Sunday, November 24, 2024
11/24/2024
Manganese (Mn) is an established neurotoxicant that causes parkinsonism and cognitive impairment with features overlapping with Parkinson disease (PD), PD dementia (PDD), and mild cognitive impairment (MCI). The causes of PD and related dementias are mostly unknown although growing evidence suggests that exposure to environmental toxicants such as Mn may induce alterations in gene expression that can be linked to disease susceptibility. Our team has conducted key studies using positron emission tomography (PET) that demonstrate Mn dose-dependent dopaminergic dysfunction in the midbrain and striatum contribute to clinical parkinsonism. However, the role of the dopaminergic system in the cognitive dysfunction that is associated with clinical Mn neurotoxicity is unknown. Recent pre-clinical data also implicate dysfunction of the cholinergic system in Mn neurotoxicity. The extensive degeneration of the cholinergic system is a well-known hallmark of age-related dementias, and recent molecular imaging innovations have led to a re-emerging interest in the cholinergic system as an important mechanism of cognitive dysfunction in PDD. Within the striatum, cholinergic and dopaminergic systems are highly integrated with extensive reciprocal innervations. Current models of cognitive decline in PD and PDD propose a “two-hit” effect in which the combined dopaminergic and cholinergic deficits lead to early cognitive impairment and eventual dementia. Similarly, dysfunction in these two vital striatal systems has been proposed as a core mechanism for Mn neurotoxicity. Given the dose- response relationship between Mn-exposure, dopaminergic dysfunction, and parkinsonism this occupationally exposed cohort provides an invaluable opportunity to study the in-vivo pathophysiology of parkinsonism and cognitive impairment in humans. In this proposal of 60 Mn-exposed workers, we will use a targeted neuropsychiatric battery of validated cognitive tasks with the dopaminergic ligand [11C](N-methyl)benperidol (NMB) to measure D2 receptor (D2R) function and the novel cholinergic PET radioligand (-)-(1-(8-(2- [(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone (VAT) to measure in-vivo vesicular acetylcholine transporter (VAChT) concurrently. The specific aims of this project are 1) to use NMB PET to evaluate the relationships between Mn exposure, dopaminergic dysfunction, and cognitive impairment; 2) to use VAT PET to evaluate the relationships between Mn exposure, cholinergic dysfunction, and cognitive impairment; and 3) to use mediation analysis to quantify the amount of cognitive dysfunction due to Mn exposure that is attributable to dopaminergic and cholinergic dysfunction respectively. We will use state-of-the-art imaging methods combined with an innovative statistical approach to understand the dual roles of the cholinergic and dopaminergic systems in Mn-induced cognitive dysfunction. Ultimately, our goal is to understand the role of environmental neurotoxicants and the combined effect of these key neurotransmitters in the pathophysiology of age-related neurodegenerative dementias such as PDD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
