Small Vessel Disease Patients Research Articles

Are central and systemic inflammation associated with fatigue in cerebral small vessel disease?

Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET-MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (β = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. Data for this study are available from the corresponding author upon reasonable request.

Memory deficit in patients with cerebral small vessel disease: evidence from eye tracking technology.

Cerebral small vessel disease is the one of the most prevalent causes of vascular cognitive impairment. We aimed to find objective and process-based indicators related to memory function to assist in the detection of memory impairment in patients with cerebral small vessel disease. Thirty-nine cerebral small vessel disease patients and 22 healthy controls were invited to complete neurological examinations, neuropsychological assessments, and eye tracking tasks. Eye tracking indicators were recorded and analyzed in combination with imaging features. The cerebral small vessel disease patients scored lower on traditional memory task and performed worse on eye tracking memory task performance compared to the healthy controls. The cerebral small vessel disease patients exhibited longer visit duration and more visit count within areas of interest and targets and decreased percentage value of total visit duration on target images to total visit duration on areas of interest during decoding stage among all levels. Our results demonstrated the cerebral small vessel disease patients performed worse in memory scale and eye tracking memory task, potentially due to their heightened attentional allocation to nontarget images during the retrieval stage. The eye tracking memory task could provide process-based indicators to be a beneficial complement to memory assessment and new insights into mechanism of memory impairment in cerebral small vessel disease patients.

The Clinical Characteristics of Cerebral Small Vessel Disease Patients with Motoric Cognitive Risk Syndrome During Single- and Dual-Task Walking

ObjectiveWe aimed to (1) identify neuroimaging biomarkers of distinguishing motoric cognitive risk syndrome (MCRS) risk among older Chinese adults with cerebral small vessel disease (CSVD) and (2) detect differences in gait parameters and neuroimaging biomarkers between CSVD individual with and without MCRS, especially during dual-task walking (DTW). MethodsWe enrolled 126 inpatients with CSVD who were divided into two groups according to MCRS status. Data on basic parameters, variability, asymmetry, and coordination were collected during single-task walking (STW) and DTW. Neuroimaging features (white matter hyperintensities, lacunes, and microbleeds) and total disease burden were calculated. Analysis of variance and logistic regression analyses were applied to assess the role of STW, DTW, and neuroimaging biomarkers in MCRS. ResultsIn total, 126 consecutive inpatients with CSVD were included (84 and 42 patients were classified as MCRS-negative and MCRS-positive, respectively). The MCRS-positive group showed poorer performance for nearly all gait parameters compared with the MCRS-negative group during cognitive DTW. Meanwhile, all gait parameters except asymmetry were assessed in participants with MCRS for significant deterioration during cognitive DTW compared with that during STW. However, only basic parameters differed between STW and cognitive DTW in participants without MCRS. A significant independent association between total CSVD scores and MCRS was also detected. ConclusionsFor CSVD patients, with higher total CSVD burden rather than any single neuroimaging marker, was linked to a greater risk of MCRS. In addition, CSVD individuals with MCRS had higher variability and phase coordination index (PCI), especially in cognitive DTW. Thus, they should concentrate more on their gait variability or coordination and reduce secondary task loads while walking in daily life, especially in cognitive secondary tasks.

Abstract 61: The Effect of Remote Ischemic Conditioning in Stroke Subtypes: A Subgroup Analysis From the RESIST Trial

Introduction: Remote ischemic conditioning (RIC) is a simple and non-invasive procedure that has proved safe and feasible in numerous smaller clinical trials. Still, mixed results have been found in recent large randomized controlled trials. Here we present a predefined subgroup analysis of the RESIST trial on the effect of RIC in subgroups of acute ischemic stroke (AIS) and whether this effect is modified by adherence to RIC. Methods: The subgroups were defined as large artery atherosclerotic disease (LAA), small vessel disease (SVD), cardioembolic, and unknown/other/multiple/rare, and were based on ICD-10 discharge diagnoses assigned by the treating physician to define stroke etiology. Acceptable treatment adherence was defined as at least 80% received out of planned cycles. The outcome analysis used the entire range (‘shift analysis’) of the 90-day modified Rankin Scale score (ordinal logistic regression). ClinicalTrials.gov:NCT03481777. Results: A total of 902 patients were included in the target population group, 466 in the sham group, and 436 in the RIC group. RIC did not significantly improve functional outcome in adherent patients with LAA, cardioembolic or multiple/unknown etiologies. In SVD patients (n=94), with good treatment adherence, RIC treatment was associated with a significantly improved 90-day functional outcome, unadjusted OR (95% CI): 2.47 (1.01-6.02), p= 0.047. In patients with SVD, 4 patients (8%) in the RIC group compared to 0 patients in the sham group had atrial fibrillation (AF), p=0.050. The association remained significant after adjusting for AF, adjusted OR (95% CI): 2.64 (1.07-6.54), p= 0.035. Conclusions: In patients with AIS due to SVD, who had good treatment adherence, RIC treatment was associated with improved functional outcome at 90 days. These results are encouraging but should only be hypothesis-generating for future studies.

Associations of Lipoprotein(a) Level with Cerebral Small Vessel Disease in Patients with Alzheimer's Disease.

This study aimed to examine the association of lipoprotein(a) [Lp(a)] level with the burden of cerebral small vessel disease (CSVD) in patients with Alzheimer's disease (AD). Data from 111 consecutive patients with AD admitted to Nanjing First Hospital from 2015 to 2022 were retrospectively analyzed in this study. Serum Lp(a) concentrations were grouped into tertiles (T1-T3). Brain magnetic resonance imaging (MRI) was rated for the presence of CSVD, including enlarged perivascular spaces (EPVS), lacunes, white-matter lesions, and cerebral microbleeds (CMBs). The CSVD burden was calculated by summing the scores of each MRI marker at baseline. A binary or ordinal logistic regression model was used to estimate the relationship of serum Lp(a) levels with CSVD burden and each MRI marker. Patients with higher tertiles of Lp(a) levels were less likely to have any CSVD (T1, 94.6%; T2, 78.4%; T3, 66.2%; p = 0.013). Multivariable analysis found that Lp(a) levels were inversely associated with the presence of CSVD (T2 vs. T1: adjusted odds ratio [aOR] 0.132, 95% confidence interval [CI] 0.018-0.946, p = 0.044; T3 vs. T1: aOR 0.109, 95% CI 0.016-0.737, p = 0.023) and CSVD burden (T3 vs. T1: aOR 0.576, 95% CI 0.362-0.915, p = 0.019). The independent relationship between Lp(a) levels and individual CSVD features was significant for moderate-to-severe EPVS in the centrum semiovale (T2 vs. T1: aOR 0.059, 95% CI 0.006-0.542, p = 0.012; T3 vs. T1: aOR 0.029, 95% CI 0.003-0.273, p = 0.002) and CMBs (T3 vs. T1: aOR 0.144, 95% CI 0.029-0.716, p = 0.018). In this study, serum Lp(a) level was inversely associated with CSVD in AD patients.

Characteristic patterns of functional connectivity-mediated cerebral small vessel disease-related cognitive impairment and depression.

Cerebral small vessel disease is common in most individuals aged 60years or older, and it is associated with cognitive dysfunction, depression, anxiety disorder, and mobility problems. Currently, many cerebral small vessel disease patients have both cognitive impairment and depressive symptoms, but the relationship between the 2 is unclear. The present research combined static and dynamic functional network connectivity methods to explore the patterns of functional networks in cerebral small vessel disease individuals with cognitive impairment and depression (cerebral small vessel disease-mild cognitive impairment with depression) and their relationship. We found specific functional network patterns in the cerebral small vessel disease-mild cognitive impairment with depression individuals (P < 0.05). The cerebral small vessel disease individuals with depression exhibited unstable dynamic functional network connectivity states (transitions likelihood: P = 0.040). In addition, we found that the connections within the lateral visual network between the sensorimotor network and ventral attention network could mediate white matter hyperintensity-related cognitive impairment (indirect effect: 0.064; 95% CI: 0.003, 0.170) and depression (indirect effect: -0.415; 95% CI: -1.080, -0.011). Cognitive function can negatively regulate white matter hyperintensity-related depression. These findings elucidate the association between cognitive impairment and depression and provide new insights into the underlying mechanism of cerebral small vessel disease-related cognitive dysfunction and depression.

Correlation between Carotid Blood Flow Velocity and Total Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease in Patients with Recent Small Subcortical Infarcts

Background: The common and internal carotid arteries are the upstream vessels of the small cerebral vessels. The relationship between hemodynamic changes in the significant cervical vessels and cerebral small vessel disease (CSVD) remains uncertain. This research sought to analyze the correlation between carotid blood flow velocity and the total magnetic resonance imaging (MRI) burden of CSVD in patients with recent small subcortical infarcts (RSSIs). background: The common and internal carotid arteries are the upstream vessels of the small cerebral vessels. The relationship between hemodynamic changes in the significant cervical vessels and cerebral small vessel disease (CSVD) remains uncertain. Methods: Data were gathered from individuals diagnosed with RSSIs admitted to Changzhou Second People's Hospital between January 2022 and June 2023. Brain MRI was performed on every patient to determine the overall MRI burden of CSVD, along with carotid duplex ultrasound to evaluate carotid blood flow velocity and pulsatility index (PI) of the common carotid (CCA) and internal carotid (ICA) arteries. The association between carotid blood flow velocity and the total MRI load of CSVD was examined using univariate and multivariate analyses. objective: This research sought to analyze the correlation between carotid blood flow velocity and the total magnetic resonance imaging (MRI) burden of CSVD in patients with recent small subcortical infarcts(RSSIs). Results: For our investigation, 272 individuals with RSSIs were screened. 82 individuals had a moderate to severe load of CSVD, while 190 participants showed a mild burden. Patients with moderate to severe burden of CSVD had lower end-diastolic velocity (EDV) and higher PI in CCA and ICA than those with mild load (P &lt; 0.001). After adjusting for variables like age, hypertension, systolic blood pressure, and blood homocysteine levels, multivariate logistic regression analysis showed that EDV in CCA (OR, 0.894; P = 0.011), PI in CCA (OR, 5.869; P = 0.017), EDV in ICA (OR, 0.909; P = 0.008), and PI in ICA (OR, 5.324; P = 0.041) were independently related to moderate to severe CSVD burden. Spearman correlation analysis showed that EDV in CCA and ICA was negatively related to the total MRI load of CSVD in patients with RSSIs (P &lt; 0.001). PI in CCA and ICA was positively associated with the whole MRI load of CSVD (P &lt; 0.001). Conclusion: Low carotid blood flow velocity and high carotid pulsatility index are independently associated with moderate to severe burden of CSVD. other: none

Relationships between intracranial arterial dolichoectasia and small vessel disease in patients with ischaemic stroke: a systematic review and meta-analysis.

Intracranial arterial dolichoectasia (IADE) is a common arterial finding of dilation, elongation, or both, affecting large intracranial vessels, and associated with vascular risk factors, including hypertension. Associations of IADE with neuroimaging cerebral small vessel disease (CSVD) may be relevant for diagnosis and prognosis in patients with stroke. The study aimed to conduct an updated systematic review and meta-analysis of observational studies to investigate the relationships of IADE with well-defined CSVD markers in patients with ischaemic stroke. We systematically searched PubMed, Embase, and Scopus for studies on IADE in ischaemic stroke patients with fulfilling predefined inclusion criteria. We pooled data to conduct a meta-analysis to compare the prevalence of SVD markers between patients with and without IADE groups using risk ratios (RRs) and 95% confidence intervals (CIs). From 157 retrieved abstracts, we included six studies from seven publications comprising 6102 patients with ischaemic stroke. The mean age of patients was 52.8years, and 3691 (60.5%) were male. IADE was diagnosed in 11.4% (95% CI 8.9-13.9) (761) of included patients; 51.8% (3160) had hypertension. Compared to patients without IADE, individuals diagnosed with IADE had a significantly increased prevalence of lacune (RR 1.67, 95% CI 1.36-2.06, P < 0.01, I2 = 0.00%), cerebral microbleeds (CMBs) (RR 2.56, 95% CI 1.53-4.28, P < 0.01, I2 = 84.95%) and white matter hyperintensities (WMHs) (RR 2.17, 95% CI 1.84-2.56, P < 0.01, I2 = 0.00%). In patients with ischaemic stroke, IADE is associated with a higher prevalence of CSVD markers, including lacunes, CMBs, and WMHs. Further studies are needed to clarify the mechanisms underlying these associations and their potential relevance for the understanding, diagnosis, and treatment of CSVD.

Comparison of Clinical Outcomes Among Various Percutaneous Coronary Intervention Strategies for Small Coronary Artery Disease

It remains unclear which percutaneous coronary intervention (PCI) strategy is the most preferable in small-vessel coronary artery disease (CAD) patients. We sought to evaluate the clinical efficacy of various PCI strategies for patients with small-vessel CAD through a network meta-analysis of randomized controlled trials (RCTs). We searched multiple databases for RCTs investigating the efficacy of the following PCI strategies for small-vessel CAD (<3 mm in diameter): drug-coated balloons (DCB), early-generation paclitaxel-eluting stents and sirolimus-eluting stents (SES), newer-generation drug-eluting stents (DES), bare-metal stents (BMS), cutting balloon angioplasty, and balloon angioplasty (BA). The primary outcome was the trial-defined major adverse cardiovascular events (MACE), mostly defined as a composite of death, myocardial infarction, and revascularization. The secondary outcomes included each component of MACE and angiographic binary restenosis. We performed a sensitivity analysis for RCTs without BMS or 1st-generation DES. Our search identified 29 eligible RCTs including 8,074 patients among the 8 PCI strategies. SES significantly reduced MACE compared with BA (HR: 0.23; 95% CI [0.10 to 0.54]) with significant heterogeneity (I2 = 55.9%), and the rankogram analysis showed that SES was the best. There were no significant differences between DCB and newer-generation DES in any clinical outcomes, which was consistent in the sensitivity analysis. BMS and BA were ranked as the worst two for most clinical outcomes. In conclusion, SES was ranked as the best for reducing MACE. There were no significant differences in clinical outcomes between DCB and newer-generation DESs. BMS and BA were regarded as the worst strategies for small-vessel CAD.

Blood-brain barrier pathology in cerebral small vessel disease.

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly. Although at first it was considered innocuous, small vessel disease is nowadays regarded as one of the major vascular causes of dementia. Radiological signs of small vessel disease include small subcortical infarcts, white matter magnetic resonance imaging hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy; however, great heterogeneity in clinical symptoms is observed in small vessel disease patients. The pathophysiology of these lesions has been linked to multiple processes, such as hypoperfusion, defective cerebrovascular reactivity, and blood-brain barrier dysfunction. Notably, studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease. Therefore, the purpose of this review is to provide a new foundation in the study of small vessel disease pathology. First, we discuss the main structural domains and functions of the blood-brain barrier. Secondly, we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease. Finally, we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

Disrupted Gray Matter Networks Associated with Cognitive Dysfunction in Cerebral Small Vessel Disease.

This study aims to investigate the disrupted topological organization of gray matter (GM) structural networks in cerebral small vessel disease (CSVD) patients with cerebral microbleeds (CMBs). Subject-wise structural networks were constructed from GM volumetric features of 49 CSVD patients with CMBs (CSVD-c), 121 CSVD patients without CMBs (CSVD-n), and 74 healthy controls. The study used graph theory to analyze the global and regional properties of the network and their correlation with cognitive performance. We found that both the control and CSVD groups exhibited efficient small-world organization in GM networks. However, compared to controls, CSVD-c and CSVD-n patients exhibited increased global and local efficiency (Eglob/Eloc) and decreased shortest path lengths (Lp), indicating increased global integration and local specialization in structural networks. Although there was no significant global topology change, partially reorganized hub distributions were found between CSVD-c and CSVD-n patients. Importantly, regional topology in nonhub regions was significantly altered between CSVD-c and CSVD-n patients, including the bilateral anterior cingulate gyrus, left superior parietal gyrus, dorsolateral superior frontal gyrus, and right MTG, which are involved in the default mode network (DMN) and sensorimotor functional modules. Intriguingly, the global metrics (Eglob, Eloc, and Lp) were significantly correlated with MoCA, AVLT, and SCWT scores in the control group but not in the CSVD-c and CSVD-n groups. In contrast, the global metrics were significantly correlated with the SDMT score in the CSVD-s and CSVD-n groups but not in the control group. Patients with CSVD show a disrupted balance between local specialization and global integration in their GM structural networks. The altered regional topology between CSVD-c and CSVD-n patients may be due to different etiological contributions, which may offer a novel understanding of the neurobiological processes involved in CSVD with CMBs.

Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment

Cerebral small vessel disease is characterised by decreased cerebral blood flow and blood–brain barrier impairments which play a key role in the development of white matter lesions. We hypothesised that cerebral hypoperfusion causes local hypoxia, affecting oligodendrocyte precursor cell—endothelial cell signalling leading to blood–brain barrier dysfunction as an early mechanism for the development of white matter lesions. Bilateral carotid artery stenosis was used as a mouse model for cerebral hypoperfusion. Pimonidazole, a hypoxic cell marker, was injected prior to humane sacrifice at day 7. Myelin content, vascular density, blood–brain barrier leakages, and hypoxic cell density were quantified. Primary mouse oligodendrocyte precursor cells were exposed to hypoxia and RNA sequencing was performed. Vegfa gene expression and protein secretion was examined in an oligodendrocyte precursor cell line exposed to hypoxia. Additionally, human blood plasma VEGFA levels were measured and correlated to blood–brain barrier permeability in normal-appearing white matter and white matter lesions of cerebral small vessel disease patients and controls. Cerebral blood flow was reduced in the stenosis mice, with an increase in hypoxic cell number and blood–brain barrier leakages in the cortical areas but no changes in myelin content or vascular density. Vegfa upregulation was identified in hypoxic oligodendrocyte precursor cells, which was mediated via Hif1α and Epas1. In humans, VEGFA plasma levels were increased in patients versus controls. VEGFA plasma levels were associated with increased blood–brain barrier permeability in normal appearing white matter of patients. Cerebral hypoperfusion mediates hypoxia induced VEGFA expression in oligodendrocyte precursor cells through Hif1α/Epas1 signalling. VEGFA could in turn increase BBB permeability. In humans, increased VEGFA plasma levels in cerebral small vessel disease patients were associated with increased blood–brain barrier permeability in the normal appearing white matter. Our results support a role of VEGFA expression in cerebral hypoperfusion as seen in cerebral small vessel disease.

Associations of renal function with cerebral small vessel disease and functional outcome in acute intracerebral haemorrhage: A hospital-based prospective cohort study

BackgroundIntracerebral haemorrhage (ICH) is a severe clinical consequence of cerebral small vessel disease (SVD), but associations between renal impairment and SVD in patients with ICH have not been fully characterised. MethodsUsing data from the CROMIS-2 ICH observational study, we compared SVD neuroimaging markers and total burden (score 0–3) identified using CT brain imaging in patients with and without renal impairment (estimated glomerular filtration rate, eGFR<60). We assessed functional outcome at 6-month follow-up using the modified Rankin scale. Results1027 participants were included (mean age 72.8, 57.1% male); 274 with and 753 without renal impairment. 18.7% of the eGFR<60 group had moderate-to-severe SVD burden (score 2–3), compared with 14.0% of those with eGFR>60 (p = 0.039). SVD burden was associated with renal impairment after adjusting for hypertension (OR 1.36, 95% CI 1.04–1.77, p = 0.023), but not after adjusting for age. Cerebral atrophy was more prevalent in patients with eGFR<60 (81.2% vs. 72.0%, p = 0.002), as were WMH (45.6% vs. 36.6%, p = 0.026). Neither was associated with renal function after adjusting for age and vascular risk factors. Renal impairment was associated with functional outcome (OR 0.65, 95% CI 0.47–0.89, p = 0.007), but not after adjusting for age, pre-morbid function and comorbidities (OR 0.95, 95% CI 0.65–1.38, p = 0.774). ConclusionIn acute ICH, renal impairment is associated with a higher cerebral SVD burden independent of hypertension, but not age. Reduced eGFR is associated with worse functional outcome, but not independent of age and comorbidities. Since CT has limited sensitivity to detect SVD severity and distribution, further studies including MRI are needed.

Evaluation of BCAS1-positive immature oligodendrocytes after cerebral ischemic stroke and SVD

Ischemic cerebrovascular disease is an important cause of physical disability and dementia. Oligodendrocytes (OLGs), which differentiate from oligodendrocyte precursor cells (OPCs), are crucial for remyelination of the damaged brain and functional recovery. Breast carcinoma amplified sequence 1 (BCAS1) has recently been shown to be highly expressed in newly formed pre-myelinating oligodendrocytes (pre-mOLGs), while its expression level is reduced in mature OLGs. In this study, we analyzed BCAS1 expression by immunohistochemical analysis of human post-mortem brain tissue from six stroke patients (death within 2 months after stroke onset) and eight small vessel disease (SVD) patients. Control post-mortem brain tissue was from eight age-matched patients without any obvious central nervous system (CNS) pathology. The Olig2 expression in the area corresponding to the same section of the BCAS1-stained slice was analyzed to determine the total oligodendrocyte lineage. The percentage of differentiating OPCs in the oligodendrocyte lineage was calculated as the ratio of BCAS1+ to Olig2+ cells (BCAS1+/Olig2+). The stroke and SVD cases showed demyelination with decreased expression of myelin basic protein (MBP, a mature OLG marker). The stroke cases showed significantly increased numbers of early-stage BCAS1+ cells with an immature morphology and Olig2+ cells (pan-oligodendrocyte lineages) in the peri-infarct areas in both the cortex and white matter, but showed no increase in the number of late-stage BCAS1+ cells with a mature morphology. In contrast, the SVD cases showed no significant increase in Olig2+ and BCAS1+ cells. These results indicated that remyelination dysfunction could be attributed to insufficient maturation of OPCs in stroke and impaired recruitment of OPCs in SVD.

Serum alkaline phosphatase was independently associated with depression in patients with cerebrovascular disease.

Blood markers have important value in the diagnosis of depressive disorders. Serum alkaline phosphatase (ALP) not only predicts stroke recurrence and poor functional prognosis in cerebrovascular disease (CVD) patients but also increases significantly in middle-aged women with depression. Thus, it has not been reported whether serum ALP is associated with the development of depression and/or vascular depression (VDe) in CVD patients. This was a cross-sectional study of 353 CVD patients (stroke patients, n = 291; cerebral small vessel disease (CSVD) patients, n = 62). Baseline demographic information, fasting blood markers (such as blood counts, liver function, kidney function and lipids), and brain CT/MRI scans were collected. CVD patients were divided into non-depression, suspected vascular depression (SVD), and positive vascular depression (PVD) groups according to their Hamilton Rating Scale for Depression (HAMD) scores. Univariate analysis of baseline data, blood markers, and the prevalence of lesions (> 1.5 cm) was performed. Subsequently, the diagnostic performance of the univariate and combined variables for SVD and PVD was analyzed using binary logistic regression. The diagnostic value of the multivariate model for VDe was analyzed by ordinal logistic regression. (1) Serum ALP (p = 0.003) and hypersensitive C-reactive protein (hs-CRP, p = 0.001) concentrations increased as HAMD scores increased, and the prevalence of brain atrophy (p = 0.016) and lesions in the basal ganglia (p = 0.001) and parietal (p = 0.001), temporal (p = 0.002), and frontal lobes (p = 0.003) also increased, whereas the concentrations of hemoglobin (Hb, p = 0.003), cholinesterase (ChE, p = 0.001), and high-density lipoprotein cholesterol (HDL-C, p = 0.005) declined. Among these variables, hs-CRP (r = 0.218, p < 0.001) had a weak positively association with HAMD scores, and ChE (r = -0.226, p < 0.001) had a weak negative association. (2) The combination of Hb, hs-CRP, ChE, ALP, and HDL-C improved diagnostic performance for VDe [AUC = 0.775, 95% CI (0.706, 0.844), p < 0.001]. (3) Hb (OR = 0.986, p = 0.049), ChE (OR = 0.999, p = 0.020), ALP (OR = 1.017, p = 0.003), and basal ganglia lesions (OR = 2.197, p < 0.001) were important factors impacting VDe development. After adjusting for Hb, hs-CRP, ChE, HDL-C, lesions in the above mentioned four locations, sex, age and the prevalence of CSVD and brain atrophy, ALP [OR = 1.016, 95% CI (1.005, 1.027), p = 0.004] was independently associated with VDe. Hb, hs-CRP, ChE, ALP, and HDL-C concentrations are potential blood markers of depression in CVD patients and, when combined, may improve diagnostic performance for VDe. Serum ALP was independently associated with VDe in patients with CVD.

Brain perfusion imaging by multi-delay arterial spin labeling: Impact of modeling dispersion and interaction with denoising strategies and pathology.

Arterial spin labeling (ASL) acquisitions at multiple post-labeling delays may provide more accurate quantification of cerebral blood flow (CBF), by fitting appropriate kinetic models and simultaneously estimating relevant parameters such as the arterial transit time (ATT) and arterial cerebral blood volume (aCBV). We evaluate the effects of denoising strategies on model fitting and parameter estimation when accounting for the dispersion of the label bolus through the vasculature in cerebrovascular disease. We analyzed multi-delay ASL data from 17 cerebral small vessel disease patients (50 ± 9 y) and 13 healthy controls (52 ± 8 y), by fitting an extended kinetic model with or without bolus dispersion. We considered two denoising strategies: removal of structured noise sources by independent component analysis (ICA) of the control-label image timeseries; and averaging the repetitions of the control-label images prior to model fitting. Modeling bolus dispersion improved estimation precision and impacted parameter values, but these effects strongly depended on whether repetitions were averaged before model fitting. In general, repetition averaging improved model fitting but adversely affected parameter values, particularly CBF and aCBV near arterial locations in patients. This suggests that using all repetitions allows better noise estimation at the earlier delays. In contrast, ICA denoising improved model fitting and estimation precision while leaving parameter values unaffected. Our results support the use of ICA denoising to improve model fitting to multi-delay ASL and suggest that using all control-label repetitions improves the estimation of macrovascular signal contributions and hence perfusion quantification near arterial locations. This is important when modeling flow dispersion in cerebrovascular pathology.

Rare neurovascular genetic and imaging markers across neurodegenerative diseases.

Cerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)-based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status. The Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non-synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1). NOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood. Further studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases.

YKL-40 as a novel biomarker related to white matter damage and cognitive impairment in patients with cerebral small vessel disease.

YKL-40 is a novel neuroinflammatory marker associated with white matter damage and cognitive dysfunction. 110 CSVD patients, including 54 with mild cognitive impairment (CSVD-MCI), 56 with no cognitive impairment (CSVD-NCI), and 40 healthy controls (HCs) underwent multimodal magnetic resonance examination, serum YKL-40 level detection and cognitive function assessment to investigate the association between YKL-40 and white matter damage and cognitive impairment in cerebral small vessel disease (CSVD) patients. White matter hyperintensities volume was calculated using the Wisconsin White Matter Hyperintensity Segmentation Toolbox (W2MHS) for white matter macrostructural damage evaluation. For white matter microstructural damage evaluation, fractional anisotropy (FA) and mean diffusivity (MD) indices of the region of interest were analyzed based on diffusion tensor imaging (DTI) images using the Tract-Based Spatial Statistics (TBSS) pipeline. The serum YKL-40 level of CSVD was significantly higher than those of HCs, and the CSVD-MCI was higher than in HCs and CSVD-NCI. Furthermore, serum YKL-40 provided high diagnostic accuracy for CSVD and CSVD-MCI. The macroscopic and microstructure of white matter in CSVD-NCI and CSVD-MCI patients indicated different degrees of damage. Disruption of white matter macroscopic and microstructure was significantly associated with YKL-40 levels and cognition deficits. Moreover, the white matter damage mediated the associations between the increased serum YKL-40 levels and cognitive impairment. Our findings demonstrated that YKL-40 might be a potential biomarker of white matter damage in CSVD, whereas white matter damage was associated with cognitive impairment. Serum YKL-40 measurement provides complementary information regarding the neural mechanism of CSVD and its associated cognitive impairment.

Low vitamin D status is associated with inflammatory response in older patients with cerebral small vessel disease.

This study aimed to determine the association of the NF-κB inflammatory signaling pathway with vitamin D status in older cerebral small vessel disease (SVD) patients. We measured serum 25(OH)D, pro-and anti-inflammatory cytokines, and mRNA levels of the vitamin D-activating enzyme, CYP27B1, as well as NF-kB, COX-2, the chemokine-CCL2, IL-1β, IL-6, TNF-α, TGF-β, and IL-10, in cerebral SVD patients aged ≥60years presenting with vascular dementia and age and gender-matched healthy controls. Low vitamin D status (insufficiency: serum 25(OH)D 12-20ng/ml; deficiency: ≤12ng/ml) was more prevalent among patients compared to controls. The mRNA levels of NF-kB, COX-2, CCL2, IL-1β, and IL-6, and serum levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, and TNF-α) were significantly higher in cases compared to controls. There was a significant correlation between CYP27B1 and NF-kB, COX-2, CCL2, and IL-1β gene expression. Serum IL-1α, IL-1β, and IL-6 concentrations and the expression of CCL-2, NF-kB2, and NF-kB3 genes were higher in vitamin D-deficient subjects compared to vitamin D-sufficient subjects. There was a significant negative correlation between serum 25(OH)D and IL-1α, IL-6, and TNF-α, and a positive correlation between 25(OH)D and IL-10. Low vitamin D is associated with an inflammatory response via NF-kB signaling, which could play a role in the etio-pathogenesis of SVD. Further large-scale studies are required to validate our findings.

Echocardiographic correlates of MRI imaging markers of cerebral small-vessel disease in patients with atrial-fibrillation-related ischemic stroke.

Atrial fibrillation (AF) has been linked to dementia risk, partly explained by cerebral small vessel disease (CSVD). Since AF and cardiovascular comorbidities were associated with cardiac dysfunction, we aimed to determine the association between echocardiographic parameters and neuroimaging markers of CSVD in patients with AF-related ischemic stroke. This cross-sectional study enrolled patients with AF-related ischemic stroke from March 2013 to December 2019 who underwent transthoracic echocardiography and brain 3T MRI, including T1, T2, Flair, and SWI imaging sequences. We assessed the presence of lacunes and cerebellar microbleeds (CMBs), the severity of white matter hyperintensity (WMH) scored by the Fazekas scale (0-6), and the severity of enlarged perivascular spaces (EPVS) in basal ganglia (BG) and centrum semiovale (CSO) classified into three categories (0-10, 10-25, and >25). CSVD burden was rated on a 0-to-4 ordinal scale. Generalized linear regression analysis and post hoc comparisons with Bonferroni correction were performed to assess the association between various echocardiographic parameters and these lesions, adjusted for demographics and potential confounders. 119 patients (68.38 ± 12.692 years; male 45.4 %) were included for analysis, of whom 55 (46.2%) had lacunes, 40 (33.6%) had CMBs, and median severity for WMH, BG-EPVS, CSO-EPVS, and CSVD burden were 2 (IQR: 1-3), 1 (IQR: 1-2), 1 (IQR: 0-1), and 1 (IQR: 1-2) respectively. In multivariable, fully adjusted models, left ventricular posterior wall thickness (LVPW) was associated with a higher risk of lacunes (RR 1.899, 95% CI: 1.342-2.686) and CSVD burden (RR = 2.081, 95%CI: 1.562-2.070). Right atrial diameter (RAD) was associated with greater CSO-EPVS (RR = 2.243, 95%CI: 1.234-4.075). No echocardiographic parameters were revealed to be associated with CMBs and WMH. In patients with AF-related ischemic stroke, LVPW is associated with a higher risk of lacunes and CSVD burden, while RAD was associated with greater CSO-EPVS. Larger studies are required to determine these associations and to elucidate if these associations can help facilitate cognitive evaluation and brain MRI screening.