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Gray to White Matter Signal Ratio Validated As Novel Biomarker of Neurodegeneration in Alzheimer's Disease

Key findings

  • Measuring the gray matter to white matter signal intensity ratio (GWR) on structural MRI is a relatively new approach to investigating brain changes relevant to aging and Alzheimer's disease (AD)
  • This study evaluated GWR in 29 patients with symptomatic atypical AD syndromes who had amyloid and tau deposition detected with positron emission tomography (PET) and had reduced cortical thickness, a conventional MRI sign of neurodegeneration
  • GWR was associated with cortical thickness, tau PET signal, and amyloid PET signal, and GWR showed a larger magnitude of abnormality than cortical thickness did
  • Cortical thickness, GWR, and amyloid PET each predicted tau PET signal independently, and the combination of the three biomarkers performed better than any of them alone
  • The findings validate GWR as a uniquely sensitive in vivo marker of neurodegenerative change that may reflect pathological mechanisms occurring before cortical atrophy

Modern research into Alzheimer's disease (AD) relies on quantifying amyloid plaque, tau neurofibrillary tangles, and neurodegeneration. Amyloid and tau can be measured with positron emission tomography (PET), but MRI markers of neurodegeneration—cortical thickness and volumetric measurements—aren't sensitive to early pathology as neuronal death typically follows the spread of amyloid and tau.

A promising new approach to measuring early AD-related neurodegeneration is the gray matter to white matter signal intensity ratio (GWR) on MRI. This biomarker reflects structural brain change and can be measured from the same conventional T1-weighted sequence that evaluates regional brain volume. Several studies have shown that decreased GWR tracks with worsening scores on the Clinical Dementia Rating scale—a measure of functional decline in AD.

Researchers at Massachusetts General Hospital recently completed the first study of how GWR is related to regional amyloid and tau deposition and the first to examine GWR in atypical AD syndromes. In NeuroImage: ClinicalDeepti Putcha, PhD, director of the Posterior Cortical Atrophy Program in the Department of PsychiatryYuta Katsumi, PhD, instructor in the Department of NeurologyAlexandra Touroutoglou, PhD, director of imaging operations at Mass General's Frontotemporal Disorders UnitBradford C. Dickerson, MD, director of the Frontotemporal Disorder Unit, and colleagues published evidence supporting GWR as a uniquely sensitive in vivo marker of neurodegeneration in AD.


29 study participants with atypical variants of AD underwent structural MRI, 11C-Pittsburgh compound B PET to quantify amyloid and 18F-flortaucipir PET to quantify tau:

  • 16 individuals with posterior cortical atrophy, the visual variant of AD
  • 10 individuals with the logopenic primary progressive aphasia, the language variant of AD
  • 3 individuals with a dysexecutive variant of AD

The study also included 24 cognitively normal individuals who had normal brain structure based on MRI and low cerebral amyloid detected on PET.

Comparing Biomarkers of Neurodegeneration

Consistent with reports in typical amnestic AD, abnormal GWR was closely co-localized with abnormal cortical thickness in posterior cortical areas, but the abnormalities in GWR were of much greater magnitude in those regions and extended beyond them.

Additionally, the two MRI measures of neurodegeneration were dissociated: cortical atrophy was minimal in the prefrontal cortex, but GWR was substantially reduced there.

Bivariate Relationships

Bivariate correlational analyses revealed only moderate correlation between cortical thickness and GWR (r, 0.36; P<0.001), suggesting those two biomarkers may be sensitive to different aspects of AD neuropathologic changes.

The strongest relationship was between cortical thickness and tau PET signal (r, −0.79, P<0.001), indicating regions with the highest tau burden also had greatest atrophy. A strong relationship was also observed between GWR and tau PET (r, −0.56; P<0.001).

GWR and Tau PET

Cortical thickness, GWR, and amyloid PET each predicted tau PET signal independently. As in the results of the bivariate analyses, cortical thickness showed the strongest relationship with tau PET, followed by GWR.

However, the combination of all three predictors explained variance in the distribution of tau pathology better than any of those modalities alone.

New Directions for Research

GWR seems to be more sensitive than cortical thickness to some aspects of neurodegeneration, probably capturing local changes in gray and white matter in earlier stages of AD.

Considering all four imaging biomarkers of AD together may improve the ability to capture neuropathologic changes and possibly predict them. That approach should ultimately contribute to better endpoints for clinical trials of therapeutic interventions as the field moves toward disease-modifying treatments.

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