Neurofilament light (NfL) protein is a marker of neuro-axonal damage and can be measured not only in cerebrospinal fluid but also in serum, which allows for repeated assessments. There is still ...limited knowledge regarding the association of serum NfL (sNfL) with age and subclinical morphologic brain changes and their dynamics in the normal population. We measured sNfL by a single molecule array (Simoa) assay in 335 individuals participating in a population-based cohort study and after a mean follow-up time of 5.9 years (n = 103). Detailed clinical examination, cognitive testing and 3T brain MRI were performed to assess subclinical brain damage. We show that rising and more variable sNfL in individuals >60 years indicate an acceleration of neuronal injury at higher age, which may be driven by subclinical comorbid pathologies. This is supported by a close association of sNfL with brain volume changes in a cross-sectional and especially longitudinal manner.
Extracellular free water (FW) increases are suggested to better provide pathophysiological information in brain aging than conventional biomarkers such as fractional anisotropy. The aim of the ...present study was to determine the relationship between conventional biomarkers, FW in white matter hyperintensities (WMH), FW in normal appearing white matter (NAWM) and in white matter tracts and executive functions (EF) with a speed component in elderly persons.
We examined 226 healthy elderly participants (median age 69.83 years, IQR: 56.99–74.42) who underwent brain MRI and neuropsychological examination. FW in WMH and in NAWM as well as FW corrected diffusion metrics and measures derived from conventional MRI (white matter hyperintensities, brain volume, lacunes) were used in partial correlation (adjusted for age) to assess their correlation with EF with a speed component. Random forest analysis was used to assess the relative importance of these variables as determinants. Lastly, linear regression analyses of FW in white matter tracts corrected for risk factors of cognitive and white matter deterioration, were used to examine the role of specific tracts on EF with a speed component, which were then ranked with random forest regression.
Partial correlation analyses revealed that almost all imaging metrics showed a significant association with EF with a speed component (r = -0.213 – 0.266). Random forest regression highlighted FW in WMH and in NAWM as most important among all diffusion and structural MRI metrics. The fornix (R2=0.421, p = 0.018) and the corpus callosum (genu (R2 = 0.418, p = 0.021), prefrontal (R2 = 0.416, p = 0.026), premotor (R2 = 0.418, p = 0.021)) were associated with EF with a speed component in tract based regression analyses and had highest variables importance.
In a normal aging population FW in WMH and NAWM is more closely related to EF with a speed component than standard DTI and brain structural measures. Higher amounts of FW in the fornix and the frontal part of the corpus callosum leads to deteriorating EF with a speed component.
OBJECTIVE:Cerebral small vessel disease is the most common cause of vascular cognitive impairment and typically manifests with slowed processing speed. We investigated the impact of lesion location ...on processing speed in age-related small vessel disease.
METHODS:A total of 584 community-dwelling elderly underwent brain MRI followed by segmentation of white matter hyperintensities. Processing speed was determined by the timed measure of the Trail Making Test part B. The impact of the location of white matter hyperintensities was assessed by voxel-based lesion-symptom mapping and graph-based statistical models on regional lesion volumes in major white matter tracts.
RESULTS:Voxel-based lesion-symptom mapping identified multiple voxel clusters where the presence of white matter hyperintensities was associated with slower performance on the Trail Making Test part B. Clusters were located bilaterally in the forceps minor and anterior thalamic radiation. Region of interest–based Bayesian network analyses on lesion volumes within major white matter tracts depicted the same tracts as direct predictors for an impaired Trail Making Test part B performance.
CONCLUSIONS:Our findings highlight damage to frontal interhemispheric and thalamic projection fiber tracts harboring frontal-subcortical neuronal circuits as a predictor for processing speed performance in age-related small vessel disease.
Cerebral white matter hyperintensities (WMH) have been associated with subclinical atherosclerosis including coronary artery calcification (CAC). However, previous studies on this association are ...limited by only cross-sectional analysis. We aimed to explore the relationship between WMH and CAC in elderly individuals both cross-sectionally and longitudinally. The study population consisted of elderly stroke- and dementia-free participants from the community-based Austrian Stroke Prevention Family Study (ASPFS). WMH volume and CAC levels (via Agatston score) were analyzed at baseline and after a 6-year follow-up period. Of 324 study participants (median age: 68 years), 115 underwent follow-up. Baseline WMH volume (median: 4.1 cm
) positively correlated with baseline CAC levels in multivariable analysis correcting for common vascular risk factors (p = 0.010). While baseline CAC levels were not predictive for WMH progression (p = 0.447), baseline WMH volume was associated CAC progression (median Agatston score progression: 27) in multivariable analysis (ß = 66.3 ± 22.3 per cm
, p = 0.004). Ten of 11 participants (91%) with severe WMH (Fazekas Scale: 3) at baseline showed significant CAC progression > 100 during follow-up. In this community-based cohort of elderly individuals, WMH were associated with CAC and predictive of its progression over a 6-year follow-up. Screening for coronary artery disease might be considered in people with more severe WMH.
Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral ...small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.
Introduction
Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these ...locations in a large multicenter study.
Methods
Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel‐based and region of interest tract‐based analyses.
Results
WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto‐occipital fasciculus were significantly related to domain‐specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains.
Discussion
The data show that the impact of WMH on cognition is location‐dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment.
Highlights
We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts
The impact of WMH on cognition depends on location
We identified four strategic white matter tracts
A single strategic WMH score was derived from these four strategic tracts
The strategic WMH score was an independent determinant of four cognitive domains
The etiology of idiopathic normal pressure hydrocephalus (iNPH) remains unclear. Little is known about the pre-symptomatic stage. This study aimed to investigate the association of neuropsychological ...data with iNPH-characteristic imaging changes compared to normal imaging and unspecific atrophy in a healthy population.
We extracted data from the community-dwelling Austrian Stroke Prevention Family Study (ASPS-Fam) database (2006-2010). All subjects underwent a baseline and identical follow-up examination after 3-5 years with MR imaging and an extensive neuropsychological test battery (Trail Making Test B, short physical performance balance, walking speed, memory, visuo-practical skills, composite scores of executive function and g-factor). We categorized the subjects into "iNPH"-associated, non-specific "atrophy," and "normal" based on the rating of different radiological cerebrospinal fluid (CSF) space parameters. We noted how the categories developed over time. We assessed the association of the image categories with the neuropsychological data, different demographic, and lifestyle parameters (age, sex, education, alcohol intake, arterial hypertension, hypercholesterolemia), and the extent of white matter hyperintensities. We investigated whether neuropsychological data associated with the image categories were independent from other parameters as confounders.
One hundred and thirteen subjects, aged 50-70 years, were examined. The imaging category "iNPH" was only present at follow-up. A third of subjects with "atrophy" at baseline changed to the category "iNPH" at follow-up. More white matter hyperintensities (WMH) were present in later "iNPH" subjects. Subjects with "iNPH" performed worse than "normal" subjects on executive function (p = 0.0118), memory (p = 0.0109), and Trail Making Test B (TMT-B. p < 0.0001). Education, alcohol intake, diabetes, arterial hypertension, and hypercholesterolemia had no effect. Age, number of females, and the extent of white matter hyperintensities were higher in "iNPH" than in "normal" subjects but did not significantly confound the neuropsychological results.
Apparent asymptomatic subjects with "iNPH" imaging characteristics presented with subclinical cognitive decline and showed worse executive function, memory, and TMT-B results than "normal" subjects. WMH seem to play a role in the etiology before ventriculomegaly. Clinical screening of individuals with incidental iNPH-characteristic imaging and conspicuous results sof these neurocognitive tests needs further validation.
Cellular senescence can be induced by a variety of extrinsic stimuli, and sustained exposure to sunlight is a key factor in photoaging of the skin. Accordingly, irradiation of skin fibroblasts by UVB ...light triggers cellular senescence, which is thought to contribute to extrinsic skin aging, although molecular mechanisms are incompletely understood. Here, we addressed molecular mechanisms underlying UVB induced senescence of human diploid fibroblasts.
We observed a parallel activation of the p53/p21(WAF1) and p16(INK4a)/pRb pathways. Using genome-wide transcriptome analysis, we identified a transcriptional signature of UVB-induced senescence that was conserved in three independent strains of human diploid fibroblasts (HDF) from skin. In parallel, a comprehensive screen for microRNAs regulated during UVB-induced senescence was performed which identified five microRNAs that are significantly regulated during the process. Bioinformatic analysis of miRNA-mRNA networks was performed to identify new functional mRNA targets with high confidence for miR-15a, miR-20a, miR-20b, miR-93, and miR-101. Already known targets of these miRNAs were identified in each case, validating the approach. Several new targets were identified for all of these miRNAs, with the potential to provide new insight in the process of UVB-induced senescence at a genome-wide level. Subsequent analysis was focused on miR-101 and its putative target gene Ezh2. We confirmed that Ezh2 is regulated by miR-101 in human fibroblasts, and found that both overexpression of miR-101 and downregulation of Ezh2 independently induce senescence in the absence of UVB irradiation. However, the downregulation of miR-101 was not sufficient to block the phenotype of UVB-induced senescence, suggesting that other UVB-induced processes induce the senescence response in a pathway redundant with upregulation of miR-101.
We performed a comprehensive screen for UVB-regulated microRNAs in human diploid fibroblasts, and identified a network of miRNA-mRNA interactions mediating UVB-induced senescence. In addition, miR-101 and Ezh2 were identified as key players in UVB-induced senescence of HDF.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The measurement of neurofilament light chain (NfL) in blood is a promising biomarker of neurological injury and disease. We investigated the genetic factors that underlie serum NfL levels (sNfL) of ...individuals without neurological conditions.
We performed a discovery genome-wide association study (GWAS) of sNfL in participants of the German BiDirect Study (
= 1,899). A secondary GWAS for meta-analysis was performed in a small Austrian cohort (
= 287). Results from the meta-analysis were investigated in relation with several clinical variables in BiDirect.
Our discovery GWAS identified 12 genomic loci at the suggestive threshold ((
< 1 × 10
). After meta-analysis, 7 loci were suggestive of an association with sNfL. Genotype-specific differences in sNfL were observed for the lead variants of meta-analysis loci (rs34523114, rs114956339, rs529938, rs73198093, rs34372929, rs10982883, and rs1842909) in BiDirect participants. We identified potential associations in meta-analysis loci with markers of inflammation and renal function. At least 6 protein-coding genes (
, and
) were suggested as genetic factors contributing to baseline sNfL levels.
Our findings suggest that polygenic regulation of neuronal processes, inflammation, metabolism and clearance modulate the variability of NfL in the circulation. These could aid in the interpretation of sNfL measurements in a personalized manner.
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