Dementia With Lewy Bodies Patients Research Articles

Ligand Profiling as a Diagnostic Tool to Differentiate Patient-Derived α-Synuclein Polymorphs.

Amyloid fibrils are characteristic of many neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. While different diseases may have fibrils formed of the same protein, the supramolecular morphology of these fibrils is disease-specific. Here, a method is reported to distinguish eight morphologically distinct amyloid fibrils based on differences in ligand binding properties. Eight fibrillar polymorphs of α-synuclein (αSyn) were investigated: five generated de novo using recombinant αSyn and three generated using protein misfolding cyclic amplification (PMCA) of recombinant αSyn seeded with brain homogenates from deceased patients diagnosed with Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Fluorescence binding assays were carried out for each fibril using a toolkit of six different ligands. The fibril samples were separated into five categories based on a binary classification of whether they bound specific ligands or not. Quantitative binding measurements then allowed every fibrillar polymorph to be uniquely identified, and the PMCA fibrils derived from PD, MSA, and DLB patients could be unambiguously distinguished. This approach constitutes a novel and operationally simple method to differentiate amyloid fibril morphologies and to identify disease states using PMCA fibrils obtained by seeding with patient samples.

Grey matter networks in women and men with dementia with Lewy bodies

Sex differences permeate many aspects of dementia with Lewy bodies (DLB), yet sex differences in patterns of neurodegeneration in DLB remain largely unexplored. Here, we test whether grey matter networks differ between sexes in DLB and compare these findings to sex differences in healthy controls. In this cross-sectional study, we analysed clinical and neuroimaging data of patients with DLB and cognitively healthy controls matched for age and sex. Grey matter networks were constructed by pairwise correlations between 58 regional volumes after correction for age, intracranial volume, and centre. Network properties were compared between sexes and diagnostic groups. Additional analyses were conducted on w-scored data to identify DLB-specific sex differences. Data from 119 (68.7 ± 8.4 years) men and 45 women (69.9 ± 9.1 years) with DLB, and 164 healthy controls were included in this study. Networks of men had a lower nodal strength compared to women. In comparison to healthy women, the grey matter networks of healthy men showed a higher global efficiency, modularity, and fewer modules. None of the network measures showed significant sex differences in DLB. Comparing DLB patients with healthy controls revealed global differences in women and more local differences in men. Modular analyses showed a more distinct demarcation between cortical and subcortical regions in men compared with women. While topologies of grey matter networks differed between sexes in healthy controls, those sex differences were diluted in DLB patients. These findings suggest a disease-driven convergence of neurodegenerative patterns in women and men with DLB, which may inform precision medicine in DLB.

Progressive QTc prolongation and reduced heart rate variability in dementia with Lewy bodies compared to Alzheimer's disease

IntroductionAutonomic dysfunction (AuD) is a significant clinical challenge in patients with Dementia with Lewy Bodies (DLB). Manifestations of AuD such as orthostatic hypotension (OH) is associated with falls and decreased quality of life. Cardiac autonomic denervation is an early phenomenon in DLB and a potential contributor to OH. This retrospective study was undertaken to explore whether routine ECG tracings could be used to identify signs of autonomic dysfunction in DLB. Methods18 patients with DLB and 18 age-matched patients with Alzheimer's disease (AD) were included. ECGs and clinical data were analyzed retrospectively for heart rate variability (HRV) and QTc interval prolongation. ResultsDuring an average of 10 years observation time (first to last ECG recording), the QTc interval increased in the DLB group, but not in the AD group. HRV was significantly lower at end of follow-up in the DLB group than in the AD group. DLB patients with OH had greater QTc prolongation. ConclusionLongitudinal ECG analysis indicates that signs of AuD in DLB are reflected on routine ECG tracings. If confirmed in larger cohorts, this could influence risk stratification and help direct preventive measures.

Focused Ultrasound Thalamotomy for Tremor Relief in Atypical Parkisnsonism.

Magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) VIM-thalamotomy has established efficacy and safety in tremor relief in patients with essential tremor and Parkinson's disease. The efficacy and safety in patients with atypical parkinsonism have not been reported. To report on the efficacy and safety of FUS VIM-thalamotomy in 8 patients with parkinsonism, multiple system atrophy-Parkinsonian type (MSA-P) (n = 5), and dementia with Lewy bodies (DLB) (n = 3). Tremor was assessed in the treated hemibody using the Clinical Rating Scale for Tremor (CRST). The motor Unified MSA Rating Scale (UMSAR) was used in the MSA-P and motor sections of the Unified Parkinson's Disease Rating Scale (UPDRS-III) in DLB patients. Cognition was measured using the Montreal Cognitive Assessment (MoCA). In MSA-P and DLB patients, there was immediate tremor relief. CRST scores measured on the treated side improved compared to baseline. During the follow-up of up to 1 year tremor reduction persisted. The change in CRST scores at different time points did not reach statistical significance, probably due to the small sample size. Adverse events were transient and resolved within a year. In our experience, FUS VIM-thalamotomy was effective in patients with MSA-P and DLB. Larger, controlled studies are needed to verify our preliminary observations.

Efficacy and safety of donepezil in patients with dementia with Lewy bodies: results from a 12-week multicentre, randomised, double-blind, and placebo-controlled phase IV study.

Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase. Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937). The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.

Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism.Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR.On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB.These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Diagnostic value of CSF chromogranin A to discriminate between Alzheimer's disease and dementia with Lewy bodies.

Chromogranin A (CgA) seems to be involved in the pathophysiology of different neurodegenerative pathologies such as Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB). CgA is present in the aggregates of amyloid plaques and in Lewy bodies but CgA also has a function in neuroinflammatory processes via microglia. Our objective was to determine if there is a difference in the CgA concentration in the cerebrospinal fluid (CSF) of AD and DLB patients and whether the CgA concentration can discriminate between the two diseases. Using the previously described AlphaLewyMA cohort, we included 117 patients with a CSF CgA assay: 15 control subjects (CS group), 64 DLB patients, 17 AD patients and 21 patients with both AD and probable DLB criteria (AD/DLB group). CgA concentration was assessed using the MSD platform. CSF CgA was increased in the AD and AD/DLB groups compared with the DLB group (p = 0.0006 between AD and DLB, p = 0.0013 between AD/DLB and DLB). No significant difference in CgA concentration was found between DLB and CS. ROC curve analysis showed an area under the curve of 0.791 between AD and DLB. CgA concentrations were correlated with t-Tau and P-Tau regardless of the pathology (for Tau: p = 0.022 for AD; p < 0.0001 for DLB; p = 0.004 for AD/DLB; for P-Tau: p = 0.032 for AD; p < 0.0001 for DLB; p = 0.0009 for AD/DLB). Aβ42 was positively correlated with CgA in the DLB group but not in the AD and AD/DLB groups (for DLB: p < 0.0001; for AD: p = 0.57; for AD/DLB: p = 0.58). CSF CgA concentrations are increased in AD but not in DLB and correlate with P-Tau and Tau whatever the disease. These results suggest a link between tauopathy/neurodegeneration and CgA.

Autophagy Markers Are Altered in Alzheimer's Disease, Dementia with Lewy Bodies and Frontotemporal Dementia.

The accumulation of protein aggregates defines distinct, yet overlapping pathologies such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). In this study, we investigated ATG5, UBQLN2, ULK1, and LC3 concentrations in 66 brain specimens and 120 plasma samples from AD, DLB, FTD, and control subjects (CTRL). Protein concentration was measured with ELISA kits in temporal, frontal, and occipital cortex specimens of 32 AD, 10 DLB, 10 FTD, and 14 CTRL, and in plasma samples of 30 AD, 30 DLB, 30 FTD, and 30 CTRL. We found alterations in ATG5, UBQLN2, ULK1, and LC3 levels in patients; ATG5 and UBQLN2 levels were decreased in both brain specimens and plasma samples of patients compared to those of the CTRL, while LC3 levels were increased in the frontal cortex of DLB and FTD patients. In this study, we demonstrate alterations in different steps related to ATG5, UBQLN2, and LC3 autophagy pathways in DLB and FTD patients. Molecular alterations in the autophagic processes could play a role in a shared pathway involved in the pathogenesis of neurodegeneration, supporting the hypothesis of a common molecular mechanism underlying major neurodegenerative dementias and suggesting different potential therapeutic targets in the autophagy pathway for these disorders.

Quantitative EEG in the Differential Diagnosis of Dementia Subtypes.

Most neurodegenerative dementias present with substantial overlap in clinical features. Therefore, differential diagnosis is often a challenging task necessitating costly and sometimes invasive diagnostic procedures. A promising, non-invasive and cost-effective method is the widely available electroencephalography (EEG). Twenty-three subjects with Alzheimer's disease (AD), 28 subjects with dementia with Lewy bodies (DLB), 15 subjects with frontotemporal dementias (FTDs), and 22 healthy controls (HC) were enrolled. Nineteen channel computerized EEG recordings were acquired. Mean relative powers were calculated using the standard frequency bands. Theta/alpha ratio (TAR), theta/beta ratio (TBR), a spectral index of (alpha + beta)/(theta + delta) and an alpha reactivity index (alpha in eyes-open condition/alpha in eyes-closed condition) were also calculated. Receiver operating characteristic (ROC) analyses were performed to assess diagnostic accuracy. For the comparison of EEG measures across groups, we performed a multivariate ANOVA followed by univariate ANOVAs controlling for the effects of age, with post hoc tests. Theta power and TBR were increased in DLB compared to other groups. Alpha power was decreased in DLB compared to HC and FTD; and in AD compared to FTD. Beta power was decreased in DLB compared to AD and HC. Furthermore, regional analyses demonstrated a unique pattern of theta power increase in DLB; affecting frontal, central, parietal, occipital, and temporal regions. In AD, theta power increased compared to HC in parietal, occipital, and right temporal regions. TAR was increased in DLB compared to other groups; and in AD compared to HC. Finally, alpha reactivity index was higher in DLB compared to HC and FTD. In AD, EEG slowing was associated with cognitive impairment, while in DLB, this was associated with higher DLB characteristics. In the ROC analyses to distinguish DLB from FTD and AD, measures of EEG slowing yielded high area under curve values, with good specificities. Also, decreased alpha reactivity could distinguish DLB from FTD with good specificity. EEG slowing in DLB showed a diffuse pattern compared to AD, where a posterior and temporal slowing predominated. We showed that EEG slowing was satisfactory in distinguishing DLB patients from AD and FTD patients. Notably, this slowing was a characteristic finding in DLB patients, even at early stages, while it paralleled disease progression in AD. Furthermore, EEG slowing in DLB showed a diffuse pattern compared to AD, where a posterior and temporal slowing predominated. These findings align with the previous evidence of the diencephalic dysfunction in DLB.

Neural basis of writing in prodromal to mild dementia with lewy bodies.

We have previously demonstrated difficulties in written production in dementia with Lewy bodies (DLB) patients. We now aim to determine the neural correlates of writing production in DLB, combining clinical data and structural MRI measures. Sixteen prodromal to mild DLB patients were selected to participate in the study. The GREMOTS test was used to assess writing production. Using three-dimensional T1 brain MRI images, correlations between the GREMOTS test and grey matter (GM) volume were performed using voxel-based morphometry (VBM; SPM12, XjView and Matlab R2021b softwares). VBM analysis (p<0.001, uncorrected) revealed a positive and significant correlation between both left anterior insula and left supramarginal gyrus GM volumes and DLB patients' ability to write logatoms using the phonological route. The handwriting deficit was negatively and significantly correlated to the supplementary motor area. The parkinsonism-like characteristics of agraphia were negatively and significantly correlated with both right anterior and right posterior cerebellum GM volumes. Our study also revealed a negative and significant correlation between grammatical spelling impairments and an area of the orbitofrontal gyrus, and a negative and significant correlation between supramarginal gyrus and general slowness in dictation tasks. Writing disorders in early DLB patients appears to be GM decreases in several brain regions, such as the left anterior insula, the left supramaginal gyrus, as well as two areas of the right cerebellum.

Characterization of de novo Dementia with Lewy Body with different duration of rapid eye movement sleep behavior disorder

BackgroundCognitive disorder, parkinsonism, autonomic dysfunction (AuD) and rapid eye movement sleep behavior disorder (RBD) can occur prior to or simultaneously with Dementia with Lewy Body (DLB) onset. RBD is generally linked with progressive neurodegenerative traits. However, associations between RBD with DLB, RBD without DLB, and RBD duration effects on DLB symptoms remain unclear. ObjectivesTo examine DLB symptom frequency and subtypes in RBD, and explore the effects of different RBD onset times on symptoms in de novo DLB patients. MethodsIn this multicenter investigation, we consecutively recruited 271 de novo DLB patients. All had standardized clinical and comprehensive neuropsychological evaluations. Subgroup analyses, performed based on the duration of RBD confirmed by polysomnography before the DLB diagnosis, we compared the proportion of patients with cognitive impairment, parkinsonism, and AuD features between groups. ResultsParkinsonism and AuD incidences were significantly elevated in DLB patients with RBD when compared with patients without RBD. Subgroup analyses indicated no significant differences in parkinsonism between DLB patients who developed RBD ≥10 years prior to the DLB diagnosis and DLB patients without RBD. The incidence of non-tremor-predominant parkinsonism and AuD was significantly higher in DLB patients whose RBD duration before the DLB diagnosis was <10 years when compared with DLB patients without RBD. ConclusionsWe identified significant symptom and phenotypic variability between DLB patients with and without RBD. Also, different RBD duration effects before the DLB diagnosis had a significant impact on symptomatic phenotypes, suggesting the existence of a slowly progressive DLB neurodegenerative subtype.

Sex differences in brain atrophy in dementia with Lewy bodies.

Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n=327; 73±8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n=165; 69±9 years, 72% males). We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

Separating Alzheimer’s disease from Dementia with Lewy bodies using a volumetric MRI classifier

AbstractBackgroundSeparating Alzheimer’s dementia (AD) from dementia with Lewy bodies (DLB) can be challenging, especially in DLB patients with concomitant AD pathology. It is imperative to distinguish the diseases for optimal patient management. To date, no single MRI feature can accurately separate the two diseases. This study examines whether a linear combination of regional atrophy measures can differentiate cognitively normal (CN), AD, and DLB patients.MethodWe computed volumes of 70 brain regions using an automatic segmentation tool. For each region, we derived age, sex, and head size‐dependent z‐scores. A linear classifier with all brain regions was used to predict if a patient belonged to CN, AD, or DLB. Diagnoses were based on international consensus criteria and CSF‐biomarkers. The classifier was tested in 327 CN (mean age 67±10y, 48%F), 501 AD (70±9y, 49%F), and 99 DLB (69±7y, 15%F) patients from three cohorts (ADNI, PredictND, ADC). The ADC cohort was assessed separately, as almost all DLB patients were from the ADC. In addition, we assessed classification performance in a subgroup of DLB patients with AD‐like CSF (DLB+, n = 57). Performance was evaluated using 10‐fold cross‐validation.ResultPerformance measures for the classifier are summarized in Table 1. The classifier accuracy was assessed in the three‐class classification task and in two‐class classifications where one of the groups was excluded from the analysis. The balanced accuracy in the three‐class classification was 67% for the DLB group and the DLB+ subgroup. For AD vs. DLB, the AUC was 0.77(95% CI:0.70‐0.82), for AD vs. DLB+ AUC was 0.72(0.64‐0.80). The classifier correctly classified CN and AD patients more often than DLB patients (Table 2). Most DLB+ patients were misclassified as AD. The hippocampus was the best single region for distinguishing AD vs. DLB, with an AUC of 0.70(0.64‐0.76).ConclusionThe joint classifier achieved high accuracy in separating AD vs. DLB patients. Although the accuracy was lower, the classifier could distinguish DLB patients with concomitant AD pathology from AD. Next, we will combine different brain regions to discern disease‐specific patterns and add clinical data to the classifier to improve differential diagnostic accuracy for DLB and DLB with concomitant AD pathology.

Statistical analysis to identify MRI markers for Alzheimer’s Disease: why moving towards AI?

AbstractBackgroundAlzheimer’s disease (AD) is characterized by progressive neurodegeneration of some brain structures and cognitive function decline. To evaluate the anatomical changes, structural Magnetic Resonance Imaging (sMRI) is a non‐invasive examination and allows the quantification of brain atrophy. Some of the affected structures could be common with other dementia types such as frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). The objective of this work is to identify specific affected structures in patients with AD to healthy individuals, and to patients suffering from FTD and DLB. This is a part of a larger effort to develop methods to better diagnose AD and to find specific markers of this dementia type.MethodThe ADDIA clinical study (EU‐H2020 project led by Firalis company) enrolled 800 participants and was designed to obtain high‐quality samples for the discovery of novel biomarkers for early and differential diagnosis of AD. The sMRI of 623 participants with the above‐mentioned pathologies and healthy individuals were analyzed and the volume of different areas measured with the software FreeSurfer. Statistics were performed to define significant differences in brain volumes between groups.ResultOne hundred and twelve brain areas were analyzed for volume by study participant. Compared with a healthy population, the atrophy of structures observed in AD patients almost completely overlaps with the one observed in DLB and FTD patients. When the DLB and FTD groups are compared to a healthy population, one brain area is specific in DLB patients and fifty‐eight in FTD patients. However, on these fifty‐eight affected brain areas, forty‐seven overlap with the mild AD patient group.ConclusionThe measurement from imaging modality is not enough precise to report biomarkers as affected areas specific to the type of dementia. However, a promising framework lies in the application of machine and deep learning algorithms on a set of modalities: imaging, clinical and omics. These new tools allow for a finer understanding of data and a personalized approach to diagnosis. In preparation for this multimodal integration framework, the above categories of algorithms will be applied on MRI images. This will permit to discriminate AD from other dementia types at the individual level.

Data‐driven analysis of most common neurodegenerative dementias reveals atrophy patterns associated with overlapping cognitive symptoms

AbstractBackgroundA precise understanding of the neuroanatomical basis of clinical manifestation of dementia is an important step for timely diagnosis. Dementia due to proteinopathies, such as Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Frontotemporal dementia (FTD), have different yet overlapping atrophy patterns which could account for their overlapping clinical presentations. To disentangle these relationships and facilitate timely differential diagnosis, we estimated distinct and overlapping atrophy patterns and associated them with cognitive deficits.MethodWe included 1702 AD (age = 66.1±8.3), 319 FTD (age = 63.3±7.7), 213 DLB (age = 69.7±7.0), and 1330 subjective cognitive decline (SCD) (age = 59.8±9.0) participants from the Amsterdam Dementia Cohort. MRIs were processed with Freesurfer and outputs were manually checked. Scanner‐related bias in outputs was corrected using NeuroHarmony pipeline. Participants’ cognition was evaluated using standardized neuropsychological tests. Z‐scores for cognitive domains of memory, executive functioning, attention, language, and visuospatial functioning were derived using SCD group as reference. We estimated distinct and overlapping atrophy patterns in each disease by computing odds ratio in each region, using SCD group as reference. Furthermore, we computed group‐wise Pearson partial correlation between the (sub‐)cortical measures and cognition while correcting for confounding effects of age, sex, and education level.ResultAtrophy in bilateral inferior temporal, and right hippocampus was more prevalent in AD and FTD patients than in DLB patients (Figures 1‐3). Temporal pole atrophy was more prevalent in FTD than in AD or DLB patients. Superior parietal and supra marginal atrophy was more prevalent in AD than in FTD or DLB patients. Bilateral hippocampus and amygdala atrophy associated with memory impairment in AD, whereas left hemisphere atrophy associated with memory impairment in FTD. Frontal atrophy associated with worse executive functioning and attention in FTD, but not in AD. Language deficit associated with left temporal lobe atrophy in both FTD and AD. Visuospatial dysfunction associated with parietal lobe atrophy in both AD and FTD. In DLB, we observed no significant correlation between atrophy and cognitive deficits.ConclusionWe identified distinct and overlapping atrophy patterns and associations of atrophy patterns with cognitive deficits in AD, FTD, and DLB. These data‐driven insights are crucial for accurate diagnosis and prognosis.

ATN Cerebrospinal Fluid Biomarkers in Dementia with Lewy Bodies: Initial Results from the United States Dementia with Lewy Bodies Consortium

AbstractBackgroundNeuropathological hallmarks of AD, amyloid plaques and neurofibrillary tangles, have been described in dementia with Lewy bodies (DLB). Less is known about changes in pre‐mortem cerebrospinal fluid (CSF) amyloid and tau biomarker status in DLB. CSF biomarkers for amyloid (A), tau (T), and neurodegeneration (N) can be utilized to define pre‐mortem pathological status. The overall aim of this investigation was to utilize the ATN research framework to characterize pre‐mortem AD‐related pathology longitudinally in a rigorously characterized cohort of DLB from the Dementia with Lewy Bodies Consortium (DLBC) study. Our hypothesis was that ATN biomarkers would identify DLB with coexistent AD and ATN status would remain the same after 12 months.MethodCerebrospinal fluid (CSF) samples from an AD/ADRD cohort were obtained from the Cleveland Alzheimer’s Disease Research Center (CADRC), Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank (CBH‐biobank) and DLBC. CSF Aβ40, Aβ42, Aβ42/40 (A), p‐Tau181 (T), and t‐Tau (N), were evaluated. The cohort was subtyped by CSF ATN category and sub‐group of DLB cases were neuropathologically evaluated. A sub‐cohort of DLB cases had longitudinal data with an evaluation at baseline and 12 months later.ResultDLB patients who were positive for both CSF Aβ42/40 (A+) and p‐Tau181 (T+) remained positive from baseline to 12 months. In contrast, some DLB patients who were positive for CSF Aβ42/40 (A+), but negative for p‐Tau181 (T‐), changed from CSF Aβ42/40 positive to negative at 12 months (p‐value = 0.0153) in the A+T‐N‐ and A+T‐N+ group. Findings from a small DLB subgroup with post‐mortem neuropathologic analyses indicated that most of the cases that were p‐Tau181 positive (T+) also had high Braak stage.ConclusionThese findings suggest that DLB patients who are positive for CSF Aβ42/40 (A+), but negative for p‐Tau181 (T‐), may have CSF Aβ42/40 levels that can fluctuate over time. In the small DLB subgroup with post‐mortem neuropathologic analysis, there appeared to be a relationship between AD pathologic change and ATN findings that warrants further study in a larger autopsied cohort to fully understand the relationship between ATN status and underlying AD neuropathologic change in DLB.

Clinical Validation and Correlates of the Cingulate Island Sign Visual Rating Scale for the Diagnosis of Dementia with Lewy Bodies

AbstractBackgroundThe cingulate island sign (CIS) is a metabolic pattern on [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) associated with dementia with Lewy bodies (DLB). The aim of this study was to validate the visual CIS rating scale (CISRs) for the diagnosis of DLB and to explore the clinical correlates.MethodThis single‐center, retrospective study included 166 consecutive patients with DLB and 161 patients with Alzheimer’s disease (AD). The CIS on [18F]FDG‐PET scans was rated using the CISRs (0‐4) independently by three readers blinded to other patient data.ResultThe optimal cut‐off to differentiate DLB from AD was a CISRs score ≥ 1 (sensitivity = 66%, specificity = 84%) whereas a CISRs score ≥ 2 (sensitivity = 58%, specificity = 92%) was optimal to differentiate amyloid positive DLB (n = 43 (82.7%)) and AD. To identify DLB with abnormal (n = 53 (72.6%)) versus normal (n = 20 (27.4%)) dopamine transporter imaging (DaT), a CISRs cut‐off of 4 had a specificity of 95% for abnormal DaT. DLB patients with a CISRs score of 4 performed significantly better in tests of free verbal recall and picture based cued recall, but worse in test of processing speed compared with DLB with a CISRs score of 0.ConclusionThis study confirms the CISRs as a valid marker for the diagnosis of DLB with a high specificity and a lower, but acceptable, sensitivity. Concomitant AD pathology does not influence diagnostic accuracy of the CISRs. In DLB patients, presence of CIS is associated with relative preserved memory function and impaired processing speed.

Plasma biomarkers of Alzheimer´s disease in the continuum of dementia with Lewy bodies

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aβ), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aβ40, Aβ42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aβ40/42. Lower Aβ40/42 indicates increased Aβ pathology. Plasma Aβ40, Aβ42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aβ and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p&lt;0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p&lt;0.001) and NfL (p&lt;0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p&lt;0.001). After accounting for age, plasma Aβ40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

Using spatial transcriptomics to investigate region‐specific gene expression in J20 mice

AbstractBackgroundAlzheimer’s disease (AD) and dementia with Lewy bodies (DLB) share various pathological and symptomatic traits. As such, providing an accurate diagnosis of DLB can be difficult, ultimately impacting patient support and care. It is therefore imperative to establish biomarkers which reliably differentiate between disease states. Plasma‐derived exosomes appear to be promising in this regard. Exosomes are extracellular vesicles, containing cargos from the cell from which they originate. Increased concentrations of exosomal disease‐associated proteins, such as p‐T181‐tau and Aβ‐42, have previously been associated with cognitive decline and disease progression among AD patients (Winston et al., 2016; Kapogiannis et al., 2019).MethodWe aim to quantify exosome‐associated proteins from AD patients, DLB patients and healthy controls in order to establish exosomal signatures to differentiate between disease states. Exosomes are being isolated using differential ultracentrifugation. Nanoparticle track analysis (NTA) and western blots are being used to verify isolation, and ELISA assays against p‐T181‐tau, Aβ‐42 and α‐synuclein will be used to quantify proteins of interest. Plasma samples are being collected at baseline and after a 6 month follow‐up period in order to monitor the stability of these potential biomarkers.ResultTo date, full ethics approval has been granted for this study, and the differential ultracentrifugation protocol has been established. Successful isolation of particles in the size range of exosomes (30 – 100nm) has been confirmed using NTA. ELISA assays will be undertaken in the up‐coming months, with the aim of collecting and analysing baseline results by May 2023.ConclusionExosomes already appear to be a reliable, and relatively non‐invasive biomarker for assessing disease state and progression among dementia patients. Our preliminary findings have shown successful isolation, and we believe the findings could be invaluable with regards to improved diagnosis options for DLB.

White matter changes in the cholinergic system in Alzheimer’s disease and dementia with Lewy bodies

AbstractBackgroundThe early degeneration of the cholinergic nucleus basalis of Meynert (NBM) and its cortical projections is a hallmark of both dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). In addition to the NBM, the other major cholinergic projection system originates in the pedunculopontine nucleus (PPN) and provides innervation to the thalamus. Given that visual hallucinations are a hallmark of DLB, but not AD, and have recently been attributed to thalamic degeneration, we tested whether the PPN projection system is differentially altered in DLB compared to AD.MethodsNBM‐cortical and PPN‐thalamus white matter pathways were tracked using diffusion‐weighted imaging data from 46 patients with AD, 48 with DLB, 35 with mild cognitive impairment (MCI) with AD, 38 with MCI with Lewy bodies, and 71 control participants. A free‐water corrected DTI model was estimated. Free water fraction along the cholinergic pathways was compared between groups controlling for age, sex, and free water fraction from a white matter control mask. Multiple linear regression was applied to test associations with cognitive function, core Lewy body symptoms with a focus on visual hallucinations, and changes in cognition using longitudinal follow‐up data.ResultsFree water fraction in the NBM lateral pathway was increased in both dementia and MCI groups compared to controls and this was associated with performance on overall cognition and phonemic fluency tests as well as with longitudinal changes in cognition (Figure 1). Free water fraction along the PPN‐thalamus tract was increased only in DLB patients while it appeared relatively spared in AD and this increase in the Lewy body patients was related to the presence of visual hallucinations (Figure 2). These results were largely replicated in an independent validation cohort (34 AD, 34 DLB, 35 controls).ConclusionOur cross‐validated findings show that the cholinergic input to the thalamus from the PPN is selectively affected in DLB and contributes to visual hallucinations.