Objective: To characterise symbol digit modality test (SDMT) performance and its relationship with striatal phosphodiesterase 10A (PDE10A) binding potential across different Huntington’s Disease (HD) stages

Background: HD is an autosomal dominant neurodegenerative disorder caused by a high expansion of CAG repeat in the HTT gene, leading to brain atrophy, particularly within the striatum area (1). Processing speed decline is an early cognitive feature, with SDMT as a sensitive tool to measure it (2). 

PDE10A is highly expressed in the striatal neurons, (3) and its inhibition is linked to cognitive decline in HD animal models (4).

Method: We analysed data from the iMarkHD study, an observational longitudinal neuroimaging study in people with HD at different disease stages including pre-manifest (n=22), peri-manifest (n=20) and manifest (n=21), and healthy controls (HC, n=35) (5). SDMT scores were compared across groups. An ANCOVA adjusted by age, education and sex was used to assess groups differences. Association between SDMT scores and PDE10A binding potential in the striatum area were examined using Pearson correlations and regression models controlling for demographic variables.

Results: A total of 98 individuals were included. SDMT scores were highest in premanifest PwHD and lowest in manifest PwHD compared to HC. After adjusting for age, sex, and years of education, SDMT performance showed statistically significant differences across clinical stages F (3, 90) = 32.82, p < .001, partial η² = 0.52, with clinical groups explaining 52.2% of the variance. Higher SDMT scores were positively associated with caudate PDE10A binding potential (r = 0.622, p < .001, r²= 0.39) and this association remained significant after adjusting for age, education, and sex (β = 0.56, p < .001). Similar independent association was observed with putamen PDE10A binding potential (β = 0.46, p < .001); however, this association differed across clinical groups (interaction p<0.5)

Conclusion: Processing speed declines in advanced stages of HD and is independently associated with striatal PDE10A uptake. The caudate PDE10A association was consistent across stages, whereas the putamen relationship showed stage-dependent differences. These findings support a link between striatal synaptic integrity and cognitive performance and highlight the use of PDE10A as an imaging biomarker in HD.

References: (1) Stoker TB, Mason SL, Greenland JC, Holden ST, Santini H, Barker RA. Huntington’s disease: diagnosis and management. Pract Neurol. 2022 Feb;22(1):32-41. doi: 10.1136/practneurol-2021-003074. Epub 2021 Aug 19. PMID: 34413240.
(2) Braisch U, Muche R, Rothenbacher D, Landwehrmeyer GB, Long JD, Orth M; REGISTRY Investigators of the European Huntington’s Disease Network and COHORT Investigators of the Huntington Study Group. Identification of symbol digit modality test score extremes in Huntington’s disease. Am J Med Genet B Neuropsychiatr Genet. 2019 Apr;180(3):232-245. doi: 10.1002/ajmg.b.32719. Epub 2019 Feb 20. PMID: 30788902.
(3) Erro R, Mencacci NE, Bhatia KP. The Emerging Role of Phosphodiesterases in Movement Disorders. Mov Disord. 2021 Oct;36(10):2225-2243. doi: 10.1002/mds.28686. Epub 2021 Jun 21. PMID: 34155691; PMCID: PMC8596847.
(4) Hebb AL, Robertson HA, Denovan-Wright EM. Phosphodiesterase 10A inhibition is associated with locomotor and cognitive deficits and increased anxiety in mice. Eur Neuropsychopharmacol. 2008 May;18(5):339-63. doi: 10.1016/j.euroneuro.2007.08.002. Epub 2007 Oct 29. PMID: 17913473.
(5) van Wamelen DJ, Martin NH, Makos O, et al. Study protocol for the iMarkHD study in individuals with Huntington’s disease. J Huntingtons Dis. 2024;13(4):479-489. doi:10.1177/18796397241288165

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MDS Abstracts - https://www.mdsabstracts.org/abstract/processing-speed-across-huntingtons-disease-stages-and-its-association-with-striatal-pde10a-density/