DOI: 10.1002/alz.077885 ISSN: 1552-5260

Brain glutathione may be associated with white matter hyperintensities in patients with cardiovascular disease

Jinghan Jenny Chen, Nathan Herrmann, Kate Survilla, Sandra E. Black, Joel Ramirez, Ana C. Andreazza, Paul I. Oh, Damien Gallagher, Simon J. Graham, Krista L. Lanctôt
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



White matter hyperintensity (WMH) is a marker of age‐related cerebrovascular damage and is correlated with cognitive impairment; ischemia and inflammatory mechanisms have been proposed to be involved in its pathogenesis. These processes are associated with oxidative stress (OS), which may impair cellular function and affect antioxidant balance; however, the role of central antioxidant responses is still unclear.


Patients (age 55‐85) with ≥2 vascular risk factors or a previous vascular event were assessed at baseline for an exercise rehabilitation program. All participants completed the Montreal Cognitive Assessment (MoCA). Baseline WHM severity was determined using the standardized Canadian Dementia Imaging Protocol and semiautomatic protocols. Brain glutathione (GSH) at baseline was obtained in the anterior cingulate (AC) and occipital region (OC) using 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b).


Of 30 participants (mean age: 66.2 ± 7.42 SD; 80% male) currently enrolled, brain volumetric measurements were completed for 25 participants. Lower MoCA score was associated with greater total WMH volume, controlling for age (b[SE] = ‐0.017 [0.005], t(22) = ‐3.24, p = 0.004); this relationship remained significant when controlling for years of education separately (b[SE] = ‐0.016 [0.006], t(22) = ‐2.86, p = 0.01). Correcting for cerebrospinal fluid volume, lower AC‐GSH level was associated with higher deep WMH volume in the medial middle frontal (MMF) region of interest (b[SE] = ‐0.056 [0.023], t(23) = ‐2.38, p = 0.026), but not with MMF paraventricular WMH volume. After controlling for age, the model was no longer significant (F (2, 22) = 2.87, p = 0.078). No significant associations were found between OC‐GSH and occipital lobe WMH.


As expected, total white matter hyperintensity volume was associated with poorer global cognition. In the medial middle frontal (MMF) region of interest, higher deep WMH was associated with lower GSH levels, suggesting altered brain antioxidant levels may be associated with the presence or formation of WMH. Recruitment is ongoing, and additional participants are needed to reinforce findings and to control for confounders in the analysis.

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