Network-based meta-analysis and the candidate gene association studies reveal novel ethnicity-specific variants in MFSD3 and MRPL43 associated with dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia in elderly people, following Alzheimer's disease. Only three genes, SNCA (α-synuclein), APOE (apolipoprotein E), and GBA (glucosylceramidase), have been convincingly demonstrated to be associated with DLB. Here, we applied whole-genome sequencing to blood samples from 61 DLB patients and 45 cognitively normal controls. We used accumulation of candidate mutations to detect novel DLB-associated genes. Subsequent single nucleotide polymorphism (SNP) genotyping and association studies in a large number of samples from Japanese individuals revealed novel heterozygous variants in MFSD3 (rs143475431, c.888T>A:p.C296*; n = 5,421, p = 0.00063) and MRPL43 (chr10:102746730, c.241A>C:p.N81H; n = 4,782, p = 0.0029). We further found that the MFSD3 variant increased plasma levels of butyrylcholinesterase (n = 1,206, p = 0.029). We believe that our findings will contribute to the understanding of DLB and provide insight into its pathogenic mechanism for future studies.

Association of Lewy Bodies With Age-Related Clinical Characteristics in Black and White Decedents.

OBJECTIVE: The associations of Lewy bodies (LBs) with olfactory dysfunction, parkinsonism, and higher odds of dementia were assessed in Black and White community-dwelling elders and racial differences in these associations were tested. METHODS: Black decedents (n = 81) were matched 2-to-1 by age, sex, years of education, and follow-up time in the study with White decedents (n = 154) from 4 longitudinal studies of dementia and aging. Participants underwent uniform clinical examination and cognitive, motor, and olfactory testing. LBs were detected in 7 brain regions by α-synuclein immunohistochemistry and racial differences in their association with olfaction, parkinsonism, and odds of dementia were determined using regression analyses. RESULTS: The mean scores of the odor test, global parkinsonism signs, and global cognition were lower in Black than White decedents; the frequency of dementia was similar in both groups. The frequency of LBs was similar in Black and White decedents (∼25%), as was the frequency of LBs in individual brain regions, while the mean LB counts/mm2 were similar in all regions except the cingulate cortex, which showed higher mean LB counts in Black decedents. In regression analyses, LBs were associated with impaired olfaction (-2.23, 95% confidence interval [CI] -3.45 to -1.01) and higher odds of dementia (odds ratio 3.0, 95% CI 1.10-8.17) in both racial groups; an association with parkinsonism was stronger in Black than White decedents. CONCLUSIONS: The frequency, distribution, and clinical manifestations of LBs are similar in Black and White elders.

Dementia with Lewy bodies in first-generation immigrants in a European memory clinic.

We wanted to explore possible differences in disease presentation, frequency, and age of onset of dementia with Lewy bodies (DLB) between first-generation immigrants (FGI) and patients born in Belgium (PBIB). We conducted a retrospective study on all patients of our Memory Clinic between June 1, 2010 and January 31, 2020. A synucleinopathy was diagnosed in 150 of 2702 patients (5.5%): 91 received a diagnosis of DLB (3.4%). FGI were two times more likely to receive a diagnosis of DLB, due to a higher prevalence in North-Africans and Latin-Americans. Visual hallucinations were less frequent in North-Africans than in other immigrants. FGI were younger than PBIB and reported more often parasomnia. Our data suggest a higher risk for DLB in certain immigrant groups. Especially for North-African patients, a genetic factor can be suspected, namely mutations in Leucine-rich repeat kinase 2 (LRRK2). Memory clinics with a high rate of FGI may provide interesting data and insights into the prevalence of DLB, genetic and environmental differences.

Ethnoracial Differences in Lewy Body Diseases with Cognitive Impairment.

BACKGROUND: Increasing research focuses on ethnic differences in Alzheimer's disease, but such efforts in other neurodegenerative dementias are lacking. Currently, data on the ethnic profile of cognitively impaired persons with Lewy body disease (LBD) is limited, despite Lewy body dementia being the second most common neurodegenerative dementia. OBJECTIVE: The study aimed to investigate presenting characteristics among ethnoracially diverse individuals with cognitive impairment secondary to LBD using the National Alzheimer's Coordinating Center database. METHODS: Participants self-identified as African American, Hispanic, or White. We used Kruskal-Wallis and Pearson χ2 analyses to investigate group differences in presenting characteristics and linear regression to compare neuropsychological test performance. RESULTS: Presentation age was similar between groups (median 74-75 years). Compared to Whites (n = 1782), African Americans (n = 130) and Hispanics (n = 122) were more likely to be female and single, have less educational attainment, report more cardiovascular risk factors, describe less medication use, and perform worse on select cognitive tests. Hispanics reported more depressive symptoms. CONCLUSION: Cohorts differences highlight the need for population-based LBD studies with racial-ethnic diversity. Culturally-sensitive neuropsychological tests are needed to determine whether observed differences relate to cultural, social, testing, or disease-related factors. More research is needed regarding how social and biological factors impact LBD care among diverse populations.

Multicentre population-based dementia prevalence survey in Japan: a preliminary report.

Community-based surveys were performed in seven rural areas in Japan to investigate the prevalence of dementia and illnesses causing dementia. A total of 5431 elderly subjects were selected based on census data from 1 October 2009. In total, 3394 participants were examined (participation rate: 62.5%), and 768 dementia cases and 529 mild cognitive impairment cases were identified. Of the illnesses causing dementia, Alzheimer's disease was the most frequent (67.4%), followed by vascular dementia (18.9%), dementia with Lewy body disease (4.6%), mixed dementia (4.2%) and other illnesses. The prevalence of dementia according to 5-year age strata between 65 and 99 years was 5.8-77.7% among the participants. The prevalence of dementia in this study was higher than in previous reports in Japan and other countries. To verify the upward trend of dementia prevalence and its background factors, we have scheduled surveys for three other urban areas in 2011-2012.

Prevalence of dementia and its subtypes in an elderly urban korean population: results from the Korean Longitudinal Study on Health And Aging (KLoSHA).

BACKGROUND/AIMS: We estimated the prevalence of dementia and its major subtypes in an elderly urban Korean population. METHODS: A study population of 1,118 Korean elders was randomly sampled from the residents aged 65 years or older living in Seongnam, Korea. Standardized face-to-face interviews, and neurological and physical examinations were conducted on 714 respondents. Dementia was diagnosed according to the DSM-IV diagnostic criteria, and its subtypes were determined according to the criteria of the NINCDS-ADRDA, the NINDS-AIREN, and the consensus guideline proposed by McKeith et al. [Neurology 1996;47:1113-1124]. RESULTS: The estimated age- and gender-standardized prevalences were 6.3% for dementia (95% CI = 4.5-8.1), 4.8% for Alzheimer's disease (AD; 95% CI = 3.3-6.4), 1.0% for vascular dementia (VD; 95% CI = 0.3-1.8), and 0.4% for dementia with Lewy bodies (DLB; 95% CI = 0.0-0.9). The prevalence of AD consistently increased with age, whereas that of VD peaked at age 75-79 years and decreased thereafter. Of the dementia patients, 72.0% were in the very mild or mild stages of the disease. CONCLUSIONS: The prevalence of dementia in a typical urban area of Korea was estimated to be 6.3%, and AD was the most prevalent subtype. DLB was less prevalent than VD among these community-dwelling Korean elders.

Ankle-to-brachial index and dementia: the Honolulu-Asia Aging Study.

BACKGROUND: Measurement of the ankle-to-brachial index (ABI) is a noninvasive test to assess peripheral arterial disease. A low ABI is a strong correlate of cardiovascular disease and subsequent mortality. Evidence indicates the existence of vascular components in the pathogenesis of dementia. Here, we examine the association of ABI with dementia and subtypes. METHODS AND RESULTS: Data are from the Honolulu-Asia Aging Study (HAAS), a prospective community-based study of 3734 Japanese American men 71 to 93 years of age at baseline in 1991 to 1993. The analysis included 2588 men who were free of dementia at the first assessment, had an ABI measure, and were examined up to 2 more times for dementia between 1994 and 1999. The sample included 240 incident cases of dementia (144 of Alzheimer's disease, 46 of vascular dementia, and 50 of dementia of other causes). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from Cox proportional-hazards models with age as the time scale after adjustment for education, year of birth, high blood pressure, body mass index, diabetes mellitus, cholesterol concentration, smoking status, alcohol consumption, and apolipoprotein E epsilon4 allele. A low ABI was associated with an increased risk of dementia and vascular dementia (HR, 1.66; 95% CI, 1.16 to 2.37; and HR, 2.25; 95% CI, 1.07 to 4.73, respectively). ABI was weakly associated with Alzheimer's disease (HR, 1.57; 95% CI, 0.98 to 2.53), particularly in the apolipoprotein E epsilon4 carriers (HR, 1.43; 95% CI, 1.02 to 1.96). CONCLUSIONS: These results suggest that ABI, a measure of atherosclerosis, is associated with the incidence of total dementia, vascular dementia, and Alzheimer's disease in carriers of the apolipoprotein E epsilon4 allele.

Dementia with Lewy bodies in an elderly Greek male due to alpha-synuclein gene mutation.

We report the case of an elderly man of Greek background who presented with progressive cognitive decline and motor parkinsonism on a background of a strong family history of Parkinson's disease. Associated symptoms included visual hallucinations, excessive daytime drowsiness, recurrent falls, orthostatic hypotension and urinary incontinence. His major clinical symptoms and signs fulfilled consensus criteria for a clinical diagnosis of dementia with Lewy bodies. An alpha-synuclein gene mutation analysis for the G209A substitution was positive. We conclude that the alpha-synuclein (G209A) gene mutation genotype should be considered in the differential diagnosis of dementia with Lewy bodies, particularly in patients with European ancestry and a family history of Parkinson's disease.

Influence of neuroticism, ethnicity, familism, and social support on perceived burden in dementia caregivers: pilot test of the transactional stress and social support model.

In this study we assessed the new transactional stress and social support model, postulating the role of neuroticism, ethnicity, familism, and social support in perceived burden in dementia caregivers. We used a convenience sample (N=77) of African American and White dementia caregivers. Results substantiated interrelationships among social support variables, and the influence of perceived positive social support on burden. Neuroticism was related to the perception of positive social support and burden. Results corroborated the model, focusing on neuroticism and quality of social support in modeling perceived burden in family caregivers. Findings call attention to the role of presumably long-standing individual differences in neuroticism that influence caregiver appraisals of stress and social support.

Familial Lewy body diseases.

Lewy body disease includes clinically and pathologically defined disorders in which Lewy bodies occur in the nervous system. In recent years, the molecular features of these disorders have been emerging. Several genetic loci have been identified in association with familial Lewy body disease; however, the genetic risks underlying most cases of familial Lewy body disease remain to be discovered. The fact that Lewy bodies stain strongly with antibodies to asynuclein and that mutations in the alpha-synuclein gene lead to syndromes in which parkinsonism and dementia occur gives us important clues regarding the biologic processes leading to disease. Pursuit of additional mendelian causes of familial Lewy body disease and study of the factors contributing to the complex phenotypes associated with Lewy body disorders will elucidate underlying disease pathways and, thus, possible targets for therapeutic intervention.