Unveiling the molecular landscape of cognitive aging: insights from polygenic risk scores, DNA methylation, and gene expression.

BACKGROUND: Aging represents a significant risk factor for the occurrence of cerebral small vessel disease, associated with white matter (WM) lesions, and to age-related cognitive alterations, though the precise mechanisms remain largely unknown. This study aimed to investigate the impact of polygenic risk scores (PRS) for WM integrity, together with age-related DNA methylation, and gene expression alterations, on cognitive aging in a cross-sectional healthy aging cohort. The PRSs were calculated using genome-wide association study (GWAS) summary statistics for magnetic resonance imaging (MRI) markers of WM integrity, including WM hyperintensities, fractional anisotropy (FA), and mean diffusivity (MD). These scores were utilized to predict age-related cognitive changes and evaluate their correlation with structural brain changes, which distinguish individuals with higher and lower cognitive scores. To reduce the dimensionality of the data and identify age-related DNA methylation and transcriptomic alterations, Sparse Partial Least Squares-Discriminant Analysis (sPLS-DA) was used. Subsequently, a canonical correlation algorithm was used to integrate the three types of omics data (PRS, DNA methylation, and gene expression data) and identify an individual "omics" signature that distinguishes subjects with varying cognitive profiles. RESULTS: We found a positive association between MD-PRS and long-term memory, as well as a correlation between MD-PRS and structural brain changes, effectively discriminating between individuals with lower and higher memory scores. Furthermore, we observed an enrichment of polygenic signals in genes related to both vascular and non-vascular factors. Age-related alterations in DNA methylation and gene expression indicated dysregulation of critical molecular features and signaling pathways involved in aging and lifespan regulation. The integration of multi-omics data underscored the involvement of synaptic dysfunction, axonal degeneration, microtubule organization, and glycosylation in the process of cognitive aging. CONCLUSIONS: These findings provide valuable insights into the biological mechanisms underlying the association between WM coherence and cognitive aging. Additionally, they highlight how age-associated DNA methylation and gene expression changes contribute to cognitive aging.

Migraine and brain structure in the elderly: The Rotterdam Study.

BACKGROUND: Recent studies suggested that persons with migraine might be at higher risk of structural brain changes, including cerebral small vessel disease and atrophy. However, findings in the literature are inconsistent, with variations observed in the direction, magnitude, and population characteristics of reported effects, and large-scale population-based evidence remains scarce. Hence, we investigated the association of migraine with structural brain changes in a middle-aged and elderly population. METHODS: Within the population-based Rotterdam Study, lifetime history of migraine was assessed using a validated questionnaire between 2006 and 2011. Magnetic resonance imaging of the brain was performed in 4920 participants (median age 61.7 [IQR 45.5, 97.5] years, 55.4% female) to assess imaging markers of cerebral small vessel disease and brain atrophy. We used linear and logistic regression models to examine the cross-sectional association of migraine with brain volumes (total grey and white matter volumes in mL) and cerebral small vessel disease markers (white matter hyperintensity volume in mL, presence of lacunes and cerebral microbleeds). Adjustments were made for age, sex, intracranial volume and cardiovascular variables. Analyses were also stratified by sex and presence of aura. RESULTS: The lifetime prevalence of migraine was 15.3% (752/4920). In multivariable adjusted regression models, we found no statistically significant differences between participants with and without migraine in terms of total brain volume (mean difference [MD]: 2.21 mL, 95% confidence interval [CI]: -0.38 ; 4.81), grey matter volume (MD: 0.38 mL, 95% CI: -1.98 ; 2.74), white matter volume (MD: 2.19 mL, 95% CI: -0.56 ; 4.93), log white matter hyperintensity volume (MD: -0.04 mL, 95% CI: -0.10 ; 0.02), presence of lacunes (odds ratio [OR]: 0.82, 95% CI: 0.58-1.15), and presence of cerebral microbleeds (OR: 0.95, 95% CI: 0.76-1.18). CONCLUSION: In this study, we found that middle-aged and elderly participants with migraine were not more likely to have structural brain changes on magnetic resonance imaging.

Decreased water exchange rate across blood-brain barrier in hereditary cerebral small vessel disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and heterozygous HTRA1 mutation-related cerebral small vessel disease (CSVD) are the two types of dominant hereditary CSVD. Blood-brain barrier (BBB) failure has been hypothesized in the pathophysiology of CSVD. However, it is unclear whether there is BBB damage in the two types of hereditary CSVD, especially in heterozygous HTRA1 mutation-related CSVD. In this study, a case-control design was used with two disease groups including CADASIL (n = 24), heterozygous HTRA1 mutation-related CSVD (n = 9) and healthy controls (n = 24). All participants underwent clinical cognitive assessments and brain MRI. Diffusion-prepared pseudo-continuous arterial spin labelling was used to estimate the water exchange rate across the BBB (kw). Correlation and multiple linear regression analyses were used to examine the association between kw and disease burden and neuropsychological performance, respectively. Compared with the healthy controls, kw in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients (Bonferroni-corrected P < 0.007). In the CADASIL group, decreased kw in the whole brain (ß = -0.634, P = 0.001), normal-appearing white matter (ß = -0.599, P = 0.002) and temporal lobe (ß = -0.654, P = 0.001) was significantly associated with higher CSVD score after adjusting for age and sex. Reduced kw in the whole brain was significantly associated with poorer neuropsychological performance after adjusting for age, sex and education in both CADASIL and heterozygous HTRA1 mutation-related CSVD groups (ß = 0.458, P = 0.001; ß = 0.884, P = 0.008). This study showed that there was decreased water exchange rate across the BBB in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients, suggesting a common pathophysiological mechanism underlying the two types of hereditary CSVD. These results highlight the potential use of kw for monitoring the course of CADASIL and heterozygous HTRA1 mutation-related CSVD, a possibility which should be tested in future research.

Association of novel lipid indices with the white matter hyperintensities in cerebral small vessel disease: a cross-sectional study.

BACKGROUND: Lipids are associated with atherosclerosis, and novel lipid indices have been recently identified to be closely linked to cardiovascular diseases. This study explored the association between four novel lipid indices and the white matter hyperintensities (WMHs) in patients diagnosed with cerebral small vessel disease (CSVD). METHODS: Between January 2023 and February 2024, 219 patients were recruited, including 165 patients with CSVD WMHs and 54 healthy controls. Based on WMHs severity, patients with CSVD were categorised into mild and moderate-to-severe cohorts using the Fazekas rating scale. The plasma levels of four novel lipid indices (low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio [LDL-C/HDL-C], triglyceride/high-density lipoprotein cholesterol ratio [TG/HDL-C], total cholesterol/high-density lipoprotein cholesterol ratio [TC/HDL-C], and non-high-density lipoprotein cholesterol [Non-HDL-C]), were rigorously monitored in the enrolled patients. RESULTS: A total of 165 patients with CSVD WMHs were enrolled, including 94 with mild WMHs and 71 with moderate-to-severe WMHs. Multivariable logistic regression analysis revealed that LDL-C/HDL-C, TG/HDL-C, TC/HDL-C, and Non-HDL-C levels were significantly associated with WMHs (all P ≤ 0.001). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of plasma lipid levels for WMHs in patients with CSVD. The novel lipid indicators outperformed traditional lipid indicators in assessing the diagnostic capability of WMHs. The combined index of the four blood lipid indices had an optimal cutoff point (OCP) of 0.489, with 88.3% sensitivity and 60.6% specificity. The area under the curve (AUC) is 0.800 (95% confidence interval [CI], 0.731-0.869; P < 0.001). Compared with males (OR = 1.126, 95% CI = 0.779-1.628), females (OR = 2.484, 95% CI = 1.398-4.414; P for interaction = 0.023) had a higher risk of developing WMHs. CONCLUSION: This study demonstrates a significant association between four novel lipid indices and the cerebral WMHs in CSVD, highlighting the potential of these markers as novel plasma biomarkers and predictive indicators for assessing CSVD progression and guiding clinical management.

Heterogeneous blood-brain barrier dysfunction in cerebral small vessel diseases.

INTRODUCTION: We explored how blood-brain barrier (BBB) leakage rate of gadolinium chelates (Ktrans) and BBB water exchange rate (kw) varied in cerebral small vessel disease (cSVD) subtypes. METHODS: Thirty sporadic cSVD, 40 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 13 high-temperature requirement factor A serine peptidase 1 (HTRA) -related cSVD subjects were investigated parallel to 40 healthy individuals. Subjects underwent clinical, cognitive, and MRI assessment. RESULTS: In CADASIL, no difference in Ktrans, but lower kw was observed in multiple brain regions. In sporadic cSVD, no difference in kw, but higher Ktrans was found in the whole brain and normal-appearing white matter. In HTRA1-related cSVD, both higher Ktrans in the whole brain and lower kw in multiple brain regions were observed. In each patient group, the altered BBB measures were correlated with lesion burden or clinical severity. DISCUSSION: In cSVD subtypes, distinct alterations of kw and Ktrans were observed. The combination of Ktrans and kw can depict the heterogeneous BBB dysfunction. HIGHLIGHTS: We measured BBB leakage to gadolinium-based contrast agent (Ktrans) and water exchange rate (kw) across BBB in three subtypes of cSVD. CADASIL is characterized by lower kw, HTRA1-related cSVD exhibits both higher Ktrans and lower kw, while sporadic cSVD is distinguished by higher Ktrans. There are distinct alterations in kw and Ktrans among subtypes of cSVD, indicating the heterogeneous nature of BBB dysfunction.

An integration of neuroimaging and serum proteomics analysis suggests immune and inflammation are associated with white matter microstructure changes in cerebral small vessel disease with depressive symptoms.

INTRODUCTION: Depressive symptoms are a common concomitant of cerebral small vessel disease (CSVD), of which pathogenesis requires more study. White matter microstructural abnormalities and proteomic alternation have been widely reported regarding depression in the elderly with CSVD. Exploring the relationship between cerebral white matter microstructural alterations and serum proteins may complete the explanation of molecular mechanisms for the findings from neuroimaging research of CSVD combined with depressive symptoms. METHODS: An untargeted proteomics approach based on mass spectrometry was used to obtain serum proteomic profiles, which were clustered into co-expression protein modules. White matter microstructural integrity was measured using the FMRIB Software Library (FSL) and MATLAB to analyze diffusion tensor imaging (DTI) data and calculate the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) for 50 regions of interest (ROI). Integrating the proteome with the DTI results, weighted gene co-expression analysis (WGCNA) was used to identify protein modules related to white matter microstructural alterations, and the proteins of the corresponding modules were analyzed for functional enrichment through bioinformatics techniques. RESULTS: DTI measurements were analCerebral small vessel disease (CSVD); Depression; Diffusion tensor imaging (DTI); Proteomics; Inflammationyzed between individuals with CSVD and depressive symptoms (CSVD+D) (n = 24) and those without depressive symptoms (CSVD-D) (n = 35). Results showed an overall increase in MD, AD, and RD within the left hemisphere of the CSVD+D group, suggesting widespread loss of white matter integrity and axonal demyelination, including left superior longitudinal fasciculus (SLF), left posterior corona radiata (PCR) and right external capsule (EC). We identified two protein modules associated with DTI diffusivity, and functional enrichment analyses revealed that complement and coagulation cascades and immune responses participate in the alternation of white matter microstructure in the CSVD+D group. CONCLUSION: The results suggested immune- and inflammation-related mechanism was associated with white matter microstructure changes in CSVD with depressive symptoms.

Mutations in ARHGEF15 cause autosomal dominant hereditary cerebral small vessel disease and osteoporotic fracture.

Cerebral small vessel disease (CSVD) is a prominent cause of ischemic and hemorrhagic stroke and a leading cause of vascular dementia, affecting small penetrating vessels of the brain. Despite current advances in genetic susceptibility studies, challenges remain in defining the causative genes and the underlying pathophysiological mechanisms. Here, we reported that the ARHGEF15 gene was a causal gene linked to autosomal dominant inherited CSVD. We identified one heterozygous nonsynonymous mutation of the ARHGEF15 gene that cosegregated completely in two families with CSVD, and a heterozygous nonsynonymous mutation and a stop-gain mutation in two individuals with sporadic CSVD, respectively. Intriguingly, clinical imaging and pathological findings displayed severe osteoporosis and even osteoporotic fractures in all the ARHGEF15 mutation carriers. In vitro experiments indicated that ARHGEF15 mutations resulted in RhoA/ROCK2 inactivation-induced F-actin cytoskeleton disorganization in vascular smooth muscle cells and endothelial cells and osteoblast dysfunction by inhibiting the Wnt/ß-catenin signaling pathway in osteoblast cells. Furthermore, Arhgef15-e(V368M)1 transgenic mice developed CSVD-like pathological and behavioral phenotypes, accompanied by severe osteoporosis. Taken together, our findings provide strong evidence that loss-of-function mutations of the ARHGEF15 gene cause CSVD accompanied by osteoporotic fracture.

Association of intracranial atherosclerosis with cerebral small vessel disease in a community-based population.

BACKGROUND AND PURPOSE: The purpose of this study was to explore the relationship between intracranial atherosclerosis and cerebral small vessel disease (CSVD). METHODS: Community-dwelling residents of Lishui, China in the PRECISE (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) study were involved. Intracranial atherosclerosis was grouped by the severity of intracranial artery plaques with stenosis and burden. Four imaging markers including lacunes, white matter hyperintensity (WMH), cerebral microbleeds (CMBs), and perivascular spaces (PVS) as well as the CSVD burden scores were assessed. Logistic regression or ordinal logistic regression models with odds ratio (OR) or common OR (cOR) were used to estimate the relationship between intracranial atherosclerosis and CSVD markers and burdens. RESULTS: The mean age was 61.20 ± 6.68 years, and 1424 (46.52%) were men among 3061 participants included at baseline. Intracranial atherosclerotic burden was associated with the severity of the lacunes (OR = 4.18, 95% confidence interval [CI] = 1.83-9.58), modified WMH burden (cOR = 1.94, 95% CI = 1.01-3.71), presence of CMBs (OR = 2.28, 95% CI = 1.05-4.94), and CMB burden (OR = 2.23, 95% CI = 1.03-4.80). However, it was not associated with the WMH burden and PVS. Intracranial atherosclerotic burden was associated with CSVD burden (Wardlaw: cOR = 2.73, 95% CI = 1.48-5.05; Rothwell: cOR = 2.70, 95% CI = 1.47-4.95). The association between intracranial atherosclerosis and CSVD was obvious in participants with both anterior and posterior circulation artery stenosis. CONCLUSIONS: Based on a Chinese community population, there may be an association between intracranial atherosclerosis and CSVD, but its mechanism in relation to vascular risk factors still needs to be clarified.

Effects of intensive blood pressure control on cognitive function in patients with cerebral small vessel disease.

OBJECTIVE: This study aimed to investigate the effects of intensive blood pressure control on cognitive function in elderly patients with cerebral small vessel disease (CSVD). METHODS: From May 2020 to June 2022, 140 outpatients and inpatients with CSVD and hypertension in the Department of Neurology of Beijing Shijingshan Hospital were selected. They were randomly divided into the standard and intensive blood pressure control groups, and the dosage of antihypertensive drugs was adjusted to reduce the blood pressure to the target level. The patients were followed up for 2 years. The medical records or data at "enrollment" and "2-year follow-up" were analyzed and evaluated. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate cognitive function. Cranial magnetic resonance imaging was performed to evaluate lacunar infarctions (LIs) and white matter hyperintensity (WMH). Multiple linear regression was used to analyze the correlation between MMSE scores and blood pressure, WMH, and LIs. RESULTS: (1) The MMSE and MoCA scores in the standard group were significantly lower than those at enrollment. The WMH score in the standard group was significantly higher than that at enrollment. (2) After the 2-year follow-up, the 24-h systolic blood pressure (SBP), 24-h diastolic blood pressure (DBP), daytime mean SBP, daytime mean DBP, and nighttime mean SBP in the two groups significantly decreased, which had significant statistical significance (P < 0.05). (3) The correlation between blood pressure and MMSE score was analyzed using multiple linear regression analysis. The WMH score, LIs, 24-h SBP, and 24-h DBP were independently correlated with MMSE scores. CONCLUSION: In elderly patients with hypertension, a decrease in SBP to 126 mmHg, compared with 134 mmHg, can delay cognitive impairment as well as reduce LIs and cerebral WMH lesions in patients with CSVD.

Epidermal Growth Factor Receptors in Vascular Endothelial Cells Contribute to Functional Hyperemia in the Brain.

Functional hyperemia-activity-dependent increases in local blood perfusion-underlies the on-demand delivery of blood to regions of enhanced neuronal activity, a process that is crucial for brain health. Importantly, functional hyperemia deficits have been linked to multiple dementia risk factors, including aging, chronic hypertension, and cerebral small vessel disease (cSVD). We previously reported crippled functional hyperemia in a mouse model of genetic cSVD that was likely caused by depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) in capillary endothelial cells (EC) downstream of impaired epidermal growth factor receptor (EGFR) signaling. Here, using EC-specific EGFR-knockout (KO) mice, we directly examined the role of endothelial EGFR signaling in functional hyperemia, assessed by measuring increases in cerebral blood flow in response to contralateral whisker stimulation using laser Doppler flowmetry. Molecular characterizations showed that EGFR expression was dramatically decreased in freshly isolated capillaries from EC-EGFR-KO mice, as expected. Notably, whisker stimulation-induced functional hyperemia was significantly impaired in these mice, an effect that was rescued by administration of PIP2, but not by the EGFR ligand, HB-EGF. These data suggest that the deletion of the EGFR specifically in ECs attenuates functional hyperemia, likely via depleting PIP2 and subsequently incapacitating Kir2.1 channel functionality in capillary ECs. Thus, our study underscores the role of endothelial EGFR signaling in functional hyperemia of the brain.

The influence of cerebral small vessel diseases on the efficacy of repositioning therapy and prognosis of benign paroxysmal positional vertigo.

Background: Although vascular risk factors have been found to be closely related to the development of benign paroxysmal positional vertigo (BPPV), the relationship between BPPV and cerebral small vessels diseases (CSVDs) has rarely been discussed in literature. This study set out to investigate the efficacy of repositioning therapy and prognosis among BPPV patients with CSVDs. Methods: We enrolled 553 BPPV patients who had undergone brain MRI, and categorized them into two groups based on the presence or absence of CSVDs. After controlling for other confounders using a propensity score matching (PSM) approach, we compared the incidence of recurrence and residual dizziness (RD). Then, we analyzed the recurrence rate and RD incidence in 176 BPPV patients with CSVDs, and assessed potential risk factors. Results: White matter hyperintensity (WMH, 72.2%) and lacunar infarction (LI, 65.9%) were the two CSVDs that were present in the highest proportion among the BPPV patients. The incidence of RD in patients with CSVDs was significantly higher compared to subjects without CSVDs. Patients with RD (n=100, 56.8%) were older, had more severe WMH, and had a higher incidence of brain atrophy; age and higher Fazekas score were independent risk factors. Among the recurrent patients (n=61, 34.7%), the ages were older, the Fazekas score of WMH was higher, and number of LIs was increased; age was the sole independent risk factor. Conclusion: BPPV patients with a combination of CSVD comorbidities, especially elderly patients with WMHs, are more likely to develop RD, which needs to be paid more attention.

The Role of Immunosenescence in Cerebral Small Vessel Disease: A Review.

Cerebral small vessel disease (CSVD) is one of the most important causes of vascular dementia. Immunosenescence and inflammatory response, with the involvement of the cerebrovascular system, constitute the basis of this disease. Immunosenescence identifies a condition of deterioration of the immune organs and consequent dysregulation of the immune response caused by cellular senescence, which exposes older adults to a greater vulnerability. A low-grade chronic inflammation status also accompanies it without overt infections, an "inflammaging" condition. The correlation between immunosenescence and inflammaging is fundamental in understanding the pathogenesis of age-related CSVD (ArCSVD). The production of inflammatory mediators caused by inflammaging promotes cellular senescence and the decrease of the adaptive immune response. Vice versa, the depletion of the adaptive immune mechanisms favours the stimulation of the innate immune system and the production of inflammatory mediators leading to inflammaging. Furthermore, endothelial dysfunction, chronic inflammation promoted by senescent innate immune cells, oxidative stress and impairment of microglia functions constitute, therefore, the framework within which small vessel disease develops: it is a concatenation of molecular events that promotes the decline of the central nervous system and cognitive functions slowly and progressively. Because the causative molecular mechanisms have not yet been fully elucidated, the road of scientific research is stretched in this direction, seeking to discover other aberrant processes and ensure therapeutic tools able to enhance the life expectancy of people affected by ArCSVD. Although the concept of CSVD is broader, this manuscript focuses on describing the neurobiological basis and immune system alterations behind cerebral aging. Furthermore, the purpose of our work is to detect patients with CSVD at an early stage, through the evaluation of precocious MRI changes and serum markers of inflammation, to treat untimely risk factors that influence the burden and the worsening of the cerebral disease.

[Analysis of CiteSpace knowledge map for traditional Chinese medicine prevention and treatment of cerebral small vessel diseases].

This study aims to analyze the research on the prevention and treatment of cerebral small vessel diseases(CSVDs) with traditional Chinese medicine(TCM) based on knowledge map, and to preliminarily explore the research hotspots and trends. To be specific, articles on TCM treatment of CSVDs in CNKI, Wanfang, and VIP(from establishment to November 2021) were retrieved, followed by bibliometric analysis. Then CiteSpace 5.7 R4 and Gephi were employed for generation of maps on annual number of articles, author cooperation, institution cooperation, keyword co-occurrence, keyword clustering, and keyword emergence. A total of 106 eligible articles were screened out, and the annual number of articles presented a steady upward trend. A total of 277 authors were included in the author cooperation network, among whom CHEN Zhigang published the most articles. A total of 87 institutions were included in the institution cooperation network, among which Dongfang Hospital of Beijing University of Chinese Medicine showed the most frequent cooperation with other institutions. Keyword clustering showed that research on the TCM treatment of CSVDs mainly focused on five aspects: related disease research, neurological function deficits, disease nature and location in TCM, TCM treatment methods, and formulas. The prevention and treatment of CSVDs with TCM in China has been developing steadily in the past ten years, and TCM has unique advantages in the prevention and treatment of this disease. The knowledge maps vividly demonstrated the development and research hotspots and trends in this field. The result is expected to provide a reference for further research in this field.

Left ventricular ejection fraction and right atrial diameter are associated with deep regional CBF in arteriosclerotic cerebral small vessel disease.

BACKGROUND: Systemic cardiac hypoperfusion is a well-acknowledged contributor to ischemic leukoencephalopathy. However, it has remained elusive how atherosclerosis-mediated cardiac remodelling modifies cerebral perfusion homeostasis as well as neuroimaging burden in cerebral small vessel disease (CSVD) development. METHODS: This retrospective study identified 103 arteriosclerotic CSVD (aCSVD) patients (CSVD burdenlow 0 ~ 1, n = 61 and CSVD burdenhigh 2 ~ 4, n = 42) from Sep. 2017 to Dec. 2019 who underwent transthoracic echocardiography(n = 81), structural magnetic resonance imaging and arterial spin labelling (ASL). Total CSVD burden was graded according to the ordinal "small vessel disease" rating score (0-4). We investigated the univariate and multivariate linear regression of mean deep regional cerebral blood flow (CBF) as well as logistic regression analysis of CSVD burdenhigh. RESULTS: Right atrial diameter (B coefficient, - 0.289; 95% CI, - 0.578 to - 0.001; P = 0.049) and left ventricular ejection fraction (B coefficient, 32.555; 95% CI, 7.399 to 57.711; P = 0.012) were independently associated with deep regional CBF in aCSVD patients. Binary logistic regression analysis demonstrated decreased deep regional CBF (OR 0.894; 95% CI 0.811-0.985; P = 0.024) was independently associated with higher CSVD burden after adjusted for clinical confounders. Multivariate receiver operating characteristics curve integrating clinical risk factors, mean deep CBF and echocardiographic parameters showed predictive significance for CSVD burdenhigh diagnosis (area under curve = 84.25, 95% CI 74.86-93.65%, P < 0.0001). CONCLUSION: The interrelationship of "cardiac -deep regional CBF-neuroimaging burden" reinforces the importance and prognostic significance of echocardiographic and cerebral hemodynamic assessment in CSVD early-warning.

Explore the correlation between cerebral vessel characteristics with cognitive impairment among elder individuals: a community study from China.

BACKGROUND: Brain Magnetic Resonance Imaging (MRI) examination of cerebral small vessel disease (CSVD) may help screen vascular cognitive impairment. A recently estimated CSVD score system was suggested to capture the overall CSVD burden. The study aimed to detect the association between systemic evaluation score of cerebral vascular imaging parameters with cognitive functions. METHODS: This was a cross-sectional study in community settings. From October 2017 to September 2018, elder (≧60) residents were recruited through on-site visit in 6 communities from Shanghai, China. The participants underwent brain MRI, carotid ultrasound, laboratory tests of blood and urine samples. Cognitive function was evaluated using Mini-Mental State Examination (MMSE). MRI score of CSVD was calculated according to the 2012 standard for the evaluation of statistical changes in imaging. RESULTS: Total 171 subjects completed survey and examinations. There were 55 participants diagnosed with cognitive impairment, with a total percentage of 32.2%. Participants with and without cognitive impairment showed significant differences in age, BMI and education level. Cognitive impaired participant had more disease history/comorbidity of hypertension and chronic renal insufficiency, higher level of creatinine, as well as lower level of full blood count (FBC) and alanine aminotransferase (ALT). A significant difference was detected in CSVD score between participants with and without cognitive impairment. Results of linear regression analysis showed significant negative correlations between MMSE score and both left and right carotid artery peak systolic velocity (PSV), however the CSVD score was only borderline (P = 0.0566) positively correlated with MMSE. Multivariate linear correlation analysis including all collected risk factor data showed that left carotid artery PSV score was among the independent negative correlated factors of MMSE. Multivariate binary logistic analysis showed that age, education and history of hypertension were the only statistically associated factors of cognitive impairment. CONCLUSIONS: The current study identified high prevalence of cognitive impairment in a Chinese community. In addition, correlations between cerebral vascular disease imaging status and cognitive functions were confirmed although the sample size limited the possibility of screening cognitive impairment with imaging technique.

Case Report of a pathologically confirmed vascular parkinsonism with early cognitive impairment and Behavioral disturbance.

BACKGROUND: Vascular Parkinsonism(VaP) is defined as parkinsonism resulting from cerebral vascular disease(CVD), with presence of variable motor and non-motor signs that are corroborated by clinical, anatomic or imaging findings of cerebrovascular disease. Overlapping syndromes with mixed pathologies make VaP difficult to distinguish from primary neurodegenerative parkinsonism.To understand the clinical and pathological features of VaP,we report a case of autopsy confirmed vascular Parkinsonism that was clinical misdiagnosed as idiopathic Parkinson's disease.Clinical features include early mixed symptoms of dementia,behavioral disturbance and parkinsonism that were similar to Dementia with lewy Body(DLB) and Parkinson disease Dementia(PDD). CASE PRESENTATION: A 84-year-old man presented progressive parkinsonism with prominent postural instability, gait impairment, pseudobulbar, early cognitive impairment, irritability, hallucination, urinary symptoms and poor responsiveness to dopaminergic drugs. He was clinically diagnosed as Parkinson disease(PD). In the post-mortem study, we examined Aß and phospho-tau as pathological biomarker for Alzheimer's disease(AD), α-synucleing in medulla, pons and midbrain for PD and DLB. Hematoxylin and eosin staining in cerebral cortex, cerebellum and brainstem examines vascular pathological changes and microvascular lesion.Neither Lewy bodies in the substantia nigra ,locus ceruleus and cerebrumnor accumulation of Aß, neurofibrillary tangles were noted. Instead, there were many cerebral infarctions and widespread arteriosclerosis in the brain. The final brain autopsy supported a diagnosis of VaP not PD. CONCLUSIONS: This case of pathologically confirmed VaP misdiagnosed as idiopathic PD suggested that we must be vigilant about the possibility of VaP for patients with parkinsonisms, cognitive impairments, early behavioral and psychological symptoms,imaging performances of cerebral small vessel disease and other vascular damages.

Hippocampal vascular reserve associated with cognitive performance and hippocampal volume.

Medial temporal lobe dependent cognitive functions are highly vulnerable to hypoxia in the hippocampal region, yet little is known about the relationship between the richness of hippocampal vascular supply and cognition. Hippocampal vascularization patterns have been categorized into a mixed supply from both the posterior cerebral artery and the anterior choroidal artery or a single supply by the posterior cerebral artery only. Hippocampal arteries are small and affected by pathological changes when cerebral small vessel disease is present. We hypothesized, that hippocampal vascularization patterns may be important trait markers for vascular reserve and modulate (i) cognitive performance; (ii) structural hippocampal integrity; and (iii) the effect of cerebral small vessel disease on cognition. Using high-resolution 7 T time-of-flight angiography we manually classified hippocampal vascularization patterns in older adults with and without cerebral small vessel disease in vivo. The presence of a mixed supplied hippocampus was an advantage in several cognitive domains, including verbal list learning and global cognition. A mixed supplied hippocampus also was an advantage for verbal memory performance in cerebral small vessel disease. Voxel-based morphometry showed higher anterior hippocampal grey matter volume in mixed, compared to single supply. We discuss that a mixed hippocampal supply, as opposed to a single one, may increase the reliability of hippocampal blood supply and thereby provide a hippocampal vascular reserve that protects against cognitive impairment.

Association Between the Angiotensin-Converting Enzyme I/D Polymorphism and Risk of Cerebral Small Vessel Disease: A Meta-Analysis Based on 7186 Subjects.

INTRODUCTION: Cerebral small vessel disease (CSVD) causes a quarter of all strokes and is the most common pathology underlying vascular dementia. However, the mechanism of CSVD remains unclear. Numerous studies have investigated whether the angiotensin-converting enzyme (ACE) intersection/deletion (I/D) polymorphism influences the risk of CSVD, but the results are controversial. METHODS: We searched English and Chinese databases and calculated the odds ratio (OR) and 95% confidence interval (CI) to examine the existence of genetic associations between the ACE I/D polymorphism and the risk of CSVD. All relevant studies were screened and meta-analyzed using Review Manager 5.4. RESULTS: A total of 27 studies involving 7,186 subjects were identified for the meta-analysis. The results of five genetic models showed a significantly increased risk of CSVD (allelic, OR=1.30; recessive, OR=1.41; dominant, OR=1.34; homozygous, OR=1.55 and heterozygous OR=1.22) in the overall analysis. Furthermore, in subgroup analysis, increased CSVD risks were also observed in Asian and Caucasian populations. We also found no relationship between ACE I/D and leukoaraiosis (LA) in patients with lacunar infarction (LI). CONCLUSION: The ACE I/D polymorphism was positively associated with CSVD in both populations. However, this polymorphism did not increase the risk of LA in LI patients.

Decreased visible deep medullary veins is a novel imaging marker for cerebral small vessel disease.

PURPOSE: Visibility of deep medullary veins (DMVs) seen at SWI is predictive of poor prognosis in ischemic stroke. Few attentions have been paid to DMVs in atherosclerotic cerebral small vessel disease (aCSVD) which is attributed to long-term imbalanced microhemodynamics. We conducted this retrospective study to explore the association between DMVs profiles and aCSVD risk factors, neuroimaging markers. METHODS: Two hundred and two patients identified as aCSVD from January 2017 to March 2019 were included in the study. Their demographic, clinical, laboratory, and neuroimaging data were reviewed. The quantity and morphology of DMVs were assessed with a 5-grade (range 0~4) visual rating scale. Total CSVD burden was calculated with an ordinal "SVD score" (range 0~4). Spearman rank correlation and multivariable logistic regression analysis were performed to determine the association between DMV scale and CSVD markers. RESULTS: DMV scale showed strong positive correlation with CSVD burden (rs = 0.629, P < 0.001). Age (OR 1.078, 95% CI 1.015-1.145, P = 0.015) and hypertension (OR 2.629, 95% CI 1.024-6.749, P = 0.045) were two demographic risk factors for high DMV scale. Among CSVD neuroimaging markers, periventricular WMH (OR 2.925, 95% CI 1.464-5.845, P = 0.002), deep WMH (OR 2.872, 95% CI 1.174-7.022, P = 0.021), lacunae (OR 1.961, 95% CI 1.181-3.254, P = 0.009), and cerebral atrophy (OR 2.046, 95% CI 1.079-3.880, P = 0.028) were associated with high DMV scale after adjusting for clinical and metabolic confounders. CONCLUSION: Multifactorial association between DMV scale and epidemiological, radiological contributors of aCSVD suggests DMV's involved pathomechanism may participate in aCSVD development. Attach importance to DMV radiological profile in aCSVD will provide more neuroimaging information for diagnosis and prognosis.

Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) represents a cluster of various vascular disorders with different pathological backgrounds. The advanced vasculature net of cerebral vessels, including small arteries, capillaries, arterioles and venules, is usually affected. Processes of oxidation underlie the pathology of CSVD, promoting the degenerative status of the epithelial layer. There are several classifications of cerebral small vessel diseases; some of them include diseases such as Binswanger's disease, leukoaraiosis, cerebral microbleeds (CMBs) and lacunar strokes. This paper presents the characteristics of CSVD and the impact of the current knowledge of this topic on the diagnosis and treatment of patients.