# Neurobiological drivers of mobility resilience: the dopaminergic system

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $1,118,836

## Abstract

ABSTRACT
 In older age, walking becomes slower and less automated, requiring more attention and prefrontal resources.
Common causes of age-related walking impairments are cerebral small vessel disease (cSVD) and changes in
peripheral systems. We have recently discovered that ~20% of older adults maintain fast gait speed even in the
presence of common locomotor risk factors, thus appearing resilient. Our work suggests that the nigrostriatal
dopamine (DA) system may be a source of this resilience. We hypothesize that higher nigrostriatal DA
neurotransmission drives resilience to locomotor risk factors via higher connectivity with sensorimotor
networks, thus reducing prefrontal-mediated motor control and restoring automated control of walking.
 Resilience due to the nigrostriatal DA system is a novel and highly promising area of inquiry. Unlike vascular
lesions and brain structural impairments, DA neurotransmission is potentially modifiable, thereby offering novel
approaches to reduce age-related walking impairments. Although of substantial potential value to wellbeing in
aging, there is a critical gap in knowledge of age-related mobility with simultaneous measures of nigrostriatal
DA system, cSVD and peripheral system impairments. Our aims are:
 AIM 1: Quantify the DA-related contribution to mobility resilience, cross-sectionally and longitudinally.
We hypothesize that nigrostriatal DA neurotransmission predicts walking performance, during usual and dual
task conditions and reduces the negative effects of cSVD and peripheral system impairment on walking
performance.
 AIM 2: Assess DA-related automated control of walking, cross-sectionally and longitudinally. We
hypothesize nigrostriatal DA neurotransmission acts synergistically with connectivity of sensorimotor networks
to predict higher walking performance and lower prefrontal activation while walking.
 As a first translational step in testing the effects of DA on resilience, we propose to collect pilot data for a
mechanistic target-engagement study in slow-walking older adults with cSVD and pronounced age-associated
striatal DA loss. Exploratory AIM 3: To assess the effects of 1 week of L-DOPA administration on connectivity
and gait speed as a function of molecular markers of striatal DA release in non-resilient elderly with
pronounced age-associated striatal DA losses.
 This research is innovative in that it goes beyond explaining impairments, to revealing resilience factors and
their mechanisms as the basis for novel interventions. It has high impact because recent findings suggest that
pharmacological and behavioral interventions can improve DA signaling. Our team has unique expertise in the
use of novel technologies and represents decades as thought leaders in the study of aging, brain and mobility.

## Key facts

- **NIH application ID:** 10214483
- **Project number:** 5U01AG061393-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Nicolaas Ida Bohnen
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,118,836
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214483

## Citation

> US National Institutes of Health, RePORTER application 10214483, Neurobiological drivers of mobility resilience: the dopaminergic system (5U01AG061393-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10214483. Licensed CC0.

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