White Matter Tract Injury by MRI in CADASIL Patients is Associated With Iron Accumulation

Abstract

Background Widespread white matter (WM) injury is a hallmark feature of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, controversies about the mechanism of WM tract injury exist persistently. Excessive iron accumulation, frequently reported in CADASIL patients, might cause WM tract injury. Purpose To test the association between iron accumulation and WM tract injury in CADASIL patients. Study Type Retrospective. Population A total of 35 CADASIL patients (age = 50.4 ± 6.4, 62.9% female) and 48 healthy controls (age = 55.7 ± 8.0, 68.8% female). Field Strength/Sequence Diffusion‐weighted spin‐echo echo‐planar sequence; enhanced susceptibility‐weighted angiography (ESWAN) gradient echo sequence on a 3 T scanner. Assessment The phase images acquired by ESWAN were used to calculate quantitative susceptibility mapping (QSM). Iron accumulation was evaluated in deep gray matters using QSM. WM tract injury was quantified by diffusion metrics based on WM major tracts skeleton. We compared iron deposition between groups and analyzed the correlation between WM tract injury and iron deposition in regions showing significant differences from healthy controls. Exploratory analysis was carried out to investigate whether WM tract injury mediated the relationship between iron deposition and cognitive impairment evaluated by Mini‐Mental State Examination (MMSE). Statistical Tests General linear model (GLM), partial correlation, stepwise linear regression and mediation analysis were used. The threshold of statistical significance was set as p < 0.05. Results Compared with healthy controls, CADASIL patients had significantly increased iron deposition in the caudate and putamen. Aberrant iron deposition in these two regions was significantly associated with decreased WM fractional anisotropy (FA) (caudate, r = −0.373； putamen, r = − 0.421), and increased radial diffusivity (RD) (caudate, r = 0.372; putamen, r = 0.386). Furthermore, WM tract injury mediated the relationship between iron deposition and cognitive impairment. Data Conclusion Patients with CADASIL show increased iron deposition in the caudate and putamen that is correlated to WM tract injury, which may in turn mediate the association with cognitive impairment. Evidence Level 2 Technical Efficacy Stage 2

High cortical iron is associated with the disruption of white matter tracts supporting cognitive function in healthy older adults

“…Within these deep GM regions, CADASIL patients showed a negative association between iron load and DTI-based metrics in WM tracts. In contrast, no associations were observed in the healthy control group ( Hong et al. 2022 ).…”

“…2018 ) or patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADISIL), a small vessel disease characterized by widespread WM tract injury ( Jokinen et al. 2013 ; Hong et al. 2022 ).…”

Effect of corticosubcortical iron deposition on dysfunction in CADASIL is mediated by white matter microstructural damage

“…Normal-appearing white matter (NAWM) was generated by extracting the WMH from the WM. CMBs were recorded as binary variables, indicating the presence (1) or absence (0) ( Hong et al, 2023 ). The total cSVD score was used to evaluate the disease burden of CADASIL, ranging from 0 to 4, by counting four features of cSVD on MRI, including WMH, lacunes, microbleeds, and enlarged perivascular space ( Staals et al, 2014 ) .…”

Value of Quantitative Susceptibility Mapping in Clinical Neuroradiology

“…Widespread injury to the white matter tract, including demyelination and axonal injury, is commonly observed, and QSM revealed increased iron deposition in the caudate and putamen that correlates with the extent of white matter tract injury. 68…”

“…Hyperintensity on FLAIR in the temporopolar regions and external capsules are characteristic MR findings of CADASIL. Widespread injury to the white matter tract, including demyelination and axonal injury, is commonly observed, and QSM revealed increased iron deposition in the caudate and putamen that correlates with the extent of white matter tract injury 68 …”