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White Matter Hyperintensities on Magnetic Resonance Imaging: What Is a Clinician to Do?

  • José G. Merino
    Correspondence
    Correspondence: Address to José G. Merino, MD, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD.
    Affiliations
    Department of Neurology, University of Maryland School of Medicine, Baltimore, MD
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      As a neurologist, I am often asked to see patients because they have a magnetic resonance image (MRI) of the brain showing white matter hyperintensities (WMHs). These patients, and the clinicians who refer them to me, want to know the answers to several questions: What are WMHs and what causes them? Are they the same as a stroke? Are they a marker for impending stroke, dementia, or death? Do they get worse over time and can the progression be slowed? Studies such as the one by Hasan et al
      • Hasan T.
      • Barrett K.
      • Brott T.
      • et al.
      Severity of white matter hyperintensities and effects on all-cause mortality in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry.
      in this issue of Mayo Clinic Proceedings have expanded our understanding of the etiology and clinical significance of WMHs. However, despite many discoveries during the past 2 decades, many uncertainties still remain. Based on what we know now, what can I tell my patients?
      Changes in the white matter of presumed vascular origin were first identified as hypoattenuation of the white matter on computed tomography but now are more often seen as patchy areas of signal hyperintensity in deep and periventricular white matter areas on T2-weighted sequences, particularly fluid-attenuated inversion recovery. This radiologic phenomenon was first recognized in the 1980s, and Hachinski et al
      • Hachinski V.C.
      • Potter P.
      • Merskey H.
      Leuko-araiosis.
      coined the term leuko-araiosis (white matter rarefaction) to describe and define it. White matter hyperintensities are common in MRIs of asymptomatic individuals, and their prevalence increases with age from approximately 10% to 20% in those approximately 60 years old to close to 100% in those older than 90 years.
      • Smith E.E.
      • Saposnik G.
      • Biessels G.J.
      • et al.
      American Heart Association Stroke CouncilCouncil on Cardiovascular Radiology and InterventionCouncil on Functional Genomics and Translational Biology; and Council on Hypertension
      Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association.
      They are more common in individuals with a history of cognitive impairment, dementia, or cerebrovascular disease. Aging and hypertension are the main predictors of WMHs, and genome-wide association studies have identified associations with genes involved in blood pressure regulation. Other risk factors associated with WMHs include diabetes, hypercholesterolemia, smoking, carotid artery disease, atrial fibrillation, and heart failure.
      • Moroni F.
      • Ammirati E.
      • Rocca M.A.
      • Filippi M.
      • Magnoni M.
      • Camici P.G.
      Cardiovascular disease and brain health: focus on white matter hyperintensities.
      Genetic factors may play a role in the development of WMHs because twin studies suggest that heritability of WMHs is 55% to 80%. In addition, some monogenic disorders, such as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), also lead to severe WMHs.
      These changes in the white matter are predictors of a future risk of stroke, even after adjusting for the presence of vascular risk factors; decline in global cognitive performance, executive function, and processing speed; dementia (Alzheimer type, vascular, and mixed); and death, particularly due to cardiovascular causes. Some studies suggest that progression of these WMHs is associated with incident stroke and more rapid decline in cognitive function.
      • Debette S.
      • Markus H.S.
      The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis.
      The study by Hasan et al
      • Hasan T.
      • Barrett K.
      • Brott T.
      • et al.
      Severity of white matter hyperintensities and effects on all-cause mortality in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry.
      confirms the association of white matter changes and mortality in patients with cerebrovascular disease and provides evidence that as the severity of white matter changes increases, so does the mortality. The presence of WMHs on MRI has also been associated with functional decline, gait disturbance, and depression, perhaps because they disrupt neural networks. Most of these associations hold for the general population and for high-risk groups with cerebrovascular or neurodegenerative brain abnormalities. The observed associations with adverse outcomes suggest that these lesions are a surrogate marker for the burden of vascular risk factors and a marker of diffuse vascular pathology involving different cerebral, cardiac, and systemic vasculatures.
      Similar to small subcortical infarcts, lacunes, cerebral microbleeds, and enlarged perivascular spaces, WMHs are a manifestation of small vessel disease.
      • Ter Telgte A.
      • van Leijsen E.M.C.
      • Wiegertjes K.
      • Klijn C.J.M.
      • Tuladhar A.M.
      • de Leeuw F.E.
      Cerebral small vessel disease: from a focal to a global perspective.
      Some WMHs are caused by small subcortical infarcts, but more often, WMHs are due to a process called incomplete infarction, reflecting chronically reduced blood flow in deep areas of the brain caused by arteriolosclerosis, lipohyalinosis, and fibrinoid necrosis of small brain arteries and arterioles. Such reduced blood flow leads to hypoxia, alters mechanisms of cerebral autoregulation, and promotes transcription of inflammatory genes, breakdown of the blood-brain barrier, and entry of proinflammatory proteins into vessel walls and the brain parenchyma. Even in the absence of frank infarction, these processes lead to demyelination, axonal loss, reduced glial density, vacuolation, and atrophy of the overlying cortex, the traditional pathologic hallmarks of late-stage WMHs.
      • Rosenberg G.A.
      • Wallin A.
      • Wardlaw J.M.
      • et al.
      Consensus statement for diagnosis of subcortical small vessel disease.
      Results from genome-wide association studies highlight the central role of neuroinflammation.
      • Verhaaren B.F.
      • Debette S.
      • Bis J.C.
      • et al.
      Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.
      In addition, other processes that may be involved in the genesis of WMHs include dysfunction of oligodendrocyte precursor cells, failure of the glymphatic system, venous collagenosis, and alterations in RNA transcription. The MRI studies that use techniques such as diffusion-tensor imaging and magnetization transfer to examine water diffusivity and the integrity of the white matter show that some of the early pathophysiologic changes also occur in white matter areas that appear normal on conventional MRI.
      • Wardlaw J.M.
      • Valdés Hernández M.C.
      • Muñoz-Maniega S.
      What are white matter hyperintensities made of? relevance to vascular cognitive impairment.
      These MRI studies suggest that visible WMHs are “only the tip of the iceberg” and that the underlying pathophysiology is a diffuse process affecting small blood vessels in much of the white matter and other parts of the brain. Studies using serial imaging have shown that WMH can increase in size, shrink, or, in rare instances, disappear and, thus, raise the possibility that the process may be reversible before axonal damage and demyelination have occurred.
      • Wardlaw J.M.
      • Valdés Hernández M.C.
      • Muñoz-Maniega S.
      What are white matter hyperintensities made of? relevance to vascular cognitive impairment.
      Many studies of WMHs use volumetric analyses or complex MRI techniques to look at white matter integrity and tissue fluid shifts, but these techniques are not available for routine clinical use.
      • Wardlaw J.M.
      • Valdés Hernández M.C.
      • Muñoz-Maniega S.
      What are white matter hyperintensities made of? relevance to vascular cognitive impairment.
      In their study, Hasan et al
      • Hasan T.
      • Barrett K.
      • Brott T.
      • et al.
      Severity of white matter hyperintensities and effects on all-cause mortality in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry.
      used a visual rating scale to assess the severity of WMHs. Several such scales have been validated and allow semiquantitative measurement of WMH burden and progression.
      • Kapeller P.
      • Barber R.
      • Vermeulen R.J.
      • et al.
      European Task Force of Age Related White Matter Changes
      Visual rating of age-related white matter changes on magnetic resonance imaging: scale comparison, interrater agreement, and correlations with quantitative measurements.
      These scales could standardize the reporting of WMHs in trials and in clinical practice and can be used as a surrogate outcome in early-phase trials of risk factor modification.
      Although we have learned a great deal about the etiology, associations, and implications of WMHs in the past 2 decades, there is still much uncertainty about what to do when they are identified. Because they are a manifestation of small vessel disease and have been associated with several vascular risk factors, it makes sense to screen patients who harbor WMHs in their scans for these risk factors. Patients who do not have additional cerebrovascular disease should be treated according to guidelines for primary prevention of stroke; if they have had a stroke, secondary prevention guidelines apply.
      • Smith E.E.
      • Saposnik G.
      • Biessels G.J.
      • et al.
      American Heart Association Stroke CouncilCouncil on Cardiovascular Radiology and InterventionCouncil on Functional Genomics and Translational Biology; and Council on Hypertension
      Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association.
      In summary, I can tell my patients that WMHs are not a benign marker of aging; rather, they are a marker of diffuse small vessel disease and may warrant clinical action. We can use their presence to motivate our patients to look for and manage risk factors. We need more studies to understand the clinical implications of the tempo of progression of WMH lesions and the effect of risk factor modification on the process. We also need trials of interventions that may reduce WMH burden or progression, and these trials should have clinical outcomes (cognitive impairment, stroke, death). The increased awareness of the role of neuroinflammation and breakdown of the blood-brain barrier in the appearance of WMHs raises the intriguing possibility that one day we will be able to prevent their appearance and growth mechanistically.

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