DLBC Research Articles

Clinicopathological Heterogeneity of Lewy Body Diseases: The Profound Influence of Comorbid Alzheimer's Disease.

In recent years, proposals have been advanced to redefine or reclassify Lewy body disorders by merging the long-established entities of Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). These proposals reject the International DLB Consortium classification system that has evolved over three decades of consensus collaborations between neurologists, neuropsychologists and neuropathologists. While the Consortium's "one year rule" for separating PD and DLB has been criticized as arbitrary, it has been a pragmatic and effective tool for splitting the continuum between the two entities. In addition to the decades of literature supporting the non-homogeneity of PD and DLB, it has become increasingly apparent that Lewy body disorders may fundamentally differ in their etiology. Most PD subjects, as well as most clinically-presenting DLB subjects, might best be classified as having a "primary synucleinopathy" while most clinically-unidentified DLB subjects, who also have concurrent neuropathology-criteria AD (AD/DLB), as well as those with neuropathological AD and amygdala-predominant LBD insufficient for a DLB diagnosis, may best be classified as having a "secondary synucleinopathy. Importantly, the DLB Consortium recognized the importance of comorbid AD pathology by defining "Low", "Intermediate" and "High" subdivisions of DLB based on the relative brain stages of both Lewy body and AD pathology. If the one-year rule for separating PD from DLB, and for then dividing DLB into subtypes based on the presence and severity of comorbid AD pathology, is effective, then the divided groups should statistically differ in important ways. In this study we used the comprehensive clinicopathological database of the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) to empirically test this hypothesis. Furthermore, we used multivariable statistical models to test the hypothesis that comorbid AD neuropathology is a major predictor of the presence and severity of postmortem Lewy synucleinopathy. The results confirm the clinicopathological heterogeneity of Lewy body disorders as well as the profound influence of comorbid AD pathology.

Cerebrovascular and Alzheimer's disease biomarkers in dementia with Lewy bodies and other dementias.

Co-pathologies are common in dementia with Lewy bodies and other dementia disorders. We investigated cerebrovascular and Alzheimer's disease co-pathologies in patients with dementia with Lewy bodies in comparison with patients with mild cognitive impairment, Alzheimer's disease, mixed dementia, vascular dementia or Parkinson's disease with dementia and cognitively unimpaired participants. We assessed the association of biomarkers of cerebrovascular and Alzheimer's disease co-pathologies with medial temporal atrophy and global cognitive performance. Additionally, we evaluated whether the findings were specific to dementia with Lewy bodies. We gathered a multi-cohort dataset of 4549 participants (dementia with Lewy bodies = 331, cognitively unimpaired = 1505, mild cognitive impairment = 1489, Alzheimer's disease = 708, mixed dementia = 268, vascular dementia = 148, Parkinson's disease with dementia = 120) from the MemClin Study, Karolinska Imaging in Dementia Study, Gothenburg H70 Birth Cohort Studies and the European DLB Consortium. Cerebrovascular co-pathology was assessed with visual ratings of white matter hyperintensities using the Fazekas scale through structural imaging. Alzheimer's disease biomarkers of β-amyloid and phosphorylated tau were assessed in the cerebrospinal fluid for a subsample (N = 2191). Medial temporal atrophy was assessed with visual ratings and global cognition with the mini-mental state examination. Differences and associations were assessed through regression models, including interaction terms. In dementia with Lewy bodies, 43% had a high white matter hyperintensity load, which was significantly higher than that in cognitively unimpaired (14%), mild cognitive impairment (26%) and Alzheimer's disease (27%), but lower than that in vascular dementia (62%). In dementia with Lewy bodies, white matter hyperintensities were associated with medial temporal atrophy, and the interaction term showed that this association was stronger than that in cognitively unimpaired and mixed dementia. However, the association between white matter hyperintensities and medial temporal atrophy was non-significant when β-amyloid was included in the model. Instead, β-amyloid predicted medial temporal atrophy in dementia with Lewy bodies, in contrast to the findings in mild cognitive impairment where medial temporal atrophy scores were independent of β-amyloid. Dementia with Lewy bodies had the lowest performance on global cognition, but this was not associated with white matter hyperintensities. In Alzheimer's disease, global cognitive performance was lower in patients with more white matter hyperintensities. We conclude that white matter hyperintensities are common in dementia with Lewy bodies and are associated with more atrophy in medial temporal lobes, but this association depended on β-amyloid-related pathology in our cohort. The associations between biomarkers were overall stronger in dementia with Lewy bodies than in some of the other diagnostic groups.

Association of CSF α-Synuclein Seeding Amplification Assay Results With Clinical Features of Possible and Probable Dementia With Lewy Bodies.

The clinical diagnosis of dementia with Lewy bodies (DLB) depends on identifying significant cognitive decline accompanied by core features of parkinsonism, visual hallucinations, cognitive fluctuations, and REM sleep behavior disorder (RBD). Hyposmia is one of the several supportive features. α-Synuclein seeding amplification assays (αSyn-SAAs) may enhance diagnostic accuracy by detecting pathologic αSyn seeds in CSF. In this study, we examine how different clinical features associate with CSF αSyn-SAA positivity in a large group of clinically diagnosed participants with DLB. Cross-sectional and longitudinal CSF samples from the multicentered observational cohort study of the DLB Consortium and similar studies within the Parkinson's Disease Biomarker Program, contributed by academic medical centers in the United States, underwent αSyn-SAA testing. Participants included those clinically diagnosed with DLB and 2 control cohorts. Associations between core DLB features and olfaction with αSyn-SAA positivity were evaluated using logistic regression. CSF samples from 191 participants diagnosed with DLB (mean age 69.9 ± 6.8, 15% female), 50 age-matched and sex-matched clinical control participants, and 49 younger analytical control participants were analyzed. Seventy-two percent (137/191) of participants with DLB had positive αSyn-SAAs vs 4% of the control groups. Among participants with DLB, those who were αSyn-SAA-positive had lower Montreal Cognitive Assessment scores (18.8 ± 5.7 vs 21.2 ± 5.2, p = 0.01), had worse parkinsonism on the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (33.8 ± 15.1 vs 25.6 ± 16.4, p = 0.001), were more likely to report RBD (114/133 [86%] vs 33/53 [62%], p < 0.0001), and had worse hyposmia on the University of Pennsylvania Smell Identification Test (UPSIT) (94/105 [90%] below 15th percentile vs 14/44 [32%], p < 0.0001). UPSIT percentile had the highest area under the curve (0.87, 95% CI 0.81-0.94) in predicting αSyn-SAA positivity and participants scoring at or below the 15th percentile of age and sex normative values had 18.3 times higher odds (95% CI 7.52-44.6) of having a positive αSyn-SAA test. Among 82 participants with longitudinal CSF samples, 81 (99%) had the same αSyn-SAA result for initial and follow-up specimens. A substantial proportion of clinically diagnosed participants with DLB had negative αSyn-SAA results. Hyposmia was the strongest clinical predictor of αSyn-SAA positivity. Hyposmia and αSyn-SAA may have utility in improving the diagnostic assessment of individuals with potential DLB. This study provided Class III evidence that CSF αSyn-SAA distinguishes patients with clinically diagnosed DLB from normal controls.

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.

Developing Topics.

Hippocampal and amygdala subfields variably affect cognitive impairment in neurodegenerative diseases. Subfields of these regions can be well segmented using modern neuroimaging tools but their role in neurodegenerative disease is under active investigation. In this study, we identified hippocampal and amygdala subregions predictive of cognitive performance and motor symptoms severity measured by MoCA (Montreal Cognitive Assessment) and MDS-UPDRS III, respectively, in patients with dementia with Lewy Bodies (DLB). We selected all participants with probable DLB (N = 48, mean age = 71±7 years, 15% female) enrolled in the Dementia with Lewy Bodies Consortium (DLBC) as of July 2022, with concurrent measures of 3D T1 MRI sequence, MoCA, and MDS-UPDRS III scores. We performed cortical reconstruction and volumetric segmentation of hippocampal subfields and nuclei of the amygdala using FreeSurfer (v 7.2). We used combat harmonization to account for site and scanner differences. We trained and applied a bootstrapped, bidirectional stepwise regression model of 29 predictor variables comprised of sub-fields and mean cortical thickness against MoCA and MDS-UPDRS III, respectively, with an 80-20 train-test split ratio, and 5000 repetitions, corrected for age and sex. Subfield segmentation is shown in Figure 1A. The best fitting model for MoCA included mean cortical thickness, parasubiculum, hippocampal and amygdala transition area, corticoamygdaloid transition area, and CA3 body (Figure 1B, adjusted R2 = 0.51). The best fitting model for MDS-UPDRS III included the cortical nucleus of the amygdala and CA1 body (Figure 1C, adjusted R2 = 0.22). This model was considered a poor fit. We considered MoCA for further analysis and closely predicted scores in our 20% partitioned test sample (Figure 2A, R2 = 0.38). We report model-based selection of hippocampal and amygdala subfields to predict MoCA scores in DLB. Atrophy in these regions has been associated with global cognitive deficit in mild cognitive impairment and Alzheimer disease cohorts. The model fit for MDS-UPDRS III scores was poor, providing evidence that these brain regions do not serve a role in motor control.

123I‐Ioflupane SPECT Striatal Binding Ratio Predicts Progression of Parkinsonism in a Dementia with Lewy Bodies Cohort

AbstractBackgroundThe criteria for diagnosis of dementia with Lewy bodies (DLB) remain predominantly clinical. However, use of striatal dopamine transporter visualization is suggested as an “indicative” biomarker for DLB under the most recent published DLB criteria (McKeith, Neurology, 2017). The objective of this study is to determine if 123I‐ioflupane SPECT (DaTscan) striatal binding ratio (SBR) correlates with parkinsonian symptoms measured on the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale Part III (MDS‐UPDRS‐III) in patients with either probable DLB or high‐likelihood DLB individuals with mild cognitive impairment (MCI). A secondary aim of this study is to determine if DaTscan SBR measured at baseline can predict progression of parkinsonian symptoms over 2 years in this study population.MethodsThis is a retrospective cohort study using the U.S. Dementia with Lewy Bodies Consortium (DLBC) dataset (U01 NS100610). The sample group included in this study are individuals with either probable DLB (McKeith, Neurology, 2017) or MCI‐LB (McKeith, 2020). Each participant had a baseline DaTscan analyzed with DaTQUANT software and physical examination scored with MDS‐UPDRS‐III. Participants without these data were excluded. Mixed effect models were fit with UPDRS score as the dependent variable and SBR z‐score as the primary independent variable. Data were adjusted for age, gender, diagnosis, and dopaminergic medication at time of examination.ResultsAn analysis between 53 participants’ baseline MDS‐UPDRS‐III and SBR z‐scores revealed a moderate negative correlation, indicating SBR is a significant predictor of baseline MDS‐UPDRS‐III score. An analysis between 23 participants’ baseline SBR z‐scores and 24‐month MDS‐UPDRS‐III revealed a moderate negative correlation, indicating that baseline SBR is a significant predictor of 24‐month MDS‐UPDRS‐III scores.ConclusionThese data reveal a significant relationship between DaTscan SBR and motor examination in DLB. Additionally, there is a significant relationship between baseline SBR and progression of parkinsonian features. We conclude that in DLB, DaTscan at time of diagnosis could be used to confirm underlying dopamine deficiency in the context of clinical parkinsonism and predict progression of parkinsonian symptoms in DLB. This could aid in guiding therapies and prognostication of symptom progression.

Differential performance of cerebrospinal fluid biomarker ratios and formulas to discriminate dementia with Lewy bodies from Alzheimer’s dementia and cognitively healthy people reflects high level of amyloidosis across dementia syndromes

AbstractBackgroundNeurodegeneration is a common hallmark of all dementia syndromes, whereas cerebrospinal fluid amyloid‐β may reflect amyloidosis both in Alzheimer’s dementia (AD) and in dementia with Lewy bodies (DLB). It is unknown if any biomarker profiles may help discriminate DLB from AD.MethodsConsecutive outpatients with probable DLB (fourth consensus report of the DLB Consortium) were paired with outpatients with late‐onset AD (National Institute on Aging – Alzheimer’s Association) by sex, Clinical Dementia Rating and Mini‐Mental State Examination scores, and with cognitively healthy controls by sex and age (±1 year). Genotyping of rs7412 &amp; rs429358 (APOE) was undertaken with TaqMan® Real‐Time PCR technology. Cerebrospinal fluid concentrations of amyloid‐β (Aβ42, Aβ40, Aβ38), α‐synuclein, t‐tau and p‐tau Thr181, were assessed by enzyme‐linked immunosorbent assays. The following ratios and restructured traditional regression formulas were compared among participants: Aβ42/Aβ40, Aβ42/Aβ38, t‐tau/p‐tau, t‐tau/Aβ42, p‐tau/Aβ42, α‐synuclein/Aβ42, t‐tau/α‐synuclein, (240+1.18Xt‐tau)/Aβ42, (3.694+0.0105Xt‐tau)Xp‐tau/Aβ42, (373+0.82Xt‐tau)/Aβ42, (152+8.25Xp‐tau)/Aβ42. In addition, all formulas were considered to correspond to an AD profile if &gt;1, while t‐tau/Aβ42&gt;0.5 and p‐tau/Aβ42&gt;0.08 were also measured, significance at p&lt;0.05.ResultsOverall, 27 participants with DLB (78.48±9.0 years‐old, CDR sum‐of‐boxes 10.96±3.8, eleven APOE‐ε4 carriers) were paired with 27 participants with AD (81.00±5.8 years‐old, CDR sum‐of‐boxes 10.44±3.9, twelve APOE‐ε4 carriers) and 27 controls (78.48±8.7 years‐old, CDR sum‐of‐boxes 0.30±0.8, four APOE‐ε4 carriers); two thirds were women. Only for APOE‐ε4 carriers, t‐tau/Aβ42 (p = 0.065) and t‐tau/α‐synuclein (p = 0.073) were marginally significantly higher in AD. Only for APOE‐ε4 non‐carriers, Aβ42/Aβ38 was higher (p = 0.009) and α‐synuclein/Aβ42 was lower (p = 0.043) in DLB. The t‐tau/Aβ42&gt;0.5 (p = 0.039) and p‐tau/Aβ42&gt;0.08 (p = 0.042) ratios were able to discriminate patients with AD from controls, but not from patients with DLB, regardless of APOE‐ε4 carrier status. All formulas were able to discriminate patients with AD from controls (p&lt;0.02), but only (152+8.25Xp‐tau)/Aβ42&gt;1 was able to discriminate patients with AD from patients with DLB (p = 0.025), regardless of APOE‐ε4 carrier status.ConclusionsAmyloidosis and neurodegeneration are modulated by APOE‐ε4 carrier status and may differentially affect the discriminative power of cerebrospinal fluid biomarker ratios for diagnosis of dementia syndromes. The best formula to discriminate patients with AD from patients with DLB and controls was (152+8.25Xp‐tau)/Aβ42&gt;1. (Supported by FAPESP grant #2015/10109‐5)

Biofluid activity and levels of the angiotensin‐converting enzyme may translate into distinct neuropsychiatric symptoms associated with cerebrospinal fluid amyloid‐beta effects and tauopathy in dementia with Lewy bodies and Alzheimer’s dementia

AbstractBackgroundAmyloid‐β‐degrading enzymes such as the angiotensin‐converting enzyme (ACE‐1) might be surrogates of the amyloid‐β load in the brain potentially triggering tauopathy and behavioral features in dementia.MethodsConsecutive outpatients with probable dementia with Lewy bodies (fourth consensus report of the DLB Consortium) were paired with outpatients with late‐onset Alzheimer’s dementia (AD, National Institute on Aging – Alzheimer’s Association) by sex, Clinical Dementia Rating and Mini‐Mental State Examination scores, and with cognitively healthy controls by sex and age (±1 year). Behavioral symptoms were assessed by way of the Neuropsychiatric Inventory. APOE genotyping (rs7412&amp;rs429358) was undertaken with TaqMan® Real‐Time PCR technology, while conventional PCR was used for the ACE insertion/deletion polymorphism. Cerebrospinal fluid (CSF) amyloid‐β42, amyloid‐β38, ACE‐1, tau and phospho‐tau Thr181 were quantified with enzyme‐linked immunosorbent assays, whereas CSF and plasma ACE‐1 activities were measured using a fluorescence method. Adjusted general linear models were used to examine relationships between log‐transformed behavioral symptoms and biomarkers of interest at p&lt;0.05.ResultsParticipants with DLB (n = 27;78.48±9.0years‐old;eleven APOE‐ε4 carriers) were paired with participants with AD (n = 27;81.00±5.8years‐old;twelve APOE‐ε4 carriers) and controls (n = 27;78.48±8.7years‐old;four APOE‐ε4 carriers); two thirds were women. CSF ACE‐1 activity was associated with CSF ACE‐1 levels (p&lt;0.0001) and with plasma ACE‐1 activity (p&lt;0.0001), no differences among the participants. Only in DLB, the ACE deletion allele was cumulatively associated with higher plasma ACE‐1 activity (p = 0.049). Use of ACE inhibitors did not affect CSF ACE‐1 levels. For APOE‐ε4 carriers with DLB, agitation was inversely associated with amyloid‐β38, CSF and plasma ACE‐1 activities. For APOE‐ε4 non‐carriers with DLB, appetite and eating abnormalities were associated with CSF ACE‐1 levels and activity, tau and tau/phospho‐tau, and inversely associated with amyloid‐β42/amyloid‐β38. CSF ACE‐1, tau, tau/phospho‐tau, and tau/amyloid‐β42 were associated with disinhibition for APOE‐ε4 carriers with AD, and with aberrant motor behavior for APOE‐ε4 non‐carriers with AD. For APOE‐ε4 carriers with AD, irritability was associated with CSF ACE‐1 and inversely associated with amyloid‐β42. All other behavioral associations with ACE‐1 were independent of measures of amyloidosis or tauopathy.ConclusionsBiofluid activity and CSF levels of ACE‐1 may be surrogates for CSF amyloid‐β levels and tauopathy unevenly associated with behavioral symptoms across dementia syndromes.

123I-Ioflupane SPECT Striatal Binding Ratio Predicts Progression of Parkinsonism in a Dementia with Lewy Bodies Cohort (P11-6.004)

<h3>Objective:</h3> This research aims to determine if 123I-ioflupane SPECT (DaTscan) striatal binding ratio (SBR) correlates with parkinsonian symptoms measured on the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III) in patients with either probable dementia with Lewy bodies (DLB) or high-likelihood DLB individuals with mild cognitive impairment (MCI). Additionally, it aims to determine if DaTscan SBR predicts progression of parkinsonian symptoms over 2 years in this patient population. <h3>Background:</h3> The criteria for diagnosis of DLB remain predominantly clinical. Striatal dopamine transporter visualization using DaTscan is used to aid in diagnosis when exam findings of parkinsonism are equivocal. Further clinical utility of DaTscan in DLB, such as for screening or confirmatory tests or monitoring of disease progression or response to therapy, remains unclear. <h3>Design/Methods:</h3> This is a retrospective cohort study using the Dementia with Lewy Bodies Consortium (DLBC) dataset. The sample group included in this study are individuals with either probable DLB (based on 2017 McKeith Criteria) or high-likelihood DLB individuals with MCI. Each participant had a baseline and 24-month DaTscan analyzed with DaTQUANT software and physical examination scored with MDS-UPDRS-III. Participants without these data were excluded. <h3>Results:</h3> An analysis between baseline MDS-UPDRS-III and SBR z-scores revealed a moderate negative correlation, indicating SBR is a significant predictor of baseline MDS-UPDRS-III score. An analysis between baseline SBR z-scores and 24-month MDS-UPDRS-III revealed a moderate negative correlation, indicating that baseline SBR is a significant predictor of 24-month MDS-UPDRS-III scores. <h3>Conclusions:</h3> These data reveal a significant relationship between DaTscan SBR and motor examination in DLB. Additionally, there is a relationship between baseline SBR and progression of parkinsonian features. We conclude that DaTscan at time of diagnosis could be used to predict progression of parkinsonian symptoms in DLB which can aid in guiding therapies and prognostication of symptom progression. <b>Disclosure:</b> Dr. Maly has nothing to disclose. Dr. Leverenz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia. Dr. Leverenz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Leverenz has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. The institution of Dr. DiFilippo has received research support from NIH. Dr. DiFilippo has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with American College of Radiology.

MRI data-driven clustering reveals different subtypes of Dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder with a wide heterogeneity of symptoms, which suggests the existence of different subtypes. We used data-driven analysis of magnetic resonance imaging (MRI) data to investigate DLB subtypes. We included 165 DLB from the Mayo Clinic and 3 centers from the European DLB consortium and performed a hierarchical cluster analysis to identify subtypes based on gray matter (GM) volumes. To characterize the subtypes, we used demographic and clinical data, as well as β-amyloid, tau, and cerebrovascular biomarkers at baseline, and cognitive decline over three years. We identified 3 subtypes: an older subtype with reduced cortical GM volumes, worse cognition, and faster cognitive decline (n = 49, 30%); a subtype with low GM volumes in fronto-occipital regions (n = 76, 46%); and a subtype of younger patients with the highest cortical GM volumes, proportionally lower GM volumes in basal ganglia and the highest frequency of cognitive fluctuations (n = 40, 24%). This study shows the existence of MRI subtypes in DLB, which may have implications for clinical workout, research, and therapeutic decisions.

Distribution of Lewy-related pathology in the brain, spinal cord, and periphery: the population-based Vantaa 85 + study

Evolving evidence has supported the existence of two anatomically distinct Lewy-related pathology (LRP) types. Investigation of spinal cord and peripheral LRP can elucidate mechanisms of Lewy body disorders and origins of synuclein accumulation. Still, very few unselected studies have focused on LRP in these regions. Here we analysed LRP in spinal cord, dorsal root ganglion, and adrenal gland in the population-based Vantaa 85 + study, including every ≥ 85 years old citizen living in the city of Vantaa in 1991 (n = 601). Samples from spinal cord (C6-7, TH3-4, L3-4, S1-2) were available from 303, lumbar dorsal root ganglion from 219, and adrenal gland from 164 subjects. Semiquantitative scores of LRP were determined from immunohistochemically stained sections (anti-alpha-synuclein antibody 5G4). LRP in the ventral and dorsal horns of spinal cord, thoracic intermediolateral column, dorsal root ganglion and adrenal gland were compared with brain LRP, previously determined according to DLB Consortium criteria and by caudo-rostral versus amygdala-based LRP classification. Spinal LRP was found in 28% of the total population and in 61% of those who had LRP in the brain. Spinal cord LRP was found only in those subjects with LRP in the brain, and the quantity of spinal cord LRP was associated with the severity of brain LRP (p < 0.001). Unsupervised K-means analysis identified two cluster types of spinal and brain LRP corresponding to caudo-rostral and amygdala-based LRP types. The caudo-rostral LRP type exhibited more frequent and severe pathology in spinal cord, dorsal root ganglion and adrenal gland than the amygdala-based LRP type. Analysis of specific spinal cord regions showed that thoracic intermediolateral column and sacral dorsal horn were the most frequently affected regions in both LRP types. This population-based study on brain, spinal and peripheral LRP provides support to the concept of at least two distinct LRP types.

Parsing heterogeneity within dementia with Lewy bodies using clustering of biological, clinical, and demographic data

BackgroundDementia with Lewy bodies (DLB) includes various core clinical features that result in different phenotypes. In addition, Alzheimer’s disease (AD) and cerebrovascular pathologies are common in DLB. All this increases the heterogeneity within DLB and hampers clinical diagnosis. We addressed this heterogeneity by investigating subgroups of patients with similar biological, clinical, and demographic features.MethodsWe studied 107 extensively phenotyped DLB patients from the European DLB consortium. Factorial analysis of mixed data (FAMD) was used to identify dimensions in the data, based on sex, age, years of education, disease duration, Mini-Mental State Examination (MMSE), cerebrospinal fluid (CSF) levels of AD biomarkers, core features of DLB, and regional brain atrophy. Subsequently, hierarchical clustering analysis was used to subgroup individuals based on the FAMD dimensions.ResultsWe identified 3 dimensions using FAMD that explained 38% of the variance. Subsequent hierarchical clustering identified 4 clusters. Cluster 1 was characterized by amyloid-β and cerebrovascular pathologies, medial temporal atrophy, and cognitive fluctuations. Cluster 2 had posterior atrophy and showed the lowest frequency of visual hallucinations and cognitive fluctuations and the worst cognitive performance. Cluster 3 had the highest frequency of tau pathology, showed posterior atrophy, and had a low frequency of parkinsonism. Cluster 4 had virtually normal AD biomarkers, the least regional brain atrophy and cerebrovascular pathology, and the highest MMSE scores.ConclusionsThis study demonstrates that there are subgroups of DLB patients with different biological, clinical, and demographic characteristics. These findings may have implications in the diagnosis and prognosis of DLB, as well as in the treatment response in clinical trials.

Long‐term cognitive and motor decline across the spectrum of Lewy body disease

AbstractBackgroundThis study aims to compare the progression of motor and cognitive decline in dementia with Lewy bodies (DLB) compared with Parkinson’s disease (PD) using a large multicentre international consortium with up to 15 years of follow‐up.MethodLongitudinal data from 12 cohorts of patients with PD and DLB were included. The PD cohort (n=1108) included newly diagnosed patients from large, on‐going studies. The DLB cohort (n=290) included patients with probable DLB from the European DLB consortium (Table 1). The Mini Mental State Examination (MMSE) was used to explore cognitive functioning and UPDRS‐III for motor impairment. The differences in the rate of progression of MMSE and UPDRS‐III were analyzed with Linear Mixed Effects Model (LMEM) adjusted for baseline variables, with interactions for time. We used square root transformation of the number of errors to obtain an MMSE variable with normal distribution.ResultBoth DLB and PD groups presented motor and cognitive decline. The MMSE (figure 1A) showed a mean annual worsening of 2.35 points (95% CI 1.67‐3.03) for DLB patients and 1.05 points (95% CI 0.62‐1.47) for PD patients (P &lt;0.001). In PD the rate of decline increased with time and from the tenth year, the annual rate of decline of the transformed MMSE scores matched the rate in the DLB group. While DLB patients had lower UPDRS‐III scores at baseline, the rate of decline in UPDRS‐III (figure 1B) scores was faster in DLB compared to PD (P &lt;0.001). The annual increase in UPDRS III in DLB was 5.8 points (95% CI 5.71‐5.90), while in PD it was 1.9 points (95% CI 1.76‐1.97).ConclusionOur findings suggest that patients with DLB experience not only more rapid cognitive decline, but also accelerated motor deterioration compared to patients with PD. After ten years of follow‐up (and 12.9 years from the onset of symptoms), PD patients reach DLB's degree of yearly cognitive decline. This is the first large study to compare the natural history of PD and DLB and provides important information about the prognosis of these diseases.

Dementia with Lewy bodies subtypes identified by cluster analysis on structural MRI

AbstractBackgroundDementia with Lewy bodies (DLB) is a neurodegenerative disorder that presents with a variety of clinical symptoms. Part of the clinical heterogeneity within DLB has been related to the atrophy/sparing of the hippocampus. We extended that previous research by investigating whether different atrophy patterns exist in DLB, beyond and above the atrophy/sparing of the hippocampus, and whether those patterns contribute to the clinical heterogeneity in DLB. We aimed to identify DLB atrophy subtypes using a hypothesis‐free data‐driven clustering approach based on regional gray matter (GM) volumes and characterize the resulting subtypes across key measures.MethodWe included data from three centers of the European DLB consortium. A high‐resolution 3D T1‐weigthed magnetization prepared rapid gradient echo (MPRAGE) sequence was acquired for 97 DLB patients. Eighty‐four cortical regions and 12 subcortical regions from Mayo Clinic Adult Lifespan Template (https://www.nitrc.org/projects/mcalt/) atlases were obtained. Clusters of DLB patients were then determined using the random forest method. Between‐group differences in key demographic, clinical, MRI volumes and cerebrospinal fluid biomarkers (CSF) (amyloid‐beta, phosphorylated‐tau) were performed for clusters characterization.ResultWe identified three subtypes of DLB patients, with distinct patterns of GM volumes and differences in several clinical and demographic measures. Cluster 1 (C1) included 32 DLB patients (33%), cluster 2 (C2) included 29 DLB patients (30%), and cluster 3 (C3) included 36 DLB patients (37%). The clusters differed in age, with C1 being significantly older (72±8.6) than C3 (66±9.5) (F=3.93, p=0.02). C1 was characterized by lower volumes in fronto‐temporal regions and had a higher frequency of visual hallucinations (68%, vs. C2 35%). C2 showed lower volumes in occipital regions. C3 had higher GM volumes overall compared with the other two clusters and presented with a higher frequency of cognitive fluctuations (91%, vs. C1 67%). There were no differences between groups in CSF biomarkers. These results were independent of cluster differences in age and global GM volume.ConclusionThere are distinct patterns of brain atrophy in patients with DLB. These patterns seem to differentially contribute to the frequencies of visual hallucinations and cognitive fluctuations, independently of differences in age and global GM volume across subtypes.

Genetic Architecture and Molecular, Imaging and Prodromic Markers in Dementia with Lewy Bodies: State of the Art, Opportunities and Challenges.

Dementia with Lewy bodies (DLB) is one of the most common causes of dementia and belongs to the group of α-synucleinopathies. Due to its clinical overlap with other neurodegenerative disorders and its high clinical heterogeneity, the clinical differential diagnosis of DLB from other similar disorders is often difficult and it is frequently underdiagnosed. Moreover, its genetic etiology has been studied only recently due to the unavailability of large cohorts with a certain diagnosis and shows genetic heterogeneity with a rare contribution of pathogenic mutations and relatively common risk factors. The rapid increase in the reported cases of DLB highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods proposed by the International DLB consortium rely on a list of criteria that comprises both clinical observations and the use of biomarkers. Herein, we summarize the up-to-now reported knowledge on the genetic architecture of DLB and discuss the use of prodromal biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.

Prevalence and severity of neuropsychiatric symptoms in the prodromal stages of dementia with Lewy bodies and Alzheimer’s disease

AbstractBackgroundThere has been minimal investigation into the prodromal features dementia with Lewy bodies (DLB) and how they may differ from prodromal features of Alzheimer’s disease (AD).MethodThe data analyzed for this investigation were collected as part of a large, prospective longitudinal study conducted by the National Alzheimer’s Coordinating Center (NACC database is funded by NIA/NIH Grant U01 AG016976). We identified 110 non‐demented participants who converted to DLB at a subsequent visit. Participants were age and sex matched to 220 non‐demented participants who later converted to AD. We examined between group differences in the prevalence of symptoms on the Neuropsychiatric Inventory Questionnaire (NPI‐Q) at time of dementia diagnosis and in the 1‐3 years preceding conversion to dementia using Chi‐Square or Fisher Exact Test analyses.ResultsFor the DLB and AD groups, 82% were male and the average age at the time of dementia diagnosis was 75.4 years (SD=7.9). There was no significant difference in education between the two groups. The DLB group was significantly less culturally diverse than the AD group (See Table 1). Nighttime behaviors and hallucinations were significantly more common in the DLB group compared to the AD group at all time points during the prodromal phase and at the time of dementia diagnosis. There was no significant difference in the informant’s report of motor symptoms in the prodromal phases between the two groups (See Table 2).ConclusionThe DLB group demonstrated a significantly higher prevalence of nighttime behaviors and hallucinations than the AD group in both the prodromal phase and at the time of dementia diagnosis. These findings support the occurrence of core clinical features of DLB during the prodromal phase of the disease [1]; however, there was no significant difference in the informant’s report of motor symptoms within the prodromal phases, which warrants a comparison utilizing more objective motor data. Reference: 1. McKeith IG, Boeve BF, Dickson DW, et al.; Dementia with Lewy Bodies Consortium. Diagnosis and management of Dementia with Lewy Bodies: Fourth consensus report of the DLB Consortium. Neurol. 2017;89:1‐13.

The ANeED study: Ambroxol in new and early dementia with Lewy bodies

AbstractBackgroundThe mechanisms by which GBA and APOE mutations result in PD or DLB are not fully understood, however there is evidence that it may be connected to reduced levels of GCase enzyme activity. CNS penetration has been confirmed for Ambroxol, and has been shown to increase glucocerebrosidase activity and protein levels in animal and human studies. One small open study with Ambroxol 420mg TID in PD for 186 days found excellent target engagement and improved motor symptoms, and a RCT with 50 PDD patients is ongoing in London, Canada.MethodWe will execute a national multicenter phase III RCT clinical intervention study with Ambroxol in prodromal and mild DLB in Memory Clinics in Norway. We will include persons living with prodromal (DLB‐MCI) or mild DLB with MMSE &gt;=15 to Ambroxol or placebo. We will stratify participants based on genotypes for APOE and GBA and the CSF biomarkers A‐beta, total and phosphorylated tau protein. We will build a national trial platform for drug trials in neurodegenerative disorders in Norway and aim to include more centers in Europe for next phase studies via the European DLB Consortium (E‐DLB). We will execute a PPI program to raise awareness and reduce stigma for people living with DLB and their families.ResultThe ANeED‐study has received funding from the national Norwegian health authorities. Formal approvals for ethics, data protection and Medicine Agency are ongoing. We are planning a national start‐up meeting in Norway in September 2020, and we are currently building a national platform in Norway to be able to run clinical intervention studies in neurodegenerative disorders. We are building a PPI program to recruit patients and caregivers to clinical studies.ConclusionPhase III studies with Ambroxol in PD, PDD and DLB are currently being planned. APOE, GBA and GCase are central to the disease process in both PD, PDD and in DLB. Patients, carers and health providers now need to be offered participation in clinical studies also when diagnosed with one of the α‐synucleinopathies. Preliminary data find Ambroxol to be potentially disease modifying in these disorders.

Prolonged therapy of dementia with Lewy bodies with quaternary ammonium anti‐muscarinic/high‐dose cholinesterase inhibitor (QAAM/HDCI)

AbstractBackgroundDementia with Lewy Bodies (DLB) is the second most common human neurodegenerative disease and the most reduction in CNS choline acetyl‐transferase. This case series demonstrates beneficial effects from a level inhibition of cholinesterase inhibition that can only be achieved with concurrent peripheral muscarinic blockade.MethodPatients were selected from those seen in a single geriatric consultation clinic after 2010. DLB was diagnosed by the Consensus criteria of the third report (2005) or fourth (2017) of the DLB consortium by a geriatrician, with concurring neurologist in most cases. Patients received rivastigmine at doses greater that the upper limit of FDA approved dosing. Does greater than 12 mg oral, or 13.3 mg transdermal were paired with glycopyrrolate 1‐4 mg orally twice daily. Concurrent use of carbidopa/levodopa, selegiline was permitted but use of dopamine receptor agonists other than low dose quetiapine, other acetyl‐cholinesterase inhibitors or centrally acting anti‐muscarinic agents was not. Criteria for selection included treatment more than one year, the ability to perform a Mini Mental State Examination (MMSE) at the time of initiation and the availability of follow up data. The MMSE was performed in a standardized format. Functional Assessment Stage (FAST) was determined by nurse and physician after an interview with patient and caregivers.ResultMMSE values over time were compared to recently published rates of decline of DLB. All patients had MMSE and functional improvement, with most having a reduction in the rate of decline of MMSE scores.ConclusionThe results show that prolonged symptomatic, cognitive and functional improvement of dementia with Lewy Bodies is possible with the high‐level inhibition of central nervous system cholinesterase achievable when rivastigmine is combined with glycopyrrolate. The discussion correlates these observations with current experimental, clinical and epidemiological evidence regarding the mechanism and treatment of this, and other, neurodegenerative diseases.

Data‐assisted differential diagnosis of dementia by deep neural networks using MRI: A study from the European DLB consortium

AbstractBackgroundClinicopathological overlap between neurodegenerative diseases contributes to challenging differentiation between dementia types. Improving differential diagnosis is important to provide optimal patient care and better predict future needs. Deep learning techniques such as convolutional neural networks have in recent years gained much attention for their high performance in image classification. Magnetic resonance imaging (MRI) computer‐assisted diagnosis (CAD) systems based on deep learning could potentially contribute to increased reliability of clinical diagnosis.MethodAn ensemble model of 3D‐convolutional neural networks was trained and tested on a class‐balanced dataset consisting of T1‐weighted MRI brain scans for the differentiation of subjects diagnosed with Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and normal controls (NC). Total number of brain scans used for training and testing were 690 (nAD=nDLB=nNC=230) and 171 (nAD=nDLB=nNC=57) respectively. Diagnoses were clinical, not including MRI, and in a subgroup of the DLB patients the diagnosis was supported by DAT scan. All scans were skull‐stripped and spatially normalized. All classes were matched for age and sex. Data augmentation was applied using the left and right hemisphere as separate instances and a Bayesian approach was used for hyperparameter optimization. Experiments were conducted using 6‐fold cross‐validation, with the final model constructed as an ensemble of all models.ResultA final accuracy of 71.9% was reported for the three‐class differential classification of 171 stand‐out test subjects. The model classified the NC, DLB and AD subjects with 71.9%, 86.0% and 57.9% accuracy respectively. Further inspection showed that most of the miss‐classified AD patients were wrongly classified as DLB by the CAD system.ConclusionThe results of this work show promising potential for deep learning based CAD systems trained on MR brain images for differential diagnosis of dementia. Most data‐driven dementia classification models, including the one presented in this work, are limited by the amount of available data, comorbidity, and the inaccuracy of clinical diagnosis. Increasing the amount of data might significantly improve such models. The prospective E‐DLB study will provide more brain MRI data for future improvement of the suggested deep learning based CAD system.

Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressive supranuclear palsy

Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer’s disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (nTotal = 2008, nPSP = 1037, nLBD-NP = 971) and Thal phase amyloid plaque scores (nTotal = 1786, nPSP = 1018, nLBD-NP = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46–4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = − 0.822, 95% CI − 1.439 to − 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = − 0.995, 95% CI − 1.773 to − 0.218, p = 0.012) than LBD-NP patients (ß = − 0.292, 95% CI − 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = − 0.638, 95% CI − 1.139 to − 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.