Mobility impairments are often the most visible symptom of Multiple Sclerosis (MS) and the clinical hallmark of the disease. Falls are also very common in MS. The loss of mobility and the frequent falls that are observed in patients with MS are associated with a multitude of adverse outcomes including disability and death. Recent epidemiological evidence suggests a shift in the peak prevalence of MS into older age groups, and this will likely coincide with co-occurring aging and MS-related declines in mobility and cognition. Research concerning brain systems of mobility and falls in MS, notably among older adults with MS, is scarce. This proposal offers a novel theoretical and empirical approach specifically designed to address existing limitations in mobility and falls research in older adults with MS. Our overarching hypothesis is that the prefrontal cortex (PFC) and related functional circuits – including the basal ganglia and thalamus – and white matter integrity are critical for cognitive control of mobility. We aim to identify brain systems of walking under single and dual-task conditions and of falls in 120 older (age≥60) adults with a definite diagnosis of MS and 120 controls (age≥60). We propose that according to “neural inefficiency,” patients with MS will demonstrate higher HbO2 levels during locomotion to support similar or worse walking performance compared to controls. We further postulate that higher (i.e., inefficient) HbO2 levels during dual-task walking will predict increased risk of incident falls among MS patients. Finally, white matter integrity is proposed as mechanism underlying inefficient brain activation during locomotion. In aim 1 we will determine PFC HbO2 patterns associated with Single-Task-Walk (STW) and Dual-Task-Walk (DTW) in 120 MS patients and 120 controls. Using DTI, we will examine the moderating effect of white matter integrity on PFC HbO2 patterns assessed during active walking. In aim 2 we will use multi-modal neuroimaging methods to establish brain systems controlling STW and DTW in 120 MS patients and 120 healthy controls. In aim 3 we will use PFC HbO2 levels, assessed with fNIRS during DTW, to predict incident falls among 120 MS patients over a longitudinal follow-up (years 1-5). Identifying novel and potentially modifiable biomarkers of falls and mobility impairments in older adults with MS is of paramount epidemiological and clinical significance. Elucidating the mechanistic underpinnings of brain systems controlling mobility in older adults with MS will have a major impact on knowledge and important implications for treatment of mobility impairments and falls.

Mobility impairments are often the most visible symptom of Multiple Sclerosis (MS) and the clinical hallmark of the disease. Falls are also very common in MS. The loss of mobility and notably the frequent falls in MS are associated with a multitude of adverse outcomes including disability and death. Recent epidemiological evidence suggests a shift in the peak prevalence of MS into older age groups, and this will likely coincide with co-occurring aging and MS-related declines in mobility and cognition. Research concerning brain systems of mobility and falls in MS, notably older adults with MS, is scarce. In aim 1 we will determine PFC HbO2 patterns associated with Single-Task-Walk (STW) and Dual-Task-Walk (DTW) in 120 MS patients and 120 controls. Using DTI, we will examine the moderating effect of white matter integrity on PFC HbO2 patterns assessed during active walking. In aim 2 we will use multi-modal neuroimaging methods to establish brain systems controlling STW and DTW in 120 MS patients and 120 healthy controls. In aim 3 we will use PFC HbO2 levels, assessed with fNIRS during DTW, to predict incident falls among 120 MS patients over a longitudinal follow-up (years 1-5). Identifying novel and potentially modifiable biomarkers of falls and mobility impairments in older adults with MS is of paramount epidemiological and clinical significance. Elucidating the mechanistic underpinnings of brain systems controlling mobility in older adults with MS will have a major impact on knowledge and important implications for treatment of mobility impairments and falls.