A pontine-medullary loop crucial for REM sleep and its deficit in Parkinson's disease.

Identifying the properties of the rapid eye movement (REM) sleep circuitry and its relation to diseases has been challenging due to the neuronal heterogeneity of the brainstem. Here, we show in mice that neurons in the pontine sublaterodorsal tegmentum (SubLDT) that express corticotropin-releasing hormone-binding protein (Crhbp+ neurons) and project to the medulla promote REM sleep. Within the medullary area receiving projections from Crhbp+ neurons, neurons expressing nitric oxide synthase 1 (Nos1+ neurons) project to the SubLDT and promote REM sleep, suggesting a positively interacting loop between the pons and the medulla operating as a core REM sleep circuit. Nos1+ neurons also project to areas that control wide forebrain activity. Ablating Crhbp+ neurons reduces sleep and impairs REM sleep atonia. In Parkinson's disease patients with REM sleep behavior disorders, CRHBP-immunoreactive neurons are largely reduced and contain pathologic α-synuclein, providing insight into the mechanisms underlying the sleep deficits characterizing this disease.

Impaired disassembly of the axon initial segment restricts mitochondrial entry into damaged axons.

The proteasome is essential for cellular responses to various physiological stressors. However, how proteasome function impacts the stress resilience of regenerative damaged motor neurons remains unclear. Here, we develop a unique mouse model using a regulatory element of the activating transcription factor (Atf3) gene to label mitochondria in a damage-induced manner while simultaneously genetically disrupting the proteasome. Using this model, we observed that in injury-induced proteasome-deficient mouse motor neurons, the increase of mitochondrial influx from soma into axons is inhibited because neurons fail to disassemble ankyrin G, an organizer of the axon initial segment (AIS), in a proteasome-dependent manner. Further, these motor neurons exhibit amyotrophic lateral sclerosis (ALS)-like degeneration despite having regenerative potential. Selectively vulnerable motor neurons in SOD1G93A ALS mice, which induce ATF3 in response to pathological damage, also fail to disrupt the AIS, limiting the number of axonal mitochondria at a pre-symptomatic stage. Thus, damage-induced proteasome-sensitive AIS disassembly could be a critical post-translational response for damaged motor neurons to temporarily transit to an immature state and meet energy demands for axon regeneration or preservation.

Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.

Phosphorylation of α-synuclein at T64 results in distinct oligomers and exerts toxicity in models of Parkinson's disease.

α-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of α-synuclein in the pathogenesis of PD. However, the molecular and cellular mechanisms of α-synuclein toxicity remain elusive. Here, we describe a novel phosphorylation site of α-synuclein at T64 and the detailed characteristics of this post-translational modification. T64 phosphorylation was enhanced in both PD models and human PD brains. T64D phosphomimetic mutation led to distinct oligomer formation, and the structure of the oligomer was similar to that of α-synuclein oligomer with A53T mutation. Such phosphomimetic mutation induced mitochondrial dysfunction, lysosomal disorder, and cell death in cells and neurodegeneration in vivo, indicating a pathogenic role of α-synuclein phosphorylation at T64 in PD.

A microtubule-LUZP1 association around tight junction promotes epithelial cell apical constriction.

Apical constriction is critical for epithelial morphogenesis, including neural tube formation. Vertebrate apical constriction is induced by di-phosphorylated myosin light chain (ppMLC)-driven contraction of actomyosin-based circumferential rings (CRs), also known as perijunctional actomyosin rings, around apical junctional complexes (AJCs), mainly consisting of tight junctions (TJs) and adherens junctions (AJs). Here, we revealed a ppMLC-triggered system at TJ-associated CRs for vertebrate apical constriction involving microtubules, LUZP1, and myosin phosphatase. We first identified LUZP1 via unbiased screening of microtubule-associated proteins in the AJC-enriched fraction. In cultured epithelial cells, LUZP1 was found localized at TJ-, but not at AJ-, associated CRs, and LUZP1 knockout resulted in apical constriction defects with a significant reduction in ppMLC levels within CRs. A series of assays revealed that ppMLC promotes the recruitment of LUZP1 to TJ-associated CRs, where LUZP1 spatiotemporally inhibits myosin phosphatase in a microtubule-facilitated manner. Our results uncovered a hitherto unknown microtubule-LUZP1 association at TJ-associated CRs that inhibits myosin phosphatase, contributing significantly to the understanding of vertebrate apical constriction.

Delineating three distinct spatiotemporal patterns of brain atrophy in Parkinson's disease.

The clinical manifestation of Parkinson's disease exhibits significant heterogeneity in the prevalence of non-motor symptoms and the rate of progression of motor symptoms, suggesting that Parkinson's disease can be classified into distinct subtypes. In this study, we aimed to explore this heterogeneity by identifying a set of subtypes with distinct patterns of spatiotemporal trajectories of neurodegeneration. We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that combined disease progression modelling with clustering methods, to cortical and subcortical neurodegeneration visible on 3 T structural MRI of a large cross-sectional sample of 504 patients and 279 healthy controls. Serial longitudinal data were available for a subset of 178 patients at the 2-year follow-up and for 140 patients at the 4-year follow-up. In a subset of 210 patients, concomitant Alzheimer's disease pathology was assessed by evaluating amyloid-ß concentrations in the CSF or via the amyloid-specific radiotracer 18F-flutemetamol with PET. The SuStaIn analysis revealed three distinct subtypes, each characterized by unique patterns of spatiotemporal evolution of brain atrophy: neocortical, limbic and brainstem. In the neocortical subtype, a reduction in brain volume occurred in the frontal and parietal cortices in the earliest disease stage and progressed across the entire neocortex during the early stage, although with relative sparing of the striatum, pallidum, accumbens area and brainstem. The limbic subtype represented comparative regional vulnerability, which was characterized by early volume loss in the amygdala, accumbens area, striatum and temporal cortex, subsequently spreading to the parietal and frontal cortices across disease stage. The brainstem subtype showed gradual rostral progression from the brainstem extending to the amygdala and hippocampus, followed by the temporal and other cortices. Longitudinal MRI data confirmed that 77.8% of participants at the 2-year follow-up and 84.0% at the 4-year follow-up were assigned to subtypes consistent with estimates from the cross-sectional data. This three-subtype model aligned with empirically proposed subtypes based on age at onset, because the neocortical subtype demonstrated characteristics similar to those found in the old-onset phenotype, including older onset and cognitive decline symptoms (P < 0.05). Moreover, the subtypes correspond to the three categories of the neuropathological consensus criteria for symptomatic patients with Lewy pathology, proposing neocortex-, limbic- and brainstem-predominant patterns as different subgroups of α-synuclein distributions. Among the subtypes, the prevalence of biomarker evidence of amyloid-ß pathology was comparable. Upon validation, the subtype model might be applied to individual cases, potentially serving as a biomarker to track disease progression and predict temporal evolution.

Basal temporal language area revisited in Japanese language with a language function density map.

We revisited the anatomo-functional characteristics of the basal temporal language area (BTLA), first described by Lüders et al. (1986), using electrical cortical stimulation (ECS) in the context of Japanese language and semantic networks. We recruited 11 patients with focal epilepsy who underwent chronic subdural electrode implantation and ECS mapping with multiple language tasks for presurgical evaluation. A semiquantitative language function density map delineated the anatomo-functional characteristics of the BTLA (66 electrodes, mean 3.8 cm from the temporal tip). The ECS-induced impairment probability was higher in the following tasks, listed in a descending order: spoken-word picture matching, picture naming, Kanji word reading, paragraph reading, spoken-verbal command, and Kana word reading. The anterior fusiform gyrus (FG), adjacent anterior inferior temporal gyrus (ITG), and the anterior end where FG and ITG fuse, were characterized by stimulation-induced impairment during visual and auditory tasks requiring verbal output or not, whereas the middle FG was characterized mainly by visual input. The parahippocampal gyrus was the least impaired of the three gyri in the basal temporal area. We propose that the BTLA has a functional gradient, with the anterior part involved in amodal semantic processing and the posterior part, especially the middle FG in unimodal semantic processing.

Association of Cortical Superficial Siderosis with Post-Stroke Epilepsy.

OBJECTIVE: To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case-control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE. METHODS: We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models. RESULTS: The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT-S and 0.88 [p = 0.001] for CAVE-S at the testing data). INTERPRETATION: Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2023;93:357-370.

Distinct Clinical Implications of Patient- Versus Clinician-Rated Motor Symptoms in Parkinson's Disease.

BACKGROUND: Patient-rated motor symptoms (PRMS) and clinician-rated motor symptoms (CRMS) often differ in Parkinson's disease (PD). OBJECTIVE: Our goal was to investigate the determinants and clinical implications of PRMS compared with CRMS in PD. METHODS: This retrospective, observational cohort study analyzed the cross-sectional associations and longitudinal impacts of PRMS as assessed by the Movement Disorders Society-sponsored Unified PD Rating Scale (MDS-UPDRS) part 2, while controlling for CRMS measured by MDS-UPDRS part 3. Longitudinal analyses used Cox proportional hazards models and multiple linear mixed-effects random intercepts/slope models, adjusting for many clinical predictors. We conducted propensity score matching (PSM) to reinforce our analyses' robustness and surface-based morphometry to investigate neural correlates. RESULTS: We enrolled 442 patients with early-stage PD. At baseline, regardless of CRMS, PRMS were associated with the severity of postural instability and gait disturbance (PIGD). Notably, PRMS independently and more accurately predicted faster long-term deterioration in motor function than CRMS (Hoehn and Yahr 4, adjusted hazard ratio per +1 point = 1.19 [95% confidence intervals, 1.08-1.32]), particularly in PIGD (PIGD subscore, ß-interaction = 0.052 [95% confidence intervals, 0.018-0.086]). PSM confirmed these findings' robustness. Surface-based morphometry suggested that enhanced sensory processing was distinctively associated with PRMS. CONCLUSIONS: In early-stage PD, PRMS weighed different aspects of symptoms and more effectively predicted motor deterioration compared to CRMS, with distinctive brain structural characteristics. The superior sensitivity of PRMS to subtle declines in drug-refractory symptoms like PIGD likely underlie our results, highlighting the importance of understanding the differential clinical implications of PRMS to prevent long-term motor deterioration. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Research Priorities on the Role of α-Synuclein in Parkinson's Disease Pathogenesis.

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice.

Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Acute inhibition of AMPA receptors by perampanel reduces amyloid ß-protein levels by suppressing ß-cleavage of APP in Alzheimer's disease models.

Hippocampal hyperexcitability is a promising therapeutic target to prevent Aß deposition in AD since enhanced neuronal activity promotes presynaptic Aß production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with in vivo brain microdialysis and primary neurons under oligomeric Aß-evoked neuronal hyperexcitability, the acute effects of PER on Aß metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aß40 and Aß42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aß40 /Aß42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP ßCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPß levels, a direct byproduct of ß-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aß-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aß clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aß, indicating that the acute effect of PER is predominantly on Aß production. In conclusion, acute treatment of PER reduces Aß production by suppressing ß-cleavage of amyloid-ß precursor protein effectively, indicating a potential effect of PER against Aß pathology in AD.

Specific consistency score for rational selection of epilepsy resection surgery candidates.

OBJECTIVE: Degree of indication for epilepsy surgery is determined by taking multiple factors into account. This study aimed to investigate the usefulness of the Specific Consistency Score (SCS), a proposed score for focal epilepsy to rate the indication for epilepsy focal resection. METHODS: This retrospective cohort study included patients considered for resective epilepsy surgery in Kyoto University Hospital from 2011 to 2022. Plausible epileptic focus was tentatively defined. Cardinal findings were scored based on specificity and consistency with the estimated laterality and lobe. The total points represented SCS. The association between SCS and the following clinical parameters was assessed by univariate and multivariate analysis: (1) probability of undergoing resective epilepsy surgery, (2) good postoperative seizure outcome (Engel I and II or Engel I only), and (3) lobar concordance between the noninvasively estimated focus and intracranial electroencephalographic (EEG) recordings. RESULTS: A total of 131 patients were evaluated. Univariate analysis revealed higher SCS in the (1) epilepsy surgery group (8.4 [95% confidence interval (CI) = 7.8-8.9] vs. 4.9 [95% CI = 4.3-5.5] points; p < .001), (2) good postoperative seizure outcome group (Engel I and II; 8.7 [95% CI = 8.2-9.3] vs. 6.4 [95% CI = 4.5-8.3] points; p = .008), and (3) patients whose focus defined by intracranial EEG matched the noninvasively estimated focus (8.3 [95% CI = 7.3-9.2] vs. 5.4 [95% CI = 3.5-7.3] points; p = .004). Multivariate analysis revealed areas under the curve of .843, .825, and .881 for Parameters 1, 2, and 3, respectively. SIGNIFICANCE: SCS provides a reliable index of good indication for resective epilepsy surgery and can be easily available in many institutions not necessarily specializing in epilepsy.

Current trends in basic research on Parkinson's disease: from mitochondria, lysosome to α-synuclein.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and other brain regions. A key pathological feature of PD is the abnormal accumulation of α-synuclein protein within affected neurons, manifesting as Lewy bodies and Lewy neurites. Despite extensive research efforts spanning several decades, the underlying mechanisms of PD and disease-modifying therapies remain elusive. This review provides an overview of current trends in basic research on PD. Initially, it discusses the involvement of mitochondrial dysfunction in the pathogenesis of PD, followed by insights into the role of lysosomal dysfunction and disruptions in the vesicular transport system. Additionally, it delves into the pathological and physiological roles of α-synuclein, a crucial protein associated with PD pathophysiology. Overall, the purpose of this review is to comprehend the current state of elucidating the intricate mechanisms underlying PD and to outline future directions in understanding this disease.

The dynamics of cortical interactions in visual recognition of object category: living versus nonliving.

Noninvasive brain imaging studies have shown that higher visual processing of objects occurs in neural populations that are separable along broad semantic categories, particularly living versus nonliving objects. However, because of their limited temporal resolution, these studies have not been able to determine whether broad semantic categories are also reflected in the dynamics of neural interactions within cortical networks. We investigated the time course of neural propagation among cortical areas activated during object naming in 12 patients implanted with subdural electrode grids prior to epilepsy surgery, with a special focus on the visual recognition phase of the task. Analysis of event-related causality revealed significantly stronger neural propagation among sites within ventral temporal lobe (VTL) at early latencies, around 250 ms, for living objects compared to nonliving objects. Differences in other features, including familiarity, visual complexity, and age of acquisition, did not significantly change the patterns of neural propagation. Our findings suggest that the visual processing of living objects relies on stronger causal interactions among sites within VTL, perhaps reflecting greater integration of visual feature processing. In turn, this may help explain the fragility of naming living objects in neurological diseases affecting VTL.

Early Postoperative Stiffness After Arthroscopic Rotator Cuff Repair Correlates With Improved Tendon Healing.

PURPOSE: To assess whether early postoperative stiffness predicts long-term stiffness and its relationship with repair integrity in patients who undergo arthroscopic rotator cuff repair (ARCR). METHODS: This was a single-center retrospective study; 427 patients undergoing primary ARCR by a board-certified orthopaedic surgeon over 4 years were considered. Patients with at least 1 year of follow-up were categorized into stiff and non-stiff groups based on their range of motion (ROM) at 3 months' postoperatively. Stiffness was defined as passive forward flexion <120°, external rotation <30°, or internal rotation below L3. We evaluated clinical outcomes using demographics, ROM, Constant Shoulder (CS) score, University of California, Los Angeles (UCLA) score, and visual analog scale (VAS) for pain preoperatively and at 3, 6, and 12 months' postoperatively. Stiffness, retear rates, and tendon integrity were assessed via magnetic resonance imaging at 12 months. RESULTS: Of 155 patients meeting the inclusion criteria, 68 (43.9%) were stiff, and 87 (56.1%) were non-stiff. The stiff group had significantly lower preoperative CS and UCLA scores (P = .013/.014) and greater VAS score (P = .034). At 3 months, this group showed lower ROM and functional scores (P < .001), persisting at 6 and 12 months (except internal rotation) (P < .001). Their 12-month VAS score was greater (P = .024). Postoperative stiffness occurred in 10.3% of the stiff group and 2.3% of the non-stiff group (P = .035). The 12-month retear rate was 5.9% in the stiff group and 17.2% in the non-stiff group (P = .032). Minimal clinically important difference analysis indicated ROM changes but limited functional score changes in the 2 groups. CONCLUSIONS: This study showed that early postoperative shoulder stiffness correlates with lower preoperative functional scores and greater pain levels. Shoulder stiffness at 3 months' post-ARCR predicts 12-month shoulder stiffness but indicates better tendon integrity. While early stiffness is linked to lower functional scores and more pain, its long-term clinical impact seems limited. LEVEL OF EVIDENCE: Level III, retrospective comparison study.

YKL40/Integrin ß4 Axis Induced by the Interaction between Cancer Cells and Tumor-Associated Macrophages Is Involved in the Progression of High-Grade Serous Ovarian Carcinoma.

Macrophages in the tumor microenvironment, termed tumor-associated macrophages (TAMs), promote the progression of various cancer types. However, many mechanisms related to tumor-stromal interactions in epithelial ovarian cancer (EOC) progression remain unclear. High-grade serous ovarian carcinoma (HGSOC) is the most malignant EOC subtype. Herein, immunohistochemistry was performed on 65 HGSOC tissue samples, revealing that patients with a higher infiltration of CD68+, CD163+, and CD204+ macrophages had a poorer prognosis. We subsequently established an indirect co-culture system between macrophages and EOC cells, including HGSOC cells. The co-cultured macrophages showed increased expression of the TAM markers CD163 and CD204, and the co-cultured EOC cells exhibited enhanced proliferation, migration, and invasion. Cytokine array analysis revealed higher YKL40 secretion in the indirect co-culture system. The addition of YKL40 increased proliferation, migration, and invasion via extracellular signal-regulated kinase (Erk) signaling in EOC cells. The knockdown of integrin ß4, one of the YKL40 receptors, suppressed YKL40-induced proliferation, migration, and invasion, as well as Erk phosphorylation in some EOC cells. Database analysis showed that high-level expression of YKL40 and integrin ß4 correlated with a poor prognosis in patients with serous ovarian carcinoma. Therefore, the YKL40/integrin ß4 axis may play a role in ovarian cancer progression.

Identifying and reverting the adverse effects of white matter hyperintensities on cortical surface analyses.

The Human Connectome Project (HCP)-style surface-based brain MRI analysis is a powerful technique that allows precise mapping of the cerebral cortex. However, the strength of its surface-based analysis has not yet been tested in the older population that often presents with white matter hyperintensities (WMHs) on T2-weighted (T2w) MRI (hypointensities on T1w MRI). We investigated T1-weighted (T1w) and T2w structural MRI in 43 healthy middle-aged to old participants. Juxtacortical WMHs were often misclassified by the default HCP pipeline as parts of the gray matter in T1w MRI, leading to incorrect estimation of the cortical surfaces and cortical metrics. To revert the adverse effects of juxtacortical WMHs, we incorporated the Brain Intensity AbNormality Classification Algorithm into the HCP pipeline (proposed pipeline). Blinded radiologists performed stereological quality control (QC) and found a decrease in the estimation errors in the proposed pipeline. The superior performance of the proposed pipeline was confirmed using an originally-developed automated surface QC based on a large database. Here we showed the detrimental effects of juxtacortical WMHs for estimating cortical surfaces and related metrics and proposed a possible solution for this problem. The present knowledge and methodology should help researchers identify adequate cortical surface biomarkers for aging and age-related neuropsychiatric disorders.

A RaPID Macrocyclic Peptide That Inhibits the Formation of α-Synuclein Amyloid Fibrils.

There is considerable interest in drug discovery targeting the aggregation of α-synuclein (αSyn) since this molecular process is closely associated with Parkinson's disease. However, inhibiting αSyn aggregation remains a major challenge because of its highly dynamic nature which makes it difficult to form a stable binding complex with a drug molecule. Here, by exploiting Random non-standard Peptides Integrated Discovery (RaPID) system, we identified a macrocyclic peptide, BD1, that could interact with immobilized αSyn and inhibit the formation of fibrils. Furthermore, improving the solubility of BD1 suppresses the co-aggregation with αSyn fibrils while it kinetically inhibits more effectively without change in their morphology. We also revealed the molecular mechanism of kinetic inhibition, where peptides bind to fibril ends of αSyn, thereby preventing further growth of fibrils. These results suggest that our approach for generating non-standard macrocyclic peptides is a promising approach for developing potential therapeutics against neurodegeneration.

Motor Progression and Nigrostriatal Neurodegeneration in Parkinson Disease.

OBJECTIVE: The motor severity in Parkinson disease (PD) is believed to parallel dopaminergic terminal degeneration in the striatum, although the terminal was reported to be virtually absent by 4 years postdiagnosis. Meanwhile, neuromelanin-laden dopamine neuron loss in the substantia nigra (SN) elucidated a variability at early stages and gradual loss with less variability 10 years postdiagnosis. Here, we aimed to clarify the correlation between motor impairments and striatal dopaminergic terminal degeneration and nigral neuromelanin-laden dopamine neuron loss at early to advanced stages of PD. METHODS: Ninety-three PD patients were divided into early and advanced subgroups based on motor symptom duration and whether motor fluctuation was present. Striatal dopaminergic terminal degeneration was evaluated using a presynaptic dopamine transporter tracer, 123 I-ioflupane single photon emission computed tomography (SPECT). Nigral neuromelanin-laden dopamine neuron density was assessed by neuromelanin-sensitive magnetic resonance imaging (NM-MRI). RESULTS: In patients with early stage PD (motor symptoms for ≤8 or 10 years), motor dysfunction during the drug-off state was paralleled by a decline in 123 I-ioflupane uptake in the striatum despite the absence of a correlation with reductions in NM-MRI signals in SN. Meanwhile, in patients with advanced stage PD (motor symptoms for >8 or 10 years and with fluctuation), the degree of motor deficits during the drug-off state was not correlated with 123 I-ioflupane uptake in the striatum, despite its significant negative correlation with NM-MRI signals in SN. INTERPRETATION: We propose striatal dopaminergic terminal loss measured using 123 I-ioflupane SPECT and nigral dopamine neuron loss assessed with NM-MRI as early stage and advanced stage motor impairment biomarkers, respectively. ANN NEUROL 2022;92:110-121.