Who am I with my Lewy bodies? The insula as a core region of the self-concept networks.

BACKGROUND: Dementia with Lewy bodies (DLB) is characterized by insular atrophy, which occurs at the early stage of the disease. Damage to the insula has been associated with disorders reflecting impairments of the most fundamental components of the self, such as anosognosia, which is a frequently reported symptom in patients with Lewy bodies (LB). The purpose of this study was to investigate modifications of the self-concept (SC), another component of the self, and to identify neuroanatomical correlates, in prodromal to mild DLB. METHODS: Twenty patients with prodromal to mild DLB were selected to participate in this exploratory study along with 20 healthy control subjects matched in terms of age, gender, and level of education. The Twenty Statements Test (TST) was used to assess the SC. Behavioral performances were compared between LB patients and control subjects. Three-dimensional magnetic resonance images (MRI) were acquired for all participants and correlational analyses were performed using voxel-based morphometry (VBM) in whole brain and using a mask for the insula. RESULTS: The behavioral results on the TST showed significantly impaired performances in LB patients in comparison with control subjects (p < .0001). Correlational analyses using VBM revealed positive correlations between the TST and grey matter volume within insular cortex, right supplementary motor area, bilateral inferior temporal gyri, right inferior frontal gyrus, and left lingual gyrus, using a threshold of p = .001 uncorrected, including total intracranial volume (TIV), age, and MMSE as nuisance covariates. Additionally, correlational analysis using a mask for the insula revealed positive correlation with grey matter volume within bilateral insular cortex, using a threshold of p = .005. CONCLUSIONS: The behavioral results confirm the existence of SC impairments in LB patients from the prodromal stage of the disease, compared to matched healthy controls. As we expected, VBM analyses revealed involvement of the insula, among that of other brain regions, already known to be involved in other self-components. While this study is exploratory, our findings provide important insights regarding the involvement of the insula within the self, confirming the insula as a core region of the self-networks, including for high-order self-representations such as the SC.

Alteration of medial temporal lobe metabolism related to Alzheimer's disease and dementia with lewy bodies.

BACKGROUND: Association of medial temporal lobe (MTL) metabolism with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) has not been evaluated considering their mixed disease (MD). METHODS: 131 patients with AD, 133 with DLB, 122 with MD, and 28 normal controls (NCs) underwent neuropsychological tests, assessments for parkinsonism, cognitive fluctuation (CF), and visual hallucinations (VH), and 18F-fluorodeoxyglucose PET to quantify MTL metabolism in the amygdala, hippocampus, and entorhinal cortex. The effects of AD and DLB on MTL metabolism were evaluated using general linear models (GLMs). Associations between MTL metabolism, cognition, and clinical features were evaluated using GLMs or logistic regression models separately performed for the AD spectrum (NC + AD + MD), DLB spectrum (NC + DLB + MD), and disease groups (AD + DLB + MD). Covariates included age, sex, and education. RESULTS: AD was associated with hippocampal/entorhinal hypometabolism, whereas DLB was associated with relative amygdalar/hippocampal hypermetabolism. Relative MTL hypermetabolism was associated with lower attention/visuospatial/executive scores and severe parkinsonism in both the AD and DLB spectra and disease groups. Left hippocampal/entorhinal hypometabolism was associated with lower verbal memory scores, whereas right hippocampal hypometabolism was associated with lower visual memory scores in both the AD spectrum and disease groups. Relative MTL hypermetabolism was associated with an increased risk of CF and VH in the disease group, and relative amygdalar hypermetabolism was associated with an increased risk of VH in the DLB spectrum. CONCLUSIONS: Entorhinal-hippocampal hypometabolism and relative amygdala-hippocampal hypermetabolism could be characteristics of AD- and DLB-related neurodegeneration, respectively.

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

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

Identifying Mixed Dementia With Lewy Bodies and Alzheimer Disease Using Multitracer PET Imaging: A Case Study.

ABSTRACT: We reported imaging findings with complex signs that were corresponded with both dementia with Lewy bodies (DLB) and Alzheimer disease (AD) in the case of a 78-year-old woman. Initially suspected as DLB due to cognitive and movement issues, diagnostic support included the cingulate island sign on 18 F-FDG PET, positive 131 I-MIBG cardiac scintigraphy, and DAT PET. However, MRI indicated hippocampal atrophy, and 18 F-FDG PET showed hypometabolism in the medial temporal lobe, suggesting the possibility of concomitant AD. Subsequent detection of ß-amyloid pathology and tau accumulation in the brain further supported the concurrent presence of AD pathology.

Identifying parkinsonism in mild cognitive impairment.

INTRODUCTION: Clinical parkinsonism is a core diagnostic feature for mild cognitive impairment with Lewy bodies (MCI-LB) but can be challenging to identify. A five-item scale derived from the Unified Parkinson's Disease Rating Scale (UPDRS) has been recommended for the assessment of parkinsonism in dementia. This study aimed to determine whether the five-item scale is effective to identify parkinsonism in MCI. METHODS: Participants with MCI from two cohorts (n = 146) had a physical examination including the UPDRS and [123I]-FP-CIT SPECT striatal dopaminergic imaging. Participants were classified as having clinical parkinsonism (P+) or no parkinsonism (P-), and with abnormal striatal dopaminergic imaging (D+) or normal imaging (D-). The five-item scale was the sum of UPDRS tremor at rest, bradykinesia, action tremor, facial expression, and rigidity scores. The ability of the scale to differentiate P+D+ and P-D- participants was examined. RESULTS: The five-item scale had an AUROC of 0.92 in Cohort 1, but the 7/8 cut-off defined for dementia had low sensitivity to identify P+D+ participants (sensitivity 25%, specificity 100%). Optimal sensitivity and specificity was obtained at a 3/4 cut-off (sensitivity 83%, specificity 88%). In Cohort 2, the five-item scale had an AUROC of 0.97, and the 3/4 cut-off derived from Cohort 1 showed sensitivity of 100% and a specificity of 82% to differentiate P+D+ from P-D- participants. The five-item scale was not effective in differentiating D+ from D- participants. CONCLUSIONS: The five-item scale is effective to identify parkinsonism in MCI, but a lower threshold must be used in MCI compared with dementia.

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

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

Getting to the heart of Lewy body disease.

Early identification of neurodegenerative diseases before extensive neuronal loss or disabling symptoms have occurred is imperative for effective use of disease-modifying therapies. Emerging data indicate that central Lewy body diseases - Parkinson disease and dementia with Lewy bodies - can begin in the peripheral nervous system, opening up a therapeutic window before central involvement. In this issue of the JCI, Goldstein et al. report that cardiac 18F-dopamine positron emission tomography reveals lower activity selectively in individuals with several self-reported Parkinson disease risk factors who later develop Parkinson disease or dementia with Lewy bodies. Accurately identifying which at-risk individuals will develop central Lewy body disease will optimize early patient selection for disease-modifying therapies.

Functional connectivity in Lewy body disease with visual hallucinations.

BACKGROUND AND PURPOSE: Visual hallucinations are a common, potentially distressing experience of people with Lewy body disease (LBD). The underlying brain changes giving rise to visual hallucinations are not fully understood, although previous models have posited that alterations in the connectivity between brain regions involved in attention and visual processing are critical. METHODS: Data from 41 people with LBD and visual hallucinations, 48 with LBD without visual hallucinations and 60 similarly aged healthy comparator participants were used. Connections were investigated between regions in the visual cortex and ventral attention, dorsal attention and default mode networks. RESULTS: Participants with visual hallucinations had worse cognition and motor function than those without visual hallucinations. In those with visual hallucinations, reduced functional connectivity within the ventral attention network and from the visual to default mode network was found. Connectivity strength between the visual and default mode network correlated with the number of correct responses on a pareidolia task, and connectivity within the ventral attention network with visuospatial performance. CONCLUSIONS: Our results add to evidence of dysfunctional connectivity in the visual and attentional networks in those with LBD and visual hallucinations.

Gray matter loss relates to dual task gait in Lewy body disorders and aging.

BACKGROUND: Within the spectrum of Lewy body disorders (LBD), both Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by gait and balance disturbances, which become more prominent under dual-task (DT) conditions. The brain substrates underlying DT gait variations, however, remain poorly understood in LBD. OBJECTIVE: To investigate the relationship between gray matter volume loss and DT gait variations in LBD. METHODS: Seventy-nine participants including cognitively unimpaired PD, PD with mild cognitive impairment, PD with dementia (PDD), or DLB and 20 cognitively unimpaired controls were examined across a multi-site study. PDD and DLB were grouped together for analyses. Differences in gait speed between single and DT conditions were quantified by dual task cost (DTC). Cortical, subcortical, ventricle, and cerebellum brain volumes were obtained using FreeSurfer. Linear regression models were used to examine the relationship between gray matter volumes and DTC. RESULTS: Smaller amygdala and total cortical volumes, and larger ventricle volumes were associated with a higher DTC across LBD and cognitively unimpaired controls. No statistically significant interaction between group and brain volumes were found. Adding cognitive and motor covariates or white matter hyperintensity volumes separately to the models did not affect brain volume and DTC associations. CONCLUSION: Gray matter volume loss is associated with worse DT gait performance compared to single task gait, across cognitively unimpaired controls through and the LBD spectrum. Impairment in DT gait performance may be driven by age-related cortical neurodegeneration.

A systematic literature review of fMRI and EEG resting-state functional connectivity in Dementia with Lewy Bodies: Underlying mechanisms, clinical manifestation, and methodological considerations.

Previous studies suggest that there may be important links between functional connectivity, disease mechanisms underpinning the Dementia with Lewy Body (DLB) and the key clinical symptoms, but the exact relationship remains unclear. We performed a systematic literature review to address this gap by summarising the research findings while critically considering the impact of methodological differences on findings. The main methodological choices of fMRI articles included data-driven, seed-based or regions of interest approaches, or their combinations. Most studies focused on examining large-scale resting-state networks, which revealed a consistent decrease in connectivity and some associations with non-cognitive symptoms. Although the inter-network connectivity showed mixed results, the main finding is consistent with theories positing disconnection between visual and attentional areas of the brain implicated in the aetiology of psychotic symptoms in the DLB. The primary methodological choice of EEG studies was implementing the phase lag index and using graph theory. The EEG studies revealed a consistent decrease in connectivity on alpha and beta frequency bands. While the overall trend of findings showed decreased connectivity, more subtle changes in the directionality of connectivity were observed when using a hypothesis-driven approach. Problems with cognition were also linked with greater functional connectivity disturbances. In summary, connectivity measures can capture brain disturbances in the DLB and remain crucial in uncovering the causal relationship between the networks' disorganisation and underlying mechanisms resulting in psychotic, motor, and cognitive symptoms of the DLB.

Impaired cholinergic integrity of the colon and pancreas in dementia with Lewy bodies.

Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = -0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = -0.52, P = 0.0104) and a measure of non-motor symptoms (rs = -0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia.

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

PURPOSE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Dopamine transporter positron emission tomography in patients with Alzheimer's disease with Lewy body disease features.

In 36 normal controls (NC), 37 patients with Alzheimer's disease (AD) without parkinsonism (ADP-), 31 AD with parkinsonism (ADP+), and 40 AD with dementia with Lewy bodies (ADDLB), dual-phase dopamine transporter (DAT) positron emission tomography (PET) were performed to evaluate the diagnostic performance of DAT and early-to-delayed uptake ratios (E/Ds) in the anterior caudate (AC), posterior caudate (PC), anterior putamen (AP), posterior putamen (PP), and substantia nigra (SN) to differentiate ADP+/ADDLB from NC, and their effects on parkinsonism and cognition. DAT-SN and E/D-PP showed higher accuracies to differentiate ADP+/ADDLB from NC than DAT-PP. Among AD patients, lower DAT in the putamen and PC and higher E/Ds in the striatum were associated with severe parkinsonism, while higher E/Ds in the putamen, PC, and SN were associated with executive dysfunction. Our results suggest that decreased DAT-SN and increased E/D-PP could be biomarkers differentiating ADP+/ADDLB from pure AD and controls. Meanwhile, increased E/Ds in the putamen could reflect the severity of DLB presenting with parkinsonism and executive dysfunction among AD patients.

Differential diagnosis of MCI with Lewy bodies and MCI due to Alzheimer's disease by visual assessment of occipital hypoperfusion on SPECT images.

PURPOSE: Predicting progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) is important. We evaluated morphological and functional differences between MCI with Lewy bodies (MCI-LB) and MCI due to AD (MCI-AD), and a method for differentiating between these conditions using brain MRI and brain perfusion SPECT. METHODS: A continuous series of 101 subjects, who had visited our memory clinic and met the definition of MCI, were enrolled retrospectively. They were consisted of 60 MCI-LB and 41 MCI-AD subjects. Relative cerebral blood flow (rCBF) on SPECT images and relative brain atrophy on MRI images were evaluated. We performed voxel-based analysis and visually inspected brain perfusion SPECT images for regional brain atrophy, occipital hypoperfusion and the cingulate island sign (CIS), for differential diagnosis of MCI-LB and MCI-AD. RESULTS: MRI showed no significant differences in regional atrophy between the MCI-LB and MCI-AD groups. In MCI-LB subjects, occipital rCBF was significantly decreased compared with MCI-AD subjects (p < 0.01, family wise error [FWE]-corrected). Visual inspection of occipital hypoperfusion had sensitivity, specificity, and accuracy values of 100%, 73.2% and 89.1%, respectively, for differentiating MCI-LB and MCI-AD. Occipital hypoperfusion was offered higher diagnostic utility than the CIS. CONCLUSIONS: The occipital lobe was the region with significantly decreased rCBF in MCI-LB compared with MCI-AD subjects. Occipital hypoperfusion on brain perfusion SPECT may be a more useful imaging biomarker than the CIS for visually differentiating MCI-LB and MCI-AD.

Tau in dementia with Lewy bodies.

OBJECTIVE: Neurofibrillary tangles are present in a proportion of people with dementia with Lewy bodies and may be associated with worse cognition. Recent advances in biomarkers for Alzheimer's disease include second-generation tau positron emission tomography as well as the detection of phosphorylated tau at threonine 181 (p-tau181) in plasma. This study aimed to investigate tau in people with dementia with Lewy bodies using a second-generation tau positron emission tomography tracer as well as plasma p-tau181. METHODS: Twenty-seven participants (mean age 74.7 ± 5.5) with clinically diagnosed probable dementia with Lewy bodies underwent comprehensive clinical assessment and positron emission tomography imaging (18F-MK6240 and 18F-NAV4694). Plasma p-tau181 levels were measured using Simoa technology. RESULTS: Five dementia with Lewy bodies participants (18.5%) had an abnormal tau positron emission tomography (increased tau uptake in the temporal meta-region-of-interest). Higher plasma p-tau181 concentrations correlated with higher tau deposition in the temporal region (ρ = 0.46, 95% confidence interval = [0.10, 0.72]) and classified abnormal tau positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.95 (95% confidence interval = [0.86, 0.99]). Plasma p-tau181 also correlated positively with cortical amyloid-beta binding (ρ = 0.68, 95% confidence interval = [0.40, 0.84]) and classified abnormal amyloid-beta positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.91 (95% confidence interval = [0.79, 0.99]). There was no association found between tau deposition and any of the clinical variables. CONCLUSIONS: Tau is a common co-pathology in dementia with Lewy bodies. Plasma p-tau181 correlated with abnormal tau and amyloid-beta positron emission tomography and may potentially be used as a marker to identify co-morbid Alzheimer's disease-related pathology in dementia with Lewy bodies. The clinical implications of tau in dementia with Lewy bodies need to be further evaluated in larger longitudinal studies.

Sex differences in brain atrophy in dementia with Lewy bodies.

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

Diagnostic performance of the cingulate island sign ratio for differentiating dementia with Lewy bodies from Alzheimer's disease changes depending on the mini-mental state examination score.

BACKGROUND: The cingulate island sign (CIS) ratio is a diagnostic adjunct for differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). A recent study showed that the CIS ratio in DLB changed depending on the Mini-Mental State Examination (MMSE) score. We aimed to evaluate whether the diagnostic performance (sensitivity and specificity) of the CIS ratio for differentiating DLB from AD changes depending on the MMSE score. METHODS: Twenty-two patients with DLB and 26 amyloid-positive patients with AD, who underwent 18F-FDG PET and completed an MMSE examination, were classified into three groups according to MMSE scores: Group A (MMSE >24), Group B (20 ≤ MMSE ≤24), and Group C (MMSE <20). In each group, we compared the CIS ratio between patients with DLB and AD and conducted receiver operating characteristic (ROC) curve analysis to calculate the sensitivity and specificity. RESULTS: Within Group B, the CIS ratio in DLB was significantly higher than that in AD (p = 0.0005), but not within Groups A (p = 0.5117) and C (p = 0.8671). ROC curve analyses showed that the sensitivities and specificities of the CIS ratio for differentiating DLB from AD were 66.7% and 77.8% in Group A, 91.7% and 100.0% in Group B, and 75.0% and 66.7% in Group C, respectively. CONCLUSIONS: The present study suggests that the diagnostic performance of the CIS ratio for differentiating DLB from AD changes depending on the MMSE score, with higher sensitivity and specificity at MMSE scores of 20-24.

Cardiac 18F-dopamine positron emission tomography predicts the type of phenoconversion of pure autonomic failure.

PURPOSE: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), no known secondary cause, and lack of a neurodegenerative movement or cognitive disorder. Clinically diagnosed PAF can evolve ("phenoconvert") to a central Lewy body disease [LBD, e.g., Parkinson's disease (PD) or dementia with Lewy bodies (DLB)] or to the non-LBD synucleinopathy multiple system atrophy (MSA). Since cardiac 18F-dopamine-derived radioactivity usually is low in LBDs and usually is normal in MSA, we hypothesized that patients with PAF with low cardiac 18F-dopamine-derived radioactivity would be more likely to phenoconvert to a central LBD than to MSA. METHODS: We reviewed data from all the patients seen at the National Institutes of Health Clinical Center from 1994 to 2023 with a clinical diagnosis of PAF and data about 18F-dopamine positron emission tomography (PET). RESULTS: Nineteen patients (15 with low 18F-dopamine-derived radioactivity, 4 with normal radioactivity) met the above criteria and had follow-up data. Nine (47%) phenoconverted to a central synucleinopathy over a mean of 6.6 years (range 1.5-18.8 years). All 6 patients with low cardiac 18F-dopamine-derived radioactivity who phenoconverted during follow-up developed a central LBD, whereas none of 4 patients with consistently normal 18F-dopamine PET phenoconverted to a central LBD (p = 0.0048), 3 evolving to probable MSA and 1 upon autopsy having neither a LBD nor MSA. CONCLUSION: Cardiac 18F-dopamine PET can predict the type of phenoconversion of PAF. This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs.

Midbrain atrophy in pathologically diagnosed Lewy body disease and clinically diagnosed Parkinson's disease.

OBJECTIVE: Midbrain atrophy is considered specific to progressive supranuclear palsy (PSP) compared with Parkinson's disease (PD). We aimed to determine how often midbrain atrophy is observed in pathologically diagnosed Lewy body disease (LBD) and clinically diagnosed PD and the robustness of midbrain atrophy assessed by the One-Line Method previously developed for the diagnosis of PSP. METHODS: We studied two separate cohorts with MRI: the first pathologically diagnosed cohort consisted of patients with LBD (n = 13), PSP (n = 6), multiple system atrophy (MSA, n = 7), and corticobasal degeneration (CBD, n = 2); the second cohort consisted of patients with PD (n = 122). Midbrain length was measured using the One-Line Method and FreeSurfer estimated volumes of the subcortical nuclei. RESULTS: The area under the curve of midbrain length differentiating PSP from LBD, MSA, and CBD in a pathologically diagnosed cohort was 0.91. Midbrain length with cut-off values of 10.5 mm and 9.5 mm had a sensitivity of 100% and 67% and a specificity of 68% and 96%, respectively. In the first cohort, 7.7% and 23.0% of patients with LBD showed midbrain lengths <9.5 mm and 10.5 mm, respectively, and in the second cohort, 4.9% and 19.7% showed midbrain lengths <9.5 mm and 10.5 mm, respectively. INTERPRETATION: Midbrain length measured using the One-Line Method is helpful in the diagnosis of PSP. Some cases of pathologically diagnosed LBD and clinically diagnosed PD present with midbrain atrophy.

Brain olfactory-related atrophy in isolated rapid eye movement sleep behavior disorder.

OBJECTIVE: To investigate structural and functional connectivity changes in brain olfactory-related structures in a longitudinal prospective cohort of isolated REM sleep behavior disorder (iRBD) and their clinical correlations, longitudinal evolution, and predictive values for phenoconversion to overt synucleinopathies, especially Lewy body diseases. METHODS: The cohort included polysomnography-confirmed iRBD patients and controls. Participants underwent baseline assessments including olfactory tests, neuropsychological evaluations, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, 3T brain MRI, and 18 F-FP-CIT PET scans. Voxel-based morphometry (VBM) was performed to identify regions of atrophy in iRBD, and volumes of relevant olfactory-related regions of interest (ROI) were estimated. Subgroups of patients underwent repeated volumetric MRI and resting-state functional MRI (fMRI) scans after four years. RESULTS: A total of 51 iRBD patients were included, with 20 of them converting to synucleinopathy (mean time to conversion 3.08 years). Baseline VBM analysis revealed atrophy in the right olfactory cortex and gyrus rectus in iRBD. Subsequent ROI comparisons with controls showed atrophy in the amygdala. These olfactory-related atrophies tended to be associated with worse depression, anxiety, and urinary problems in iRBD. Amygdala 18 F-FP-CIT uptake tended to be reduced in iRBD patients with hyposmia (nonsignificant after multiple comparison correction) and correlated with urinary problems. Resting-state fMRI of 23 patients and 32 controls revealed multiple clusters with aberrant olfactory-related functional connectivity. Hypoconnectivity between the putamen and olfactory cortex was associated with mild parkinsonian signs in iRBD. Longitudinal analysis of volumetric volumetric MRI in 22 iRBD patients demonstrated four-year progression of olfactory-related atrophy. Cox regression analysis revealed that this atrophy significantly predicted phenoconversion. INTERPRETATION: Progressive atrophy of central olfactory structures may be a potential indicator of Lewy body disease progression in iRBD.