Dementia, Lewy Body

A number sign (#) is used with this entry because dementia with Lewy bodies (DLB) can be caused by mutation in the alpha-synuclein (SNCA; 163890) or beta-synuclein (SNCB; 602569) genes.

Familial Parkinson disease-1 (PARK1; 168601) is associated with mutation in the SNCA gene.

The epsilon-4 allele of the APOE gene (107741) and the B allele of the CYP2D6 gene (124030), a cytochrome P-450 monooxygenase, have also been implicated in DLB.

A mutation in the prion protein gene (PRNP; see 176640.0017) has been identified in 1 patient with DLB. Some patients with a diagnosis consistent with Lewy body disease or dementia have mutations in the LRRK2 gene (609007), which is associated with Parkinson disease-8 (PARK8; 607060) (Giasson et al., 2006; Ross et al., 2006).

One family with a mutation in the PSEN2 gene (600759.0009), usually associated with Alzheimer disease-4 (AD4; 606889), had clinical and neuropathologic findings consistent with DLB (Piscopo et al., 2008).

Description

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder clinically characterized by dementia and parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Pathologically, Lewy bodies are present in a pattern more widespread than usually observed in Parkinson disease (see PD; 168600). Alzheimer disease (AD; 104300)-associated pathology and spongiform changes may also be seen (McKeith et al., 1996; Mizutani, 2000; McKeith et al., 2005).

Clinical Features

Ishikawa et al. (1997) reported 2 unrelated families with familial autosomal dominant diffuse Lewy body disease. In family A, 4 patients over 3 generations presented with parkinsonism, vertical ocular limitation, progressive dementia, and delusions or visual hallucinations. Two of the patients developed neuroleptic malignant syndrome (NMS). Family S had 3 affected members over 3 generations. One was examined in detail and presented with parkinsonism and progressive dementia and later developed NMS. In a member of family S reported by Ishikawa et al. (1997), Ishikawa et al. (2005) identified a mutation in the PSEN1 gene (104311.0032). No mutations were identified in the SNCA gene. The phenotype was an overlap between DLB and Alzheimer disease with spastic paraparesis (607822).

Denson et al. (1997) reported 10 individuals with Lewy body disease in 3 successive generations of 2 closely intermarried families. The phenotype was variable: 4 patients displayed parkinsonian features only, 3 had dementia only, and 3 had combined parkinsonism and dementia. Mean age of onset was 62 years. Linkage studies were inconclusive.

Wakabayashi et al. (1998) described a Japanese family with parkinsonism and later-onset dementia. The proband developed parkinsonism at the age of 61 years, followed by dementia starting when she was 67. Her uncle, who was also her husband, died at the age of 78 years after 7- and 5-year histories of parkinsonism and dementia, respectively. Her 2 sons developed similar parkinsonism at the ages of 39 and 28 years and also suffered later-onset dementia. The apolipoprotein E genotype of the proband, her uncle, and 1 of their sons was E3/4 and that of the other son was E4/4. The authors concluded that this represented autosomal dominant diffuse Lewy body disease.

Ohara et al. (1999) presented a familial case of dementia with Lewy bodies in 3 sibs, born of first-cousin parents, who demonstrated progressive dementia with a progressive language disorder characterized by dysarthria, paraphasia, and difficulty in finding words. The 2 brothers presented with parkinsonism and fluctuating cognition. The sister and one of the brothers also had visual hallucinations. No mutations in the alpha-synuclein gene (SNCA; 163890), the parkin gene (PARK2; 602544), or the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1; 191342) were found.

Graeber and Muller (2003) provided a review of DLB, which they stated is the second most common degenerative dementia after Alzheimer disease. Clinically, DLB differs from Alzheimer disease in that disease symptoms are prone to fluctuate and patients often suffer from visual hallucinations, though short-term memory is relatively preserved. As many as 70% of patients have parkinsonism and up to 50% are sensitive to the extrapyramidal side effects of neuroleptic drugs. Graeber and Muller (2003) suggested that DLB is a complex disorder with both genetic and environmental factors involved in the pathogenesis, as is the case for many common disorders.

Ohtake et al. (2004) reported a patient with DLB and a mutation in the SNCB gene (602569.0002). He presented at age 64 years with a 3-year history of mild dementia and deterioration in his handwriting. He had frontal lobe involvement manifesting as executive and language dysfunction. He later developed depression, motor apraxia, parkinsonism, and audio and visual hallucinations. Neuropathologic examination showed extensive Lewy bodies in the hippocampus, amygdala, and substantia nigra. Several family members were affected or possibly affected in an autosomal dominant pattern of inheritance.

Pathologic Findings

Khachaturian (1985) performed 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 that of Lewy bodies found in subcortical and cortical regions. Patients with such 'Lewy body dementia' also have a sufficient number of hippocampal and neocortical senile plaques to meet the diagnostic criteria for Alzheimer disease. Hansen et al. (1990) referred to such patients as having the 'Lewy body variant of Alzheimer disease.' 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 et al. (1998) reported that pathologic examination of their 2 patients showed marked neuronal loss with Lewy bodies in the brainstem, pigmented nuclei, and numerous cortical Lewy bodies and ubiquitin-positive hippocampal neurites. Brain examination of 1 patient studied by Ishikawa et al. (1997) showed neuronal loss with gliosis and many Lewy bodies in the cerebral cortex and brainstem. One affected individual from the kindred reported by Denson et al. (1997) showed neuronal loss and gliosis as well as many Lewy bodies throughout the cerebral cortex and brainstem. Neurofibrillary tangles and neuritic plaques were present, but rare. Neuropathology of the proband reported by Ohara et al. (1999) demonstrated numerous Lewy bodies in the cerebral cortex and brain stem, with no neurofibrillary tangles or neuritic plaques.

Obi et al. (2008) reported the neuropathologic findings of a Japanese patient with PD and later-onset dementia who was heterozygous for a duplication of the SNCA gene (163890.0005) (Nishioka et al., 2006). The patient presented with classic levodopa-responsive parkinsonism at age 47. Loss of memory, visual hallucinations, and progressive cognitive decline began at age 60. Brain MRI showed medial temporal lobe atrophy on both sides, and single photon emission computed tomography (SPECT) showed hypoperfusion of the frontotemporal and occipital lobes. He later became bedridden and died of pneumonia at age 67. Postmortem examination showed mild frontal lobe atrophy and severe depigmentation of the substantia nigra and locus ceruleus. Severe neuronal loss was noted in the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus nerve, the amygdala, and the CA2/3 of the hippocampus. SNCA-immunostaining revealed multiple Lewy bodies in the cerebral cortex, hippocampus, and brainstem. The Lewy body-related pathology was graded as diffuse neocortical type based on the pathologic classification of dementia with Lewy bodies.

Diffuse Lewy Body Disease with Gaze Palsy

Lewis and Gawel (1990) and Fearnley et al. (1991) each presented a case report in which a patient (71 and 76 years old) with dementia and parkinsonism also presented with horizontal and vertical supranuclear gaze palsy, prompting an initial diagnosis of progressive supranuclear palsy (PSP; 601104). Pathologic diagnosis in both cases revealed diffuse Lewy body disease with Lewy bodies in areas believed to be associated with gaze control.

De Bruin et al. (1992) reported a 67-year-old man with a family history of parkinsonism who presented with supranuclear gaze palsy and later developed parkinsonism and mental impairment. A diagnosis of PSP was made initially, but postmortem pathologic examination revealed diffuse Lewy body disease with multiple Lewy bodies in the neocortex and brainstem, as well as lesser numbers of neuritic plaques and neurofibrillary tangles.

Brett et al. (2002) reported 2 sibs with onset in their 60s of a disorder characterized by parkinsonism, dementia, and visual hallucinations, which progressed to incapacity. One patient exhibited vertical supranuclear gaze palsy, and the other patient could not be tested. Pathologic examination of both cases showed diffuse Lewy body disease, with changes in the posterior commissure, the rostral interstitial nucleus of the medial longitudinal fasciculus, and the interstitial nucleus of Cajal, areas that subserve vertical gaze.

Diagnosis

The International Consortium on Dementia with Lewy bodies in 1995 established guidelines for the clinical and pathologic diagnosis of DLB. Mental impairment leading to dementia is the central core feature, with fluctuation in cognitive function, visual hallucinations, and motor features of parkinsonism being other key symptoms. Brainstem or cortical Lewy bodies are the only essential pathologic features, although other pathologic changes may be present as well (McKeith et al., 1996). The guidelines were updated in 2005 (McKeith et al., 2005) to include sleep disturbances, neuroleptic sensitivity, reduced striatal dopamine transporter activity on functional neuroimaging, and pathologic grading.

Pathogenesis

In Lewy body diseases, including Parkinson disease with or without dementia, dementia with Lewy bodies, and Alzheimer disease with Lewy body copathology, alpha-synuclein aggregates in neurons as Lewy bodies and Lewy neurites. By contrast, in multiple system atrophy (146500) alpha-synuclein accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs). Peng et al. (2018) reported that pathologic alpha-synuclein in GCIs and Lewy bodies is conformationally and biologically distinct. GCI-alpha-synuclein forms structures that are more compact and is about 1,000-fold more potent than Lewy body alpha-synuclein in seeding alpha-synuclein aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-alpha-synuclein and Lewy body alpha-synuclein show no cell-type preference in seeding alpha-synuclein pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. Peng et al. (2018) found that oligodendrocytes, but not neurons, transform misfolded alpha-synuclein into a GCI-like strain, highlighting the fact that distinct alpha-synuclein strains are generated by different intracellular milieus. Moreover, GCI-alpha-synuclein maintains its high seeding activity when propagated in neurons. Thus, alpha-synuclein strains are determined by both misfolded seeds and intracellular environments.

Molecular Genetics

SNCA Gene

Zarranz et al. (2004) reported a Spanish family with autosomal dominant parkinsonism and dementia with Lewy bodies, diagnosed using strict criteria. Neuropathologic examination showed diffuse distribution of Lewy bodies in cortical and subcortical areas. Molecular analysis identified a mutation in the SNCA gene (163890.0004) that cosegregated with the disease phenotype. Zarranz et al. (2004) noted that because there is clinical and pathologic overlap between PD and DLB, the distinction and/or relationship between the 2 disorders is difficult to discern.

In affected members of 1 of the Japanese families reported by Ishikawa et al. (1997) with early-onset parkinsonism and dementia, Ikeuchi et al. (2008) identified a duplication of the SNCA gene (163890.0005). Three patients were heterozygous for the duplication, and 1 was homozygous for the duplication, having 4 copies of the SNCA gene. The entire duplication segment spanned 5 Mb and included at least 10 neighboring genes. The homozygous patient showed earlier onset and earlier death, with more severe cognitive impairment.

Uchiyama et al. (2008) reported a Japanese mother and son with duplication of the SNCA gene associated with variable features of parkinsonism and dementia. The son had prominent parkinsonism in his late forties, followed by fluctuating cognitive decline, visual hallucinations, and deficits in verbal fluency a few years later. The mother presented later at age 72 with memory disturbances and fluctuating cognitive deficits. She then developed mild parkinsonism and visual hallucinations. PET studies showed that both patients had diffuse hypometabolism in the brain that extended to the occipital visual cortex in the mother. Uchiyama et al. (2008) noted that the diagnoses in the son and mother were compatible with PD dementia and Lewy body dementia, respectively.

SNCB Gene

In 2 unrelated patients with dementia with Lewy bodies, 1 of whom had a family history of the disorder, Ohtake et al. (2004) identified 2 different heterozygous mutations in the SNCB gene (602569.0001; 602569.0002). Ohtake et al. (2004) postulated that an alteration in SNCB may impair its normal inhibitory action on the formation of toxic alpha-synuclein fibrils, thereby indirectly contributing to disease pathogenesis.

PRNP Gene

In a 55-year-old man with slowly progressive dementia, dysarthria, gait disturbance, and rigidity, but no myoclonus or EEG abnormalities, Koide et al. (2002) identified a heterozygous met232-to-arg mutation in the PRNP gene (M232R; 176640.0017). The patient was given a preliminary diagnosis of Creutzfeldt-Jakob disease (CJD; 123400). However, postmortem brain examination showed many Lewy bodies in the substantia nigra and cerebral cortices as well as lack of prion protein immunoreactivity, and final diagnosis was dementia with Lewy bodies.

Gene Associations

Galasko et al. (1994) analyzed the frequency of the apolipoprotein epsilon-4 allele (APOE4) in 74 subjects with Alzheimer disease, 40 patients with the Lewy body variant of Alzheimer disease, and 8 with diffuse Lewy body disease. The APOE4 allele frequency was 39.6% in pure Alzheimer disease, 29% in the Lewy body variant of Alzheimer disease, and only 6.25% in the 8 patients with diffuse Lewy body disease. Galasko et al. (1994) argued that this further supported their conclusion that dementia in the Lewy body variant is caused by the Alzheimer disease lesions, whereas the cause of the dementia in diffuse Lewy body disease is distinct.

Saitoh et al. (1995) analyzed the allele frequency of debrisoquine 4-hydroxylase (CYP2D6; 124030.0001) in an autopsy series consisting of all Caucasian samples. Forty-four of these had Lewy body dementia, which they defined as meeting neuropathologic criteria for Alzheimer disease, having at least 1 Lewy body, and having a primary clinical manifestation of dementia rather than Parkinson disease. In addition, there were 83 controls who had pure Alzheimer disease and 37 controls who had dementia without Alzheimer disease. The CYP2D6B allele frequency in Lewy body dementia was 0.307, considerably higher than the 0.163 allele frequency in pure Alzheimer disease and the 0.122 frequency in non-Alzheimer disease dementia. Saitoh et al. (1995) suggested that the CYP2D6B allele is a risk factor for Lewy body disease, and that this may have therapeutic implications.

Beyer et al. (2008) found different disease-specific expression of isoforms of the SNCA, PARK2, and synphilin-1 (SNCAIP; 603779) genes in frontal lobe cortices from patients with 4 diseases: pure Lewy body dementia, so-called 'common' Lewy body disease, in which amyloid plaques can also be seen, Parkinson disease, and Alzheimer disease. The data indicated that each disease can be characterized by its own molecular mechanisms and that different molecular mechanisms can lead to the development of similar neuropathologic changes.

Goker-Alpan et al. (2006) identified heterozygous mutations in the glucocerebrosidase gene (GBA; 606463) in 8 (23%) of 35 patients with dementia with Lewy bodies. The authors postulated that a mutant GBA enzyme may take on a different and unexpected role that may contribute to the development of synucleinopathies. In 2 (3.5%) of 57 European patients with Lewy body dementia, Mata et al. (2008) identified heterozygous mutations in the GBA gene: 1 patient had the L444P mutation (606463.0001), and the other had the N370S mutation (606463.0003). The authors estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry.