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Updated: Jan 26, 2026

A Machine Learning Approach to Design an Efficient Selective Screening of Mild Cognitive Impairment
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Frontal white matter hyperintensity burden predicts cognitive response to N-acetylcysteine and exercise in vascular

Ethan Mah1, Damien Gallagher2, Fuqiang Gao3

  • 1Hurvitz Brain Sciences Program, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.

Neurobiology of Aging
|January 24, 2026
PubMed

Insights

Vascular mild cognitive impairment (vaMCI) patients improved executive function (EF) with exercise. Lower frontal white matter hyperintensity (WMH) predicted better TMT-B performance at 3 months with N-acetylcysteine (NAC).

Area of Science:

  • Neurology
  • Neuroscience
  • Gerontology

Background:

  • Vascular mild cognitive impairment (vaMCI) is a precursor to dementia, characterized by cognitive deficits from cerebrovascular disease.
  • Increased white matter hyperintensity (WMH) volume is linked to reduced executive function (EF) in vaMCI.
  • Understanding factors influencing EF improvement is crucial for developing targeted vaMCI interventions.

Purpose of the Study:

  • To investigate if baseline frontal and global WMH volume predicts EF improvement in vaMCI patients undergoing N-acetylcysteine (NAC) and exercise therapy.
  • To compare the effects of NAC plus exercise versus placebo plus exercise on EF outcomes.
  • To explore the interaction between WMH burden, treatment, and time on cognitive performance.

Main Methods:

  • Fifty-eight vaMCI participants received exercise therapy and were randomized to NAC or placebo.
  • Executive function was assessed using Trail Making Test Part B (TMT-B), Digit Symbol-Coding Test (DSCT), and phonemic fluency at baseline, 3, and 6 months.
  • White matter hyperintensity (WMH) volumes were quantified from baseline MRI scans, and analyzed using linear mixed models.

Main Results:

  • All participants showed significant improvements in TMT-B and phonemic fluency over 6 months.
  • A significant interaction indicated lower baseline frontal WMH volume predicted greater TMT-B improvement at 3 months in the NAC group compared to placebo.
  • No significant interactions were observed for DSCT or phonemic fluency, and global WMH did not predict treatment response.

Conclusions:

  • vaMCI patients exhibit EF improvements with exercise, irrespective of NAC treatment or WMH volume.
  • Baseline frontal WMH volume may identify individuals who benefit more from NAC treatment for specific EF tasks in the short term.
  • Participant heterogeneity, particularly WMH burden, is important to consider in vaMCI clinical trials.
Keywords:
Clinical trialsExecutive functionMRINeuropsychologyVascular mild cognitive impairmentWhite matter hyperintensities

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