Abstract
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Introduction: The brain-body, specifically muscle, connection has been explored but remains incompletely understood. Frailty stands out as a complex challenge with a growing aging population, marked by the accumulation of multiple deficits across various functions — mobility, gait, muscle strength, cognition, and physical activity—heightening patient vulnerability to adverse health outcomes, including falls and increased mortality rates. Notably, frailty is prevalent in people with Parkinson's Disease (PwPD). Despite emerging understandings of the neurobiological association between brain structure and muscle function, particularly through the somato-cognitive action network (SCAN) system, brain network mechanisms of frailty in PD remain unclear. Definitions of frailty often neglect the brain as a vital player in frailty, creating challenges due to the lack of a standardized frailty assessment. Our study addresses this gap by exploring for the first time in humans the relationships between established clinical proxies for frailty, focusing on muscles and action-planning, and monoaminergic-related brain networks, using an advanced imaging technique: the vesicular monoamine type 2 transporter (VMAT2) PET ligand, 11C-dihydrotetrabenazine (11C-DTBZ).
Methods: Our cohort of PwPD underwent total body dual-energy x-ray (DXA) scan to assess appendicular lean mass index (ALMI) or sarcopenia, brain 11C-DTBZ and MR imaging, and comprehensive clinical testing including frailty proxy measures of grip strength via handheld dynamometer. We entered the grip strength and ALMI in two separate regression models to test voxel-wise correlation with whole brain 11C-DTBZ uptake, after controlling for age. The significance threshold was set at p < 0.05, K>100 corrected for FWE at cluster level.
Results: The voxel-wise correlations showed a significant positive association between grip strength and the binding of 11C-DTBZ in various brain regions within subcortical and limbic areas (refer to Figure 1). To be specific, weaker grip strength was linked to reduced 11C-DTBZ binding, particularly in the left basal forebrain more than the right, as well as in the hippocampus, amygdala, and anterior cingulate. Additionally, there was a significant association with the left caudate nucleus, bilateral thalamus regions, superior colliculus, and vermis. Similarly, ALMI demonstrated a significant positive correlation with subcortical and limbic areas, as illustrated in Figure 2. This correlation was particularly prominent in various brain regions, including the bilateral basal forebrain, amygdala, hippocampus, parahippocampus, insula, and anterior cingulate cortex. Additionally, there was a left-sided predominance in the correlation, specifically observed in the caudate nucleus, while the correlation extended bilaterally for the putamen, thalamus, and superior colliculus.
Conclusions: Our findings reveal that sarcopenia and hand grip strength (a clinical proxy of frailty) in PwPD are linked to monoaminergic-related networks encompassing brainstem, thalamostriatal, limbic and paralimbic brain regions. This indicates, for the first time in humans, the presence of a neurobiological neural network subserving the long-time hypothesized brain-muscle loop. Evidence of a neural network involved with muscular and clinical frailty may augur novel treatment approaches to manage this debilitating late stage systemic condition in PwPD
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