Risk For Dementia With Lewy Bodies Research Articles

Impact of Mild Behavioral Impairment and Mild Cognitive Impairment on Risk for Dementia

AbstractBackgroundThere has been a shift in research to explore early indicators associated with preclinical/prodromal dementia. Recent research highlights the importance of non‐cognitive factors, such as neuropsychiatric symptoms (NPS), as articulated in criteria for mild behavioral impairment (MBI). Previous research suggests MBI is a risk factor for dementia regardless of if one is cognitively healthy or diagnosed with mild cognitive impairment (MCI). The goal of this study is to examine risk for dementia subtypes based on the presence of MBI and/or MCI.MethodSecondary data analysis of participants (n = 17,289) from the National Alzheimer’s Coordinating Center who were cognitively healthy (n = 11,770) or diagnosed with MCI (n = 5,519). Risk for dementia, Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) were examined using Cox proportional hazard models.ResultAlmost 25% of the entire sample met the operationalized diagnostic criteria for MBI (n = 4,274). The risk for dementia almost tripled among persons with MBI and increased by almost seven‐fold if they had MCI. Among persons with MBI, the risk for FTD was six times greater and the risk for DLB and AD was three times greater, compared to those without MBI. Additionally, for participants who had MCI, the risk for DLB was six times greater, the risk for AD was over nine times greater, and the risk for FTD was almost sixteen times greater, compared to those who were cognitively healthy. There was a significant interaction found between MBI and MCI status. For cognitively healthy older adults with MBI, the risk was almost eleven times greater for FTD, whereas for older adults with MCI and MBI, the risk was three times greater for DLB.ConclusionOlder adults with MBI and MCI are at an increased risk for all types of dementia. Additionally, cognitively healthy participants with MBI are found to have a greater risk for FTD, where participants with MCI and MBI had a greater risk for DLB. These results provide support for MBI as a prodromal state of all‐cause dementia, and highlight the importance of recognizing these symptoms across the spectrum of cognitive decline.

Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures

Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.

Effect of GBA gene variants on clinical characteristics of dementia with Lewy bodies: a review and meta-analyses

Glucocerebrosidase (GBA) gene may be a risk factor for dementia with Lewy bodies (DLB). However, due to the small number of existing studies and the small sample size of previous investigations, it is necessary to conduct objective and quantitative analyses of the association between GBA variants and DLB. There is no consensus regarding the relationship between GBA and the clinical characteristics of DLB. Therefore, we conducted multiple systematic reviews and meta-analyses with a particular focus on the age of onset, sex, and cognitive impairment. PubMed, Cochrane, and EMBASE databases were searched to retrieve related studies. The odds ratios and 95% confidence interval were calculated to determine the association between GBA and DLB and between GBA and the clinical characteristics of DLB. Our meta-analysis confirmed that the GBA variant rate was significantly higher in the DLB group than in the control group, as were the variant rates of L444P, N370S, and E326K, whereas the variant rate of T369M showed no significant difference between the groups. Furthermore, the relevant literature was summarised again for meta-analyses. The GBA variant group had a younger age of onset and lower Montreal Cognitive Assessment score than the GBA non-variant group in DLB patients. GBA variants do not differ between sexes in DLB patients. GBA variants increased the risk of DLB, especially N370S, E326K, and L444P which are strongly associated with DLB, but T369M was not. Patients harbouring GBA variants have an earlier age of onset, more severe cognitive impairment, and rapid symptom progression; however, sex is irrelevant in DLB.

The association of APOE ‐ε4 with clinicopathological, cognitive, neuropsychiatric, and neuroimaging features in α‐synucleinopathies

The ε4-allele of apolipoprotein E (APOE-ε4) presents an elevated risk not only for Alzheimer's disease (AD), but also for Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). Indeed, the independent influence of APOE-ε4 on the promotion and exacerbation of α-synuclein pathology has recently been suggested. However, the precise phenotypic associations of APOE-ε4 in α-synucleinopathies are variable. The primary objective of this first, comprehensive systematic review was to identify biomarkers, phenotypes, or other clinicopathological characteristics that reliably associate with APOE-ε4 in α-synucleinopathies [Parkinson's disease (PD), DLB, PDD, and multiple system atrophy (MSA)], which may in turn uncover important pathophysiological mechanisms.Electronic databases were systematically searched from January 1st , 1995 through December 31st , 2020, as per the PRISMA guidelines. Studies evaluating the association of APOE-ε4 with clinicopathological, cognitive, neuropsychiatric, and neuroimaging phenotypes in clinically and/or pathologically diagnosed cases of PD, PDD, DLB, and MSA cases were reviewed.A total of 136 studies were eligible for inclusion (Figure). APOE-ε4 was found to be consistently associated with: 1) lower cerebrospinal fluid levels of amyloid-β 1-42 in PDD and DLB, 2) cognitive deficits in the memory domain in PD, PDD, and DLB, 3) mediotemporal cortical atrophy primarily in DLB, 3) cerebral amyloid angiopathy, shorter survival, and accelerated decline in global cognition in DLB, as well as 4) the co-occurrence of AD-type neuropathological features. Furthermore, APOE-ε4 was associated, albeit inconsistently, with: 1) the presence and severity of diffuse neocortical Lewy body pathology and, 2) elevated tracer retention on amyloid positron emission tomography in PD, PDD, and DLB, 3) greater odds of dementia in PD, and 4) other genetic and pathophysiological factors to enhance the cumulative risk for DLB. APOE-ε4 was not associated with disease risk or α-synuclein pathology in MSA. Studies also highlighted the relationship of APOE-ε4 with neuropsychiatric, epigenetic (DNA methylation), sleep, immunohistochemical, and biochemical factors in α-synucleinopathies, which will be presented.In addition to its role in AD, APOE-ε4 influences the disease presentation and progression particularly in PDD and DLB. Guided by reliable biomarkers, further research to unravel the underlying mechanisms will assist in developing early prevention strategies targeting the APOE protein.

501 - Prediction of Mild Cognitive Impairment (MCI) progression to Alzheimer Disease (AD) or Dementia with Lewy Bodies (DLB): Is this possible neuropsychologically?

Objective:Aim of the present review study was to describe and compare the neurocognitive features of MCI which could predict its progression to DLB vs AD.Background:Progression of MCI to AD or DLB is a relatively recent field of study with emphasis on the clinical or neuropsychological features of MCI which could potentially predict its progression to specific types of dementia.Methods:A literature review in the Pubmed database has been made, after the year 2005, using the key- words: neuropsychological assessment; MCI; AD; DLB; progression to dementia. Seventeen relevant articles have been found.Results:Data from most studies supports that, in MCI, impairment in executive, attentional and visuospatial functions, as well as letter fluency and fluctuating concentration are mainly related to progression to DLB. In contrast, prominent episodic and recognition memory deficits are mostly found in MCI which progresses in AD. Furthermore, non-amnestic MCI has been related most often to progression in DLB, whereas the amnestic type to AD, although memory loss may not necessarily predict the development of AD. Nevertheless, fewer studies suggest that MCI-DLB is related to cognitive profile similar to that of MCI-AD, while cognitive scoring alone does not accurately predict MCI-DLB vs MCI-AD. Interestingly, quantitative electroencephalogram has been found to help in predicting the progression of MCI to DLB, while preservation of hippocampal volume is associated with increased risk of DLB vs AD, especially in non-amnestic MCI. Moreover, specific patterns on neuroimaging MCI may predict progression to AD in contrast to DLB.Conclusions:Predicting the progression of MCI to AD or DLB based on neuropsychological profiles is challenging and useful for early therapeutic interventions. More studies are needed, since there are some conflicting findings and, at present, the combination of clinical symptoms with neurocognitive assessment and neuroimaging is the ideal method for the prediction of MCI progression to various types of dementia.

Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies.

Background:Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity.Objective:We tested if genetic variants in part explain the heterogeneity in DLB.Methods:We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer’s disease (AD-PRS) and Parkinson’s disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer’s dementia cohort and compared them to 2,552 control subjects. The p-tau/Aβ1–42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration.Results:We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features.Conclusion:These finding increase our understanding of the pathological and clinical heterogeneity in DLB.

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.

Pareidolias and cognition in isolated REM sleep behavior disorder

BackgroundThough visual illusions and hallucinations are common in dementia with Lewy bodies (DLB) and Parkinson's disease (PD), they are not typically observed clinically in prodromal stages, including isolated REM sleep behavior disorder (iRBD). False-noise errors on the pareidolia test (seeing faces when none are present) may be an effective measure of susceptibility to future hallucinations in iRBD. MethodsOne hundred patients with iRBD underwent the 20-image pareidolia test. Clinical markers were assessed and a neuropsychological battery was administered. An exploratory analysis on the impact of pareidolic errors on phenoconversion was also performed. ResultsIn our cohort, 17 patients (17%) made false-noise pareidolic errors. These patients had significantly lower total Montreal Cognitive Assesment (MoCA) scores (26.7 ± 2.3 vs. 24.4 ± 2.6, B = −1.88, 95% CI: [-3.17, −0.59]), with lower subcomponent MoCA scores on memory and visuospatial-executive sections. Pareidolic errors were also associated with lower visuospatial, attention/executive, and memory scores on the neuropsychological tests. Furthermore, after 1.6 years follow-up, 3/16 (19%) patients making pareidolic errors had phenoconverted at time of publication compared to 6/71 (8%) patients who did not make errors. ConclusionPareidolic errors in patients with iRBD are associated with poorer overall cognition and may indicate higher risk of DLB.

Traumatic Brain Injury and Age of Onset of Dementia with Lewy Bodies.

Traumatic brain injury (TBI) with loss of consciousness (LOC) has been associated with earlier onset of mild cognitive impairment, frontotemporal dementia, Parkinson's disease, and Alzheimer's disease (AD), but has not been examined as a risk factor for earlier onset of dementia with Lewy bodies (DLB). The purpose of this study was to assess the association between a history of TBI and the age of onset of DLB. Data from 576 subjects with a clinical diagnosis of DLB were obtained from the National Alzheimer's Coordinating Center (NACC). Analyses of Covariance examined whether self-reported history of remote TBI with LOC (i.e., >1 year prior to the first Alzheimer's Disease Center visit) was associated with earlier DLB symptom onset. Controlling for sex, those with a history of remote TBI had an approximately 1.5-year earlier clinician-estimated age of onset (F = 0.87, p = 0.35) and 0.75-years earlier age of diagnosis (F = 0.14, p = 0.71) of DLB compared to those without a history of TBI, though the differences did not reach statistical significance. Analysis of subjects with autopsy-confirmed diagnoses was underpowered due to the low number of TBI+ subjects. Remote TBI with LOC was not significantly associated with DLB onset, despite being a significant risk factor for cognitive decline and earlier age of onset in other neurodegenerative conditions. Replication of these results using a larger cohort of DLB subjects with and without a TBI history who have undergone autopsy is indicated, as our TBI+ subjects did show a slightly earlier onset of about 1.5 years. Further investigations into other potential DLB risk factors are also warranted.

A comprehensive screening of copy number variability in dementia with Lewy bodies.

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.

A Nonsynonymous Mutation in PLCG2 Reduces the Risk of Alzheimer's Disease, Dementia with Lewy-Bodies and Frontotemporal Dementia, and Increases the Likelihood of Longevity

Background: PLCG2 plays an important role in immune system signaling, and is expressed in several immune cell types including microglia in the brain. In 2017, the genetic variant rs72824905 (p.Pro522Arg) in the PLCG2 gene (Phospholipase C Gamma 2) was associated with a reduced risk of Alzheimer's disease (AD). Here we investigated whether the rs72824905 variant had a similar protective effect on six other brain diseases. We further tested if rs72824905 increases the likelihood of longevity, since a reduced risk of neurodegenerative diseases might associate with general survival. Methods: We investigated the effect of carrying rs72824905 on disease risk in a total of 53,627 patients with one of seven brain diseases. We studied AD (N = 4,985), frontotemporal dementia (FTD) (N = 2,437), dementia with Lewy-bodies (DLB) (N = 1,446), progressive supranuclear palsy (PSP) (N = 882), Parkinson's disease (PD) (N = 28,448) amyotrophic lateral sclerosis (ALS) (N = 10,953) and multiple sclerosis (MS) (N = 4,476) by comparing them with in total 149,290 controls using logistic regression models. Next, we studied the effect of carrying rs72824905 on longevity by comparing individuals who reached at least 90 years (N = 3,516) with individuals who died before age 90 years or were last screened before 90 years (N = 9,677). In addition, we studied the association of rs72824905 with survival after the age of 90 in a subset of long-lived individuals followed until death. Finally, we supported our findings by studying by-proxy phenotypes in the ~450.000 participants of the UK Biobank. We associated the rs72824905 genotypes of UK Biobank participants with parental history of dementia as proxy for dementia and as a proxy for longevity we studied parental age over 90 as well as parental age over 95 years of age. All individuals were of European ancestry. Results: The rs72824905-G allele associated with a reduced AD risk (Odds ratio (OR) = 0·57, p = 4·7×10-4), a reduced DLB risk (OR = 0·54, p = 4·5×10-2) and reduced FTD risk (OR = 0·61, p = 1·0×10 2). We did not find evidence for association of rs72824905 with the risks of PSP (OR = 1·46, p = 0·19), PD (OR = 1·18, p = 0·10), ALS (OR = 1·07, p = 0·26) or MS (OR = 0·99, p = 0·95). The rs72824905-G allele was associated with a 1·49 increased likelihood of reaching >90 years (p = 6.4×10-3): variant carriers lived longer after the age of 90 years, median 4.7 (inter quartile range = 1·9 - 7·4) years compared to non-carriers 3.3 (IQR = 1·4 - 5·8) (Hazard ratio = 0·75, p = 0·07). By-proxy analyses supported the associations of rs728824905 with dementia as well as longevity. Variant carriers had a lower likelihood of having a parent with dementia (OR = 0·88, p = 1·8×10 3) and had a significantly increased likelihood of having a parent aged >95 years (OR = 1·19, p = 2·1×10-2). Conclusions: Our results show that rs72824905 in PLCG2 protects from AD, DLB and FTD and increases the likelihood of longevity. Together, our findings highlight a central role for PLCG2 related immune signaling in the brain, which should be the subject of future studies as a drug target for multiple brain diseases. Funding Statement: The authors present a short description of 16 cohorts, often including multiple sites or studies, that contributed to this manuscript and their funding sources in Supplementary Table 1: Amsterdam dementia Cohort (ADC), 100-Plus study, German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe), Brain compendium, Clinical AD, Sweden, Danish data, Fundacio ACE (FACE), Genetics of Healthy Ageing Study (GEHA – NL), Gothenburg Birth Cohort (GBC) Studies, International FTD-Genomics Consortium (IFGC), Kompetenznetz Multiple Sklerose (KKNMS), Longitudinal Aging Study Amsterdam (LASA), Leiden Longevity Study, Maria Carolina Dalmasso, Mayo Clinic AD, DLB, PD, PSP, NDRU cohort, Oviedo, Pascual Sanchez-Juan, Project MinE, Risk and modifying factors in Fronto Temporal Dementia (RiMoD-FTD): follows The SPIN cohort, San Sebastian, UK Biobank analysis, IPDGC (The International Parkinson Disease Genomics Consortium). Declaration of Interests: The authors declare no competing interest related to this work. Ethics Approval Statement: Studies were approved by corresponding ethics committees and informed consent was obtained for all participants.

THE DISTINCT CONTRIBUTION OF SNCA-3′UTR TO PARKINSON’S AND DEMENTIA WITH LEWY BODIES

The alpha-synuclein (SNCA) gene has been implicated in the etiology of Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Both diseases share a common pathological hallmark, Lewy bodies (LBs) and Lewy-related neurites however, each disease presents distinct characteristics. Furthermore, GWAS results reported that variants defining the genetic association of the SNCA gene with PD are distinct from those SNCA-variants associated with DLB. However, the common and diverse molecular mechanisms by which SNCA genetic variants exert their effects on PD and DLB are not fully understood. A computational analysis of the SNCA-3’UTR was completed to identify potential microRNA binding-sites. Next, we used two complementary approaches. We determined the expression profiles of microRNAs that are predicted to interact with the SNCA-3’UTR in isogenic iPSCs-derived dopaminergic and cholinergic neurons that are primarily involved in PD and DLB, respectively. In addition, we performed a deep-sequencing analysis of the SNCA-3’UTR using DNA samples from autopsy confirmed cases of PD, DLB, and matched normal controls, aiming to identify genetic variability in the 3’UTR that is associated, with the neuropathological diagnoses. We identified four highly conserved microRNA binding-sites in the SNCA 3’UTR, and observed a neuronal-type specific expression profile for each microRNA in the different isogenic iPSC-derived neurons, i.e. dopaminergic vs. cholinergic neurons. In the mature cholinergic neurons, the levels of the miR-140–3p.1 and miR-223–3p were dominant. While, in mature dopaminergic neurons miR-7–5p showed the highest expression by wide-margin, followed by miR-223–3p, and miR-153–3p. Furthermore, we found that the short-structural variant rs33988309-polyT was moderately and distinctively associated with DLB but not with PD. We suggest that neuronal type-specific mechanisms regulate SNCA gene expression and involve the contribution of both cis and trans acting factors. In support of a trans acting factor, our data showed differential expression of microRNAs in pathology-relevant cells proposing that different microRNAs regulate SNCA-mRNA expression levels in a neuronal-type specific manner. As an example of a cis acting factor, we discovered a genetic variant in the SNCA-3’UTR that specifically affects DLB risk, implying that distinct genetic variability in the SNCA gene may contribute to synucleinopathies in a pathology-specific manner.

LRRK2 variation and dementia with Lewy bodies

IntroductionThe leucine-rich repeat kinase 2 (LRRK2) gene contains several variants that cause Parkinson's disease (PD) and others that modify PD risk. However, little is known about the role of LRRK2 in dementia with Lewy bodies (DLB). Aims of this study were to screen DLB patients for pathogenic LRRK2 variants and to evaluate associations between common LRRK2 variants and risk of DLB. Methods417 clinical DLB patients and 1790 controls were included in the primary analysis. Additionally, 355 Lewy body disease patients assessed as having a high likelihood of clinical DLB based on neuropathological findings were included in secondary analysis. Seven pathogenic LRRK2 variants were assessed in patients, while 17 common LRRK2 exonic variants and 1 GWAS-nominated common LRRK2 PD-risk variant were evaluated for association with DLB. ResultsWe identified carriers of 2 different pathogenic LRRK2 variants. One clinical DLB patient was a p.G2019S carrier, while in the pathological high likelihood DLB series there was one carrier of the p.R1441C mutation. However, examination of clinical records revealed the p.R1441C carrier to have PD with dementia. Evaluation of common variants did not reveal any associations with DLB risk after multiple testing adjustment. However, a non-significant trend similar to that previously reported for PD was observed for the protective p.N551K-R1398H-K1423K haplotype in the clinical DLB series (OR: 0.76, P = 0.061). ConclusionLRRK2 does not appear to play a major role in DLB, however further study of p.G2019S and the p.N551K-R1398H-K1423K haplotype is warranted to better understand their involvement in determining DLB risk.

MAPT haplotype H1G is associated with increased risk of dementia with Lewy bodies

IntroductionThe MAPT H1 haplotype has been associated with several neurodegenerative diseases. We were interested in exploring the role of MAPT haplotypic variation in risk of dementia with Lewy bodies (DLB). MethodWe genotyped six MAPT haplotype tagging SNPs and screened 431 clinical DLB cases, 347 pathologically defined high-likelihood DLB cases, and 1049 controls. ResultWe performed haplotypic association tests and detected an association with the protective H2 haplotype in our combined series (odds ratio [OR] = 0.75). We fine-mapped the locus and identified a relatively rare haplotype, H1G, that is associated with an increased risk of DLB (OR = 3.30, P = .0017). This association was replicated in our pathologically defined series (OR = 2.26, P = .035). DiscussionThese results support a role for H1 and specifically H1G in susceptibility to DLB. However, the exact functional variant at the locus is still unknown, and additional studies are warranted to fully explain genetic risk of DLB at the MAPT locus.

Dementia with Lewy bodies: The emerging role of primary care

ABSTRACTIntroduction: Dementia with Lewy bodies (DLB) is an under recognized but frequent subtype of dementia. Misdiagnosis and delays in referral from primary care are common when compared to other forms of dementia.Case: We present a case of a 63-year-old man who was eventually diagnosed with DLB three and a half years after his initial presentation.Discussion: Core features of DLB such as hallucinations, Parkinsonism and fluctuating levels of cognition need to be recognized in primary care as being part of the DLB phenotype. DLB is a complex and debilitating neurodegenerative disorder often requiring multidisciplinary support to enable affected individuals to live well in the community. Carers of DLB patients often develop higher levels of subjective burden compared to carers of patients with other forms of dementia; this needs to be recognized and managed appropriately. There is limited research into the role of primary care physicians in DLB. Efforts should be made to reduce delays in identification.Conclusion: Primary care has an important role in identifying those who are at risk for DLB and in referring these patients timely to the appropriate specialist. Adequate management of these patients in the community might reduce the burden associated with the DLB phenotype.

MULTIMODALITY IMAGING FOR EARLY DIAGNOSIS OF DEMENTIA WITH LEWY BODIES

The differential diagnosis of patients with Alzheimer's disease (AD) dementia and dementia with Lewy bodies (DLB) is challenging, because the underlying pathology is frequently complex with contribution from both AD and Lewy body disease pathologies. The potential for disease-modifying treatments for AD dementia, as well as the responsiveness to cholinesterase inhibitor treatment and marked neuroleptic sensitivity of DLB patients generate the need for surrogate markers for AD and Lewy body disease pathologies early in the course in DLB. Multimodality imaging provides complementary information on the contribution of AD and Lewy body disease pathologies in patients with DLB. Mild cognitive impairment (MCI) patients with non-amnestic features, especially those with REM sleep behavior disorder (RBD) progress more frequently to DLB than AD, however many MCI patients at risk for DLB also have additional AD pathology. Multimodality imaging in MCI patients with non-amnestic features and/or RBD was investigated. We Identified patients with MCI with non-amnestic features and/or RBD (MCI-DLB/AD) who underwent MRI, FDG PET, amyloid PET and DaTScan studies. The association of hippocampal volumes, amyloid load, DLB signature on FDG PET (cingulate island sign) and DaTScan with RBD and memory function in MCI was tested. Imaging findings associated with AD such as hippocampal atrophy and amyloid load on PET is associated with memory impairment in MCI-DLB/AD. On the contrary, patients with MCI-DLB/AD who have RBD have less hippocampal atrophy and amyloid load than those who do not have RBD, but they are more likely to have the DLB signature on FDG PET (cingulate island sign) and an abnormal DaTScan. Imaging markers of Lewy body disease and AD may provide complementary information in characterizing the underlying pathologies and their contribution to cognitive impairment in patients with MCI who are at an increased risk for DLB. Determining the contribution of Lewy body disease and AD pathologies to MCI would have important implications for secondary prevention of dementia in these individuals.

Risk factors for dementia with Lewy bodies

To determine the risk factors associated with dementia with Lewy bodies (DLB). We identified 147 subjects with DLB and sampled 2 sex- and age-matched cognitively normal control subjects for each case. We also identified an unmatched comparison group of 236 subjects with Alzheimer disease (AD). We evaluated 19 candidate risk factors in the study cohort. Compared with controls, subjects with DLB were more likely to have a history of anxiety (odds ratio; 95% confidence interval) (7.4; 3.5-16; p < 0.0001), depression (6.0; 3.7-9.5; p < 0.0001), stroke (2.8; 1.3-6.3; p = 0.01), a family history of Parkinson disease (PD) (4.6; 2.5-8.6; p < 0.0001), and carry APOE ε4 alleles (2.2; 1.5-3.3; p < 0.0001), but less likely to have had cancer (0.44; 0.27-0.70; p = 0.0006) or use caffeine (0.29; 0.14-0.57; p < 0.0001) with a similar trend for alcohol (0.65; 0.42-1.0; p = 0.0501). Compared with subjects with AD, subjects with DLB were younger (72.5 vs 74.9 years, p = 0.021) and more likely to be male (odds ratio; 95% confidence interval) (5.3; 3.3-8.5; p < 0.0001), have a history of depression (4.3; 2.4-7.5; p < 0.0001), be more educated (2.5; 1.1-5.6; p = 0.031), have a positive family history of PD (5.0; 2.4-10; p < 0.0001), have no APOE ε4 alleles (0.61; 0.40-0.93; p = 0.02), and to have had an oophorectomy before age 45 years (7.6; 1.5-39; p = 0.015). DLB risk factors are an amalgam of those for AD and PD. Smoking and education, which have opposing risk effects on AD and PD, are not risk factors for DLB; however, depression and low caffeine intake, both risk factors for AD and PD, increase risk of DLB more strongly than in either.

History of a suspected delirium is more common in dementia with Lewy bodies than Alzheimer's disease: a retrospective study

Delirium is common and is associated with an increased risk of dementia. However, it is not clear whether delirium confers increased risk of any particular type of dementia. We performed a retrospective study of Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) to ascertain whether a suspected episode of preceding delirium was more common prior to diagnosis in either type of dementia. The study was carried out in a tertiary referral unit for the diagnosis of dementia. Clinic letters from the first presentation to the unit of 85 cases with DLB and 95 cases of AD were reviewed for documentation of any previous episodes of suspected delirium. In this study, 25% of DLB cases had at least one reported episode of suspected delirium as compared to 7% of AD cases (p = 0.001). For the DLB cases who had a prior suspected delirium, 23% had more than one episode compared with 14% of the AD group. The median time between most recent suspected episode of delirium and diagnosis of dementia in both groups was less than a year A greater proportion of those presenting and diagnosed with DLB had a documentation of a suspected delirium than those diagnosed with AD. Delirium may lead to a higher risk of DLB as opposed to other forms of dementia, or delirium may, at least in some cases, represent the early stages of DLB. These data suggest that a diagnosis of DLB should be specifically considered in those presenting with a delirium.

Familial Aggregation of Dementia With Lewy Bodies

Familial aggregation of dementia with Lewy bodies (DLB) remains unclear. To determine the degree of family aggregation of DLB by comparing DLB risk between siblings of probands with clinically diagnosed DLB and siblings of probands with clinically diagnosed Alzheimer disease in a cohort of Caribbean Hispanic families and to explore the degree of aggregation of specific clinical manifestations (ie, cognitive fluctuations, visual hallucinations, and parkinsonism) in DLB. Familial cohort study. Academic research. We separately compared risks of possible DLB, probable DLB, and clinical core features of DLB (cognitive fluctuations, visual hallucinations, and parkinsonism) between siblings of probands with clinically diagnosed DLB (n = 344) and siblings of probands with clinically diagnosed Alzheimer disease (n = 280) in 214 Caribbean Hispanic families with extended neurologic and neuropsychological assessment. We applied general estimating equations to adjust for clustering within families. In these models, age and proband disease status were independent variables, and disease status of siblings was the measure of disease risk and the dependent variable. Compared with siblings of probands having clinically diagnosed Alzheimer disease, siblings of probands having clinically diagnosed DLB had higher risks of probable DLB (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.04-5.04) and visual hallucinations (2.32; 1.16-4.64). They also had increased risks of possible DLB (OR, 1.51; 95% CI, 0.97-2.34) and cognitive fluctuations (1.55; 0.95-2.53). Dementia with Lewy bodies and core features of DLB aggregate in families. Compared with siblings of probands having clinically diagnosed AD, siblings of probands having clinically diagnosed DLB are at increased risks of DLB and visual hallucinations. These findings are an important step in elucidating the genetic risk factors underlying DLB and in delineating DLB from other neurodegenerative diseases, such as Alzheimer disease.

Familial aggregation of dementia with lewy bodies

Background Familial aggregation of dementia with Lewy bodies (DLB) remains unclear. Objectives To determine the degree of family aggregation of DLB by comparing DLB risk between siblings of probands with clinically diagnosed DLB and siblings of probands with clinically diagnosed Alzheimer disease in a cohort of Caribbean Hispanic families and to explore the degree of aggregation of specific clinical manifestations (ie, cognitive fluctuations, visual hallucinations, and parkinsonism) in DLB. Design Familial cohort study. Setting Academic research. Patients We separately compared risks of possible DLB, probable DLB, and clinical core features of DLB (cognitive fluctuations, visual hallucinations, and parkinsonism) between siblings of probands with clinically diagnosed DLB (n = 344) and siblings of probands with clinically diagnosed Alzheimer disease (n = 280) in 214 Caribbean Hispanic families with extended neurologic and neuropsychological assessment. Main Outcome Measures We applied general estimating equations to adjust for clustering within families. In these models, age and proband disease status were independent variables, and disease status of siblings was the measure of disease risk and the dependent variable. Results Compared with siblings of probands having clinically diagnosed Alzheimer disease, siblings of probands having clinically diagnosed DLB had higher risks of probable DLB (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.04-5.04) and visual hallucinations (2.32; 1.16-4.64). They also had increased risks of possible DLB (OR, 1.51; 95% CI, 0.97-2.34) and cognitive fluctuations (1.55; 0.95-2.53). Conclusions Dementia with Lewy bodies and core features of DLB aggregate in families. Compared with siblings of probands having clinically diagnosed AD, siblings of probands having clinically diagnosed DLB are at increased risks of DLB and visual hallucinations. These findings are an important step in elucidating the genetic risk factors underlying DLB and in delineating DLB from other neurodegenerative diseases, such as Alzheimer disease.