What are white matter hyperintensities (WMH)?

What Are White Matter Hyperintensities?

White matter hyperintensities (WMHs) are bright signals visible on T2-weighted FLAIR MRI sequences that represent deteriorating white matter structure caused by cerebral small vessel disease, characterized pathologically by myelin loss, axonal damage, edema, perivascular space dilation, gliosis, and microvascular disease. 1

Neuroimaging Definition and Detection

• WMHs appear as hyperintense (bright) areas on T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI sequences, which is the primary modality for their detection 2, 3
• These lesions are also known as white matter lesions, leukoaraiosis, or white matter hyperintense signals 4
• FLAIR sequences are superior to standard T2-weighted imaging because they suppress cerebrospinal fluid signal, making WMHs more conspicuous 3, 4

Pathological Substrate

The underlying tissue damage in WMHs includes:

• Varying degrees of myelin loss and axonal rarefaction (thinning/loss of nerve fibers) 1
• Perivascular space dilation and edema 1
• Gliosis (scarring from glial cell proliferation) 1
• Microvascular disease and endothelial dysfunction 1, 5
• Blood-brain barrier disruption and inflammatory mediator infiltration 4

Epidemiology and Prevalence

• WMHs are extremely common, affecting 50.9% of individuals aged 40-49 years and 96.6% by ages 60-69 years 1, 6
• Prevalence increases progressively through midlife and aging 1
• The high prevalence means WMHs should not be dismissed as "normal aging" given their prognostic implications 7

Clinical Significance as a Core Feature of Small Vessel Disease

WMHs represent a core neuroimaging feature of cerebral small vessel disease (SVD), alongside:

• Lacunar infarcts 1
• Enlarged perivascular spaces 1
• Cerebral microbleeds 1

Prognostic Implications for Morbidity and Mortality

WMHs carry substantial prognostic significance for multiple adverse outcomes:

• Increased risk of incident stroke 1
• Increased all-cause mortality 1
• Increased risk of all-cause dementia 1, 5
• Cognitive impairment and decline across all diagnostic categories 1, 6
• Neuropsychiatric symptoms 1

Cognitive Impact by Domain

Executive function is the most consistently affected cognitive domain:

• All studies show significant associations between baseline WMHs and executive function decline on tests like Stroop and Trails Making Test 1, 6
• Frontal lobe WMHs specifically predict executive dysfunction 1, 2, 6

Global cognitive function is frequently impaired:

• 7 out of 9 studies in cognitively normal individuals demonstrate significant associations with global cognition measured by MMSE 6
• Baseline WMHs increase risk of incident dementia in cognitively normal populations 6

Memory impairment shows less consistent but important associations:

• Temporal lobe WMHs correlate with medial temporal lobe atrophy and memory dysfunction 2
• Corpus callosum (splenium) WMHs associate with both executive function and memory impairment 2, 7

Anatomic Location Matters for Clinical Interpretation

The location of WMHs determines which cognitive domains are affected:

• Periventricular WMHs have stronger associations with incident dementia (HR 1.51) compared to deep WMHs (HR 1.17) 2, 6
• Frontal WMHs most consistently predict executive function decline 1, 2, 6
• Temporal lobe WMHs uniquely associate with medial temporal structures and memory function 2
• Corpus callosum (splenium) WMHs correlate with medial-temporal atrophy and affect both executive function and memory 2, 7

Risk Stratification by Severity

• Severe WMHs at baseline produce the largest effect for incident dementia (HR 1.77,95% CI 1.38-2.10) 2, 6
• There is a dose-dependent relationship between WMH burden and clinical outcomes 5
• Large confluent WMHs have a demonstrated causal link with dementia and disability 5

Highest Risk Populations

WMHs carry particularly strong prognostic significance in:

• Mild cognitive impairment (MCI) populations: strongest associations with cognitive decline and conversion to dementia 1, 2, 7, 6
• Post-stroke populations: particularly strong significance for subsequent cognitive decline 1, 2, 7

Dynamic Nature and Modifiability

• WMHs can expand or shrink over time, affecting the progression of cognitive decline 1
• Hypertension represents the strongest modifiable risk factor for WMH progression 2
• Intensive systolic blood pressure control (target <120 mmHg) is the single most important intervention to prevent WMH progression 2

Common Pitfall to Avoid

Do not dismiss WMHs as benign "normal aging" changes – despite their high prevalence in older adults, WMHs predict cognitive decline, dementia risk, stroke, and mortality across all diagnostic categories, necessitating aggressive cardiovascular risk factor management and cognitive monitoring 1, 7, 5