Cardiovascular risk factors (CRFs) like hypertension, high cholesterol, and diabetes mellitus are increasingly linked to cognitive decline and dementia, especially in cerebral small vessel disease (cSVD). White matter hyperintensities (WMH) are closely associated with cognitive impairment, but the mechanisms behind their development remain unclear. Blood-brain barrier (BBB) dysfunction may be a key factor, particularly in cSVD. This study explores the relationship between CRFs, BBB integrity, and WMH burden. The study included 155 participants from the Biomarkers and Cognition Study, Singapore (BIOCIS). CRFs were assessed through blood tests for glucose and lipid profiles, and blood pressure measurements. WMH volumes were quantified using MRI. BBB integrity was evaluated using a Transendothelial Electrical Resistance (TEER) assay with human brain microvascular endothelial cells (hBMEC) exposed to participant plasma. Plasma from individuals with a higher WMH burden was associated with increased BBB disruption in hBMEC. Higher systolic and diastolic blood pressure, as well as body mass index, were correlated with greater BBB disruption. Regression analyses revealed that elevated blood glucose and lipid levels were linked to increased BBB disruption. Both periventricular and subcortical WMH burdens were associated with increased BBB disruption. This study highlights a relationship between CRFs, BBB disruption, and WMH burden, suggesting that CRFs may impair BBB integrity and contribute to WMH and cognitive decline in cSVD.

Cardiovascular risk factors (CRFs) such as hypertension, high cholesterol, and diabetes are increasingly implicated in cognitive decline and cerebral small vessel disease (cSVD). White matter hyperintensities (WMH), a hallmark of cSVD, are strongly linked to cognitive impairment, but their underlying mechanisms remain unclear. Blood-brain barrier (BBB) dysfunction has been proposed as a potential contributor to WMH development. This study aimed to explore the relationships between CRFs, BBB integrity, and WMH burden. We analyzed 155 participants from the Biomarkers and Cognition Study, Singapore, assessing CRFs through blood tests for glucose and lipid profiles, alongside blood pressure measurements. WMH volume was quantified using MRI, and an in vitro assay evaluated the impact of plasma on BBB integrity using human brain microvascular endothelial cells. Results showed that plasma from participants with higher WMH burden correlated with increased BBB disruption, which was further associated with higher blood pressure, elevated blood glucose, and lipid levels. Both periventricular and subcortical WMH were linked to BBB disruption. These findings suggest that CRFs contribute to BBB dysfunction, promoting WMH development and cognitive decline in cSVD. Further research is needed to clarify the precise mechanisms driving these associations.

Background: Behavioral and psychological symptoms are one of the earliest observable changes when a person experiences cognitive decline. These symptoms are common and are known as Neuropsychiatric symptoms(NPS), which increases risk of progression to dementia. The prevalence of NPS was compared in a cohort of Southeast Asian adults with Subjective Cognitive Decline(SCD) and Mild Cognitive Impairment(MCI).Method: This study utilized cross‐sectional data from the Biomarkers and Cognition Study, Singapore(BIOCIS). From February to December 2022, participants who met criteria for SCD and MCI in accordance with NIA‐AA’s criteria were classified into two groups, NPS and without‐NPS, based on clinical cut‐offs of Depression Anxiety Stress Scales(DASS) scores. Self‐reported questionnaires assessed behavioral symptoms ‐ Mild Behavioral Impairment‐Checklist(MBI‐C); Dementia‐Quality of Life Instrument(Dem‐QOL); International Physical Activity Questionnaire(IPAQ); and Pittsburgh Sleep Quality Index(PSQI). Group comparisons of data were applied separately using univariate analyses. A Receiver Operating Characteristic analysis was conducted to test the diagnostic performance of MBI‐C total, MBI‐C‐subdomains, and PSQI in distinguishing participants with NPS and without‐NPS.Result: 488 participants (μ age = 62.7±9.64,42.2% males) were analyzed. 133(27.25%) reported significant NPS symptoms. Participants with NPS reported significantly more symptoms on MBI‐C‐total(p<.001); interest(p<.001); mood(p<.001); control(p<.001), social(p<.001), and beliefs(p<.001) subdomains; poorer sleep(p<.001) and lower quality of life(p<.001) compared to participants without‐NPS(Table 1). MBI‐C‐total, MBI‐C‐mood and MBI‐C‐control subdomains were effective in discriminating between participants with and without NPS, with an acceptable Area Under the Curve: .782(.732‐.833) for MBI‐C‐total, .753(.699‐.807) for MBI‐C‐mood, and .753(.699‐.807) for MBI‐C‐control(Figure 1 and Table 2).Conclusion: In a prodromal cohort of southeast Asians, participants with NPS reported significantly worse scores on MBI‐C‐total and subdomains, specifically ‐ decreased motivation, emotional dysregulation, impulse control, social inappropriateness, abnormal perceptions, as well as poorer sleep quality and a lower quality of life compared to participants without‐NPS. The results are keeping with the strong evidence that behavioral changes are among the first symptoms noticeable to the person themselves as they begin to experience cognitive decline. The self‐reported questionnaires used are easily administered and brief, which has important real‐world relevance for early diagnoses of, and timely intervention for prodromal dementia. Further studies of BIOCIS is on‐going to investigate the impact of NPS on cognitive decline.

Utilizing non-invasive neuroimaging for characterization of blood brain barrier (BBB) changes and perfusion deficits underlying small vessel disease pathobiology including white matter hyperintensities (WMH) remains largely unexplored. We examined the underlying haemodynamics of WMH by assessing complex relationships between cerebral blood flow, BBB permeability and WMH burden. Cross-sectional data from study participants belonging to the community-based Biomarker and Cognition Cohort Study, Singapore was obtained. Brain structural and novel non-invasive multi-echo Arterial Spin Labeling data was obtained from 128 participants to derive cerebral blood flow (CBF), arterial transit time (ATT) and BBB time of exchange (T_ex). Neurovascular measures from BBB imaging comprising lower CBF (β=-0.005; p = 0.0139), longer ATT (β=0.644; p = 0.0132) and shorter BBB T_ex (β=-0.002; p = 0.0023) were independently associated with higher WMH and higher age-at-visit. Model fit statistics indicated good fit for the structural equation model with a comparative fit index of 0.975 and Standardized Root Mean Square Residual of 0.074. Structural equation modelling revealed CBF (β=0.533; p < 0.001) and ATT (β=-0.254; p = 0.001) as predictors of BBB permeability. Subsequently higher BBB permeability predicted higher WMH burden (β=-0.387; p < 0.001). Additionally, vascular risk factors comprising higher blood pressure and haemoglobinA1C related to lower CBF and shorter BBB T_ex. Our study highlights that CBF and ATT contribute to BBB permeability, which in turn impacts WMH burden. Vascular risk factors also impact neurovascular measures. These findings add to the growing evidence on the potential role of BBB and perfusion deficits underlying small vessel disease burden.

Background: White matter hyperintensities (WMH) are a manifestation of cerebral small vessel disease (cSVD) and are associated with cognitive impairment. However, the relationships between WMH burden, complementary cerebral haemodynamic measures, and domain specific cognition remain incompletely understood.Methods: We conducted a cross-sectional analysis of 594 community-dwelling participants in Singapore (mean age 55.7 years [SD 10.6]; 377 [63.5%] female), classified as having low (modified Fazekas score 0-4; n=538) or high (9-12; n=56) WMH burden. Multi-echo arterial spin labelling MRI quantified arterial transit time (ATT), cerebral blood flow (CBF), and blood–brain barrier water exchange time (Tex). Between-group differences and associations with four cognitive domains were assessed with adjustment for age, sex, and education.Findings: High WMH burden was associated with widespread ATT prolongation, whereas lower CBF and Tex were confined to selected regions. In exploratory within-group analyses, ATT showed the greatest number of nominally significant associations with cognition, predominantly involving processing speed and executive function. Nominally significant CBF-cognition associations were observed only in the high WMH group, whereas Tex was associated with executive function and processing speed in selected regions across burden groups.Interpretation: ATT, CBF, and Tex provide complementary information about neurovascular dysfunction in cSVD. ATT may be particularly sensitive to diffuse haemodynamic disturbance, whereas CBF and Tex could reflect more regionally selective abnormalities relevant to cognitive vulnerability. Longitudinal studies are required to establish temporal and prognostic significance.