Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

Patients with dementia with Lewy bodies (DLB) may have overlapping Alzheimer's disease pathology. We investigated the longitudinal rate of tau accumulation and its association with neurodegeneration and clinical disease progression in DLB.

β-Amyloid (Aβ) pathology is common in patients with probable dementia with Lewy bodies (DLB). However, the pathologic basis and the differential diagnostic performance of Aβ PET are not established in DLB. Our objective was to investigate the pathologic correlates of 11C-Pittsburgh compound B(PiB) uptake on PET in cases with antemortem diagnosis of probable DLB or Lewy body disease (LBD) at autopsy.

Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.(1,2) At autopsy, α-synuclein-positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease-related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.(2) The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD). A recent genetic association study examining known hits from PD and AD identified variants at both the α-synuclein (SNCA) and APOE loci as influencing the individual risk to DLB.(3) These findings would suggest that DLB may be a distinct disease with shared genetic risk factors with PD and AD.

The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.

We examined the temporal sequence of the core features in probable dementia with Lewy bodies (DLB).

Magnetic resonance spectroscopy (MRS) characteristics of dementia with Lewy bodies (DLB) Alzheimer's disease (AD) and cognitively normal controls were compared. DLB (n = 34), AD (n = 35), and cognitively normal controls (n = 148) participated in a MRS study from frontal, posterior cingulate, and occipital voxels. We investigated DLB patients with preserved hippocampal volumes to determine the MRS changes in DLB with low probability of overlapping AD pathology. DLB patients were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) in the occipital voxel. AD patients were characterized by lower NAA/Cr in the frontal and posterior cingulate voxels. Normal NAA/Cr levels in the frontal voxel differentiated DLB patients with preserved hippocampal volumes from AD patients. DLB and AD patients had elevated choline/creatine, and myo-Inositol/creatine in the posterior cingulate. MRS abnormalities associated with loss of neuronal integrity localized to the occipital lobes in DLB, and the posterior cingulate gyri and frontal lobes in AD. This pattern of MRS abnormalities may have a role in differential diagnosis of DLB and in distinguishing DLB patients with overlapping AD pathology.

Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer's disease pathology in the form of amyloid-β plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of Alzheimer's disease co-pathology on functional network changes within the default mode network (DMN) in DLB. Second, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 Alzheimer's disease and 99 cognitively unimpaired participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), amyloid-β-PET with Pittsburgh compound-B (PiB) and resting-state functional MRI scans. The resing-state functional MRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir PET and PiB PET standardized uptake value ratio (SUVr). The strength of interregional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and cold spots) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot and cold spots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r = -0.39, P = 0.04) and amyloid-PET uptake (r = -0.41, P = 0.03) in the DLB group, i.e. patients with DLB who have more concurrent Alzheimer's disease pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in cognitively unimpaired, Alzheimer's disease and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVrs in the target region, whereas higher functional connectivity to the tau cold spot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of Alzheimer's disease co-pathology in patients with DLB is associated with more Alzheimer's disease-like changes in functional connectivity. Furthermore, we found an association between the brain's functional network architecture and the distribution of tau pathology that has recently been described in Alzheimer's disease. We show that this relationship also exists in patients with DLB, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.

Dementia with Lewy bodies (DLB) is characterized by preserved whole brain and medial temporal lobe volumes compared with Alzheimer's disease dementia (AD) on magnetic resonance imaging. However, frequently coexistent AD-type pathology may influence the pattern of regional brain atrophy rates in DLB patients. We investigated the pattern and magnitude of the atrophy rates from 2 serial MRIs in autopsy-confirmed DLB patients (n = 20) and mixed DLB/AD patients (n = 22), compared with AD (n = 30) and elderly nondemented control subjects (n = 15), followed antemortem. DLB patients without significant AD-type pathology were characterized by lower global and regional rates of atrophy, similar to control subjects. The mixed DLB/AD patients displayed greater atrophy rates in the whole brain, temporoparietal cortices, hippocampus and amygdala, and ventricle expansion, similar to AD patients. In the DLB and DLB/AD patients, the atrophy rates correlated with Braak neurofibrillary tangle stage, cognitive decline, and progression of motor symptoms. Global and regional atrophy rates are associated with AD-type pathology in DLB, and these rates can be used as biomarkers of AD progression in patients with LB pathology.

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.

To predict the risk of probable dementia with Lewy bodies (DLB) competing with Alzheimer disease (AD) dementia by hippocampal volume (HV) in patients with mild cognitive impairment (MCI) with impairments in amnestic or nonamnestic cognitive domains.

Patients with probable dementia with Lewy bodies (DLB) often have Alzheimer's disease (AD)-related pathology. Our objective was to determine the pattern of positron emission tomography (PET) tau tracer AV-1451 uptake in patients with probable DLB, compared to AD, and its relationship to β-amyloid deposition on PET.

Many patients with dementia with Lewy bodies (DLB) have overlapping Alzheimer's disease (AD)-related pathology, which may contribute to white matter (WM) diffusivity alterations on diffusion tensor imaging (DTI). Consecutive patients with DLB (n = 30), age- and sex-matched AD patients (n = 30), and cognitively normal controls (n = 60) were recruited. All subjects underwent DTI, 18F 2-fluoro-deoxy-d-glucose, and (11)C Pittsburgh compound B positron emission tomography scans. DLB patients had reduced fractional anisotropy (FA) in the parietooccipital WM but not elsewhere compared with cognitively normal controls, and elevated FA in parahippocampal WM compared with AD patients, which persisted after controlling for β-amyloid load in DLB. The pattern of WM FA alterations on DTI was consistent with the more diffuse posterior parietal and occipital glucose hypometabolism of 2-fluoro-deoxy-d-glucose positron emission tomography in the cortex. DLB is characterized by a loss of parietooccipital WM integrity, independent of concomitant AD-related β-amyloid load. Cortical glucose hypometabolism accompanies WM FA alterations with a concordant pattern of gray and WM involvement in the parietooccipital lobes in DLB.

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

Excessive daytime sleepiness is a commonly reported problem in dementia with Lewy bodies (DLB). We examined the relationship between nighttime sleep continuity and the propensity to fall asleep during the day in clinically probable DLB compared to Alzheimer's disease (AD) dementia.

Reduced nigrostriatal uptake on N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-[123I]iodophenyl) nortropane (123I-FP-CIT) SPECT reflects dopamine dysfunction, while other imaging markers could be complementary when used together. We assessed how well 123I-FP-CIT SPECT differentiates dementia with Lewy bodies (DLBs) from Alzheimer's disease dementia (ADem) and whether multimodal imaging provides additional value. 123I-FP-CIT SPECT, magnetic resonance imaging, [18F]2-fluoro-deoxy-D-glucose-positron emission tomography (PET), and 11C-Pittsburgh compound B (PiB)-PET were assessed in 35 participants with DLBs and 14 participants with ADem (autopsy confirmation in 9 DLBs and 4 ADem). Nigrostriatal dopamine transporter uptake was evaluated with 123I-FP-CIT SPECT using DaTQUANT software. Hippocampal volume was calculated with magnetic resonance imaging, cingulate island sign ratio with FDG-PET, and global cortical PiB retention with PiB-PET. The DaTQUANT z-scores of the putamen showed the highest c-statistic of 0.916 in differentiating DLBs from ADem among the analyzed imaging biomarkers. Adding another imaging modality to 123I-FP-CIT SPECT had c-statistics ranging from 0.968 to 0.975, and 123I-FP-CIT SPECT in combination with 2 other imaging modalities presented c-statistics ranging from 0.987 to 0.996. These findings suggest that multimodal imaging with 123I-FP-CIT SPECT aids in differentiating DLBs and ADem and in detecting comorbid Lewy-related and Alzheimer's disease pathology in patients with DLBs and ADem.

Visually preserved metabolism in posterior cingulate cortex relative to hypometabolism in precuneus and cuneus, the cingulate island sign, is a feature of dementia with Lewy bodies (DLB) on FDG-PET. Lower cingulate island sign ratio (posterior cingulate cortex/cuneus+precuneus; FDG-CISr) values have been associated with a higher Braak neurofibrillary tangle stage in autopsied DLB. Using voxel-wise analysis, we assessed the patterns of regional cortical perfusion and metabolism, and using an atlas-based approach, we measured perfusion cingulate island sign ratio on arterial spin labeling MRI (ASL-CISr), and its associations with FDG-CISr, uptake on tau-PET and clinical severity in DLB. Our study sample (n = 114) included clinically probable DLB patients (n = 19), age-matched patients with probable Alzheimer's disease dementia (AD; n = 19) and matched controls (n = 76) who underwent MRI with 3-dimensional pseudo-continuous arterial spin labeling, 18F-FDG-PET and 18F-AV-1451 tau PET. Patterns of cortical perfusion and metabolism were derived from quantitative maps using Statistical Parametric Mapping. DLB patients showed hypoperfusion on ASL-MRI in precuneus, cuneus and posterior parieto-occipital cortices, compared to controls, and relatively spared posterior cingulate gyrus, similar to pattern of hypometabolism on FDG-PET. DLB patients had higher ASL-CISr and FDG-CISr than AD patients (p <0.001). ASL-CISr correlated with FDG-CISr in DLB patients (r = 0.67; p =0.002). Accuracy of distinguishing DLB from AD patients was 0.80 for ASL-CISr and 0.91 for FDG-CISr. Lower ASL-CISr was moderately associated with a higher composite medial temporal AV-1451 uptake (r = -0.50; p =0.03) in DLB. Lower perfusion in precuneus and cuneus was associated with worse global clinical scores. In summary, the pattern of cortical hypoperfusion on ASL-MRI is similar to hypometabolism on FDG-PET, and respective cingulate island sign ratios correlate with each other in DLB. Non-invasive and radiotracer-free ASL-MRI may be further developed as a tool for the screening and diagnostic evaluation of DLB patients in a variety of clinical settings where FDG-PET is not accessible.

The clinical and pathological phenotypes of Dementia with Lewy Bodies (DLB) and Alzheimer's disease (AD) often overlap. We examined whether plasma lipids differed among individuals with autopsy-confirmed Lewy Body pathology or AD pathology.

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson's disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.