# Fluid Biomarkers in Hereditary Spastic Paraplegia: A Narrative Review and Integrative Framework for Complex Neurodegenerative Mechanisms

## TL;DR

This paper reviews fluid biomarkers for hereditary spastic paraplegia and proposes a framework to monitor disease progression despite genetic diversity.

## Contribution

The paper introduces an integrative framework using existing fluid biomarkers to address HSP's genetic and clinical heterogeneity.

## Key findings

- Fluid biomarkers like neurofilament light chain and soluble TREM2 reflect shared neurodegeneration mechanisms in HSP.
- Ultrasensitive assays and remote sampling technologies enable minimally invasive, longitudinal monitoring of HSP patients.
- Combining biomarkers with digital infrastructure could support scalable, patient-centered care models for HSP.

## Abstract

Background: Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders marked by progressive corticospinal tract dysfunction and wide phenotypic variability. Their genetic heterogeneity has so far limited the identification of biomarkers that are broadly applicable across different subtypes. Objective: We aim to define a balanced review on the use of biomarkers in HSP. Methods: This review focuses on fluid biomarkers already available in clinical or research settings—primarily validated in other neurodegenerative diseases—and assesses their potential translation to the HSP context. Biomarkers such as neurofilament light chain, brain-derived tau, glial fibrillary acidic protein, and soluble TREM2 reflect key converging mechanisms of neurodegeneration, including axonal damage, neuronal loss, and glial activation. These shared downstream pathways represent promising targets for disease monitoring in HSP, independently of the underlying genetic mutation. Results: An integrative framework of fluid biomarkers could assist in defining disease progression and stratify patients in both clinical and research settings. Moreover, recent advances in ultrasensitive assays and remote sampling technologies, such as dried blood spot collection, offer concrete opportunities for minimally invasive, longitudinal monitoring. When combined with harmonized multicenter protocols and digital infrastructure, these tools could support scalable and patient-centered models of care. Conclusions: The integration of already available biomarkers into the HSP field may accelerate clinical translation and offer a feasible strategy to overcome the challenges posed by genetic and clinical heterogeneity.