Dementia with Lewy bodies

Pathogenesis and pathophysiology
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By Ann Marie Hake MD

In dementia with Lewy bodies, the protein alpha-synuclein aggregates into fibrils in Lewy bodies. The molecular characteristics of these aggregates are indistinguishable in dementia with Lewy bodies, Parkinson disease, and Parkinson disease with dementia, but their distribution differs. Alpha-synuclein aggregates by unknown mechanisms, but it is hypothesized that overproduction of alpha-synuclein or production of abnormal forms of the protein lead to abnormal aggregation (Eriksen et al 2003). There are thought to be multiple and complex mechanisms involved. Currently it is thought that Lewy bodies and alpha-synuclein cause pathologic conditions due to the following:

  • Repeats or mutations in the alpha-synuclein gene cause familial dementia with Lewy bodies.
  • Filamentous alpha-synuclein aggregates in Lewy bodies and Lewy neurites contain abnormally nitrated, phosphorylated, and ubiquitinated residues.
  • Alpha-synuclein transgenic animal models develop a neurodegenerative disease with filamentous alpha-synuclein deposits.
  • Cortical Lewy bodies correlate with the dementia in Parkinson disease with dementia and dementia with Lewy bodies.
  • Double transgenic mice overexpressing human familial Alzheimer disease mutant alpha-synuclein show an augmentation in alpha-synuclein pathologies.
  • Coexpression of heat shock proteins consisting of beta-synuclein with alpha-synuclein in mice ameliorates the disease phenotype.
  • Antibodies specific to alpha-synuclein detect Lewy bodies and Lewy neurites, which are the hallmarks for amyloid of dementia with Lewy bodies (Spillantini et al 1997).
  • It has been demonstrated that aggregated alpha-synuclein activates microglia and an inflammatory response as one mechanism of neurodegeneration (Zhang et al 2005).
  • Ohtake and colleagues found that an alteration in beta-synuclein (SNCB) may impair its normal inhibitory action on the formation of alpha-synuclein fibrils (Ohtake et al 2004).

Pathologic findings. A Lewy body is composed of the protein alpha-synuclein along with ubiquitin, neurofilament protein, alpha B crystallin, and glucocerebrosidase (Goker-Alpan et al 2010). Khachaturian reported an autopsy series of elderly individuals with dementia and found that the second most common pathology after the senile plaques and neurofibrillary tangles of Alzheimer disease was Lewy bodies found in subcortical and cortical regions (Khachaturian 1995). Pathologically, Lewy bodies are present in a pattern more widespread than usually observed in Parkinson disease. In addition to Lewy bodies, patients with dementia with Lewy bodies have neuronal loss, basal forebrain cholinergic deficits, and vascular pathology. Some patients with Lewy body dementia may also have a sufficient number of hippocampal and neocortical senile plaques to meet pathologic diagnostic criteria for Alzheimer disease. Hansen and colleagues referred to such patients as having the “Lewy body variant of Alzheimer disease” (Hansen et al 1990). The term “diffuse Lewy body disease” is reserved for patients with brainstem and cortical Lewy bodies but an insufficient number of senile plaques to fulfill the diagnostic criteria for Alzheimer disease.

Wakabayashi and colleagues reported that pathologic examination of their 2 patients showed marked neuronal loss with Lewy bodies in the brainstem, pigmented nuclei, numerous cortical Lewy bodies, and ubiquitin-positive hippocampal neurites (Wakabayashi et al 1998). Neuropathology of the proband reported by Ohara and colleagues demonstrated numerous Lewy bodies in the cerebral cortex and brainstem with no neurofibrillary tangles or neuritic plaques (Ohara et al 1999). Postmortem study revealed that cardiac sympathetic denervation occurs in Lewy body disease and indicates the presence of Lewy body pathology, which accounts for the decreased cardiac uptake of MIBG on scintigraphy scanning in Lewy body disease.

Additionally, these studies support current research showing an ascending pattern of Lewy body progression from brainstem to basal areas of the brain. Damage to these structures in dementia with Lewy bodies may affect a number of different neurochemical messenger systems, which possibly contributes to the clinical features of dementia with Lewy bodies (Whitwell et al 2007).

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited