Probable Dementia With Lewy Bodies Research Articles

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.

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.

Plasma metabolites distinguish dementia with Lewy bodies from Alzheimer's disease: a cross-sectional metabolomic analysis.

In multifactorial diseases, alterations in the concentration of metabolites can identify novel pathological mechanisms at the intersection between genetic and environmental influences. This study aimed to profile the plasma metabolome of patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), two neurodegenerative disorders for which our understanding of the pathophysiology is incomplete. In the clinical setting, DLB is often mistaken for AD, highlighting a need for accurate diagnostic biomarkers. We therefore also aimed to determine the overlapping and differentiating metabolite patterns associated with each and establish whether identification of these patterns could be leveraged as biomarkers to support clinical diagnosis. A panel of 630 metabolites (Biocrates MxP Quant 500) and a further 232 metabolism indicators (biologically informative sums and ratios calculated from measured metabolites, each indicative for a specific pathway or synthesis; MetaboINDICATOR) were analyzed in plasma from patients with probable DLB (n = 15; age 77.6 ± 8.2 years), probable AD (n = 15; 76.1 ± 6.4 years), and age-matched cognitively healthy controls (HC; n = 15; 75.2 ± 6.9 years). Metabolites were quantified using a reversed-phase ultra-performance liquid chromatography column and triple-quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode, or by using flow injection analysis in MRM mode. Data underwent multivariate (PCA analysis), univariate and receiving operator characteristic (ROC) analysis. Metabolite data were also correlated (Spearman r) with the collected clinical neuroimaging and protein biomarker data. The PCA plot separated DLB, AD and HC groups (R2 = 0.518, Q2 = 0.348). Significant alterations in 17 detected metabolite parameters were identified (q ≤ 0.05), including neurotransmitters, amino acids and glycerophospholipids. Glutamine (Glu; q = 0.045) concentrations and indicators of sphingomyelin hydroxylation (q = 0.039) distinguished AD and DLB, and these significantly correlated with semi-quantitative measurement of cardiac sympathetic denervation. The most promising biomarker differentiating AD from DLB was Glu:lysophosphatidylcholine (lysoPC a 24:0) ratio (AUC = 0.92; 95%CI 0.809-0.996; sensitivity = 0.90; specificity = 0.90). Several plasma metabolomic aberrations are shared by both DLB and AD, but a rise in plasma glutamine was specific to DLB. When measured against plasma lysoPC a C24:0, glutamine could differentiate DLB from AD, and the reproducibility of this biomarker should be investigated in larger cohorts.

Different effect of hypo- and hypermetabolism on cognition in dementia with Lewy bodies: are they coupled or independent?

Patients with dementia with Lewy bodies (DLB) show widespread brain metabolic changes. This study investigated whether brain hypo- and hypermetabolism in DLB have differential effects on cognition. We enrolled 55 patients with DLB (15 prodromal DLB [MCI-LB] and 40 probable DLB) and 13 healthy controls who underwent 18F-fluorodeoxyglucose positron emission tomography and detailed neuropsychological tests. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism were calculated as follows: index(-) for hypometabolism [DLB-hypo] and index(+) for hypermetabolism [DLB-hyper]. The effects of DLB-hypo or DLB-hyper on cognitive function were assessed using a multivariate linear regression model. Additionally, a linear mixed model was used to investigate the association between each index and the longitudinal cognitive decline. There was no correlation between DLB-hypo and DLB-hyper in the disease group. The multivariate linear regression model showed that DLB-hypo was associated with language, visuospatial, visual memory, and frontal/executive functions; whereas DLB-hyper was responsible for attention and verbal memory. There was significant interaction between DLB-hypo and DLB-hyper for verbal and visual memory, which was substantially affected by DLB-hyper in relatively preserved DLB-hypo status. A linear mixed model showed that DLB-hypo was associated with longitudinal cognitive outcomes, regardless of cognitive status, and DLB-hyper contributed to cognitive decline only in the MCI-LB group. The present study suggests that DLB-hypo and DLB-hyper may be independent of each other and differentially affect the baseline and longitudinal cognitive function in patients with DLB.

Development and Validation of a Screening Questionnaire for Dementia With Lewy Bodies (DLB): the DLB Screening Questionnaire (DLBSQ).

Although dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia, its clinical prevalence is low. We developed a short and easy-to-complete DLB screening questionnaire (DLBSQ) to raise diagnostic sensitivity in routine clinical settings. A total of 501 participants were retrospectively enrolled, including 71 controls, 184 patients without DLB, and 246 patients with probable DLB. All patients underwent clinical evaluation, including core features of DLB, the DLBSQ, brain magnetic resonance imaging, and detailed neuropsychological assessments. The diagnostic performance of the DLBSQ for probable DLB was investigated using a receiver operating characteristic curve analysis. Total DLBSQ score was associated with visuospatial and frontal/executive dysfunction and the diagnosis of probable DLB. The area under the receiver operating characteristic curve for total DLBSQ score was 0.727. Youden's method revealed an optimal cutoff value of 3. The sensitivity and specificity of the DLBSQ were 68.7% and 62.4%, respectively. Its discriminating performance improved when cognitive test profiles were additionally considered (area under the curve: 0.822, sensitivity: 80.6%, and specificity: 70.4%). The DLBSQ might be a useful screening tool for DLB in routine clinical practice with good sensitivity and specificity.

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.

Characteristics associated with progression to probable Dementia with Lewy Bodies in a cohort with late onset psychosis

AbstractBackgroundA psychiatric‐onset prodrome is increasingly recognised in Dementia with Lewy Bodies (DLB) and while late‐onset psychosis is associated with increased risk of developing dementia, it is not clear what proportion of patients with psychotic disorders go onto develop DLB. Among patients with late onset psychosis, we aimed to identify the proportion who developed DLB and to characterise the clinical features and characteristics of those who convert to DLB.MethodAnonymised data collected between 2006‐2021 was retrieved from clinical records from a large London mental health service for patients who were ≥50 years when first diagnosed with a psychotic disorder. Patients with dementia diagnoses &gt;3 months later were identified and a natural language processing (NLP) algorithm was used to identify patients with probable DLB, with two of the core features (visual hallucinations, parkinsonism, fluctuations or sleep disturbance) identified in the free text at the time of dementia diagnosis. Predictors of progression to DLB were investigated including demographic factors, Health of the National Outcome scale for older people (HoNOS65+) and key clinical features at the time of psychosis diagnosis identified with NLP.ResultIn 3784 patients with late onset psychosis, 321 (8.5%) received a diagnosis of dementia from mental health services during the follow‐up period (mean time to dementia diagnosis 3.66±3.13 years). A high percentage (30.5%, n = 98) of those who developed dementia met criteria for probable DLB. Presence of hallucinations, falls, parkinsonism, fluctuations or drowsiness at the time of late onset psychosis diagnosis was associated with an increased relative risk of later developing probable DLB. Adjusted multivariate Cox proportional hazard models suggested that older age and higher scores on HoNOS cognitive and hallucinatory items at baseline were significant predictors of faster progression to DLB.ConclusionDLB is overrepresented in patients with late‐onset psychosis who later develop dementia; a psychiatric prodrome in dementia should give a high index of suspicion for DLB. In patients with late‐onset psychosis, risk factors for future progression to DLB include cognitive impairment, older age, hallucinations, falls, fluctuations, parkinsonism and drowsiness. Where these hallmarks are present at the time of psychosis, close follow up could facilitate the earlier identification of DLB.

Correlation between longitudinal changes of clinical symptoms and striatal DAT uptake in DLB

AbstractBackgroundIt is widely known that there is low striatal 123I‐FP‐CIT dopamine transporter single photon emission tomography (DaT‐SPECT) uptake in patients with dementia with Lewy bodies (DLB). There are no study about the association between longitudinal changes of clinical sign and DaT‐uptake in Parkinson syndrome, especially in DLB. The aim of this study is to investigate the association between the longitudinal changes of DaT uptake and severity of parkinsonism and cognitive funtion in DLB.MethodA total of 35 outpatients with probable DLB who underwent DaT‐SPECT twice (initial and follow up period) from the Memory Disorder Clinic at the Department of Geriatric Medicine, Tokyo Medical University, were enrolled in this study from April 2014 until September 2020. We examined the correlation between annual changes of DaT uptake and symptoms (cognitive function decline, parkinsonism) in the patients with DLB.ResultThere was significant correlation between annual changes of severity of parkinsonism and DAT uptake in left posterior putamen (r = ‐0.39, p = 0.03), MMSE scores and DaT uptake in the entire regions except right posterior putamen (P&lt; 0.05) in patients with DLB.ConclusionThese results may suggest clarifying the mechanism of dysfunction of nigrostriatal projection pathway in DLB.

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)

Identification of Hippocampal and Amygdala Subfields Predictive of MoCA Scores in Patients with Dementia with Lewy Bodies

AbstractBackgroundHippocampal 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).MethodWe 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.ResultSubfield 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).ConclusionWe 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.

Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐ß plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐ß deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐β plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐β deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

Plasma pTau‐217 and NfL concentrations across diagnoses in an unselected memory clinic cohort

AbstractBackgroundAlzheimer’s Disease (AD) plasma biomarkers have been proposed for amyloid positivity identification and for differentiating between diagnoses. Phosphorylated Tau‐217 (pTau‐217) has demonstrated good predictive ability for AD vs healthy controls. Neurofilament Light chain (NfL) differentiates between Frontotemporal Dementia (FTD) and other dementia. These factors have not be extensively tested in real‐world cohorts. The aim of this study was to investigate how pTau‐217 and NfL concentrations differ across clinical diagnoses in an unselected, real‐world memory clinic cohort.MethodWe included 418 consecutive patients from the Amsterdam Dementia Cohort. Patients were split among 12 diagnoses, including SCD, Mild Cognitive Impairment (MCI), probable AD, Dementia with Lewy Bodies (DLB) and FTD (Table 1). pTau‐217 was measured using the novel AlzPath assay, while NfL was measured using the Quanterix Simoa assay. were used to classify patients as high or low for pTau‐217 and NfL levels. The pTau‐217 cutoff (0.58 pg/mL) was the Youden index cutoff derived from the present data, based on amyloid‐positive AD vs amyloid‐negative SCD diagnosis (n = 57), using amyloid status derived from cerebrospinal fluid or Amyloid positron emission tomography for classification. (18.2 pg/mL) was chosen based on the sample’s median age (64 years) and taking the value associated with the 90th percentile of normal NfL levels (NfL interface for physicians (shinyapps.io)).ResultpTau‐217 levels were highest in patients with AD and Primary Progressive Aphasia (PPA), and lowest in those with Vascular Dementia (VaD) and other neurological diagnosis (Figure 1). NfL levels were highest in patients with VaD and FTD, and lowest in SCD and psychiatric diagnoses. The cutoffs highlighted similar trends, with higher proportions patients with elevated pTau‐217 levels observed in possible and probable AD, MCI, and DLB. Higher proportions of patients with high NfL levels were observed in FTD, PPA, VaD, and possible AD (Figure 2).ConclusionpTau‐217 concentrations vary as expected across the different diagnoses, with highest concentrations in AD pathology diagnostic groups. The elevated levels observed in DLB and PPA could be due to underlying AD co‐pathology. Following previous results, NfL concentrations were highest in FTD and lowest in psychiatry and SCD.

Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission.

Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA). FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level. Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912). Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.

B - 43 Case Study: Native Hawaiian/Pacific Islander Female Veteran with Dementia with Lewy Bodies.

Recent research suggests there is a lack of consensus regarding current data on the racial/ethnic profiles of cognitively impaired persons with dementia with Lewy bodies (DLB) despite DLB being among the most common neurodegenerative dementias. This case study reviews a Native Hawaiian/Pacific Islander (NHPI) with probable DLB and discusses challenges encountered to emphasize the importance of appropriate normative data to help detect DLB in diverse populations. A 78-year-old NHPI female veteran presented for repeat neuropsychological evaluation to track her cognitive symptoms. Chief complaints included concurrent cognitive and motor difficulties, fully formed visual hallucinations, nighttime confusion, and reduplicative paramnesias which have significantly impacted her instrumental activities of daily living. Neuropsychological testing is suggestive of progressive decline in several cognitive domains, including visuospatial ability, executive functioning, semantic fluency, and verbal and visual learning and memory. Consistent with a DLB diagnosis, her cognitive symptoms emerged concurrently with motor symptom onset. There is also evidence of significant visuospatial and executive difficulties, as well as previously reported reduplicative paramnesia, confusion, and weekly fully-formed hallucinations. Additionally, there is evidence of concurrent parkinsonism's such as bradykinesia, rigidity, hypophonia, and tremor. The constellation of symptoms reported by the patient, combined with the results of neuropsychological assessment, was highly congruent with prototypical DLB; however, lack of proper normative data to accurately assess for decline in her scores led to significant caution in interpretation of her neuropsychological performance. This case demonstrates the importance of proper normative data in diverse populations and the role of neuropsychological evaluations in specific cultural contexts.

A - 40 Assessment of Dementia with Lewy Bodies in a Patient with both Characteristic and Atypical Features.

Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer disease (ad). Its heterogeneous presentation and overlapping features with other dementias result in frequent misdiagnosis, which can delay optimal management. The present case illustrates complex symptomology, comprehensive assessment, and diagnostic challenges in a patient with DLB. A 64-year-old female presented to an academic medical center neurology clinic with rapid cognitive deterioration over the past 1.5years accompanied by visual disturbances, psychiatric and behavioral changes, and mild motor symptoms. Initial differential included Creutzfeldt-Jakob disease, atypical parkinsonism, frontotemporal lobar degeneration (FTLD), encephalopathy, and ad. Work-up in included neuropsychological, neuroimaging, cerebral spinal fluid (CSF), electroencephalogram (EEG), and skin biopsy assessments. Neuropsychological interview revealed fluctuating attention/alertness, visual hallucinations, hyposmia, paranoid and repetitive behaviors, and subtle evidence for dream enactment. Her cognitive profile showed global impairment with pronounced visuospatial and executive deficits. Recognition memory, verbal reasoning, and naming were relatively well-preserved. Magnetic resonance imaging showed mild atrophy; fluorodeoxyglucose positron emission tomography (PET) showed hypometabolism in frontal and temporal regions whereas uptake was highest in the occipital lobes and basal ganglia; skin biopsy was positive for synucleinopathy; CSF and EEG were broadly unrevealing. The preponderance of data was consistent with diagnostic criteria for probable DLB. Skin biopsy increased diagnostic confidence. Atypical features included relatively rapid cognitive decline, minimal parkinsonism, and PET imaging suggesting FTLD. The present case highlights the utility of a multidisciplinary approach (e.g., neurological exam, detailed symptom screening, neuropsychological testing, and advanced laboratory assessments) in a complex case of DLB.

Association between longitudinal changes in striatal dopamine transporter uptake and clinical features of dementia with Lewy bodies.

It is widely known that there is low striatal 123 I-2β-Carbomethoxy-3β-(4-iodophenyl)-N-(3- fluoropropyl) nortropane (123 I-FP-CIT) dopamine transporter single photon emission tomography (DaT-SPECT) uptake in patients with dementia with Lewy bodies (DLB). No studies to date have analyzed the association between longitudinal changes of clinical features and DaT uptake in patients with Parkinson syndrome, particularly those with DLB. The aim of this study was to investigate the association between the longitudinal changes in DaT uptake and the severity of parkinsonism and cognitive function in DLB patients. A total of 35 outpatients with probable DLB who underwent DaT-SPECT twice (at the initial examination and the follow-up period) in the Memory Disorder Clinic at the Department of Geriatric Medicine, Tokyo Medical University, were enrolled in this study between April 2014 and September 2020. The correlation between annual changes in DaT uptake and clinical features (cognitive function decline and parkinsonism) of the patients was analyzed. A significant correlation was detected between annual changes in parkinsonism symptom severity and DaT uptake in the left posterior putamen (r = -0.39, P = 0.03), and between Mini-Mental State Examination scores and DaT uptake in all regions except the right posterior putamen (P < 0.05) in patients with DLB. Our results suggested that the pathway from the ventrolateral tier of the substantia nigra to the putamen might be more crucial for motor function than other pathways, not only in Parkinson's disease but also in DLB.

Differential diagnosis of neurodegenerative diseases using an innovative deep learning approach

AbstractBackgroundNeurodegenerative diseases lead to memory disorders and cognitive impairments with major impacts on day‐to‐day function. Early detection of patients is essential for an efficient care approach, and differential diagnosis is essential for determining prognosis and tailoring management. Most research studies compare patients by pairwise comparison methods, but this does not correspond to daily clinical practice, in which clinicians need to distinguish many different possible types of dementia concomitantly. It has been shown that magnetic resonance imaging (MRI) can mark with good accuracy the different types of dementia, such as: Alzheimer’s disease (AD), Frontotemporal dementia (FTD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB). Recently, Deep Learning approaches have started being used although differential diagnosis is still almost ignored. The aim of this study was to develop a Convolution Neural Network (CNN) to classify probable AD, FTD, DLB, PD and healthy elderly control (CN) subjects starting from Diffusion Tensor Imaging (DTI).MethodThe cohort used in this study came from six different initiatives: ADNI1, NIFD2, NACC3, PDBP4, PPMI5 and Newcastle University6,7,8,9. We analysed a total of 108 CN, 110 AD, 135 FTD, 150 DLB, 132 PD. Demographic and neuropsychological characterization is shown in Table 1. The DTI scans were pre‐processed using the FMRIB software library (FSL) with eddy current correction, skull‐stripping and diffusion tensor calculation. We post‐processed the Fractional Anisotropy (FA) map using 3D CNN. The proposed CNN structure consisted of an image input layer, convolutional filters, several batch normalization with max‐pooling layers and, finally, the classification layer. A data augmentation approach was adopted that ultimately resulted in a dataset of 26’450 brain scans. A hold‐out validation (70% training set 30% test set) was performed.ResultWe found excellent performance of the 3D CNN in discriminating the different neurodegenerative diseases. Figure 1 shows the confusion matrix with the following values for the area under the ROC curve in each class: 0.92 for CN, 0.90 for AD, 0.97 for DLB, 0.96 for FTD, 0.99 for PD.ConclusionThese results prove that Deep Learning and the 3D CCN method are suitable for clinical practice and provide additional clues that can help clinicians in diagnosis making.

Clinical Predictors of Survival in Probable Dementia with Lewy Bodies (P13-6.006)

Clinical Predictors of Survival in Probable Dementia with Lewy Bodies (P13-6.006)

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.