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Purpose: Although neuropathological comorbidities, including Alzheimer's disease neuropathological change (AD-NC) and limbic-predominant age-related TAR DNA-binding protein 43encephalopathy neuropathological change (LATE-NC), are associated with medial temporal atrophy in patients with Lewy body disease (LBD), the diagnostic performance of magnetic resonance imaging (MRI)-derived indices remains unclear. This study aimed to investigate the diagnostic performance of MRI-derived indices representing medial temporal atrophy in differentiating between LBD with AD-NC and/or LATE-NC (mixed LBD [mLBD]) and without these comorbidities (pure LBD [pLBD]). Methods: This study included 24 and 16 patients with pathologically confirmed mLBD and pLBD, respectively. In addition to the well-known medial temporal atrophy and entorhinal cortex atrophy (ERICA) scores, the cross-sectional areas of the bilateral entorhinal cortices/parahippocampal gyri (ABEP) were segmented manually. Results: Even incorporating various covariates such as age at MRI examination, sex, argyrophilic grain, the MRI-derived indices, especially ABEP, significantly correlated with the severity of AD-NC, and showed a trend of correlation with LATE-NC. For the differentiation between all mLBD and pLBD, the ERICA score and ABEP demonstrated higher diagnostic performance (area under the receiver-operating-characteristic curve [AUC] of 0.80 and 0.87, respectively). Additionally, the highest diagnostic performance for ABEP (AUC, 0.94; sensitivity, 100%; specificity, 88.9%; accuracy, 96%) was observed in differentiating between pLBD and mLBD with two comorbidities (AD-NC and LATE-NC). Conclusion: In patients with pathologically confirmed LBD, medial temporal atrophy was significantly correlated with AD-NC, and showed a trend of correlation with LATE-NC. Moreover, MRI-derived indices indicative of medial temporal atrophy were useful in diagnosing these comorbidities. [ABSTRACT FROM AUTHOR]

Rare and common GBA variants are risk factors for both Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (β: −0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0–1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease–risk associations of GBA in PD, PD dementia, and DLB. [ABSTRACT FROM AUTHOR]

Aducanumab is one example of a class of amyloid-targeting antibodies proposed as treatment for early AD [[4], [9]], but few clinicopathological studies are available from patients given these treatments. Keywords: Alzheimer's disease; Amyloid; Lewy body disease; Aducanumab; Clinicopathological correlation EN Alzheimer's disease Amyloid Lewy body disease Aducanumab Clinicopathological correlation 777 781 5 10/12/23 20231101 NES 231101 Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00401-023-02631-8. The extensive tau neurofibrillary pathology suggests that either insufficient amyloid-lowering was achieved initially (remaining > 25 CL) or that tau spreading and propagation continue after amyloid-lowering unless maintenance dosing is administered. [Extracted from the article]

To investigate the clinical impact of mild behavioral impairment (MBI) in a predefined cohort with Lewy body disease (LBD) continuum. Eighty-four patients in the LBD continuum participated in this study, including 35 patients with video-polysomnography-confirmed idiopathic REM sleep behavior disorder (iRBD) and 49 clinically established LBD. Evaluations included the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), neuropsychological tests, and MBI Checklist (MBI-C). We examined the clinical associates of MBI-C and its diagnostic values in predicting disease severity and cognitive impairment across the LBD continuum. Participants were classified into 19 cognitively normal (CN), 45 mild cognitive impairment (MCI), and 20 dementia groups. Median MBI-C total scores were 1.0, 8.0, and 18.5 for CN, MCI, and dementia groups, respectively, with a significant increasing trend (p < 0.001). The MBI-C total score demonstrated significant correlations with the MDS-UPDRS part 1 (r = 0.504, p < 0.001) and total scores (r = 0.508, p < 0.001). Furthermore, significant correlations were observed between MBI-C and cognitive performances in frontal/executive (DSC: r = −0.314, p = 0.006; TMT-B: r = −0.338, p = 0.003) and attentional (TMT-A: r = −0.343, p = 0.002) domains. A cutoff 5.0 effectively differentiated the MCI from CN groups (area under the curve (AUC = 0.74). Furthermore, the MBI-C effectively discriminated the iRBD patients with high phenoconversion risk against those with low-risk (cut-off 4.0, AUC = 0.72). The MBI-C may be a useful screening questionnaire reflecting clinical severity across the LBD continuum. Longitudinal studies are needed to determine its value in monitoring disease progression in prodromal LBD. [ABSTRACT FROM AUTHOR]

Key Summary Points: Aim: To describe the clinical features and geriatric syndromes in newly diagnosed dementia with Lewy bodies (DLB). Findings: Functional impairment, urinary incontinence, polypharmacy, depressive symptoms, and fall history were found in more than half of the DLB participants. Women had more functional impairment than men. Message: Even in the mild stages of DLB, most of participants functionally impaired, indicating high comorbidity and geriatric syndrome burden. A comprehensive geriatric assessment is needed to help establish treatment strategies and interventions in DLB patients. Purpose: Identifying the associated clinical conditions in patients with newly diagnosed dementia with Lewy bodies (DLB) may contribute to the disease management. This study aimed to examine the clinical features and coexisting geriatric syndromes of patients with newly diagnosed DLB. Method: This cross-sectional study included newly diagnosed DLB participants who were admitted to a tertiary geriatric outpatient clinic. Of the 857 patients with dementia, 116 DLB diagnoses were eligible for analysis. The core and supportive clinical features of DLB were recorded. Geriatric syndromes including polypharmacy, depression, insomnia, dependency, a history of delirium, falls, malnutrition, urinary incontinence, functional impairment, and living alone, were assessed and recorded at baseline. Results: The mean age was 79.0 ± 6.9 years, and 50.9% of the participants were female. The majority (63.8%) had mild dementia, 31.9% had moderate, and 4.3% had severe disease. Cognitive fluctuations (78.4%), visual hallucinations (77.6%), and Parkinsonism (73.3%) were the most common clinical features. Functional impairment (59.5%) and urinary incontinence (59.5%) were the leading geriatric syndromes, followed by polypharmacy (56.9%), depressive symptoms (54.7%), falls (52.6%), insomnia (49.1%), malnutrition (24.3%), and delirium (6.0%). Women had more functional impairment and depressive symptoms than men. Conclusion: Although most patients had mild dementia, three-quarters of the DLB cohort had hallucinations, and nearly two-thirds were functionally impaired. The proportion of other serious health conditions also increased, indicating a high comorbidity and geriatric syndrome burden. Comprehensive geriatric assessment is strongly recommended for DLB patients from the time of diagnosis until death to reduce disability and comorbidities. The Clinical Trial registration number: NCT05052450. [ABSTRACT FROM AUTHOR]

Objectives: Glucocerebrosidase (GBA) gene may be a risk factor for dementia with Lewy bodies (DLB). However, due to the small number of existing studies and the small sample size of previous investigations, it is necessary to conduct objective and quantitative analyses of the association between GBA variants and DLB. There is no consensus regarding the relationship between GBA and the clinical characteristics of DLB. Therefore, we conducted multiple systematic reviews and meta-analyses with a particular focus on the age of onset, sex, and cognitive impairment.Methods: PubMed, Cochrane, and EMBASE databases were searched to retrieve related studies. The odds ratios and 95% confidence interval were calculated to determine the association between GBA and DLB and between GBA and the clinical characteristics of DLB.Results: Our meta-analysis confirmed that the GBA variant rate was significantly higher in the DLB group than in the control group, as were the variant rates of L444P, N370S, and E326K, whereas the variant rate of T369M showed no significant difference between the groups. Furthermore, the relevant literature was summarised again for meta-analyses. The GBA variant group had a younger age of onset and lower Montreal Cognitive Assessment score than the GBA non-variant group in DLB patients. GBA variants do not differ between sexes in DLB patients.Conclusions: GBA variants increased the risk of DLB, especially N370S, E326K, and L444P which are strongly associated with DLB, but T369M was not. Patients harbouring GBA variants have an earlier age of onset, more severe cognitive impairment, and rapid symptom progression; however, sex is irrelevant in DLB. [ABSTRACT FROM AUTHOR]

Objective: The clinical significance of decreased physiological lung uptake of 123I-metaiodobenzylguanidine (MIBG) has not been well investigated. This study aimed to elucidate the association between a decrease in lung MIBG uptake with antidepressant intake and the myocardial MIBG uptake in patients who were clinically diagnosed with Lewy body disease (LBD) and patients who were diagnosed as not having LBD. Methods: We retrospectively reviewed the heart and lung uptakes on 167 consecutive MIBG scans, antidepressant status, and clinical diagnosis of LBD. The images were visually classified into two groups: decreased lung uptake and preserved lung uptake. A semi-quantitative analysis was performed using the heart-to-mediastinum ratio (H/M), lung-to-mediastinum ratio (L/M), and myocardial washout rate (WR). Results: All 17 patients with decreased lung uptake were on treated with antidepressants, while none of the 150 patients with preserved lung uptake were treated with any antidepressants. Of the 17 patients with decreased lung uptake, 6 patients were clinically diagnosed as LBD and other 11 were clinically diagnosed as non-LBD. There was not significant difference in early H/M, delayed H/M, and myocardial WR between the 11 non-LBD patients with decreased lung uptake and 83 non-LBD patients with preserved lung uptake (2.87 ± 0.69 vs. 2.89 ± 0.44, 3.09 ± 0.48 vs. 2.98 ± 0.59, and 21.8 ± 11.3% vs. 21.1 ± 12.5%, respectively). Moreover, in LBD patients, there were no significant differences in those values between six patients with decreased lung uptake and 67 patients with preserved lung uptake (1.68 ± 0.32 vs. 1.73 ± 0.42, 1.34 ± 0.21 vs. 1.54 ± 0.57, 46.2 ± 22.8% vs. 42.8 ± 21.3%, respectively). Conclusions: Antidepressants probably blocked MIBG uptake in the lungs, and a decreased lung uptake was not significantly associated with heart uptake. A remarkable decrease in lung uptake can be a signal to check a patient's medication status. [ABSTRACT FROM AUTHOR]

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by the accumulation of TAR-DNA-binding protein 43 (TDP-43) aggregates in older adults. LATE coexists with Lewy body disease (LBD) as well as other neuropathological changes including Alzheimer's disease (AD). We aimed to identify the pathological, clinical, and genetic characteristics of LATE in LBD (LATE-LBD) by comparing it with LATE in AD (LATE-AD), LATE with mixed pathology of LBD and AD (LATE-LBD + AD), and LATE alone (Pure LATE). We analyzed four cohorts of autopsy-confirmed LBD (n = 313), AD (n = 282), LBD + AD (n = 355), and aging (n = 111). We assessed the association of LATE with patient profiles including LBD subtype and AD neuropathologic change (ADNC). We studied the morphological and distributional differences between LATE-LBD and LATE-AD. By frequency analysis, we staged LATE-LBD and examined the association with cognitive impairment and genetic risk factors. Demographic analysis showed LATE associated with age in all four cohorts and the frequency of LATE was the highest in LBD + AD followed by AD, LBD, and Aging. LBD subtype and ADNC associated with LATE in LBD or AD but not in LBD + AD. Pathological analysis revealed that the hippocampal distribution of LATE was different between LATE-LBD and LATE-AD: neuronal cytoplasmic inclusions were more frequent in cornu ammonis 3 (CA3) in LATE-LBD compared to LATE-AD and abundant fine neurites composed of C-terminal truncated TDP-43 were found mainly in CA2 to subiculum in LATE-LBD, which were not as numerous in LATE-AD. Some of these fine neurites colocalized with phosphorylated α-synuclein. LATE-LBD staging showed LATE neuropathological changes spread in the dentate gyrus and brainstem earlier than in LATE-AD. The presence and prevalence of LATE in LBD associated with cognitive impairment independent of either LBD subtype or ADNC; LATE-LBD stage also associated with the genetic risk variants of TMEM106B rs1990622 and GRN rs5848. These data highlight clinicopathological and genetic features of LATE-LBD. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies remains underdiagnosed in clinical practice mainly because of the low sensitivity of existing diagnostic criteria and a strong overlap with Alzheimer's pathology that can mask the Lewy phenotype. Objective: The objective of this study was therefore to develop and validate a new clinical scale designed to detect signs of Lewy body disease, called LeSCoD for Lewy body Screening scale in Cognitive Disorders. Methods: 128 patients who fulfilled the clinical criteria of dementia with Lewy bodies (DLB; n = 32), Alzheimer's disease (AD; n = 77) or both (n = 19) was prospectively enrolled. 18F-DOPA PET imaging and/or CSF biomarkers were available in some patients. LeSCoD scale was systematically administered and the potential correlation with 18F-DOPA PET imaging was evaluated in a subgroup of patients. Results: LeSCoD scale showed robust internal and external validity. We determined a cut-off of 10 above which the sensitivity and specificity for Lewy body disease diagnosis were 86% and 95%, respectively. The LeSCoD scale correlated with striatal dopamine uptake in 18F-DOPA PET. Conclusion: LeSCoD scale is a simple and reliable tool for the evaluation of Lewy body disease in routine clinical practice, with a higher sensitivity and specificity than the existing criteria. It might be an alternative to the use of dopamine-specific imaging. [ABSTRACT FROM AUTHOR]

Objective: To use arterial spin labelling to investigate differences in perfusion in mild cognitive impairment with Lewy bodies (MCI-LB) compared to Alzheimer type MCI (MCI-AD) and healthy controls. Methods: We obtained perfusion images on 32 MCI-LB, 30 MCI-AD and 28 healthy subjects of similar age. Perfusion relative to cerebellum was calculated, and we aimed to examine differences in relative perfusion between MCI-LB and the other groups. This included whole brain voxelwise comparisons, as well as using predefined region-of-interest ratios of medial occipital to medial temporal, and posterior cingulate to precuneus. Differences in occipital perfusion in eyes open vs eyes closed conditions were also examined. Results: Compared to controls, the MCI-LB showed reduced perfusion in the precuneus, parietal, occipital and fusiform gyrus regions. In our predefined regions, the ratio of perfusion in occipital/medial temporal was significantly lower, and the posterior cingulate/precuneus ratio was significantly higher in MCI-LB compared to controls. Overall, the occipital perfusion was greater in the eyes open vs closed condition, but this did not differ between groups. Conclusion: We found patterns of altered perfusion in MCI-LB which are similar to those seen in dementia with Lewy bodies, with reduction in posterior parietal and occipital regions, but relatively preserved posterior cingulate. [ABSTRACT FROM AUTHOR]

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., "absent" vs. "present") and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff's α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff's α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP. [ABSTRACT FROM AUTHOR]

Lewy body disease (LBD) is a spectrum of progressive neurodegenerative disorders characterized by the wide distribution of Lewy bodies and neurites in the central and peripheral nervous system (CNS, PNS). Clinical diagnoses include Parkinson's disease (PD), dementia with Lewy bodies, or pure autonomic failure. All types of LBD are accompanied by non-motor symptoms (NMSs) including gastrointestinal dysfunctions such as constipation. Its relationship to Lewy body-related α-synucleinopathy (Lewy pathology) of the enteric nervous system (ENS) is attracting attention because it can precede the motor symptoms. To clarify the role of ENS Lewy pathology in disease progression, we performed a clinicopathological study using the Brain Bank for Aging Research in Japan. Five-hundred and eighteen cases were enrolled in the study. Lewy pathology of the CNS and PNS, including the lower esophagus as a representative of the ENS, was examined via autopsy findings. Results showed that one-third of older people (178 cases, 34%) exhibited Lewy pathology, of which 78 cases (43.8%) exhibited the pathology in the esophagus. In the esophageal wall, Auerbach's plexus (41.6%) was most susceptible to the pathology, followed by the adventitia (33.1%) and Meissner's plexus (14.6%). Lewy pathology of the esophagus was significantly associated with autonomic failures such as constipation (p < 0.0001) and among PNS regions, correlated the most with LBD progression (r = 0.95, p < 0.05). These findings suggest that the propagation of esophageal Lewy pathology is a predictive factor of LBD. [ABSTRACT FROM AUTHOR]

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to analyze the association of autonomic dysfunction with cognition, depression, apathy, and fatigue in Lewy body disease (LBD). Methods: We included 61 patients [49 with idiopathic Parkinson's disease, 7 with dementia with Lewy bodies, and 5 E46K-SNCA mutation carriers] and 22 healthy controls. All participants underwent a comprehensive battery of neuropsychological and clinical measures, autonomic symptom assessment with the SCOPA-AUT, analysis of non-invasive hemodynamic parameters during deep breathing, the Valsalva maneuver, and a 20-min tilt test, and electrochemical skin conductance measurement at rest (Sudoscan). Student's t tests were used to assess group differences, and bivariate correlations and stepwise linear regressions to explore associations between autonomic function, cognition, depression, apathy, and fatigue. Results: Compared to controls, patients who had significant impairment (p < 0.05) in cognition, higher depression, apathy, and fatigue, more autonomic symptoms and objective autonomic dysfunction, reduced deep breathing heart rate variability [expiratory-to-inspiratory (E/I) ratio], prolonged pressure recovery time, and lower blood pressure in Valsalva late phase II and phase IV, while 24.1% had orthostatic hypotension in the tilt test. Autonomic parameters significantly correlated with cognitive and neuropsychiatric outcomes, systolic blood pressure during the Valsalva maneuver predicting apathy and depression. The E/I ratio was the main predictor of cognitive performance (17.6% for verbal fluency to 32.8% for visual memory). Conclusion: Cardiovascular autonomic dysfunction is associated with cognitive and neuropsychiatric impairment in LBD, heart rate variability during deep breathing and systolic blood pressure changes during the Valsalva procedure are the main predictors of neuropsychological performance and depression/apathy symptoms, respectively. [ABSTRACT FROM AUTHOR]

Purpose: The functional imaging methods widely used for the diagnosis of Lewy body disease (LBD) are 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropan (FP-CIT) with dopamine transporter single photon emission computed tomography (DAT-SPECT) and 123I-iodobenzylguanidine (MIBG) myocardial scintigraphy. The aim of this study was to determine whether DAT-SPECT or 123I-MIBG myocardial scintigraphy should be examined first and to evaluate whether the combined use of DAT-SPECT and MIBG myocardial scintigraphy is superior to using either modality alone for diagnosing suspected LBD.Methods: In this retrospective study, a total of 117 patients suspected of having LBD underwent DAT-SPECT imaging followed by MIBG myocardial scintigraphy. The delayed heart-to-mediastinum (H/M) ratio of MIBG scintigraphy, and the specific binding ratio (SBR) of DAT-SPECT imaging, and Combined index (defined as SBR mean × H/M in the delayed phase) were used as semi-quantitative measures. The diagnostic ability was evaluated using these indexes.Results: The sensitivity, specificity, and accuracy of diagnosing Lewy body disease were 59.6%, 71.4%, and 67.5% by SBR mean of DAT-SPECT, 85.1%, 91.4%, and 88.9% by delayed H/M ratio of MIBG myocardial scintigraphy, 76.6%, 74.3%, and 75.2% by Combined index, respectively.Conclusion: In the diagnosis of LBD, DAT-SPECT, MIBG myocardial scintigraphy, and Combined index may be reliable indices. In particular, MIBG myocardial scintigraphy was the specific modality for LBD diagnosis. Understanding the effectiveness and limits of DAT-SPECT and MIBG myocardial scintigraphy and using both properly will lead to a more accurate diagnosis and better treatment. [ABSTRACT FROM AUTHOR]

Background: Trans-active response DNA-binding protein of 43 kDa (TDP-43) can be detected in up to 63% of autopsy-confirmed Lewy body disease (LBD) cases. It is unclear whether TDP-43 is associated with a decreased likelihood of a clinical diagnosis of probable dementia with Lewy bodies (pDLB) during life. Methods: In an autopsy cohort of 395 cognitively impaired patients from the Mayo Clinic Alzheimer's Disease Research Center, we determined the presence of TDP-43 in the hippocampus [hTDP-43(+)] and examined associations between hTDP-43 and an antemortem pDLB clinical diagnosis with multiple regression analyses. For this study, given our specific question, we only counted transitional and diffuse Lewy body disease as LBD positive (LBD+). Results: One-hundred forty-five cases (37%) were hTDP-43(+) and 156 (39%) were LBD+; co-pathology was noted in 63 (16%) cases. Patients with pDLB− LBD+ were more likely to be older, hTDP-43(+) and have high Braak neurofibrillary tangle (NFT) status compared to the pDLB+ LBD+ patients. After accounting for older age at death and high Braak NFT status, hTDP-43(+) status was associated with the absence of a clinical diagnosis of pDLB despite LBD+ status (p < 0.05). Conclusion: The absence of a diagnosis of pDLB during life in patients with LBD is associated with older age, high Braak NFT stage and hTDP-43, each feature contributing independently to a lower likelihood of a clinical diagnosis of pDLB during life. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the gradual appearance of α-synuclein (α-syn)-containing neuronal protein aggregates. Although the exact mechanism of α-syn-mediated cell death remains elusive, recent research suggests that α-syn-induced alterations in neuronal excitability contribute to cell death in PD. Because the fragile X mental retardation protein (FMRP) controls the expression and function of numerous neuronal genes related to neuronal excitability and synaptic function, we here investigated the role of FMRP in α-syn-associated pathological changes in cell culture and mouse models of PD as well as in post-mortem human brain tissue from PD patients. We found FMRP to be decreased in cultured DA neurons and in the mouse brain in response to α-syn overexpression. FMRP was, furthermore, lost in the SNc of PD patients and in patients with early stages of incidental Lewy body disease (iLBD). Unlike fragile X syndrome (FXS), FMR1 expression in response to α-syn was regulated by a mechanism involving Protein Kinase C (PKC) and cAMP response element-binding protein (CREB). Reminiscent of FXS neurons, α-syn-overexpressing cells exhibited an increase in membrane N-type calcium channels, increased phosphorylation of ERK1/2, eIF4E and S6, increased overall protein synthesis, and increased expression of Matrix Metalloproteinase 9 (MMP9). FMRP affected neuronal function in a PD animal model, because FMRP-KO mice were resistant to the effect of α-syn on striatal dopamine release. In summary, our results thus reveal a new role of FMRP in PD and support the examination of FMRP-regulated genes in PD disease progression. [ABSTRACT FROM AUTHOR]

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less severe than in Alzheimer's disease. Previously, we found that familial Parkinson's disease-linked human mutant A53T αS causes aberrant localization of the microtubule-associated protein tau to postsynaptic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the synaptic and memory deficits in a mouse model of α-synucleinopathy (TgA53T) are mediated by tau. TgA53T mice exhibit progressive memory deficits associated with postsynaptic deficits in the absence of obvious neuropathological and neurodegenerative changes in the hippocampus. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau−/−), achieved by mating TgA53T mice to mouse tau-knockout mice, completely ameliorates cognitive dysfunction and concurrent synaptic deficits without affecting αS expression or accumulation of selected toxic αS oligomers. Among the known tau-dependent effects, memory deficits in TgA53T mice were associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau−/− mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results directly implicate tau as a mediator of specific human mutant A53T αS-mediated abnormalities related to deficits in hippocampal neurotransmission and suggest a mechanism for memory impairment that occurs as a consequence of synaptic dysfunction rather than synaptic or neuronal loss. We hypothesize that these initial synaptic deficits contribute to network hyperexcitability which, in turn, exacerbate cognitive dysfunction. Our results indicate that these synaptic changes present potential therapeutic targets for amelioration of memory deficits in α-synucleinopathies. [ABSTRACT FROM AUTHOR]

Objective: I-123-2β-Carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT) imaging is an established biomarker used in the diagnosis of Lewy body disease. Images are often reported with the aid of striatal binding ratios (SBRs), comparing uptake to a normal database via Z scores. It is well known that SBRs are age dependent. However, previous studies cover wide age ranges between 20 and 80 years, rather than focusing on older adults. Typically a linear relationship is reported, but some authors have suggested that SBRs do not decline as rapidly in old age. Commercial software packages usually adjust the SBR Z score to attempt to compensate for age-related decline, but the model used varies. Ensuring age correction is appropriate for older adults is important, given that the majority of patients referred for FP-CIT scans are aged over 60 years. We examined the relationship of SBR with age in older adults and the effect of age correction using research scans from 123 adults over 60 years of age.Methods: Twenty-nine healthy older adults and twenty-three with MCI due to Alzheimer's disease were included as controls, i.e. individuals with no evidence of Lewy body disease. Their ages ranged from 60 to 92 years (mean 76; SD 7.9). SBRs and Z scores were calculated using BRASS (Hermes Medical) and DaTQUANT (GE Healthcare). SBRs were plotted against age and linear mixed effect models applied. We tested the effect of removing age correction in BRASS using an independent dataset of 71 older adults with dementia or mild cognitive impairment.Results: The slopes of the linear fits between SBR and age per year were - 0.007 (p = 0.30) with BRASS and - 0.004 (p = 0.35) with DaTQUANT. The slopes are smaller than reported in the literature and show no statistically significant difference from zero. Switching age correction off in BRASS in the test subjects reduced Z scores by approximately 1 standard deviation at 80 years of age.Conclusion: We found no statistically significant age-related decline in SBR in adults over 60 years of age without Lewy body disease. Commercial software packages that apply a fixed rate of age correction may be overcorrecting for age in older adults, which could contribute to misdiagnosis. [ABSTRACT FROM AUTHOR]

This article addresses questions in the diagnosis of Lewy body dementia at the prodromal stage. Despite clinical studies using standard international criteria, cases of divergence between clinical and pathological anatomical diagnoses are not infrequent. This review addresses approaches to the early and more accurate detection of Lewy body dementia and prognostication of the course of disease, as well as problems of the optimum treatment of disease. [ABSTRACT FROM AUTHOR]

Braak et al. proposed that cases with Lewy pathology in the peripheral nervous sytem, spinal cord and brain stem are prodromal Parkinson's disease (PD), suggesting a hypothesized progression of PD pathology. However, the putative potential of peripheral α-synuclein to promote brain pathology has been questioned recently. The Braak staging is a matter of vigorous debate, since < 100% of cases with Lewy pathology fitting the proposed PD staging scheme; however, most studies assessing typical PD cases show that the vast majority (80–100%) fit the Braak staging scheme. Incidental Lewy body disease and PD can show Lewy pathology in substantia nigra or other brain areas without involvement of dorsal motor nucleus of the vagus nerve. The Braak staging system is valid for PD patients with young onset, long duration with motor symptoms, but not for others, e.g., late onset and rapid course PD. The validity of Braak staging and its relationship to various subtypes of PD warrants further studies. [ABSTRACT FROM AUTHOR]

This article describes the practical considerations in the clinical medical treatment in dementia with Lewy body (DLB) patients. It is illustrated with the voice of a DLB sufferer and his wife. According to our experience, emanating from a 15 year collaboration between a doctor and a nurse at a memory clinic, there are several possible therapeutical entrances. However, the order in which the medication is introduced is of great importance to avoid aggravation of other DLB symptoms. We start the treatment with cholinesterase inhibitor and memantine, and; thereafter, we treat the most disturbing symptom. Thereafter, we consider if orthostatic hypotension is present and treat it. In the treatment of depression and anxiety it is beneficial to use agents affecting both noradrenalin and serotonin. Dysphagia may be lethal but can be improved with carbohydrate drinks. These and other aspects are commented upon from our experience and are also reflected in relation to studies evaluating the existing level of evidence. [ABSTRACT FROM AUTHOR]

A tissue microarray (TMA) has previously been developed for use in assessment of neurodegenerative diseases. We investigated the variation of pathology loads in semi-quantitative score categories and how pathology load related to disease progression. Post-mortem tissue from 146 cases were used; Alzheimer's disease (AD) ( n = 36), Lewy body disease (LBD) ( n = 56), mixed AD/dementia with Lewy bodies ( n = 14) and controls ( n = 40). TMA blocks (one per case) were constructed using tissue cores from 15 brain regions including cortical and subcortical regions. TMA tissue sections were stained for hyperphosphorylated tau (HP-), β amyloid and α-synuclein (αsyn), and quantified using an automated image analysis system. Cases classified as Braak stage VI displayed a wide variation in HP- pathology in the entorhinal cortex (interquartile range 4.13-44.03%). The interquartile range for β amyloid in frontal cortex in cases classified as Thal phase 5 was 6.75-17.03% and for αsyn in the cingulate in cases classified as McKeith neocortical LBD was 0.04-0.58%. In AD and control cases, HP- load predicted the Braak stage ( p < 0.001), β amyloid load predicted Thal phase ( p < 0.001) and αsyn load in LBD cases predicted McKeith type of LBD ( p < 0.001). Quantitative data from TMA assessment highlight the range in pathological load across cases classified with 'severe' pathology and is beneficial to further elucidate the heterogeneity of neurodegenerative diseases. Quantifying pathology in multiple brain regions may allow identification of novel clinico-pathological phenotypes for the improvement of intra vitam stratification of clinical cohorts according to underlying pathologies. [ABSTRACT FROM AUTHOR]

Hearing deficits associated with cognitive impairment have attracted much recent interest, motivated by emerging evidence that impaired hearing is a risk factor for cognitive decline. However, dementia and hearing impairment present immense challenges in their own right, and their intersection in the auditory brain remains poorly understood and difficult to assess. Here, we outline a clinically oriented, symptom-based approach to the assessment of hearing in dementias, informed by recent progress in the clinical auditory neuroscience of these diseases. We consider the significance and interpretation of hearing loss and symptoms that point to a disorder of auditory cognition in patients with dementia. We identify key auditory characteristics of some important dementias and conclude with a bedside approach to assessing and managing auditory dysfunction in dementia. [ABSTRACT FROM AUTHOR]

Sleep and circadian disorders occur frequently in all types of dementia. Due to the multifactorial nature of sleep problems in dementia, we propose a structured approach to the evaluation and treatment of these patients. Primary sleep disorders such as obstructive sleep apnea should be treated first. Comorbid conditions and medications that impact sleep should be optimally managed to minimize negative effects on sleep. Patients and caregivers should maintain good sleep hygiene, and social and physical activity should be encouraged during the daytime. Given the generally benign nature of bright light therapy and melatonin, these treatments should be tried first. Pharmacological treatments should be added cautiously, due to the risk of cognitive side effects, sedation, and falls in the demented and older population. Regardless of treatment modality, it is essential to follow patients with dementia and sleep disorders closely, with serial monitoring of individual response to treatment. [ABSTRACT FROM AUTHOR]

Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-β protein (Aβ) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer's disease (AD) and neocortical Lewy body disease (LBD) but clinically presented either as dementia due to AD or LBD, the latter including dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Our study group consisted of 28 cases (mean age, 76.11 SE: ±1.29 years; m:f, 17:11) of which 19 were neuropathologically diagnosed as mixed AD/DLB. Clinically, 8 mixed AD/DLB cases were diagnosed as AD (cAD), 8 as DLB (cDLB) and 3 as PDD (cPDD). In addition, we investigated cases that were both clinically and neuropathologically diagnosed as either AD (pure AD; n = 5) or DLB/neocortical LBD (pure DLB; n = 4). Sections from neocortical, limbic and subcortical areas were stained with antibodies against HP-τ, Aβ and α-syn. The area covered by immunopositivity was measured using image analysis. cAD cases had higher HP-τ loads than both cDLB and cPDD and the distribution of HP-τ in cAD was similar to the one observed in pure AD whilst cDLB showed comparatively less hippocampal HP-τ load. cPDD cases showed lower HP-τ and Aβ loads and higher α-syn loads. Here, we show that in neuropathologically mixed AD/DLB cases both the amount and the topographical distribution of pathological protein aggregates differed between distinct clinical phenotypes. Large-scale clinicopathological correlative studies using a quantitative methodology are warranted to further elucidate the neuropathological correlate of clinical symptoms in cases with mixed pathology. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis (HpScl) is frequent in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), but it also occurs in dementia of the elderly with or without accompanying Alzheimer type pathology. HpScl has been hypothesized to be a neurodegenerative process given its association with TDP-43 pathology, but this is still controversial. TDP-43 pathology is found in Lewy body disease (LBD), but no study has focused on the pathologic and genetic characteristics of HpScl in LBD. We found HpScl in 5.2 % of 669 LBD cases (289 transitional and 380 diffuse). Older age, higher Braak neurofibrillary tangle (NFT) stage, and presence of TDP-43 pathology were associated with HpScl. There was no difference in the frequency of HpScl between transitional and diffuse LBD, suggesting that Lewy-related pathology appears to have no direct association with HpScl. All HpScl cases had TDP-43 pathology consistent with Type A pattern. HpScl cases harbored genetic variation in TMEM106B that has been previously associated with FTLD-TDP. Interestingly, the severity of TDP-43-positive fine neurites in CA1 sector, a possible pathologic precursor of HpScl, was associated with the TMEM106B variant. These results demonstrate HpScl in LBD is a TDP-43 proteinopathy and is similar to FTLD-TDP Type A. Furthermore, a subset of LBD cases without HpScl ('pre-HpScl') had similar pathologic and genetic characteristics to typical HpScl, suggesting that the spectrum of HpScl pathology may be wider than previously thought. Some cases with many extracellular NFTs also had a similar profile. We suggest that HpScl is 'masked' in these cases. [ABSTRACT FROM AUTHOR]

We aimed to characterize dementia with Lewy bodies (DLB) by the quantitative MRI parameters of longitudinal relaxation time (qT1) and transverse relaxation time (qT2). These parameters reflect potential pathological changes in tissue microstructures, which may be detectable noninvasively in brain areas without evident atrophy, so may have potential value in revealing the early neuropathological changes in DLB. We conducted a cross-sectional study of subjects with DLB ( N = 35) and similarly aged control participants ( N = 35). All subjects underwent a detailed clinical and neuropsychological assessment and structural and quantitative 3T MRI. Quantitative MRI maps were obtained using relaxation time mapping methods. Statistical analysis was performed on gray matter qT1 and qT2 values. We found significant alterations of quantitative parameters in DLB compared to controls. In particular, qT1 decreases in bilateral temporal lobes, right parietal lobes, basal ganglia including left putamen, left caudate nucleus and left amygdala, and left hippocampus/parahippocampus; qT2 decreases in left putamen and increases in left precuneus. These regions showed only partial overlap with areas where grey matter loss was found, making atrophy an unlikely explanation for our results. Our findings support that DLB is predominantly associated with changes in posterior regions, such as visual association areas, and subcortical structures, and that qT1 and qT2 measurement can detect subtle changes not seen on structural volumetric imaging. Hence, quantitative MRI may compliment other imaging techniques in detecting early changes in DLB and in understanding neurobiological changes associated with the disorder. [ABSTRACT FROM AUTHOR]

Lewy body diseases include Parkinson disease and dementia with Lewy bodies and are characterized by the widespread distribution of Lewy bodies in virtually every brain area. The main component of Lewy bodies is alpha-synuclein (AS). Accumulating evidence suggests that AS oligomerization and aggregation are strongly associated with the pathogenesis of Lewy body diseases. AS is a small soluble protein with aggregation-prone properties under certain conditions. These properties are enhanced by posttranslational modifications such as phosphorylation, ubiquitination, nitration, and truncation. Accordingly, Lewy bodies contain abundant phosphorylated, nitrated, and monoubiquitinated AS. However, alternative splicing of the AS gene is also known to modify AS aggregation propensities. Splicing gives rise to four related forms of the protein, the main transcript and those that lack exon 4, exon 6, or both. Since AS structure and properties have been extensively studied, it is possible to predict the consequences of the splicing out of the two aforesaid exons. The present review discusses the latest insights on the mechanisms of AS posttranslational modifications and intends to depict their role in the pathogenesis of Lewy body diseases. The implications of deregulated alternative splicing are examined as well, and a hypothesis for the development of the pure form of dementia with Lewy bodies is proposed. [ABSTRACT FROM AUTHOR]

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In this autopsy-based study, α-synuclein immunohistochemistry and lipofuscin pigment-Nissl architectonics in serial sections of 100 μm thickness were used to investigate the spinal cords and brains of 46 individuals: 28 patients with clinically and neuropathologically confirmed Parkinson's disease, 6 cases with incidental Lewy body disease, and 12 age-matched controls. α-Synuclein inclusions (particulate aggregations, Lewy neurites/bodies) in the spinal cord were present between neuropathological stages 2-6 in all cases whose brains were staged for Parkinson's disease-related synucleinopathy. The only individuals who did not have Lewy pathology in the spinal cord were a single stage 1 case (incidental Lewy body disease) and all controls. Because the Parkinson's disease-related lesions were observable in the spinal cord only after Lewy pathology was seen in the brain, it could be concluded that, within the central nervous system, sporadic Parkinson's disease does not begin in the spinal cord. In addition: (1) α-Synuclein-immunoreactive axons clearly predominated over Lewy bodies throughout the spinal cord and were visible in medial and anterior portions of the anterolateral funiculus. Their terminal axons formed dense α-synuclein-immunoreactive networks in the gray matter and were most conspicuous in the lateral portions of layers 1, 7, and in the cellular islands of layer 9. (2) Notably, this axonopathy increased remarkably in density from cervicothoracic segments to lumbosacral segments of the cord. (3) Topographically, it is likely that the spinal cord α-synuclein immunoreactive axonal networks represent descending projections from the supraspinal level setting nuclei (locus coeruleus, lower raphe nuclei, magnocellular portions of the reticular formation). (4) Following the appearance of the spinal cord axonal networks, select types of projection neurons in the spinal cord gray matter displayed α-synuclein-immunoreactive inclusions: chiefly, nociceptive neurons of the dorsal horn in layer 1, sympathetic and parasympathetic preganglionic neurons in layer 7, the cellular pools of α-motoneurons in layer 9, and the smaller motoneurons in Onuf's nucleus in layer 9 (ventral horn). The spinal cord lesions may contribute to clinical symptoms (e.g., pain, constipation, poor balance, lower urinary tract complaints, and sexual dysfunction) that occur during the premotor and motor phases of sporadic Parkinson's disease. [ABSTRACT FROM AUTHOR]

Purpose: This study was performed to demonstrate that the results obtained with a calibration phantom could be used as a tool for standardizing measurement of heart to mediastinum (H/M) ratio in cardiac metaiodobenzylguanidine (MIBG) imaging. Methods: Images of the phantom containing I-MIBG were acquired on the cameras in 10 hospitals (11 camera types) to determine the relationship between H/M ratios using different collimators: low-energy (LE) and medium-energy (ME)/low-medium-energy (LME) collimators. The effect of standardization on the ME-comparable H/M ratio was examined in two settings: a Japanese standard MIBG database ( n = 62) and multicentre studies ( n = 49). In a multicentre study, probable Alzheimer's disease (AD, n = 18) and probable dementia with Lewy bodies (DLB, n = 31) were studied and standardized by the calibration phantom method. Results: Linear regression equations between LE and ME collimators were obtained for the phantom study in all institutions. When the H/M ratio with an LE collimator was corrected based upon the calibration phantom, the corrected values were comparable to those obtained using ME collimators. The standard database also exhibited a normal distribution after standardization as determined by skewness and goodness-of-fit test. A mixture of the populations by LE and ME collimators showed significant separation of AD and DLB groups (F ratio = 24.9 for the late H/M), but the corrected values resulted in higher F ratios for both early and late H/M (F ratio = 34.9 for the late H/M). Conclusion: Standardization of H/M ratios by the heart-chest calibration phantom method is feasible among different collimator types. This method could be practically used for multicentre comparison of H/M ratios. [ABSTRACT FROM AUTHOR]

The α-synuclein gene ( SNCA) plays a major role in the aetiology of Lewy body disease (LBD) including Parkinson's disease (PD). Point mutations and genetic alterations causing elevated gene expression are causally linked to familial PD. To what extent epigenetic changes play a role in the regulation of α-synuclein expression and may contribute to the aetiology of sporadic LBD is a matter of debate. We analysed the methylation state of the promoter region and a CpG-rich region of intron 1 of α-synuclein in several brain regions in sporadic LBD and controls using 454 GS-FLX-based high-resolution bisulphite sequencing. Our results indicate that there are significant differences in the level of methylation between different brain areas. The overall methylation levels in the promoter and intron 1 of α-synuclein are rather low in controls and-in contrast to previously reported findings-are not significantly different from LBD. However, single CpG analysis revealed significant hyper- and hypomethylation at different positions in various brain regions and LBD stages. A slight overall increase in methylation related to LBD patients' age was detected. [ABSTRACT FROM AUTHOR]

Behavioral and psychological symptoms are commonly observed in a majority of demented patients at some time during the course of their illness. Many of these psychiatric manifestations, especially those related to mood, may be early expressions of dementia and/or mild cognitive impairment. The literature suggests that behavioral and psychological symptoms of dementia (BPSD) are an integral part of the disease process. The dissociation, in many cases, between BPSD and the rather linear decline in cognitive functions suggests that independent pathophysiological mechanisms give rise to these symptoms. A review of the neuroimaging and neuropathology literature indicates that BPSD are the expression of regional rather than diffuse brain pathology. Psychotic symptoms in demented patients usually demonstrate preferential involvement of the frontal lobe and/or limbic regions. Visual hallucinations differentiate themselves from other psychotic symptoms by their tendency to involve the occipital lobes. There is a significant association between apathy and structural changes of the anterior cingulate gyrus. White matter hyperintensities occur in a significant number of depressed patients; otherwise, there is lack of association between depression and either specific brain changes or affected regions. Strictly neuropathological explanations are likely to be insufficient to explain BPSD. Environmental changes, neurochemical abnormalities, past psychiatric history (including premorbid personality), social history (e.g., intellectual achievement and life-long learning), family history, and genetic susceptibility are factors, among others, that influence BPSD. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to estimate the diagnostic accuracy of I-metaiodobenzylguanidine (MIBG) scintigraphy to diagnose Lewy body disease (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies, and to clarify the relationship between MIBG parameters and the clinical findings. Methods: One hundred-and-forty-four patients with parkinsonism without diabetes mellitus or a history of cardiac disease were retrospectively selected in the study. Clinical diagnosis was confirmed by follow-up during more than 6 months by neurologists. All patients underwent MIBG imaging at 15 min (initial) and 4 h (delayed) after the tracer injection, and clinical features such as Hoehn and Yahr (H-Y) classification or symptoms specific to parkinsonism were also investigated. The heart to mediastinum ratio ( H/M) and the washout ratio (WR) of MIBG were calculated, and correlation with the clinical features was analyzed. Results: Ninety-seven and 47 patients were diagnosed as LBD and Parkinson's syndrome (PS), respectively. Initial and delayed H/M were significantly lower and WR was significantly higher in LBD than in PS ( p < 0.0001). The initial H/M was independently correlated with tremor ( F value 10.45), hesitation ( F = 4.49), and hallucinations ( F = 5.09) ( p < 0.0001). The sensitivity and specificity for the diagnosis of LBD were 64.9 and 87.2% with initial H/M, 78.4 and 68.1% with delayed H/M, and 80.4 and 61.7% with WR, respectively. Using multivariate analysis, initial H/M ( F = 39.33) and tremor ( F = 10.46) were independently correlated to the diagnosis of LBD ( r = 0.562, p < 0.0001) among the MIBG and various clinical parameters. Conclusion: The initial H/M was the most useful of the 3 different parameters of MIBG for the diagnosis of LBD, but had low sensitivity. WR and delayed H/M had no incremental value to initial H/M for the diagnosis of PD. Careful long-term follow-up is needed for patients with parkinsonism who are clinically diagnosed as LBD with normal initial H/M, or diagnosed as no LBD with low initial H/M. [ABSTRACT FROM AUTHOR]

It has been reported that the development of TDP-43 pathology in cases of Lewy body disease (LBD) might be associated with the severity of tau pathology. However, the impact of α-synuclein pathology on TDP-43 accumulation in LBD remains unclear. To clarify whether α-synuclein pathology has an effect on TDP-43 accumulation, independent of tau pathology, we examined by immunohistochemistry 56 cases of LBD using a phosphorylation-dependent TDP-43 antibody. The frequency of TDP-43 pathology in all LBD cases was 18% (10/56). In 37 LBD cases with no or low tau burden (LBD-Ltau; Braak NFT stages 0-II), the frequency of TDP-43 pathology was 19% (7/37). The frequency of TDP-43 pathology in diffuse neocortical type LBD-Ltau cases was 36% (4/11), which was higher than those in limbic and brain stem-predominant types (11-14%). The amygdala and entorhinal cortex were the most frequently affected sites of TDP-43 pathology in LBD-Ltau cases. In LBD-Ltau cases, the proportion of diffuse neocortical type LBD was higher in the TDP-43-positive cases, than that in TDP-43-negative cases (57 vs. 23%). In all LBD cases, α-synuclein pathology in the temporal cortex was significantly more severe in TDP-43-positive cases, and significantly correlated with the severity of TDP-43 pathology in the amygdala. In a multivariate model, the presence of severe α-synuclein pathology was significantly associated with the development of TDP-43 pathology independent of age at death and tau pathology. In the amygdala, TDP-43 was often colocalized with α-synuclein or tau. Given these findings, we suggest that α-synuclein pathology is associated with TDP-43 accumulation in LBD cases. [ABSTRACT FROM AUTHOR]

A retrospective autopsy-based study of the human submandibular gland, one of the three major salivary glands, together with anatomically related peripheral structures (cervical superior ganglion, cervical sympathetic trunk, vagal nerve at the level of the carotid bifurcation), was conducted on a cohort consisting of 33 individuals, including 9 patients with neuropathologically confirmed Parkinson’s disease (PD), three individuals with incidental Lewy body disease (iLBD), 2 individuals with neuropathologically confirmed multiple system atrophy (MSA), and 19 controls, using α-synuclein immunohistochemistry in 100 μm polyethylene glycol-embedded tissue sections. Lewy pathology (LP) was present in the submandibular glands and cervical superior ganglia in PD (9/9 cases) and iLBD (2/3 cases) but not in MSA or controls. The cervical sympathetic trunk (7/9 PD cases, 2/3 iLBD cases) and peripheral vagal nerves (9/9 PD cases, 2/3 iLBD cases) also displayed LP. The results are discussed within the context of hyposmia as well as autonomic dysfunction in PD (sialorrhea, sialopenia, dysphagia). Potential disease-related changes in salivary volume, contents, and viscosity might make it possible, in combination with other tests, to employ human saliva as a biomarker. [ABSTRACT FROM AUTHOR]

A 67-year-old man was referred for fluctuating neuropsychiatric symptoms, featuring depression, delirious episodes, recurrent visual hallucinations and catatonic syndrome associated with cognitive decline. No parkinsonism was found clinically even under neuroleptic treatment. F-FDG PET/CT showed hypometabolism in the posterior associative cortex including the occipital cortex, suggesting Lewy body dementia, but I-FP-CIT SPECT was normal and cardiac I-MIBG imaging showed no signs of sympathetic denervation. Alzheimer's disease was excluded by a normal F-florbetaben PET/CT. This report suggests a rare case of α-synucleinopathy without brainstem involvement, referred to as "cerebral type" of Lewy body disease. [ABSTRACT FROM AUTHOR]

Clinical and autopsy studies have consistently reported cardiac sympathetic dysfunction in the left ventricular wall in patients with Parkinson’s disease (PD). Whether the nerve fibers of the cardiac conduction system or the atrial walls are equally affected in this disease process has not yet been well documented. Therefore, the aim of this study was to investigate sympathetic nerves in the cardiac conduction system as well as in the walls of all four heart chambers in patients with PD, in incidental Lewy body disease (iLBD), and in controls. Heart tissue from five PD patients, two iLBD cases, and seven controls were investigated immunohistochemically using antibodies directed against tyrosine hydroxylase (TH) and α-synuclein (syn-1). A marked diminution of TH immunoreactivity (IR) within nerve fibers was observed in four PD patients and in both individuals with iLBD. In contrast, all control subjects displayed dense TH-IR nerve structures. The depletion in TH-IR involved not only the ventricles, but also the conduction system and the atrium showing a global change within cardiac TH-IR nerve fibers in the course of PD. In conclusion, the alterations in cardiac sympathetic nerves of patients with PD or in individuals with iLBD are homogeneous and global within the heart. The clinical implications related to this complete cardiac sympathetic dysfunction, including clinical correlates, diagnostic implications, and treatment, however, remain to be determined in a larger autopsy-controlled cohort of prospectively followed individuals. [ABSTRACT FROM AUTHOR]

Using post-embedding immunogold electron microscopy, TAR DNA-binding protein of 43 kDa (TDP-43) was localized to neuronal cytoplasmic (NCI) and intranuclear (NII) inclusions, as well as unmyelinated neurites, in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), amyotrophic lateral sclerosis (ALS), Alzheimer’s (AD), Pick’s disease (PiD) and Lewy body disease (LBD). The TDP-43 immunoreactive structures were morphologically heterogeneous. The most common was characterized by bundles of 10–20 nm diameter straight filaments with electron dense granular material within NCI, NII and neurites. This type of pathology was found in FTLD-U, ALS and some cases of AD. Less often, inclusions in neuritic processes of FTLD-U and some cases of AD contained 10-17 nm diameter straight filaments without granular material. A final type of TDP-43 immunoreactivity was labeling of filaments and granular material associated with tau filaments in neurofibrillary tangles of AD and Pick bodies of PiD or α-synuclein filaments in Lewy bodies of LBD. The results suggest that TDP-43 is the primary component of the granulofilamentous inclusions in FTLD-U and ALS. Similar inclusions sometimes accompany filamentous aggregates composed of other abnormal proteins in AD, PiD and LBD. [ABSTRACT FROM AUTHOR]

Whereas the prevalence and impact of vascular pathology in Alzheimer diease (AD) are well established, the role of vascular and Alzheimer pathologies in the progression of neurodegeneration and cognitive impairment in Parkinson disease (PD) is under discussion. A retrospective clinico-pathologic study of 100 patients with autopsy proven PD (including 44 cases with dementia/PDD) and 20 cases of dementia with Lewy bodies (DLB) confirmed essential clinical (duration of illness, Mini-Mental State Examination/MMSE, age at death) and morphologic differences between these groups; Lewy body Braak scores and Alzheimer pathologies (neuritic Braak stage, cortical Aβ plaque load, and generalized cerebral amyloid angiopathy or CAA) were significantly higher/more severe in DLB and PDD than in PD without dementia. Duration of illness showed no association to any of the examined pathologic parameters, while there was a moderate association between LB scores and neuritic Braak stages, the latter significantly increasing with age. Significant association between cerebrovascular lesions and neuritic Braak stage was seen in PDD but not in PD subjects without dementia. These data suggest an influence of Alzheimer-related lesions on the progression of the neurodegenerative process and, in particular, on cognitive decline in both PDD and DLB. On the other hand, both these factors in PD and DLB appear to be largely independent from coexistent vascular pathology, except in cases with severe cerebrovascular lesions or those related to neuritic AD pathology. Assessment of ApoE genotype in a small number of cases showed no significant differences in the severity of Aβ plaque load and CAA except for much lower intensities in non-demented ε3/3 patients. Despite increasing evidence suggesting synergistic reactions between α-synuclein (αSyn), tau and Aβ-peptides, the major protein markers of both AD and Lewy body diseases, and of both vascular pathology and AD, the molecular background and pathophysiological impact of these pathologies on the progression of neurodegeneration and development of cognitive decline in PD await further elucidation. [ABSTRACT FROM AUTHOR]

While Alzheimer and Lewy body pathologies are discussed as major substrates of dementia in Parkinson’s disease (PD/Lewy body disease of brainstem type), the incidence and impact of cerebral amyloid angiopathy (CAA) and its association with cognitive decline in PD and dementia with Lewy bodies (DLB) are unknown. The severity of CAA and other Alzheimer lesions were assessed in 68 cases of autopsy-confirmed PD, 32 of them with dementia (PDD), and in 20 cases of DLB. PDD patients were significantly older than those without dementia (mean age 84.5 vs 77.6 years; p < 0.01), the age of DLB patients was in between both groups (mean 80.0 years), while duration of disease was DLB < PDD < PD (mean 6.5 vs 8.5 and 14.3 years). PDD patients had a significantly higher neuritic Braak stage (mean 4.2 vs 2.4, p < 0.01), significantly higher cortical amyloid β (Aβ) load, capillary cerebral amyloid angiopathy (CapCAA) and generalized CAA than those without dementia (mild CapCAA in 22% vs moderate to severe CapCAA in 87%; mild generalized CAA in 5.5% vs moderate to severe generalized CAA in 82%). Mean PD stage was higher in both DLB and PDD than in PD (mean 5.2 vs 4.5 and 4.0, respectively): Mean neuritic Braak stage in DLB was 3.4, severe Aβ plaque load was seen in 95%, moderate to severe CapCAA in 90% and mild to severe generalized CAA in 70%. This and other recent studies imply an association of CAA with cognitive decline in both PD/PDD and DLB, particularly in cases with concomitant AD-type pathology. [ABSTRACT FROM AUTHOR]

Astrocytic α-synuclein-immunoreactive inclusions have recently been noted to develop in sporadic Parkinson’s disease (PD). Here, the presence of immunoreactive astrocytes is reported in 14 autopsy cases with clinically diagnosed PD and a neuropathological stage of 4 or higher. The labeled astrocytes occur preferentially in prosencephalic regions (amygdala, thalamus, septum, striatum, claustrum, and cerebral cortex). They appear first in layers V–VI of the temporal mesocortex, then in the striatum and in thalamic nuclei that project to the cortex. The topographical distribution pattern of these astrocytes closely parallels that of the cortical intraneuronal Lewy neurites and Lewy bodies, which, from their foothold in the mesocortex, gradually encroach upon neocortical association areas and even the primary fields. Thus, labeling of astrocytes appears to accompany the formation of neuronal inclusion bodies. Relatively small immunoreactive cortical pyramidal neurons in layers V–VI probably project to nearby destinations, such as the striatum and thalamus. Inasmuch as the projection neurons of both the striatum and the dorsal thalamus do not develop Lewy bodies, it is suggested that the most likely cause of the astrocytic reaction may be a slightly altered α-synuclein molecule that escapes from terminal axons of affected cortico-striatal or cortico-thalamic neurons and is taken up by astrocytes. Other aggregated proteins known to co-occur with PD-associated intraneuronal lesions, e.g., Aβ protein or neurofibrillary changes of the Alzheimer type, do not appear to influence the development of the α-synuclein immunoreactive astrocytes. [ABSTRACT FROM AUTHOR]

Purpose: In single-photon emission computed tomography (SPECT) of the dopaminergic system, measurements of striatal uptake are useful for diagnosis and patient follow-up but are strongly biased by the partial volume effect (PVE). We studied whether PVE correction might improve patient classification based on binding potential (BP) measurements. Methods: Patients with a probable diagnosis of dementia with Lewy bodies (DLB, 10 patients) or Alzheimer's disease (AD, 13 patients) were studied by 123I-FP-CIT SPECT. SPECT images were reconstructed with and without PVE correction. Each patient SPECT scan was also simulated to obtain SPECT data whose characteristics were fully known. In addition, 17 SPECT scans were simulated with striatal uptake values mimicking presymptomatic cases of DLB. Results: Without PVE correction, mean putamen BP values were 2.9±0.4 and 0.9±0.2 for AD and DLB patients respectively, while with PVE correction, they were 8.6±1.5 and 1.9±0.5 respectively. All patients were properly identified as having AD or DLB when considering mean putamen BP measured on their real or simulated SPECT scan, with and without PVE correction. All 30 simulations mimicking pre-symptomatic DLB and AD patients were accurately classified with PVE correction, but without PVE correction 15 mean putamen BP values were in a range where AD and DLB could not be distinguished. Conclusion: We conclude that putamen BP values measured without PVE correction can be used to differentiate probable DLB and AD due to the already severe reduction in dopamine transporter levels. PVE correction appeared useful for accurate differential diagnosis between AD and pre-symptomatic DLB. [ABSTRACT FROM AUTHOR]

Reduced cardiac uptake of 123I-metaiodobenzylguanidine (MIBG) is considered to represent dysfunction of the postganglionic neurons of the cardiac sympathetic nervous system. Evidence indicates that cardiac uptake of 123I-MIBG is decreased in patients with idiopathic Parkinson's disease (IPD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF),which have common pathological features with Lewy body formation. In the present article, we review previous reports that determined heart-mediastinum (H/M) ratios in early and delayed images of patients with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA) in comparison to those of IPD and controls. The majority of reports suggest that H/M ratios of patients with PSP, CBD and MSA are comparable to those of controls, while H/M ratios of patients with IPD are significantly reduced. This reduction seen in IPD may reflect the loss and/or dysfunction of postganglionic cardiac sympathetic nerve terminals. Several authors reported mild reduction of 123I-MIBG uptake in patients with MSA and PSP. However, no degeneration of postganglionic neurons of the cardiac sympathetic nervous system has been detected in patients with these diseases. These results indicate that cardiac 123I-MIBG uptake is a sensitive tool with which to differentiate IPD from neurodegenerative diseases with extrapyramidal symptoms such as PSP, CBD and MSA. [ABSTRACT FROM AUTHOR]

We investigated the occurrence and distribution of tuft-shaped astrocytes (TuSAs) in 60 brains from patients with Lewy body disease (LBD), which were clinically diagnosed as Parkinson’s disease (PD) or dementia with Lewy bodies (DLB), and 85 brains from control subjects. TuSAs have been documented as a neuropathological hallmark of progressive supranuclear palsy (PSP). We found phosphorylated tau (p-tau)-positive and α-synuclein-negative TuSAs in 10 of 60 patients with LBD and 3 of 85 control cases. TuSAs were mainly located within the precentral and premotor gyri of the frontal lobe cortex. There were only few TuSAs, but the distribution pattern and morphological and immunohistological features were similar to that in PSP. Furthermore, other p-tau positive structures, including aggregates in neurons, coiled-like glial cells and threads showed a similar distribution to those in PSP; mainly in the hippocampus, striatum, subthalamic nucleus, precentral and premotor gyri, brainstem nucleus, and dentate nucleus. In these cases, however, neuronal loss and gliosis were not seen in the regions involved in PSP, such as the subthalamic nucleus, pallidum, inferior olivary, cerebellar dentate nuclei, and periaqueductal gray matter. Clinical features were indistinguishable between the LBD with and without TuSAs. The appearance of TuSAs was not related to the frequency of Lewy bodies, neurofibrillary tangles, and senile plaques, but was significantly more pronounced with advancing age in both LBD and controls. These findings suggest that in a subgroup of elderly individual cases, especially associated with LB pathology, the glial and neuronal p-tau accumulation is increased and has a distributional pattern similar to PSP. [ABSTRACT FROM AUTHOR]

Dementia is a frequent complication of Parkinson’s disease (PD) and usually occurs late in the protracted course of the illness. We have already reported numerous MHC class II-positive microglia in the hippocampus in PD patients, and that this phenomenon may be responsible for functional changes in the neurons and the cognitive decline in PD patients. In this study, we have investigated the distribution of activated microglia and the immunohistochemical and the mRNA expression of several cytokines and neurotrophic factors of the hippocampus in PD and dementia with Lewy bodies (DLB). The brains from five cases of PD and five cases of DLB that were clinically and neuropathologically diagnosed, and those from four normal controls (NC) were evaluated by immunohistochemistry using anti-HLA-DP, -DQ, -DR (CR3/43), anti-a-synuclein, anti-brain-derived neurotrophic factor (BDNF), and anti-glial fibrillary acidic protein antibodies. In addition, the mRNA expressions of cytokines (IL-1a, IL-1ß, TNF-a, IL-6, TGF-ß) and neurotrophic factors (BDNF, GDNF, NGF, NT-3) of these brains were evaluated by the reverse transcription-PCR method. MHC class II-positive microglia were distributed diffusely in the hippocampus of PD and DLB brains. Although the cytoplasm of pyramidal and granular cells of the hippocampus in NC brains was strongly stained by anti-BDNF antibodies, it was only weakly stained in PD and DLB brains. The mRNA expression of IL-6 was significantly increased in the hippocampus of PD and DLB brains, and that of BDNF was significantly decreased in the hippocampus of DLB brains. The increased number of activated microglia and the production of neurotrophic cytokines such as IL-6, together with the decreased expression of the neurotrophic factors of neurons in the hippocampus of PD and DLB brains, may be related to functional cellular changes associated with dementia. [ABSTRACT FROM AUTHOR]

Lewy body disease (LBD) refers to a heterogeneous group of disorders presenting with parkinsonism and Lewy body (LB) formation. Although the relationship between dementing syndromes with LBs, Parkinson’s disease, and Alzheimer’s disease is unclear, the former constitute a common form of degenerative dementia and may account for up to 20% of cases in the elderly. We recently demonstrated triplication of the α-synuclein gene as the cause of disease in the Spellman-Muenter kindred. Neuropathological examination of affected members of the kindred demonstrated extensive LB pathology consistent with diffuse LBD. We examined a large collection of pathologically confirmed LBD cases and found no evidence for multiplication of the α-synuclein gene, suggesting that this mechanism is not a common cause of LBD. [ABSTRACT FROM AUTHOR]