CNS nontumor

• Dementia is defined as a progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational functions or usual daily activities (Neurology 2017;89:88)
• Lewy body dementia indicates dementia attributed to Lewy body pathology in the neocortex and limbic regions
  • Cognitive changes should occur before or simultaneously with Parkinsonian motor symptoms (see 1 year rule below)
  • Lewy body dementia and Parkinson disease with dementia are distinguished based on clinical criteria; pathologically the 2 conditions cannot be distinguished

• Lewy body dementia (or dementia with Lewy bodies [DLB]) is a clinicopathological term that encompasses a clinical dementia phenotype that precedes or coincides with Parkinsonism within a year of onset and the presence of Lewy bodies in supratentorial distribution (i.e., limbic and neocortical Lewy body pathology subtypes)
• Misfolded aggregated alpha synuclein is the main constituent of Lewy bodies
• Alzheimer disease neuropathologic changes frequently co-occur with Lewy body dementia and the relative burden of the 2 pathologies is thought to influence the clinical presentation

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• Unlike Alzheimer disease, dementia with Lewy bodies tends to affect attention, executive function and visuospatial function early in disease progression (J Neuropsychiatry Clin Neurosci 2000;12:425)
• Besides dementia, DLB patients must present with ≥ 2 core clinical features (Neurology 2017;89:88)
  • Cognitive fluctuations
  • Visual hallucinations: early clinical sign; useful clinical feature in the differential diagnosis of dementia with Lewy bodies versus Alzheimer dementia (Brain 2006;129:729)
  • Rapid eye movement (REM) sleep behavior disorder
  • Parkinsonism: present in 70 - 85% (J Neuropsychiatry Clin Neurosci 2001;13:374, Neurology 2017;89:88)
    • 1 year rule: DLB patients show Parkinsonian motor symptoms within 1 year of the dementia diagnosis; Parkinson disease with dementia is diagnosed when the cognitive symptoms occur in longstanding (i.e., > 1 year) Parkinsonism
• Supportive clinical features
  • Marked sensitivity to antipsychotic agents
  • Postural instability
  • Repeated falls
  • Syncope or other episodes of unresponsiveness
  • Severe autonomic dysfunction (e.g., urinary incontinence)
  • Hypersomnia
    • Polysomnographic evidence of REM sleep without atonia is an indicative biomarker (Neurology 2017;89:88)
  • Hyposmia
  • Hallucinations in other modalities
  • Systematized delusions
  • Apathy, anxiety and depression

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Contributed by Javier Redding-Ochoa, M.D.

• Frequent loss of dopaminergic neurons and gliosis in the substantia nigra
• Lewy bodies vary in morphology according to the brain region involved (Mol Neurodegener 2019;14:5)
  • Cortical and limbic associated Lewy bodies are often poorly demarcated, round or reniform, hyaline, amphophilic and have neuronal perikaryal inclusions
  • Most commonly found in deep cortical layers
  • May not be appreciable on standard H&E staining
  • Brainstem Lewy bodies show a central eosinophilic core, surrounded by a clear halo in pigmented neurons (J Geriatr Psychiatry Neurol 2002;15:210)
• Pale bodies are faintly stained neuronal cytoplasmic inclusions without a halo, which are composed of alpha synuclein and proposed as a possible precursor to Lewy bodies (Neuropathology 2020;40:30)
• Glial cells commonly show synuclein pathology in dementia with Lewy bodies, particularly in cortical and limbic areas (Acta Neuropathol 2003;105:163)
• Alzheimer disease neuropathologic changes (i.e., amyloid plaques and neurofibrillary tangles) occur frequently in dementia with Lewy bodies
• Lewy body pathology is scored in semiquantitative method in multiple brain regions (Neurology 2005;65:1863)
  • Lewy body (LB) pathology is scored at low power field (10x) in each region from 0 - 4
    • 0 = none
    • Stage 1 = sparse LBs or Lewy neurites (i.e., 1 LB)
    • Stage 2 = moderate (> 1 LBs and sparse neurites)
    • Stage 3 = severe (≥ 4 LBs and scattered neurites)
    • Stage 4 = very severe (numerous LBs and numerous neurites)
  • Scored regions: cranial nerve nuclei IX / X, locus coeruleus, substantia nigra, nucleus basalis of Meynert, amygdala, transentorhinal cortex, cingulate cortex, temporal cortex, frontal cortex and parietal cortex
  • Scores are used to categorize into brainstem predominant, limbic or neocortical Lewy body disease
  • Higher Lewy body pathology burden in cortical (temporal, frontal and parietal cortices) and limbic (nucleus basalis of Meynert, amygdala, transentorhinal cortex, cingulate cortex) areas are related to a clinical presentation consistent with dementia with Lewy bodies
  • Higher Alzheimer disease pathology scores are thought to inversely correlate with the likelihood of clinical presentation consistent with dementia with Lewy bodies (Neurobiol Aging 1997;18:S1, Neurology 2005;65:1863)

Contributed by Javier Redding-Ochoa, M.D.

What feature is essential for a diagnosis of dementia with Lewy bodies?

1. Dementia
2. Lewy bodies in the brainstem
3. Lewy bodies in the hippocampus
4. Parkinsonism

A. Dementia. Dementia with Lewy bodies is a clinicopathological term that should include a clinical diagnosis of dementia and distribution of Lewy body pathology that explains the neuropsychiatric manifestations (i.e., neocortical and limbic structures) (Neurology 2005;65:1863). Answers B and C are incorrect because Lewy body pathology alone is insufficient for a diagnosis of dementia with Lewy bodies. Answer D is incorrect because Parkinsonism, while a clinical feature of dementia with Lewy bodies, is not essential for the diagnosis.

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Reference: Dementia with Lewy bodies

Which of the following is the main component of Lewy bodies?

1. Alpha synuclein
2. Disrupted organelles
3. Neurofilaments
4. Synaptophysin

A. Alpha synuclein. Lewy bodies contain a multitude of components, however, their main constituent is misfolded alpha synuclein (Nature 1997;388:839). Answers C and D are incorrect because although neurofilaments and synaptophysin have been detected in Lewy bodies, these proteins show either weak IHC expression (i.e., synaptophysin) or haven’t been shown to be implicated as the main structural constituent or as a pathogenic driver (Mol Neurobiol 2013;47:495, J Comp Neurol 1991;309:150, Brain Res 1994;634:339). Answer B is incorrect because although lipid structures such as disrupted organelles are abundant in Lewy bodies, other lipid structures are also involved such as general vesicles and other membrane fragments (e.g., autophagosomes) (Nat Neurosci 2019;22:1099). The proportional contributions of these lipid structures are not clear and their pathogenic role in protein seeding, oligomerization or Lewy body maturation is not elucidated.

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Reference: Dementia with Lewy bodies