Lower Brain Parenchymal Fraction Research Articles

Lipid and brain volumetric measures in multiple sclerosis patients: findings from a large observational study.

This study aimed to investigate relationships between cholesterol profile, brain volumetric MRI, and clinical measures in a large observational cohort of multiple sclerosis (MS) patients. We included 1.505 patients with 4.966 time points including complete lipid, clinical, and imaging data. The time among lipid, brain MRI and clinical measures was under 90 days. Cross-sectional statistical analysis at baseline was performed using an adjusted linear regression and analysis of longitudinal lipid and MRI measures data was performed using adjusted linear mixed models. We found associations between higher high-density lipoprotein cholesterol (HDL-C) and lower brain parenchymal fraction (BPF) at cross-sectional analysis at baseline (B = -0.43, CI 95%: -0.73, -0.12, p = 0.005), as well as in longitudinal analysis over follow-up (B = -0.32 ± 0.072, χ2 = 36.6; p = < 0.001). Higher HDL-C was also associated with higher T2-lesion volume in longitudinal analysis (B = 0.11 ± 0.023; χ2 = 23.04; p = < 0.001). We observed a weak negative association between low-density lipoprotein cholesterol (LDL-C) levels and BPF at baseline (B = -0.26, CI 95%: -0.4, -0.11, p = < 0.001) as well as in longitudinal analysis (B = -0.06 ± 0.03, χ2 = 4.46; p = 0.03). T2-LV did not show an association with LDL-C. We did not find any association between lipid measures and disability. The effect of lipid levels on MRI measures and disability was minimal (Cohen f2 < 0.02). Our results contradict the previously described exclusively positive effect of HDL-C on brain atrophy in patients with MS. Higher LDL-C was weakly associated with higher brain atrophy but not with higher lesion burden.

Orthostatic hypotension, cognition and structural brain imaging in hemodynamically impaired patients

BackgroundOrthostatic hypotension (OH) is associated with an increased risk of dementia, potentially attributable to cerebral hypoperfusion. We investigated which patterns and characteristics of OH are related to cognition or to potentially underlying structural brain injury in hemodynamically impaired patients and healthy reference participants. MethodsParticipants with carotid occlusive disease or heart failure, and reference participants from the Heart-Brain Connection Study underwent OH measurements, neuropsychological assessment and brain MRI. We analyzed the association between OH, global cognitive functioning, white matter hyperintensity (WMH) volume and brain parenchymal fraction with linear regression. We stratified by participant group, severity and duration of OH, chronotropic incompetence and presence of orthostatic symptoms. ResultsOf 337 participants (mean age 67.3 ± 8.8 years, 118 (35.0%) women), 113 (33.5%) had OH. Overall, presence of OH was not associated with cognitive functioning (β: −0.12 [−0.24–0.00]), but we did observe worse cognitive functioning in those with severe OH (≥ 30/15 mmHg; β: −0.18 [−0.34 to −0.02]) and clinically manifest OH (β: −0.30 [−0.52 to −0.08]). These associations did not differ significantly by OH duration or chronotropic incompetence, and were similar between patient groups and reference participants. Similarly, both severe OH and clinically manifest OH were associated with a lower brain parenchymal fraction, and severe OH also with a somewhat higher WMH volume. ConclusionsSevere OH and clinically manifest OH are associated with worse cognitive functioning. This supports the notion that specific patterns and characteristics of OH determine its impact on brain health.

Understanding the relationship between type-2 diabetes, MRI markers of neurodegeneration and small vessel disease, and dementia risk: a mediation analysis.

To explore to which extent neurodegeneration and cerebral small vessel disease (SVD) could mediate the association between type-2 diabetes and higher dementia risk.The analytical sample consisted in 2228 participants, out of the Three-City study, aged 65 and older, free of dementia at baseline who underwent brain MRI. Diabetes was defined by medication intake or fasting or non-fasting elevated glucose levels. Dementia status was assessed every 2 to 3 years, during up to 12 years of follow-up. Brain parenchymal fraction (BPF) and white matter hyperintensities volume (WMHV) were selected as markers of neurodegeneration and cerebral SVD respectively. We performed a mediation analysis of the effect of baseline BPF and WMHV (mediators) on the association between diabetes and dementia risk using linear and Cox models adjusted for age, sex, education level, hypertension, hypercholesterolemia, BMI, smoking and alcohol drinking status, APOE-ε4 status, and study site.At baseline, 8.8% of the participants had diabetes. Diabetes (yes vs. no) was associated with higher WMHV (βdiab = 0.193, 95% CI 0.040; 0.346) and lower BPF (βdiab=-0.342, 95% CI -0.474; -0.210), as well as with an increased risk of dementia over 12 years of follow-up (HRdiab=1.65, 95% CI 1.04; 2.60). The association between diabetes status and dementia risk was statistically mediated by higher WMHV (HRdiab=1.05, 95% CI 1.01; 1.11, mediated part = 10.8%) and lower BPF (HRdiab=1.12, 95% CI 1.05; 1.20, mediated part = 22.9%).This study showed that both neurodegeneration and cerebral SVD statistically explained almost 30% of the association between diabetes and dementia.

Associations of sNfL with clinico-radiological measures in a large MS population.

Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice. Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay. Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable. Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.

Impact of Brain MRI Markers on Major and Mild Vascular Cognitive Impairment in CADASIL

Background: Cognitive impairment is the second most common clinical manifestation in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, understanding of cognitive impairment in CADASIL has been hampered by lack of consensus on diagnosis of vascular cognitive impairment (VCI). We used vascular impairment of cognition classification consensus study principles (VICCCS-1) and protocols (VICCCS-2) to assess the cognitive impairment in CADASIL. We also evaluated the impact of MRI markers on major and mild VCI in CADASIL.Methods: We prospectively recruited 64 patients who underwent standardized brain MRI and detailed neuropsychological test. MRI analysis included number of lacunes, number of cerebral microbleeds (CMB), normalized volume of white-matter hyperintensities (nWMH), and brain parenchymal fraction (BPF). BPF has been used to measure brain atrophy. The patients were divided into three groups: those with normal cognition (CADASIL-NC, n=14), those with mild VCI (CADASIL-mild VCI, n=38), and those with major VCI (CADASIL-major VCI, n=11).Results: The three groups differed according to age, with the major VCI group being older. The major VCI group had more lacunes, more CMB, more extensive white matter lesions and lower BPF than NC group. There were no significant differences between NC and mild VCI groups in BPF. BPF and age were the independent predictors of major VCI. There was a tendency that women were at higher risk for mild VCI, though it did not reach statistical significance. Women were older than men, but had lower number of lacunes in mild VCI.Conclusions: These findings suggest that brain atrophy and age are the main predictors of major VCI in CADASIL.

Pregnancy-induced brain magnetic resonance imaging changes in women with multiple sclerosis.

The effect of pregnancy on brain changes and radiological disease activity in women with multiple sclerosis (MS) is not well understood. This study was undertaken to describe the dynamics of lesion activity and brain volume changes during the pregnancy and postpartum periods. This observational study of 62 women with relapsing-remitting MS included magnetic resonance imaging (221 scans) as well as clinical visits at baseline (<24 and >6months before pregnancy), prepregnancy (<6months before pregnancy), postpartum (<3months after delivery), and follow-up (>12 and <24months after delivery) periods. The majority of women had a mild disability and a short disease duration (median = 5.5years). Eighteen (29.0%) women had a relapse during the year preceding pregnancy onset, nine (14.5%) during pregnancy, and 20 (32.3%) in the year following delivery. Disability status remained unchanged during follow-up. Women in the postpartum period (n=62) had higher T2 lesion volume (median = 1.18ml vs. 0.94ml), greater annualized T2 lesion volume increase (0.23ml vs. 0.0ml), lower brain parenchymal fraction (85.6% vs. 86.4%), and greater annualized brain volume loss (-1.74% vs. -0.16%) compared with the prepregnancy period (all p<0.001). At 12-24months after delivery, women (n=41) had higher T2lesion volume (1.16ml vs. 1.0ml) and lower brain parenchymal fraction (86.0% vs. 86.5%) compared to the prepregnancy period (both p<0.001). The postpartum period was associated with an increase in T2 lesion volume and accelerated brain volume loss in a considerable proportion of women. This should be considered in treatment decision-making and designing clinical trials.

Optical coherence tomography measures correlate with brain and spinal cord atrophy and multiple sclerosis disease-related disability.

Both optical coherence tomography (OCT) and magnetic resonance imaging (MRI) volumetric measures have been postulated as potential biomarkers of multiple sclerosis (MS)-related disability. The aim of the study was to investigate the association between OCT and brain volume and spinal cord area (SCA) parameters in patients with relapsing MS and to assess their independent associations with disability. This was a cross-sectional analysis of 90 patients with MS who underwent OCT and MRI examination. Values of peripapillary retinal nerve fibre layer (pRNFL), ganglion cell/inner plexiform layer (GCIPL) and inner nuclear layer of eyes without previous optic neuritis were obtained. SCA and brain parenchymal fraction (BPF), grey and white matter fractions were obtained. Multivariable regression analyses were conducted with disability as dependent variable. Lower pRNFL thickness and lower GCIPL volume as well as lower BPF, grey matter fraction and SCA were associated with a longer disease duration and a higher Expanded Disability Status Scale score. Lower pRNFL thickness and GCIPL volumes were associated with lower BPF and SCA. In the multivariable logistic regression analyses, pRNFL thickness and GCIPL volume outperformed MRI in predicting disability. The OCT measures correlate with brain and spinal cord atrophy and appear more closely associated with disability than MRI volumetric measures.

MRI phenotypes in MS: Longitudinal changes and miRNA signatures.

ObjectiveTo classify and immunologically characterize persons with MS based on brain lesions and atrophy and their associated microRNA profiles.MethodsCerebral T2-hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were quantified and used to define MRI phenotypes as follows: type I: low T2LV, low atrophy; type II: high T2LV, low atrophy; type III: low T2LV, high atrophy; type IV: high T2LV, high atrophy, in a large cross-sectional cohort (n = 1,088) and a subset with 5-year lngitudinal follow-up (n = 153). Serum miRNAs were assessed on a third MS cohort with 2-year MRI phenotype stability (n = 98).ResultsOne-third of the patients had lesion-atrophy dissociation (types II or III) in both the cross-sectional and longitudinal cohorts. At 5 years, all phenotypes had progressive atrophy (p < 0.001), disproportionally in type II (BPF −2.28%). Only type IV worsened in physical disability. Types I and II showed a 5-year MRI phenotype conversion rate of 33% and 46%, whereas III and IV had >90% stability. Type II switched primarily to IV (91%); type I switched primarily to II (47%) or III (37%). Baseline higher age (p = 0.006) and lower BPF (p < 0.001) predicted 5-year phenotype conversion. Each MRI phenotype demonstrated an miRNA signature whose underlying biology implicates blood-brain barrier pathology: hsa.miR.22.3p, hsa.miR.361.5p, and hsa.miR.345.5p were the most valid differentiators of MRI phenotypes.ConclusionsMRI-defined MS phenotypes show high conversion rates characterized by the continuation of either predominant neurodegeneration or inflammation and support the partial independence of these 2 measures. MicroRNA signatures of these phenotypes suggest a role for blood-brain barrier integrity.

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis

Background: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. Objective: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. Methods: Untreated patients (n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. Linear regression analyses were applied based on the three SNPs, smoking and BMI as exposures and MRI surrogate markers for disease severity as outcomes. Results: Current smoking was associated with reduced gray matter fraction, lower brain parenchymal fraction and increased cerebrospinal fluid fraction in comparison to non-smoking, whereas no effect was observed on white matter fraction. BMI and the SNPs in HLA and APOE were not associated with structural MRI parameters. Conclusions: Smoking may have an unfavorable effect on the gray matter fraction as a potential measure of MS severity already in early MS. These findings may impact patients’ counseling upon initial diagnosis of MS.

Convergent effects of a functional C3 variant on brain atrophy, demyelination, and cognitive impairment in multiple sclerosis

Background: Complement system activation products are present in areas of neuroinflammation, demyelination, and neurodegeneration in brains of patients with multiple sclerosis (MS). C3 is a central element in the activation of complement cascades. A common coding variant in the C3 gene (rs2230199, C3R102G) affects C3 activity. Objectives: To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures. Methods: In total, 161 relapse-onset MS patients (Expanded Disability Status Scale (EDSS) ≤ 6) underwent physical assessments, cognitive tests (Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and California Verbal Learning Test (CVLT)), and magnetic resonance imaging (MRI). Lesion volumes were quantified semi-automatically. Voxel-wise analyses were performed to assess the effects of rs2230199 genotype on gray matter (GM) atrophy (n = 155), white matter (WM) fractional anisotropy (FA; n = 105), and WM magnetization transfer ratio (MTR; n = 90). Results: While rs2230199 minor-allele dosage (C3-102G) showed no significant effect on EDSS and Multiple Sclerosis Functional Composite (MSFC), it was associated with worse cognitive performance (p = 0.02), lower brain parenchymal fraction (p = 0.003), and higher lesion burden (p = 0.02). Moreover, voxel-wise analyses showed lower GM volume in subcortical structures and insula, and lower FA and MTR in several WM areas with higher copies of rs2230199 minor allele. Conclusion: C3-rs2230199 affects white and GM damage as well as cognitive impairment in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS.

Cognitive clinico-radiological paradox in early stages of multiple sclerosis.

ObjectiveTo investigate whether the strength of the association between magnetic resonance imaging (MRI) metrics and cognitive outcomes differs between various multiple sclerosis subpopulations.MethodsA total of 1052 patients were included in this large cross‐sectional study. Brain MRI (T1 and T2 lesion volume and brain parenchymal fraction) and neuropsychological assessment (Brief International Cognitive Assessment for Multiple Sclerosis and Paced Auditory Serial Addition Test) were performed.ResultsWeak correlations between cognitive domains and MRI measures were observed in younger patients (age≤30 years; absolute Spearman's rho = 0.05–0.21), with short disease duration (<2 years; rho = 0.01–0.21), low Expanded Disability Status Scale [EDSS] (≤1.5; rho = 0.08–0.18), low T2 lesion volume (lowest quartile; <0.59 mL; rho = 0.01–0.20), and high brain parenchymal fraction (highest quartile; >86.66; rho = 0.01–0.16). Stronger correlations between cognitive domains and MRI measures were observed in older patients (age>50 years; rho = 0.24–0.50), with longer disease duration (>15 years; rho = 0.26–0.53), higher EDSS (≥5.0; rho = 0.23–0.39), greater T2 lesion volume (highest quartile; >5.33 mL; rho = 0.16–0.32), and lower brain parenchymal fraction (lowest quartile; <83.71; rho = 0.13–0.46). The majority of these observed results were confirmed by significant interactions (P ≤ 0.01) using continuous variables.InterpretationThe association between structural brain damage and functional cognitive impairment is substantially weaker in multiple sclerosis patients with a low disease burden. Therefore, disease stage should be taken into consideration when interpreting associations between structural and cognitive measures in clinical trials, research studies, and clinical practice.

Brain atrophy 15 years after CIS: Baseline and follow-up clinico-radiological correlations

Background: Brain atrophy in multiple sclerosis (MS) patients is present since the very early stages of the disease and it has been related to long-term disability. Objective: To estimate brain volume (BV) at 15 years after a clinically isolated syndrome (CIS) and to evaluate its relationship with disease outcomes. Methods: From a prospective cohort including patients presenting with a CIS, 54 patients with a brain magnetic resonance imaging (MRI) performed 15 years after CIS were included. Brain parenchymal fraction (BPF), grey matter fraction (GMF) and white matter fraction (WMF) at 15-year follow-up were obtained. Regression analyses were conducted to predict BV loss and reaching an Expanded Disability Status Scale (EDSS) of 3.0 in that 15-year period. Results: In multivariable analyses, lower values of BPF and WMF were significantly associated with being male, presenting 3–4 Barkhof criteria at baseline, presenting a second relapse, and with a decision to start treatment. In the multivariable logistic regression analysis, only lower GMF was associated with a greater risk of reaching EDSS 3.0 (odds ratio (OR) = 0.24, p = 0.028). Conclusion: Lower BPF and WMF 15 years after CIS are associated with previous markers of inflammatory disease. Lower GMF 15 years after a CIS is associated with an increased risk of reaching an EDSS of 3.0.

Cognitive functioning, wellbeing and brain correlates in HIV-1 infected patients on long-term combination antiretroviral therapy.

The objective of the current study is to integrate results from extensive neuropsychological assessment, subjective wellbeing reports and structural neuroimaging findings in successfully treated HIV-infected patients in comparison with a HIV-negative control group. A cross-sectional study. Neuropsychological functioning and self-reported wellbeing were assessed in a group of 102 virologically suppressed HIV-infected patients on combination antiretroviral therapy (cART) and 56 controls. Both groups underwent magnetic resonance (MR) examinations and grey matter, white matter and subcortical volumes were determined. Brain parenchymal fraction (BPF) was calculated as an estimated measure of global brain atrophy. HIV-infected patients showed worse information processing speed (P = 0.01) and motor function (P = 0.03) than controls. Also, higher levels of anxiety and depressive symptoms, somatic and cognitive complaints, sleep problems and health distress were found, as well as lower levels of general health perceptions, social functioning and energy (P < 0.05). No differences in wellbeing reports were found between patients on regimens containing either efavirenz or nevirapine and patients on cART without these drugs (P > 0.05). Patients had a smaller BPF (P = 0.04) and thalamus (P = 0.05) than controls. A lower BPF was related to worse motor function and information processing speed in the patients. A smaller thalamus volume was related to lower motor function in the patient group and lower speed of information processing in the controls. No profound deficits were found in the current study. The present results demonstrate that HIV has a minor impact on brain, cognition and wellbeing among HIV-infected patients who are otherwise healthy and maintained on a good control of cART.

Vitamin D metabolites are associated with clinical and MRI outcomes in multiple sclerosis patients

PurposeThe associations between vitamin D and MRI measures of brain tissue injury have not been previously investigated in multiple sclerosis (MS). This research evaluates the significance of vitamin D and...

White Matter Lesions and Lacunar Infarcts Are Independently and Differently Associated with Brain Atrophy: The SMART-MR Study

Objective: To investigate the independent association of white matter lesions (WML) and lacunar infarcts (LI) with measures of global brain atrophy on MRI. Methods: Within the SMART-MR study, a cohort study among patients with manifest arterial disease, cross-sectional analyses were performed in 840 patients (mean age 58 ± 10 years, 80% male) without cortical, large subcortical or infratentorial infarcts. Brain segmentation was used to quantify volumes of brain tissue, cerebrospinal fluid and WML. Total brain volume, ventricular volume and cortical gray matter volume were divided by intracranial volume to obtain brain parenchymal fraction (BPF), ventricular fraction (VF) and cortical gray matter fraction (GMF). Location and number of infarcts were rated visually. Results: Mean ± SD BPF was 79.3 ± 2.8%, mean ± SD VF was 2.01 ± 0.95%, and mean ± SD GMF was 36.6 ± 3.3%. Linear regression analyses, adjusted for age, sex, vascular risk factors, intima media thickness and LI showed that in patients with moderate to severe WML (upper quartile) BPF was lower (–0.51%; 95% CI –0.93 to –0.08%), VF was higher (0.48%; 95% CI 0.31–0.65%) and GMF was lower (–1.48%; 95% CI –2.07 to –0.88%) than in patients with few WML (lower quartile). Presence of LI was associated with lower BPF (–0.52%; 95% CI –0.96 to –0.07%) and higher VF (0.25%; 95% CI 0.07–0.42%), but not with GMF, independent of WML and other potential confounders. Conclusion: WML are associated with total, subcortical and cortical brain atrophy, whereas LI are associated with total and subcortical atrophy, but not with cortical atrophy, suggesting an independent role for WML and LI in the pathogenesis of brain atrophy.

Gene–environment interactions between HLA B7/A2, EBV antibodies are associated with MRI injury in multiple sclerosis

Purpose To determine the role of gene–environmental interactions between the Class I and Class II HLA alleles and the humoral anti-Epstein–Barr Virus (EBV) responses in the development of brain injury and clinical disability in multiple sclerosis (MS) patients. Methods A total of 93 MS patients (62 females; 31 males) and 122 healthy controls underwent HLA typing and testing for antibodies against EBV. The MS patients underwent brain MRI and quantitative measurements of T1- and T2-lesion volumes (LVs) and brain parenchymal fraction (BPF) were obtained. There were 54 MS cases that underwent MRI and EBV-antibody assessments at the 3-year follow-up. The anti-EBV panel included measurements of the levels of anti-EBV early antigen (EA) IgG, anti-EBV nuclear antigen (EBNA) IgG and anti-EBV viral capsid antigen (VCA) IgM and anti-EBV VCA IgG. The relationships between HLA alleles, anti-EBV antibody levels, MRI and clinical parameters were assessed in regression analysis. Results The presence of HLA B7 was associated with increased T1-LV and trends indicating increased anti-EBV VCA IgG levels, higher disability (EDSS) and more destructive MRI parameters (increased T2-LV and decreased BPF). The presence of HLA A2 was associated with lower EDSS and a trend toward decreased anti-EBV VCA IgG levels; the associations with MRI variables were not significant. The HLA B7–A2 haplotype was significantly associated with higher T2-LV and T1-LV and a trend toward lower BPF was observed. Conclusions Our data suggest that gene–environment interactions between specific HLA Class I loci and EBV exposure are associated with MRI markers of lesion injury and brain atrophy in MS patients.

Total Cerebral Blood Flow, White Matter Lesions and Brain Atrophy: The SMART-MR Study

We investigated whether total cerebral blood flow (CBF) was associated with brain atrophy, and whether this relation was modified by white matter lesions (WML). Within the Second Manifestations of ARTerial disease-magnetic resonance (SMART-MR) study, a prospective cohort study among patients with arterial disease, cross-sectional analyses were performed in 828 patients (mean age 58+/-10 years, 81% male) with quantitative flow, atrophy, and WML measurements on magnetic resonance imaging (MRI). Total CBF was measured with MR angiography and was expressed per 100 mL brain volume. Total brain volume and ventricular volume were divided by intracranial volume to obtain brain parenchymal fraction (BPF) and ventricular fraction (VF). Lower BPF indicates more global brain atrophy, whereas higher VF indicates more subcortical brain atrophy. Mean CBF was 52.0+/-10.2 mL/min per 100 mL, mean BPF was 79.2+/-2.9%, and mean VF was 2.03+/-0.96%. Linear regression analyses showed that lower CBF was associated with more subcortical brain atrophy, after adjusting for age, sex, vascular risk factors, intima-media thickness, and lacunar infarcts, but only in patients with moderate to severe WML (upper quartile of WML): Change in VF per s.d. decrease in CBF 0.18%, 95% CI: 0.02 to 0.34%. Our findings suggest that cerebral hypoperfusion in the presence of WML may be associated with subcortical brain atrophy.