Total white matter hyperintensity volume in bipolar disorder patients and their healthy relatives

The presence of excessive white matter hyperintensities (WMH) on T-2 weighted and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) sequences is one of the most consistently replicated imaging findings in bipolar disorder (BP). WMH are areas of increased signal intensity often found in the periventricular and deep white matter and have been studied in conjunction with many psychiatric disorders. Several prior studies have found a higher rate of WMH in patients with BP in comparison to appropriate healthy subjects (HS) (1–7). Two recent meta-analyses have provided additional evidence that there is an association between WMH and BP. The first study (8) demonstrated that patients with BP were 2.5 times more likely to have WMH compared to comparison subjects [odds ratio (OR) = 2.5, 95% confidence interval (CI): 1.87–3.30]. Although there was no difference in the prevalence of global WMH, Kempton and colleagues (9) found that patients with BP had an increased odds of deep WMH compared to comparison subjects (OR = 2.49, 95% CI: 1.64–3.79). When present in BP, WMH have been related to a number of adverse outcomes. For instance, Dupont and colleagues (10) found that WMH are associated with greater illness severity characterized by more hospitalizations and poorer performance on neuropsychological tests. Further, deep WMH have been correlated with poor illness outcome (11, 12) and greater treatment resistance (13), while periventricular WMH have been associated with suicide attempts in BP (14, 15). Evidence has also emerged to suggest that white matter lesions may serve as an endophenotypic marker for BP. Ahearn and colleagues (16) studied a family with a strong history of BP and observed a high prevalence of WMH in both probands and their unaffected relatives, although the study was limited by the absence of a comparison group from the general population. A subsequent study revealed that BP patients and their unaffected siblings tended to have WMH in the deep white matter of the right cerebral hemisphere in contrast to comparison subjects whose lesions were isolated to the left cerebral hemisphere (17). However, a third group found no significant difference in the prevalence of WMH among affected and unaffected relatives of BP probands and HS (18). Historically, investigations of WMH in BP have relied on a categorical method of lesion description reporting the presence or absence of white matter lesions and grading this presence on scales of differing reliabilities and lengths (19). Studies of WMH in BP have most commonly used a four-point visual-rating scale in which zero indicates the absence of lesions, and grades one through three represent the increasing presence of white matter lesions (20, 21). Although volumetric analysis is commonplace within the field of structural neuroimaging, this approach has infrequently been applied to the study of WMH in BP (13, 22). The goal of this study was to clarify the usefulness of WMH as an intermediate marker of disease burden in relation to family status and the diagnostic type of BP. In this pilot study, we utilized a dimensional, volumetric measurement of WMH to investigate the relationship between the volume of WMH and the familiality and type of BP. A second goal of this work was to demonstrate feasibility of this quantitative measure of WMH in a study of BP disorder. To test the familiality of WMH, we examined the total volume of WMH in subjects with BP, unaffected family members, and HS. We compared patients with BP-I with a history psychosis, BP-I without a history of psychosis, and BP-II to study the relationship between these volumes and the diagnostic category of BP. We limited our examination to the brains of subjects age 45 or younger as there is growing evidence to suggest that WMH are common in the elderly and increase with age (23). We hypothesized that mean total volumes of WMH would be greatest in all BP subjects followed by their relatives and then HS. Further, we hypothesized that mean total WMH volumes would correlate positively with illness type.