Parkinson’s Disease Pathology

Figures and descriptions in this table follow the Neuropathology Web chapter on Parkinson disease.

The neuropathology of Parkinson’s disease centres on loss of pigmented neurons in the substantia nigra and Lewy body deposits of alpha-synuclein that spread through brainstem, limbic and cortical regions.

Parkinson disease is the second most prevalent neurodegenerative disorder after Alzheimer disease, according to the same chapter. That makes it a core entry among the types of neurodegenerative diseases. This guide follows the disease in the order a pathologist meets it: gross findings, microscopy, the nigrostriatal pathway, the wider distribution of lesions and the staging model.

Gross findings in the midbrain and cortex

The key gross finding in Parkinson disease is the midbrain, not the cortex. The midportion of the substantia nigra, called the zona compacta, is the first and most severely affected region. As pigmented neurons are lost, the nigra shows a noticeable loss of pigment in advanced stages, according to the Neuropathology Web chapter.

Pallor is a late-stage sign, so a normally pigmented nigra does not exclude early disease. Cortical atrophy is a poor guide in this condition. The brain in diffuse Lewy body disease is not as atrophic as the brain in Alzheimer disease, which means a mildly atrophic cortex does not argue against significant Lewy pathology.

Microscopic lesions: neuromelanin and Lewy bodies

Neuromelanin is the pigment that makes the normal substantia nigra dark. When pigmented neurons die, they release neuromelanin, and macrophages and astrocytes take it up. Free pigment and pigment-laden phagocytes are therefore expected in an affected nigra, alongside fewer pigmented neurons.

A Lewy body is a round, lamellated, eosinophilic cytoplasmic inclusion formed by large alpha-synuclein aggregates. Lewy bodies and Lewy neurites are the characteristic hallmarks of the disease and are composed primarily of misfolded alpha-synuclein, as described in a King’s College London thesis on experimental models. The biology of the aggregates themselves is covered in the guide to alpha-synuclein pathology.

Work through a nigral section in this order:

1. Find the pigmented neurons. Check how many remain in the zona compacta and whether free pigment lies in macrophages or astrocytes.
2. Scan the cytoplasm for inclusions. Look for round, lamellated, eosinophilic bodies inside surviving neurons.
3. Confirm with the protein. Alpha-synuclein staining targets the protein that makes up both Lewy bodies and Lewy neurites, so it highlights deposits in processes as well as cell bodies.

Nigrostriatal degeneration and the motor syndrome

Nigrostriatal degeneration is the loss of the dopaminergic neurons whose axons run from the substantia nigra to the striatum. Dopamine made in the nigral neurons is transported along these axons to the striatum. The classic triad of rigidity, bradykinesia and resting tremor corresponds to degeneration of this pathway and the resulting fall in striatal dopamine, according to the Neuropathology Web chapter.

The clinical syndrome therefore reflects terminal and cell body loss in one defined circuit rather than diffuse brain damage. Lewy bodies and neurites also correlate closely with the clinical features of the disease, as the King’s College London thesis notes.

Regions beyond the substantia nigra

Lewy pathology is not confined to the midbrain. Lewy bodies are also found in the locus coeruleus, the dorsal motor nucleus of the vagus and the nucleus basalis of Meynert. Abnormal alpha-synuclein deposits are described throughout the central nervous system, including the cerebral cortex and limbic system.

Neurites and glial deposits add to the picture. Alpha-synuclein is also deposited in neuronal processes, astrocytes and oligodendroglial cells. Sampling only the nigra therefore captures just one part of the disease.

Staging the spread of pathology

Alpha-synuclein pathology spreads to different regions of the brain as the disease progresses, which is the basis of the Braak model described in the King’s College London thesis. The full stage definitions and how they relate to Alzheimer criteria are set out in the guide to braak staging.

Staging has clinical meaning, according to Neurotorium’s review of disease course. Cognitive function appears to decrease steadily through the six Braak stages. Greater neuropathology, defined by Braak stage, correlated significantly with MMSE scores measured 12-18 months before death, and average MMSE consistently decreased from Braak stages 3 to 6.

Cortical Lewy pathology and Alzheimer co-pathology

Cognitive decline in Parkinson disease correlates better with Lewy bodies in the hippocampus, amygdala and neocortex than with nigral findings. Aggregates of misfolded alpha-synuclein also develop in hippocampal neurons in Parkinson disease and dementia with Lewy bodies, and a university release reports that nearly eight in ten Parkinson patients develop dementia, as covered by EurekAlert.

Alzheimer pathology adds to this. A large proportion of patients have enough senile plaques and neurofibrillary tangles to qualify for the pathological diagnosis of Alzheimer disease. In a demented patient, expect Lewy and Alzheimer changes to coexist and report both rather than forcing a single explanation.

Frequency and genetic background

Parkinson disease affects approximately 1-2% of individuals over the age of 60. About 5-10% of patients have a hereditary form, according to the Neuropathology Web chapter.

The glucocerebrosidase gene, GBA1, is the best-quantified genetic link in that chapter. Patients with Gaucher disease show a 20- to 30-fold increased risk of developing Parkinson disease, and 7-10% of Parkinson patients carry GBA1 mutations. A genetic finding therefore does not change the expected nigral and brainstem pathology.

Troubleshooting common confusions

• Normal-looking nigra. Gross pigment loss is a feature of advanced stages, so confirm with microscopy instead of relying on colour.
• Dementia without heavy cortical Lewy bodies. Check for Alzheimer co-pathology before attributing cognitive decline to Lewy pathology alone.
• Treating staging as fixed. Many refinements and caveats have been added to the Braak model since its conception, so treat a stage as a framework and not a prediction for every patient (Neurotorium).
• Expecting severe atrophy. A brain that is not markedly atrophic still fits Lewy body disease.

Frequently asked questions