White matter hyperintensities drive propagating grey matter atrophy in cerebral small vessel disease

Background and Aims Older patients with advanced chronic kidney disease (CKD) often suffer from various comorbidities, including impaired cognitive (executive) functioning, depressive symptoms and apathy. It is thought that these comorbidities in CKD may have a shared underlying vascular pathophysiology, but the exact association with cerebrovascular changes remains unclear. This study therefore investigates whether cerebrovascular changes on MRI are associated with cognitive functioning, depressive symptoms and apathy in older patients with advanced CKD. Method Patients aged ≥65 years with eGFR <20ml/min/1.73 m2 not on dialysis from the Cognitive Decline in Older Patients with ESRD (COPE) study were included. Cerebrovascular changes were assessed on 3T MRI scans, including markers of cerebral large vessel disease (cortical infarcts) and cerebral small vessel disease (lobar and non-lobar microbleeds, subcortical infarcts, white matter hyperintensity volume and global cerebral blood flow). Global cognitive functioning was assessed with the Mini-Mental State Examination (MMSE), the cognitive domain executive functioning using the Trail Making Test (TMT), part B adjusted for A and Stroop card III, and the domain psychomotor speed using the Letter Digit Substitution Test (LDST, correct answers after 60 seconds), TMT-A and Stroop card II. Z-scores were calculated for each cognitive test, composite mean Z-scores were calculated for executive functioning and psychomotor speed. The number of depressive symptoms and presence of apathy were assessed using the GDS-15 and its GDS-3A subscale (≥2 symptoms being indicative of apathy). Cross-sectional associations between cerebrovascular changes and outcomes were assessed using linear and logistic regression analyses, adjusted for age, sex and educational level. Results 87 patients with advanced CKD were included (mean age 75.4 ± 6.9 years; mean eGFR 15.9 ± 3.8 mL/min/1.73 m2). The presence of cortical infarcts was significantly associated with lower global cognitive functioning (β -1.00, 95% CI -1.60–0.40, p-value 0.001) and lower psychomotor speed (β -0.67, 95% CI −1.19 –0.14, p-value 0.01). White matter hyperintensity volume was significantly associated with lower executive functioning (β -0.03, 95% CI −0.05 to −0.009, p-value 0.003). No significant associations were found between the remaining cerebral small vessel disease markers (microbleeds, subcortical infarcts, global cerebral blood flow) and cognitive functioning (global and executive), nor between any cerebrovascular changes and depressive symptoms or apathy, including both large and small vessel disease markers. Conclusion In older patients with advanced CKD, markers of cerebral small vessels disease versus markers of cerebral large vessels disease showed different significant associations with various cognitive functioning domains. These results support an underlying vascular pathophysiology of cognitive impairment in older patients with advanced CKD. In contrast, no were found between cerebrovascular changes (both large and small vessel disease markers) and depressive symptoms and apathy, which might indicate that non-vascular related factors (e.g. uremic or inflammatory factors) may play a role in the occurrence of these comorbidities.

BackgroundAlzheimer’s disease (AD) frequently coexists with cerebral small vessel disease (CSVD) is common in the aging population, yet the underlying mechanisms are not yet fully understood. Both long‐term blood pressure variability (BPV) and plasma neurofilament light (PNFL) were identified as potential biomarkers for AD and CSVD. This study aims to understand the mechanisms of comorbidity between AD and CSVD by investigating the associations among BPV, PNFL, and comorbidity. The severity of CSVD was visualized as white matter hyperintensities (WMH).MethodData was collected from the Alzheimer’s Disease Neuroimaging Initiative database. Participants with cognitively normal and mild cognitive impairment were included in the data analyses as clinical dementia rating (CDR) = 0 and 0.5. Aβ status was determined by cerebrospinal fluid Aβ levels and the WMH burden was defined by adjusting the WMH volume for intracranial volume. The differences in BPV and PNFL levels among participants with different Aβ status and varying WMH burdens were compared. Causal mediation analyses were conducted to explore whether the relationships of BPV with brain structural changes and cognition were mediated by PNFL.ResultAβ positive participants with high WMH burden had higher BPV and PNFL compared to Aβ negative individuals with low WMH burden. Systolic BPV (estimate [est] = 0.022, p = 0.004) was associated with WMH volume, and diastolic BPV (est = ‐0.053, p = 0.002) was associated with hippocampal volume. Both systolic BPV and diastolic BPV were associated with memory and executive function. Moreover, systolic (est = 0.013, p<0.001) and diastolic BPV (est = 0.012, p < 0.001) were associated with PNFL independent with average blood pressure. Mediation analyses revealed that PNFL mediated the association between systolic BPV and both WMH volume and executive function. PNFL also mediated the relationship between diastolic BPV and both hippocampal volume and memory function.ConclusionElevated BPV was linked with axonal damage, hippocampal atrophy, WMH progression, and cognitive decline. This finding suggests that the same risk factor may result in pathological changes in different brain regions and cognitive decline, which in turn may be associated with the comorbidity of AD and CSVD.

We performed a systematic review and meta-analysis on prospective studies that provided risk estimates for the impact of 3 different MRI markers of small vessel disease (SVD), namely white matter hyperintensities (WMH), cerebral microbleeds (CMB) and lacunes, on cognitive decline in relatively healthy older adults without cognitive deficits at baseline. A total of 23 prospective studies comprising 11,486 participants were included for analysis. Extracted data was pooled, reviewed and meta-analysed separately for global cognition, executive function, memory and attention. The pooled effect size for the association between cerebral SVD and cognitive decline was for global cognition −0.10 [−0.14; −0.05], for executive functioning −0.18 [−0.24; − 0.11], for memory −0.12 [−0.17; −0.07], and for attention −0.17 [−0.23; −0.11]. Results for the association of individual MRI markers of cerebral SVD were statistically significant for WMH and global cognition −0.15 [−0.24; −0.06], WMH and executive function −0.23 [−0.33; −0.13], WMH and memory −0.19 [−0.29; −0.09], WMH and attention −0.24 [−0.39; −0.08], CMB and executive function −0.07 [−0.13; −0.02], CMB and memory −0.11 [−0.21; −0.02] and CMB and attention −0.13 [−0.25; −0.02]. In conclusion, presence of MRI markers of cerebral SVD were found to predict an increased risk of cognitive decline in relatively healthy older adults. While WMH were found to significantly affect all cognitive domains, CMB influenced decline in executive functioning over time as well as (in some studies) decline in memory and attention.

White matter hyperintensities (WMH) constitute the visible spectrum of cerebral small vessel disease (SVD) markers and are associated with cognitive decline, although they do not fully account for memory decline observed in individuals with SVD. We hypothesize that WMH might exert their effect on memory decline indirectly by affecting remote brain structures such as the hippocampus. We investigated the temporal interactions between WMH, hippocampal atrophy and memory decline in older adults with SVD. Five hundred and three participants of the RUNDMC study underwent neuroimaging and cognitive assessments up to 3 times over 8.7 years. We assessed WMH volumes semi-automatically and calculated hippocampal volumes (HV) using FreeSurfer. We used linear mixed effects models and causal mediation analyses to assess both interaction and mediation effects of hippocampal atrophy in the associations between WMH and memory decline, separately for working memory (WM) and episodic memory (EM). Linear mixed effect models revealed that the interaction between WMH and hippocampal volumes explained memory decline (WM: β = .067; 95%CI[.024-0.111]; p < .01; EM: β = .061; 95%CI[.025-.098]; p < .01), with better model fit when the WMH*HV interaction term was added to the model, for both WM (likelihood ratio test, χ2 [1] = 9.3, p < .01) and for EM (likelihood ratio test, χ2 [1] = 10.7, p < .01). Mediation models showed that both baseline WMH volume (β = -.170; p = .001) and hippocampal atrophy (β = 0.126; p = .009) were independently related to EM decline, but the effect of baseline WMH on EM decline was not mediated by hippocampal atrophy (p value indirect effect: 0.572). Memory decline in elderly with SVD was best explained by the interaction of WMH and hippocampal volumes. The relationship between WMH and memory was not causally mediated by hippocampal atrophy, suggesting that memory decline during aging is a heterogeneous condition in which different pathologies contribute to the memory decline observed in elderly with SVD.

OF THESIS CEREBROVASCULAR DISEASE RISK FACTORS, ARTERIOLAR SCLEROSIS, AND COGNITIVE DECLINE IN THE KENTUCKY APPALACHIAN “STROKE-BELT.” The relationship between cerebrovascular disease (CVD) risk factors and cognitive impairment or dementia has been widely studied with significant variability in findings between groups. We hypothesized that chronic small vessel injury in the form of arteriolar sclerosis, measured quantitatively using MRI to measure total white matter hyperintensity (WMH) volumes, would identify specific association of CVD risk factors and patterns of cognitive decline, associated with mild cognitive impairment of the cerebrovascular type, that represent the core features of vascular cognitive impairment in our cohort. A Cross-sectional analysis of clinical and quantitative MRI data on 114 subjects with normal cognitive function (n=52) and mild cognitive impairment (MCI; n=62) was performed. Quantitative total WMH volumes were examined in relation to potentially causative CVD risk factors and resultant test scores across cognitive domains using linear regression models adjusted for age, gender, and education. Among CVD risk factors analyzed, age (p< 0.001), education (p= 0.003), hypertension (p= 0.012), and hyperlipidemia (p= 0.008) demonstrated the strongest associations with WMH volumes. Conversely, diabetes, smoking, history of heart attacks, atrial fibrillation, and history of stroke that have shown associations with CVD pathology on imaging in other studies were not statistically associated with increased WMH in this cohort. WMH volumes were associated with decrease performance on the Trial Making Test type A & B and long delayed free recall on the California Verbal Learning Test. Our findings suggest similarities and yet differences in comparison to other studies. Hypertension and hyperlipidemia appear to represent common shared risks across geographically disparate groups. Our findings, like others, suggest CVD pathology impact processing speed and executive function and provide further evidence for CVD effects on short-term memory in those at risk for cognitive decline and the future development of dementia in our cohort.

Temporal evolution of brain structural changes associated with anxiety sensitivity in patients with breast cancer: A causal network analysis.

Cerebral small vessel disease (SVD) is the primary cause of vascular cognitive impairment and is associated with decline in executive function (EF) and information processing speed (IPS). Imaging biomarkers are needed that can monitor and identify individuals at risk of severe cognitive decline. Recently there has been interest in combining several magnetic resonance imaging (MRI) markers of SVD into a unitary score to describe disease severity. Here we apply a diffusion tensor image (DTI) segmentation technique (DSEG) to describe SVD related changes in a single unitary score across the whole cerebrum, to investigate its relationship with cognitive change over a three-year period.98 patients (aged 43–89) with SVD underwent annual MRI scanning and cognitive testing for up to three years. DSEG provides a vector of 16 discrete segments describing brain microstructure of healthy and/or damaged tissue. By calculating the scalar product of each DSEG vector in reference to that of a healthy ageing control we generate an angular measure (DSEG θ) describing the patients' brain tissue microstructural similarity to a disease free model of a healthy ageing brain. Conventional MRI markers of SVD brain change were also assessed including white matter hyperintensities, cerebral atrophy, incident lacunes, cerebral-microbleeds, and white matter microstructural damage measured by DTI histogram parameters. The impact of brain change on cognition was explored using linear mixed-effects models. Post-hoc sample size analysis was used to assess the viability of DSEG θ as a tool for clinical trials.Changes in brain structure described by DSEG θ were related to change in EF and IPS (p < 0.001) and remained significant in multivariate models including other MRI markers of SVD as well as age, gender and premorbid IQ. Of the conventional markers, presence of new lacunes was the only marker to remain a significant predictor of change in EF and IPS in the multivariate models (p = 0.002). Change in DSEG θ was also related to change in all other MRI markers (p < 0.017), suggesting it may be used as a surrogate marker of SVD damage across the cerebrum. Sample size estimates indicated that fewer patients would be required to detect treatment effects using DSEG θ compared to conventional MRI and DTI markers of SVD severity.DSEG θ is a powerful tool for characterising subtle brain change in SVD that has a negative impact on cognition and remains a significant predictor of cognitive change when other MRI markers of brain change are accounted for. DSEG provides an automatic segmentation of the whole cerebrum that is sensitive to a range of SVD related structural changes and successfully predicts cognitive change. Power analysis shows DSEG θ has potential as a monitoring tool in clinical trials. As such it may provide a marker of SVD severity from a single imaging modality (i.e. DTIs).

Cerebral Small Vessel Disease (SVD); lacunes, Cerebral Microbleeds (CMBs), and White Matter Hyperintensities (WMH) have a vital role in cognitive impairment and dementia. SVD in lobar location is related to cerebral amyloid angiopathy, whereas SVD in a deep location with hypertensive arteriopathy. It remains unclear how different locations of SVD affect long-term cognitive decline. The present study aimed to analyse the association between different locations and severity of SVD with global and domain-specific cognitive decline over the follow-up interval of 3 years. We studied 428 participants who had performed MRI scans at baseline and at least 3 neuropsychological assessments. Locations of lacunes and CMBs were categorized into strictly lobar, strictly deep and mixed-location, WMH volume into anterior and posterior. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Harmonization Neuropsychological Battery was used to assess cognitive function. To analyse the association between baseline location and severity of SVD with cognitive decline, linear regression models with generalized estimated equations were constructed to calculate the mean difference, 95% confidence interval and two-way interaction factor between time and SVD. Increased numbers of baseline CMBs were associated with a decline in global cognition as well as a decline in executive function and memory domains. Location-specific analysis showed similar results with strictly lobar CMBs. There was no association with strictly deep and mixed-location CMBs with cognitive decline. Baseline WMH volume was associated with a decline in global cognition, executive function and memory. Similar results were obtained with anterior and posterior WMH volumes. Lacunes and their locations were not associated with cognitive decline. Strictly lobar CMBs, as well as WMH volume in anterior and posterior regions, were associated with cognitive decline. Future research focuses are warranted to evaluate interventions that may prevent cognitive decline related to SVD.

PurposeThis study aims to investigate the potential effect of compromised structural integrity on cerebral aging and cognitive function in cerebral small vessel disease (CSVD).MethodsFifty-five CSVD patients and 42 controls underwent three-dimensional T1-weighted imaging and diffusion tensor imaging. Relative brain age (RBA) was computed to assess cerebral aging. Variables of structural integrity included cortical thickness, cortical volume, white matter hyperintensity (WMH) volume, peak width of skeletonized mean diffusivity (PSMD), ventricular volume, and choroid plexus volume. Mini-Mental State Examination (MMSE) was conducted to assess general cognition. Trail Making Test (TMT) and Auditory Verbal Learning Test were administered to evaluate executive function and episodic memory, respectively. Mediation analysis and multivariate linear regression with interaction terms were performed to explore the differential impacts of RBA on cognitive function and structural integrity between CSVD patients and controls.ResultsRBA was significantly increased in CSVD patients compared to controls (p < 0.001). White matter injuries as assessed with PSMD (mediation magnitude: 41.1%) and WMH volume (mediation magnitude: 56.9%) significantly mediated the relationship between CSVD pathologies and RBA (p < 0.001). Higher RBA was significantly correlated with poorer scores of MMSE, TMT-A, and TMT-B in CSVD patients (p < 0.01). Additionally, PSMD (mediation magnitude: 57.8% in MMSE, 48.3% in TMT-A, and 28.8% in TMT-B) and WMH volume (mediation magnitude: 55.1% in MMSE) significantly mediated the relationship between RBA and cognitive function (p < 0.05).ConclusionWhite matter injuries play a critical role in the cerebral aging and cognitive decline in CSVD patients.

Evidence on the relationship between periodic limb movements during sleep (PLMS) and cerebral small vessel disease is lacking. This study aimed to assess the association between the PLMS index and the neuroimaging features of cerebral small vessel disease on magnetic resonance imaging. Consecutive patients diagnosed with cerebral small vessel disease were enrolled. Data on the clinical characteristics, polysomnography, and brain magnetic resonance imaging were collected. The Accubrain software was used to calculate automatically the volume of white matter hyperintensities, the number of lacunar infarctions, and cerebral microbleeds. The severity of white matter hyperintensities, enlarged basal ganglia perivascular spaces, and the total cerebral small vessel disease scores were also rated visually using semiquantitative scales. The severity of PLMS was measured using the PLMS index, and the patients were divided into two groups using an established cut-off value of ≥15 per hour. Logistic regression was used to examine the association between PLMS and the neuroimaging features of cerebral small vessel disease. In total, 37 patients were included in the final analyses. The mean age was 66.49±11.31years, and 73.0% were males. The mean PLMS index was 19.30±10.18. In univariate analyses, it was found that patients with cerebral small vessel disease with a PLMS index ≥15had increased enlarged basal ganglia perivascular spaces (OR 6.136, 95%CI 1.101-34.214) and increased total cerebral small vessel disease scores (OR 6.0, 95%CI 1.253-28.742). Only the association between the PLMS index and the total cerebral small vessel disease burden score remained statistically significant after adjusting for age, sex, and the presence of moderate to severe obstructive sleep apnea syndrome. In conclusion, an elevated PLMS index is likely to be associated with a greater cerebral small vessel disease burden. PLMS might be a novel potential marker of cerebral small vessel disease.

Cerebral small vessel disease (SVD) is the primary cause of vascular cognitive impairment and is associated with decline in executive function (EF) and information processing speed (IPS). Imaging biomarkers are needed that can monitor and identify individuals at risk of severe cognitive decline. Recently there has been interest in combining several magnetic resonance imaging (MRI) markers of SVD into a unitary score to describe disease severity. Here we apply a diffusion tensor image (DTI) segmentation technique (DSEG) to describe SVD related changes in a single unitary score across the whole cerebrum, to investigate its relationship with cognitive change over a three-year period. 98 patients (aged 43-89) with SVD underwent annual MRI scanning and cognitive testing for up to three years. DSEG provides a vector of 16 discrete segments describing brain microstructure of healthy and/or damaged tissue. By calculating the scalar product of each DSEG vector in reference to that of a healthy ageing control we generate an angular measure (DSEG θ) describing the patients' brain tissue microstructural similarity to a disease free model of a healthy ageing brain. Conventional MRI markers of SVD brain change were also assessed including white matter hyperintensities, cerebral atrophy, incident lacunes, cerebral-microbleeds, and white matter microstructural damage measured by DTI histogram parameters. The impact of brain change on cognition was explored using linear mixed-effects models. Post-hoc sample size analysis was used to assess the viability of DSEG θ as a tool for clinical trials. Changes in brain structure described by DSEG θ were related to change in EF and IPS (p < 0.001) and remained significant in multivariate models including other MRI markers of SVD as well as age, gender and premorbid IQ. Of the conventional markers, presence of new lacunes was the only marker to remain a significant predictor of change in EF and IPS in the multivariate models (p = 0.002). Change in DSEG θ was also related to change in all other MRI markers (p < 0.017), suggesting it may be used as a surrogate marker of SVD damage across the cerebrum. Sample size estimates indicated that fewer patients would be required to detect treatment effects using DSEG θ compared to conventional MRI and DTI markers of SVD severity. DSEG θ is a powerful tool for characterising subtle brain change in SVD that has a negative impact on cognition and remains a significant predictor of cognitive change when other MRI markers of brain change are accounted for. DSEG provides an automatic segmentation of the whole cerebrum that is sensitive to a range of SVD related structural changes and successfully predicts cognitive change. Power analysis shows DSEG θ has potential as a monitoring tool in clinical trials. As such it may provide a marker of SVD severity from a single imaging modality (i.e. DTIs).

Cerebral small vessel disease (SVD) is a major health problem for its contribution to ≈45% of dementias, and about a fifth of all strokes worldwide, representing one of the most important causes of disabilities.1 The term SVD refers to a group of pathological processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. The most common forms are age- and hypertension-related SVD and cerebral amyloid angiopathy (CAA).2 Vessel wall changes may lead to both ischemic and hemorrhagic consequences: (1) a state of chronic hypoperfusion or vascular dysfunction responsible for incomplete infarction,3,4 (2) acute focal necrosis (lacunar infarct), or (3) vessel rupture manifesting as hemorrhagic SVD. The clinical consequences of SVD are various and mainly consist of cognitive, mood, and motor dysfunctions leading to functional disability in the late stages of the disease. Magnetic resonance imaging (MRI) has become crucial in the diagnosis of SVD enabling the evaluation of the disease progression both in the clinical and research settings. However, correlations between clinical features of SVD and conventional MRI measures have been partially discordant. Some authors suggested that the cumulative effect of SVD lesions, rather than the individual lesions themselves determines the clinical impact,5 whereas others suggested that the presence and severity of alterations nonvisible on conventional MRI might also be an explanation.6 In the past decade, diffusion tensor imaging (DTI) has been increasingly used for the evaluation of SVD patients because it is sensitive to tissue damage and can show abnormalities in both areas of white matter hyperintensities (WMH) and in normal appearing WM (NAWM). Despite the high sensitivity in detecting cerebral damage, DTI has a low specificity in detecting the underlying cause. In fact, we can only infer that DTI changes reflect a loss of WM …

BackgroundRetinal vessel calibres (RVCs) are non-invasive markers of microvascular health and may serve as accessible indicators of cerebral small vessel disease (CSVD) and future cognitive impairment. This study examines whether RVCs are associated with cognitive decline, and how these associations compare with those observed for white matter hyperintensities (WMH), a known marker of CSVD.MethodsData were analysed from community-dwelling participants aged 70+ in the ASPREE trial and sub-studies, free of dementia and cardiovascular disease at baseline. RVCs were measured from fundus photography and WMH volumes from 3 T magnetic resonance imaging. Covariate-adjusted linear mixed-effects models assessed cognitive trajectories relative to baseline RVCs and WMH volumes. Cross-sectional associations between baseline RVCs and WMHs were examined via linear regression.ResultsThis study included 3540 participants with RVC data and 489 with WMH data (median [IQR] age: 73.2 [71.4-76.3] and 72.5 [71.2-75.4] years; female: 52.9% and 47.6%) over a median follow-up of 7.4 [IQR 5.5–8.5] and 3.8 [IQR 2.9-5.3] years, respectively. Baseline RVCs were not significantly associated with cognitive trajectories nor with baseline WMHs. Larger baseline WMH volumes were associated with greater global (Modified Mini-Mental State Examination) decline (mean 0.40 points/year; 95% CI 0.57, 0.22) and declines in delayed memory (HVLT-r) (−0.13 [−0.22, −0.04]), psychomotor function (Symbol Digit Modalities Test) (−0.29 [−0.52, −0.07]) and to a lesser extent, executive function (Controlled Oral Word Association Test) (−0.09 [95% CI −0.22, 0.03]).ConclusionIn contrast to WMH volumes, RVCs were not associated with cognitive decline. Exploring longitudinal changes in a broader range of retinal and brain biomarkers may provide deeper insights into the relationship between ocular and cerebral biomarkers in CSVD and clinical outcomes.

See related article, pages 55–61. Because of similarities in the vascular supply to kidney and brain, information about vascular disease in one organ may inform us about vascular disease in the other, and such knowledge may shed light on ways to treat or prevent these diseases. Unlike most organs, both kidney and brain are low resistance end-organs and are exposed to high-volume blood flow throughout the cardiac cycle, explaining their pulsating nature.1 For the kidney, impairments from vascular disease manifest as problems with glomerular filtration, detected clinically by biochemical makers such as serum creatinine, urinary albumin, and serum cystatin C. For the brain, impairments manifest with overt focal neurological deficits, such as with stroke or transient ischemic attack, or as covert global deficits affecting cognition, mobility and mood, such as has been suggested with small-vessel disease. In humans, investigation of brain vascular disease and how it causes impairment of brain function often entails looking at the structure of the brain with MRI for infarctions, white matter lesions, and volumes of brain, ventricles and sulci. Given the difficulty in getting tissue, exploration of cause usually does not include microscopic examination of brain tissue, although microinfarcts inapparent on MRI can be identified.2 For investigation of vascular disease in the kidney, structural changes detectable on imaging are limited primarily to decrements in kidney size due to chronic fibrosis and atrophy. On the other hand, tissue is more …

We examined the cross-sectional association between lipid fractions and 2 MRI markers of cerebral small vessel disease, white matter hyperintensity volume (WMHV) and lacunes, representing powerful predictors of stroke and dementia. The study sample comprised 2,608 participants from the 3C-Dijon Study (n = 1,842) and the Epidemiology of Vascular Aging Study (EVA) (n = 766), 2 large French population-based cohorts (72.8 ± 4.1 and 68.9 ± 3.0 years; 60.1% and 58.4% women, respectively). Analyses were performed separately in each study and combined using inverse variance meta-analysis. Lipid fractions (triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol) were studied as continuous variables. WMHV was studied both in a continuous and dichotomous manner, the latter reflecting the age-specific top quartile of WMHV (EXT-WMHV). Analyses were adjusted for age and sex. Increasing triglycerides were associated with larger WMHV in the 3C-Dijon Study (β ± SE = 0.0882 ± 0.0302, p = 0.0035), in the EVA Study (β ± SE = 0.1062 ± 0.0461, p = 0.021), and in the combined analysis (β ± SE = 0.0936 ± 0.0252, p = 0.0002) and with higher frequency of lacunes in the 3C-Dijon Study (odds ratio [OR] = 1.65 [95% confidence interval 1.10-2.48], p = 0.015), in the EVA Study (OR = 1.58 [95% confidence interval 0.93-2.70], p = 0.09), and in the combined analysis (OR = 1.63 [95% confidence interval 1.18-2.25], p = 0.003). Associations were attenuated but maintained after adjusting for other vascular risk factors or for inflammatory markers. Associations were present and in the same direction both in participants taking and those not taking lipid-lowering drugs but tended to be stronger in the former for EXT-WMHV. Increasing low-density lipoprotein cholesterol tended to be associated with a decreased frequency and severity of all MRI markers of cerebral small vessel disease in both studies. Increasing triglycerides but not other lipid fractions were associated with MRI markers of cerebral small vessel disease in older community persons.