Petros Takousis

Abstract Introduction Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case‐control studies remains inconclusive. Methods A systematic literature review was performed, followed by standardized multistage data extraction, quality control, and meta‐analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty. Results Data from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta‐analyses. Twenty‐five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10 −4 ) in brain, cerebrospinal fluid, and blood‐derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles. Discussion Our systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance.

Objective MicroRNA (miRNA)‐mediated (dys)regulation of gene expression has been implicated in Parkinson's disease (PD), although results of miRNA expression studies remain inconclusive. We aimed to identify miRNAs that show consistent differential expression across all published expression studies in PD. Methods We performed a systematic literature search on miRNA expression studies in PD and extracted data from eligible publications. After stratification for brain, blood, and cerebrospinal fluid (CSF)‐derived specimen, we performed meta‐analyses across miRNAs assessed in three or more independent data sets. Meta‐analyses were performed using effect‐size– and p ‐value–based methods, as applicable. Results After screening 599 publications, we identified 47 data sets eligible for meta‐analysis. On these, we performed 160 meta‐analyses on miRNAs quantified in brain (n = 125), blood (n = 31), or CSF (n = 4). Twenty‐one meta‐analyses were performed using effect sizes. We identified 13 significantly (Bonferroni‐adjusted α = 3.13 × 10 –4 ) differentially expressed miRNAs in brain (n = 3) and blood (n = 10) with consistent effect directions across studies. The most compelling findings were with hsa‐miR‐132‐3p ( p = 6.37 × 10 –5 ), hsa‐miR‐497‐5p ( p = 1.35 × 10 –4 ), and hsa‐miR‐133b ( p = 1.90 × 10 –4 ) in brain and with hsa‐miR‐221‐3p ( p = 4.49 × 10 –35 ), hsa‐miR‐214‐3p ( p = 2.00 × 10 –34 ), and hsa‐miR‐29c‐3p ( p = 3.00 × 10 –12 ) in blood. No significant signals were found in CSF. Analyses of genome‐wide association study data for target genes of brain miRNAs showed significant association (α = 9.40 × 10 –5 ) of genetic variants in nine loci. Interpretation We identified several miRNAs that showed highly significant differential expression in PD. Future studies may assess the possible role of the identified brain miRNAs in pathogenesis and disease progression as well as the potential of the top blood miRNAs as biomarkers for diagnosis, progression, or prediction of PD. ANN NEUROL 2019;85:835–851.

AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aβ plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aβ plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aβ plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele.