White matter pathology – an endophenotype for bipolar disorder?

Neuroimaging investigations of white matter abnormalities in subjects at genetic risk for bipolar disorders (BD) potentially predating the onset of BD offer several advantages. They are not confounded by the presence of illness duration or previous treatment with medication and may ultimately inform evaluation of risk for subsequent development of BD and subsequent therapeutic intervention.

Although a number of imaging studies in subjects at genetic risk for BD are available the results are conflicting and no reliable structural markers of genetic liability to bipolar disorders have been proposed. We debate that white matter pathology may be central to the genetic risk to develop BD. Thus, white matter abnormalities detectable in HR subjects but not in controls may reflect genetically driven trait markers. Similar abnormalities may be also evident both in the HR and in BD, suggesting the possibility of genetic risk factors shared by both groups. Conversely, white matter alterations observed in BD patients but not in HR and controls can be interpreted as state markers.

We suggest that white matter alterations may represent endophenotypes and neurobiological markers intermediate between the underlying susceptibility genes and the clinical expression of BD.