Impact of White Matter Hyperintensities Spatial Location on Cognition in Parkinson’s Disease

This study aims to examine how the spatial distribution of White Matter Hyperintensities (WMHs) in the brain is associated with cognition in individuals with Parkinson’s disease (PD). WMHs, which appear as bright areas on Fluid-Attenuated Inversion Recovery (FLAIR) MRI scans, are considered markers of vascular brain damage related to small vessel disease (Fazekas et al., 1993; Pantoni & Garcia, 1997). Thickening of the vessel wall and endothelial dysfunction cause hypoperfusion in small vessels, which leads to disruption of the blood-brain barrier. This eventually causes plasma leakage in the white matter which corresponds to WMHs (Debette & Markus, 2010). In healthy older adults, WMHs have been associated with cognitive impairment and an elevated risk of cognitive decline across multiple domains, such as global cognition, perceptual speed and different memory subdomains (Boyle et al., 2016). More importantly, WMHs volume in old age is associated with increased risk of mild cognitive impairment (MCI) while controlling for age, gender and education (Boyle et al., 2016). Similar associations have also been observed in PD. For instance, one study from our group showed that PD patients in the very early stage of the disease with a high WMH load at baseline showed faster cognitive decline over time than patients with low WMH baseline load (Dadar et al., 2018). While total WMH load offers a measure of the severity of the underlying vascular changes in the brain and negatively impacts cognition (Lampe et al., 2019), several studies suggest that the spatial pattern of vascular disease can be quite variable from one individual to the next, and that this spatial distribution can explain the pattern of cognitive impairment, which can also be highly variable between individuals (Bolandzadeh et al., 2012). One approach to classifying the spatial pattern of WMH is to consider periventricular WMHs (PWMHs) vs. deep WMHs (DWMHs). PWMHs are those lesions that are present near the ventricles and could result from abnormal periventricular fluid accumulation, caused by a breakdown of ventricular ependym. Their underlying pathological cause is often linked to demyelination and reactive gliosis. DWMHs are more present in the neocortex and could result from high blood pressure and are more linked to ischemic origins (De Groot et al., 2002; de Groot et al., 1998). Another approach is to separately examine WMHs across the different lobes of the brain to assess their specific cognitive correlates. Despite these varied methodologies, no clear consensus has emerged regarding the distinct cognitive consequences associated with the regional distribution of WMHs (Bolandzadeh et al., 2012; Brugulat-Serrat et al., 2020; Lu et al., 2024; Sanderson-Cimino et al., 2021; Soriano-Raya et al., 2012). The significance of WMHs spatial distribution has been previously explored in dementia such as Lewy Body dementia (Ghebremedhin et al., 2010), vascular dementia (Brown et al., 2007), Alzheimer’s disease (AD) (Yoshita et al., 2006) and even frontotemporal dementia (Caroppo et al., 2014). A meta-analysis of 36 studies found that spatial patterns of WMHs provided more detailed insights into cognitive impairment than total WMH volume burden alone in participants with these types of dementia (Hu et al., 2021). Specifically, PWMHs have been found to have stronger associations with cognitive deficits and increased rsk of dementia than DWMHs (Hu et al., 2021). DWMHs are more commonly linked to vascular dementia, whereas individuals with AD (Smith et al., 2016) tend to exhibit greater PWMH burden, and greater WMH volume in the parieto-occipital regions (Gootjes et al., 2004; Pålhaugen et al., 2021). Although, findings have been inconsistent (see Garnier et al., 2022, for a comprehensive review). In contrast, in PD much less is known about whether the spatial distribution of WMHs differs from that of the normal aging population, from other neurodegenerative conditions like AD, and whether inter-individual differences in spatial patterns of WMHs contribute to the heterogeneity in the cognitive deficits of PD. For instance, studies have reported that PWMHs are associated with greater impairment in executive function in PD (Kandiah et al., 2014). Conversely, other research suggests that DWMHs, rather than PWMHs, are more strongly correlated with cognitive deterioration in PD (Li, 2017). Using a lobar approach to quantify WMH distribution, one study found that frontal lobe WMH burden differed significantly between PD patients with MCI (PD-MCI) and those with normal cognition (PD-NC) (Jing et al., 2020), while other studies have found no such difference between PD-NC and PD-MCI patients (Wang et al., 2013). A recent meta-analysis by Zhao et al. (2023) highlights the inconsistencies across these findings. Overall, the effect of regional WMH on cognition in PD has yet to be clearly defined. This analysis, by combining both PWMHs vs. DWMHs segmentation and a lobar segmentation approach, aims to provide a more granular understanding of how regional WMHs contribute to cognitive deficits in PD.