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  • Updated 04.17.2023
  • Released 06.21.2007
  • Expires For CME 04.17.2026

Dementia with Lewy bodies



Dementia with Lewy bodies is an age-associated neurodegenerative dementia characterized by the postmortem findings of pathologically misfolded alpha-synuclein protein aggregations in the form of Lewy bodies and Lewy neurites in the CNS. The majority of patients with dementia with Lewy bodies also have a moderate to severe level of Alzheimer disease plaque and tangle pathology sufficient for a secondary neuropathological diagnosis of Alzheimer disease. Clinically, this syndrome is associated with a prominent dementia with simultaneous, or later developing, extrapyramidal symptoms (ie, parkinsonism); however, not all patients with dementia with Lewy bodies develop clinical parkinsonism. Other core clinical features include the presence of fluctuations in attentiveness, well-formed visual hallucinations, and rapid-eye movement sleep behavioral disorder. These clinical features and postmortem findings are often indistinguishable from those observed in patients with Parkinson disease who develop dementia, often several years after the onset of motor symptoms. Thus, Parkinson disease dementia and dementia with Lewy bodies exist on a clinicopathological spectrum of underlying alpha-synucleinopathy, and the clinical distinction based on the timing of dementia in relation to parkinsonism is currently under debate (the “1-year rule” has been proposed to distinguish the two) (62). There are no FDA-approved therapies for dementia with Lewy bodies, so treatment is largely symptomatic. Current research is focused on rapid diagnosis for implementing trials of emerging disease-modifying therapies targeting alpha-synuclein protein aggregation and propagation.

Key points

• Dementia with Lewy bodies is a clinical diagnosis that is highly specific but moderately sensitive to postmortem finding of alpha-synuclein Lewy pathology in the neocortex.

• Diagnosis is based on clinical history, examination, and ancillary tests to rule out alternative diagnoses, including other neurodegenerative conditions (eg, frontotemporal dementia, Alzheimer disease, Parkinson disease, etc.).

• Clinically, dementia with Lewy bodies is distinguished from Parkinson disease dementia through the “1-year rule” according to the latest consensus criteria (62), where dementia with Lewy bodies has onset of dementia within, or prior to, 1 year from the onset of parkinsonism, and Parkinson disease dementia is characterized by dementia occurring greater than 1 year after a diagnosis of established Parkinson disease.

• Parkinson disease dementia and dementia with Lewy bodies share some common genetic risks and prodromal symptoms and can sometimes be indistinguishable at autopsy; thus, Parkinson disease dementia and dementia with Lewy bodies are likely to coexist on a continuum of clinical manifestations of underlying alpha-synucleinopathy with different patterns of onset and progression. Patients with Parkinson disease dementia are usually older at the time of death than those who have dementia with Lewy bodies.

• The majority of patients with clinical dementia with Lewy bodies are found to have sufficient amyloid-beta plaque and tau tangle pathology for a secondary neuropathological diagnosis of Alzheimer disease; thus, aging and Alzheimer disease-related pathology may be synergistic with synucleinopathy to result in clinical dementia with Lewy bodies.

• Treatment of dementia with Lewy bodies is largely symptomatic. Clinical trials have shown that cholinergic therapies approved for Alzheimer disease may improve cognitive symptoms, as well as visual hallucinations and nighttime behaviors.

• The presymptomatic phase of this disease is called mild cognitive impairment with Lewy bodies (MCI-LB). These patients have more neuropsychiatric symptoms than those with the mild cognitive impairment stage that precedes Alzheimer disease (MCI-AD). They also do worse on attention and visuospatial tasks and other nonmemory tasks than MCI-AD patients.

Historical note and terminology

The term “dementia with Lewy bodies” has its origins from the initial descriptions of postmortem microscopic findings of eosinophilic intracellular proteinaceous neuronal inclusions in Parkinson disease by Fritz Heinrich Lewy in the early 20th century, which were eventually named after him (ie, Lewy bodies and Lewy neurites). These pathological findings are considered the hallmark and gold-standard for diagnosis of Parkinson disease. Advances in our knowledge of the underlying molecular substrate for Parkinson disease and related disorders have been rapid in the past few decades. Improved postmortem detection of Lewy bodies using immunohistochemistry found patients with dementia and wide-spread cortical Lewy bodies and Lewy neurites to be the second most common neuropathological substrate for aging-related dementia. There have been numerous terms used to describe the clinical syndrome associated with cortical Lewy body/Lewy neurite pathology. In 1995, the first dementia with Lewy bodies consortium meeting was held in Newcastle, United Kingdom to define clinical diagnostic criteria and terminology for dementia with Lewy bodies and to standardize pathological measures for improved diagnosis. Since that time, the consortium has met four times to refine criteria and pathological methods. The 4th International dementia with Lewy bodies Consortium meeting was held in December 2015 with the consensus report from this meeting reported by McKeith and colleagues (62). In 1997, two near-simultaneous reports found pathogenic mutations in the SNCA gene encoding alpha-synuclein protein in patients with hereditary Parkinson disease and pathogenic alpha-synuclein protein as the primary constituent of Lewy bodies/Lewy neurites in both Parkinson disease and dementia with Lewy bodies (70; 77). These two important studies demonstrated that abnormal aggregation of alpha-synuclein protein in the CNS is central to the disease process in Parkinson disease and dementia with Lewy bodies. Modern clinical diagnostic criteria use the terminology “dementia with Lewy bodies” to refer to the clinical syndrome that is specific for postmortem findings of cortical alpha-synuclein Lewy body/Lewy neurite pathology. Dementia in Parkinson disease, or Parkinson disease dementia, is common and often is clinically and pathologically indistinguishable from dementia with Lewy bodies (37); thus, the umbrella term “Lewy body dementias” is often used to encapsulate these two syndromes associated with cortical alpha-synuclein Lewy body/Lewy neurite pathology. Up to 50% of patients with sporadic Alzheimer disease have alpha-synuclein pathology at autopsy, often times restricted to the amygdala (31), whereas Lewy bodies were detected in 63% of amygdala samples from patients with familial Alzheimer disease (53). The pathological term “Lewy body disease” refers to all forms of pathological alpha-synuclein in the form of Lewy bodies/Lewy neurites regardless of clinical phenotype. Alzheimer disease biomarkers have been identified in 25% of those who have dementia with Lewy bodies (84). Finally, multiple system atrophy is also characterized by alpha-synuclein pathology, but dementia and Lewy bodies are rare in multiple system atrophy. Instead, alpha-synuclein pathology is seen in oligodendrocytes (ie, glial cytoplasmic inclusions). Thus, the term “synucleinopathies” refers to all neuropathological diagnoses characterized by proteinaceous inclusions composed of alpha-synuclein protein (ie, Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies, and multiple system atrophy).

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