Parkinson's Disease and Parkinsonism: Neuropathology
Open accessAbstract
Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and reactive gliosis in the substantia nigra found at autopsy.Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein a-synuclein or the microtubule binding protein tau.In idiopathic Parkinson's disease (PD), a-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites).The disease process is multifocal and involves select central nervous system neurons and peripheral autonomic nervous system neurons.The particular set of neurons affected determines nonmotor clinical presentations.Multiple system atrophy (MSA) is the other major a-synucleinopathy.It is also associated with autonomic dysfunction and in some cases with cerebellar signs.The hallmark histopathologic feature of MSA is accumulation of a-synuclein within glial cytoplasmic inclusions (GCI).The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls.The tau pathology of PSP also affects both neurons and glia.Given the population frequency of PD, a-synuclein pathology similar to that in PD, but not accompanied by neuronal loss, is relatively common (10% of people over 65 years of age) in neurologically normal individuals, leading to proposed staging schemes for PD progression.Although MSA-like and PSP-like pathology can be detected in neurologically normal individuals, such cases are too infrequent to permit assessment of patterns of disease progression.P arkinson's disease (PD) is a progressive neu- rological disorder defined by a characteristic clinical syndrome by bradykinesia, tremor, rigidity, and postural instability.There are a large number of different disorders that can have some or all of these clinical features, and the clinical syndrome is referred to as "parkinsonism."Disorders in which parkinsonism is a prominent part are referred to as "parkinsonian disorders."PD is but one of a host of parkinsonian disorders (Table 1).Some parkinsonian disorders are chronic and progressive and caused by an unknown degenerative disease process, whereas others may have clear genetic cause, such as cases driven by autosomal dominant mutations in the gene for a-synuclein.
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Parkinson's disease involves peripheral catecholamine neuron loss, including cardiac innervation at ventricles, right atrium, and sinus node causing orthostatic hypotension, and enteric nervous system loss causing early constipation.
“There is also loss of catecholamine neurons in the periphery (202), including cardiac innervation at the ventricles, right atrium, and sinus node (orthostatic hypotension), as well as in the enteric nervous system (constipation, an early disease stage).”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [202]
The paper’s Abstract says Parkinson’s disease affects peripheral autonomic neurons and that autonomic dysfunction may occur early. It does not specify loss of peripheral catecholamine neurons, the named sites of cardiac innervation, or a causal link from enteric neuron loss to early constipation. The indexed passages provide section labels but no page numbers. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn Parkinson's disease, earlier loss of locus coeruleus neurons in the pons alters mood, sleep, and posture.
“Lower, in the pons, an earlier loss of neurons in the locus coeruleus alters mood, sleep, and posture.”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [202]
The Braak PD Staging Scheme section places pathology in pontine locus ceruleus neurons before substantia nigra involvement, and the neuropathology section reports locus ceruleus neuronal loss in PD. But the paper cautions that this staging tracks α-synuclein deposits, not the timing of neuronal loss; it also does not attribute changes in mood, sleep, and posture to locus ceruleus neuron loss. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn Parkinson's disease there is less neuronal loss in dorsal and medial tiers, pars reticulata, and ventral tegmental area, no astrocyte loss, and no loss of nearby red nucleus neurons.
“There is less neuronal loss in the dorsal and medial tiers, the substantia nigra’s pars reticulata, or the adjacent Ventral Tegmental Area, no loss of astrocytes, and no loss of neurons in the nearby red nucleus (200–202).”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [202]
The Distribution of Pathology section says dorsal and medial neuronal groups are less vulnerable and identifies the ventral tegmental region as a medial group. Table 3 lists the red nucleus as spared in PD. The paper does not establish less neuronal loss in the pars reticulata or explicitly state that astrocytes are not lost; it describes reactive astrocyte changes instead. (LLM, conf=0.87)
Experimental — accuracy not yet measuredParkinson's disease movement disorders result from loss of neurons in the ventrolateral tier of the dopamine-releasing pars compacta of the substantia nigra.
“The movement disorders in Parkinson’s (PD) are due to loss of neurons in a specific region of the midbrain’s substantia nigra: the ventrolateral tier of the dopamine-releasing pars compacta.”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [202]
Parkinson's disease patients lose neurons in the raphe nuclei of the reticular formation and the dorsal motor nucleus of the vagus.
“Still lower in the brainstem, PD patients lose neurons in the raphe nuclei of the reticular formation (regulating mood and depression) and the dorsal motor nucleus of the vagus (controlling vocal cords and swallowing).”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [202]
Locus coeruleus neurons contain norepinephrine-derived neuromelanin, the dorsal motor nucleus of the vagus contains possibly dopaminergic neuromelanin, and raphe nuclei contain serotonin-derived neuromelanin.
“Locus coeruleus neurons contain norepinephrine-derived neuromelanin (227, 228); the dorsal motor nucleus of vagus contains neuromelanin that may be dopaminergic (202); and the raphe nuclei contain neuromelanin derived from their neurotransmitter, serotonin.”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [202]
Citation 202 is attached to the claim about the dorsal motor nucleus of the vagus. The Braak PD Staging Scheme section discusses pathology there, and the Conclusions table lists the region, but neither says it contains neuromelanin or that the pigment may be dopaminergic. Searches for those terms found no supporting passage in our copy. (LLM, conf=0.76)
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- Authors
- Dickson, D. W.
- Affiliations
- Mayo Clinic in Florida (US)
- Corresponding author
- Dickson, D. W.
- ORCID
- Dickson, D. W.
- Venue
- Cold Spring Harbor Perspectives in Medicine
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-06-20
- Volume
- 2
- Issue
- 8
- Pages
- a009258-a009258
- ISSN
- 2157-1422 (ISSN-L)
- PMC
- PMC3405828
- OpenAlex
- W2156179625
- Cited by
- 847
- References
- 94
- Citations by year
- 2026: 38 · 2025: 75 · 2024: 89 · 2023: 73 · 2022: 108 · 2021: 89 · 2020: 77 · 2019: 65 · 2018: 60 · 2017: 57 · 2016: 40 · 2015: 32 · 2014: 22 · 2013: 18 · 2012: 3
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P01AG003949, P50AG025711, P01AG017216, P50AG016574)
- National Institute of Neurological Disorders and Stroke (P50NS072187)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, parkinsonism, neuropathology, alpha-synuclein, tau protein, Lewy bodies, Lewy neurites, multiple system atrophy, progressive supranuclear palsy, glial cytoplasmic inclusions, nigrostriatal pathway, substantia nigra, reactive gliosis, non-motor symptoms, autonomic dysfunction, disease staging
- MeSH terms
- Brain, Inclusion Bodies, Diagnosis, Differential, Humans, Nerve Degeneration, Neuroglia, Parkinson Disease, Supranuclear Palsy, Progressive, Head Injuries, Closed, Lewy Bodies, Multiple System Atrophy, Parkinsonian Disorders, TDP-43 Proteinopathies
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