Lewy body

**Composition and pathophysiology:** Lewy bodies are round, eosinophilic cytoplasmic inclusions with a dense core and pale halo. They contain aggregated alpha-synuclein (a presynaptic protein, SNCA gene on chromosome 4), along with ubiquitin and neurofilaments. Misfolded alpha-synuclein aggregates into fibrils (a synucleinopathy), impairs proteasomal and lysosomal clearance, causes mitochondrial dysfunction, and leads to neuronal death. Lewy neurites are the same aggregates in neuronal processes. Stain with anti-alpha-synuclein or anti-ubiquitin immunohistochemistry.

**Parkinson disease (PD):** - Lewy bodies in dopaminergic neurons of the substantia nigra pars compacta, with depigmentation (loss of neuromelanin) and loss of dopaminergic neurons. - Decreased dopamine in the nigrostriatal pathway causes decreased direct pathway (D1) and increased indirect pathway (D2) activity, so the thalamus is inhibited and movement is reduced. - Clinical: TRAP: Tremor (resting, pill-rolling), Rigidity (cogwheel), Akinesia/bradykinesia, Postural instability. Also shuffling gait, masked facies, micrographia. - Treatment: levodopa/carbidopa, dopamine agonists (pramipexole, ropinirole), MAO-B inhibitors (selegiline, rasagiline), COMT inhibitors (entacapone), amantadine, and anticholinergics (benztropine) for tremor. Deep brain stimulation (subthalamic nucleus or globus pallidus interna) for refractory cases.

**Dementia with Lewy bodies (DLB):** - Widespread cortical Lewy bodies (also limbic and brainstem). - Core features: visual hallucinations (well-formed), fluctuating cognition/attention, parkinsonism, and REM sleep behavior disorder. Also severe neuroleptic sensitivity and autonomic dysfunction. - **1-year rule:** If dementia precedes or occurs within 1 year of parkinsonian motor symptoms, it is DLB. If parkinsonism precedes dementia by more than 1 year, it is Parkinson disease dementia. - Avoid typical antipsychotics (risk of severe sensitivity reactions). Treat with cholinesterase inhibitors (donepezil, rivastigmine). Use quetiapine or clozapine cautiously if needed.

**Other synucleinopathies (high-yield distinction):** - Multiple system atrophy (MSA): alpha-synuclein in **oligodendrocytes** (glial cytoplasmic inclusions), not neurons. Features parkinsonism, autonomic failure (orthostatic hypotension), and cerebellar signs. - Pure autonomic failure also involves alpha-synuclein.

**Differentiating from other inclusions:** - Pick bodies: round, silver-staining tau inclusions (frontotemporal dementia). - Neurofibrillary tangles: hyperphosphorylated tau (Alzheimer disease). - Negri bodies: rabies. - Hirano bodies: eosinophilic rods in hippocampus (Alzheimer disease). - Bunina bodies: ALS. - Cowdry A bodies: HSV. - Lewy bodies can co-occur with Alzheimer pathology (amyloid plaques and tangles) in many patients.

**Genetics (PD):** SNCA (alpha-synuclein) mutations or duplications, LRRK2 (most common autosomal dominant cause), PINK1 and Parkin (early-onset autosomal recessive, mitophagy), and GBA (glucocerebrosidase, a strong risk factor).

**Clinical pearls:** Definitive diagnosis of Lewy body diseases is histopathologic (at autopsy). Lewy body pathology may also be found in the enteric nervous system and olfactory bulb, which may explain early constipation and anosmia in PD.