Reduced walking endurance is common in people with multiple sclerosis (PwMS), leading to reduced social participation and increased fall risk. This highlights the importance of identifying which gait aspects should be mostly targeted by rehabilitation to maintain/increase walking endurance in this population. A total of 56 PwMS and 24 healthy subjects (HSs) executed the 6 min walk test (6 MWT), a clinical measure of walking endurance, wearing three inertial sensors (IMUs) on their shanks and lower back. Five IMU-based digital metrics descriptive of different gait domains, i.e., double support duration, trunk sway, gait regularity, symmetry, and local dynamic instability, were computed. All metrics demonstrated moderate–high ability to discriminate between HSs and PwMS (AUC: 0.79–0.91) and were able to detect differences between PwMS at minimal (PwMS_mFR) and moderate–high fall risk (PwMS_FR). Compared to PwMS_mFR, PwMS_FR walked with a prolonged double support phase (+100%), larger trunk sway (+23%), lower stride regularity (−32%) and gait symmetry (−18%), and higher local dynamic instability (+24%). Normative cut-off values were provided for all metrics to help clinicians in detecting abnormal scores at an individual level. The five metrics, entered into a multiple linear regression model with 6 MWT distance as the dependent variable, showed that gait regularity and the three metrics most related to dynamic balance (i.e., double support duration, trunk sway, and local dynamic instability) were significant independent contributors to 6 MWT distance, while gait symmetry was not. While double support duration and local dynamic instability were independently associated with walking endurance in both PwMS_mFR and PwMS_FR, gait regularity and trunk sway significantly contributed to 6 MWT distance only in PwMS_mFR and PwMS_FR, respectively. Taken together, the present results allowed us to provide hints for tailored rehabilitation exercises aimed at specifically improving walking endurance in PwMS.

Rehabilitation is a key component of Parkinson’s disease (PD) management, although individual responses differ substantially. Genetic factors involved in neuroplasticity and inflammation may contribute to this variability. We investigated whether selected polymorphisms in inflammation- and neuroplasticity-related genes influence motor outcomes following intensive multidisciplinary rehabilitation in patients with PD. Sixty-six patients with a diagnosis of idiopathic PD were consecutively enrolled and randomly allocated to an intensive multidisciplinary rehabilitation group (EXP-Group, n = 34) or a home-based stretching control group (CTRL-Group, n = 32) for six weeks. MDS-UPDRS III score was assessed at baseline (T0) and post-treatment (T1). SNPs in the TNF, IL6, IL6R, IL1A, IL1B, IL10 and BDNF genes were genotyped. Possible associations between genotype, treatment group and MDS-UPDRS III score at T1 were analyzed using ANCOVA and linear mixed-effects models, adjusting for baseline MDS-UPDRS III score, age, sex, disease duration and levodopa equivalent daily dose (LEDD). A significant treatment group x TNF rs1800629 genotype interaction was observed (p = 0.033). Among EXP-Group patients, GG homozygotes showed lower adjusted MDS-UPDRS III scores than did the A-allele carriers (29.10 vs. 36.11; p = 0.029). Longitudinal analyses revealed a significant time × treatment group × TNF rs1800629 genotype interaction (p = 0.010), with GG homozygotes showing an approximately 10-point reduction in MDS-UPDRS III score (40.87 to 30.87; p < 0.001). These findings suggest that TNF rs1800629 contributes to variability in response to intensive multidisciplinary rehabilitation in PD.