Physical Frailty and Brain White Matter Abnormalities: The Atherosclerosis Risk in Communities Study

Abstract

Background Physical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty. Methods Atherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants non-frail at baseline. Results In the cross-sectional analysis (N=1,754; mean age: 76) frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with history of stroke or dementia. Among participants non-frail at baseline who completed follow-up frailty assessment (N=1,379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk. Conclusions The current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from non-frail to frail status.

Exploring the relationship between frailty and executive dysfunction: the role of frontal white matter hyperintensities

“…Our results are consistent with growing evidence that shows an association between frailty, cognitive impairment, and subcortical white matter damage ( Maltais et al, 2019 ; Siejka et al, 2020 ; Ducca et al, 2023 ). Previous studies have shown that subjects with cognitive frailty had higher volumes of subcortical WMH than subjects with physical frailty without cognitive impairment, and than subjects with mild cognitive impairment but without physical frailty ( Sugimoto et al, 2019 ; Yoshiura et al, 2022 ).…”

“…In fact, WMH are also associated with executive dysfunction and lower processing speed ( Buchman et al, 2013 ; Prins and Scheltens, 2015 ), as well as slower gait and reduced mobility ( Zheng et al, 2011 ). Thus, possibly vascular mechanisms are implicated in cognitive impairment and lower gait in frail patients, as it had been suggested by longitudinal studies that had shown that higher brain volumes of WMH are associated with frailty progression over time ( Maltais et al, 2019 ; Siejka et al, 2020 ; Ducca et al, 2023 ).…”

Association of Physical Frailty and Cognitive Function in a Population-Based Cross-Sectional Study of American Older Adults

“…A recent clinical-pathological cohort study of US older adults ( n = 456) reported the degree of frailty among people of the same age modifies the association between AD neuropathology (measured by neurofibrillary tangles and amyloid beta plaques) and clinical expression of Alzheimer’s dementia [23]. Third, Ducca et al [40] report that physical frailty was associated cross-sectionally with greater white matter hyperintensity volume found on 3T brain MRI scans among prefrail and frail older adults. Physical frailty may serve as a clinical indicator of cerebral small vessel disease and as a sign that an individual is at increased risk for future dementia or cognitive deterioration [40].…”

“…Third, Ducca et al [40] report that physical frailty was associated cross-sectionally with greater white matter hyperintensity volume found on 3T brain MRI scans among prefrail and frail older adults. Physical frailty may serve as a clinical indicator of cerebral small vessel disease and as a sign that an individual is at increased risk for future dementia or cognitive deterioration [40]. The results from current analyses have important implications for possible clinical interventions.…”

The key role of depression and supramarginal gyrus in frailty: a cross-sectional study

“…Furthermore, the mean cortical thickness of areas involved in mobility and neurodegenerative diseases has also been linked to frailty (Lu et al, 2020). Finally, several studies showed a strong association between frailty and cerebrovascular disease explored in terms of white matter hyperintensities (WMH) (Avila-Funes et al, 2017;Siejka et al, 2020;Ducca et al, 2023).…”