Exosomal miR-320e as a Novel Potential Biomarker for Cerebral Small Vessel Disease.

Background: Cerebral small vessel disease (CSVD) with an insidious onset can cause overall neurological dysfunction and dementia, bringing a massive burden to society. However, the pathogenesis of CSVD is complex and reliable non-invasive biomarkers for diagnosis are still not available at present. Our study aimed to investigate abnormal exosomal miRNA patterns via microarray analysis and identify candidate biomarkers for CSVD. Methods: We isolated exosomes from the plasma of all subjects and identified exosomes via currently universally accepted methods. The miRNAs were profiled through microarrays, and then the expression of selected differentially expressed miRNAs was validated through RT-PCR. GO and KEGG analysis predicted possible functions of differentially expressed miRNAs. Receiver operating characteristic (ROC) curve was employed to observe the diagnostic value of selective miRNAs. Finally, the relationship between the expression of miR-320e and the CSVD burden was analyzed. Results: A total of 14 miRNAs displayed differential enrichment levels with |fold change|≥1.5 and p<0.05 through miRNA microarray analysis. The RT-PCR analysis validated that exosomal miR-320e was significantly downregulated in CSVD patients (p<0.0001). ROC curve analysis of exosomal miR-320e showed the area under the curve of 0.752. According to the multivariable analysis, miR-320e was an independent predictor of white matter hyperintensity ([aOR]= 0.452, 95% confidence interval [CI]= 0.258-0.792, p=0.006) and exhibited a negative correlation with the load of periventricular white matter hyperintensities (p=0.0021) and deep white matter hyperintensities (p=0.0018), respectively. In addition, it exhibited a negative correlation with total CSVD burden score (r=-0.276, p=0.001). Conclusion: In our study, plasma exosomal miR-320e has a certain diagnostic value for CSVD, and a significant correlation with imaging burden of CSVD. Overall, exosomal miR-320e has the potential to be a novel biomarker for CSVD, but further research with a large sample size is necessary to assess its clinical utility.

Impact of SORL1 genetic variations on MRI markers in non-demented elders.

The sorting protein-related receptor 1 (SORL1 or LR11) gene has been verified to play an important role in the pathologic process of ß-amyloid (Aß) formation and trafficking in Alzheimer's Disease (AD) by plenty of cytological and molecular biological studies. But there were few studies investigated the association of SORL1 gene and neurodegeneration features from a rather macroscopic perspective. In the present study, we explored the effect of SORL1 genotypes on AD-related brain atrophy. We recruited 812 individuals with both baseline and two-year follow-up information from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and applied multiple linear regression models to examine the association between eight single nucleotide polymorphisms (SNPs) and neuroimaging phenotypes. Finally, four SNPs (rs11219350, rs2298813, rs3781836, rs3824968) showed trend of association with the volume of hippocampus and parahippocampal gyrus but failed to survive the false discovery rate (FDR) correction. Only rs1784933 and rs753780 showed significant association with right parahippocampal gyrus. According to our findings, SORL1 variations influence the atrophy of specific AD-related brain structures, which suggested the potential role of SORL1 in the neurodegeneration of cognitive related regions.

The Role of SORL1 in Alzheimer's Disease.

Genetic variation in SORL1 gene, also known as LR11, has been identified to associate with Alzheimer's disease (AD) through replicated genetic studies. As a type I transmembrane protein, SORL1 is composed of several distinct domains and belongs to both the low-density lipoprotein receptor (LDLR) family and the vacuolar protein sorting 10 (VPS10) domain receptor family. The level of SORL1 was found to be decreased in the AD brain which positively correlated with ß-amyloid (Aß) accumulation. Emerging data suggests that SORL1 contributes to AD through various pathways, including emerging as a central regulator of the trafficking and processing of amyloid precursor protein (APP), involvement in Aß destruction, and interaction with ApoE and tau protein. Primarily, SORL1 interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network (TGN) and early endosomes, thereby restricting the delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. In this article, we review recent epidemiological and genetical findings of SORL1 that related with AD and speculate the possible roles of SORL1 in the progression of this disease. Finally, given the potential contributions of SORL1 to AD pathogenesis, targeting SORL1 might present novel opportunities for AD therapy.

Magnetic Resonance Spectroscopy in Alzheimer's Disease: Systematic Review and Meta-Analysis.

BACKGROUND: The application of non-invasive proton magnetic resonance spectroscopy (1H-MRS) could potentially identify changes in cerebral metabolites in the patients with Alzheimer's disease (AD). However, whether these metabolites can serve as biomarkers for the diagnosis of AD remains unclear. OBJECTIVE: Using meta-analysis, we aimed to investigate the patterns of cerebral metabolite changes in several cerebral regions that are strongly associated with cognitive decline in AD patients. METHODS: Using Hedges' g effect size, a systematic search was performed in PubMed, Cochrane Library, Ovid, Embase, and EBSCO, and 38 studies were integrated into the final meta-analysis. RESULTS: According to the observational studies, N-acetyl aspartate (NAA) in AD patients was significantly reduced in the posterior cingulate (PC) (effect size (ES) =-0.924, p <  0.005) and bilateral hippocampus (left hippocampus: ES =-1.329, p <  0.005; right hippocampus: ES =-1.287, p <  0.005). NAA/Cr (creatine) ratio decreased markedly in the PC (ES =-1.052, p <  0.005). Simultaneously, significant elevated myo-inositol (mI)/Cr ratio was found not only in the PC but also in the parietal gray matter. For lack of sufficient data, we failed to elucidate the efficacy of pharmacological interventions with the metabolites changes. CONCLUSION: The available data indicates that NAA, mI, and the NAA/Cr ratio might be potential biomarkers of brain dysfunction in AD subjects. Choline (Cho)/Cr and mI/NAA changes might also contribute toward the diagnostic process. Thus, large, well-designed studies correlated with cerebral metabolism are needed to better estimate the cerebral extent of alterations in brain metabolite levels in AD patients.

Voxel-based meta-analysis of grey matter changes in Alzheimer's disease.

BACKGROUND: Voxel-based morphometry (VBM) using structural brain MRI has been widely used for the assessment of impairment in Alzheimer's disease (AD), but previous studies in VBM studies on AD remain inconsistent. OBJECTIVE: We conducted meta-analyses to integrate the reported studies to determine the consistent grey matter alterations in AD based on VBM method. METHODS: The PubMed, ISI Web of Science, EMBASE and Medline database were searched for articles between 1995 and June 2014. Manual searches were also conducted, and authors of studies were contacted for additional data. Coordinates were extracted from clusters with significant grey matter difference between AD patients and healthy controls (HC). Meta-analysis was performed using a new improved voxel-based meta-analytic method, Effect Size Signed Differential Mapping (ES-SDM). RESULTS: Thirty data-sets comprising 960 subjects with AD and 1195 HC met inclusion criteria. Grey matter volume (GMV) reduction at 334 coordinates in AD and no GMV increase were found in the current meta-analysis. Significant reductions in GMV were robustly localized in the limbic regions (left parahippocampl gyrus and left posterior cingulate gyrus). In addition, there were GM decreases in right fusiform gyrus and right superior frontal gyrus. The findings remain largely unchanged in the jackknife sensitivity analyses. CONCLUSIONS: Our meta-analysis clearly identified GMV atrophy in AD. These findings confirm that the most prominent and replicable structural abnormalities in AD are in the limbic regions and contributes to the understanding of pathophysiology underlying AD.

Multimodal Voxel-Based Meta-Analysis of White Matter Abnormalities in Alzheimer's Disease.

An increasing number of MRI investigations suggest that patients with Alzheimer's disease (AD) show not only gray matter decreases but also white matter (WM) abnormalities, including WM volume (WMV) deficits and integrity disruption of WM pathways. In this study, we applied multimodal voxel-wise meta-analytical methods to study WMV and fractional anisotropy in AD. Fourteen studies including 723 participants (340 with AD and 383 controls) were involved. The meta-analysis was performed using effect size signed differential mapping. Significant WMV reductions were observed in bilateral inferior temporal gyrus, splenium of corpus callosum, right parahippocampal gyrus, and hippocampus. Decreased fractional anisotropy was identified mainly in left posterior limb of internal capsule, left anterior corona radiata, left thalamus, and left caudate nucleus. Significant decreases of both WMV and fractional anisotropy were found in left caudate nucleus, left superior corona radiata, and right inferior temporal gyrus. Most findings showed to be highly replicable in the jackknife sensitivity analyses. In conclusion, AD patients show widespread WM abnormalities mainly in bilateral structures related to advanced mental and nervous activities.

Prion-like Mechanisms in Alzheimer's Disease.

The misfolding and aggregation of specific proteins within nervous system occur in most age-associated neurodegenerative diseases including Alzheimer's disease (AD). This kind of disorders have been classified as the protein misfolding disease or proteopathy which share key biophysical and biochemical characteristics with prion diseases. In AD, ß-amyloid (Aß) and tau protein, capital agents for the senile plaques and intracellular neurofibrillary tangles, are called 'prionoids' indicating that proteins exhibit prion-like properties. In this review, we describe the prion-like mechanisms in the progression that the Aß and tau are induced to misfold and self-assemble by a process of templated conformational change and then the lesion caused by the pathogenic agents spread out through the cell-to-cell transportation, including release of intracellular seeds by the donor cell, cellular uptake by the recipient and intercellular transport. This hypothesis will suggest new therapeutic strategies for AD, especially valuable in the pre-symptomatic phase.