White Matter Hyperintensities on MRI – Coincidental Finding or Something Sinister?
Time to read: 5 minutes
White matter hyperintensities (WMHs) are lesions in the brain that show up as areas of increased brightness when visualised by T2-weighted magnetic resonance imaging (MRI).
WMH’s are also referred to as Leukoaraiosis and are often found in CT or MRI’s of older patients. The prevailing view is that these intensities are a marker of small-vessel vascular disease and in clinical practice, are indicative of cognitive and emotional dysfunction, particularly in the ageing population.
The initial discovery of WMH’s was made in the late 1980’s by Hachinski and colleagues. They described WMH’s as patchy low attenuation in the periventricular and deep white matter.
WHAT DO WMH'S LOOK LIKE ON MRI?
As MRI’s have greater sensitivity to subtle changes in brain water content, they are better at visualising WMH’s. These areas are hyperintense on T2-weighted (T2) and fluid-attenuated inversion recovery (FLAIR) MRI sequences, and by consensus are now referred to as “white matter hyperintensities” (WMH), or “subcortical hyperintensities” where deep gray matter is also involved.
Periventricular White Matter Hyperintensities on a T2 MRI image
WHAT IS THE NEUROPATHOLOGY OF WMH'S?
WMH’s are associated with vascular risk factors such as diabetes, smoking and hypertension and hence WMH’s are considered part of small vessel disease.
Some potential neuropathological associations are:
- Demyelination and axonal loss
- Reduced glial density and atrophy
- Cortical thinning and cerebral atrophy
- Endothelial and immune activation
- Ischaemic damage
- Hypoxia and hypoperfusion
WMH’s are known to disappear as they do not always signify permanent glial or axonal loss; instead subtle shifts in water content.
WHAT IS THE CLINICAL SIGNIFICANCE OF WMH'S?
Until relatively recently, WMH were generally dismissed as inevitable consequences of “normal” advancing age. This is clearly not true. Although WMH do become more common with advancing age, their prevalence is highly variable.
There is strong evidence that WMH are clinically important markers of increased risk of stroke, dementia, death, depression, impaired gait, and mobility, in cross-sectional and in longitudinal studies. They associate with brain damage such as global atrophy and other features of small vessel brain damage, with focal progressive visible brain damage, are markers of underlying subvisible diffuse brain damage, and predict infarct growth and worse outcome after large artery stroke. They could be considered as the neuroimaging marker of brain frailty. (Wardlaw et al., 2015)
A review by Debette and Markus sought to review the evidence of the association between WMHs and the risk of cognitive impairment, dementia, death and stroke.
WMH'S AND STROKE
White matter hyperintensities are a predictor for vascular disease for which age and high blood pressure are the main risk factors.
The review showed that WMHs are significantly associated with an increased risk of stroke. Even when adjusting for vascular disease risk factors, such as age and high blood pressure, this association was still significant.
WMH'S AND COGNITIVE IMPAIRMENT
White matter hyperintensities are also associated with both impaired mobility and reduced cognitive functioning.
Specifically, WMHs can impact on memory, vigilance and executive functioning, depending on its localisation and severity.
Periventricular WMHs can affect cognitive functioning while subcortical WMHs disrupt specific motor functions based on location.
WMH'S AND DEMENTIA
Although WMH’s are associated with a faster decline in global cognitive performance as well as in executive function and processing speed, the jury is out in relation to their association with dementia.
WMH’s have a high association with Vascular dementia but their role in Alzheimer’s dementia is unclear.
According to Debette and Markus –
The presence of white matter hyperintensities may increase the risk that an individual will develop mild cognitive impairment or have declining performances on cognitive tests but may not be enough to facilitate progression from mild cognitive impairment to dementia, the latter being overwhelmingly driven by neurodegenerative lesions. An exception could be the rare cases of pure vascular dementia, where diffuse white matter hyperintensities could be important also at later stages of cognitive decline and conversion.
WMH'S AND MORTALITY
There seems to be a significant association between WMHs and mortality in both the general population and in high-risk populations such as those with a history of stroke and depression.
The Rotterdam and the Framingham Offspring Study showed an association between WMH’s and mortality independent of vascular risk events and risk factors. The association is particularly strong with cardiovascular mortality.
WMH’s may, therefore, be a marker for diffuse vascular involvement including peripheral and coronary arteries increasing the risk of cardiovascular mortality.
WMH'S AND SEVERE AND RESISTANT DEPRESSION
Deep white matter hyperintensities (DWMH’s) are associated with a more severe (melancholic) AND resistant form of depression [Khalaf A et al., 2015] and the patient is more likely to present with cognitive dysfunction, psychomotor slowing, and apathy. [Read more on melancholic depression and association of WMHs with structural melancholia)
They are also closely associated with late-onset depression and their progression is associated with worse outcomes in geriatric depression. [Taylor W et al., 2003]
WMH accumulation occurs over significantly shorter intervals (ie 12 weeks) than has been previously shown. Additionally, these changes are differentially distributed among those patients who are eventually classified as non-remitters, which indicates that the relationship between WMH accumulation and Late life depression (LLD) is consequential even during short antidepressant treatment courses. [Khalaf A et al., 2015]
This ‘Vascular depression’ is regarded as a subtype of late-life depression characterised by a distinct clinical presentation and an association with cerebrovascular damage.
49 year old female presenting with resistant depression and mixed features. Frontal lobe testing showed executive dysfunction. Required augmentation strategies to achieve remission
54 year old female presenting with resistant depression, cognitive impairment and somatic symptomatology
Moderate to severe leukoaraiosis with scattered areas of T2 hyperintensity involving subcortical white matter, right and left corona radiata of the frontoparietal and to a lesser extent temporal lobes. Area of old cortical damage involving the ventral left frontal and very small area involving the ventral left temporal lobe with some surrounding gliosis, very suggestive of previous trauma.
THE BIG PICTURE
The presence of WMHs significantly increases the risk of stroke, dementia, and death. WMH’S are significantly associated with resistant depression.
Detecting WMHs by diagnostic brain imaging gives clinicians an opportunity to screen for other vascular risk factors and proactively treat them.
They have important clinical and risk factor associations, and that they should not simply be overlooked as inevitable “silent” consequences of the aging brain.
Want to learn more? We covered the neuropsychiatric aspects of Multiple Sclerosis, an autoimmune condition characterised by significant involvement of white matter.
QUIZ
References
Debette et al., The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis, BMJ 2010; 341: c3666.