Dementia With Lewy Bodies Group Research Articles

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.

Neuropsychiatric symptoms profile and markers of Alzheimer disease–type pathology in patients with Lewy body dementias

BackgroundTo determine whether Lewy body dementia (LBD) patients with likely copathology of Alzheimer’s disease (AD) exhibit greater neuropsychiatric symptom (NPS) compared to those without likely AD-type copathology. MethodsWe enrolled 69 individuals diagnosed with Lewy body dementia (LBD), comprising both dementia with Lewy bodies (DLB) (n = 36) and Parkinson's disease dementia (PDD) (n = 33). These participants had accessible cerebrospinal fluid (CSF) markers related to Alzheimer's disease (AD) and cognitive data. We assessed CSF levels of β-amyloid 42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Employing autopsy-validated CSF thresholds (t-tau/Aβ42 ratio > 0.3, n = 69), we categorized individuals into LBD with AD pathology (LBD + AD, n = 31) and LBD without apparent AD co-pathology (LBD - AD, n = 38). Moreover, the Hamilton Depression Scale (HAMD24), Hamilton Anxiety Scale (HAMA14), and Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess the NPS. Spearman correlations were utilized to explore links between NPS and CSF marker profiles. ResultsIn terms of neuropsychiatric symptoms, LBD + AD patients demonstrated notably elevated levels of depressive symptoms (HAMD24) in comparison to LBD - AD patients (P < 0.001). However, based on PDD and DLB groups, no significant variations were noted in the neuropsychiatric symptoms(P＞0.05). Moreover, CSF-derived biomarkers of Aβ42, and t-tau/Aβ42 were also associated with HAMD24 total scores in the LBD + AD subsample (P < 0.05). ConclusionThere is an association between AD pathological markers and the NPS of LBD. The biologically based classification of LBD may be more advantageous in elucidating clinical heterogeneity than clinically defined syndromes.

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.

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.

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.

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 (Aß), 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 Aß40, Aß42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aß40/42. Lower Aß40/42 indicates increased Aß pathology. Plasma Aß40, Aß42, 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 Aß 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 Aß40/42 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.

P185: Comparison of social function in mild cognitive impairment and mild dementia using the Japanese version of the Social Functioning in Dementia scale (SF-DEM-J)

Objective:The present study aimed to compare the social function between mild cognitive impairment (MCI), mild Alzheimer’s disease (AD) dementia, and mild dementia with Lewy bodies (DLB) using the Japanese version of Social Functioning in Dementia scale (SF-DEM-J).Methods:We interviewed 103 patients and family caregivers from June 2020 to March 2021: 54 patients with MCI, 34 with mild AD dementia, and 15 with mild DLB. We compared the caregiver-rated SF-DEM-J, Clinical Dementia Rating (CDR), MMSE, age, length of education, Geriatric Depression Scale (GDS), the University of California, Los Angeles Loneliness Scale (UCLA-LS), Neuropsychiatric Inventory (NPI), and informant version of the Apathy Evaluation Scale (AES) between MCI, mild AD dementia, and mild DLB groups using Kruskal-Wallis test with Dunn-Bonferroni correction for post-hoc analyses. We compared sex, living situation, and caregiver demographics between three groups using chi-square test. We performed correlation analysis between the score of each psychological test and the scores of SF-DEM-J within group using Spearman’s rank correlation coefficient.Results:For SF-DEM-J, the score of section 2 (communicating with others) was significantly worse in mild AD dementia than in mild DLB. The scores of section 1 (spending with others) and section 3 (sensitivity to others) and the total score did not significantly differ between three groups. The score of section 1 was significantly associated with MMSE in MCI, with anxiety and disinhibition of NPI, and AES in mild AD dementia, and with GDS in mild DLB. The score of section 2 was significantly associated with AES in MCI and mild AD dementia, with UCLA-LS in MCI, and with the length of education in mild DLB. The score of section 3 was significantly associated with agitation and irritability of NPI in MCI and mild AD dementia. The total score was associated with UCLA-LS and AES in MCI, and with AES in mild AD dementia.Conclusion:Factors affecting social functioning differed between MCI, mild AD dementia, and mild DLB. Apathy, agitation and irritability affected social functioning in MCI and mild AD dementia while depressive mood affected social functioning in mild DLB.

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.

Plasma p‐tau181 levels in Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB)

AbstractBackgroundThe fundamental pathological process in AD involves amyloid(Aβ) deposition and Tau hyperphosphorylation (ptau). Plasma ptau has been proven as more accessible and less invasive biomarker than CSF for the assessment of AD pathological features. DLB is another common cause of dementia in the elderly and has overlapping features with AD. Thus, the detection of Alzheimer’s biomarkers might be useful for distinguishing the underlying pathology of AD from other concurrent pathologic processes. In this study, we compared the plasma levels of p‐tau181 in patients with clinically diagnosed DLB and AD.MethodWe examined EDTA plasma samples of patients assessed at the UBC Hospital Clinic for AD. The cohort was clinically characterized as control (n = 89) if no significant cognitive impairment was found, AD (n = 195) if they fulfill the NIA‐AA criteria (McKhann 2011), and DLB (n = 39) if they fulfill the consensus criteria for DLB (McKeith 2005; McKeith 2017). The samples were analyzed by a p‐tau181‐specific Simoa assay.ResultThe mean age of the cohort is 69.2 ± 10.3 with the control 63.4 ± 8.7, AD 70.1 ±9.9 and DLB 77.8 ± 8. There are 74.2% females in the controls, 52.8% in AD, and 35.9% in DLB.).The patients with DLB were older than the cases of AD and controls (p&lt;0.001) and there was no significant effect of age on plasma ptau‐181 concentrations (p = 0.65). There were more females in the controls and AD groups compared to DLB (p&lt;0.001), however, there was no significant correlation between sex and plasma ptau‐181 (p = 0.24). While the plasma p‐tau181 concentrations of cases with AD (74.1 ± 35.6 pg/ml) were slightly higher than DLB (73.2 ± 44.4 pg/ml), they were not significantly different. However, they were significantly higher than the control group (26.5 ± 23 pg/ml) (p &lt; 0.001).ConclusionIn current study, plasma p‐tau181 levels did not differentiate the DLB group from the AD, but both groups were significantly higher than controls. This suggests that DLB often have co‐existing AD pathology, making their p‐tau measurements like the AD group. Further studies with autopsy‐defined samples will be needed to clarify the role of plasma p‐tau181 in DLB.

Within and between‐network functional connectivity disruptions in posterior cortical atrophy and dementia with Lewy bodies

AbstractBackgroundPosterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show overlapping patterns of hypometabolism affecting posterior regions of the brain. Both syndromes show disruptions in functional connectivity, but it is unknown how patterns of disruption within and between networks compare between PCA and DLB.MethodThirty amyloid‐positive PCA, 27 amyloid‐positive DLB (DLB+), 24 amyloid‐negative DLB (DLB‐) patients and 30 cognitively normal amyloid‐negative (CN) individuals were recruited at Mayo Clinic, Rochester, MN, and underwent structural and resting state functional MRI. Spatially preprocessed data was analyzed using the CONN functional connectivity toolbox to explore nine networks: visual, sensorimotor, dorsal‐attention, cerebellar, frontoparietal, memory, language, salience, and default mode networks (DMN). Multivariate linear regression models corrected for multiple comparisons and adjusted for age and sex were fit to analyze within‐network connectivity (Fisher’s R‐to‐Z transformations). Between‐network connectivity was assessed with group level difference maps (two‐sample t‐test) corrected for false discovery rate at p&lt;0.05.ResultMultivariate linear regression models showed reduced within‐network connectivity across all DMN components, sensorimotor, and dorsal‐attention networks, with trends for the visual network in PCA compared to CN. Both DLB‐ and DLB+ showed reduced within‐network connectivity for the cerebellar network, with DLB+ showing reduced connectivity in the posterior‐DMN, memory, and salience networks compared to CN. DLB‐ showed increased connectivity in dorsal‐attention and DMN, while DLB+ showing reduced connectivity in the memory network compared to PCA. Between‐network analysis showed an increase in cerebellar‐to‐sensorimotor connectivity in all three groups, with increase in cerebellar‐to‐dorsal‐attention connectivity in DLB‐ and PCA compared to CN. DLB‐ showed a decrease in posterior‐DMN‐to‐sensorimotor connectivity, while PCA showed reduced connectivity between all DMN components and dorsal‐attention‐to‐sensorimotor connectivity compared to CN. There was an increase in connectivity between all DMN components and a reduction in dorsal‐DMN‐to‐sensorimotor connectivity in both DLB‐ and DLB+ compared to PCA.ConclusionPCA was associated with connectivity disruptions across all DMN components, sensorimotor, dorsal‐attention and visual networks, while both DLB groups showed disruptions in cerebellar networks, with DLB+ showing further disruptions in posterior‐DMN, memory and salience networks. These findings suggest that both PCA and DLB have unique brain network disruptions, with amyloid status influencing connectivity in DLB.

Differences in Retinal and Choroidal Microvasculature and Structure in Dementia With Lewy Bodies Compared With Normal Cognition.

Purpose: To evaluate the retinal and choroidal microvasculature and structure in individuals with dementia with Lewy bodies (DLB) compared with controls with normal cognition using optical coherence tomography (OCT) and OCT angiography (OCTA). Methods: An institutional review board-approved cross-sectional comparison of patients with DLB and cognitively normal controls was performed. The Cirrus HD-OCT 5000 with AngioPlex (Carl Zeiss Meditec) was used to obtain OCT and OCTA images. Results: Thirty-four eyes of 18 patients with DLB and 85 eyes of 48 cognitively normal patients were analyzed. The average capillary perfusion density (CPD) was higher in the DLB group than in the control group (P = .005). The average capillary flux index (CFI) and ganglion cell inner-plexiform layer (GC-IPL) thickness were lower in the DLB group than in the control group (P = .016 and P = .040, respectively). Conclusions: Patients with DLB had an increased peripapillary CPD, decreased peripapillary CFI, and attenuated GC-IPL thickness compared with those with normal cognition.

A characteristic of olfactory function in four types of dementia and non-dementia subjects using smell identification test.

For those outpatients who were consulted for memory loss, the Japanese version of University of Pennsylvania Smell Identification Test (UPSIT-J) was performed to examine olfactory function. In the same way, the revised version of Hasegawa Dementia Scale, Mini Mental State Examination, Clinical Dementia Rating and brain magnetic resonance imaging were used to investigate the cognitive function. In the present study, we evaluated the olfactory function of elderly subjects, including those with dementia, by means of UPSIT-J and we examined their characteristics. The characteristics of dementia as Alzheimer type group (AD.G), mixed type group (MixD.G), vascular type group (VaD.G), dementia with Lewy bodies group (DLB.G) and the groups which had no dementia as low score group (LS.G), high score group (HS.G), and healthy group (H.G), were examined. The numbers of olfactory discriminating scores (nODS) were significantly lower in all the dementia groups than in all the LS.G, HS.G and the H.G. No significant difference was observed in nODS between AD.G and DLB.G. The rate of nODS with less than five scores were as follows: AD.G (80.1%), MixD.G (91.5%), VaD.G (63.1%), DLB.G (89.6%), LS.G (50.8%), HS.G (18.6%), H.G (15.6%). A significant positive correlation was found between nODS and Hasegawa Dementia Scale and Mini Mental State Examination scores (r = 0.567, r = 0.532, respectively), which was significant negatively correlated for Clinical Dementia Rating (r = -0.578). A significant negative correlation was observed between nODS and Z score of voxel-based specific regional analysis for Z score of Alzheimer's disease (VSRAD) (r = 0.463). nODS showed a significant correlation between cognitive function tests and brain atrophy level. These results indicate that UPSIT-J is considered a psycho-physiological index useful for the diagnosis and early detection of dementia.

54 Neuropsychiatric Symptoms in Mild Cognitive Impairment and Dementia with Lewy Bodies

Objective:Neuropsychiatric symptoms (NPS) can be observed in mild cognitive impairment (MCI) and dementia. Hallucinations are a core clinical symptom of Dementia with Lewy Bodies (DLB). In this study, we investigated NPS in healthy control and MCI groups who would later be diagnosed with DLB to determine which symptoms would present early.Participants and Methods:Participants included those originally diagnosed as healthy controls (n=55), MCI with DLB etiology (n=215), and DLB (n=1059). The control and MCI groups progressed to DLB at later visits in the study. NPS data were collected using the Neuropsychiatric Inventory Questionnaire (NPI-Q) that was obtained from the National Alzheimer's Coordinating Center.Results:To determine which NPS presented early in the DLB course, we ran ANCOVAs to assess the role of original diagnosis on each NPS, using age as a covariate and applying Bonferroni correction. The control and MCI groups, who were later diagnosed with DLB, had greater severity of delusions, hallucinations, agitation, and apathy than the DLB group. The MCI group that would later be diagnosed with DLB had greater severity of anxiety and motor symptoms than the DLB group. The control group had greater irritability severity than the DLB group, and the controls had greater nighttime behavior severity than the MCI group, who had greater severity than the DLB group.Conclusions:Overall, we found that NPS present early in those who will be diagnosed with DLB, even when they are diagnosed as healthy controls. These results suggest that examination of NPS is important even in healthy adults, and their presence may be the onset of the DLB process before an official diagnosis of the condition.

Involvement of ApoE4 in dementia with Lewy bodies in the prodromal and demented stages: evaluation of the Strasbourg cohort.

ApoE4 as a risk factor for dementia with Lewy bodies (DLB) is still an issue. We sought to determine the involvement of ApoE4 according to different clinical parameters in our cohort of patients from Strasbourg, France. ApoE genotyping was performed on the AlphaLewyMA cohort. In this cohort, 197 patients were genotyped: 105 DLB patients, 37 Alzheimer's disease (AD) patients, 29 patients with AD/DLB comorbidity, and 26 control subjects (CS). The groups of patients were also classified according to the stage of evolution of the disease: prodromal or demented. We analyzed other parameters in relation to ApoE4 status, such as years of education (YOE) and Alzheimer CSF biomarkers. We observed a higher proportion of ApoE4 carriers in the AD (51.4%) and AD/DLB (72.4%) groups compared to the DLB (25.7%) and CS (11.5%) groups (p < 0.0001). We found a correlation between age at disease onset and YOE in the AD group (p = 0.039) but not in the DLB group (p = 0.056). Interestingly, in the DLB group, the subgroup of patients with high YOE (≥ 11) had significantly more patients with ApoE4 than the subgroup with low YOE (< 11). AD biomarkers did not seem to be impacted by the presence of ApoE4, except for Aβ42: DLB ApoE4-positive demented patients showed a more marked Aβ42 decrease. ApoE4 does not appear to be a risk factor for "pure" DLB patients. These results suggest a strong link between ApoE4 and amyloidopathy and consequently with AD. Trial registration: AlphaLewyMa, Identifier: NCT01876459, date of registration: June 12, 2013.

Comparison of caregiver burden between dementia with Lewy bodies and Alzheimer's disease.

Caring for patients with dementia with Lewy bodies (DLB) would be more stressful for their caregivers than those with Alzheimer's disease (AD). In this study, we compared levels of caregiver burden and the possible influential factors on the caregiver burden between DLB and AD. Ninety-three DLB patients and 500 AD patients were selected from the Kumamoto University Dementia Registry. Caregiver burden, neuropsychiatric symptoms, basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were assessed by the Japanese version of the Zarit Caregiver Burden Interview (J-ZBI), the Neuropsychiatric Inventory (NPI), the Physical Self-Maintenance Scale (PSMS), and the Lawton IADL scale, respectively. Despite the comparable Mini-Mental State Examination score, the J-ZBI score was significantly higher in the DLB group than the AD group (P = 0.012). A stepwise multiple regression analysis revealed that IADL score (β = -0.23, P = 0.049), PSMS score (β = -0.31, P = 0.010), disinhibition (β = 0.22, P = 0.008), and anxiety (β = 0.19, P = 0.027) were significantly associated with J-ZBI score in DLB. In AD, caregiver's relationship with patient (child) (β = 0.104, P = 0.005), caregiver's gender (female) (β = 0.106, P = 0.004), IADL score (β = -0.237, P < 0.001), irritability (β = 0.183, P < 0.001), apathy (β = 0.132, P = 0.001), agitation (β = 0.118, P = 0.007), and aberrant motor behaviour (β = 0.107, P = 0.010) were associated with caregiver burden. Caring for DLB patients caused a higher degree of caregiver burden than AD patients in the same level of cognitive decline. The factors responsible for the caregiver's burden were different between DLB and AD. The caregiver burden for DLB patients was associated with the disability of basic ADL, IADL impairment, anxiety and disinhibition.

Abnormal resting state EEG and vigilance in neurodegenerative dementias

AbstractBackgroundAlzheimer’s disease dementia (ADD) is the most common neurodegenerative dementing disorder explaining about 60‐70% of 50 million patients worldwide (www.who.int). Dementia with Lewy Bodies (DLB) is another diffuse neurodegenerative dementing disorder inducing abnormalities in vigilance (visual hallucinations, cognitive fluctuations, and REM sleep behavior disorder). These abnormalities may be reflected in the reduction in amplitude (“reactivity”) of resting‐state EEG (rsEEG) alpha rhythms (7‐9 Hz) in posterior cortical areas from eye‐closed to ‐open conditions. Indeed, this “reactivity” probes cholinergic inputs from the basal forebrain to thalamocortical mechanisms regulating vigilance. The present study tested such a hypothesis.MethodClinical and rsEEG rhythms in demographic‐ and age‐matched AD (N = 48), DLB (N = 42), and healthy cognitively unimpaired (Nold, N = 38) persons were enrolled. Pathological groups were matched as cognitive status (i.e., dementia grade). The eLORETA freeware estimated rsEEG alpha cortical sources on individual basis.ResultThere was a substantial (&gt; ‐10%) reduction in the posterior alpha source activities from the eyes‐closed to the eyes‐open condition in 93% of the Nold seniors, 77% of the ADD patients, and 64% of the DLB patients. In these participants, there was less reactivity of the posterior rsEEG alpha source activities in the ADD and DLB groups than in the Nold group. Furthermore, there was less reactivity of the occipital rsEEG alpha source activities in the DLB than in the ADD group (p &lt; 0.05 corrected; Figure 1).ConclusionThese novel results suggest that neurophysiological oscillatory mechanisms regulating cortical arousal in the visual system during changes in vigilance may be more abnormal in DLB than ADD patients with dementia, possibly concurring to visual misperceptions, hallucinations, and vigilance fluctuations reported in DLB patients as a function of cholinergic functional connectivity to visual cortical areas. Furthermore, the present results suggest that many DLB patients may suffer from a pathological transition from “reactive” posterior rsEEG alpha rhythms during eye‐opening to “unreactive” theta rhythms becoming a dominant background frequency. Importantly, this transition may be erroneously considered as “alpha” if the reactivity of those rsEEG rhythms is not tested during both eyes‐closed and ‐opening conditions.

Different cutoffs definitions to evaluate the concordance between CSF Ab42 and Ab42/Ab40 across neurodegenerative diseases

AbstractBackgroundCerebrospinal fluid (CSF) Aβ1‐42 and the Aβ1‐42/Aβ1‐40 ratio are markers of amyloid pathology. We aimed to compare their agreement in different neurodegenerative disorders applying different cutoffs.MethodWe included 1564 participants from the Sant Pau Initiative on Neurodegeneration (SPIN), with AD, dementia with Lewy bodies (DLB), frontotemporal lobar degeneration‐related syndromes (FTLD), cognitively impaired but non‐neurodegenerative conditions (others), and cognitively normal individuals (CN). Cutoffs were defined as one‐sided 97.5%, 95% and 90% (Q97.5%, Q95% and Q90%, respectively) quantiles values in a middle‐aged cognitively normal population. These cutoffs for Aβ1‐42 (617 pg/mL, 637 pg/mL and 732 pg/mL, respectively) and Aβ1‐42/Aβ1‐40 (0.060, 0.070 and 0.082, respectively) were used to classify all participants as “positive” or “negative” according to each marker. We compared concordance of Aβ1‐42 and the Aβ1‐42/Aβ1‐40 ratio between groups through X2 test and correlations with Spearman test.ResultCorrelation between Aβ1‐42 and the Aβ1‐42/Aβ1‐40 ratio in CSF was strong (0.71, p&lt;0.001) in the whole cohort, DLB and others groups (0.69 and 0.64, respectively, both p&lt;0.0001); correlation was weak in AD, FTLD and CN groups (0.33, 0.52 and 0.51, respectively, all p&lt;0.0001). Using Q97.5%, Q95% and Q90% cutoffs, Aβ1‐42 and ratio had an overall agreement of 76.6%, 78.3% and 82.9%, respectively in the whole sample. Both measures were normal (« negative ») in 46.1%, 41.6% and 35.8%, and both were abnormal (« positive ») in 30.5%, 36.7% and 47.1% of participants, respectively. Within each diagnostic category, the agreement ranged from 64% (AD) to 91.5% (CN) using Q97.5%, from 69.6% (AD) to 88.7% (CN) using Q95% and from 78.9% (DLB) to 85.9% (AD) using Q90%. Regardless of the cutoff definition, most discordant cases in AD and DLB were due to normal Aβ1‐42 and low ratio, while discordant cases in FTLD were more frequently due to low Aβ1‐42 and normal ratio.ConclusionAlthough Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio may reflect the same pathophysiological pathway, their agreement depends on cutoff definition. Our results confirm that both parameters show medium to high concordance, and that in case of discordance, Aβ1‐42 positivity with negative ratio is more associated to non‐AD dementias, independently of the cutoff used.

Neural Correlates of Photophobia in Prodromal and Mild Dementia with Lewy Bodies.

Photophobia is a sensory disturbance provoked by light. Little is known about the association between photophobia and dementia with Lewy bodies (DLB). In this study, we aimed to identify the frequency and the neural basis of photophobia in prodromal and mild DLB. One hundred thirteen DLB patients, 53 Alzheimer's disease (AD) patients, 20 AD and DLB patients, 31 patients with other neurocognitive diseases - including prodromal and mild demented patients -, and 31 healthy elderly controls were included in this case-control study. Photophobia was systematically looked for and compared between groups. Among a selection of 77 DLB patients, we used voxel-based morphometry (VBM) to compare those with and those without photophobia (gray matter volume; SPM12, XjView and Matlab R2021b software). The frequency of photophobia was higher in the DLB group (47.3%) than in the other groups (P=.002). The photophobia questionnaire score was higher in the DLB group than in the AD group (P=.001). Comparison between DLB patients with and those without photophobia showed decreased gray matter in the photophobia subgroup, in the right precentral cortex, in the eyelid motor region of Penfield's homunculus (P=.007, FWE corrected). Photophobia is a quite frequent symptom of prodromal and mild DLB. The neural basis of photophobia in DLB involves the right precentral cortex, which could have a role in the decrease of cerebral excitability, but also the motricity of the eyelids.

β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies.

β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB. We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and APOE ε4 status on PiB SUVR along the DLB continuum. Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB (p < 0.001) and MCI-LB (p = 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in APOE ε4 carriers compared with that in APOE ε4 noncarriers in MCI-LB (p < 0.001) and DLB groups (p = 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014, p = 0.02). In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically, APOE ε4 carriers had higher Aβ levels than APOE ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.