Search Results (188)

Background: The predictive performance of pre-screening phenotype-based algorithms in selecting patients with cerebral small vessel disease (cSVD), one of the main causes of ischaemic and haemorrhagic stroke and dementia, more likely to harbor clinically relevant genetic variants (CRGVs) has to date been poorly defined, making it a clinical challenge to decide which patients to screen for hereditary cSVD (hcSVD). Methods: We designed a high-throughput gene panel to identify variants in 27 candidate genes associated with cSVD and screened patients selected by a specific phenotype-based algorithm at one comprehensive stroke center from 2020 to 2023. We categorized participants into two sub-groups defined by pre-screening likelihood of hcSVD (hcSVD; High-Probability Group, HPG vs. Low-Probability Group, LPG) and compared the results of molecular analysis. Results: Among 65 probands, we detected four (6.1%) pathogenic CRGVs and seven (10.7%) variants of unknown significance (VUSs) in 11 (16.9%) patients. Pathogenic CRGVs were exclusively detected in the HPG (4/22 probands), corresponding to an 18.2% prevalence of hcSVD in this group. Of the seven VUSs, five (22.7%) were detected in the HPG vs. two (4.6%) in the LPG. Conclusions: The pragmatic algorithm we are proposing has the potential to help clinicians in identifying patients who are more likely to harbor monogenic disease. Full article

Background: Endothelial and microvascular dysfunction play a central role in the pathogenesis of both cardiovascular and neurodegenerative disorders. However, whether impaired peripheral endothelial function independently predicts cognitive decline, cerebral small-vessel disease (SVD) progression, or stroke remains uncertain. Methods: We conducted a systematic review and meta-analysis of prospective cohort studies assessing the prognostic value of non-invasive peripheral endothelial tests—flow-mediated dilation (FMD), peripheral arterial tonometry (PAT/EndoPAT), and sublingual microcirculatory imaging—for cognitive or cerebrovascular outcomes. Databases (PubMed, Embase, Scopus, Web of Science) were searched from inception through 30 September 2025. Study quality was appraised using the Newcastle–Ottawa Scale (NOS), and evidence certainty was graded via GRADE. Random-effects models (DerSimonian–Laird or REML) pooled hazard ratios (HRs) using inverse-variance weighting. PROSPERO-registered (CRD42025211876). Results: Fifteen prospective cohorts (n = 13,972 participants; median follow-up 4.3 years) met inclusion criteria. Across all modalities, impaired endothelial or microvascular function predicted cognitive decline, SVD progression, or cerebrovascular events (pooled HR = 1.72, 95% CI 1.38–2.14, p < 0.001; I² = 57%). Subgroup analyses confirmed consistent associations for FMD (HR = 1.59, 95% CI 1.27–1.98) and PAT/EndoPAT (HR = 1.84, 95% CI 1.40–2.41). Evidence certainty was rated moderate-to-high according to GRADE. Conclusions: Peripheral endothelial dysfunction, measured by validated non-invasive techniques, independently predicts future cognitive and cerebrovascular events. These findings support the concept of a vascular–neural continuum, suggesting that endothelial health represents a modifiable biomarker for early neurovascular risk stratification. Routine assessment of endothelial function may help identify high-risk individuals and guide preventive interventions aimed at preserving brain and vascular health. Full article

Background: COPD patients may be prone to cerebral small vessel disease resulting in perivascular white matter lesions and consequent cognitive decline. The pathophysiological background of these observations is not completely understood. It is hypothesized that COPD may involve systemic vascular dysfunction extending to the brain. The present study aimed to assess whether acetazolamide-induced cerebral vasoreactivity and cerebrovascular reserve capacity are impaired in patients with COPD. Methods: A total of 17 patients with COPD and 20 healthy control subjects underwent transcranial Doppler monitoring before and after IV administration of 15 mg/kgBW acetazolamide for 20 min. Cerebrovascular reactivity (CVR) was defined as a percent increase in blood flow velocity in the middle cerebral artery (MBFV) after acetazolamide. Cerebrovascular reserve capacity (CVRC) was defined as the maximal percent change in MBFV during the entire registration. Results: Administration of acetazolamide resulted in a slight decrease in pH and a mild increase in PaCO₂ (both p < 0.001) in COPD patients. Absolute MBFV values were consequently higher, and pulsatility indices were lower in control subjects compared to those measured in patients with COPD. The CVR at different time points after acetazolamide and CVRC did not show any difference between COPD patients and control subjects. Conclusions: In the present study, in normocapnic mild and normocapnic moderate COPD patients, cerebrovascular reactivity is not impaired, indicating that in mild stages, cerebral arteriolar function is preserved. Further studies, using patient selection based on different severity stages of the disease, may show whether alteration of the cerebral arteriolar function is responsible for the white matter lesions and cognitive decline observed in severe COPD patients. Full article

We carried out a comprehensive literature search for publications on the range of vascular events that have been linked to adenomyosis. This covered vascular diseases, blood coagulation disorders, thrombosis, hypercoagulation, stroke (embolic, ischemic, thrombotic, hemorrhagic), cerebrovascular episodes, cerebral infarction, cerebral hemorrhage) and renal disease. This review covers 63 articles. Nineteen articles reported clinical manifestations of intravascular thrombosis in women with adenomyosis. Eleven publications were identified that reported on cerebral involvement and adenomyosis, including cases of ischemic stroke or infarction. Dysregulation primarily seems to occur via local factors leading to altered angiogenesis. Five case reports were identified that reported on various vascular complications attributed to the presence of adenomyosis. The search also identified reports of cerebral complications in women with adenomyosis. Through a secondary search, we identified publications dealing with a possible connection between cardiac complications and renal pathology, which the authors attributed to adenomyosis. Vascular involvement in adenomyosis is documented in rare cases by the presence of endometrial tissue in myometrial vessels both in menstrual and non-menstrual uteri. Women with adenomyosis have a higher platelet count, a shorter thrombin and prothrombin time and an activated partial thromboplastin time. These findings has been applied to attempts to identify therapies for adenomyosis based on targeting the vasculature, but the existence of a link between the two conditions is under question for several reasons: only case reports (or very small series) have been published; all published cases come from one region of the world (the Far East); the published literature does not contain objective proof of a causal relationship between the two pathologies, except for the elevation of some markers. In summary, it is not possible to conclude that the presence of adenomyosis has a pathogenetic role in causing vascular events, first and foremost because available evidence consists mostly of case reports. Full article

Background/Objectives: Cerebral small vessel disease (cSVD) and vascular cognitive impairment (VCI) are major contributors to stroke and dementia. Despite their importance, there are few effective treatments for cSVD and VCI. Variability in cSVD/VCI populations, intervention targets, and outcome selection may contribute to inconsistencies and challenges in clinical trial design. We reviewed the design of cSVD and VCI clinical trials to describe current practice in the selection of populations, interventions, and outcomes. Methods: We systematically searched Ovid Medline, Embase, and PsychInfo databases for recently completed cSVD/VCI trials and searched online trial registries (ClinicalTrials.gov, European Union Clinical Trials Register, and International Clinical Trials Registry Platform) for ongoing cSVD/VCI trials. We determined the use of specific categories of inclusion and exclusion criteria, interventions, and outcomes in the included trials and described these as counts and percentages. Results: We included a total of 82 cSVD trials and 120 VCI trials. Neuroimaging features were most frequently used as inclusion criteria for cSVD (88%) and cognition for VCI (88%). There was substantial variation in eligible ages for participation. Both cSVD and VCI trials largely excluded patients with comorbidities, vascular risk factors, and neuropsychiatric disorders, with a notable proportion of cSVD trials excluding on the basis of functional impairment. The most studied intervention classes were repurposed cardiovascular drugs (40%) for cSVD and Traditional Chinese Medicine (35%) in VCI. The most common primary outcome category was neuroimaging for cSVD (53%) and cognition for VCI (86%). Notably, functional outcomes were underused in both cSVD and VCI trials (13% and 12%, respectively, for primary outcomes). Conclusions: We have identified substantial variability in all aspects of cSVD and VCI clinical trial design. Inconsistent neuroimaging criteria and exclusions based on common long-term conditions limit the generalisability of findings. There is a need for greater focus on clinical outcomes, particularly functional ability, to better reflect treatment impact. Increased integration and standardisation of cSVD and VCI trial design is needed to accelerate progress in developing treatments. Full article

Intact regulation of cerebral blood flow (CBF) is essential for preserving cognitive function and reducing the risk of cerebrovascular events, particularly in the aging population. Autoregulation of CBF is one of the fundamental mechanisms that ensure constant supply for brain tissue by maintaining relatively stable perfusion despite fluctuations in systemic blood pressure. It also acts as a critical protective mechanism, shielding the fragile cerebral microcirculation from potentially harmful pressure fluctuations and hence excessive pulsatility. The loss or attenuation of this protective mechanism with aging or disease increases the vulnerability of the microvasculature to structural damage, blood–brain barrier (BBB) disruption, and the development of cerebral small vessel disease. This mini-review summarizes current understanding of how aging affects cerebral autoregulation, highlighting underlying mechanisms, clinical consequences, and potential strategies to preserve cerebrovascular health in older adults. Full article

Background/Objectives: Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline and dementia. The comparative prognostic value of MRI-based neuroimaging markers and genetic risk factors such as the APOE ε4 allele for cognitive outcomes remains uncertain. The objectives of this study were to estimate the pooled prevalence of cognitive impairment in CSVD, evaluate the associations of key neuroimaging markers (white matter hyperintensities [WMHs], cerebral microbleeds [CMBs], lacunes) and APOE ε4 with cognitive outcomes, and assess their diagnostic performance. Methods: This study included a systematic review and meta-analysis in accordance with PRISMA and MOOSE guidelines, searching five databases (2005–2025). Eligible studies included adults with CSVD and MRI-visible markers reporting cognitive outcomes (mild cognitive impairment [MCI], global cognitive impairment [GCI], all-cause dementia [ACD], vascular dementia [VaD], and Alzheimer’s disease [AD]). Thirty-nine studies comprising 18,425 participants were included. Pooled prevalence and associations were estimated using random-effects models, and diagnostic accuracy was evaluated. Certainty of evidence was assessed using the GRADE framework. Results: The pooled prevalence of GCI in CSVD was 57% (95% CI: 51–62%), while MCI prevalence was 46% (95% CI: 42–51%). WMHs were strongly associated with VaD (OR 10.35, 95% CI: 7.32–14.64), lacunes with ACD (OR 3.18, 95% CI: 1.24–8.20), and CMBs with AD (OR 1.52, 95% CI: 1.04–2.24). APOE ε4 carriage increased the risk of GCI (OR 1.80, 95% CI: 1.41–2.29). Across markers, diagnostic sensitivity was low, specificity was moderate-to-high, and AUROC values were modest. GRADE certainty ranged from low to moderate, with the highest confidence for WMHs and VaD. Conclusions: CSVD-related MRI markers and APOE ε4 are significantly associated with both early and late cognitive outcomes, supporting the integrated vascular–neurodegenerative continuum. The limited diagnostic sensitivity and variable certainty of evidence highlight the need for harmonized definitions, lesion quantification, and multimodal imaging–genetic approaches to improve early detection and risk stratification of CSVD-related cognitive impairment. Full article

Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke, disproportionately affecting older adults and is associated with high rates of mortality, functional dependence, and long-term cognitive decline. Aging profoundly alters the structure and function of the cerebral vasculature, predisposing the brain to both covert hemorrhage and the development of cerebral microbleeds (CMBs), small, often subclinical lesions that share common pathophysiological mechanisms with ICH. These mechanisms include endothelial dysfunction, impaired cerebral autoregulation, blood–brain barrier breakdown, vascular senescence, and chronic inflammation. Systemic factors such as age-related insulin-like growth factor 1 (IGF-1) deficiency further exacerbate microvascular vulnerability. CMBs and ICH represent distinct yet interconnected manifestations along a continuum of hemorrhagic small vessel disease, with growing recognition of their contribution to vascular cognitive impairment and dementia (VCID). Despite their increasing burden, older adults remain underrepresented in clinical trials, and few therapeutic approaches specifically target aging-related mechanisms. This review synthesizes current knowledge on the cellular, molecular, and systemic drivers of ICH and CMBs in aging, highlights diagnostic and therapeutic challenges, and outlines opportunities for age-sensitive prevention and individualized care strategies. Full article

Background/Objectives: Frank’s sign, a diagonal earlobe crease, may reflect systemic microvascular dysfunction. We investigated whether Frank’s sign serves as a clinical marker of white matter hyperintensity (WMH) burden in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a monogenic model of pure cerebral small vessel disease. Methods: We analyzed 81 genetically confirmed CADASIL patients (61.8 ± 12.6 years, 40.7% female) and 54 age/sex-matched controls (70.3 ± 6.6 years, 48.1% female). Frank’s sign was detected using deep learning from brain MRI-reconstructed 3D facial surfaces. WMH volumes were automatically quantified and adjusted for confounders using Random Forest regression residuals. We compared Frank’s sign prevalence between groups, assessed within-CADASIL associations, and evaluated dose–response relationships across WMH tertiles. Results: Frank’s sign prevalence was significantly higher in CADASIL versus controls (66.7% vs. 42.6%, p = 0.020), with strengthened association after multivariate adjustment (OR = 4.214, 95% CI: 1.128–15.733, p = 0.032). Within CADASIL, Frank’s sign-positive patients showed 72% greater WMH burden (51.5 ± 27.1 vs. 30.0 ± 26.1 mL, p < 0.001) and lower Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total scores (57.7 ± 19.6 vs. 71.2 ± 22.8, p = 0.006), but similar lacunes, microbleeds, and hippocampal volumes. A robust dose–response relationship emerged across WMH tertiles, with Frank’s sign prevalence increasing from 37.0% (lowest) to 74.1% (highest tertile; adjusted OR = 3.571, 95% CI: 1.134–11.253, p = 0.030). Conclusions: Frank’s sign represents an accessible biomarker of WMH burden in CADASIL, demonstrating disease-specificity and dose–response characteristics independent of vascular risk factors. The automated MRI-based detection method of Frank’s sign enables retrospective analysis of existing neuroimaging databases, transforming a bedside observation into a quantifiable neuroimaging biomarker for genetic small vessel disease stratification. Full article

Background/Objectives: Cerebral small vessel disease (cSVD) is one of the leading causes of gait disorders (GDs) in the elderly. Clinical diversity and lack of standardization in assessment of GDs in cSVD patients are associated with late diagnosis. The comparative value of clinical rating scales used for gait assessment in clinical studies of cSVD has not been previously clarified. The purpose of the study was to assess GDs in cSVD patients with different scales and evaluate the advantages of their usage in clinical practice. Materials and methods: The study included 124 cSVD patients (STRIVE, 2013) (average age 62.2 ± 7.9, women—53.2%) and 30 healthy volunteers (average age 59.77 ± 6.361, women—56.7%). Gait and balance function were assessed with the Tinetti test, “6-m walk” test, and the Clinical Scale for Assessing the Severity of Gait Disorders in SVD (RCN, 2019). Results: In total, 85 (68.5%) patients had gait disturbances. The “6-MWT” showed a general tendency to decrease gait speed, step length, and increase in base width. ROC analysis established their thresholds for GD diagnosis. Moderate- or high-risk of falls was found in 52 (41.9%) patients. Gait parameters assessed by two tests (Tinneti and 6-WMT) showed a high degree of intercorrelations. Comparative analysis of the quantitative parameters of Tinneti and 6-WMT tests revealed significant differences depending on the severity of the GD assessed by the Clinical Scale for Assessing the Severity of GDs in cSVD (RCN, 2019). Conclusions: GDs in cSVD are characterized by slowness, changes in step length, base width, and a high risk of falls. The Tinetti test and “6-MWT” have good reproducibility in cSVD, high correlations between the tests, as well as significant differences between the categories of GD severity, which justifies their use in cSVD patients. The advantage of the Tinetti test is the ability to perform a fall risk assessment, while “6-MWT” allows for the diagnosis of GD based on gait parameter thresholds, which is important in the early stages of the disease and in dynamic observation. The Clinical Scale for Assessing the Severity of Gait Disorders in cSVD is a convenient screening tool for assessing the severity of GDs in clinical practice. Full article

Vascular dementia (VaD) represents the second-most common dementia type after Alzheimer’s disease since it results from complications of cerebrovascular disease. Mixed pathologies combining vascular and neurodegenerative processes are the rule rather than exception in elderly dementia patients. The condition known as VaD includes various types of vascular damage that affect both large and small blood vessels in the brain which results in cerebral hypoperfusion, blood–brain barrier disruption, glymphatic dysfunction, and molecular cascades causing neuronal damage. The mechanisms of VaD include endothelial dysfunction, oxidative stress, chronic neuroinflammation, impaired glymphatic clearance, white matter demyelination, and synaptic failure. The disease susceptibility of individuals depends on genetic factors which include NOTCH3 mutations and vascular risk polymorphisms. The diagnostic field uses neuroimaging tools and fluid biomarkers such as neurofilament light chain, inflammatory markers, and Aβ/tau ratios for mixed pathology. The current practice of vascular risk management combines with new therapeutic approaches that use phosphodiesterase inhibitors for cerebral perfusion and NLRP3 inflammasome inhibitors for neuroinflammation, senolytics for cellular senescence, and remyelination agents for white matter repair. However, the majority of new treatment methods remain investigational with limited Phase III data. Future medical treatment development will depend on precision medicine approaches which use biomarker-guided treatment selection and combination strategies targeting multiple pathological mechanisms. Full article

Background: Cerebral small vessel disease (cSVD) is a major contributor to intracerebral hemorrhage (ICH). Its presence carries significant implications for stroke prevention, acute management, post-stroke recovery, and socioeconomic burden. Despite its clinical significance, the impact of cSVD on functional outcomes after ICH, particularly concerning aging, remains uncertain. Objective: This study evaluated how cSVD influences post-ICH functional recovery, using age stratification (<65 and ≥65 years) and a multidomain functional assessment approach. Methods: We retrospectively analyzed data from 356 patients with primary spontaneous ICH. Functional status was evaluated at baseline and at three months post-ICH across multiple domains, including global disability, activities of daily living, gait, upper-extremity function, and swallowing ability, using validated assessment tools. Patients were categorized based on age and the presence or absence of cSVD. Results: Patients without cSVD consistently exhibited better functional status than those with cSVD at both baseline and three-month evaluations across age groups. Although all groups showed statistically significant functional improvement over time, the degree of improvement was significantly lower in patients with cSVD, particularly among those aged 65 years or older. Multivariable logistic regression analysis confirmed that cSVD was a strong and independent predictor of poor functional outcomes at three months after ICH. Conclusions: Our findings emphasize that cSVD is not merely a passive comorbidity but an active and independent determinant of poor prognosis and limited recovery following ICH. The clinical importance of early detection of cSVD supports the need for more intensive, individualized rehabilitation strategies in ICH survivors. Full article

Free fatty acids (FFAs) are a risk factor for recurrent ischemic stroke, primarily via the overproduction of reactive oxygen species. However, the association between FFA concentrations and cerebral small vessel disease (SVD), including lacunes, cerebral microbleeds, and white matter lesions on brain magnetic resonance imaging, remains unclear. This study included 95 patients with acute ischemic stroke (median age: 59 [interquartile range: 49–73] years). The patients were divided into two groups: those aged ≤59 years (midlife patients) and those aged ≥60 years (late-life patients). In the midlife patients, the low serum total FFA concentration was an independent risk factor of lacunes (adjusted odds ratio [aOR]: 0.82, 95% confidence interval [CI]: 0.69–0.96; p = 0.013). Among FFA fractions, low serum free C14:0 (aOR: 0.80, 95% CI: 0.66–0.98; p = 0.028), and free C18:3n-3 (aOR: 0.93, 95% CI: 0.87–0.99; p = 0.015) concentrations were independent risk factors of lacunes in the midlife patients. However, the serum total FFA concentrations did not differ according to the SVD findings in the late-life patients. Therefore, low blood FFA concentrations in midlife can be a novel “nonvascular,” nonatheromatous risk factor of SVD, including the presence of lacunes identified on brain magnetic resonance imaging. Full article

Cerebral amyloid angiopathy (CAA) is an increasingly recognized cause of cognitive decline and lobar intracerebral hemorrhage in older adults. Recent research highlights that neuropsychiatric symptoms (NPSs)—including depression, anxiety, apathy, and irritability—are highly prevalent in CAA, often emerging prior to overt cognitive impairment or major vascular events. Compared to other cerebrovascular diseases, CAA presents a distinctive and multifaceted NPS profile, with symptoms closely linked to disease severity and neuroimaging biomarkers such as white matter hyperintensities and microbleeds. Critically, NPSs in CAA can complicate cognitive assessment and predict worse functional outcomes, yet remain underappreciated in clinical and research contexts. Management is complicated by pharmacologic risks—including heightened bleeding risk associated with SSRIs and novel anti-amyloid therapies—underscoring the need for individualized and multidisciplinary approaches. We highlight the urgent need for standardized NPS assessment, targeted research into mechanisms and treatment, and greater integration of neuropsychiatric evaluation into CAA care. We suggest that recognizing NPSs as core clinical features—not secondary complications—of CAA is essential to improving both patient outcomes and scientific understanding. Future studies should focus on longitudinal analyses, the development of tailored interventions, and robust comparative research to clarify the pathophysiology, clinical trajectory, and optimal management of NPSs in CAA. Full article