Tracking the Cognitive, Social, and Neuroanatomical Profile in Early Neurodegeneration: Type III Cockayne Syndrome

Abstract

Cockayne syndrome (CS) is an autosomal recessive disease associated with premature aging, progressive multiorgan degeneration, and nervous system abnormalities including cerebral and cerebellar atrophy, brain calcifications, and white matter abnormalities. Although several clinical descriptions of CS patients have reported developmental delay and cognitive impairment with relative preservation of social skills, no previous studies have carried out a comprehensive neuropsychological and social cognition assessment. Furthermore, no previous research in individuals with CS has examined the relationship between brain atrophy and performance on neuropsychological and social cognition tests. This study describes the case of an atypical late-onset type III CS patient who exceeds the mean life expectancy of individuals with this pathology. The patient and a group of healthy controls underwent a comprehensive assessment that included multiple neuropsychological and social cognition (emotion recognition, theory of mind, and empathy) tasks. In addition, we compared the pattern of atrophy in the patient to controls and to its concordance with ERCC8 gene expression in a healthy brain. The results showed memory, language, and executive deficits that contrast with the relative preservation of social cognition skills. The cognitive profile of the patient was consistent with his pattern of global cerebral and cerebellar loss of gray matter volume (frontal structures, bilateral cerebellum, basal ganglia, temporal lobe, and occipito-temporal/occipito-parietal regions), which in turn was anatomically consistent with the ERCC8 gene expression level in a healthy donor's brain. The study of exceptional cases, such as the one described here, is fundamental to elucidating the processes that affect the brain in premature aging diseases, and such studies provide an important source of information for understanding the problems associated with normal and pathological aging.

Keywords: Cockayne syndrome; ERCC8; VBM; cognitive profile; early-onset neurodegeneration; executive functions; social cognition.

Figure 1

Performance of the CS patient and controls in neuropsychological tests. (A) Montreal Cognitive Assessment (MOCA). V/E, visuo-spatial/executive skills; N, naming; AT, attention; L, language; AB, abstraction; DR, delayed recall; O, orientation. (B) Memory capacity test total scores. (C) Vocabulary and similarities raw scores. (D) INECO frontal screening subtests. MP, motor programing; CI, conflicting instructions; MIC, motor inhibitory control; BDS, backward digits span; VWM, verbal working memory; SWM, spatial working memory; AB, abstraction; VIC, verbal inhibitory control. (E) Semantic processing tasks. KDT, kissing and dancing test; PPT, palm and pyramids test. (F) Boston test. SP, syntactic processing; TA-B, touch A with B; N, naming. Asterisk (*) indicates significant differences.

Figure 2

Performance of the CS patient and controls in social cognition tasks. (A) Emotional morphing (accuracy per category). H, happiness; D, disgust; A, anger; F, fear; SU, surprise; SA, sadness. (B) Reading the mind in the eyes total score. (C) EPT, Empathy for pain task; intentionality accuracy. Asterisk (*) indicates significant differences.

Figure 3

(A) Patient F atrophy obtained through voxel-based morphometry analysis. All slices are p < 0.001, Bonferroni-corrected (α, 0.05, FWE). (B,C) Surface-based 3D reconstruction of patient F’s atrophy plotted over a standard brain in MNI space.

Figure 4

Overlap of brain sites for ERCC8 gene expression level in healthy donor and atrophy in CS patient. (A,C) Coronal sections depicting two sites of gene expression/atrophy overlap: orbitofrontal cortex and insular cortex in donor H0351.1016 (Allen Human Brain). (B) Three-dimensional surface rendering of the same data as in (A,C). (D) Left view of three-dimensional surface rendering of CS patient, showing fronto-insular-temporal and parietal atrophy areas.