Background. The CLN3 Staging System (CLN3SS) classifies individuals with CLN3 disease into four distinct stages using cardinal disease milestones – diagnosis, vision loss, seizure onset, and loss of independent ambulation. Cognitive decline is another core feature of CLN3 disease but is not represented in the CLN3SS. This study aimed to assess whether cognitive function changes across disease stages among individuals with CLN3 disease.
Methods. We evaluated the relationship between cognitive test performance and CLN3SS Stage in 84 individuals (47 males, 37 females) with genetically confirmed CLN3 disease. Analyses were performed on 245 paired assessments (neuropsychological evaluation + CLN3SS).
Results. The mean age at most recent assessment was 13.7 years old (SD=4.3, range=6.4-27.1 yrs). All cognitive test scores except for one (WRAML-2 Recognition memory) decreased with increasing age; bivariate correlations between most scores (except for recognition memory) were significant but weak (Pearson r values range from -0.26 to -0.43). However, one-way ANOVA tests revealed a significant difference by CLN3 disease stage for all cognitive tests analyzed: Similarities, F (2, 170) = 8.96, p < .001; Vocabulary, F (2, 215) = 16.88, p <.001; Information, F (2,170) = 10.39, p <.0001; Digit Span, F (2, 220) = 13.34, p <.0001. Post-hoc testing (Tukey) showed that mean scores on all cognitive tests were lower (i.e., worse performance) when subjects were at more advanced disease stages. In a subset (n=197) of the assessments, alphabet recitation was evaluated. A chi-square test showed a significant association between CLN3 disease stage and ability to recite the alphabet, χ2 = 12.1, p < .01.
Conclusions. Cognitive test performance and declines in cognition map consistently to the CLN3 Staging System. By contrast, age may be an imperfect surrogate for disease severity. Progression is variable across individuals; this underscores the need for alignment under a structured disease classification system.