Differential Associations of Mobility With Fronto-Striatal Integrity and Lesion Load in Older Adults With and Without Multiple Sclerosis

Abstract

Background: Mobility impairment is common in older persons with multiple sclerosis (MS), and further compounded by general age-related mobility decline but its underlying brain substrates are poorly understood.

Objective: Examine fronto-striatal white matter (WM) integrity and lesion load as imaging correlates of mobility outcomes in older persons with and without MS.

Methods: Fifty-one older MS patients (age 64.9 ± 3.7 years, 29 women) and 50 healthy, matched controls (66.2 ± 3.2 years, 24 women), participated in the study, which included physical and cognitive test batteries and 3T MRI imaging session. Primary imaging measures were fractional anisotropy (FA) and WM lesion load. The relationship between mobility impairment, defined using a validated short physical performance battery cutoff score, and neuroimaging measures was assessed with stratified logistic regression models. FA was extracted from six fronto-striatal circuits (left/right): dorsal striatum (dStr)-to-anterior dorsolateral prefrontal cortex (aDLPFC), dStr-to-posterior DLPFC, and ventral striatum (vStr)-to-ventromedial prefrontal cortex (VMPFC).

Results: Mobility impairment was significantly associated with lower FA in two circuits, left dStr-aDLPFC (P = .003) and left vStr-VMPFC (P = .004), in healthy controls but not in MS patients (P > .20), for fully adjusted regression models. Conversely, in MS patients but not in healthy controls, mobility impairment was significantly associated with greater lesion volume (P < .02).

Conclusions: Comparing older persons with and without MS, we provide compelling evidence of a double dissociation between the presence of mobility impairment and two neuroimaging markers of white matter integrity, fronto-striatal fractional anisotropy, and whole brain lesion load.

Keywords: diffusion tensor imaging; fronto-striatal; gait; mobility impairment; motor control; older persons with multiple sclerosis.

Figure 1:

The fronto-striatal atlas construction pipeline, which consisted of: a) identification of MNI-based striatal seed regions and prefrontal cortical targets, b) T1-based registration of seeds and targets to 10 control participants, c) subject-space probabilistic tractography of 3 circuits x 2 (right/left), d) calculation of voxel-wise, tract density images (i.e., per-circuit probability maps), e) registration of TDI back to MNI space and averaging to obtain MNI-based tract probability maps. Not shown are subsequent steps of f) registration of MNI-averaged circuits into subject space, for all participants in the study, g) multiplication by subject FA maps, and h) extraction of mean per-circuit, per-subject FA values for entry into logistic regression models.

Figure 2:

Illustration of the striatal (light blue/purple) and cortical (blue/orange/green) regions used for fronto-striatal atlas tractography, along with the three resultant fronto-striatal circuit: a) dStr → aDLPFC circuit (left panel, red arrow), b) dStr → pDLPFC circuit (middle panel, blue arrow), and c) vStr → VMPFC circuit (right panel, green arrow).