The cholinergic system and Parkinson disease

Abstract

Although Parkinson disease (PD) is viewed traditionally as a motor syndrome secondary to nigrostriatal dopaminergic denervation, recent studies emphasize non-motor features. Non-motor comorbidities, such as cognitive impairment, are likely the result of an intricate interplay of multi-system degenerations and neurotransmitter deficiencies extending beyond the loss of dopaminergic nigral neurons. The pathological hallmark of parkinsonian dementia is the presence of extra-nigral Lewy bodies that can be accompanied by other pathologies, such as senile plaques. Lewy first identified the eponymous Lewy body in neurons of the nucleus basalis of Meynert (nbM), the source of cholinergic innervation of the cerebral cortex. Although cholinergic denervation is recognized as a pathological hallmark of Alzheimer disease (AD), in vivo neuroimaging studies reveal loss of cerebral cholinergic markers in parkinsonian dementia similar to or more severe than in prototypical AD. Imaging studies agree with post-mortem evidence suggesting that basal forebrain cholinergic system degeneration appears early in PD and worsens coincident with the appearance of dementia. Early cholinergic denervation in PD without dementia appears to be heterogeneous and may make specific contributions to the PD clinical phenotype. Apart from well-known cognitive and behavioral deficits, central, in particular limbic, cholinergic denervation may be associated with progressive deficits of odor identification in PD. Recent evidence indicates also that subcortical cholinergic denervation, probably due to degeneration of brainstem pedunculopontine nucleus neurons, may relate to the presence of dopamine non-responsive gait and balance impairments, including falls, in PD.

Amyloid-β deposition and regional grey matter atrophy rates in dementia with Lewy bodies

“…While the dopaminergic degeneration has been widely documented to affect the striatum of patients with DLB (Walker et al, 2004;Klein et al, 2010), a cholinergic network alteration involving the striatum has been postulated in the Lewy body disease spectrum of disorders (Langlais et al, 1993) but its mechanism is still poorly understood (Bohnen and Albin, 2011). In this setting, our finding of an association between higher PiB retention and higher atrophy rates in the caudate and putamen nuclei suggest an accelerated subcortical neuronal injury involving the global PiB SUVR (x-axes) and regional grey matter annualized log Jacobian (y-axes) in patients with DLB, after adjusting for age.…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…It is presentlyrecognizedthat early neuronal loss occurs in other regions involved in motor control [58,59] and in neurons of the mesocortical system [60]. The involvement of other neuronal populations takes place later in PD or only in certain clinical phenotypes and includes neuronal loss in the cholinergic basal forebrain [61], in the hypothalamic hypocretin system [62,63] and in the upper brainstem serotonin system [64]. Neuronal loss is very restricted to areas containing LBs, such as the amygdala, the dorsal motor nucleus of the vagus nerve, locus coeruleus and the neocortex [65Ͳ68].…”

Mechanisms of α‐Synuclein Pathology and Treatment in the Enteric Nervous System

“…Similarly, cholinergic neural deficits and functional impairment have long been recognized as symptomatic features of PD and NCDLB [22][23][24][25][26][27][28]. Increasingly, cholinergic impairments in PD and NCDLB are attributed to Lewy Body pathology (Cholinergic impairment does not appear to be a consistent finding in Alzheimer's disease (AD) [27,42].…”