Arterial Territories Mediate White Matter Hyperintensities association to Processing Speed in MCI/AD

147 

Abstract Submission 

Ikrame Housni^1,2,3,4, Natalie Phillips⁵, Ali Filali-Mouhim⁴, Simon Duchesne^6,7, Sridar Narayanan^8,9, AmanPreet Badhwar^1,2,3,4

¹Multiomics investigation of neurodegenerative diseases (MIND) Laboratory, Montreal, Canada, ²Département de pharmacologie et physiologie, Faculté de médecine, Université de Montréal, Montreal, Canada, ³Institut de génie biomédical, Université de Montréal, Montreal, Canada, ⁴Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal (CRIUGM), Montreal, Canada, ⁵Department of Psychology, Concordia University, Montreal, Canada, ⁶Département de radiologie et médecine nucléaire, Université Laval, Quebec, Canada, ⁷Quebec Heart and Lung Institute, Quebec, Canada, ⁸McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Canada, ⁹Department of Neurology and Neurosurgery, McGill University, Montreal, Canada

Ikrame Housni  
Multiomics investigation of neurodegenerative diseases (MIND) Laboratory|Département de pharmacologie et physiologie, Faculté de médecine, Université de Montréal|Institut de génie biomédical, Université de Montréal|Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal (CRIUGM)
Montreal, Canada|Montreal, Canada|Montreal, Canada|Montreal, Canada

Natalie Phillips  
Department of Psychology, Concordia University
Montreal, Canada

Ali Filali-Mouhim  
Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal (CRIUGM)
Montreal, Canada

Simon Duchesne  
Département de radiologie et médecine nucléaire, Université Laval|Quebec Heart and Lung Institute
Quebec, Canada|Quebec, Canada

Sridar Narayanan  
McConnell Brain Imaging Centre, Montreal Neurological Institute|Department of Neurology and Neurosurgery, McGill University
Montreal, Canada|Montreal, Canada

AmanPreet Badhwar  
Multiomics investigation of neurodegenerative diseases (MIND) Laboratory|Département de pharmacologie et physiologie, Faculté de médecine, Université de Montréal|Institut de génie biomédical, Université de Montréal|Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal (CRIUGM)
Montreal, Canada|Montreal, Canada|Montreal, Canada|Montreal, Canada

MRI-detected white matter hyperintensities (WMHs) are widely recognized as markers of cerebrovascular abnormalities and can serve as an index of vascular brain injury (Wardlaw et al., 2013). The literature (i) strongly establishes a link between an increase in WMH volume (WMHv) and cognitive decline (Guo and Shi, 2022), and (ii) suggests that the anatomical distribution of WMHs exerts a mediating effect on cognitive dysfunction (Garnier-Crussard et al., 2022). It has also been reported that pathological remodeling of the major cerebral arteries (anterior, ACA; middle, MCA; posterior, PCA) potentially increases WMHv in an arterial territory (AT)-specific manner (Gutierrez et al., 2018). Recently, we characterized the anatomical distribution of WMH within ATs in age-related neurodegenerative diseases (NDDs), and demonstrated NDD-specific signatures of WMHv distribution across ATs (Housni et al., 2023). However, the relationship between AT-specific WMHv and cognitive performance remains largely unexplored, and our current study addresses this gap in knowledge.

We selected participants from six clinical groups (cognitively unimpaired, subjective cognitive decline, mild cognitive impairment (MCI), Alzheimer's disease (AD), and MCI and AD with high vascular brain injury (Fig. 1a)) from the CCNA COMPASS-ND cohort (N=756;7th-release)(Chertkow et al., 2019). WMHs were segmented from FLAIR MRI (Dadar et al., 2017) and mapped onto an arterial atlas (Schirmer et al., 2019). The cognitive performance of participants was measured using four psychometric tests: Simple Reaction Time (SRT), Choice Reaction Time (CRT), Digit Symbol Substitution Test (DSST), and Montreal Cognitive Assessment (MoCA) (Fig. 1b). Statistical analyses consisted of a series of linear regression models, with cognitive performance as the dependent variable and region-size-normalized AT-WMHv as the independent variable, controlling for age and sex. We investigated the interaction between cognition and AT-specific WMHv both (i) adjusting for diagnosis, and (ii) within each clinical category, to identify disease-specific effects. A 5% False Discovery Rate threshold was applied to correct for multiple comparisons.

Adjusting for clinical diagnosis: (i) SRT scores were associated with ACA WMHv (p=0.002;t=2.44); (ii) CRT and MoCA scores were associated with PCA WMHv (CRT: p=0.002;t=2.40 | MoCA: p=0.001;t=-3.21); and (iii) DSST scores were associated with WMHv across all ATs (PCA: p<0.001;t=-3.96 | MCA: p=0.004;t=-2.83 | ACA: p=0.02;t=-2.26). NDD-specific analyses showed that MCI and AD were the only categories to show AT-specific WMHv associations with cognitive performance (Fig. 1c). In MCI, lower DSST scores were associated with higher PCA WMHv (p=0.02;t=-2.78) (Fig. 1d). In AD, a lower % of correct answers in CRT tasks was associated with higher ACA (p=0.006;t=-3.32) and MCA (p=0.02;t=-2.59) WMHv (Fig. 1e).

Overall, greater WMHv was associated with poorer cognitive performance (i.e., higher SRT, CRT | lower MoCA, DSST, % of correct answers in CRT tasks). Mounting evidence suggests that WMHs exert an independent effect on cognition in AD, which is additive to that exerted by the core proteinopathies (i.e., beta-amyloid, tau) (Ng et al., 2023). A study found that WMHv in PCA sub-regions contributes to lower cognition, independent of amyloid deposition or atrophy in early AD (Garnier-Crussard et al., 2022). Adding strength to this finding, we observed an association between PCA WMHv and processing speed at the MCI stage. This association however evolved to the ACA and MCA at the AD stage. As AD is characterized by increased amyloid deposits in areas perfused by the ACA and MCA (Adlard et al., 2014), further investigation is warranted to determine whether the observed associations are driven by WMH or other AD pathologies.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Higher Cognitive Functions Other ²

Segmentation and Parcellation

Neuroanatomy Other

Anatomical MRI

Aging

Cerebrovascular Disease

Cognition

Degenerative Disease

WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC

Other - Arterial Territories