Elderly CADASIL patients with intact neurological status

Abstract

Background and purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most devastating cerebral small vessel diseases. However, despite its progression with aging, some patients remain neurologically intact (Nint) even when they get older. Their main characteristics are poorly known. We aimed to delineate their clinical, imaging, and molecular features.

Methods: Individuals aged over 65 years were selected from a cohort of 472 CADASIL patients. Subjects who had no focal deficit, cognitive impairment, or disability were considered Nint. Their demographic, genetic, clinical, and imaging features were compared to those with permanent neurological symptoms (Nps).

Results: Among 129 patients, 23 (17.8%) individuals were considered Nint. The frequency of vascular risk factors and NOTCH3 cysteine mutations in epidermal growth factor-like repeat (EGFr) domains 7-34 did not differ between Nint and Nps patients but Nint patients had less stroke events and were more likely to have migraine with aura. The number of lacunes and microbleeds and degree of brain atrophy were lower in the Nint group, but the volume of white matter hyperintensities did not differ between the two groups.

Conclusions: Nearly one in five CADASIL patients can remain Nint after the age of 65 years. Their clinical and imaging profile differed from that of other age-matched CADASIL patients. The location of NOTCH3 mutation inside or outside EGFr domains 1-6 cannot fully explain this discrepancy. The factors involved in their relative preservation of brain tissue from severe damage despite aging remain to be determined.

Keywords: Aging; CADASIL; Cerebral small vessel diseases; Magnetic resonance imaging; Mutation.

Figure 1.

Magnetic resonance fluid-attenuated inversion recovery images of the 23 elderly neurologically intact (N_int) patients at the level of basal ganglia. (A) Eleven patients had their cysteine mutation in epidermal growth factor-like repeat (EGFr) domain 1-6 (Patient #1 to #11), (B) 12 others in EGFr domain 7-34 (Patient #12 to #23). Only three patients (Patient #1, #2, and #5) were from the same family. The patients were sorted according to their white matter hyperintensities load (from the highest to the lowest) in the two EGFr groups, respectively.

Figure 2.

Magnetic resonance fluid-attenuated inversion recovery images of the neurologically intact (N_int) patients already presented in Figure 1 (same order) at the level of temporal pole. (A) Eleven patients had their cysteine mutation in epidermal growth factor-like repeat (EGFr) domain 1-6 (Patient #1 to #11), (B) 12 others in EGFr domain 7-34 (Patient #12 to #23).