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. 2024 May;11(5):1160-1171.
doi: 10.1002/acn3.52031. Epub 2024 Mar 27.

Cognitive phenotype and neurodegeneration associated with Tau in Huntington's disease

Saul Martinez-Horta  1   2   3   4   5 , Jesús Perez-Perez  1   2   3   4   5 , Rocío Perez-Gonzalez  3   6 , Frederic Sampedro  2   7 , Andrea Horta-Barba  1   2   3   5 , Antonia Campolongo  1   2   4 , Elisa Rivas-Asensio  1   2   3 , Arnau Puig-Davi  1   2   3   4   5 , Javier Pagonabarraga  1   2   3   4   5 , Jaime Kulisevsky  1   2   3   4   5
Affiliations

Cognitive phenotype and neurodegeneration associated with Tau in Huntington's disease

Saul Martinez-Horta et al. Ann Clin Transl Neurol. 2024 May.

Abstract

Objective: The clinical phenotype of Huntington's disease (HD) can be very heterogeneous between patients, even when they share equivalent CAG repeat length, age, or disease burden. This heterogeneity is especially evident in terms of the cognitive profile and related brain changes. To shed light on the mechanisms participating in this heterogeneity, the present study delves into the association between Tau pathology and more severe cognitive phenotypes and brain damage in HD.

Methods: We used a comprehensive neuropsychological examination to characterize the cognitive phenotype of a sample of 30 participants with early-to-middle HD for which we also obtained 3 T structural magnetic resonance image (MRI) and cerebrospinal fluid (CSF). We quantified CSF levels of neurofilament light chain (NfL), total Tau (tTau), and phosphorylated Tau-231 (pTau-231). Thanks to the cognitive characterization carried out, we subsequently explored the relationship between different levels of biomarkers, the cognitive phenotype, and brain integrity.

Results: The results confirmed that more severe forms of cognitive deterioration in HD extend beyond executive dysfunction and affect processes with clear posterior-cortical dependence. This phenotype was in turn associated with higher CSF levels of tTau and pTau-231 and to a more pronounced pattern of posterior-cortical atrophy in specific brain regions closely linked to the cognitive processes affected by Tau.

Interpretation: Our findings reinforce the association between Tau pathology, cognition, and neurodegeneration in HD, emphasizing the need to explore the role of Tau in the cognitive heterogeneity of the disease.

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Conflict of interest statement

SMH has received honoraria for lecturing from Teva, Zambon, UCB, and Roche, and reports grants from Huntington's disease Society of America (Human Biology Project), and from Fondo de Investigaciones Sanitarias (FIS) from Instituto de Salud Carlos III (ISCIII). JPP reports a grant from Fondo de Investigaciones Sanitarias (FIS) from Instituto de Salud Carlos III (ISCIII). JK has received honoraria for advisory boards or lecturing from: Teva, Zambon, UCB, Bial, General Electric, Sanofi, and Roche, and reports grants from Fundació la Marato de TV3, Fondo de Investigaciones Sanitarias (FIS) from Instituto de Salud Carlos III (ISCIII), and Fondo Europeo de Desarrollo Regional (FEDER). JP has served on advisory or speakers' boards, and received honoraria from UCB, Zambon, AbbVie, Italfarmaco, Allergan, Ipsen, and Bial and reports grants from Fundació la Marato de TV3, Fondo de Investigaciones Sanitarias (FIS) and from Instituto de Salud Carlos III (ISCIII). The authors declare that there is no conflict of interest regarding the publication of this article.

Figures

Figure 1
Figure 1
Biomarker profile of the initial sample. The figure shows the differences (p < 0.05) between premanifest and manifest HD groups in the biomarker's levels and global association with the CAP score.
Figure 2
Figure 2
Biomarker differences in subjects with and without cognitive impairment. The figure shows the differences (p < 0.05) in biomarker's levels between different cognitive status and the associations between biomarkers and clinical parameters. NfL: NC‐HD = 1614.96 pg/mL vs IC‐HD = 3116.08 pg/mL; tTau: NC‐HD = 92.31 pg/mL vs IC‐HD = 121.35 pg/mL; pTau: NC‐HD = 31.39 pg/mL vs IC‐HD = 41.56 pg/mL. NC‐HD refers to “normal cognition” and IC‐HD refers to “impaired cognition”.
Figure 3
Figure 3
Biomarker differences as a function of cognitive impairment profile. The figure shows differences (p < 0.05) in biomarker's levels as a function of the cognitive profile of cognitive impairment in terms of single vs multi‐domain. Associations with specific cognitive measures are also shown.
Figure 4
Figure 4
Correlates in GMV of different biomarker levels and clinical parameters. (top) VBM‐GMV correlates of NfL, tTau and pTau (p < 0.05 corrected), including an overlay map. (bottom) Scatter plots illustrating the associations between the biomarker‐related imaging alterations and cognitive performance.
Figure 5
Figure 5
Correlates in Cth of different biomarker levels and clinical parameters. (top) Vertex‐wise Cth correlates tTau and pTau (p < 0.05 corrected). No significant clusters were found in the NfL GLM analysis. (bottom) Scatter plots illustrating the associations between the biomarker‐related cortical thinning and cognitive performance.
See this image and copyright information in PMC

References

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