Dementia With Lewy Bodies Subjects Research Articles

Eating problems in people with dementia with Lewy bodies: Associations with various symptoms and the physician's understanding.

Eating problems frequently occur in people with dementia with Lewy bodies (DLB), but few studies have investigated the clinical background of this phenomenon. This study examined the relationship between eating problems and various symptoms of DLB and the relation between the treatment needs for DLB people with eating problems and the understanding of their eating problems by caregivers and physicians. This was a subanalysis of a cross-sectional, questionnaire-based survey study. Two hundred sixty-one subjects with DLB were divided into subjects with or without eating problems. Logistic or linear regression analysis was used to investigate the factors influencing eating problems. The treatment needs of DLB people for their eating problems and the understanding of these needs by caregivers and physicians were calculated as participant-caregiver and participant-physician kappa coefficient. Of the 261 participants, 27% suffered from eating problems. The presence of eating problems in participants with DLB was related to depression (p = 0.01, OR : 2.19, 95% CI: 1.23-3.91) and apathy (p = 0.01, OR 2.15, 95% CI: 1.20-3.87), while the worsening of eating problems was related to dysphagia (β = 0.24, p = 0.03), apathy (β = 0.23, p = 0.05), and nighttime behavior (β = 0.24, p = 0.04). The participant-physician kappa coefficient for physician understanding of constipation, weight loss, dysphagia, weight gain, and increase in appetite was significantly lower than the corresponding participant-caregiver kappa coefficient (p-value of five symptoms < 0.01). Physicians need to pay more attention to eating problems and their neuropsychiatric background in the long-term support and management of DLB subjects.

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

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

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.

ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium.

The National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis. The cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated. We observed a significant difference in Aβ42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage. This suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity. Some A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.

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.

Assessment of Plasma Biomarkers by ImmunoMagnetic Reduction in Parkinson’s Disease Dementia and Dementia with Lewy Bodies (P10-6.008)

<h3>Objective:</h3> To use ImmunoMagnetic Reduction (IMR) assay to assess the diagnostic utility of plasma Aβ42, total Tau (t-Tau), phosphorylated Tau-181 (p-Tau-181) and α-synuclein in identifying and differentiating cases of Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). <h3>Background:</h3> PDD and DLB represent pathological subtypes along a continuum of synucleinopathies. Clinical differentiation is ultimately based on arbitrary and subjectively-reported timing of cognitive and motor symptoms. Ancillary tests are invasive, costly, and exhibit suboptimal sensitivity and specificity. Developments in plasma biomarker assays have increased detection thresholds and provide the opportunity to reassess whether core PDD/DLB plasma biomarkers would be useful for diagnosis. <h3>Design/Methods:</h3> Plasma samples from 61 total subjects (37 normal controls (NC), 12 with PDD, 12 with DLB) and were sent for IMR assay to quantify α-synuclein, Aβ42, t-Tau, and p-Tau-181. To determine discrimination between NC, PDD, and DLB, receiver operating characteristic (ROC) curve analysis was used to obtain sensitivity, specificity, and area under curve (AUC). <h3>Results:</h3> Plasma p-tau levels were significantly higher in DLB compared to NC and PD (p&lt;0.05). Plasma α-synuclein levels were significantly higher in PDD compared to DLB and NC. Plasma t-Tau and Aβ42 levels did not differ between NC, PDD and DLB subjects. When plasma biomarkers were combined, Aβ42 x t-Tau revealed no differences between DLB, PDD and NC. For the α-synuclein x p-Tau-181 combination, both PDD and DLB were greater than NC. <h3>Conclusions:</h3> Investigations into the discrimination of DLB vs. PDD are rare. In this pilot study, we show that IMR assays of plasma for α-synuclein, p-Tau-181, and Aβ42 x t-tau are useful in differentiating PDD from DLB, as well as NC. Thus, our data suggest clinical utility of these novel biomarker modalities and panels. Differentiating DLB from PDD could be consequential in clinical characterization. Future studies will aim to replicate our findings on larger group sizes. <b>Disclosure:</b> Dr. Malaty has nothing to disclose. Dr. Lue has nothing to disclose. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amneal Pharmaceuticals. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine Biosciences. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbive. Dr. Decourt has received personal compensation for serving as an employee of Cleveland Clinic. Dr. Decourt has received personal compensation in the range of $0-$499 for serving as a Reviewer with NIH. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genetech=Roche. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Synaptogenix. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for T3D. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for EIP Pharma. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Quince-Cortexyme. Dr. Sabbagh has stock in Neurotau. Dr. Sabbagh has stock in Seq Biomarque. Dr. Sabbagh has stock in uMethod Health. Dr. Sabbagh has stock in Athira. Dr. Sabbagh has stock in Lighthouse Pharmaceuticals. Dr. Sabbagh has stock in Alzheom. The institution of Dr. Sabbagh has received research support from NIH. The institution of Dr. Sabbagh has received research support from ADDF. Dr. Sabbagh has received publishing royalties from a publication relating to health care.

Identifying mixed Lewy body and Alzheimer’s disease pathologies using functional neuroimaging (P6-12.002)

<h3>Objective:</h3> To distinguish between Alzheimer’s disease, Lewy body dementia and Parkinson’s disease using functional neuroimaging. <h3>Background:</h3> Lewy body dementia (LBD) and Alzheimer’s disease (AD) are the two most common neurodegenerative causes of dementia. Autopsy studies report many cases with these clinical diagnoses having mixed pathology with alpha-synuclein, tau and amyloid proteinopathies. There is limited research in trying to distinguish these potential mixed pathology conditions prior to death. <h3>Design/Methods:</h3> 43 subjects were recruited from Ohio State University Memory Disorder and Movement Clinics. Subjects were diagnosed based on standard clinical criteria for DLB, PD and AD by fellowship trained cognitive and movement disorders faculty. Cognitive testing performed included MMSE and SAGE. We used neuroimaging methods including FDG PET, amyloid PET, and DaTscan SPECT to evaluate subjects diagnosed with dementia with Lewy bodies (DLB), AD and PD to investigate how often potential mixed pathologies could be present. The neuroimaging evaluations were blinded to clinical diagnosis. <h3>Results:</h3> 28 subjects with clinical diagnosis of Lewy body disease (15 DLB and 13 PD) and 15 subjects with clinical diagnosis AD were compared. The Lewy body subjects were 69.5 ± 7.2 years old, MMSE 26.6 ± 4, and SAGE 18.4 ± 4.7. AD subjects were 68.4 ± 9.3 years old, MMSE 16.3 ± 6.4, and SAGE 7.4 ± 6.1. 5 subjects (33%) of the clinical AD cases showed abnormal DAT scan uptake, 3 subjects (20%) of the clinical AD cases were negative for amyloid with normal DaTscan uptake, 3 subjects (20%) of the clinical DLB cases showed mixed LBD and AD features, 2 subjects (13%) of the clinical DLB cases were positive for amyloid with normal DaTscan uptake, and 1 (8%) subject with clinical PD had normal DAT scan. <h3>Conclusions:</h3> Based on functional neuroimaging, 26% of clinically diagnosed AD or DLB subjects had evidence of potential mixed pathologies and 25% were misdiagnosed. <b>Disclosure:</b> Dr. Bouchachi has nothing to disclose. Ms. Truelove has nothing to disclose. Ms. Rawson has nothing to disclose. Mrs. Icenhour has nothing to disclose. Michael Knopp has nothing to disclose. Prof. Wright has a non-compensated relationship as a Board of Directors Member with American Board of Science in Nuclear Medicine that is relevant to AAN interests or activities. Dr. Scharre has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for BrainTest, Inc. Dr. Scharre has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vascular Scientific. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acadia. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Acadia. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Scharre has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Hickman &amp; Lowder Co.. The institution of Dr. Scharre has received research support from InSightec. The institution of Dr. Scharre has received research support from Alzheimer’s Therapeutic Research Institute (ATRI). The institution of Dr. Scharre has received research support from Eisai. The institution of Dr. Scharre has received research support from vTv Therapeutics. The institution of Dr. Scharre has received research support from National Institute of Health. The institution of Dr. Scharre has received research support from Eli Lilly. The institution of Dr. Scharre has received research support from Johns Hopkins. The institution of Dr. Scharre has received research support from Biogen. The institution of Dr. Scharre has received research support from Roche. The institution of Dr. Scharre has received research support from AZ Therapies. The institution of Dr. Scharre has received research support from Biohaven. The institution of Dr. Scharre has received research support from Novartis. The institution of Dr. Scharre has received research support from Avanir. The institution of Dr. Scharre has received research support from PrecisionMed, Inc. Dr. Scharre has received intellectual property interests from a discovery or technology relating to health care. Dr. Scharre has received intellectual property interests from a discovery or technology relating to health care.

Muscarinic Receptors Expression in the Peripheral Blood Cells Differentiate Dementia with Lewy Bodies from Alzheimer's Disease.

Central nervous system disruption of cholinergic (ACh) signaling, which plays a major role in cognitive processes, is well documented in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). The expression of muscarinic ACh receptors type 1 and 4 (CHRM1 and CHRM4) has been reported to be altered in the brain of DLB patients. We aim to assess the peripheral gene expression of CHRM1 and 4 in DLB as a possible marker as compared to AD and healthy control (HC) subjects. Peripheral blood mononuclear cells were collected from 21 DLB, 13 AD, and 8 HC matched subjects. RT-PCR was performed to estimate gene expression of CHRM1 and CHRM4. Peripheral CHRM1 expression was higher and CHRM4 was lower in DLB and AD compared to HC, whereas both CHRM1 and CHRM4 levels were higher in AD compared to DLB patients. Receiver operating characteristics curves, with logistic regression analysis, showed that combining peripheral CHRM1 and CHRM4 levels, DLB and AD subjects were classified with an accuracy of 76.0%. Alterations of peripheral CHRM1 and CHRM4 was found in both AD and DLB patients as compared to HC. CHRM1 and CHRM4 gene expression resulted to be lower in DLB patients compared to AD. In the future, peripheral CHRM expression could be studied as a possible marker of neurodegenerative conditions associated with cholinergic deficit and a possible marker of response to acetylcholinesterase inhibitors.

Identifying mixed Lewy body and Alzheimer’s disease pathologies using functional neuroimaging

AbstractBackgroundLewy body dementia (LBD) and Alzheimer’s disease (AD) are the two most common neurodegenerative causes of dementia. Autopsy studies report many cases with these clinical diagnoses having mixed pathology with alpha‐synuclein, tau and amyloid proteinopathies. There is limited research in trying to distinguish these potential mixed pathology conditions prior to death. We used functional neuroimaging methods including FDG PET, amyloid PET, and DaTscan SPECT to evaluate clinically diagnosed subjects with dementia with Lewy bodies (DLB), AD and PD to investigate how often potential mixed pathologies could be present.MethodEighteensubjects (all Caucasian, male/female ratio 15:3) so far were recruited from Ohio State University Memory Disorder and Movement Disorder Clinics in this currently enrolling study. Subjects were diagnosed based on standard clinical criteria for DLB, PD and AD by fellowship trained cognitive and movement disorders faculty. Cognitive testing including Mini‐Mental State Examination (MMSE) and Self‐Administered Gerocognitive Examination (SAGE) were performed. Neuroimaging evaluations performed by neuroradiology faculty were blinded to clinical diagnosis.ResultNine subjects with clinical diagnosis of Lewy body disease (5 DLB and 4 PD) and nine subjects with clinical diagnosis AD were compared. The Lewy body subjects were 71.3 ± 7.4 years old, MMSE 22.3 ± 5.4, and SAGE 9.7 ± 4.8. AD subjects were 67.1 ± 9.6 years old, MMSE 18.6 ± 5.2, and SAGE 9.0 ± 5.2. One subject (11%) of the clinical AD cases showed mixed LBD and AD features, one subject (11%) of the clinical AD cases was negative for amyloid with normal DaTscan uptake, two subjects (40%) of the clinical DLB cases showed mixed LBD and AD features, one subject (20%) of the clinical DLB cases was positive for amyloid with normal DaTscan uptake, and all four subjects with clinical PD showed neuroimaging findings consistent with PD.ConclusionBased on functional neuroimaging, 21% of clinically diagnosed AD or DLB subjects had evidence of potential mixed pathologies and 14% were misdiagnosed. Although the sample size is small, functional neuroimaging studies revealed possibly incomplete or incorrect diagnoses in about one third of subjects clinically diagnosed by subspecialists using standard clinical diagnostic criteria. Larger studies are required to confirm these findings.

Dissecting the Interplay Between Time of Dementia and Cognitive Profiles in Lewy Body Dementias.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are differentiated by the time of onset of cognitive and motor symptoms ('1-year rule'). We explored the neuropsychological continuum of DLB and PDD subjects with different timing of dementia onset. Our aim was to compare the neuropsychological profile of DLB and PDD patients with different timing of dementia onset. Neuropsychological findings at the diagnosis of dementia of 66 PDD and 42 DLB patients were retrospectively compared. Patients with PDD were divided into three tertile subgroups according to the time interval between the onset of parkinsonism and dementia (N = 24, 2-4 years; N = 17, 5-7 years; N = 25 ≥8 years, respectively). DLB patients performed worse on the Stroop and semantic fluency tests than PDD, even in comparison to PD with early dementia onset. No significant differences among PDD subgroups were reported. Executive and semantic language tests could differentiate DLB and PD patients with earlier development of dementia relative to parkinsonism.

Altered structural connectivity networks in dementia with lewy bodies

The impairment of large-scale brain networks has been observed in dementia with Lewy bodies (DLB) using functional connectivity, but the potential for an analogous effect on structural covariance patterns has not been determined. Twenty-four probable DLB subjects (mean age 74.3 ± 6.7 years, 16.7% female) and 23 similarly aged Controls were included. All participants underwent 3T MRI imaging with high-resolution T1-weighted magnetization-prepared rapid gradient echo (MPRAGE) sequence. Graph theoretical analyses were performed using variation in regional cortical thickness to construct a structural association matrix with pairwise Pearson correlations. Global and nodal graph parameters were computed to assess between-group differences and community structure was studied in order to quantify large-scale brain networks in both groups. In comparison to Controls, DLB subjects had decreased global efficiency, clustering, modularity and small-worldness of structural networks (all p < 0.05). Nodal measures showed that DLB subjects also had decreased clustering in bilateral temporal regions and decreased closeness centrality in extensive areas including right middle frontal, left cingulate and bilateral occipital lobe (all false-discovery rate (FDR)-corrected q < 0.05). Whereas four distinct modules could be clearly identified in Controls, DLB showed extensively disorganized modules, including default-mode network and dorsal attentional network. Our results suggest a marked impairment in large-scale brain structural networks in DLB, mirroring functional connectivity networks disruption.

Premotor and fronto-striatal mechanisms associated with presence hallucinations in dementia with Lewy bodies

Introductionpresence hallucinations (PH) are frequent in dementia with Lewy bodies (DLB), but their cortico-subcortical origin is unknown. Recent studies have defined key frontal and temporal areas contributing to the occurrence of PH (PH-network) and tested their relevance in subjects with Parkinson’s disease (PD). With the present study, we aimed at disentangling the metabolic and dopaminergic correlates of pH as well as their relation to a recently defined PH brain network in DLB. Methodsfor the present study, we included 34 DLB subjects (10 with PH (PH + ); 24 without PH (PH-)), who underwent 18F-FDG PET and 123I-FP-CIT SPECT imaging. We performed 18F-FDG PET group comparisons, as well as interregional correlation analyses using 18F-FDG PH-network regions as a seed. ResultsPH + versus PH- had reduced 18F-FDG uptake in precentral, superior frontal and parietal gyri, involving ventral premotor cortex (vPMC) of the PH-network that showed strongly reduced functional connectivity with bilateral cortical regions. 18F-FDG vPMC uptake was negatively correlated with caudate 123I-FP-CIT uptake in PH+ (p = 0.028) and interregional correlation analysis seeding from the vPMC showed widespread fronto-parietal 18F-FDG decreases in PH + . Discussionthese findings uncover the pivotal role of vPMC (involved in a PH-network) and its cortico-striatal connections in association with PH in DLB, improving our understanding of psychosis in neurodegeneration.

Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF.

Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease where synaptic loss and reduced synaptic integrity are important neuropathological substrates. Neuronal Pentraxin 2(NPTX2) is a synaptic protein that drives the GABAergic inhibitory circuit. Our aim was to examine if NPTX2 cerebral spinal fluid (CSF) levels in DLB patients were altered and how these levels related to other synaptic protein levels and to cognitive function and decline. Methods: NPTX2, VGF, and α-synuclein levels were determined in CSF of cognitive healthy (n = 27), DLB (n = 48), and AD (n = 20) subjects. Multiple cognitive domains were tested, and data were compared using linear models. Results: Decreased NPTX2 levels were observed in DLB (median = 474) and AD (median = 453) compared to cognitive healthy subjects (median = 773). Strong correlations between NPTX2, VGF, and α-synuclein were observed dependent on diagnosis. Combined, these markers had a high differentiating power between DLB and cognitive healthy subjects (AUC = 0.944). Clinically, NPTX2 levels related to global cognitive function and cognitive decline in the visual spatial domain. Conclusion: NPTX2 CSF levels were reduced in DLB and closely correlated to decreased VGF and α-synuclein CSF levels. CSF NPTX2 levels in DLB related to decreased functioning in the visual spatial domain.

Proteomic Characterization of the Olfactory Molecular Imbalance in Dementia with Lewy Bodies.

Olfactory dysfunction is one of the prodromal symptoms in dementia with Lewy bodies (DLB). However, the molecular pathogenesis associated with decreased smell function remains largely undeciphered. We generated quantitative proteome maps to detect molecular alterations in olfactory bulbs (OB) derived from DLB subjects compared to neurologically intact controls. A total of 3214 olfactory proteins were quantified, and 99 proteins showed significant alterations in DLB cases. Protein interaction networks disrupted in DLB indicated an imbalance in translation and the synaptic vesicle cycle. These alterations were accompanied by alterations in AKT/MAPK/SEK1/p38 MAPK signaling pathways that showed a distinct expression profile across the OB–olfactory tract (OT) axis. Taken together, our data partially reflect the missing links in the biochemical understanding of olfactory dysfunction in DLB.

Specific occupational profiles as proxies of cognitive reserve induce neuroprotection in dementia with Lewy bodies.

Cognitive reserve (CR) delays cognitive decline due to neurodegeneration. Heterogeneous evidence suggests that education may act as CR in Dementia with Lewy Bodies (DLB). No data, however, are currently available on the role of occupation as proxy of CR in this neuropathology. Thirty-three patients with probable DLB were retrospectively included. We performed regression analyses models (TFCE p< 0.05) and seed-based interregional correlation analyses (p= 0.001, FWE-corrected at cluster-level) with brain metabolism. We aimed at exploring the relationship between brain metabolic connectivity, as assessed by FDG-PET, in the relevant resting-state networks and CR proxies (education, 6-levels occupation, and the specific O*Net occupational profiles). Education modulates executive (ECN), attentive (ATTN) and posterior default mode (PDMN) networks in the highly educated DLB subjects, as shown by an increased metabolic connectivity, acting as a compensatory mechanism. High scores of the 6-levels occupation scale were associated with a decreased connectivity in the anterior default mode (ADMN) and high visual network (HVN), suggesting brain reserve mechanisms. As for the specific O*Net occupational profiles, these modulated ADMN, PDMN, ATTN, ECN, HVN and primary visual network (PVN) connectivity according to different neuroprotection mechanisms, namely neural reserve and compensation against neurodegeneration. This study highlights the relevance of life-long occupational activities at individual level in the neural expression of compensatory and neuroprotective mechanisms in DLB.

Evidence that the Kennedy and polyamine pathways are dysregulated in human brain in cases of dementia with Lewy bodies

Disruptions of brain metabolism are considered integral to the pathogenesis of dementia, but thus far little is known of how dementia with Lewy bodies (DLB) impacts the brain metabolome. DLB is less well known than other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease which is perhaps why it is under-investigated. This exploratory study aimed to address current knowledge gaps in DLB research and search for potentially targetable biochemical pathways for therapeutics. It also aimed to better understand metabolic similarities and differences with other dementias. Combined metabolomic analyses of 1H NMR and tandem mass spectrometry of neocortical post-mortem brain tissue (Brodmann region 7) from autopsy confirmed cases of DLB (n = 15) were compared with age/gender-matched, non-cognitively impaired healthy controls (n = 30). Following correction for multiple comparisons, only 2 metabolites from a total of 219 measured compounds significantly differed. Putrescine was suppressed (55.4%) in DLB and O-phosphocholine was elevated (52.5%). We identified a panel of 5 metabolites (PC aa C38:4, O-Phosphocholine, putrescine, 4-Aminobutyrate, and SM C16:0) capable of accurately discriminating between DLB and control subjects. Deep Learning (DL) provided the best predictive model following 10-fold cross validation (AUROC (95% CI) = 0.80 (0.60–1.0)) with sensitivity and specificity equal to 0.92 and 0.88, respectively. Altered brain levels of putrescine and O-phosphocholine indicate that the Kennedy pathway and polyamine metabolism are perturbed in DLB. These are accompanied by a consistent underlying trend of lipid dysregulation. As yet it is unclear whether these are a cause or consequence of DLB onset.

123I-FP-CIT SPECT validation of nigro-putaminal MRI tractography in dementia with Lewy bodies

BackgroundAssessment of nigrostriatal degeneration is a key element to discriminate between dementia with Lewy bodies (DLB) and Alzheimer disease (AD), and it is often evaluated using ioflupane (123I-FP-CIT) single-photon emission computed tomography (SPECT). Given the limited availability of 123I-FP-CIT SPECT, we evaluated if a mask-based approach to nigroputaminal magnetic resonance imaging (MRI) diffusion-weighted tractography could be able to capture microstructural changes reflecting nigroputaminal degeneration in DLB.MethodsA nigroputaminal bundle mask was delineated on 12 healthy volunteers (HV) and applied to MRI diffusion-weighted data of 18 subjects with DLB, 21 subjects with AD and another group of 12 HV. The correlation between nigroputaminal fractional anisotropy (FA) values and 123I-FP-CIT SPECT findings was investigated. Shapiro-Wilk, ANOVA, ANCOVA, and parametric correlation statistics as well as receiver operating characteristic (ROC) analysis were used.ResultsDLB patients showed a higher nigroputaminal FA values compared with both AD and HV-controls groups (p = 0.001 for both comparisons), while no difference was observed between HV-controls and AD groups (p = 0.450); at ROC analysis, the area under the curve for the discriminating DLB and AD subjects was 0.820; FA values correlated with 123I-FP-CIT values (on the left, r = -0.670; on the right, r = -720). No significant differences were observed for the FA of the corticospinal tract across the three groups (p = 0.740).ConclusionsIn DLB, nigroputaminal degeneration could be reliably assessed on MRI diffusion scans using a mask of nigroputaminal bundle trajectory. Nigroputaminal FA in DLB patients correlated with 123I-FP-CIT values data may allow to differentiate these patients from AD patients and HV-controls.

Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer's disease dementia.

Many subjects with neuropathologically-confirmed dementia with Lewy bodies (DLB) are never diagnosed during life, instead being categorized as Alzheimer’s disease dementia (ADD) or unspecified dementia. Unrecognized DLB therefore is a critical impediment to clinical studies and treatment trials of both ADD and DLB. There are studies that suggest that olfactory function tests may be able to distinguish DLB from ADD, but few of these had neuropathological confirmation of diagnosis. We compared University of Pennsylvania Smell Identification Test (UPSIT) results in 257 subjects that went on to autopsy and neuropathological examination. Consensus clinicopathological diagnostic criteria were used to define ADD and DLB, as well as Parkinson’s disease with dementia (PDD), with (PDD+AD) or without (PDD-AD) concurrent AD; a group with ADD and Lewy body disease (LBD) not meeting criteria for DLB (ADLB) and a clinically normal control group were also included. The subjects with DLB, PDD+AD and PDD-AD all had lower (one-way ANOVA p < 0.0001, pairwise Bonferroni p < 0.05) first and mean UPSIT scores than the ADD, ADLB or control groups. For DLB subjects with first and mean UPSIT scores less than 20 and 17, respectively, Firth logistic regression analysis, adjusted for age, gender and mean MMSE score, conferred statistically significant odds ratios of 17.5 and 18.0 for the diagnosis, vs ADD. For other group comparisons (PDD+AD and PDD-AD vs ADD) and UPSIT cutoffs of 17, the same analyses resulted in odds ratios ranging from 16.3 to 31.6 (p < 0.0001). To our knowledge, this is the largest study to date comparing olfactory function in subjects with neuropathologically-confirmed LBD and ADD. Olfactory function testing may be a convenient and inexpensive strategy for enriching dementia studies or clinical trials with DLB subjects, or conversely, reducing the inclusion of DLB subjects in ADD studies or trials.

Prevalence and Clinical Implications of the Mirror and TV Signs in Advanced Alzheimer’s Disease and Dementia with Lewy Bodies

Objective: To explore the prevalence and clinical implications of the mirror and TV signs in the moderate to advanced stages of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Methods: We retrospectively examined the prevalence of clinical and psychiatric symptoms including the mirror and TV signs in 200 subjects with AD and 200 with DLB and evaluated the relationships among the symptoms. Results: The mirror sign was found in 3.0% of AD and 4.5% of DLB subjects. The TV sign was found in 1.5% of AD and 4.0% of DLB subjects. The prevalence of the mirror and TV signs was not significantly different between the AD and DLB groups. Visual hallucination, visual illusion, misidentification of person, and sleep talking were significantly more frequent in DLB than in AD subjects. The mirror sign was significantly associated with lower Mini-Mental State Examination scores, whereas the TV sign was significantly associated with the misidentification of person. Conclusions: Both the mirror and TV signs were rare even in the moderate to advanced stages of AD and DLB. The mirror sign may be independent from other delusional misidentification syndromes (DMSs). Being associated mainly with global cognitive decline, the mirror sign is unlikely attributed to any specific cognitive impairment or the dysfunction of localized brain areas. In contrast, the TV sign was significantly more often coexistent with the misidentification of person, suggesting that the TV sign may partly share common neuropsychological mechanisms with DMSs.

Microbleeds in dementia with Lewy bodies

IntroductionMicrobleeds are associated with the development of dementia in older people and are common in Alzheimer’s disease (AD). Their prevalence and clinical importance in dementia with Lewy bodies (DLB) is unclear. The objective of this study was to compare the rates of microbleeds in DLB with those in AD and healthy older people, and investigate associations between microbleeds and amyloid deposition, vascular risk and disease severity in DLB.MethodsDLB (n = 30), AD (n = 18) and control (n = 20) participants underwent clinical assessment at baseline and 1 year in this longitudinal observational study. 3T MRI (including T2* susceptibility weighted imaging) and florbetapir PET were carried out at baseline. Microbleeds were rated visually and a standardised uptake value ratio (SUVR) was calculated from florbetapir PET scans.Results40% of DLB subjects had microbleeds compared with 50% of AD and 15% of controls. Compared to DLB without microbleeds, those with microbleeds had higher systolic BP (156 ± 26 v. 135 ± 19 mmHg; p = 0.03), but did not have greater levels of vascular disease or amyloid deposition (SUVR 1.25 ± 0.24 v. 1.25 ± 0.22; p = 0.33). There was evidence of less severe dementia in DLB participants with microbleeds, but these differences may have been driven by a shorter disease duration in those with microbleeds.ConclusionThe presence of microbleeds in DLB is associated with higher blood pressure, but not with other measures of vascular disease or amyloid deposition. The relationship between microbleeds and clinical presentation remains unclear.