GRONINGEN, THE NETHERLANDS — While evidence is strong that altered cholinergic innervation plays a key role in cognitive impairment in Parkinson’s disease (PD), at least in advanced stages, less is known about the relationship between cognitive impairment and cholinergic innervation early in the disease.
Better understanding could provide more insight into disease prognosis and possible early intervention, according to a new study in The Lancet Neurology.
Dutch researchers and colleagues, including the VA Ann Arbor, MI, Healthcare System, sought to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment.1
To do that, they assembled a cohort of 57 newly diagnosed, treatment-naive, PD patients (32 men, mean age 64.6 ± 8.2 years) and 10 healthy controls (five men, mean age 54.6 ±6.0 year. All participants underwent cholinergic [18 F]fluoroethoxybenzovesamicol positron emission tomography and detailed neuropsychological assessment.
PD patients were also classified as either cognitively normal (PD-NC) or as having mild cognitive impairment (PD-MCI). Whole brain voxel-based group comparisons were performed.
Researchers reported that their results indicated bidirectional cholinergic innervation changes in PD. They also noted that both PD-NC and PD-MCI groups showed significant cortical cholinergic denervation compared to controls (P < 0.05, false discovery rate corrected), primarily in the posterior cortical regions.
“Higher-than-normal binding was most prominent in PD-NC in both cortical and subcortical regions, including the cerebellum, cingulate cortex, putamen, gyrus rectus, hippocampus, and amygdala,” the authors wrote.
Advising that altered cholinergic innervation is already present in de novo patients with PD, the study team pointed out that posterior cortical cholinergic losses were identified in all patients independent of cognitive status.
“Higher-than-normal binding in cerebellar, frontal, and subcortical regions in cognitively intact patients may reflect compensatory cholinergic upregulation in early-stage PD,” the researchers suggested. “Limited or failing cholinergic upregulation may play an important role in early, clinically evident cognitive impairment in PD.”
Another study published in Lancet Neurology, led by Ann Arbor VAMC researchers, pointed out that, in patients with Parkinson’s disease, heterogeneous cholinergic system changes can occur in different brain regions. “These changes correlate with a range of clinical features, both motor and nonmotor, that are refractory to dopaminergic therapy and can be conceptualized within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions.”2
In fact, the authors advised, “Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes.”
The study went on to describe how postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes, adding that cholinergic system deficits can involve also peripheral organs.
The authors posited that hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behavior disorder, as well as in the hippocampi of cognitively normal patients with Parkinson’s disease, suggests early compensation during the prodromal and early stages of Parkinson’s disease. “Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and nonmotor features of Parkinson’s disease” they added.
- Van der Zee S, Kanel P, Gerritsen MJJ, Boertien JM, Slomp AC, Müller MLTM, Bohnen NI, Spikman JM, van Laar T. Altered Cholinergic Innervation in De Novo Parkinson’s Disease with and without Cognitive Impairment. Mov Disord. 2022 Jan 17. doi: 10.1002/mds.28913. Epub ahead of print. PMID: 35037719.
- Bohnen NI, Yarnall AJ, Weil RS, Moro E, Moehle MS, Borghammer P, Bedard MA, Albin RL. Cholinergic system changes in Parkinson’s disease: emerging therapeutic approaches. Lancet Neurol. 2022 Apr;21(4):381-392. doi: 10.1016/S1474-4422(21)00377-X. Epub 2022 Feb 4. PMID: 35131038; PMCID: PMC8985079.
