Editorial for “Association Between Gas‐Free Cerebrovascular Reactivity ( <scp>CVR</scp> ) and Cognitive Function in Older Adults With a High Risk for Vascular Dementia”

Vascular cognitive impairment and dementia (VCID) is the second leading cause of cognitive decline and dementia in the elderly after Alzheimer's disease. To date, imaging biomarkers for VCID primarily focus on parenchymal vascular brain injury (e.g., white matter hyperintensity, microinfarcts, microbleeds, and lacunar infarcts [1]) rather than blood vessels themselves. Developing imaging biomarkers for directly assessing cerebrovascular function may improve our understanding of VCID pathophysiology and help identify specific targets for VCID prevention and treatment. Cerebrovascular reactivity (CVR) is an important indicator of vascular health, representing the capacity of cerebral blood vessels to dilate or constrict in response to physiological stimuli. In the recent National Institute on Neurological Disorders and Stroke (NINDS) funded MarkVCID consortium that aims to identify and validate clinical-trial-ready biomarkers for VCID, CVR was selected as one of the neuroimaging biomarkers for small vessel disease (SVD) contributing to VCID [2]. A recent MarkVCID study demonstrated that whole-brain CVR measured with gas challenge had a significant association with SVD-associated cognitive impairment [3]. Another study also observed that global CVR was significantly associated with cognitive performance independently of AD pathology [4]. These findings indicate that CVR can be a promising marker for VCID. However, CVR has not been widely adopted in clinical practice due to the complexity of the procedure and substantial cooperation required from participants, as CVR is typically measured under a vascular challenge, such as hypercapnic gas inhalation or breath holding. For example, CO2 inhalation is commonly used for CVR mapping, which requires additional apparatus setup as well as active participant compliance [5]. The procedural demands and participant burden make CVR assessments with gas challenge particularly challenging in patient populations, especially elderly adults. Recent methodological advancements have enabled the assessment of CVR without gas challenge [6], substantially simplifying the procedure and reducing patients' burden. Among them, a gas-free CVR technique that introduces intermittent modulation of breathing pattern during resting-state fMRI scan has been developed [7], which eliminates external gas inhalation while preserving good sensitivity for generating reliable CVR maps. In this issue of JMRI, the article “Association between gas-free cerebrovascular reactivity (CVR) and cognitive function in older adults with a high risk for vascular dementia” [8] aimed to investigate whether CVR measured by this gas-free technique can serve as a sensitive imaging marker for VCID. In this study, 82 older participants enriched for vascular risks underwent the breath-modulated CVR scans without gas challenge. The associations of CVR with cognitive and physical functions were studied. Significant associations of global CVR with MoCA and composite cognitive score were observed. These findings suggest that CVR may serve as a sensitive marker for cognitive impairment in VCID. The primary strength of this study is that it demonstrated the clinical potential of a gas-free CVR technique as a sensitive marker for VCID in an aged cohort with a reasonable sample size. Lower CVR values measured using the gas-free method were associated with impaired cognitive function, consistent with previous findings using gas challenge [3, 4]. Meanwhile, this study has several limitations. First, this study followed a cross-sectional design, which cannot conclude any causal relationships between CVR and cognitive function. Second, VCID often coexists with AD pathology, especially with aging. Although the enrolled participants were enriched for vascular risk factors, the observed association between CVR and cognition cannot be explained exclusively because of VCID. Future studies are needed to disentangle the contribution of CVR measured by the gas-free approach to cognitive impairment related to VCID from mixed AD pathology. Overall, this study can be clinically important, as it demonstrates the potential utility of a gas-free CVR method in aging research and may facilitate the translation of CVR into clinical applications.