Dementia with Lewy bodies

David J Irwin MD (Dr. Irwin of the University of Pennsylvania has no relevant financial relatioships to disclose.)
John Q Trojanowski MD PhD (Dr. Trojanowski of the University of Pennsylvania School of Medicine has no relevant financial relationships to disclose.)
Martin R Farlow MD, editor. (

Dr. Farlow of Indiana University received research grant support from AbbVie, Biogen, Boehringer Ingelheim, Eisai,  Eli Lilly, Genentech, Roche, Lundbeck, Novartis, and Suven Life Sciences Ltd; fees from Accera, Allergan, Avanir, AZ Therapies, Eli Lilly, Kyowa Kirin Pharma, Longeveron, Medavante, Merck, Neurotrope Biosciences, Proclara, Takeda, and vTv Therapeutics for consultancy, or advisory board/DSMB membership; licensing fees from Elan; and consulting fees from Cortexyme, Green Valley, Regenera, Samumed, Zhejiang Hisun Pharmaceuticals, and Cognition Therapeutics.

)
Originally released June 21, 2007; last updated November 20, 2017; expires November 20, 2020

This article includes discussion of dementia with Lewy bodies, Lewy body disease, Lewy body dementia, and synucleinopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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. There are no FDA-approved therapies for dementia with Lewy bodies, and treatment is largely supportive. Current research is focused on rapid diagnosis for implementing emerging symptomatic and 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 examination and ancillary tests to rule out alternative diagnoses, including other neurodegenerative conditions (eg, frontotemporal dementia, Alzheimer disease).

 

• Clinically, dementia with Lewy bodies is distinguished from Parkinson disease dementia through the “1-year rule” according to the latest consensus criteria (McKeith et al 2017), where dementia with Lewy bodies has onset of dementia within, or prior to, 1 year from the onset of Parkinson disease, 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 genetic risk and prodromal symptoms and can be indistinguishable at autopsy; thus, Parkinson disease dementia and dementia with Lewy bodies are likely a spectrum of clinical manifestations of underlying alpha-synucleinopathy with different patterns of onset and progression.

 

• 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 is largely supportive, and data for symptomatic therapies are limited, however, cholinergic therapies approved for Alzheimer disease may improve cognitive symptoms.

 

• Future work aims to identify pre-symptomatic phase of the disease for more rapid diagnosis and implementation of emerging disease-modifying therapies targeting the pathological process of pathological alpha-synuclein aggregation and propagation throughout the CNS.

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, Lewy bodies and Lewy neurites, Lewy neurites). These pathological findings (Lewy bodies and Lewy neurites) 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 4 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 (McKeith et al 2017). 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 (Polymeropoulos et al 1997; Spillantini et al 1997). 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 (Irwin et al 2013b); 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. The clinical distinction of Parkinson disease dementia and dementia with Lewy bodies relies largely on the timing of dementia in relationship to motor symptoms (Lippa et al 2007; McKeith et al 2017); however, the utility of this distinction is currently under debate (Boeve et al 2016). Up to 50% of sporadic Alzheimer disease patients have alpha-synuclein pathology at autopsy, often times restricted to the amygdala (Hamilton 2000), whereas Lewy bodies were detected in 63% of amygdala samples from familial Alzheimer disease patients (Lippa et al 1998). 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. Finally, multiple system atrophy is also characterized by alpha-synuclein pathology, but dementia and Lewy bodies are rare in multiple system atrophy, and, instead, alpha-synuclein pathology is seen in oligodendrocytes (ie, glial cytoplasmic inclusions). Thus, the term “synucleinopathies” refer to all neuropathological diagnoses characterized by proteinaceous inclusions composed of alpha-synuclein protein (ie, Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies, multiple system atrophy).

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