Dataset Information

Exome sequencing in dementia with Lewy bodies.

ABSTRACT: Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ?4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ?4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.

SUBMITTER: Keogh MJ

PROVIDER: S-EPMC4872424 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Exome sequencing in dementia with Lewy bodies.

Keogh M J MJ Kurzawa-Akanbi M M Griffin H H Douroudis K K Ayers K L KL Hussein R I RI Hudson G G Pyle A A Cordell H J HJ Attems J J McKeith I G IG O'Brien J T JT Burn D J DJ Morris C M CM Thomas A J AJ Chinnery P F PF

Translational psychiatry 20160202

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Gene ...[more]

PMID: 26836416

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Project description:Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X-linked Parkinson's disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha-Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined. Here, analysis of the spatial distribution and expression of RAB39B was conducted in post-mortem human brain tissue from cases of dementia with Lewy bodies (DLB, n = 10), Alzheimer's disease (AD, n = 12) and controls (n = 12). Assessment of cortical RAB39B immunoreactivity using tissue microarrays revealed an overall reduction in the area of RAB39B positive gray matter in DLB cases when compared to controls and AD cases. Strikingly, RAB39B co-localized with beta-amyloid (Aβ) plaques in all cases examined and was additionally present in a subpopulation of Lewy bodies (LBs) in DLB. Biochemical measures of total RAB39B levels within the temporal cortex were unchanged between DLB, AD and controls. However, upon subcellular fractionation, a reduction of RAB39B in the cytoplasmic pool was found in DLB cases, alongside an increase of phosphorylated aSyn and Aβ in whole tissue lysates. The reduction of cytoplasmic RAB39B is consistent with an impaired reserve capacity for RAB39B-associated functions, which in turn may facilitate LB aggregation and synaptic impairment. Collectively, our data support the involvement of RAB39B in the pathogenesis of DLB and the co-aggregation of RAB39B with Aβ in plaques suggests that age-associated cerebral Aβ pathology may be contributory to the loss of RAB39B. Thus RAB39B, its associated functional pathways and its entrapment in aggregates may be considered as future targets for therapeutic interventions to impede the overall pathological burden and cellular dysfunction in Lewy body diseases.

Project description:Patients rarely experience visual hallucinations while being observed by clinicians. Therefore, instruments to detect visual hallucinations directly from patients are needed. Pareidolias, which are complex visual illusions involving ambiguous forms that are perceived as meaningful objects, are analogous to visual hallucinations and have the potential to be a surrogate indicator of visual hallucinations. In this study, we explored the clinical utility of a newly developed instrument for evoking pareidolic illusions, the Pareidolia test, in patients with dementia with Lewy bodies-one of the most common causes of visual hallucinations in the elderly. Thirty-four patients with dementia with Lewy bodies, 34 patients with Alzheimer's disease and 26 healthy controls were given the Pareidolia test. Patients with dementia with Lewy bodies produced a much greater number of pareidolic illusions compared with those with Alzheimer's disease or controls. A receiver operating characteristic analysis demonstrated that the number of pareidolias differentiated dementia with Lewy bodies from Alzheimer's disease with a sensitivity of 100% and a specificity of 88%. Full-length figures and faces of people and animals accounted for >80% of the contents of pareidolias. Pareidolias were observed in patients with dementia with Lewy bodies who had visual hallucinations as well as those who did not have visual hallucinations, suggesting that pareidolias do not reflect visual hallucinations themselves but may reflect susceptibility to visual hallucinations. A sub-analysis of patients with dementia with Lewy bodies who were or were not treated with donepzil demonstrated that the numbers of pareidolias were correlated with visuoperceptual abilities in the former and with indices of hallucinations and delusional misidentifications in the latter. Arousal and attentional deficits mediated by abnormal cholinergic mechanisms and visuoperceptual dysfunctions are likely to contribute to the development of visual hallucinations and pareidolias in dementia with Lewy bodies.

Dataset Information

Exome sequencing in dementia with Lewy bodies.

Publications

Exome sequencing in dementia with Lewy bodies.

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