Loss of white matter integrity mediates the association between cortical cerebral microinfarcts and cognitive dysfunction:, 2024, Huang et al

[SNT Gatchaman]

Loss of white matter integrity mediates the association between cortical cerebral microinfarcts and cognitive dysfunction: A longitudinal study
Jiannan Huang; Megan Oh; Caroline Robert; Xiangyuan Huang; Marco Egle; Daniel J Tozer; Christopher Chen; Saima Hilal

Cortical cerebral microinfarcts (CMIs) are associated with loss of white matter (WM) integrity and cognitive impairment in cross-sectional studies, while further investigation using longitudinal datasets is required. This study aims to establish the association between cortical CMIs and WM integrity assessed by diffusion-tensor imaging (DTI) measures and to investigate whether DTI measures mediate the relationship between cortical CMIs and cognitive decline.

Cortical CMIs were graded on 3T MRI. DTI measures were derived from histogram analysis of mean diffusivity (MD) and fractional anisotropy (FA). Cognitive function was assessed using a neuropsychological test battery. Linear mixed-effect models were employed to examine associations of cortical CMIs with longitudinal changes in DTI measures and cognitive function.

Final analysis included 231 patients (71.14 ± 7.60 years). Presence of cortical CMIs at baseline was associated with longitudinal changes in MD median and peak height and FA median and peak height, as well as global cognition (b = -0.50, 95%CI: -0.91, -0.09) and executive function (b = -0.77, 95%CI: -1.25, -0.28). MD median mediated the cross-sectional association between cortical CMIs and global cognition.

Further studies are required to investigate whether cortical CMIs and loss of WM integrity are causally related or if they are parallel mechanisms that contribute to cognitive decline.

Link | PDF (Journal of Cerebral Blood Flow & Metabolism, paywall)

 

[SNT Gatchaman]

A rapid bullet-point precis.

NAWM = normal appearing white matter (search), CMI = cortical microinfarct, DTI = diffusion tensor imaging (search), WHM = white matter hyperintensities (search), MD = mean diffusivity (search), FA = fractional anisotropy (search)

• This study found that the presence of cortical CMIs was associated with both baseline and longitudinal DTI measures derived from NAWM

• presence of cortical CMIs was related to impairment in global cognition and executive function

• findings align with a previous study in memory clinic patients, which showed that cortical CMIs were associated with greater decline in global cognition, memory, and language domains

• Our study has demonstrated a significant association between cortical CMIs and longitudinal changes in global cognition and executive function

• While some previous studies have shown an association between imaging markers of cerebral small vessel disease (CSVD) (e.g., lacunes and WMHs) and WM integrity assessed by DTI measures

• another study conducted in patients with cognitive impairment found a significant association between cortical CMIs and impaired WM network

• Our study echoed this finding and found that the presence of cortical CMIs was significantly associated with MD and FA measures from the NAWM, both cross-sectionally and longitudinally, which indicates that WM alterations related to cortical CMIs may occur long before the formation of apparent WM lesions.

• our study observed a borderline interaction between cortical CMIs and MD median by time, suggesting that cortical CMIs may be associated with progressive impairment in the WM network.

• suggested that cortical CMIs can lead to cognitive dysfunction via both direct neuron injury within the microinfarct core and their influence on remote brain tissue.

• remote effects of cortical CMIs include their association with cortical atrophy and WM dysconnectivity

• considered that cortical CMIs may affect WM connectivity at a global level rather than only in the perilesional regions, as detecting a single cortical CMI indicates hundreds to thousands of such lesions throughout the brain

• WM network plays a crucial role in maintaining normal brain function and facilitating communication between different brain regions

• existing evidence has shown that cortical CMIs can disrupt WM connectivity through mechanisms involving inflammation, oxidative damage, and blood-brain barrier leakage

• may lead to proximal axonal injury and secondary degeneration in distal fiber pathways, affecting the NAWM even distant from the microinfarct core

• NAWM was investigated rather than the whole WM, facilitating our understanding about the subclinical change in WM and its association with cognitive dysfunction caused by cortical CMIs

• In conclusion, this study provides compelling evidence of the cross-sectional and longitudinal associations between cortical CMIs, DTI measures from the NAWM, and cognitive function. [... but] did not establish the mediation effect of WM dysconnectivity on the association between cortical CMIs and cognitive dysfunction in a longitudinal setting

 

[SNT Gatchaman]

The key points would seem to be that cortical microinfarcts associate with both —

• cognitive dysfunction / executive dysfunction
• disruption of white matter microstructure and function

And that the evidence of white matter damage can be shown when it otherwise looks normal (NAWM, "all tests are normal"). In this scenario of cerebral small vessel ischaemic disease, the suggestion is that a microinfarct in the cortex (grey matter) can have remote effects on white matter — "existing evidence has shown that cortical CMIs can disrupt WM connectivity through mechanisms involving inflammation, oxidative damage, and blood-brain barrier leakage".

So, could you have disrupted white matter connectivity for other upstream reasons, but still leading to similar inflammation, oxidative damage, and blood-brain barrier leakage?

 

[SNT Gatchaman]

See also Post-COVID microvascular dysfunction in hospitalized COVID-19 survivors is associated with acute disease severity and persistent cognitive complaints (2025, Journal of the Neurological Sciences) —

Interestingly, microvascular dysfunction was not only observed in predefined damaged regions (e.g., WMH [White Matter Hyperintensities]), but also in regions that appeared to be ‘normal’ on structural images. […] As cerebral microbleeds are a typical marker of cSVD [cerebral Small Vessel Disease], this finding may suggest that the smallest vessels in the brain are indeed affected in COVID-19 patients. Our results provide additional evidence for microvascular damage in the NAWM [Normal Appearing White Matter], which may indicate subtle damage preceding WMH formation. This may be particularly relevant since macroscale abnormalities (e.g., microbleeds and WMH) alone do not always correlate with long COVID complaints.