Cholinergic transmission is impaired in patients with idiopathic normal-pressure hydrocephalus: a TMS study

Miriam Maccarrone,Kerstin Schwenker,Francesco Brigo,Leopold Saltuari,Raffaele Nardone,Luca Sebastianelli,Viviana Versace,Yvonne Höller,Stefan Golaszewski

doi:10.1007/s00702-019-02036-6

Abstract

The pathophysiological mechanisms of cognitive and gait disturbances in subjects with normal-pressure hydrocephalus (NPH) are still unclear. Cholinergic and other neurotransmitter abnormalities have been reported in animal models of NPH. The objective of this study was to evaluate the short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain, in subjects with idiopathic NPH (iNPH). We applied SAI technique in twenty iNPH patients before ventricular shunt surgery. Besides SAI, also the resting motor threshold and the short intracortical inhibition to paired stimulation were assessed. A significant reduction of the SAI (p = 0.016), associated with a less pronounced decrease of the resting motor threshold and the short latency intracortical inhibition to paired stimulation, were observed in patients with iNPH at baseline evaluation. We also found significant (p < 0.001) correlations between SAI values and the gait function tests, as well as between SAI and the neuropsychological tests. These findings suggest that the impairment of cholinergic neurons markedly contributes to cognitive decline and gait impairment in subjects with iNPH.

Highlights

Idiopathic normal-pressure hydrocephalus is characterized by the classic Adams triad of cognitive dysfunction, urinary incontinence, and gait impairment
We evaluated the following transcranial magnetic stimulation (TMS) parameters: the resting motor threshold (RMT), the short latency intracortical inhibition (SICI) to paired TMS, and the short latency afferent inhibition (SAI)
We evaluated the correlation between SAI and the gait function tests (TUG and 6MWT), as well as between SAI and the neuropsychological tests (MMSE, Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT) A and B, Digit Span) for the two groups

Summary

Introduction

Idiopathic normal-pressure hydrocephalus (iNPH) is characterized by the classic Adams triad of cognitive dysfunction, urinary incontinence, and gait impairment. Gait and balance disorders are the leading presentations, whereas cognitive decline and incontinence appear as the disease progresses (Williams and Relkin 2013). Despite the clinical importance of the symptoms, the pathophysiological mechanisms of iNPH cognitive and gait disturbances remain unclear and objective methods for its assessment are lacking. Cholinergic dysfunction was found to be an important contributor to gait dysfunction in subjects with Parkinson’s disease (PD) (Rochester et al 2012), a condition that is characterized by loss of balance, slowness and small steps, NPH patients perform worse (Bugalho et al 2013)

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