Objective: To explore if patients can be clustered into different groups based on dissimilar patterns of cognitive deterioration in a 2-year follow-up; to study the predictors of falling into one specific group; and to address which are the more characteristic cognitive changes within each group.

Background: Progressive cognitive deterioration is an essential feature of Huntington’s disease (HD). However, the rate of decline in global cognitive functioning is highly variable between patients. It suggests that HD could associate different cognitive syndromes with dissimilar rates of progression.

Methods: Three-hundred and twenty HD participants (CAG>39-<55, UHDRS≥4, TFC>6 and MMSE>24) and one-hundred and twenty-eight healthy controls with age comprised between 20-80 years old from the Enroll-HD study were included in the analysis. We collected motor (UHDRS-TMS), cognitive (MMSE), behavioural and functional measures at baseline and at one and at 2-year follow-up. For each group, we computed a two-step Schwarz Bayesian cluster analysis. Clusters were defined using the rate of change between baseline and 2-year follow-up in the total MMSE. The obtained clusters were subjected to repeated measures ANOVA to explore the effect of the factors group (cluster) and time (visits). Paired t-tests were used to explore which changes in specific MMSE domains characterise each cluster. T-test was also used to explore predictors of falling into different clusters.

Results: HD patients showed a significant worse MMSE performance at baseline (t(370)=-10.4;p<0.001) and a pronounced worsening at follow-up (F(2,448)=6.09;p<0.001). Two cluster separated the controls into a) no change between baseline and follow-up (n=30) and b) significant improvement between visits (n=98). In the HD group, two clusters separated patients as a) 210 cases that remained stable between visits and b) 125 cases who experienced a significant worsening of about -4 points at follow-up (p<0.001). In this cluster, changes were seen in orientation, attention, delayed recall, language and construction. This different pattern of cognitive progression appeared to be independent of functional, behavioural and cognitive status at baseline, but was associated with higher UHDRS-TMS.

Conclusions: In HD, patients matched for age, education, CAG length, functional and cognitive performance can evolve in a dissimilar manner along 2-year follow-up. A pattern of rapid progression of global cognitive deterioration appears to characterise an important subgroup of patients whereas others remains stable. This data highlights the existence of at least two distinct cognitive syndromes in HD that exhibits different rates of progression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-distinct-cognitive-syndromes-of-huntingtons-disease-a-two-year-follow-up-study/