Danny R. Rose, Jr., MD

Increasing evidence indicates that small vessel-type intracranial disease is not a homogeneous entity. Pathologic studies demonstrate that the radiographic manifestations of small vessel disease such as white matter hyperintensities (WMHs) and lacunar infarctions have distinct histopathological appearances. Even for lacunar infarctions, the work of CM Fisher and others dating back several decades suggest a different pathogenesis for larger lacunes (i.e., microatheroma formation) versus smaller lacunes (i.e., lipohyalinosis). Given this, it is reasonable to hypothesize that the risk factors for these different processes also differ. Dearborn et al. sought to investigate these potential associations using the Atherosclerosis Risk in Communities (ARIC) study cohort, specifically evaluating radiographic progression of small vessel disease reflected by MRI over 10-years.

The ARIC study was designed to investigate the causes of atherosclerosis and its outcomes and includes a prospective cohort that began recruitment in 1987. The analytic population for the current analysis consisted of 934 participants without a prior history of stroke who had two brain MRI scans approximately 10-years apart that were analyzed for the presence and size of incident lacunar infarctions as well as the presence and extent of white matter hyperintensities using both a visual scale and volumetric measurements. Risk factor assessment included components of metabolic syndrome (i.e., abdominal girth, HDL, blood pressure, triglycerides, fasting glucose) as well as an ad-hoc Insulin Resistance score, which was intended to examine the clustering of metabolic risk factors. The IR score included seven variables selected to exclude highly correlated factors and included log-transformed values for insulin and homeostatic model analysis for insulin resistance (HOMA-IR), BMI, waist-to-hip ratio and waist circumference.

Elevated triglycerides and decreased HDL were associated with an increase incident of all lacunar infarction, but not WMHs. Systolic blood pressure was associated with WMH and incident lacunes in unadjusted models, but did not reach statistical significance for lacunes in adjusted models. No significant difference was observed comparing the progression of WMH in patients with and without metabolic syndrome, but patients with metabolic syndrome did have more incident lacunes, with the increase being predominantly due to an increase in the number of larger lacunes.

Higher insulin levels, HOMA-IR and BMI were not associated with either measure. Increasing HOMA-IR and BMI were associated with incident large lacunes, but only in unadjusted models. Abdominal obesity as measured by waist circumference and waist-to-hip ratio was associated with incident lacunes, with a larger effect size for larger lacunes. The IR score was associated with increased odds of incident lacunes, with increased effect size for larger lacunes.

The results of this cohort study reinforce previously held assumptions, provide suggestions of novel associations, and question some previously reported associations. Given the different histopathologic appearance of WMH, small lacunes and large lacunes, the different associations found in the study are not surprising. The association of WMHs with hypertension and not with other metabolic factors mirrors the pathophysiology of leukoaraiosis. The role of atherosclerosis in the presumed pathogenesis of larger lacunes seems to be supported by its association with dyslipidemia. The IR score may represent a useful measure of the metabolic sequelae of insulin resistance aside from the effects of hyperglycemia. 

The study does have limitations. It is based on an observational cohort, which limits statistical adjustment for potential cofounders. The categorization of lacune sizes established in prior ARIC studies is somewhat arbitrary, but reflects the pathologic spectrum of lacunar disease for separating what are probably distinct pathophysiologic mechanisms for Fisher’s two “types” of lacunar infarcts. Prospective studies focusing on interventions for these presumed causative factors would further support these associations and potentially provide novel therapeutic targets.