2 Neuroscience2.13 Neurodegeneration

2.13.5 Lewy body diseases including Parkinson's disease

Creator: Resident Doctor Committee
Published: 2026-10-14T21:05:16.259Z

3 min read2 figures

Written by Resident Doctor Committee · Published 14 October 2026

Alpha-synuclein and the Lewy body

Lewy bodies are cytoplasmic inclusions in neurones made mainly of aggregated, misfolded alpha-synuclein. They define Parkinson's disease and dementia with Lewy bodies, and alpha-synuclein immunoreactivity identifies them.
Ubiquitin is also present in Lewy bodies, but it only tags the aggregate for clearance and is not the defining protein.
About half of people with Alzheimer's disease have Lewy bodies, mainly in the amygdala, but a diagnosis of Lewy body disease requires alpha-synuclein inclusions.

Feature	Brainstem (nigral) Lewy body	Cortical Lewy body
Appearance	Dense eosinophilic core with a pale peripheral halo	Less compact, with no halo
Best shown by	Haematoxylin and eosin staining or immunostaining	Alpha-synuclein immunostaining

High-power haematoxylin and eosin micrograph of a substantia nigra neurone. A round pink inclusion with a paler rim, marked by a black arrowhead, sits inside the cell among brown pigment granules. — This haematoxylin and eosin stained neurone from the substantia nigra shows a classic Lewy body beside the arrowhead, with a dense pink core, pale halo and surrounding brown neuromelanin pigment. Tulemo, CC BY-SA 4.0, via Wikimedia Commons

Parkinson's disease

The defining pathology is loss of dopaminergic neurones, with Lewy bodies, in the substantia nigra pars compacta.
At post-mortem, the death of neuromelanin-containing neurones leaves the substantia nigra and the noradrenergic locus coeruleus pale. This is the classic gross finding in Lewy body disease.
When nigrostriatal dopamine input is lost, postsynaptic striatal D2 receptors show upregulation and supersensitivity, not loss.
The motor features are bradykinesia with decrement, rigidity, rest tremor and, later, postural instability, and they usually start on one side.
The tremor is a slow rest tremor of about 4 to 6 Hz that settles with voluntary movement. This sets it apart from cerebellar, dystonic and essential tremor and from the faster physiological tremor.

Post-mortem transverse slices of midbrain and upper pons from a control and from Lewy body disease. In the control the substantia nigra is a dark curved band and the locus coeruleus a dark spot, while in Lewy body disease the same arrowed structures are pale. — Compare the arrowed substantia nigra (SN) and locus coeruleus (LC): dark with neuromelanin in the control, pale in Lewy body disease after their pigmented neurones die, the classic gross finding at post-mortem. Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW, Mol Neurodegener 2021;16:83, CC BY 4.0

Genetics

Most Parkinson's disease is sporadic. Its risk is built from many common low-penetrance variants rather than a single mutation.

Gene	Role	Notes
SNCA	Monogenic, dominant	Encodes alpha-synuclein at chromosome 4q22; point variants or extra copies directly cause familial early-onset Lewy body disease
LRRK2	Monogenic, dominant, variable penetrance	Kinase; the commonest cause of autosomal dominant familial Parkinson's disease, more common than SNCA
PRKN (parkin)	Monogenic, recessive	Early-onset; E3 ubiquitin ligase
PINK1	Monogenic, recessive	Early-onset; mitochondrial quality control
GBA1	Susceptibility allele, low penetrance	Glucocerebrosidase; lysosomal function
APOE e4	Susceptibility allele	Raises risk only

Dementia with Lewy bodies

Dementia with Lewy bodies is diagnosed when dementia comes before parkinsonism or within a year of it. Dementia that starts more than a year into established Parkinson's disease is Parkinson's disease dementia.

The pathology is intraneuronal inclusions that stain for alpha-synuclein and ubiquitin in cortical, subcortical and brainstem regions, with moderate plaques, few tangles and mild atrophy.
Pigmented dopaminergic neurones are also lost from the substantia nigra.
The core clinical features are fluctuating attention or alertness, recurrent well-formed visual hallucinations, rapid eye movement sleep behaviour disorder and spontaneous parkinsonism.
Patients show marked antipsychotic sensitivity, so avoid antipsychotics where possible.

Imaging

Technique	What it shows
Dopamine transporter single-photon emission computed tomography (SPECT) (123I-ioflupane, DaTscan)	Reduced striatal uptake from nigrostriatal loss in dementia with Lewy bodies, but largely not in Alzheimer's disease
Perfusion SPECT	Blood flow
Amyloid positron emission tomography	Amyloid, a pathology both diseases share

Reduced dopamine transporter uptake also occurs in other parkinsonian disorders.

Multiple system atrophy

Multiple system atrophy is a synucleinopathy in which neuronal loss falls on the striatum.

Feature	Parkinson's disease	Multiple system atrophy
Gross pathology	Pale nigra, putamen spared	Shrunken, discoloured putamen
Levodopa response	Good early response	Poor or transient, because postsynaptic putaminal neurones degenerate along with the nigra

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.