The Epidermal Growth Factor Domain of the Mutation Does Not Appear to Influence Disease Progression in CADASIL When Brain Volume and Sex Are Taken into Account

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FIG 1.
Flow diagram of patients included in the study.
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FIG 2.
Evolution of brain volume with age. Scatterplot of brain volume measured at the first time point for each patient against age, with (A) and without (B) the “older with larger brains” group (red points in B). Weighted regressions were reconstructed separately for men and women, given the known detrimental effect of the disease in male patients (black and gray solid lines). When we built regression lines without considering the older with larger brains group (in red), they looked similar in male and female patients across the whole life span, though shifted downward in men, for yet-unknown reasons.
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FIG 3.
K-means clustering analysis in men. The clustering analysis used with the Silhouette criteria led to the definition of 4 distinct groups of patients. The group of young patients comprised nearly all individuals younger than 50 years of age. The middle-aged and older patient groups seemed to follow the age trend of female patients. In total contrast, the group of older with larger brains patients showed strikingly different characteristics, with larger brain volume and lower brain atrophy.

Table 1:

Baseline characteristics of the study sample^{^a}

Note: —IQR indicates interquartile range.
↵^aCharacteristics of included and nonincluded patients were compared according to variable type and distribution (Mann-Whitney test by default or χ² test of independence for categoric variables).
↵^bComparisons performed using the χ² test of independence.
↵^cOn 228 studied patients and 94 excluded patients.
↵^dReference levels of education: 0 = illiterate, 3 = incomplete secondary school (<9 years), 6 = secondary school (13 years), 7 = university (≥16 years).
↵^eOn 216 and 100 patients, respectively.
↵^fOn 200 and 94 patients, respectively.
↵^gOn 209 and 90 patients, respectively.
↵^hOn 194 and 85 patients, respectively.
↵ⁱOn 182 and 76 patients, respectively

Table 2:

Baseline characteristics of “older with larger brains” men and older men in CADASIL^{^a}

	Older with Larger Brains Men (n = 22)	Older Men (n = 23)	P Value
Age (mean) (range) (yr)	59.3 (SD, 8.5) (43.6–77.8)	56.4 (SD, 10.7) (42.1–79.4)	.12
Genetic profile^{^b}			.92
Mutation in EGFR domains 1–6	15 (68%)	17 (74%)
Mutation in EGFR domains 7–34	7 (32%)	6 (26%)
Level of education^{^b} (yr)			.30
1–3	2 (9%)	6 (26%)
4–6	13 (59%)	10 (43%)
7	7 (32%)	7 (30%)
mRS^{^b}^,^{^c} (median) (IQR)	1 (0–2)	3 (1–5)	.009
MDRS^{^d} (mean)	136.2 (SD, 8.7)	120.8 (SD, 28.5)	.04
MMSE^{^e} (mean)	28.2 (SD, 2.2)	22.9 (SD, 6.7)	.45
TMTAT^{^f} (mean)	52.6 (SD, 30.3)	42.9 (SD, 20.3)	.004
TMTBT^{^g} (mean)	125.4 (SD, 87.0)	142.0 (SD, 97.7)	.003
Normalized brain volume (mean) (cm³)	1043.5 (SD, 30.8)	944.2 (SD, 40.1)	<.001
Annual PBVC (%)	−0.4 (0.7)	−2.0 (0.7)	<.001
Normalized WMH volume (%)	0.1 (0.1)	0.1 (0.0)	.03
No. of lacunes	6.8 (7.7)	10.6 (8.0)	.01
No. of microbleeds	11.0 (23.4)	8.6 (18.2)	.36

Note:—PBVC indicates percentage of brain volume change
↵^aCharacteristics of older men with larger brains and older men were compared with appropriate methods, depending on variable type and distribution (Mann-Whitney test by default or χ² test of independence for categoric variables).
↵^bComparisons performed using the χ² test of independence.
↵^cOn 22 older with men larger brains and 21 older men.
↵^dOn 20 and 12 patients, respectively.
↵^eOn 22 and 16 patients, respectively.
↵^fOn 19 and 9 patients, respectively.
↵^gOn 17 and 9 patients, respectively.