What are White Matter Hyperintensities Made of?

W hite matter hyperintensities (WMH) of presumed vascular origin, also referred to as leukoaraiosis, are a very common finding on brain magnetic resonance imaging (MRI) or computed tomography (CT) in older subjects and in patients with stroke and dementia. They are associated with cognitive impairment, triple the risk of stroke and double the risk of dementia. Knowledge of their pathology derives mostly from post mortem studies, many from some years ago. These, by their nature, were generally small, sampled from selected brain regions and probably reflect late-stage disease. They focus on features of demyelination and axonal degeneration, which may be easier to detect histopathologically than changes in extracellular fluid. Here we review advances in brain magnetic resonance imaging (MRI) that are revealing white matter hyperintensities at earlier stages, and changes in normal-appearing white matter that indicate tissue pathology, less marked than those found in WMH. These “pre-visible” changes show that altered interstitial fluid mobility and water content, which may be reversible, probably predate demyelination and axonal damage, which are less likely to be reversible and are probably a late-stage phenomenon. Neuroimaging is also revealing the dynamic nature of WMH, their interactions with other pathological features such as secondary cortical and long tract damage, and contribution to accumulating brain damage. These insights provide opportunities to improve understanding the etiology and pathogenesis of small vessel disease, and represents an enormous unfinished agenda for preventing accumulation of brain damage, and its associated cognitive and physical problems, from mid to later life. Recognizing the earliest stages leading to WMH development will provide important opportunities to prevent (or even reverse) brain damage due to small vessel disease at the earliest stages, and ameliorate its cognitive, physical, stroke and dementia consequences.