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People with Huntington鈥檚 disease may exhibit subtle cognitive changes up to 15 years prior to receiving a motor-based diagnosis. Although cytosine-adenine-guanine (CAG) repeat length is associated with the presentation and progression of cognitive impairment in Huntington鈥檚 disease, the timing and pattern of cognitive decline can vary greatly between patients, even in individuals of a similar age, stage of disease, education level, and CAG repeat length.¹

With these facts in mind, researchers in Spain conducted a study to determine whether there are different cognitive phenotypes present during the earlier stages of Huntington鈥檚 disease, and, if so, to characterize their contributing clinical and sociodemographic variables.¹

Huntington鈥檚 patients are matched to healthy controls

Data were obtained from the longitudinal, observational, multinational Enroll-HD study.¹ Participants were between the ages of 21 and 60 years at diagnosis or at first symptom manifestation, had early or early-mid Huntington鈥檚 disease, and had between 40 and 55 CAG repeats.

The study population included 528 participants with Huntington鈥檚 disease. They were matched to 566 healthy controls with a CAG length <27 who were either gene-negative relatives or healthy controls with similar sociodemographic characteristics to those of the participants with Huntington鈥檚 disease. At baseline, the mean age of the Huntington鈥檚 disease group was 49.5 (standard deviation [SD] 10.1) years, mean CAG repeat length was 43.7 (SD 3.1), mean age at onset was 43.9 (SD 9.0) years, and mean duration of disease was 5.45 (SD 4.20) years.

Two cohorts, with different rates of decline, are identified

Two main groups of Huntington鈥檚 patients were revealed by cluster analysis: one with a relatively benign, slow profile of cognitive progression (S-CogHD; n=293) and the other with a faster or more aggressive pattern of cognitive decline (F-CogHD; n=235).¹ The only difference between the two groups at baseline was a Unified Huntington鈥檚 Disease Rating Scale鈥揟otal Motor Score that was 3.88 points higher in the F-CogHD group (t528=3.39; P<.005) than in the S-CogHD group.

The F-CogHD group demonstrated a significant pattern of decline in Mini-Mental State Examination (MMSE) scores at 12 months (t235=7.7) and at 36 months (t235=6.1), as well as between baseline and 36 months (t235=14.9; P<.001 for all). By comparison, MMSE scores remained stable over time in the S-CogHD group.

Both groups exhibited a pattern of significant decline in Symbol Digit Modalities Test (SDMT) performance between visits; however, the pattern was more pronounced in the F-CogHD group between baseline and 12 months (t235=9.89), between 12 and 24 months (t235=6.35), between 24 and 36 months (t235=10.39), and between baseline and 36 months (t235=24.2; P<.001 for all).

Similarly, although the pattern of decline in Stroop word-reading test results was significant in both groups, this pattern was more pronounced in the F-CogHD group between baseline and 12 months (t235=9.98), at 24 months (t235=7.11), at 36 months (t235=9.37), and between baseline and 36 months (t235=24.35; P<.001 for all).

How participants and controls measured up

An exploratory analysis revealed two main groups of healthy controls. The first group (n=135) was slightly older (t566=1.19; P=.048), had lower baseline SDMT scores (t566=鈥�2.18; P<.05), and had higher MMSE scores (t566=7.45; P<.001) than the second group (n=431). In this case, advanced age and lower performance scores at baseline were able to explain the healthy controls鈥� differing progression patterns.

On the other hand, the two distinct cognitive phenotypes uncovered among the participants with Huntington鈥檚 disease in this study were not explained by the effects of CAG repeat length, age, disease duration, or other core clinical characteristics at baseline. These phenotypes鈥攎arked by slow annual declines in cognition and function in the S-CogHD group and a significantly more aggressive progression pattern in the F-CogHD group鈥攄id not appear among healthy controls.

The study authors concluded that Huntington鈥檚 disease 鈥渃an be associated with very different cognitive trajectories in terms of progression over 3 years. Therefore, we must go deeper in identifying the mechanisms that could contribute to this cognitive heterogeneity, and we must emphasize the need to assume the existence of multiple possible phenotypes, forms of presentation, and progression of the disease, as has already been evidenced in other neurodegenerative processes.鈥�¹

Published: November 08, 2023