Abstract Background and aims Elevated heart rate is associated with hypertension and poor cardiovascular health, but low heart rates may reflect either cardiovascular fitness or disease, may predispose to paroxysmal atrial fibrillation (AF) and are associated with increased cerebral pulsatility and thus small vessel disease. However, the relationship with stroke risk is unclear. We determined these relationships in UK Biobank. Methods UK-Biobank is a large, community-based, longitudinal cohort recruiting > 500,000 UK participants since 2007, with face-to-face assessment and healthcare data-linkage. Associations between baseline heart-rate and stroke were determined by incidence rate and Cox proportional hazards regression, unadjusted and adjusted for age, sex and cardiovascular risk factors, including AF at any time. Results Over 13.2 years (6.1 million person-years), 11,733 strokes occurred among 460,554 participants (194/100,000 person-years). Risk of stroke was lowest with baseline heart rates of 60–69 bpm (173/100,000Pyrs) and increased at both low (<50 bpm) and high (≥90 bpm) heart rate (236 and 271/100,000Pyrs), quadratic P < 0.001. After full adjustment, low heart-rate was significantly associated with stroke risk (HR 1.29, 95%CI 1.17–1.43, P < 0.001) as was high heart-rate (HR 1.17, 95%CI 1.08–1.27, P < 0.001). In stratified analyses, the U-shaped pattern was only significant in participants without AF (n = 458,098), with no significant interaction between heart rate and AF (P = 0.078). Conclusions Resting heart rate demonstrates a significantly U-shaped relationship with incident stroke, independent of a diagnosis of AF. Whether low heart rates are a marker of cardiovascular dysfunction or could have a causal role is unclear in the absence of interventional studies. Conflict of interest Dexter Penn: nothing to disclose. Figure 1 - belongs to Methods Figure 2 - belongs to Results

Abstract Background and aims Cerebrovascular reactivity (CVR) is impaired in cerebral small vessel disease (CSVD), commonly assessed using CO₂ inhalation during MRI. However, this is methodologically challenging and uncomfortable. We assessed whether resting-state BOLD may provide a non-invasive alternative. Methods The crossover-design OxHARP trial tested three weeks of sildenafil versus placebo on MRI-CVR, assessed by 6%-CO₂ gas challenge. Resting-state, high-frequency BOLD-MRI (TR=0.4s, multiband 6) was also acquired with concurrent measurement of end-tidal CO2. After motion correction, high-pass filtering, brain extraction and voxel-wise correction for temporal delays, CVR was determined as correlation between standardised BOLD per mmHg change in etCO2, within grey (GM) and white matter (WM). Agreement between scans was determined by ICC and linear regression, and effects of drug treatment by mixed-effects linear models. Results Across 93 scans, there was significant agreement between challenge-CVR and resting-state CVR in GM (r=0.629, p<0.001, ICC=0.773) and WM (r=0.598, p<0.001, ICC=0.749). There was a similar voxel-wise pattern of increased CVR on sildenafil with both acquisitions, but the average difference by ROIs was only significant with challenge-CVR (Challenge: GM p=0.0108, WM p=0.0020; Resting-state: GM p=0.20, WM: p=0.099). Conclusions Optimised resting-state scanning demonstrates strong agreement with CO₂ gas challenge measures of CVR and may provide a feasible alternative for large-scale CVR assessment, or in populations where individuals are less able to tolerate a gas challenge. However, gas challenges remain optimal for cleanly detecting drug-induced CVR changes in clinical trials. Conflict of interest Vanessa Hyde: nothing to disclose Figure 1 - belongs to Results Figure 2 - belongs to Results

BACKGROUND:Alzheimer's disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one-third of the population-attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50-70%). The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy), and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischemic stroke and intracerebral hemorrhage also contributes. AIMS AND METHODS:In this World Stroke Organization (WSO) scientific statement, we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive. RESULTS:We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalog transcriptomic and proteomic studies that have revealed novel candidate molecules (COL4A1/4A2, HTRA1, TRIM47, FOXF2) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease and potential biochemical markers (vascular endothelial growth factor-A, placental growth factor, interleukin-6, matrix metalloproteinase-9, cathepsin-B). We highlight the potential for vascular interventions to treat not only vascular dementia but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signaling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3 fatty acids, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia. CONCLUSION:The vascular contribution to dementia is i) substantial, ii) increasingly understood at molecular and mechanistic levels, iii) a source of potential treatment opportunities.Data Access Statement:no original data are presented in this document.

Abstract Background and aims Cerebral small vessel disease (cSVD) is associated with cerebral endothelial and haemodynamic dysfunction but the role of impaired cerebral autoregulation (CA) is unknown. Methods OxHARP is a randomised, double-blind, crossover trial, comparing the cerebrovascular haemodynamic effects of sildenafil versus placebo in mild-moderate cSVD. During at-least 5 minutes of bilateral TCD and BP monitoring, we derived autoregulatory indices in the frequency domain (Transfer-function gain, phase and coherence at <0.05Hz(VLF),0.05-0.15Hz(LF),0.15-0.4Hz(HF)) and time domain (Autoregulatory Index-ARI and Mx). Standardised linear regression adjusting for age, sex and cerebral blood flow velocity examined associations between CA, WMH burden (as volume on MRI or ordinal severity on any imaging) and age. Results Among 60/75 participants (mean 68 years, 58% male), ARI reduced with increasing WMH-severity (Figure-1), comparing mild versus moderate or severe disease, whilst Mx reduced with increasing WMH-volume. Unadjusted frequency domain indices were non-significantly reduced. Associations between WMH volume and ARI or Mx were no longer significant when adjusting for age, despite similar magnitudes, and only reduced VLF gain remained independently associated with WMH (β=-0.40/SD, 95%CI 0.78 to -0.02, p = 0.040). Conclusions Cerebral autoregulation was impaired with increasing white matter hyperintensities in time-domain analyses, suggesting potential mechanistic links between CA and cSVD. However, it was unclear if this relationship was independent of age and further research will be required to discriminate the potential of autoregulation as a marker of endothelial dysfunction. Conflict of interest Kevin Wong. nothing to disclose. Figure 1 - belongs to Results

Cerebral autoregulation is the fundamental mechanism that regulates cerebral blood flow in the face of blood pressure variability. It is a dynamic process that depends on vascular smooth muscle cell contractile function, driven by myogenic, chemical, and autonomic mechanisms. Cerebral small vessel disease (cSVD) is associated with increased blood pressure variation due to systemic hemodynamic dysfunction, as well as dysfunction of the cerebral small vessels, characterized by endothelial dysfunction and vascular reactivity. As such, cerebral autoregulation may be impaired in cSVD, either as a manifestation of the disease or as a cause. This narrative review addresses current clinical evidence for involvement of autoregulatory dysfunction in cSVD. It discusses the mechanisms of autoregulation; how these overlap with vascular mechanisms involved in cSVD; methods of measurement of autoregulation in these patients; evidence for altered autoregulation in patients with either sporadic cSVD, previous stroke, or specific forms of cSVD; and effects of potential therapies for cSVD on autoregulation. This review thereby identifies the potential importance of autoregulation in cSVD, highlights current limitations in our understanding, and outlines future research avenues.

Abstract Background and aims Cerebral small vessel disease (cSVD) is responsible for 30% of all-cause stroke. Endothelin-1 (ET-1) is the most potent cerebral endothelial vasoconstrictor. ET-1 is elevated during acute stroke and predicts cognitive outcomes. However, its potential in stroke prevention remains undetermined. We therefore performed a meta-analysis of stroke incidence in randomised controlled trials (RCTs) of ET-1 antagonists. Methods MEDLINE, EMBASE and CENTRAL were searched from inception until October 2025, including RCTs of ET-1 antagonists versus placebo/standard care (≥12 weeks) which reported stroke incidence. We excluded trials requiring large vessel cerebrovascular pathologies (subarachnoid haemorrhage, Moya-moya etc). Results were combined by inverse-variance weighted random effects meta-analysis. Results 6/7 eligible RCTs (N=4,177) reported lower incidence of stroke during ET-1 inhibition versus controls (pooled incidence rate ratio (IRR)=0.35, 95% CI:0.19-0.66, p=0.00113; I2=0, p-heterogeneity=0.979), although event rates were low in most trials. Effects were consistent in trials with ≥52 weeks of follow-up (pooled IRR=0.301, 95% CI:0.143-0.634, p=0.0016; I2=0, p-heterogeneity=0.99). Although no longer significant (pooled IRR=0.48, p=0.177), the effect was similar when excluding the large SONAR trial in chronic kidney disease (CKD) which independently demonstrated a significant benefit using atrasentan (IRR= 0.296, p=0.0024; 8 vs 27 events in 2,648 participants). Conclusions ET-1 antagonism was associated with reduced incidence of stroke in RCTs of populations at risk of cSVD, consistent with a significant effect in the large SONAR trial in CKD which dominated results. Endothelin-1 antagonism warrants testing as a novel target to reduce risk of cSVD-related stroke. Conflict of interest Caoimhe Byrne: PhD funded by the Alzheimer's Society Doctoral Training Centre for Vascular and Immune Contributors to Dementia (VIDA). Prof Webb: Nothing to disclose. Figure 1 - belongs to Results

BACKGROUND AND AIMS:Vasodilating drugs targeting the endothelium could reduce long-term harms due to cerebral small vessel disease (cSVD) but there are no commonly accepted methods to measure short-term disease activity or drug response. In the OxHARP clinical trial, we determined the most sensitive physiological markers of treatment response to sildenafil versus placebo on either transcranial ultrasound (TCD) or magnetic resonance imaging (MRI), and their validity compared to disease severity and other measures of other physiological mechanisms. METHODS:In the OxHARP double-blind, randomized, placebo-controlled crossover trial we measured aortic blood pressure, mean flow velocity (MFV), cerebral pulsatility, cerebrovascular conductance index (CVCi = MFV/aortic mean BP), cerebral perfusion (pcASL-MRI) and cerebrovascular reactivity to inhaled CO2 on TCD (CVR-TCD) and MRI in white (CVR-WM), gray (CVR-GM) and white matter hyperintensities (CVR-WMH). Effects of 3 weeks of sildenafil were compared to placebo. Validity of markers were determined by between-visit repeatability (intraclass correlation coefficient (ICC)); associations with CVR-TCD, CVR-WMH and CVR-GM; associations with other markers; the magnitude of response, and sensitivity, to sildenafil. RESULTS:In 69 participants, repeatability was greatest for MFV, pulsatility, CVCi and CVR-WMH (ICC > 0.8), very good for CVR-TCD and GM-perfusion (ICC > 0.7), and good for CVR-GM (ICC > 0.6). CVR-TCD was associated with CVR on MRI (CVR-WMH: r2 = 0.12, p = 0.02; CVR-GM: r2 = 0.22, p = 0.001), while blood flow measures on TCD (MFV, CVCi) were associated with CVR-TCD and perfusion-MRI (all p < 0.05). All markers were associated with WMH volume and improved by sildenafil, but CVCi was most sensitive, requiring only 20 patients for a crossover trial at 80% power, compared to 26 for GM-perfusion or 84 for CVR-GM. CONCLUSIONS:Multiple markers were associated with cSVD, but no single marker reflected all physiological drug effects. CVCi and gray matter perfusion on MRI were the most sensitive markers of disease activity and drug response, although CVR indices may be more specific for endothelial dysfunction.

BACKGROUND:In the Oxford Haemodynamic Adaptation to Reduce Pulsatility trial (OxHARP), sildenafil increased cerebrovascular reactivity but did not reduce cerebral pulsatility, a marker of vascular aging. This analysis of OxHARP tested whether these potentially causative mechanisms were independently associated with the severity of white matter hyperintensities (WMHs). AIMS:The aims were to determine independence of the relationship between severity of WMHs with both cerebral pulsatility and cerebrovascular reactivity in the same population. METHODS:OxHARP was a double-blind, randomized, placebo-controlled, crossover trial of phosphodiesterase inhibitors in patients with mild-to-moderate WMH and previous minor cerebrovascular events. It determined effects on cerebrovascular pulsatility and reactivity on transcranial ultrasound and reactivity on magnetic resonance imaging (MRI). Associations were determined between baseline ultrasound measures, and averaged MRI measures across follow-up, with the severity of WMH on clinical imaging (Fazekas or modified Blennow scores) and WMH volume in the MRI substudy, by ordinal and linear regression. RESULTS:In 75/75 patients (median 70 years, 78% male), cerebral pulsatility was associated with age (p < 0.001) whereas reactivity on ultrasound was not (p = 0.29). Severity of WMH in all participants was independently associated with decreased cerebrovascular reactivity and increased cerebral pulsatility (pulsatility p = 0.016; reactivity p = 0.03), with a trend to a synergistic interaction (p = 0.075). Reactivity on ultrasound was still associated with WMH after further adjustment for age (p = 0.017), but pulsatility was not (p = 0.31). Volume of WMH in the MRI substudy was also independently associated with both markers on ultrasound (pulsatility p = 0.005; reactivity p = 0.029) and was associated with reduced cerebrovascular reactivity within WMH on MRI (p < 0.0001). CONCLUSION:WMHs are independently associated with cerebral pulsatility and reactivity, representing complementary potential disease mechanisms and treatment targets. TRIAL REGISTRATION:clinicaltrials.org: https://classic. CLINICALTRIALS:gov/ct2/show/NCT03855332.

Background: Internal carotid artery (ICA) blood flow may be an alternative target to measure cerebrovascular reactivity (CVR) and endothelium-dependent vasodilatory dysfunction. We investigated the feasibility of testing CVR in the ICA during routine clinical carotid investigation. Methods: CVR was assessed by effects of breath-hold (BH) and rapid-breathing (RB) on ICA diameter, blood velocities (peak systolic velocity [PSV], end diastolic velocity [EDV], and mean velocity [MV]), volume flow, and relative to changes in end-tidal carbon dioxide (end-tidal CO2 [etCO2]; CVRPSV, CVREDV, CVRMV, and CVRFlow). Feasibility and validity were determined by data quality, agreement between challenges, and association with age. Results: In 50 patients (68 ± 13 years old, 15 female), recordings during rest, BH, and RB were of good quality in 96%, 90%, and 88%, respectively. Age-related reductions in blood velocities were evident during rest (EDV: r2 = 0.37, P < 0.0001), BH (EDV: r2 = 0.42, P < 0.001), and RB (EDV, r2 = 0.50, P < 0.0001). During BH, the absolute changes in blood velocities (EDV: r2 = 0.15, P < 0.01), etCO2 (r2 = 0.10, P = 0.03), CVREDV (r2 = 0.13, P = 0.02), and CVRMV (r2 = 0.11, P = 0.03) were smaller in older patients. In contrast, during RB, absolute changes in blood velocities and etCO2 were not age related, but changes in volume flow (r2 = 0.12, P = 0.02), CVRMV (r2 = 0.11, P = 0.03), and CVRFlow (r2 = 0.16, P < 0.01) were greater in older patients. Conclusion: During routine carotid duplex assessment, assessing CVR in the ICA was feasible, practical, and associated with high quality recordings. Differential associations with age between hypercapnic and hypocapnic stimuli imply a greater tendency to vasoconstriction in older patients.

BACKGROUND:Cerebral small vessel disease (CSVD) causes between 25% and 30% of all ischemic strokes. In acute lacunar ischemic stroke, despite often mild initial symptoms, early neurological deterioration (END) occurs in approximately 15-20% of patients and is associated with poor functional outcome, yet its mechanisms are not well understood. AIMS:In this review, we systematically evaluated data on: (1) definitions and incidence of END, (2) mechanisms of small vessel occlusion, (3) predictors and mechanisms of END, and (4) prospects for the prevention or treatment of patients with END. SUMMARY OF REVIEW:We identified 67 reports (including 13,407 participants) describing the incidence of END in acute lacunar ischemic stroke. The specified timescale for END varied from <24 h to 3 weeks. The rate of END ranged between 2.3% and 47.5% with a pooled incidence of 23.54% (95% confidence interval (CI) = 21.02-26.05) but heterogeneity was high (I2 = 90.29%). The rates of END defined by National Institutes of Health Stroke Scale (NIHSS) decreases of ⩾1, ⩾2, ⩾3, and 4 points were as follows: 24.17 (21.19-27.16)%, 22.98 (20.48-25.30)%, 23.33 (16.23-30.42)%, and 10.79 (2.09-23.13)%, respectively, with lowest heterogeneity and greatest precision for a cutoff of ⩾2 points. Of the 20/67 studies (30%) reporting associations of END with clinical outcome, 19/20 (95%) reported worse outcomes (usually measured using the modified Rankin score at 90 days or at hospital discharge) in patients with END. In a meta-regression analysis, female sex, hypertension, diabetes, and smoking were associated with END. CONCLUSIONS:END occurs in more than 20% of patients with acute lacunar ischemic stroke and might provide a novel target for clinical trials. A definition of an NIHSS ⩾2 decrease is most used and provides the best between-study homogeneity. END is consistently associated with poor functional outcome. Further research is needed to better identify patients at risk of END, to understand the underlying mechanisms, and to carry out new trials to test potential interventions.

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.

Mid-life vascular risk factors predict late-life cerebrovascular diseases and poor global brain health. Although endothelial dysfunction is hypothesized to contribute to this process, evidence of impaired neurovascular function in early stages remains limited. In this cross-sectional study of 31,934 middle-aged individuals from UK Biobank without established cerebrovascular disease, the overall 10-year risk of cardiovascular events was associated with reduced neurovascular coupling (p < 2 × 10-16) during a visual task with functional MRI, including in participants with no clinically apparent brain injury on MRI. Diabetes, smoking, waist-hip ratio, and hypertension were each strongly associated with decreased neurovascular coupling with the strongest relationships for diabetes and smoking, whilst in older adults there was an inverted U-shaped relationship with DBP, peaking at 70-80 mmHg DBP. These findings indicate that mid-life vascular risk factors are associated with impaired cerebral endothelial-dependent neurovascular function in the absence of overt brain injury. Neurovascular dysfunction, measured by neurovascular coupling, may play a role in the development of late-life cerebrovascular disease, underscoring the need for further longitudinal studies to explore its potential as a mediator of long-term cerebrovascular risk.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (triangle peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; triangle end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9x10(-8); cilostazol-placebo, 0.06, 0.03-0.09; P=5.1x10(-5)). Both drugs increased headaches (P=1.1x10(-4)), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease.

Circadian and diurnal variation in cerebral blood flow directly contributes to the diurnal variation in the risk of stroke, either through factors that trigger stroke or due to impaired compensatory mechanisms. Cerebral blood flow results from the integration of systemic hemodynamics, including heart rate, cardiac output, and blood pressure, with cerebrovascular regulatory mechanisms, including cerebrovascular reactivity, autoregulation, and neurovascular coupling. We review the evidence for the circadian and diurnal variation in each of these mechanisms and their integration, from the detailed evidence for mechanisms underlying the nocturnal nadir and morning surge in blood pressure to identifying limited available evidence for circadian and diurnal variation in cerebrovascular compensatory mechanisms. We, thus, identify key systemic hemodynamic factors related to the diurnal variation in the risk of stroke but particularly identify the need for further research focused on cerebrovascular regulatory mechanisms.

BackgroundCerebral small vessel disease (cSVD) is associated with endothelial dysfunction but the pathophysiology is poorly understood. Low-frequency oscillations (LFOs) in the BOLD signal partly reflect cerebrovascular function and have the potential to identify endothelial dysfunction in cSVD. A systematic review was performed to assess the reported relationships between imaging markers of cSVD and LFOs.MethodsMedline and EMBASE were searched for original studies reporting an association between LFOs and STRIVE-defined imaging markers of cSVD, including: white matter hyperintensities (WMH), enlarged perivascular spaces, lacunes, CADASIL, and cerebral microbleeds, from inception to September 1, 2022. Variations in LFOs were extracted, where available, on a global, tissue-specific, or regional level, in addition to participant demographics, data acquisition, methods of analysis, and study quality. Where a formal meta-analysis was not possible, differences in the number of studies reporting LFO magnitude by presence or severity of cSVD were determined by sign test.Results15 studies were included from 841 titles. Studies varied in quality, acquisition parameters, and in method of analysis. Amplitude of low-frequency fluctuation (ALFF) in resting state fMRI was most commonly assessed (12 studies). Across 15 studies with differing markers of cSVD (9 with WMH; 1 with cerebral microbleeds; 1 with lacunar infarcts; 1 with CADASIL; 3 with multiple markers), LFOs in patients with cSVD were decreased in the posterior cortex (22 of 32 occurrences across all studies, p = 0.05), increased in the deep grey nuclei (7 of 7 occurrences across all studies, p = 0.016), and potentially increased in the temporal lobes (9 of 11 occurrences across all studies, p = 0.065).ConclusionDespite limited consensus on the optimal acquisition and analysis methods, there was reasonably consistent regional variation in LFO magnitude by severity of cSVD markers, supporting its potential as a novel index of endothelial dysfunction. We propose a consistent approach to measuring LFOs to characterise targetable mechanisms underlying cSVD.

Purpose: The pathogenesis of cerebral small vessel disease (cSVD) remains elusive despite evidence of an association between white matter hyperintensities (WMH) and endothelial cerebrovascular dysfunction. Neurovascular coupling (NVC) may be a practical alternative measure of endothelial function. We performed a systematic review of reported associations between NVC and cSVD. Methods: EMBASE and PubMed were searched for studies reporting an association between any STRIVE-defined marker of cSVD and a measure of NVC during functional magnetic resonance imaging, transcranial Doppler, positron emission tomography, near-infrared spectroscopy or single-photon emission computed tomography, from inception to November 3rd, 2022. Where quantitative data was available from studies using consistent tests and analyses, results were combined by inverse-variance weighted random effects meta-analysis. Findings: Of 29 studies (19 case-controls; 10 cohorts), 26 reported decreased NVC with increasing severity of cSVD, of which 18 were individually significant. In 28 studies reporting associations with increasing WMH, 25 reported reduced NVC. Other markers of cSVD were associated with reduced NVC in: eight of nine studies with cerebral microbleeds (six showing a significant effect); three of five studies with lacunar stroke; no studies reported an association with enlarged perivascular spaces. Specific SVD diseases were particularly associated with reduced NVC, including six out of seven studies in cerebral amyloid angiopathy and all four studies in CADASIL. In limited meta-analyses, %BOLD occipital change to a visual stimulus was consistently reduced with more severe WMH (seven studies, SMD −1.51, p < 0.01) and increasing microbleeds (seven studies, SMD −1.31, p < 0.01). Discussion and Conclusion: In multiple, small studies, neurovascular coupling was reduced in patients with increasing severity of all markers of cSVD in sporadic disease, CAA and CADASIL. Cerebrovascular endothelial dysfunction, manifest as impaired NVC, may be a common marker of physiological dysfunction due to small vessel injury that can be easily measured in large studies and clinical practice.

Studies of neurodegenerative disease risk in gout are contradictory. Relationships with neuroimaging markers of brain structure, which may offer insights, are uncertain. Here we investigated associations between gout, brain structure, and neurodegenerative disease incidence. Gout patients had smaller global and regional brain volumes and markers of higher brain iron, using both observational and genetic approaches. Participants with gout also had higher incidence of all-cause dementia, Parkinson's disease, and probable essential tremor. Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis. These findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases. Motor and cognitive impairments may affect gout patients, particularly in early years after diagnosis.

Objective: Arterial stiffness, cerebral pulsatility, and beat-to-beat blood pressure variability partly mediate the relationship between hypertension and stroke, but it is unknown if these intermediate phenotypes of vascular ageing differ between stroke aetiologies. We therefore aimed to characterize differences in these intermediate cardiovascular phenotypes between patients presenting with strokes of different aetiologies. Methods: In consecutive patients on best medical management 1 month after TIA or nondisabling stroke (Oxford Vascular Study), arterial stiffness (PWV) was measured by applanation tonometry (Sphygmocor), middle cerebral blood flow velocity, and pulsatility index (MCA-PI) were measured by transcranial ultrasound (TCD, DWL Doppler Box), and beat-to-beat BP variability was measured with a Finometer. Differences between patients with large artery (LAS), small vessel (SVD), cardioembolic (CE), or undetermined events were derived, including adjustment for cardiovascular risk factors. Relationships were characterized by mixed linear models. Results: In 909 eligible patients, MCA-PI, PWV, and SBPV were all positively skewed. Mean values were greatest in LAS than CE and lowest in SVD (p < 0.001). However, after adjustment for age, sex, and risk factors, PI was greatest in LAS and lowest in CE stroke, whilst PWV was greatest in SVD and undetermined stroke (p < 0.001). In multivariate linear models, age was more strongly associated with PWV and PI in patients with small vessel stroke than other aetiologies, particularly under the age of 65, but SBPV was only weakly associated with demographic indices in all stroke subtypes. Conclusions: Intermediate cardiovascular phenotypes of vascular ageing had similar demographic associations between stroke aetiologies, but these were particularly strong in patients with small vessel stroke under the age of 65, implying a potential role of these phenotypes in increasing stroke risk in this patient group.