Loss of cholinergic neurons in the pedunculopontine nucleus in Parkinson's disease is related to disability of the patients

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Abstract

We investigated neuronal number and size in the pars compacta of the pedunculopontine nucleus (PPN) in Parkinson's disease (PD). In PD, the number of Luxol fast blue (LFB) neurons was reduced by 27% from the mean control value (p = 0.04) and the cholinergic (choline acetyltransferase, ChAT-positive) neuron number was reduced by 36% (p = 0.03). In addition to neuronal loss, the remaining neurons in the PPN in PD were smaller than in controls. The profile area of LFB neurons was reduced by 14% (p = 0.009) and that of ChAT-positive neurons by 26% (p = 0.001).

There was more severe loss of ChAT-positive neurons with a more severe stage of the disease, evaluated by the modified Hoehn and Yahr scale (r = −0.66, p = 0.03). The neuron number decreased much more than could be expected on the basis of decrease in cell size alone.

Introduction

The main pathophysiological mechanism of Parkinson's disease (PD) is a progressive loss of dopaminergic neurons in the substantia nigra (SN), leading to deficiency of dopamine. Dopaminergic therapy is the most common drug treatment for PD, and alleviates many of the parkinsonian symptoms. However, deficits such as gait disturbances, postural instability, freezing, unexplained falls and sleep disturbances do not respond well or at all to dopaminergic therapy, and cannot be explained only by dysfunction of the nigrostriatal dopaminergic system [1], [2], [3], [4]. Dopamine-resistant parkinsonian deficits of this kind are more frequently seen in patients with widespread degenerative brainstem disorders such as progressive supranuclear palsy (PSP) [5], [6]. The pedunculopontine nucleus (PPN) is located in the dorsolateral part of the caudal mesencephalic tegmentum. PPN has reciprocal connections with the limbic system, basal ganglia nuclei and brainstem reticular formation [7]. There are connections to many thalamic nuclei, the globus pallidus, subthalamic nucleus, substantia nigra and ventral tegemental area [8], [9], [10], [11]. In addition, the PPN is connected to the prefrontal and motor cortex [7], [9]. In non-human primates, most of the large neurons and in humans 58% of the medium to large neurons in the PPN are cholinergic [12], [13], [14]. About 30–40% of the large cholinergic neurons also contain substance P [15], [16].

In PD about 40–57% loss of large PPN neurons has been found [17], [18], [19], which is slightly less than the loss seen in PSP [18], [20]. In these studies no immunocytochemical staining was used to separate cholinergic and non-cholinergic neurons. In addition, it is unclear at present whether the loss of PPN neurons is related to the clinical symptoms of PD patients, although abnormalities in gait and posture in addition to rigidity and akinesia may partly be due to neuronal loss or reduced neuronal activity in PPN [7]. Moreover, there is a high correlation between neuronal loss in PPN and that in the SN pars compacta [19]. The role of PPN in motor control is further supported by recent targeting of PPN for deep brain stimulation in PD [21], [22], [23].

The purpose of this study was to investigate the number and size of cholinergic and non-cholinergic PPN neurons in PD in relation to clinical disability. Our hypothesis was that neuronal loss in the PPN is associated with more severe stage of PD.

Section snippets

Patients

Nine controls (4 M/5 W) and 11 PD patients (7 M/4 W) were studied. The mean age; SD of controls was 73; 14 and that of the PD patients 79.3; 4.4 years (p = 0.17). The duration of disease in the PD patients was 9.3; 3.4 years (mean; SD). The patients were distributed between the modified Hoehn and Yahr stages [24] as follows: stage 2.5, two patients; stage 3, four patients; stage 4, four patients and stage 5, one patient. The PD patients were diagnosed and followed-up until death in the Department

Results

The distribution of LFB and ChAT-positive neurons in different levels of the PPN in controls and PD patients is shown in Fig. 1. As can be seen, the number of both LFB and ChAT-positive neuron profiles is greatest in the rostral part of the nucleus both in the controls and PD patients. However, the decline in neuron number in PD is most severe in the mid-portion of the PPN. On average, in PD patients, the number of LFB neuron profiles was significantly reduced by 27% from the mean control value

Discussion

In the present study we show cholinergic neuronal loss in the PPN in PD with immunochemical staining with an antibody against ChAT. In addition, we were also able to estimate the number of non-cholinergic neurons in same patients. The mean reduction in profile number from controls was 36% for cholinergic, 23% for non-cholinergic neurons and 27% for all neurons.

The degree of neuronal loss in PPN in PD in previous studies has varied from 40 to 57% [17], [18], [19]. Thus, in our study the loss of

Acknowledgements

This study was financially supported by the Turku University Foundation, the Medical Research Council of the Academy of Finland and clinical grants (EVO) of Turku University Hospital.

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