LAUSR

Parkinson’s disease (PD) is increasingly viewed as a multisystem neurodegenerative disorder affecting, besides the dopaminergic function, multiple other neurotransmission systems (Braak et al., 2003). Of particular interest is the degeneration of the cholinergic system (Müller and Bohnen, 2013), since there is evidence that a cholinergic deficit is present in several cortical regions in PD patients (Hilker et al., 2005). Central cholinergic circuits of the human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation (TMS) of motor cortex. This TMSbased protocol is named short-latency afferent inhibition (SAI) (Tokimura et al., 2000). SAI is considered a marker of central cholinergic activity because it can be reduced or abolished by intravenous injection of the muscarinic antagonist scopolamine (Di Lazzaro et al., 2000) and modulated by acetylcholine (Di Lazzaro et al., 2005; Fujiki et al., 2006). Visual hallucinations (VHs) represent a frequent and disturbing complication of PD. SAI was found to be significantly decreased in PD patients with VHs compared with healthy subjects and PD patients without VHs (Manganelli et al., 2009). In PD patients with VHs the performance of some tasks evaluating visuospatial functions and attentional/frontal lobe functions was significantly more impaired than in patients without VHs. REM sleep behavior disorder (RBD) is also frequently associated with synucleinopathies, including PD. A significant reduction in SAI has been reported in PD patients with RBD when compared with PD patients without RBD and controls (Nardone et al., 2013). SAI values correlated positively with neuropsychological tests measuring episodic verbal memory, executive functions, visuoconstructive and visuoperceptual abilities. These findings indicate that RBD and VHs are an important determinant of mild cognitive impairment in PD, and SAI abnormalities may indicate an increased risk of cognitive impairment and eventually dementia in PD patients. Oropharyngeal dysphagia may also be associated with cognitive dysfunction in PD patients. SAI values significantly correlated with the total score of the oral phase components of videofluoroscopic studies in early PD patients (Lee et al., 2015). Logistic regression analysis showed that SAI was a factor that independently contributed to the presence of dysphagia. These findings suggest that SAI may represent a good biomarker for predicting the risk of dysphagia in PD patients. The cholinergic dysfunction is also thought to be a nondopaminergic contributor to gait disturbance in PD (Rochester et al., 2012). In PD patients, but not control subjects, significant associations were found between SAI, age and postural instability, gait disorder and attention. Regression analysis in patients with PD showed that reduced SAI is an independent predictor of slower gait speed. However, in another study, SAI testing failed to detect any significant decrease of cholinergic activity in PD patients with freezing of gait (Picillo et al., 2015). It has been hypothesized that the integrity or even increased activation of cholinergic neurons of the pedunculopontine nucleus could mask an eventual dysfunction of the nucleus basalis of Meynert, thus resulting in normal SAI findings. However, it cannot be excluded that the pathophysiology of this gait disturbance is underpinned by abnormalities in noncholinergic neurotransmitter systems. In this issue of Clinical Neurophysiology, an inverse correlation has been reported between SAI and the severity of olfactory dysfunction in PD (Oh et al., 2017). These findings indicate that cholinergic dysfunction might contribute to the pathogenesis of olfactory dysfunction in PD, and raise the possibility that the presence of olfactory impairment may suggest increased risk of cognitive dysfunction in patients with PD. Interestingly, reduced olfactory performance in subjects with PD may indicate increased risk of VHs, implying higher risk for developing dementia 2–6 years later. Also, in PD patients with olfactory dysfunction longitudinal studies are needed to verify to what extent SAI abnormalities might predict a future severe cognitive impairment. In conclusion, cholinergic degeneration is an important contributor to a number of clinical features of PD. TMS techniques may provide new insights into underlying pathophysiological mechanisms of many non-motor features and motor impairments in PD. In particular, SAI results, together with neuroimaging findings, have suggested the presence of common neurobiological processes leading to emergence of RBD, VHs, olfactory and cognitive impairment in PD patients. Early recognition of PD patients with cholinergic system degeneration might allow targeted cholinergic treatment approaches aimed to ameliorate, in addition to dopaminergic therapy, non-motor and motor clinical symptoms in these patients.