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Background: White Matter Hyperintensities (WMH) are features of cerebral small vessel disease (cSVD) along with lacunes, cerebral microbleeds and perivascular spaces. Vascular risk factors account for only a small proportion of the variability of the presence of WMH, and the role of additional risk factors including drug use/dependence or infections is not well defined.Objective: Examine prevalence and risk factors associated with WMH of presumed vascular origin within the HOTEL cohort, a population living in marginal housing with a high prevalence of prior homelessness, substance dependence, head trauma, mental illness and infectious diseases.Methods: Baseline imaging on 3T MRI included T1, T2-FLAIR and SWI sequences. WMH not consistent with vascular origins were excluded. Two raters assessed WMH using the Fazekas scale. Participants were divided into those with or without moderate-severe WMH (periventricular Fazekas score >2 or deep score >1). Potential cSVD risk factors which were significant on univariate analysis were entered into a multivariable stepwise binomial logistic regression to identify independent risk factors for moderate-severe WMH.Results: Intraclass coefficient for inter-rater reliability was 0.948 (95% CI, 0.924 to 0.965) for periventricular WMH and 0.848 (95% CI, 0.782 to 0.895) for deep WMH. Baseline prevalence of moderate-severe WMH (mean age 43.6 ± 9.5 years, 78% male) was 24.5%, much higher than in other, older healthy aging cohorts (Table). Age (OR 1.085, 95%CI 1.042-1.130), systolic blood pressure (OR 1.033, 95%CI 1.008-1.058) and regular injection drug use (OR 3.655, 95%CI 1.284-10.403) together explained 23.5% of variance in the presence of moderate-severe WMH within this population, with injection drug use having the largest effect.Conclusions: This young cohort appears to have an accelerated burden of cSVD, with injected drug use as a major risk factor. Further research is needed to elucidate potential mechanisms.