American journal of neurodegenerative disease最新文献

Neurosurgical evidences show that the aging process is initiated between 25 to 30 years of age, in the arcuate nucleus of the hypothalamus. Likewise, experimental and neurosurgical findings indicate that the progressive ischemia in the arcuate nucleus and adjacent nuclei are responsibles at the onset of obesity and, type 2 diabetes mellitus in adults, and essential arterial hypertension (EAH). On the contrary, an omental transplantation on the optic chiasma, carotid bifurcation and anterior perforated space can provoke rejuvenation, gradual loss of body weight, decrease or normalization of hyperglycemia and normalization of EAH; all of them, due to revascularization of the hypothalamic nuclei. Besides, our surgical method have best advantages than the bariatric surgery, against obesity and type 2 diabetes mellitus.

Multiple systems tauopathy with presenile dementia (MSTD), a form of frontotemporal dementia with parkinsonism-17 with tau inclusions (FTDP-17T), is a neurodegenerative disorder caused by an (a) to (g) transition at position +3 of intron 10 of the microtubule associated protein tau (MAPT) gene. The mutation causes overexpression of 4 repeat (4R) tau isoforms with increased 4R/3R ratio leading to neurodegeneration. Clinically, these patients primarily present with behavioral variant FTD (bvFTD) and show disinhibition, disordered social comportment, and impaired executive function, memory, and speech. While altered glucose metabolism has been reported in subjects with sporadic bvFTD, it has yet to be investigated in an FTDP-17 sample of this size. In this study, eleven mutation carriers (5 males; mean age = 48.0 ± 6.9 years) and eight non-carriers (2 males; mean age = 43.7 ± 12.0 years) from a MSTD family were imaged using [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Eight of the MAPT intron 10 +3 mutation carriers met diagnostic criteria for bvFTD at the time of the PET scan, while three MAPT intron 10 +3 carriers were not cognitively impaired at the time of scan. Non-carriers had no clinically-relevant cognitive impairment at the time of the PET scan. Additionally, ten mutation carriers (5 males; mean age = 48.04 ± 2.1 years) and seven non-carriers (2 males; mean age 46.1 ± 4.1 years) underwent magnetic resonance imaging (MRI) which is an expanded sample size from a previous study. Seven MAPT mutation carriers met diagnostic criteria for bvFTD at the time of the MRI scan. Images were assessed on a voxel-wise basis for the effect of mutation carrier status. SPM8 was used for preprocessing and statistical analyses. Compared to non-carriers, MAPT mutation carriers showed lower [(18)F]FDG uptake bilaterally in the medial temporal lobe, and the parietal and frontal cortices. Anatomical changes were predominantly seen bilaterally in the medial temporal lobe areas which substantially overlapped with the hypometabolism findings. These anatomical and metabolic changes overlap previously described patterns of neurodegeneration in MSTD patients and are consistent with the characteristics of their cognitive dysfunction. These results suggest that neuroimaging can describe the neuropathology associated with this MAPT mutation.

Aging is a major risk factor for Alzheimer's disease (AD). Aggregation of amyloid beta (Aβ) in cerebral cortex and hippocampus is a hallmark of AD. Many factors have been identified as causative elements for onset and progression of AD; for instance, tau seems to mediate the neuronal toxicity of Aβ, and downregulation of macroautophagy (autophagy) is thought to be a causative element of AD pathology. Expression of autophagy-related genes is reduced with age, which leads to increases in oxidative stress and aberrant protein accumulation. In this study, we found that expression of the autophagy-related genes atg1, atg8a, and atg18 in Drosophila melanogaster was regulated with aging as well as their own activities. In addition, the level of atg18 was maintained by dfoxo (foxo) and dsir2 (sir2) activities in concert with aging. These results indicate that some autophagy-related gene expression is regulated by foxo/sir2-mediated aging processes. We further found that reduced autophagy activity correlated with late-onset neuronal dysfunction caused by neuronal induction of Aβ. These data support the idea that age-related dysfunction of autophagy is a causative element in onset and progression of AD.

Background: The present study was designed to validate the ability of our recently identified set of small noncoding RNA candidate mild traumatic brain injury (mTBI) biomarkers to diagnose mTBI in the presence or absence of post-traumatic stress disorder (PTSD) comorbidity. Using qPCR, we explored the regulation of the candidate biomarkers in peripheral blood mononuclear cells (PBMC) from 58 veterans.

Results: We confirmed that 4 small nucleolar RNAs (snoRNAs), ACA48, U35, U55, and U83A, are significantly down-regulated in PBMC from veterans with mTBI and PTSD compared to non-TBI, control subjects with PTSD only. We found that the snoRNA biomarkers are able to dissect subjects with comorbid mTBI and PTSD from PTSD subjects without mTBI with 100% sensitivity, 81% accuracy, and 72% specificity. No significant differential expression of snoRNA biomarkers was found in mTBI subjects without comorbid PTSD. However, we found significantly lower U55 contents in subjects with PTSD. We explored the regulation of ACA48 in rodent models of PTSD or blast-induced mTBI to gather proof-of-concept evidence that would connect the regulation of the biomarkers and the development of mTBI or PTSD. We found no change in the regulation of ACA48 in the mTBI rat model. We did, however, find significant down-regulation of ACA48 in the PTSD mouse model 24 hours following psychological trauma exposure. This may reflect a short-term response to trauma exposure, since we found no change in the regulation of ACA48 in veteran PTSD subjects 3.6 years post-deployment.

Conclusions: Additional application of the 4 snoRNA biomarker to current diagnostic criteria may provide an objective biomarker pattern to help identify veterans with comorbid mTBI and PTSD. Our observations suggest that biological interactions between TBI and PTSD may contribute to the clinical features of veterans with comorbid mTBI and PTSD. Future investigations on mTBI mechanisms or TBI biomarkers should consider their interactions with PTSD.

Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by great phenotypic variability regarding clinical course and neuropathology. The most prominent disease modifiers are a polymorphism in Codon 129 of the prion protein gene and conformational variations of the misfolded prion protein. The cellular form of the prion protein restricts replication of viruses and may be involved in viral host defense, and viral infections influence the presentation and neuropathology in prion diseased mice. We investigated the occurrence of reactivated persistent viral infections of the brain in brain tissue samples of 25 sCJD patients. No evidence of reactivated JCV and CMV infections could be detected. This suggests that JCV and CMV infections are not reactivated as consequence of prion disease and do not act as disease modifiers in sCJD.

There is a lack of validated tools for assessing Alzheimer's disease (AD) across Asia. This study evaluates the psychometric properties of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Disability Assessment for Dementia (DAD), and Neuropsychological Test Battery (NTB) in Asian participants. Participants with mild to moderate AD (n=251) and healthy controls (n=51) from Mainland China, Taiwan, Singapore, Hong Kong, and South Korea completed selected instruments at several time points. Test-retest reliability was better than 0.70 for all tests. AD participants performed significantly more poorly than controls on every score. Within the AD group, greater disease severity corresponded to significantly poorer performance. The AD group test performance worsened over time and there was a trend for worse performance in AD compared to healthy controls over time. The ADAS-Cog, DAD, and NTB are reliable, valid, and responsive measures in this population and could be used for clinical trials across Asian countries/regions.

Amyloid deposition has been implicated as the key determinant of Alzheimer's disease (AD) pathogenesis. Interventions to antagonize amyloid accumulation and mitigate dementia are now under active investigation. We conducted a combined clinical, biochemical and neuropathological assessment of a participant in a clinical trial of the γ-secretase inhibitor, semagacestat. This patient received a daily oral dose of 140 mg of semagacestat for approximately 76 weeks. Levels of brain amyloid-β (Aβ) peptides were quantified using enzyme-linked immunosorbent assays (ELISA). Western blot/scanning densitometry was performed to reveal BACE1, presenilin1, amyloid precursor protein (APP) and its proteolysis-produced C-terminal peptides APP-CT99 and APP-CT83 as well as several γ-secretase substrates. To serve as a frame of reference, the ELISA and Western analyses were performed in parallel on samples from neuropathologically confirmed non-demented control (NDC) and AD subjects who did not receive semagacestat. Neuropathology findings confirmed a diagnosis of AD with frequent amyloid deposits and neurofibrillary tangles in most areas of the cortex and subcortical nuclei as well as cerebellar amyloid plaques. Mean levels of Tris-soluble Aβ40 and glass-distilled formic acid (GDFA)/guanidine hydrochloride (GHCl)-extractable Aβ40 in the frontal lobe and GDFA/GHCl-soluble Aβ40 in the temporal lobe were increased 4.2, 9.5 and 7.7-fold, respectively, in the semagacestat-treated subject compared to those observed in the non-treated AD group. In addition, GDFA/GHCl-extracted Aβ42 was increased 2-fold in the temporal lobe relative to non-treated AD cases. No major changes in APP, β- and γ-secretase and CT99/CT83 were observed between the semagacestat-treated subject compared to either NDC or AD cases. Furthermore, the levels of γ-secretase substrates in the semagacestat-treated subject and the reference groups were also similar. Interestingly, there were significant alterations in the levels of several γ-secretase substrates between the NDC and non-treated AD subjects. This is the first reported case study of an individual enrolled in the semagacestat clinical trial. The subject of this study remained alive for ~7 months after treatment termination, therefore it is difficult to conclude whether the outcomes observed represent a consequence of semagacestat therapy. Additional evaluations of trial participants, including several who expired during the course of treatment, may provide vital clarification regarding the impacts and aftermath of γ-secretase inhibition.

Introduction: Biomarkers represent a promising adjunct to clinical techniques in the diagnosis of Alzheimer's Disease (AD) and other neurodegenerative diseases. At present, the potential of cerebrospinal fluid (CSF) biomarkers in diagnosing AD has been suggested but the degree of clinical utility is yet to be defined due to variability between studies. In this paper we compare the performance of two cerebrospinal fluid assay methods in predicting clinically diagnosed AD.

Methods: CSF biomarker concentrations for Aβ1-42, P-tau181P and T-tau were analysed using INNOTEST (ELISA) and INNO-BIA AlzBio3 (Luminex) assay methods from Innogenetics, Belgium. Patients were clinically diagnosed based on NINCDS-ADRDA criteria supplemented with structural MRI, (18)F-fluorodeoxy-glucose positron emission tomography (FDG-PET) and cognitive profiling.

Results: An abnormally low Aβ1-42 was the most useful biomarker in predicting clinical AD. Depending on the assay method, the predictive accuracy remained constant or improved slightly when abnormalities in P-tau181P and T-tau were considered in addition to Aβ1-42. The Luminex method with our optimised reference concentrations performed best for patients ≤ 65 years with sensitivity = 1 and a specificity = 0.60 for both Aβ1-42 and when one or more abnormal biomarkers were considered.

Conclusion: Given accurate, robust and reproducible CSF analytical methods, of which the Luminex method seems the most useful and practicable, our investigation suggests that measuring CSF Aβ1-42, P-tau and T-tau has utility in the diagnosis of probable AD and, when used with clinical diagnostic techniques, seems especially helpful in the diagnosis of AD with onset prior to the age of 65 years.

Previous studies have shown a selective reduction of von Economo neurons (VENs) in behavioral variant frontotemporal dementia (bvFTD). However, the alleged selectivity rests on the comparison between VENs and other neurons in cortical layer V, while it has been established that neurons in the superficial cortical layers (I-III) are particularly affected in bvFTD. The purpose of this study was to examine loss the loss of VENs in comparison with that of non-VEN-neurons of superficial cortical layers. VENs and non-VEN-neurons of cortical layer V and layers II+III were quantified in the anterior cingulate cortex in 16 cases of bvFTD, 12 non-demented controls and 10 cases of Alzheimer's disease (AD). In bvFTD VENs were more depleted than non-VEN-neurons of layers V and II+III. Also, non-VEN-neurons of layer II+III showed a greater density reduction than those of layer V in bvFTD. VEN density was also reduced in AD, albeit to a lesser extent than in bvFTD, and the differences between bvFTD and AD were only significant when relating VEN loss to that of layer V neurons. Our study strengthens the view of VENs as a particularly sensitive neuronal type of bvFTD, and appears to be on a continuum with the loss of other neurons both in bvFTD and between conditions.

Up to date, almost all researchers consider that there is still no effective therapy for neurodegenerative diseases (NDDs) and therefore, these diseases are incurable. However, since May 1998, we know that a progressive ischemia in the medial temporal lobes and subcommissural regions can cause Alzheimer's disease; because, in contrast to this, its revascularization by means of omental tissue can cure or improve this disease. Likewise we observed that the aging process, Huntington's disease, Parkinson's disease, and Amyotrophic lateral sclerosis; all of them are of ischemic origin caused by cerebral atherosclerosis, associated with vascular anomalies and/or environmental chemicals. On the contrary, an omental transplantation on the affected zone can stop and improve these diseases. For these reasons, I believe that NDDs, are wrongly classified as neurodegenerative disorders.