Neuroimaging Biomarkers of Disease Progression and Cognitive Change in Patients With Retinal Vasculopathy With
Andria L Ford1,2, Peter Kang1, Slim Fellah1
1Department of Neurology, Washington University School of Medicine, St. Louis, MO.
Insights
Elevated oxygen extraction fraction (OEF) is linked to worsening white matter lesions and microstructural changes in RVCL-S, a rare genetic disease. This suggests hypoxia-ischemia plays a role and OEF may predict disease progression.
Area of Science:
- Neurology
- Genetics
- Biomarkers
Background:
- Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare monogenic disorder causing premature vascular dementia and vision loss.
- The pathophysiology of RVCL-S remains poorly understood, necessitating studies on its natural history and progression.
- Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are potential indicators of cerebral hypoxia-ischemia relevant to RVCL-S.
Purpose of the Study:
- To define the rate and variability of disease progression in a prospective cohort of RVCL-S patients.
- To investigate the association between CBF, OEF, and neurologic disease progression, including neuroimaging and cognitive endpoints.
- To explore the potential of OEF as a predictive biomarker for RVCL-S.
Main Methods:
- A prospective cohort of 25 RVCL-S participants underwent sequential brain MRI and cognitive testing over a median of 2.2 years.
- Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were quantified in normal-appearing white matter (WM).
- Neuroimaging (WM hyperintensity volume, WM microstructure, WM volume) and cognitive/motor endpoints (DSST, fluency, recall, MoCA, gait speed) were assessed using linear mixed-effects models.
Main Results:
- All assessed neuroimaging and cognitive endpoints, except MoCA, showed progression over time.
- WM hyperintensity volume increased by 31.3%/year, and processing speed (DSST) declined by 13.1 T-score points/decade.
- Elevated OEF, but not CBF, was independently associated with increased WM hyperintensity volume and altered WM microstructure.
Conclusions:
- Tissue hypoxia-ischemia, indicated by elevated OEF in white matter, is associated with RVCL-S progression.
- Cerebral OEF shows promise as a predictive biomarker for risk-stratifying patients with RVCL-S and other cerebral small vessel diseases (cSVD).
Background And Objectives:
A monogenic, age-related cerebral small vessel disease (cSVD), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), causes accelerated vascular dementia, vision loss, and premature death. Given knowledge is limited regarding its pathophysiology, we examined the natural history of progression in imaging and cognitive endpoints to define the rate and variability of progression in a prospective RVCL-S cohort. We hypothesized that cerebral blood flow (CBF) and oxygen extraction fraction (OEF), as metrics of cerebral hypoxia-ischemia, would be associated with neurologic disease progression.
Methods:
We performed sequential brain MRI and a cognitive battery in a prospective RVCL-S cohort. Arterial spin labeling and asymmetric spin echo quantified CBF and OEF in normal-appearing white matter (WM), respectively. Three neuroimaging endpoints of cSVD included the following: log-transformed, normalized fluid-attenuated inversion recovery WM hyperintensity (WMH) volume; WM microstructure using mean diffusivity; and normalized WM volume. Five cognitive and motor endpoints included Digit Symbol Substitution Test (DSST), category fluency, free recall, Montreal Cognitive Assessment (MoCA), and gait speed. Linear mixed-effects models examined age, CBF, and OEF in association with neuroimaging and cognitive progression.
Results:
Twenty-five participants, aged 23-68 years (median 47 years, 56% female), underwent 151 scans over a median (25th, 75th) of 2.2 (1.8, 4.4) years. All neuroimaging and cognitive endpoints progressed over time, except for MoCA. Of neuroimaging endpoints, WMH volume demonstrated the largest rate of change (+31.3%/year, 95% CI 20.8%-42.3%). Of cognitive endpoints, DSST, a metric of processing speed, showed the steepest decline (-13.1 T-score points/decade, 95% CI -21.2 to -5.32), followed by free recall and category fluency (-5 [-7.9 to -2.4] and -4.1 [-7.2 to -1.2] T-score points per decade, respectively). The age at first brain lesion was estimated to be 30.6 (23.8, 35.8) years, modeled from individual WMH volume trajectories. In multivariable analysis, OEF, but not CBF, was independently associated with WMH growth (β = 3.73, 95% CI 0.63-6.83, p = 0.029) and change in WM microstructure (β = 0.175, 95% CI 0.029-0.32, p = 0.029). Neither OEF nor CBF was independently associated with cognitive decline.
Discussion:
Elevated OEF in at-risk WM was associated with progression in WMH and impairment in WM microstructure, suggesting a role for tissue hypoxia-ischemia in underlying RVCL-S pathophysiology. Cerebral OEF holds promise as a predictive biomarker to risk-stratify patients with RVCL-S and other forms of cSVD.
