUN) (p<0.05) were significantly higher in LOAD. The APOE ε4 alleles was more likely to be found among LOAD compared to APOE ε2 or APOE ε3. EOAD had significantly lower MMSE at baseline and this difference significantly increased over time. Despite an insignificant differential in ADAS-Cog between EOAD and LOAD at baseline, the differential was enlarged gradually and became more significant with time. Our findings suggest that elevated inflammatory markers, impaired renal function and APOE ε4 alleles are overrepresented in LOAD, possibly indicating that different factors determine the development of EOAD and its more rapid cognitive deterioration.

Introduction: Aging is typically associated with impairing behavioral patterns that are frequently and inappropriately seen as normal. Circadian rhythm changes and depressive disorders have been increasingly proposed as the two main overlapping and interpenetrating changes that take place in older age. This study aims to review the state of the art on the subject concerning epidemiology, pathophysiological mechanism, clinical findings and relevance, as well as available treatment options.

Materials and methods: A nonsystematic review of all English language PubMed articles published between 1995 and December 2012 using the terms "circadian rhythms", "mood disorders", "depression", "age", "aging", "elderly" and "sleep".

Discussion and conclusion: Sleep disorders, mainly insomnia, and depression have been demonstrated to be highly co-prevalent and mutually precipitating conditions in the elderly population. There is extensive research on the pathophysiological mechanisms through which age conditions circadian disruption, being the disruption of the Melatonin system one of the main changes. However, research linking clearly and unequivocally circadian disruption and mood disorders is still lacking. Nonetheless, there are consistently described molecular changes on shared genes and also several proposed pathophysiological models linking depression and sleep disruption, with clinical studies also suggesting a bi-directional relationship between these pathologies. In spite of this suggested relation, clinical evaluation of these conditions in elderly patients consistently reveals itself rather complicated due to the frequently co-existing co-morbidities, some of them having been demonstrated to alter sleep and mood patters. This is the case of strokes, forms of dementia such as Alzheimer and Parkinson, several neurodegenerative disorders, among others. Although there are to the present no specific treatment guidelines, available treatment options generally base themselves on the premise that depression and sleep disturbances share a bidirectional relationship and so, the adoption of measures that address specifically one of the conditions will reciprocally benefit the other. Treatment options range from Cognitive Behavioral Therapy, Chronotherapy, and Light therapy, to drugs such as Melatonin/Melatonin agonists, antidepressants and sedatives.

The clinical features of the genetically determined forms of familial Parkinson's disease (PD) have been described in multiple reports, but there have been few comparative neuropathologic studies. Five familial PD cases, with mutations in SNCA, were matched for age, sex, and Alzheimer type pathology with sporadic PD cases. Immunohistochemistry for phospho-tau and α-synuclein was performed in 8 brain regions. The frequency of tau pathology and the morphologic features of α-synuclein pathology in familial PD were compared with sporadic PD using semi-quantitative methods. In familial PD, there were significantly more tau positive extra-perikaryal spheroid-like and thread-like lesions than in the sporadic PD. There was no significant difference in the amount of α-synuclein positive neuronal perikaryal pathology between familial PD and sporadic PD, but α-synuclein positive oligodendroglial and neuritic lesions were significantly greater in familial PD compared to sporadic PD. In the substantia nigra, familial PD had more marked neuronal loss and fewer residential neurons with Lewy bodies than the sporadic PD, suggesting a close relationship between the severity of neuronal loss and Lewy body formation. The results show a diversity of pathological features of genetically determined familial PD, and they draw attention to the possible role of tau protein in neurodegeneration. Moreover, the presence of oligodendroglial inclusions at the light and electron microscopic levels in familial PD suggests that PD and multiple system atrophy form a continuum of α-synuclein pathology.

Pathogenic mechanisms of Alzheimer's disease (AD) are intensely investigated as it is the most common form of dementia and burdens society by its costs and social demands. While key molecules such as A-beta peptides and tau have been identified decades ago, it is still enigmatic what drives the disease in its sporadic manifestation. Synthesis of A-beta peptides as well as phosphorylation of tau proteins comprise normal cellular functions and occur in principle in the healthy as well as in dementia-affected persons. Dyshomeostasis of Amyloid Precursor Protein (APP) cleavage, energy metabolism or kinase/phosphatase activity due to stressors has been suggested as a trigger of the disease. One way for cells to escape stress based on dysfunction of ER is the unfolded protein response - the UPR. This pathway is composed out of three different routes that differ in proteins involved, targets and consequences for cell fate: activation of transmembrane ER resident kinases IRE1-alpha and PERK or monomerization of membrane-anchored activating transcription factor 6 (ATF6) induce activation of versatile transcription factors (XBP-1, eIF2-alpha/ATF4 and ATF6 P50). These bind to specific DNA sequences on target gene promoters and on one hand attenuate general ER-prone protein synthesis and on the other equip the cell with tools to de-stress. If cells fail in stress compensation, this signaling also is able to evoke apoptosis. In this review we summarized knowledge on how APP processing and phosphorylation of tau might be influenced by ER-stress signaling. In addition, we depicted the effects UPR itself seems to have on molecules closely related to AD and describe what is known about UPR in AD animal models as well as in human patients.

The discovery of causative genetic mutations in affected family members has historically dominated our understanding of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Nevertheless, most cases of neurodegenerative disease are not explained by Mendelian inheritance of known genetic variants, but instead are thought to have a complex etiology with numerous genetic and environmental factors contributing to susceptibility. Although unbiased genome-wide association studies (GWAS) have identified novel associations to neurodegenerative diseases, most of these hits explain only modest fractions of disease heritability. In addition, despite the substantial overlap of clinical and pathologic features among major neurodegenerative diseases, surprisingly few GWAS-implicated variants appear to exhibit cross-disease association. These realities suggest limitations of the focus on individual genetic variants and create challenges for the development of diagnostic and therapeutic strategies, which traditionally target an isolated molecule or mechanistic step. Recently, GWAS of complex diseases and traits have focused less on individual susceptibility variants and instead have emphasized the biological pathways and networks revealed by genetic associations. This new paradigm draws on the hypothesis that fundamental disease processes may be influenced on a personalized basis by a combination of variants - some common and others rare, some protective and others deleterious - in key genes and pathways. Here, we review and synthesize the major pathways implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and PD. Using literature mining, we also discover a novel regulatory network that is enriched with AD- and PD-associated genes and centered on the SP1 and AP-1 (Jun/Fos) transcription factors. Overall, this pathway- and network-driven model highlights several potential shared mechanisms in AD and PD that will inform future studies of these and other neurodegenerative disorders. These insights also suggest that biomarker and treatment strategies may require simultaneous targeting of multiple components, including some specific to disease stage, in order to assess and modulate neurodegeneration. Pathways and networks will provide ideal vehicles for integrating relevant findings from GWAS and other modalities to enhance clinical translation.