Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous and mutations.

BACKGROUND

Heterozygous mutations are the second most common cause of monogenic dominant cerebral small vessel disease (-AD-cSVD or CADASIL2), after cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) due to cysteine-altering mutations. However, there have been few studies of cohorts of -AD-cSVD and whether it can be differentiated clinically and on neuroimaging from CADASIL is unclear.

AIMS

This retrospective study aims to characterize and compare the clinical and neuroimaging features of -AD-cSVD with those of CADASIL.

METHODS

We identified 21 unrelated Taiwanese subjects carrying 15 heterozygous variants, all functionally validated as pathogenic through in vitro protease activity assays. -AD-cSVD patients were compared with 406 CADASIL patients, including 44 cases carrying mutations within the high-risk epidermal growth factor-like repeat domains (EGFr), 358 with moderate-risk EGFr mutations, and 4 with low-risk EGFr mutations. Multivariate regression analyses were conducted with adjustments for age at MRI examination and hypertension.

RESULTS

Stroke occurred in 81.0% of -AD-cSVD patients, and 47.6% exhibited cognitive dysfunction. MRI revealed moderate-to-severe white matter hyperintensity (WMH) in the deep white matter and external capsule (modified Scheltens' scale: 5.3 ± 1.0 and 4.1 ± 1.7), mild WMH in the temporal pole (1.0 ± 1.7), lacunes in 90.5%, ⩾10 cerebral microbleeds (CMBs) in 66.7%, and intracranial hemorrhage (ICH) lesions in 46.7%, indicating susceptibility to both ischemic and hemorrhagic strokes. Patients with loss-of-function mutations or protease domain missense mutations exhibited a higher prevalence of ⩾10 CMBs on SWI/T2* imaging (100% and 83.3%) compared to those with missense mutations outside this domain (20%). Symptom onset occurred earliest in patients with high-risk EGFr mutations (49.2 ± 10.5 years), followed by those with heterozygous mutations (54.3 ± 10.7 years), and latest in moderate-risk EGFr mutations carriers (59.7 ± 9.5 years). Temporal pole involvement was most prevalent in high-risk EGFr mutations (88.6%), followed by moderate-risk EGFr mutations (32.4%), and least common in heterozygous mutations (28.6%). Even after adjusting for age and hypertension, -AD-cSVD patients exhibited significantly milder temporal pole WMH severity compared to high-risk EGFr mutation carriers (adjusted  < 0.001). In addition, ICH lesions were more frequently observed in -AD-cSVD patients (46.7%) than in patients with high-risk or moderate-risk EGFr mutations (18.2% and 21.2%), although the difference was not statistically significant.

CONCLUSION

-AD-cSVD shares overlapping clinical and neuroimaging features with CADASIL. Temporal pole WMH involvement can occur in -AD-cSVD but is more common in CADASIL. The high prevalence of ICH in -AD-cSVD has been under-recognized.Data access statement:Data are available upon reasonable request from third parties.