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Stroke, ischaemic stroke and subtypes of ischaemic stroke display substantial heritability. When compared with related vascular conditions, the number of established risk loci reaching genome-wide significance for association with stroke is still in the lower range, particularly for aetiological stroke subtypes such as large artery atherosclerotic stroke or small vessel stroke. Nevertheless, for individual loci substantial progress has been made in determining the specific mechanisms mediating stroke risk. In this review, we present a roadmap for functional follow-up of common risk variants associated with stroke. First, we discuss in silico strategies for characterizing signals in non-coding regions and highlight databases providing information on quantitative trait loci for mRNA and protein expression, as well as methylation, focussing on those with presumed relevance for stroke. Next, we discuss experimental strategies for following up on non-coding risk variants and regions such as massively parallel reporter assays, proteome-wide association studies, and chromatin conformation capture (3C) assays. These and other approaches are relevant for gaining insight into the specific variants and mechanisms mediating genetic stroke risk. Finally, we discuss how genetic findings could influence clinical practice by adding to diagnostic algorithms and eventually improve treatment options for stroke. [ABSTRACT FROM AUTHOR]

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly Iocalised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations. [ABSTRACT FROM AUTHOR]

Ischaemic stroke is a leading cause of disability and death for which no acute treatments exist beyond recanalization. The development of novel therapies has been repeatedly hindered by translational failures that have changed the way we think about tissue damage after stroke. What was initially a neuron-centric view has been replaced with the concept of the neurovascular unit (NVU), which encompasses neuronal, glial and vascular compartments, and the biphasic nature of neural-glial-vascular signalling. However, it is now clear that the brain is not the private niche it was traditionally thought to be and that the NVU interacts bidirectionally with systemic biology, such as systemic metabolism, the peripheral immune system and the gut microbiota. Furthermore, these interactions are profoundly modified by internal and external factors, such as ageing, temperature and day-night cycles. In this Review, we propose an extension of the concept of the NVU to include its dynamic interactions with systemic biology. We anticipate that this integrated view will lead to the identification of novel mechanisms of stroke pathophysiology, potentially explain previous translational failures, and improve stroke care by identifying new biomarkers of and treatment targets in stroke. [ABSTRACT FROM AUTHOR]

Presents a study which was conducted to investigate aldolase C which is regarded at the brain-specific form of fructose-1, 6-bisophosphate aldolase. Materials used in the study; Methodology used to conduct the study; Results of the study.

Background: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study.Methods: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance-weighted meta-analysis, weighted-median analysis, Mendelian randomization-Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364 434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data.Results: Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02-1.09; P=0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02-1.10; P=0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09-1.30; P=0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06-1.23; P=0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99-1.17; P=0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97-1.18; P=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00-1.08; P=0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01-1.09; P=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls.Conclusions: Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Peripheral Artery Disease As a Manifestation of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) and Practical Implications" by D. F. Briceno, P. Navarro et al. in a 2013 issue of the journal.

Background: Migraine is a disabling neurological disorder with the pathophysiology yet to be understood. The microstructural alteration in brain white matter (WM) has been suggested to be related to migraine in recent studies, but these evidence are observational essentially and cannot infer a causal relationship. The present study aims to reveal the causal relationship between migraine and microstructural WM using genetic data and Mendelian randomization (MR). Methods: We collected the Genome-wide association study (GWAS) summary statistics of migraine (48,975 cases / 550,381 controls) and 360 WM imaging-derived phenotypes (IDPs) (31,356 samples) that were used to measure microstructural WM. Based on instrumental variables (IVs) selected from the GWAS summary statistics, we conducted bidirectional two-sample MR analyses to infer bidirectional causal associations between migraine and microstructural WM. In forward MR analysis, we inferred the causal effect of microstructural WM on migraine by reporting the odds ratio (OR) that quantified the risk change of migraine for per 1 standard deviation (SD) increase of IDPs. In reverse MR analysis, we inferred the causal effect of migraine on microstructural WM by reporting the β value that represented SDs of changes in IDPs were caused by migraine. Results: Three WM IDPs showed significant causal associations (p < 3.29 × 10− 4, Bonferroni correction) with migraine and were proved to be reliable via sensitivity analysis. The mode of anisotropy (MO) of left inferior fronto-occipital fasciculus (OR = 1.76, p = 6.46 × 10− 5) and orientation dispersion index (OD) of right posterior thalamic radiation (OR = 0.78, p = 1.86 × 10− 4) exerted significant causal effects on migraine. Migraine exerted a significant causal effect on the OD of left superior cerebellar peduncle (β = − 0.09, p = 2.78 × 10− 4). Conclusions: Our findings provided genetic evidence for the causal relationships between migraine and microstructural WM, bringing new insights into brain structure for the development and experience of migraine. [ABSTRACT FROM AUTHOR]

Alzheimer's disease and cerebral small vessel disease are the two leading causes of cognitive decline and dementia and coexist in most memory clinic patients. White matter damage as assessed by diffusion MRI is a key feature in both Alzheimer's and cerebral small vessel disease. However, disease-specific biomarkers of white matter alterations are missing. Recent advances in diffusion MRI operating on the fixel level (fibre population within a voxel) promise to advance our understanding of disease-related white matter alterations. Fixel-based analysis allows derivation of measures of both white matter microstructure, measured by fibre density, and macrostructure, measured by fibre-bundle cross-section. Here, we evaluated the capacity of these state-of-the-art fixel metrics to disentangle the effects of cerebral small vessel disease and Alzheimer's disease on white matter integrity. We included three independent samples (total n = 387) covering genetically defined cerebral small vessel disease and age-matched controls, the full spectrum of biomarker-confirmed Alzheimer's disease including amyloid- and tau-PET negative controls and a validation sample with presumed mixed pathology. In this cross-sectional analysis, we performed group comparisons between patients and controls and assessed associations between fixel metrics within main white matter tracts and imaging hallmarks of cerebral small vessel disease (white matter hyperintensity volume, lacune and cerebral microbleed count) and Alzheimer's disease (amyloid- and tau-PET), age and a measure of neurodegeneration (brain volume). Our results showed that (i) fibre density was reduced in genetically defined cerebral small vessel disease and strongly associated with cerebral small vessel disease imaging hallmarks; (ii) fibre-bundle cross-section was mainly associated with brain volume; and (iii) both fibre density and fibre-bundle cross-section were reduced in the presence of amyloid, but not further exacerbated by abnormal tau deposition. Fixel metrics were only weakly associated with amyloid- and tau-PET. Taken together, our results in three independent samples suggest that fibre density captures the effect of cerebral small vessel disease, while fibre-bundle cross-section is largely determined by neurodegeneration. The ability of fixel-based imaging markers to capture distinct effects on white matter integrity can propel future applications in the context of precision medicine. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), fibrillar tau initially occurs locally and progresses preferentially between closely connected regions. However, the underlying sources of regional vulnerability to tau pathology remain unclear. Previous brain-autopsy findings suggest that the myelin levels—which differ substantially between white matter tracts in the brain—are a key modulating factor of region-specific susceptibility to tau deposition. Here, we investigated whether myelination differences between fiber tracts of the human connectome are predictive of the interregional spreading of tau pathology in AD. Methods: We included two independently recruited samples consisting of amyloid-PET-positive asymptomatic and symptomatic elderly individuals, in whom tau-PET was obtained at baseline (ADNI: n = 275; BioFINDER-1: n = 102) and longitudinally in a subset (ADNI: n = 123, mean FU = 1.53 [0.69–3.95] years; BioFINDER-1: n = 39, mean FU = 1.87 [1.21–2.78] years). We constructed MRI templates of the myelin water fraction (MWF) in 200 gray matter ROIs and connecting fiber tracts obtained from adult cognitively normal participants. Using the same 200 ROI brain-parcellation atlas, we obtained tau-PET ROI values from each individual in ADNI and BioFINDER-1. In a spatial regression analysis, we first tested the association between cortical myelin and group-average tau-PET signal in the amyloid-positive and control groups. Secondly, employing a previously established approach of modeling tau-PET spreading based on functional connectivity between ROIs, we estimated in a linear regression analysis, whether the level of fiber-tract myelin modulates the association between functional connectivity and longitudinal tau-PET spreading (i.e., covariance) between ROIs. Results: We found that higher myelinated cortical regions show lower tau-PET uptake (ADNI: rho = − 0.267, p < 0.001; BioFINDER-1: rho = − 0.175, p = 0.013). Fiber-tract myelin levels modulated the association between functional connectivity and tau-PET spreading, such that at higher levels of fiber-tract myelin, the association between stronger connectivity and higher covariance of tau-PET between the connected ROIs was attenuated (interaction fiber-tract myelin × functional connectivity: ADNI: β = − 0.185, p < 0.001; BioFINDER-1: β = − 0.166, p < 0.001). Conclusion: Higher levels of myelin are associated with lower susceptibility of the connected regions to accumulate fibrillar tau. These results enhance our understanding of brain substrates that explain regional variation in tau accumulation and encourage future studies to investigate potential underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: Interleukin 6 (IL-6) signaling is being investigated as a therapeutic target for atherosclerotic cardiovascular disease (CVD). While changes in circulating high-sensitivity C-reactive protein (hsCRP) are used as a marker of IL-6 signaling, it is not known whether there is effect heterogeneity in relation to baseline hsCRP levels or other cardiovascular risk factors. The aim of this study was to explore the association of genetically predicted IL-6 signaling with CVD risk across populations stratified by baseline hsCRP levels and cardiovascular risk factors.Methods: Among 397,060 White British UK Biobank participants without known CVD at baseline, we calculated a genetic risk score for IL-6 receptor (IL-6R)-mediated signaling, composed of 26 variants at the IL6R gene locus. We then applied linear and non-linear Mendelian randomization analyses exploring associations with a combined endpoint of incident coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, and cardiovascular death stratifying by baseline hsCRP levels and cardiovascular risk factors.Results: The study participants (median age 59 years, 53.9% females) were followed-up for a median of 8.8 years, over which time a total of 46,033 incident cardiovascular events occurred. Genetically predicted IL-6R-mediated signaling activity was associated with higher CVD risk (hazard ratio per 1-mg/dL increment in absolute hsCRP levels: 1.11, 95% CI: 1.06-1.17). The increase in CVD risk was linearly related to baseline absolute hsCRP levels. There was no evidence of heterogeneity in the association of genetically predicted IL-6R-mediated signaling with CVD risk when stratifying the population by sex, age, body mass index, estimated glomerular filtration rate, or systolic blood pressure, but there was evidence of greater associations in individuals with low-density lipoprotein cholesterol ≥ 160 mg/dL.Conclusions: Any benefit of inhibiting IL-6 signaling for CVD risk reduction is likely to be proportional to absolute reductions in hsCRP levels. Therapeutic inhibition of IL-6 signaling for CVD risk reduction should therefore prioritize those individuals with the highest baseline levels of hsCRP. [ABSTRACT FROM AUTHOR]

Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (-3.47, -3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [-0.05 mg/dl per year, (-0.07, -0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage. [ABSTRACT FROM AUTHOR]

Background: Complicated nonstenosing carotid artery plaques (CAPs) are an under-recognized cause of stroke.Objectives: The purpose of this study was to determine whether complicated CAP ipsilateral to acute ischemic anterior circulation stroke (icCAP) are associated with recurrent ischemic stroke or transient ischemic attack (TIA).Methods: The CAPIAS (Carotid Plaque Imaging in Acute Stroke) multicenter study prospectively recruited patients with ischemic stroke restricted to the territory of a single carotid artery. Complicated (AHA-lesion type VI) CAP were defined by multisequence, contrast-enhanced carotid magnetic resonance imaging obtained within 10 days from stroke onset. Recurrent events were assessed after 3, 12, 24, and 36 months. The primary outcome was recurrent ischemic stroke or TIA.Results: Among 196 patients enrolled, 104 patients had cryptogenic stroke and nonstenosing CAP. During a mean follow-up of 30 months, recurrent ischemic stroke or TIA occurred in 21 patients. Recurrent events were significantly more frequent in patients with icCAP than in patients without icCAP, both in the overall cohort (incidence rate [3-year interval]: 9.50 vs 3.61 per 100 patient-years; P = 0.025, log-rank test) and in patients with cryptogenic stroke (10.92 vs 1.82 per 100 patient-years; P = 0.003). The results were driven by ipsilateral events. A ruptured fibrous cap (HR: 4.91; 95% CI: 1.31-18.45; P = 0.018) and intraplaque hemorrhage (HR: 4.37; 95% CI: 1.20-15.97; P = 0.026) were associated with a significantly increased risk of recurrent events in patients with cryptogenic stroke.Conclusions: Complicated CAP ipsilateral to acute ischemic anterior circulation stroke are associated with an increased risk of recurrent ischemic stroke or TIA. Carotid plaque imaging identifies high-risk patients who might be suited for inclusion into future secondary prevention trials. (Carotid Plaque Imaging in Acute Stroke [CAPIAS]; NCT01284933). [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) is an age-related condition and a major cause of intracerebral hemorrhage and cognitive decline that shows close links with Alzheimer's disease (AD). CAA is characterized by the aggregation of amyloid-β (Aβ) peptides and formation of Aβ deposits in the brain vasculature resulting in a disruption of the angioarchitecture. Capillaries are a critical site of Aβ pathology in CAA type 1 and become dysfunctional during disease progression. Here, applying an advanced protocol for the isolation of parenchymal microvessels from post-mortem brain tissue combined with liquid chromatography tandem mass spectrometry (LC–MS/MS), we determined the proteomes of CAA type 1 cases (n = 12) including a patient with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and of AD cases without microvascular amyloid pathology (n = 13) in comparison to neurologically healthy controls (n = 12). ELISA measurements revealed microvascular Aβ1-40 levels to be exclusively enriched in CAA samples (mean: > 3000-fold compared to controls). The proteomic profile of CAA type 1 was characterized by massive enrichment of multiple predominantly secreted proteins and showed significant overlap with the recently reported brain microvascular proteome of patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease (SVD) characterized by the aggregation of the Notch3 extracellular domain. We found this overlap to be largely attributable to the accumulation of high-temperature requirement protein A1 (HTRA1), a serine protease with an established role in the brain vasculature, and several of its substrates. Notably, this signature was not present in AD cases. We further show that HTRA1 co-localizes with Aβ deposits in brain capillaries from CAA type 1 patients indicating a pathologic recruitment process. Together, these findings suggest a central role of HTRA1-dependent protein homeostasis in the CAA microvasculature and a molecular connection between multiple types of brain microvascular disease. [ABSTRACT FROM AUTHOR]

Age-related loss of white matter microstructural integrity is a major determinant of cognitive decline, dementia and gait disorders. However, the mechanisms and molecular pathways that contribute to this loss of integrity remain elusive. We performed a genome-wide association study of white matter microstructural integrity as quantified by diffusion MRI metrics (mean diffusivity and fractional anisotropy) in up to 31 128 individuals from UK Biobank (age 45-81 years) based on a two degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP × Age effects. We identified 18 loci that were associated at genome-wide significance with either mean diffusivity (n = 16) or fractional anisotropy (n = 6). Among the top loci was a region on chromosome 6 encoding the human major histocompatibility complex (MHC). Variants in the MHC region were strongly associated with both mean diffusivity [best SNP: 6:28866209_TTTTG_T, beta (standard error, SE) = -0.069 (0.009); 2df P = 6.5 × 10-15] and fractional anisotropy [best SNP: rs3129787, beta (SE) = -0.056 (0.008); 2df P = 3.5 × 10-12]. Of the imputed human leukocyte antigen (HLA) alleles and complement component 4 (C4) structural haplotype variants in the human MHC, the strongest association was with the C4-BS variant [for mean diffusivity: beta (SE) = -0.070 (0.010); P = 2.7 × 10-11; for fractional anisotropy: beta (SE) = -0.054 (0.011); P = 1.6 × 10-7]. After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older participants [age ≥ 65; interaction P = 0.0019 (mean diffusivity), P = 0.015 (fractional anisotropy)] and in participants without a history of smoking [interaction P = 0.00093 (mean diffusivity), P = 0.021 (fractional anisotropy)]. Taken together, our findings demonstrate a role of the complement system and of gene-environment interactions in age-related loss of white matter microstructural integrity. [ABSTRACT FROM AUTHOR]

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na+ channel NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1aL1649Q knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na+ -channel inactivation and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K+ -sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1aL1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na+ currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD. [ABSTRACT FROM AUTHOR]

Background: To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment. Methods: In this longitudinal study, we included 396 cognitively normal to dementia subjects with 18F-Florbetapir/18F-Florbetaben-amyloid-PET, 18F-Flortaucipir-tau-PET and ~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive(+)/negative(−) at pre-established cut-offs, classifying subjects as Braak0/BraakI+/BraakI–IV+/BraakI–VI+/Braakatypical+. In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia. Results: Baseline global tau-PET SUVRs explained more variance (partial R2) in future cognitive decline than Centiloid across all cognitive tests (Cohen's d ~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group (p < 0.001), and elevated conversion risk to MCI/dementia. Conclusion: Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, β = -0.74, standard error (SE) = 0.13, P = 9.7 × 10-9]. Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10-6, false discovery rate = 0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204-364; β = 0.79, SE = 0.14, P = 9.4 × 10-8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by ∼11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (β = 0.26, SE = 0.02, P = 2.9 × 10-59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (β = 0.44, SE = 0.14, P = 0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (P = 1.5 × 10-4, false discovery rate = 0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (odds ratio = 12.24, 95%CI: 2.54-35.25; P = 8.3 × 10-5]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population. [ABSTRACT FROM AUTHOR]

Background: To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment. Methods: In this longitudinal study, we included 396 cognitively normal to dementia subjects with 18F-Florbetapir/18F-Florbetaben-amyloid-PET, 18F-Flortaucipir-tau-PET and ~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive(+)/negative(−) at pre-established cut-offs, classifying subjects as Braak0/BraakI+/BraakI–IV+/BraakI–VI+/Braakatypical+. In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia. Results: Baseline global tau-PET SUVRs explained more variance (partial R2) in future cognitive decline than Centiloid across all cognitive tests (Cohen's d ~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group (p < 0.001), and elevated conversion risk to MCI/dementia. Conclusion: Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings. [ABSTRACT FROM AUTHOR]

Background: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk.Methods: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies.Results: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; P=0.003) and CAD (marginal inclusion probability, 0.92; P=0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84-0.91]; P=9×10-10) and CAD (odds ratio,0.66 [95% CI, 0.63-0.69]; P=4×10-73), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29-4.60]; P<1×10-6). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; P=2.3×10-4), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; P=0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 [95% CI, 1.03-1.04]; P=1.0×10-33).Conclusions: ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD. [ABSTRACT FROM AUTHOR]

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer's disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Ab deposition. Germ-free (GF) AD mice exhibit a substantially reduced Ab plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Ab plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Ab plaques upon SCFA supplementation, microglia contained less intracellular Ab. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Ab deposition likely via modulation of the microglial phenotype. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. [ABSTRACT FROM AUTHOR]

The article discusses in Alzheimer's disease the Braak staging scheme suggests a stereotypical tau spreading pattern that has not capture interindividual variability in tau deposition. Topics include a connectivity-based, patient-centered tau spreading model improved the assessment of tau accumulation rates compared to Braak stage–specific readouts and reduced sample sizes by 40%; and tau pathology have hallmark pathologies of Alzheimer's disease.

Background: The underlying etiology of ischemic stroke remains unknown in up to 30% of patients.Objectives: This study explored the causal role of complicated (American Heart Association-lesion type VI) nonstenosing carotid artery plaques (CAPs) in cryptogenic stroke (CS).Methods: CAPIAS (Carotid Plaque Imaging in Acute Stroke) is an observational multicenter study that prospectively recruited patients aged older than 49 years with acute ischemic stroke that was restricted to the territory of a single carotid artery on brain magnetic resonance imaging (MRI) and unilateral or bilateral CAP (≥2 mm, NASCET [North American Symptomatic Carotid Endarterectomy Trial] <70%). CAP characteristics were determined qualitatively and quantitatively by high-resolution, contrast-enhanced carotid MRI at 3T using dedicated surface coils. The pre-specified study hypotheses were that that the prevalence of complicated CAP would be higher ipsilateral to the infarct than contralateral to the infarct in CS and higher in CS compared with patients with cardioembolic or small vessel stroke (CES/SVS) as a combined reference group. Patients with large artery stroke (LAS) and NASCET 50% to 69% stenosis served as an additional comparison group.Results: Among 234 recruited patients, 196 had either CS (n = 104), CES/SVS (n = 79), or LAS (n = 19) and complete carotid MRI data. The prevalence of complicated CAP in patients with CS was significantly higher ipsilateral (31%) to the infarct compared with contralateral to the infarct (12%; p = 0.0005). Moreover, the prevalence of ipsilateral complicated CAP was significantly higher in CS (31%) compared with CES/SVS (15%; p = 0.02) and lower in CS compared with LAS (68%; p = 0.003). Lipid-rich and/or necrotic cores in ipsilateral CAP were significantly larger in CS compared with CES/SVS (p < 0.05).Conclusions: These findings substantiate the role of complicated nonstenosing CAP as an under-recognized cause of stroke. (Carotid Plaque Imaging in Acute Stroke [CAPIAS]; NCT01284933). [ABSTRACT FROM AUTHOR]

The fate of subcortical diffusion-weighted imaging (DWI) lesions in stroke patients is highly variable, ranging from complete tissue loss to no visible lesion on follow-up. Little is known about within-lesion heterogeneity and its relevance for stroke outcome. Patients with subcortical stroke and recruited through the prospective DEDEMAS study (NCT01334749) were examined at baseline (n = 45), six months (n = 45), and three years (n = 28) post-stroke. We performed high-resolution structural MRI including DWI. Tissue fate was determined voxel-wise using fully automated tissue segmentation. Within-lesion heterogeneity at baseline was assessed by free water diffusion imaging measures. The majority of DWI lesions (66%) showed cavitation on six months follow-up but the proportion of tissue turning into a cavity was small (9 ± 13.5% of the DWI lesion). On average, 69 ± 25% of the initial lesion resolved without any visually apparent signal abnormality. The extent of cavitation at six months post-stroke was independently associated with clinical outcome, i.e. modified Rankin scale score at six months (OR = 4.71, p = 0.005). DWI lesion size and the free water-corrected tissue mean diffusivity at baseline independently predicted cavitation. In conclusion, the proportion of cavitating tissue is typically small, but relevant for clinical outcome. Within-lesion heterogeneity at baseline on advanced diffusion imaging is predictive of tissue fate. [ABSTRACT FROM AUTHOR]

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial. [ABSTRACT FROM AUTHOR]

Recovery after stroke is a multicellular process encompassing neurons, resident immune cells, and brain-invading cells. Stroke alters the gut microbiome, which in turn has considerable impact on stroke outcome. However, the mechanisms underlying gut- brain interaction and implications for long-term recovery are largely elusive. Here, we tested the hypothesis that short-chain fatty acids (SCFAs), key bioactive microbial metabolites, are the missing link along the gut- brain axis and might be able to modulate recovery after experimental stroke. SCFA supplementation in the drinking water of male mice significantly improved recovery of affected limb motor function. Using in vivo wide-field calcium imaging, we observed that SCFAs induced altered contralesional cortex connectivity. This was associated with SCFA-dependent changes in spine and synapse densities. RNA sequencing of the forebrain cortex indicated a potential involvement of microglial cells in contributing to the structural and functional remodeling. Further analyses confirmed a substantial impact of SCFAs on microglial activation, which depended on the recruitment of T cells to the infarcted brain. Our findings identified that microbiota-derived SCFAs modulate poststroke recovery via effects on systemic and brain resident immune cells. [ABSTRACT FROM AUTHOR]

Background: Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide.Methods: Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank.Results: Suitable genetic proxies for angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01-1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04-2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83-1.32).Conclusions: Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation. [ABSTRACT FROM AUTHOR]

Cognitive impairment associated with aging has emerged as one of the major public health challenges of our time. Although Alzheimer's disease is the leading cause of clinically diagnosed dementia in Western countries, cognitive impairment of vascular etiology is the second most common cause and may be the predominant one in East Asia. Furthermore, alterations of the large and small cerebral vasculature, including those affecting the microcirculation of the subcortical white matter, are key contributors to the clinical expression of cognitive dysfunction caused by other pathologies, including Alzheimer's disease. This scientific expert panel provides a critical appraisal of the epidemiology, pathobiology, neuropathology, and neuroimaging of vascular cognitive impairment and dementia, and of current diagnostic and therapeutic approaches. Unresolved issues are also examined to shed light on new basic and clinical research avenues that may lead to mitigating one of the most devastating human conditions. [ABSTRACT FROM AUTHOR]

Previous studies showed that various types of cerebral lesions, as assessed on MRI, largely contribute to the clinical severity of CADASIL. However, the clinical impact of longitudinal changes of classical markers of small vessel disease on conventional MRI has been only poorly investigated. One hundred sixty NOTCH3 mutation carriers (mean age ± SD, 49.8 ± 10.9 years) were followed over three years. Validated methods were used to determine the percent brain volume change (PBVC), number of incident lacunes, change of volume of white matter hyperintensities and change of number of cerebral microbleeds. Multivariable logistic regression analyses were performed to assess the independent association between changes of these MRI markers and incident clinical events. Mixed-effect multiple linear regression analyses were used to assess their association with changes of clinical scales. Over a mean period of 3.1 ± 0.2 years, incident lacunes are found independently associated with incident stroke and change of Trail Making Test Part B. PBVC is independently associated with all incident events and clinical scale changes except the modified Rankin Scale at three years. Our results suggest that, on conventional MRI, PBVC and the number of incident lacunes are the most sensitive and independent correlates of clinical worsening over three years in CADASIL. [ABSTRACT FROM AUTHOR]

The article discusses how Moyamoya Disease Susceptibility Variant RNF213 p.R4810K Increases the Risk of Ischemic Stroke Attributable to Large-Artery Atherosclerosis. Topics include how Ischemic stroke (IS) is the leading cause of disability and early death in Asia, where large-artery atherosclerosis (LAA) attributable to intracranial stenosis is the predominant etiology.

White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain. [ABSTRACT FROM AUTHOR]

Small vessel diseases (SVDs) are a group of disorders that result from pathological alteration of the small blood vessels in the brain, including the small arteries, capillaries and veins. Of the 35–36 million people that are estimated to suffer from dementia worldwide, up to 65% have an SVD component. Furthermore, SVD causes 20–25% of strokes, worsens outcome after stroke and is a leading cause of disability, cognitive impairment and poor mobility. Yet the underlying cause(s) of SVD are not fully understood. Magnetic resonance imaging has confirmed enlarged perivascular spaces (PVS) as a hallmark feature of SVD. In healthy tissue, these spaces are proposed to form part of a complex brain fluid drainage system which supports interstitial fluid exchange and may also facilitate clearance of waste products from the brain. The pathophysiological signature of PVS and what this infers about their function and interaction with cerebral microcirculation, plus subsequent downstream effects on lesion development in the brain has not been established. Here we discuss the potential of enlarged PVS to be a unique biomarker for SVD and related brain disorders with a vascular component. We propose that widening of PVS suggests presence of peri-vascular cell debris and other waste products that form part of a vicious cycle involving impaired cerebrovascular reactivity, blood-brain barrier dysfunction, perivascular inflammation and ultimately impaired clearance of waste proteins from the interstitial fluid space, leading to accumulation of toxins, hypoxia, and tissue damage. Here, we outline current knowledge, questions and hypotheses regarding understanding the brain fluid dynamics underpinning dementia and stroke through the common denominator of SVD. [ABSTRACT FROM AUTHOR]

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity. [ABSTRACT FROM AUTHOR]

Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell-expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed “deNEDDylase”) and a subunit of the cullin-RING E3 ligase-regulating COP9 signalosome complex, attenuates proinflammatory NF-κB signaling. We previously showed that CSN5 is up-regulated in human atherosclerotic arteries. Here, we investigated the role of CSN5 in atherogenesis in vivo by using mice with myeloid-specific Csn5 deletion. Genetic deletion of Csn5 in Apoe−/− mice markedly exacerbated atherosclerotic lesion formation. This was broadly observed in aortic root, arch, and total aorta of male mice, whereas the effect was less pronounced and site-specific in females. Mechanistically, Csn5 KO potentiated NF-κB signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1α levels were reduced. Inversely, inhibition of NEDDylation by MLN4924 blocked proinflammatory gene expression and NF-κB activation while enhancing HIF-1α levels and the expression of M2 marker Arginase 1 in inflammatory-elicited macrophages. MLN4924 further attenuated the expression of chemokines and adhesion molecules in endothelial cells and reduced NF-κB activation and monocyte arrest on activated endothelium in vitro. In vivo, MLN4924 reduced LPS-induced inflammation, favored an antiinflammatory macrophage phenotype, and decreased the progression of early atherosclerotic lesions in mice. On the contrary, MLN4924 treatment increased neutrophil and monocyte counts in blood and had no net effect on the progression of more advanced lesions. Our data show that CSN5 is atheroprotective. We conclude that MLN4924 may be useful in preventing early atherogenesis, whereas selectively promoting CSN5-mediated deNEDDylation may be beneficial in all stages of atherosclerosis. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and best known monogenic small vessel disease. Here, we review the clinical, neuroimaging, neuropathological, genetic, and therapeutic aspects based on the most relevant articles published between 1994 and 2016 and on the personal experience of the authors, all directly involved in CADASIL research and care. We conclude with some suggestions that may help in the clinical practice and management of these patients. [ABSTRACT FROM AUTHOR]

Acute brain ischemia induces a local neuroinflammatory reaction and alters peripheral immune homeostasis at the same time. Recent evidence has suggested a key role of the gut microbiota in autoimmune diseases by modulating immune homeostasis. Therefore, we investigated the mechanistic link among acute brain ischemia, microbiota alterations, and the immune response after brain injury. Using two distinct models of acute middle cerebral artery occlusion, we show by next-generation sequencing that large stroke lesions cause gut microbiota dysbiosis, which in turn affects stroke outcome via immune-mediated mechanisms. Reduced species diversity and bacterial overgrowth of bacteroidetes were identified as hallmarks of poststroke dysbiosis, which was associated with intestinal barrier dysfunction and reduced intestinal motility as determined by in vivo intestinal bolus tracking. Recolonizing germ-free mice with dysbiotic poststroke microbiota exacerbates lesion volume and functional deficits after experimental stroke compared with the recolonization with a normal control microbiota. In addition, recolonization of mice with a dysbiotic microbiome induces a proinflammatory T-cell polarization in the intestinal immune compartment and in the ischemic brain. Using in vivo cell-tracking studies, we demonstrate the migration of intestinal lymphocytes to the ischemic brain. Therapeutic transplantation of fecal microbiota normalizes brain lesion-induced dysbiosis and improves stroke outcome. These results support a novel mechanism in which the gut microbiome is a target of stroke-induced systemic alterations and an effector with substantial impact on stroke outcome. [ABSTRACT FROM AUTHOR]

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease represents a heterogeneous group of disorders leading to stroke and cognitive impairment. While most small vessel diseases appear sporadic and related to age and hypertension, several early-onset monogenic forms have also been reported. However, only a minority of patients with familial small vessel disease carry mutations in one of known small vessel disease genes. We used whole exome sequencing to identify candidate genes in an autosomal dominant small vessel disease family in which known small vessel disease genes had been excluded, and subsequently screened all candidate genes in 201 unrelated probands with a familial small vessel disease of unknown aetiology, using high throughput multiplex polymerase chain reaction and next generation sequencing. A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family. Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (P = 4.2 × 10(-6); odds ratio = 15.4; 95% confidence interval = 4.9-45.5), strongly suggesting causality. Seven of these variants were located within or close to the HTRA1 protease domain, three were in the N-terminal domain of unknown function and one in the C-terminal PDZ domain. In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect. Clinical features of this autosomal dominant small vessel disease differ from those of CARASIL and CADASIL by a later age of onset and the absence of the typical extraneurological features of CARASIL. They are similar to those of sporadic small vessel disease, except for their familial nature. Our data demonstrate that heterozygous HTRA1 mutations are an important cause of familial small vessel disease, and that screening of HTRA1 should be considered in all patients with a hereditary small vessel disease of unknown aetiology. [ABSTRACT FROM AUTHOR]

The velocity of collateral filling can be assessed in dynamic time-resolved computed tomography (CT) angiographies and may predict initial CT perfusion (CTP) and follow-up lesion size. We included all patients with an M1± internal carotid artery (ICA) occlusion and follow-up imaging from an existing cohort of 1791 consecutive patients who underwent multimodal CT for suspected stroke. The velocity of collateral filling was quantified using the delay of time-to-peak (TTP) enhancement of the M2 segment distal to the occlusion. Cerebral blood volume (CBV) and mean transit time (MTT)-CBV mismatch were assessed in initial CTP. Follow-up lesion size was assessed by magnetic resonance imaging (MRI) or non-enhanced CT (NECT). Multivariate analyses were performed to adjust for extent of collateralization and type of treatment. Our study comprised 116 patients. Multivariate analysis showed a short collateral blood flow delay to be an independent predictor of a small CBV lesion (P<0.001) and a large relative mismatch (P<0.001) on initial CTP, of a small follow-up lesion (P<0.001), and of a small difference between initial CBV and follow-up lesion size (P=0.024). Other independent predictors of a small lesion on follow-up were a high morphologic collateral grade (P=0.001), lack of an additional ICA occlusion (P=0.009), and intravenous thrombolysis (P=0.022). Fast filling of collaterals predicts initial CTP and follow-up lesion size and is independent of extent of collateralization. [ABSTRACT FROM AUTHOR]

High temperature requirement protein A1 (HtrA1) is a primarily secreted serine protease involved in a variety of cellular processes including transforming growth factor β (TGF-β) signaling. Loss of its activity causes cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an inherited form of cerebral small vessel disease leading to early-onset stroke and premature dementia. Dysregulated TGF-β signaling is considered to promote CARASIL pathogenesis, but the underlying molecular mechanisms are incompletely understood. Here we present evidence from mouse brain tissue and embryonic fibroblasts as well as patient skin fibroblasts for a facilitating role of HtrA1 in TGF-β pathway activation. We identify latent TGF-β binding protein 1 (LTBP-1), an extracellular matrix protein and key regulator of TGF-β bioavailability, as a novel HtrA1 target. Cleavage occurs at physiological protease concentrations, is prevented under HtrA1-deficient conditions as well as by CARASIL mutations and disrupts both LTBP-1 binding to fibronectin and its incorporation into the extracellular matrix. Hence, our data suggest an attenuation of TGF-β signaling caused by a lack of HtrA1-mediated LTBP-1 processing as mechanism underlying CARASIL pathogenesis. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) histogram metrics are correlated with clinical parameters in cerebral small vessel diseases (cSVD). Whether ADC histogram parameters derived from simple diffusion weighted imaging (DWI) can provide relevant markers for long term studies of cSVD remains unknown. CADASIL patients were evaluated by DWI and DTI in a large cohort study overa6-year period. ADC histogram parameters were compared to those derived from mean diffusivity (MD) histograms in 280 patients using intra-class correlation and Bland-Altman plots. Impact of image corrections applied to ADC maps was assessed and a mixed effect model was used for analyzing the effects of scanner upgrades. The results showed that ADC histogram parameters are strongly correlated to MD histogram parameters and that image corrections have only limited influence on these results. Unexpectedly, scanner upgrades were found to have major effects on diffusion measures with DWI or DTI that can be even larger than those related to patients’ characteristics. These data support that ADC histograms from daily used DWI can provide relevant parameters for assessing cSVD, but the variability related to scanner upgrades as regularly performed in clinical centers should be determined precisely for longitudinal and multicentric studies using diffusion MRI in cSVD. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to conduct a systematic review and meta-analysis to determine precise estimates of the predictive value of carotid intraplaque hemorrhage (IPH) as determined by magnetic resonance imaging (MRI) for cerebrovascular events. Background: There is emerging evidence that MR-based carotid atherosclerotic plaque assessment identifies high-risk features associated with cerebrovascular events. However, available data are based on smaller samples with heterogeneous source populations despite a promising value for noninvasive risk stratification. Methods: We searched PubMed, EMBASE, and the Cochrane Library through September 2012 for studies that followed >35 individuals after baseline MRI. Independent observers abstracted information on populations, MR techniques, outcomes, and study quality. Risk estimates of the presence of IPH for cerebrovascular events were derived in random effects regression analysis, and causes of heterogeneity were determined in meta-regression analysis. Results: We identified 8 eligible studies including 689 participants who underwent carotid MRI. The prevalence of IPH at baseline was high (49.0%). Over a median follow-up of 19.6 months, a total of 108 cerebrovascular events occurred (15.7% event rate). The presence of IPH was associated with an ∼6-fold higher risk for events (hazard ratio [HR]: 5.69; 95% confidence interval [CI]: 2.98 to 10.87). The annualized event rate in subjects with detectable IPH was 17.71% compared with 2.43% in patients without IPH. Meta-regression analysis showed symptomatic subjects had higher risks as compared with asymptomatic subjects (HR: 11.71, 95% CI: 5.17 to 26.48 vs. HR: 3.50, 95% CI: 2.59 to 4.73, p = 0.0065), Also, differences were observed for sex and sample size (all p < 0.01), with moderate visual publication bias due to missing smaller sample-size studies (p = 0.18). Conclusions: Presence of IPH on MRI strongly predicts cerebrovascular events. Homogenization of future studies is warranted to allow for sufficient assessment of level of evidence for intervention trials. [Copyright &y& Elsevier]

White matter hyperintensities and lacunes are among the most frequent abnormalities on brain magnetic resonance imaging. They are commonly related to cerebral small vessel disease and associated with both stroke and dementia. We examined the spatial relationships between incident lacunes and white matter hyperintensities and related these findings to information on vascular anatomy to study possible mechanistic links between the two lesion types. Two hundred and seventy-six patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetically defined small vessel disease with mutations in the NOTCH3 gene were followed with magnetic resonance imaging over a total of 633 patient years. Using difference images and Jacobian maps from registered images we identified 104 incident lacunes. The majority (n = 95; 91.3%) of lacunes developed at the edge of a white matter hyperintensity whereas few lacunes were found to develop fully within (n = 6; 5.8%) or outside (n = 3; 2.9%) white matter hyperintensities. Adding information on vascular anatomy revealed that the majority of incident lacunes developed proximal to a white matter hyperintensity along the course of perforating vessels supplying the respective brain region. We further studied the spatial relationship between prevalent lacunes and white matter hyperintensities both in 365 patients with CADASIL and in 588 elderly subjects from the Austrian Stroke Prevention Study. The results were consistent with the results for incident lacunes. Lesion prevalence maps in different disease stages showed a spread of lesions towards subcortical regions in both cohorts. Our findings suggest that the mechanisms of lacunes and white matter hyperintensities are intimately connected and identify the edge of white matter hyperintensities as a predilection site for lacunes. Our observations further support and refine the concept of the white matter hyperintensity penumbra. [ABSTRACT FROM PUBLISHER]

Background In up to 30% of patients with ischemic stroke no definite etiology can be established. A significant proportion of cryptogenic stroke cases may be due to non-stenosing atherosclerotic plaques or low grade carotid artery stenosis not fulfilling common criteria for atherothrombotic stroke. The aim of the CAPIAS study is to determine the frequency, characteristics, clinical and radiological long-term consequences of ipsilateral complicated American Heart Association lesion type VI (AHA-LT VI) carotid artery plaques in patients with cryptogenic stroke. Methods/ design 300 patients (age >49 years) with unilateral DWI-positive lesions in the anterior circulation and non- or moderately stenosing (<70% NASCET) internal carotid artery plaques will be enrolled in the prospective multicenter study CAPIAS. Carotid plaque characteristics will be determined by high-resolution black-blood carotid MRI at baseline and 12 month follow up. Primary outcome is the prevalence of complicated AHA-LT VI plaques in cryptogenic stroke patients ipsilateral to the ischemic stroke compared to the contralateral side and to patients with defined stroke etiology. Secondary outcomes include the association of AHA-LT VI plaques with the recurrence rates of ischemic events up to 36 months, rates of new ischemic lesions on cerebral MRI (including clinically silent lesions) after 12 months and the influence of specific AHA-LT VI plaque features on the progression of atherosclerotic disease burden, on specific infarct patterns, biomarkers and aortic arch plaques. Discussion CAPIAS will provide important insights into the role of non-stenosing carotid artery plaques in cryptogenic stroke. The results might have implications for our understanding of stroke mechanism, offer new diagnostic options and provide the basis for the planning of targeted interventional studies. [ABSTRACT FROM AUTHOR]