Project III: Cingulo-Opercular Task Control Network Cholinergic Dysfunction in PD

PROJECT III: SUMMARY/ABSTRACT
Cognitive deficits are a morbid dopamine replacement therapy-refractory feature of Parkinson disease (PD).
The pathophysiology of PD-related cognitive deficits is complex, likely involving interacting and variable
impairments of several brain systems, particularly in early to moderate disease. Incidence and natural history
of PD cognitive deficits is heterogeneous. Understanding the pathophysiologies of PD cognitive impairments is
essential for development of personalized therapies. PD heterogeneity is a major obstacle to effective clinical
research. Identifying PD subgroups will enhance discovery of useful interventions through subgroup specific or
stratified clinical trials, identify biomarkers, improve prognosis assessment in clinical care, and assist
etiopathogenic research. Some of the “highest priority recommendations” of the NINDS PD 2014 Research
Report call for research to understand the pathophysiology of cognitive impairments and for PD subgroup
identification. The U-M Udall Center established a deeply phenotyped PD cohort imaged with the vesicular
acetylcholine transporter PET ligand [18F]FEOBV, revealing heterogeneous cholinergic deficits. Cholinergic
terminal deficits in Cingulo-Opercular Task Control network (COTC) nodes – Anterior Cingulate and Insular
Cortices (AC-I) – correlate with both domain specific and global cognitive deficits. An important component of
the Attentional-Motor Interface (AMI; Overall Component), the COTC subserves tonic attention, coordinating
network activities across different cognitive domains. Preliminary analysis suggests that early COTC node (AC-
I) cholinergic deficits are a subgroup defining-feature in PD, predicting more rapid cognitive decline. The central
hypothesis of Project III is that early COTC node (AC-I) cholinergic denervation contributes significantly to
cognitive impairment in early to moderate PD and identifies a PD subgroup with accelerated cognitive decline.
In addition to our established Udall subject cohort, we have access to a separate cohort of incident PD subjects
through collaboration with the University of Groningen, deeply phenotyped and imaged with [18F]FEOBV PET,
for rigorous experimental replication and validation of our primary hypothesis. We will correlate early COTC
node (AC-I) cholinergic denervation with domain-specific and general measures of cognitive function. In a
prospective analyses, we will determine if early COTC node (AC-I) cholinergic denervation predicts more rapid
cognitive decline. In an integrated analysis with Project I, we will determine if COTC node (AC-I) cholinergic
denervation is associated with Freezing of Gait (FoG). In exploratory analyses, we will assess if more accessible
MRI or other measures correlate with COTC node (AC-I) cholinergic denervation, identifying potential,
accessible biomarkers of COTC node (AC-I) cholinergic denervation. Project III will identify an important
substrate of PD cognitive impairment and identify a PD subgroup with a more aggressive natural history - a
“malignant hypocholinergic disease phenotype.” These results will identify potential targets for therapeutic
interventions and biomarker development.

Grant Number: 5P50NS123067-05
NIH Institute/Center: NIH
Principal Investigator: Roger Albin