The pathomechanisms underlying Parkinson's disease

Abstract

Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is a progressive multi-organ proteinopathy caused by misfolded α-synuclein (αSyn) with variegated motor and nonmotor deficits owing to a spreading process of synaptic and neuronal loss in the nervous system. The motor core deficits of PD including rigidity, akinesia, rest tremor, and postural instability are attributed to the loss of dopaminergic nigrostriatal system, while the nonmotor alterations, such as hyposmia, autonomic and other dysfunctions frequently antedating motor symptoms are linked to widespread distribution of αSyn in the central, autonomic and peripheral nervous system and multiple organs. Recent studies have shown that αSyn aggregation in presynaptic terminals that predates the formation of Lewy bodies (LB), the characteristic markers of PD, is a key event in the pathogenesis of PD and other synucleinopathies. Progress in our understanding of the underlying mechanisms include insights into the functional organization of the basal ganglia and related cortico-subcortical circuits and their relations with morphological and pathophysiological lesions in the nervous system. The pathomechanisms underlying the cardinal motor abnormalities and nonmotor manifestations are briefly reviewed.

Keywords::

• basal ganglia organization
• clinico-pathological subtypes
• motor and nonmotor symptoms
• nigrostriatal dopaminergic system
• pathomechanisms of Parkinson's disease
• pathophysiology

Financial & competing interests disclosure

KA Jellinger is the Director of the Institute of Clinical Neurobiology, Vienna, Austria, which is supported by the Society for Support of Research in Experimental Neurology, Vienna, Austria. The study was partially supported by the Society for Support of Research in Experimental Neurology, Vienna, Austria. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Parkinson's disease (PD) is one of the most common neurodegenerative disorders in the aged.

• PD, in addition to core motor symptoms – rigidity, akinesia, resting tremor and postural instability – is frequently associated with variegated nonmotor (NM) symptoms that frequently antedate the motor deficiencies.

• NM symptoms include impaired olfaction (hyposmia), sleep disorders, gastrointestinal and genitourinary, cardiovascular, respiratory dysfunction, sensory, visual disorders, pain and neuropsychiatric features that may occur up to 20 years before the diagnosis of PD is established and then worsen with disease progression.

• While the core motor symptoms of PD are mainly caused by dysfunctions of the dopaminergic nigrostriatal system, a relationship between most of the NM alterations with αSyn and Lewy pathology exists, which is characterized by widespread involvement of distinct neuronal populations (networks) in the cerebrospinal, autonomic and peripheral nervous system and multiple organs.

• The anatomical basis of olfactory dysfunction in early (preclinical) phases of PD includes αSyn pathology in the olfactory bulb and related olfactory nuclei in the brain, but appears mainly related to involvement of the central olfactory pathways.

• Sleep disturbances that can occur decades before manifest PD, in addition to insomnia and daytime sleepiness, include REM sleep behavior disorder that, together with olfactory dysfunction, is an early indicator for PD and related synucleinopathies.

• Gastrointestinal disorders are related to αSyn pathology involving autonomic control areas and the enteric neuronal system, the analysis of which colonoscopy may be a useful tool for the premortem diagnosis of PD.

• Genitourinary dysfunctions in both presymptomatic PD and in up to 25% of healthy adults, due to damage to the peripheral autonomic system, have significant impact on the quality of life.

• Cardiovascular dysfunctions are due to the effect on the cardiac sympathetic system, while parasympathetic denervation is seen in late stages of PD.

• αSyn pathology in periadrenal tissues and in the adrenal gland has been associated with orthostatic hypotension in Lewy bodies disease.

• Pain manifestations in PD are associated with early involvement of the pain control system in the brainstem and, later, to dysfunction of the dopaminergic systems in the basal ganglia, while sensory deficits are related to cutaneous denervation by αSyn pathology.

• Frequent visual symptoms in PD are related to involvement of several levels of the visual pathways ranging from retinal to higher cortical areas.

• Neuropsychiatric symptoms (affective, cognitive changes, apathy, psychosis, etc.) occurring in both early and late phases of PD are caused by dysfunction of subcortico-cortical (striato-subfrontal, limbic) networks of cholinergic and dopaminergic transmission.

• The major clinical subtypes of PD featured by different motor deficits show specific morphological lesion patterns of pathophysiological importance, with different involvement of the striato-pallido-nigral-cortical and the cerebello-thalamocortical pathways.

• Current models of basal ganglia organization and dysfunction suggest that rigidity and tremor are generated by different basal ganglia downstream mechanisms struggling to compensate for PD akinesia.

• The essential pathophysiological feature of the rigid–akinetic type, occurring in about 50% of all PD patients, is increased neuronal firing activity of the striatal output nuclei (internal pallidum and reticular substantia nigra) leading to excessive inhibition of thalamocortical and brainstem motor systems, caused by dopamine deficiency and impairment of striatal synaptic plasticity. Rigidity may be associated with widespread changes in the brain.

• The development of motor fluctuations and dyskinesias, typically occurring 5–10 years after L-dopa treatment is basically caused by uncoupling of striatal receptor systems (dopamine, glutamate receptors and nondopaminergic transmitter systems)

• The tremor-dominant type of PD (about 25% of patients) is related to increased activity of the ventral intermediate thalamus and involvement of the cerebellar-thalamocortical circuit in the presence of striato-pallidal dopaminergic dysfunction, which has considerable implications for the stereotactic treatment of tremor.

• The pathomechanisms of postural instability in PD are suggested to be related to impaired integrity of the cholinergic pedunculopontine nucleus and its thalamic efferents, possibly participating in the integration of multimodal sensory input information.

• Treatment options for motor and motor symptoms in PD should be considered carefully with respect to their complex pathomechanisms and complications.

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