Differential Effects of Confluent and Nonconfluent White Matter Hyperintensities on Functional Connectivity in Mild Cognitive Impairment
Abstract
Background: White matter hyperintensities (WMHs) indicate active small vessel disease. Emerging evidence suggests that confluent WMH (C-WMH) results in greater cognitive impairment compared with nonconfluent WMH (NC-WMH) visualized as punctate lesions. However, the mechanism linking C-WMH and early cognitive impairment is not clearly understood. Aims: To investigate the effects of C-WMH and NC-WMH on whole-brain functional connectivity (FC) across 138 regions of interest (ROIs) and cognition in 63 subjects with mild cognitive impairment (MCI). Methods: MCI subjects were classified as C-WMH or NC-WMH using the Staals criteria on the Fazekas WMH scale. Group-level ROI-to-ROI FC trends and differences based on WMH subtypes were computed using standard resting-state functional magnetic resonance imaging analysis. Global cognitive performance was measured with mini-mental state examination (MMSE). Results: Subjects with C-WMH exhibited increased inter-regional FC in the fronto-parietal, fronto-occipital, parieto-occipital, and temporo-parietal regions of the salience, dorsal-attention, default-mode, and visual networks compared with NC-WMH. Increased intra-regional FC was also observed within the frontal and parietal lobes in C-WMH. In addition to widespread increased FC in C-WMH, a few regions in the fronto-temporal and intra-frontal areas demonstrated reduced FC in C-WMH compared with NC-WMH. Analyses of cognitive correlates demonstrated increased parieto-occipital FC to be negatively associated with MMSE in the C-WMH. The increased parieto-occipital FC may be related to loss of higher order inhibitory control in the parieto-occipital regions induced by C-WMH or alternatively a compensatory mechanism to FC alterations induced by C-WMH. Conclusion: C-WMH in subjects with MCI is associated with widespread increase in intra- and inter-regional FC. These findings provide novel insights into divergent FC related to confluence of WMH in MCI. Impact statement White matter hyperintensities (WMHs) have been demonstrated to be a major risk factor for progressive cognitive decline. However, the relationship between structural and functional brain changes related to different types of WMH lesions as well as different stages of WMH progression remains unclear. In this study, we demonstrate that confluent WMH is significantly associated with divergent functional connectivity changes in patients with mild cognitive impairment (MCI). This finding may allow identification of MCI subjects who are adversely affected by WMH and thus provides a window of opportunity to introduce pharmacological and nonpharmacological interventional measures.
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Executive function performance is dependent on both intact white matter pathway connectivity and pathologic integrity of the cortical regions themselves.
“Indeed, the present findings support the hypothesis that executive function performance is dependent on both intact white matter pathway connectivity, as well as pathologic integrity of the cortical regions themselves [12,45,46]”
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- Authors
- Kumar, D., Vipin, A., Wong, B., Ng, K. P., & Kandiah, N.
- Affiliations
- National Neuroscience Institute (SG)
- Duke-NUS Medical School (SG)
- Nanyang Technological University (SG)
- Corresponding author
- Kandiah, Nagaendran
- Venue
- Brain Connectivity
- Publisher
- SAGE Publications
- Published
- 2020-12
- Volume
- 10
- Issue
- 10
- Pages
- 547-554
- ISSN
- 2158-0014 (ISSN-L)
- 2158-0022
- OpenAlex
- W3092259481
- Cited by
- 14
- References
- 43
- Citations by year
- 2026: 4 · 2025: 1 · 2023: 3 · 2022: 2 · 2021: 4
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Connectivity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- white matter hyperintensities, functional connectivity, mild cognitive impairment, cerebral small vessel disease, resting-state fMRI, cognitive decline, compensatory mechanisms, salience network, default mode network, dorsal attention network, visual network, inhibitory control
- MeSH terms
- Aged, Brain, Cognition, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Nerve Net, Neuropsychological Tests, Disease Progression, Cognitive Dysfunction, White Matter
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