Beyond language: Exploring the potential for combined linguistic and molecular measures in Fragile X Premutation Carriers (FXPCs).

Abstract

Biomarkers are measurable indicators of biological processes that respond to interventions and are crucial in drug development, particularly for rare disorders lacking validated measures. Particularly, complex biomarkers integrating interdisciplinary data can help identify new clinical targets. Fragile X Syndrome (FXS) and Fragile X Premutation Carriers (FXPCs) have a CGG repeat expansions on the FMR1 gene, which encodes the FMRP protein, essential for brain function. In FXS, >200 CGG repeats cause silencing of the gene FMR1, and loss of the FMRP protein leading to the neurodevelopmental disorder FXS affecting 1 in 4,000 males and 1 in 5,000-8,000 females. FXPCs carry what is called a premutation (55-200 repeats) impacting 1/148 females and 1/290 males, increasing the risk of cognitive, psychiatric, and motor symptoms, including Fragile X Tremor Ataxia Syndrome (FXTAS), a Parkinson-like disorder. To date there is no cure for FXS and there is still a lack of research on the associated conditions and disorders; new measures to advance treatment discovery are therefore needed. Language abilities are promising non-invasive markers in neurodevelopmental and neurodegenerative disorders. FXS patients show expressive language deficits, while FXTAS patients exhibit disfluent speech, suggesting disruptions in common linguistic mechanisms like word retrieval. Additionally, plasma-based biomarkers are gaining ground as less invasive alternatives to CSF for detecting protein dysregulation in these conditions. In this work we combine the investigation of language abilities and plasma-based proteins to detect potential differences between FXPCs and a control group, that could point to cognitive alteration. Additionally, we retrospectively measured the same plasma-based proteins on FXS patients' samples. We used three linguistic tasks, a picture naming task, a visual word paradigm, and a picture description task, to assess language production and reception in FXPCs, with both online and in-person participants, and we collected blood samples to measures three different plasma-based proteins, acetylated alpha-tubulin, tyrosinated alpha-tubulin, and Neurofilament Light Chain (NfL). Our findings confirmed the presence of detectable differences between the groups: -The FXPCs group displayed potentially delayed Reaction Times (RTs) and a more disfluent language pattern, potentially caused by disruption to the lexical retrieval process, often disrupted in neurodegeneration, as the presence of correlations among task performance revealed. -FXPCs and FXS patients showed dysregulation of plasma-based proteins, potentially indicating similar altered mechanisms. -Disfluencies were correlated with plasma proteins dysregulation, suggesting potential measurable connections between the biochemical markers and language characteristics. In conclusion, this research provides a first step towards the identification of measures that combined could help advance treatment discoveries for FXS and FXPCs. In addition, it shows the importance of fuelling research through patient engagement to achieve the overall goal of improving the patients' quality of life and that of their family.