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Objectives Although whole and individual regional brain volume loss have been separately reported to correlate with disability in multiple sclerosis (MS), hierarchical cluster analyses of the whole and regional brain to find their pattern in MS are few. Methods We cross-sectionally conducted high-resolution, T1-weighted volumetric MRI examinations in 75 MS patients and 21 healthy controls (HCs) to measure the volumes of whole brain and a total of 56 brain regions of interest. Using a hierarchical cluster analysis with multivariate imaging data, we classified the patients into clusters according to their brain-volume patterns. Principal component analysis was also applied. Clinical features and brain volumes were then compared among the MS clusters. Results The MS patients were categorized into three major clusters (Clusters 1, 2, and 3) with increasing disability in that order. Principal component analysis also identified Clusters 1, 2 and 3. Whole brain volume and supratentorial regional brain volumes, including thalamus and corpus callosum, decreased severely in Cluster 3 and moderately in Cluster 2, while equally preserved in Cluster 1 and the HCs. Only the volumes of the ventral diencephalon and T1 white matter hypointensities significantly differed in Clusters 1, 2 and 3 and HCs. In contrast, the volumes of the cerebellar cortex and brainstem were significantly different between Clusters 3 and 1, whereas there were no significant differences between Clusters 1 and 2 and Clusters 2 and 3. Conclusion We identified brain regions that exhibit different degree of atrophy in a background of global brain atrophy in MS.

In recent years, there has been increasing evidence that several lipid metabolism abnormalities play an important role in the pathogenesis of neurodegenerative diseases. However, it is still unclear which lipid metabolism abnormalities play the most important role in neurodegenerative diseases. Plasma lipid metabolomics (lipidomics) has been shown to be an unbiased method that can be used to explore lipid metabolism abnormalities in neurodegenerative diseases. Plasma lipidomics in neurodegenerative diseases has been performed only in idiopathic Parkinson's disease (IPD) and Alzheimer's disease (AD), and comprehensive studies are needed to clarify the pathogenesis. In this study, we investigated plasma lipids using lipidomics in individuals with neurodegenerative diseases and healthy controls (CNs). Plasma lipidomics was evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in those with IPD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), AD, and progressive supranuclear palsy (PSP) and CNs. The results showed that (1) plasma sphingosine-1-phosphate (S1P) was significantly lower in all neurodegenerative disease groups (IPD, DLB, MSA, AD, and PSP) than in the CN group. (2) Plasma monohexylceramide (MonCer) and lactosylceramide (LacCer) were significantly higher in all neurodegenerative disease groups (IPD, DLB, MSA, AD, and PSP) than in the CN group. (3) Plasma MonCer levels were significantly positively correlated with plasma LacCer levels in all enrolled groups. S1P, Glucosylceramide (GlcCer), the main component of MonCer, and LacCer are sphingolipids that are biosynthesized from ceramide. Recent studies have suggested that elevated GlcCer and decreased S1P levels in neurons are related to neuronal cell death and that elevated LacCer levels induce neurodegeneration by neuroinflammation. In the present study, we found decreased plasma S1P levels and elevated plasma MonCer and LacCer levels in those with neurodegenerative diseases, which is a new finding indicating the importance of abnormal sphingolipid metabolism in neurodegeneration.

Visual hallucinations are a core clinical feature of dementia with Lewy bodies (DLB), and this symptom is important in the differential diagnosis and prediction of treatment response. The pareidolia test is a tool that evokes visual hallucination-like illusions, and these illusions may be a surrogate marker of visual hallucinations in DLB. We created a simplified version of the pareidolia test and examined its validity and reliability to establish the clinical utility of this test. The pareidolia test was administered to 52 patients with DLB, 52 patients with Alzheimer's disease (AD) and 20 healthy controls (HCs). We assessed the test-retest/inter-rater reliability using the intra-class correlation coefficient (ICC) and the concurrent validity using the Neuropsychiatric Inventory (NPI) hallucinations score as a reference. A receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of the pareidolia test to differentiate DLB from AD and HCs. The pareidolia test required approximately 15 minutes to administer, exhibited good test-retest/inter-rater reliability (ICC of 0.82), and moderately correlated with the NPI hallucinations score (rs = 0.42). Using an optimal cut-off score set according to the ROC analysis, and the pareidolia test differentiated DLB from AD with a sensitivity of 81% and a specificity of 92%. Our study suggests that the simplified version of the pareidolia test is a valid and reliable surrogate marker of visual hallucinations in DLB.

ObjectivePatients with Lewy body disease develop a variety of psychotic and misperception symptoms, including visual hallucinations and delusions, as well as ‘minor hallucinations’, that is, a sense of presence, passage hallucinations and visual illusions. Although these symptoms have been suggested to have common underlying mechanisms, the commonalities and differences among them have not been systematically investigated at the neural level.MethodsSixty-seven patients with Parkinson’s disease underwent neuropsychological and behavioural assessments, volumetric MRI and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). A factor analysis was performed to discover correlations among psychotic and misperception symptoms, other behavioural symptoms and neuropsychological performances. Partial least-squares correlation analysis was used to investigate the relationship between these symptoms and the joint features of MRI and FDG-PET.ResultsA sense of presence, passage hallucinations and visual illusions constituted a single behavioural factor (minor hallucinations/illusions). Visual hallucinations formed another behavioural factor along with delusions, depression and fluctuating cognition (psychosis/dysphoria). Three distinct brain–behaviour correlation patterns were identified: (1) posterior cortical atrophy/hypometabolism associated with minor hallucinations/illusions and visuospatial impairment; (2) upper brainstem and thalamic atrophy/hypometabolism associated with psychosis/dysphoria and (3) frontal cortical atrophy/hypometabolism associated with non-visual cognition. No significant differences in neuroimaging findings were identified between patients who had minor hallucinations/illusions alone and patients who also had visual hallucinations.ConclusionsOur findings suggest that combined damage to the upper brainstem/thalamus and the posterior neocortex underlies both minor hallucinations/illusions and visual hallucinations and that the former pathology is more associated with visual hallucinations/frank psychosis and the latter is more associated with minor hallucinations/illusions.

An early and accurate diagnosis of Dementia with Lewy bodies (DLB) is critical because treatments and prognosis of DLB are different from Alzheimer's disease (AD). This study was carried out in Japan to validate an Electroencephalography (EEG)-derived machine learning algorithm for discriminating DLB from AD which developed based on a database of EEG records from two different European countries. In a prospective multicenter study, patients with probable DLB or with probable AD were enrolled in a 1:1 ratio. A continuous EEG segment of 150 seconds was recorded, and the EEG data was processed using MC-004, the EEG-based machine learning algorithm, with all clinical information blinded except for age and gender. Eighteen patients with probable DLB and 21 patients with probable AD were the included for the analysis. The performance of MC-004 differentiating probable DLB from probable AD was 72.2% (95% CI 46.5-90.3%) for sensitivity, 85.7% (63.7-97.0%) for specificity, and 79.5% (63.5-90.7%) for accuracy. When limiting to subjects taking ≤5 mg donepezil, the sensitivity was 83.3% (95% CI 51.6-97.9), the specificity 89.5% (66.9-98.7), and the accuracy 87.1% (70.2-96.4). MC-004, the EEG-based machine learning algorithm, was able to discriminate between DLB and AD with fairly high accuracy. MC-004 is a promising biomarker for DLB, and has the potential to improve the detection of DLB in a diagnostic process.

Mirror writing (MW) is the production of individual letters, words, or word strings in the reverse direction. Parkinson’s disease (PD) is a progressive neurodegenerative disorder, and high MW rates have been reported in patients with PD. Thus, the present study sought to identify the factors that cause MW in patients with PD. We examined the frequency of MW in patients with PD and investigated the area of the brain where such frequency inversely correlates with reduced regional cerebral metabolic rates of glucose (rCMRglc). We also examined whether this area satisfied the motor and visual monitoring hypotheses of MW that have been presented in previous studies. Thirty-six subjects with idiopathic PD and 23 healthy controls were included in the study. We asked the participants to write down words, numerals, and sentences from left to right using their dominant and non-dominant hands. Patients with PD underwent an 18F-fluorodeoxyglucose positron emission tomography scan to measure the rCMRglc. Neither the patients with PD nor the healthy subjects exhibited MW in the use of the right hand. In the use of the left hand, MW occurred in 15 of the 36 patients with PD, but in none of the healthy controls. The right intraparietal sulcus was identified as the area where rCMRglc was inversely correlated with the number of left–right reversed characters. Previous functional imaging studies have suggested that the right superior parietal cortex and intraparietal sulcus play an important role in recognizing left–right reversed letters. Therefore, dysfunction in the intraparietal sulcus may hinder the recognition of left–right reversed characters, resulting in MW. Consequently, our findings in patients with PD are consistent with the visual-monitoring hypothesis of MW.

Background Delayed diagnosis of critical congenital heart disease (CCHD) carries a serious risk of mortality, morbidity, and handicap. As echocardiography is commonly used to diagnose congenital heart disease (CHD), echocardiographic investigations in newborns may be helpful in detecting CCHD earlier and with higher sensitivity than when using other screening methods. The present study aimed to evaluate the effectiveness of echocardiographic screening for CCHD in a tertiary care center. Methods A retrospective chart review was conducted among newborns delivered at Hamamatsu University Hospital between June 2009 and May 2016. The study included consecutive newborns who underwent early echocardiographic screening (within the first 5 days of life) performed by pediatric cardiologists, were born at ≥36 weeks of gestation, had a birthweight ≥2300 g, and were cared for in the well-baby nursery. Newborns admitted to the neonatal intensive care unit, as well as those with prenatal diagnosis of CHD and/or clinical symptoms or signs of CHD were excluded. Four CHD outcome categories were defined: critical, serious, clinically significant, and clinically non-significant. Results A total of 4082 live newborns were delivered during the study period. Of 3434 newborns who met the inclusion criteria and had complete echocardiography data, 104 (3.0%) were diagnosed as having CHD. Among these, none was initially diagnosed as having critical or serious CHD. Of the 95 newborns who continued follow-up with a cardiologist, 61 (64%) were determined to have non-significant CHDs that resolved within 6 months of life. Review of excluded newborns revealed nine cases of critical or serious CHD; among these newborns, six were diagnosed prenatally and three had some clinical signs of CHD prior to hospital discharge. Conclusions In our tertiary care center, echocardiography screening within the first 5 days of life did not help improve CCHD detection rate in newborns without prenatal diagnosis or clinical signs of CHD. Echocardiographic screening may be associated with increased rate of false-positives (defects resulting in clinically non-significant CHDs) in newborns without prenatal diagnosis or suspicion of CHD.

Many neurodegenerative diseases share a common pathological feature: the deposition of amyloid-like fibrils composed of misfolded proteins. Emerging evidence suggests that these proteins may spread from cell-to-cell and encourage the propagation of neurodegeneration in a prion-like manner. Here, we demonstrated that α-synuclein (αSYN), a principal culprit for Lewy pathology in Parkinson's disease (PD), was present in endosomal compartments and detectably secreted into the extracellular milieu. Unlike prion protein, extracellular αSYN was mainly recovered in the supernatant fraction rather than in exosome-containing pellets from the neuronal culture medium and cerebrospinal fluid. Surprisingly, impaired biogenesis of multivesicular body (MVB), an organelle from which exosomes are derived, by dominant-negative mutant vacuolar protein sorting 4 (VPS4) not only interfered with lysosomal targeting of αSYN but facilitated αSYN secretion. The hypersecretion of αSYN in VPS4-defective cells was efficiently restored by the functional disruption of recycling endosome regulator Rab11a. Furthermore, both brainstem and cortical Lewy bodies in PD were found to be immunoreactive for VPS4. Thus, VPS4, a master regulator of MVB sorting, may serve as a determinant of lysosomal targeting or extracellular secretion of αSYN and thereby contribute to the intercellular propagation of Lewy pathology in PD.

Endosomal sorting required for transport (ESCRT) complexes orchestrate endo-lysosomal sorting of ubiquitinated proteins, multivesicular body formation and autophagic degradation. Defects in the ESCRT pathway have been implicated in many neurodegenerative diseases, but the underlying molecular mechanisms that link them to neurodegeneration remain unknown. In this study, we showed that forebrain-specific ablation of ESCRT-0/Hrs induced marked hippocampal neuronal cell loss accompanied by the accumulation of ubiquitinated proteins, including α-synuclein, TDP-43 and huntingtin as well as the autophagic substrate SQSTM1/p62. Consistent with this, silencing of Hrs in cultured cells not only led to α-synuclein and TDP-43 accumulation in addition to impaired autophagic flux but also suppressed cell viability through the induction of ER stress followed by the activation of JNK and RIPK1, a key regulator of necroptosis. Moreover, necrostatin-1, a specific inhibitor of RIPK1 and pan-caspase inhibitors partially reduced the neurotoxicity in the Hrs-silenced cells. Altogether, these findings suggest that the disruption of ESCRT-0/Hrs in the nervous system compromises autophagic/lysosomal degradation of neurodegenerative disease-related proteins, which thereby triggers ER stress-mediated apoptotic and necroptotic cell death.

Prescription doses of levodopa in patients with advanced Parkinson’s disease (PD) are generally lower in Japan than in the United States or Europe, although Japanese guidelines for the management of PD recommend increasing the dosage as the disease progresses. However, data regarding levodopa prescription practices in patients with advanced PD in the clinical setting are limited. This retrospective observational study analyzed patterns of drug use for patients with advanced PD in Japan using claims data from hospitalized patients in the Medical Data Vision Co. database. Eligible patients had at least two PD-associated claims in two different quarters between April 1, 2008, and November 30, 2018, and a 10-item activities of daily living score <60 upon hospital discharge (as a proxy for advanced PD). The primary endpoint was the prescribed dosage of levodopa at the index hospitalization. Dosages of other PD drugs (medications with an on-label indication for PD) and non-PD drugs were also assessed. Overall, 4029 patients met the inclusion criteria (mean age, 76.9 years; 83.3% aged ≥70 years). At the index date, 74.0% were receiving levodopa. Patients received a median of one PD drug in addition to levodopa, and 27.4% and 20.2% received one or two concomitant PD drugs, respectively. Patients received a median of two non-PD drugs. The median levodopa dosage and total levodopa equivalent dosage (LED) at the index hospitalization were 418.2 and 634.8 mg/day (adjusted for body weight, 9.0 and 13.7 mg/kg/day), respectively. The median levodopa and total LED dosage in each 6-month increment during the 5 years before and after the index date ranged between 263.9 and 330.2 mg/day (5.0 and 6.5 mg/kg/day) and 402.0 and 504.9 mg/day (8.3 and 10.1 mg/kg/day), respectively. This study suggests that many Japanese patients with advanced PD could receive more intensive treatment with higher doses of levodopa.