References for this Review were identified through searches of PubMed with the search terms “basal ganglia”, “Parkinson's disease”, “akinesia”, “rigidity”, “tremor”, “executive dysfunctions”, “psychiatric complications” “apathy”, “depression”, and “PET” as main keywords between January, 1960, and August, 2009. Papers published in English, French, and Spanish were considered.
ReviewInitial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms
Introduction
Parkinson's disease (PD) has typically been considered to be a motor disorder1, 2 secondary to basal ganglia dysfunction. The definition in the 1960s of the nigrostriatal dopaminergic pathway and the discovery of dopamine striatal loss provided one of the best established correlations between clinical features and biochemical pathology.3 The main manifestations of PD—akinesia or bradykinesia, rigidity, and tremor—are now known to be directly related to dopaminergic striatal loss. Other clinical manifestations, albeit usually less noticeable, that are also seen at the time of diagnosis include sensory symptoms (eg, pain and tingling), hyposmia, sleep alterations, depression and anxiety, and abnormal executive, working memory-related functions.
The clinical manifestations of PD after diagnosis comprise a mixture of disease-related and treatment-induced manifestations. Motor and non-motor side-effects directly related to treatment such as dyskinesias or hallucinations, and other features arising after long-term disease progression (eg, gait problems and disequilibrium, autonomic failure, and dementia), are not covered in this Review. We discuss the pathophysiological mechanisms underlying the main clinical features of PD at the time of diagnosis and, therefore, when the clinical features are mainly affected by catecholaminergic (ie, mainly dopaminergic) deficits. We provide a differential explanation for the anatomo-functional basis of the major clinical manifestations of PD (ie, tremor, rigidity, akinesia, dysexecutive syndrome, and depression) to expand the views and concepts held by the classic pathophysiological model.
Section snippets
Key motor features: basic concepts
PD motor manifestations begin focally, typically in one limb segment, when dopamine concentrations fall below 60–70% in the contralateral striatum. The onset of motor features correlates with loss of dopamine in the posterior putamen (figure 1), corresponding to the motor region of the striatum. The main features of PD (ie, akinesia or bradykinesia, rigidity, and tremor) are therefore mainly related to dysfunction of the motor circuit (figure 2).
Pathophysiology of key motor features: the classic model
The classic pathophysiological model of the basal ganglia, which was elaborated in the 1980s,9, 10, 11 triggered a large amount of experimental and clinical activity and led to the revitalisation of surgery for PD and other movement disorders. Figure 3 provides a summary of this original model in the healthy and pathological states, and the table summarises the main experimental findings that support this model. The initial model, based on cortico-basal ganglia-cortical loops and changes in
Pathophysiology of PD: expanding classic concepts
The basal ganglia networks are now known to be anatomically and physiologically subdivided into motor, oculomotor, associative, and limbic territories that are involved in functions such as learning, planning, working memory, and emotions19, 20 (figure 4). The dopaminergic system innervates all striatal regions, as well as other non-striatal basal ganglia nuclei and limbic and associative cortical areas.21 Progressive loss of dopaminergic striatal innervation (figure 1) is associated with the
Conclusions
The basal ganglia networks involve complex sets of cortical and subcortical connections involved in motor control, cognitive functions, and emotional processing, probably through a common pathway, whereas the nigrostriatal dopaminergic system modulates input and the glutamatergic subthalamic projection regulates output. The wide clinical range of symptoms in patients with PD, even in early stages, could be due to dysfunction in distinct cortico-basal ganglia loops. The classic
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