Journal of Alzheimer's disease & Parkinsonism最新文献

Background: A blood-test that could serve as a potential first step in a multi-tiered neurodiagnostic process for ruling out Parkinson's disease (PD) in primary care settings would be of tremendous value. This study therefore sought to conduct a large-scale cross-validation of our Parkinson's disease Blood Test (PDBT) for use in primary care settings.

Methods: Serum samples were analyzed from 846 PD and 2291 volunteer controls. Proteomic assays were run on a multiplex biomarker assay platform using Electrochemiluminescence (ECL). Diagnostic accuracy statistics were generated using area under the receiver operating characteristic curve (AUC), Sensitivity (SN), Specificity (SP) and Negative Predictive Value (NPV).

Results: In the training set, the PDBT reached an AUC of 0.98 when distinguishing PD cases from controls with a SN of 0.84 and SP of 0.98. When applied to the test set, the PDBT yielded an AUC of 0.96, SN of 0.79 and SP of 0.97. The PDBT obtained a negative predictive value of 99% for a 2% base rate.

Conclusion: The PDBT was highly successful in discriminating PD patients from control cases and has great potential for providing primary care providers with a rapid, scalable and cost-effective tool for screening out PD.

The human gastrointestinal (GI)-tract microbiome is a rich, complex and dynamic source of microorganisms that possess a staggering diversity and complexity. Importantly there is a significant variability in microbial complexity even amongst healthy individuals-this has made it difficult to link specific microbial abundance patterns with age-related neurological disease. GI-tract commensal microorganisms are generally beneficial to human metabolism and immunity, however enterotoxigenic forms of microbes possess significant potential to secrete what are amongst the most neurotoxic and pro-inflammatory biopolymers known. These include toxic glycolipids such as lipopolysaccharide (LPS), enterotoxins, microbial-derived amyloids and small non-coding RNA. One major microbial species of the GI-tract microbiome, about ~100-fold more abundant than Escherichia coli in deep GI-tract regions is Bacteroides fragilis, an anaerobic, rod-shaped Gram-negative bacterium. B. fragilis can secrete: (i) a particularly potent, pro-inflammatory and unique LPS subtype (BF-LPS); and (ii) a zinc-metalloproteinase known as B. fragilis-toxin (BFT) or fragilysin. Ongoing studies indicate that BF-LPS and/or BFT disrupt paracellular-and transcellular-barriers by cleavage of intercellular-proteins resulting in 'leaky' barriers. These barriers: (i) become defective and more penetrable with aging and disease; and (ii) permit entry of microbiome-derived neurotoxins into the systemic-circulation from which they next transit the blood-brain barrier and gain access to the CNS. Here LPS accumulates and significantly alters homeostatic patterns of gene expression. The affinity of LPS for neuronal nuclei is significantly enhanced in the presence of amyloid beta 42 (Aβ42) peptides. Recent research on the appearance of the brain thanatomicrobiome at the time of death and the increasing likelihood of a complex brain microbiome are reviewed and discussed. This paper will also highlight some recent advances in this extraordinary research area that links the pro-inflammatory exudates of the GI-tract microbiome with innate-immune disturbances and inflammatory-signaling within the CNS with reference to Alzheimer's disease (AD) wherever possible.

Background: Alzheimer's Disease (AD) is a neurodegenerative complex brain disease that represents a public health concern. AD is considered the fifth leading cause of death in Americans who are older than 65 years which prioritizes the importance of understanding the etiology of AD in its early stages before the onset of symptoms. This study attempted to further understand Alzheimer's disease (AD) etiology by investigating the dysregulated genes using gene expression data from multiple brain regions.

Methods: A linear mixed-effects model for differential gene expression analysis was used in a sample of 15 AD and 30 control subjects, each with data from four different brain regions, in order to deal with the hierarchical multilevel data. Post-hoc Gene Ontology and pathway enrichment analyses provided insights on the biological implications in AD progression. Supervised machine learning algorithms were used to assess the discriminative power of the top 10 candidate genes in distinguishing between the two groups.

Results: Enrichment analyses revealed biological processes and pathways that are related to structural constituents and organization of the axons and synapses. These biological processes and pathways imply dysfunctional axon and synaptic transmission between neuronal cells in AD. Random Forest classification algorithm gave the best accuracy on the test data with F1-score of 0.88.

Conclusion: The differentially expressed genes were associated with axon and synaptic transmissions which affect the neuronal connectivity in cognitive systems involved in AD pathophysiology. These genes may open ways to explore new effective treatments and early diagnosis before the onset of clinical symptoms.

There is a known relationship between Alzheimer's disease (AD) and Down syndrome (DS), with the latter typically developing AD-like neuropathology in mid-life. In order to further understand this relationship we examined intersectin-1 (ITSN1) and the regulator of calcineurin-1 (RCAN1), proteins involved in endosomal and lysosomal trafficking that are over-expressed in DS. We examined RCAN1 and ITSN1 levels (both long (-L) and short (-S) isoforms) and the level of endogenous metals in White Blood Cells (WBCs) collected from AD patients who were enrolled in the Australian Imaging, Biomarker and Lifestyle Study on Ageing (AIBL). We also examined RCAN1 and ITSN1-S and -L in post-mortem brain tissue in a separate cohort of patients with AD or other types of dementia including Dementia with Lewy Bodies (DLB) and non-Alzheimer's disease dementia. We found that RCAN1 was significantly elevated in AD and DLB brain compared with controls, but there was no difference in the level of RCAN1 in WBCs of AD patients. There were no differences in the levels of ITSN1-L and -S between AD and the control, nor between other types of dementia and the control. We found that there were no differences in the levels of metals between AD and the control WBCs. In conclusion, our data demonstrate that RCAN1 is differentially regulated between the peripheral and central compartments in AD and should be further investigated to understand its potential role in dementia of AD and DLB.

Aluminum is a ubiquitous neurotoxin highly enriched in our biosphere, and has been implicated in the etiology and pathology of multiple neurological diseases that involve inflammatory neural degeneration, behavioral impairment and cognitive decline. Over the last 36 years our group has analyzed the aluminum content of the temporal lobe neocortex of 511 high quality coded human brain samples from 18 diverse neurological and neurodegenerative disorders, including 2 groups of age-matched controls. Brodmann anatomical areas including the inferior, medial and superior temporal gyrus (A20-A22) were selected for analysis: (i) because of their essential functions in massive neural information processing operations including cognition and memory formation; and (ii) because subareas of these anatomical regions are unique to humans and are amongst the earliest areas affected by progressive neurodegenerative disorders such as Alzheimer's disease (AD). Coded brain tissue samples were analyzed using the analytical technique of: (i) Zeeman-type electrothermal atomic absorption spectrophotometry (ETAAS) combined with (ii) an experimental multi-elemental analysis using the advanced photon source (APS) ultra-bright storage ring-generated hard X-ray beam (7 GeV) and fluorescence raster scanning (XRFR) spectroscopy device at the Argonne National Laboratory, US Department of Energy, University of Chicago IL, USA. These data represent the largest study of aluminum concentration in the brains of human neurological and neurodegenerative disease ever undertaken. Neurological diseases examined were AD (N=186), ataxia Friedreich's type (AFT; N=6), amyotrophic lateral sclerosis (ALS; N=16), autism spectrum disorder (ASD; N=26), dialysis dementia syndrome (DDS; N=27), Down's syndrome (DS; trisomy21; N=24), Huntington's chorea (HC; N=15), multiple infarct dementia (MID; N=19), multiple sclerosis (MS; N=23), Parkinson's disease (PD; N=27), prion disease (PrD; N=11) including bovine spongiform encephalopathy (BSE; 'mad cow disease'), Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Sheinker syndrome (GSS), progressive multifocal leukoencephalopathy (PML; N=11), progressive supranuclear palsy (PSP; N=24), schizophrenia (SCZ; N=21), a young control group (YCG; N=22) and an aged control group (ACG; N=53). Amongst these 18 common neurological conditions and controls we report a statistically significant trend for aluminum to be increased only in AD, DS and DDS compared to age- and gender-matched brains from the same anatomical region. The results continue to suggest that aluminum's association with AD, DDS and DS brain tissues may contribute to the neuropathology of these neurological diseases but appear not to be a significant factor in other common disorders of the human central nervous system (CNS).

Background: Alzheimer's disease (AD) is the most common form of senile dementia. However, its pathological mechanisms are not fully understood. In order to comprehend AD pathological mechanisms, researchers employed AD-related DNA microarray data and diverse computational algorithms. More efficient computational algorithms are needed to process DNA microarray data for identifying AD-related candidate genes.

Methods: In this paper, we propose a specific algorithm that is based on the following observation: When an acrobat walks along a steel-wire, his/her body must have some swing; if the swing can be controlled, then the acrobat can maintain the body balance. Otherwise, the acrobat will fall. Based on this simple idea, we have designed a simple, yet practical, algorithm termed as the Amplitude Deviation Algorithm (ADA). Deviation, overall deviation, deviation amplitude, and 3δ are introduced to characterize ADA.

Results: 52 candidate genes for AD have been identified via ADA. The implications for some of the AD candidate genes in AD pathogenesis have been discussed.

Conclusions: Through the analysis of these AD candidate genes, we believe that AD pathogenesis may be related to the abnormality of signal transduction (AGTR1 and PTAFR), the decrease in protein transport capacity (COL5A2 (221729_at), COL5A2 (221730_at), COL4A1), the impairment of axon repair (CNR1), and the intracellular calcium dyshomeostasis (CACNB2, CACNA1E). However, their potential implication for AD pathology should be further validated by wet lab experiments as they were only identified by computation using ADA.

Background: Developing methods for accurately diagnosing prion diseases has been a challenge in the search for successful diagnosis and treatment of rapidly progressive dementia. prion diseases are rare. However, they should be considered in the differential diagnosis. Despite their rarity, several other conditions are often misdiagnosed as prion diseases. Most Alzheimer's (AD) and Lewy Body Disease (LBD) patients also meet Creutzfeldt-Jakob Disease (CJD) criteria. The similarities in symptomology and pathology between these two patient groups complicates diagnosis and can compromise patient care. Prevalent methods for the diagnosis of CJD lack the heightened sensitivity to conclusively detect CJD. Of all currently available methods, real-time quaking induced conversion (RT-QuIC) analysis provides the highest sensitivity necessary to allow for an accurate diagnosis and yields early, quantitative results.

Clinical case: A 75-year-old woman with rapidly progressing dementia, for which CJD could not be ruled out, appeared for care at a neurological center. Laboratory test results, Magnetic Resonance Imaging (MRI), Cerebrospinal Fluid (CSF) studies, Positron Emission Tomography (PET), and an Electroencephalogram (EEG) proved inadequate to confirm CJD. In addition to AD, LBD, or CJD, other potential, yet improbable, pathologies could have caused the patient's symptoms. The patient's diagnosis ultimately was limited to either LBD or prion disease. Spongiform encephalogy was confirmed by a brain biopsy, and further testing confirmed sporadic CJD.

Conclusion: RT-QuIC offers higher sensitivity than currently prevalent diagnostic methods and appears most promising for CJD diagnosis.