Recently, the Huntington's Disease (HD) Integrated Staging System (HD‐ISS) was developed as a new framework to standardize clinical research for HD. 1 Nevertheless, HD patients can show variable performance in certain tests at a particular visit, therefore not always consistently meeting the criteria for one or the other disease stage. This also includes the prediction of onset and severity of HD in premotor individuals. In this study (local ethics committee approval: AN1979 336/4.19401/5.10, 4464a), we aimed to better characterize biomarker changes in different disease stages of HD, including serum neurofilament light (sNFL) and clinical biomarkers including olfaction and cognitive tests. To this end, genetically confirmed HD patients (n = 54) and premotor HD mutation carriers (preHD; n = 19; ie, without distinct motor symptoms) were consecutively recruited during their routine follow up visits. Results were compared with HD‐unaffected participants (healthy controls, HC). Group comparisons of demographic and all clinical as well as sNFL levels are summarized in the supplementary material. We found significant differences between controls and preHD participants in sNfL levels and odor identification, but no difference in cognitive tasks. preHD near to estimated disease onset (NEAR‐preHD) based on group median for years to predicted disease onset age using a universal prediction model, 2 but not preHD far to estimated disease onset (FAR‐preHD) showed significantly higher sNfL levels compared to HC. Results on cognitive tasks, olfactory functioning and sNfL significantly correlated with the Prognostic Index for Huntington's Disease (PIHD; or its normed version PINHD) PINHD score (see supplementary material), indicating neurobiological changes with disease progression.
Recently, the relationship between sNfL and CAG repeat length was studied in HD mutation carriers in various disease stages. 3 Moreover, different plasma NfL levels have been reported across all HD‐ISS stages with approximately 50% of stage 1 participants having plasma NfL levels indicative of predicted clinical motor diagnosis. 4
Apart from the association between sNfL and both PINHD scores and odor identification, we showed that NEAR‐preHD, but not FAR‐preHD participants, had significantly higher sNfL levels than HC. However, the small sample size should be considered when interpreting our results, which need to be replicated in a larger cohorts. Early deficits on olfaction have already been shown in different neurodegenerative disorders including HD, and former studies assessing cognition and olfaction in HD showed that olfactory recognition is more affected than visual or verbal recognition, possibly because odor memory paradigms depend on a various number of functions (ie, working memory) which may be comprised early in HD. 5 In line with this, we found worse odor identification but no differences in cognitive tests between preHD carriers compared with HC.
These results of relatively unaffected cognition compared to HC but hyposmia could also be explained by the early disease stages of the preHD participants included in our study as well as the small sample size. Our results suggest that olfactory function may be indicative of underlying neurobiological changes in very early disease stages, prior to cognitive dysfunction.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
B.H.: 1A, 1B, 1C, 2A, 2B, 3B
E.M.: 1B, 1C, 2C, 3B
A.B.: 1C, 3B
A.G.: 1B, 1C, 2C, 3B
M.P.: 1B, 1C, 2C, 3B
D.V.: 1B, 1C, 2C, 3B
F.C.: 1B, 1C, 2C, 3A, 3B
A.D.: 1B, 1C, 2C, 3A, 3B
P.M.: 1B, 1C, 2C, 3B
M.K.: 1A, 2B, 2C, 3B
F.K.: 2A, 2B, 2C, 3B
K.S.: 1A, 1B, 1C, 2A, 2B, 3A, 3B
Disclosures
Ethical Compliance Statement: The study protocol was approved by the local ethics committees. All participants gave written informed consent prior to their participation. The interviews and examinations were carried out in accordance with the principles expressed in the Declaration of Helsinki. On behalf of all co‐authors, the first and corresponding author confirm that all authors have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for Previous 12 Months: BH reports honoraria from Novartis AG, BIAL, AbbVie and grants from the Austrian science fund (FWF) outside the submitted work. KS reports honoraria from the International Parkinson and Movement Disorders Society, grants from the FWF Austrian Science Fund, the Michael J. Fox Foundation, and the International Parkinson and Movement Disorder Society, as well as personal fees from Teva, UCB, Lundbeck, AOP Orphan Pharmaceuticals AG, AbbVie, Roche, and Grünenthal outside the submitted work. FK receives personal fees from Institut de Recherches Internationales Servier, Clarion Healthcare, Takeda Pharmaceuticals, and the Austrian Society of Neurology as well as a grant support from the MSA Coalition outside of the submitted work. AD reports honoraria from Novo Nordisk, Roche, Bial, and Abbvie. MK has received funding for travel and speaker honoraria from Novartis, Merck, and Biogen Idec and serves on scientific advisory boards for Biogen Idec, Merck Serono, Roche, Novartis, and Bristol‐Myers Squibb outside the submitted work.
Supporting information
Table S1. Demographic characteristics and results for olfaction and sNfL compared between groups.
Table S2. Results of cognitive tests compared between groups.
Table S3. Multiple linear regression analysis (sensitivity analysis*): sNfL levels and odor identification related to PINHD.
Table S4. Partial Spearman rank correlation between PINHD and clinical parameters, corrected for age.
Acknowledgments
We want to thank all participants who voluntarily took part in this study. BH, AD, FK, FC, and KS are members of the European Reference Network for Rare Neurological Diseases—Project ID No 739510.
Potential conflict of interest: The authors have no conflict of interests to report. AB was trained within the frame of the PhD Program Molecular Medicine of the Medical University of Graz.
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Associated Data
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Supplementary Materials
Table S1. Demographic characteristics and results for olfaction and sNfL compared between groups.
Table S2. Results of cognitive tests compared between groups.
Table S3. Multiple linear regression analysis (sensitivity analysis*): sNfL levels and odor identification related to PINHD.
Table S4. Partial Spearman rank correlation between PINHD and clinical parameters, corrected for age.