Multi-omics integration of scRNA-seq time series data predicts new intervention points for Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder without a cure. The onset of PD symptoms corresponds to 50% loss of midbrain dopaminergic (mDA) neurons, limiting early-stage understanding of PD. To shed light on early PD development, we study time series scRNA-seq datasets of mDA neurons obtained from patient-derived induced pluripotent stem cell differentiation. We develop a new data integration method based on Non-negative Matrix Tri-Factorization that integrates these datasets with molecular interaction networks, producing condition-specific "gene embeddings". By mining these embeddings, we predict 193 PD-related genes that are largely supported (49.7%) in the literature and are specific to the investigated PINK1 mutation. Enrichment analysis in Kyoto Encyclopedia of Genes and Genomes pathways highlights 10 PD-related molecular mechanisms perturbed during early PD development. Finally, investigating the top 20 prioritized genes reveals 12 previously unrecognized genes associated with PD that represent interesting drug targets.

Serum uric acid is associated with midbrain enlarged perivascular spaces: Results from Multi-modality Medical imaging sTudy bAsed on KaiLuan Study (META-KLS).

BACKGROUND: Serum uric acid (SUA) is a major cause of cardiovascular and cerebrovascular diseases. Whether and to what extent the excess risk of enlarged perivascular spaces (EPVS) conferred by SUA is unknown. The study was conducted to investigate the association between SUA and EPVS in different brain regions. METHODS: Data are from Multi-modality medical imaging study based on Kailuan study (META-KLS) in this cross-sectional study. Participants were divided into five groups based on SUA levels, and EPVS in basal ganglia (BG), centrum semiovale (CSO) and midbrain (MB) was systematically assessed and divided into Low and High group. Odds ratio (OR) and 95% confidence intervals (95% CIs) for high EPVS outcomes were estimated using multivariable logistic regression analysis. Restricted cubic spline (RCS) was used to further investigate dose-response relationship. RESULTS: A total of 1014 participants aged 25-83 years from 11 centers were enrolled in the study. In the multivariable-adjusted model, SUA, as an independent risk factor, correlated positively with high degree of MB-EPVS (OR, 1.002; 95% CI, 1.000 to 1.004; p = 0.023) in general population. In addition, RCS further demonstrated the linear association between SUA and MB-EPVS (p = 0.072). No association was found between SUA and BG-EPVS or CSO-EPVS. CONCLUSION: SUA was an independent risk factor of MB-EPVS. High SUA levels were more predictive of increased risk occurrence of high degree of MB-EPVS, supporting a linear association between SUA and MB-EPVS and further indicating that SUA may play an important role in cerebral small vessel disease. TRIAL REGISTRATION: The KaiLuan Study and META-KLS were registered online (ChiCTR2000029767 on chictr.org.cn and NCT05453877 on Clinicaltrials.gov, respectively).

Midbrain organoids for Parkinson's disease (PD) - A powerful tool to understand the disease pathogenesis.

Brain Organiods (BOs) are a promising technique for researching disease progression in the human brain. These organoids, which are produced from human induced pluripotent stem cells (HiPSCs), can construct themselves into structured frameworks. In the context of Parkinson's disease (PD), recent advancements have been made in the development of Midbrain organoids (MBOs) models that consider key pathophysiological mechanisms such as alpha-synuclein (α-Syn), Lewy bodies, dopamine loss, and microglia activation. However, there are limitations to the current use of BOs in disease modelling and drug discovery, such as the lack of vascularization, long-term differentiation, and absence of glial cells. To address these limitations, researchers have proposed the use of spinning bioreactors to improve oxygen and nutrient perfusion. Modelling PD utilising modern experimental in vitro models is a valuable tool for studying disease mechanisms and elucidating previously unknown features of PD. In this paper, we exclusively review the unique methods available for cultivating MBOs using a pumping system that mimics the circulatory system. This mechanism may aid in delivering the required amount of oxygen and nutrients to all areas of the organoids, preventing cell death, and allowing for long-term culture and using co-culturing techniques for developing glial cell in BOs. Furthermore, we emphasise some of the significant discoveries about the BOs and the potential challenges of using BOs will be discussed.

Development of Midbrain Dopaminergic Neurons and the Advantage of Using hiPSCs as a Model System to Study Parkinson's Disease.

Midbrain dopaminergic (mDA) neurons are significantly impaired in patients inflicted with Parkinson's disease (PD), subsequently affecting a variety of motor functions. There are four pathways through which dopamine elicits its function, namely, nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular dopamine pathways. SHH and Wnt signalling pathways in association with favourable expression of a variety of genes, promotes the development and differentiation of mDA neurons in the brain. However, there is a knowledge gap regarding the complex signalling pathways involved in development of mDA neurons. hiPSC models have been acclaimed to be effective in generating complex disease phenotypes. These models mimic the microenvironment found in vivo thus ensuring maximum reliability. Further, a variety of therapeutic compounds can be screened using hiPSCs since they can be used to generate neurons that could carry an array of mutations associated with both familial and sporadic PD. Thus, culturing hiPSCs to study gene expression and dysregulation of cellular processes associated with PD can be useful in developing targeted therapies that will be a step towards halting disease progression.

Alpha-synuclein pathology is associated with astrocyte senescence in a midbrain organoid model of familial Parkinson's disease.

Parkinson's disease (PD) is a complex, progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain. Despite extensive research efforts, the molecular and cellular changes that precede neurodegeneration in PD are poorly understood. To address this, here we describe the use of patient specific human midbrain organoids harboring the SNCA triplication to investigate mechanisms underlying dopaminergic degeneration. Our midbrain organoid model recapitulates key pathological hallmarks of PD, including the aggregation of α-synuclein and the progressive loss of dopaminergic neurons. We found that these pathological hallmarks are associated with an increase in senescence associated cellular phenotypes in astrocytes including nuclear lamina defects, the presence of senescence associated heterochromatin foci, and the upregulation of cell cycle arrest genes. These results suggest a role of pathological α-synuclein in inducing astrosenescence which may, in turn, increase the vulnerability of dopaminergic neurons to degeneration.

Bilateral thalamic and brainstem anaplastic astrocytoma: A case report.

RATIONALE: Bilateral thalamic glioma is extremely rare and characterized by strictly limited involvement of bilateral thalami. To investigate its clinical and neuroimaging features, we herein reported a rare case of anaplastic astrocytoma (AA) involving both thalami and the brainstem and reviewed the literature. PATIENT CONCERNS: A-33-year-old Chinese woman was referred to our department owing to persistent headache and nausea and vomiting. Neurological examination showed mild cognitive impairment and positive Kernig sign. DIAGNOSIS: Brain magnetic resonance imaging (MRI) demonstrated asymmetrical and swollen lesions involving both thalami, midbrain and pontine tegmentum, without restricted diffusion or enhancement. On day 7 after admission, she was transferred to the department of neurosurgery and underwent a stereotactic brain biopsy of the right thalamic lesion. Histopathological features and immunohistochemistry were consistent with AA, IDH wild-type, World Health Organization grade III. INTERVENTIONS: She was administrated with mannitol and glycerin fructose for decreasing intracranial pressure. OUTCOMES: In spite of receiving chemotherapy, she died on 2-month after her initial diagnosis. LESSONS: AA involving in both thalami and brainstem is a rare entity with poor prognosis. The clinicians and radiologists should deepen their awareness of the specific MRI feature of bilateral thalamic involvement. When MRI alone is insufficient, the utility of stereotactic biopsy is essential for making a definitive diagnosis.

Midbrain lesion-induced disconjugate gaze: a unifying circuit mechanism of ocular alignment?

BACKGROUND: Disconjugate eye movements are essential for depth perception in frontal-eyed species, but their underlying neural substrates are largely unknown. Lesions in the midbrain can cause disconjugate eye movements. While vertically disconjugate eye movements have been linked to defective visuo-vestibular integration, the pathophysiology and neuroanatomy of horizontally disconjugate eye movements remains elusive. METHODS: A patient with a solitary focal midbrain lesion was examined using detailed clinical ocular motor assessments, binocular videooculography and diffusion-weighted MRI, which was co-registered to a high-resolution cytoarchitectonic MR-atlas. RESULTS: The patient exhibited both vertically and horizontally disconjugate eye alignment and nystagmus. Binocular videooculography showed a strong correlation of vertical and horizontal oscillations during fixation but not in darkness. Oscillation intensities and waveforms were modulated by fixation, illumination, and gaze position, suggesting shared visual- and vestibular-related mechanisms. The lesion was mapped to a functionally ill-defined area of the dorsal midbrain, adjacent to the posterior commissure and sparing nuclei with known roles in vertical gaze control. CONCLUSION: A circumscribed region in the dorsal midbrain appears to be a key node for disconjugate eye movements in both vertical and horizontal planes. Lesioning this area produces a unique ocular motor syndrome mirroring hallmarks of developmental strabismus and nystagmus. Further circuit-level studies could offer pivotal insights into shared pathomechanisms of acquired and developmental disorders affecting eye alignment.

Unravelling cell type-specific responses to Parkinson's Disease at single cell resolution.

Parkinson's Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nucleus transcriptome analysis of human post-mortem SNpc obtained from 15 sporadic Parkinson's Disease (PD) cases and 14 Controls. Our dataset comprises ∼84K nuclei, representing all major cell types of the brain, allowing us to obtain a transcriptome-level characterization of these cell types. Importantly, we identify multiple subpopulations for each cell type and describe specific gene sets that provide insights into the differing roles of these subpopulations. Our findings reveal a significant decrease in neuronal cells in PD samples, accompanied by an increase in glial cells and T cells. Subpopulation analyses demonstrate a significant depletion of tyrosine hydroxylase (TH) enriched astrocyte, microglia and oligodendrocyte populations in PD samples, as well as TH enriched neurons, which are also depleted. Moreover, marker gene analysis of the depleted subpopulations identified 28 overlapping genes, including those associated with dopamine metabolism (e.g., ALDH1A1, SLC6A3 & SLC18A2). Overall, our study provides a valuable resource for understanding the molecular mechanisms involved in dopaminergic neuron degeneration and glial responses in PD, highlighting the existence of novel subpopulations and cell type-specific gene sets.

A novel radiological classification of midbrain pilocytic astrocytomas and its implication for surgical management: a single-institution experience of 57 cases.

OBJECTIVE: Surgery for midbrain pilocytic astrocytoma (PA) remains a formidable challenge. To facilitate decision-making and achieve a better outcome in the management of patients with midbrain PA, the authors have proposed a novel radiological classification of midbrain PAs with long-term follow-up. METHODS: Fifty-seven midbrain PA patients who underwent surgery at Beijing Tiantan Hospital, Capital Medical University, from January 2008 to June 2021, were reviewed. Based on tumor location and the topological anatomical change identified on MRI, midbrain PAs were categorized into four types: crural (12/57, 21.1%), tegmental (25/57, 43.9%), aqueductal (5/57, 8.8%), and tectal (15/57, 26.3%) PAs. The relevant clinical, radiological, and pathological data; surgical procedures and results; and long-term outcomes were collected and analyzed. RESULTS: The 1-, 3-, and 5-year survival rates reached 98%, 96%, and 96%, respectively, with gross-total resection achieved in 66.7% of cases, followed by near-total resection in 17.5% cases. The clinical and radiological features, selection of surgical approaches, and long-term postoperative deficits were distinct among each type. Crural PAs were associated with younger age (median 9 years, IQR 5.0-12.8 years); the largest tumor volume (median 31.9 cm3, IQR 17.2-42.6 cm3); the lowest preoperative Karnofsky Performance Scale (KPS) score (median 65, IQR 50-70); the most frequent preoperative motor deficit (91.7%); a mixed solid-cystic component (75%); occupation of the crural cistern; elevation and rotation of the thalamus (medial and/or lateral); displacement of the anterior third ventricle, uncus, and anterior commissure; the most diverse surgical approaches; more frequent use of multimodality image-guided surgery (58.3%); and the most remarkable improvement in KPS score at long-term follow-up. Tegmental PAs were associated with adolescents and young adults (median age 21 years, IQR 8-33 years); tumor volume (median 13.9 cm3, IQR 9.5-20.5 cm3); a good preoperative KPS score (median 80, IQR 70-80); a mixed solid-cystic component (72%); occupation of the ambient cistern and cerebellomesencephalic fissure; a close relationship with the dorsal pons, superior cerebellar peduncle, and posterior inferior third ventricle; and a higher probability of permanent postoperative sensory deficits (40%). Aqueductal and tectal PAs were associated with small tumor volume (median 9.14 cm3, IQR 5.1-17.4 cm3 and median 11.84 cm3, IQR 5.7-18.3 cm3, respectively), a higher percentage of hydrocephalus (80% and 86.7%, respectively), and a straightforward selection of limited surgical approaches. CONCLUSIONS: A novel and comprehensive radiological classification of midbrain PAs was established, which will serve as a valuable tool in patient management and promote uniform communication and comparison across different studies and publications.

Volumetric alteration of brainstem in female migraineurs with and without aura.

BACKGROUND AND AIM: Brainstem descending modulatory circuits have been postulated to be involved in migraine. Differences in brainstem volume between migraineurs and healthy controls have been demonstrated in previous research, nevertheless, the effect of migraine aura on brainstem volume is still uncertain. The aim of this study was to investigate the brainstem volume in migraineurs and examine the effect of migraine aura on brainstem volume. METHODS: Our study included 90 female migraine patients without white matter lesions. (29 migraine patients with aura (MwA) and 61 migraine patients without aura (MwoA) and 32 age-matched female healthy controls (HC). Using the FreeSurfer image analysis suite, the volumes of the entire brainstem and its subfields (medulla, pons, and midbrain) were measured and compared between migraine subgroups (MwA vs. MwoA) and the healthy control group. The possible effects of migraine characteristics (i.e., disease duration and migraine attack frequency) on brainstem volume were also investigated. RESULTS: Migraineurs had greater medulla volume (MwoA 3552 ± 459 mm3, MwA 3424 ± 448 mm3) than healthy controls (3236 ± 411 mm3). Statistically, MwA vs. HC p = 0.040, MwoA vs. HC p = 0.002, MwA vs. MwoA p = 0.555. A significant positive correlation was found between disease duration and the volume of medulla in the whole migraine group (r = 0.334, p = 0.001). Neither the whole brainstem nor its subfields were significantly different in volume between migraine subgroups. CONCLUSION: Brainstem volume changes in migraine are mainly localized to the medulla and not specific to the presence of aura.

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

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

Structural correlates of survival in progressive supranuclear palsy.

INTRODUCTION: Many studies of the Richardson's syndrome phenotype of progressive supranuclear palsy (PSP) have elucidated regions of progressive atrophy and neural correlates of clinical severity. However, the neural correlates of survival and how these differ according to variant phenotypes are poorly understood. We set out to identify structural changes that predict severity and survival from scanning date to death. METHODS: Structural magnetic resonance imaging data from 112 deceased people with clinically defined 'probable' or 'possible' PSP were analysed. Neuroanatomical regions of interest volumes, thickness and area were correlated with 'temporal stage', defined as the ratio of time from symptom onset to death, time from scan to death ('survival from scan'), and in a subset of patients, clinical severity, adjusting for age and total intracranial volume. Forty-nine participants had post mortem confirmation of the diagnosis. RESULTS: Using T1-weighted magnetic resonance imaging, we confirmed the midbrain, and bilateral cortical structural correlates of contemporary disease severity. Atrophy of the striatum, cerebellum and frontotemporal cortex correlate with temporal stage and survival from scan, even after adjusting for severity. Subcortical structure-survival relationships were stronger in Richardson's syndrome than variant phenotypes. CONCLUSIONS: Although the duration of PSP varies widely between people, an individual's progress from disease onset to death (their temporal stage) reflects atrophy in striatal, cerebellar and frontotemporal cortical regions. Our findings suggest magnetic resonance imaging may contribute to prognostication and stratification of patients with heterogenous clinical trajectories and clarify the processes that confer mortality risk in PSP.

Brain MRI in Progressive Supranuclear Palsy with Richardson's Syndrome and Variant Phenotypes.

BACKGROUND: Brain magnetic resonance imaging (MRI) is used to support the diagnosis of progressive supranuclear palsy (PSP). However, the value of visual descriptive, manual planimetric, automatic volumetric MRI markers and fully automatic categorization is unclear, particularly regarding PSP predominance types other than Richardson's syndrome (RS). OBJECTIVES: To compare different visual reading strategies and automatic classification of T1-weighted MRI for detection of PSP in a typical clinical cohort including PSP-RS and (non-RS) variant PSP (vPSP) patients. METHODS: Forty-one patients (21 RS, 20 vPSP) and 46 healthy controls were included. Three readers using three strategies performed MRI analysis: exclusively visual reading using descriptive signs (hummingbird, morning-glory, Mickey-Mouse), visual reading supported by manual planimetry measures, and visual reading supported by automatic volumetry. Fully automatic classification was performed using a pre-trained support vector machine (SVM) on the results of atlas-based volumetry. RESULTS: All tested methods achieved higher specificity than sensitivity. Limited sensitivity was driven to large extent by false negative vPSP cases. Support by automatic volumetry resulted in the highest accuracy (75.1% ± 3.5%) among the visual strategies, but performed not better than the midbrain area (75.9%), the best single planimetric measure. Automatic classification by SVM clearly outperformed all other methods (accuracy, 87.4%), representing the only method to provide clinically useful sensitivity also in vPSP (70.0%). CONCLUSIONS: Fully automatic classification of volumetric MRI measures using machine learning methods outperforms visual MRI analysis without and with planimetry or volumetry support, particularly regarding diagnosis of vPSP, suggesting the use in settings with a broad phenotypic PSP spectrum. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Co-transplantation of autologous Treg cells in a cell therapy for Parkinson's disease.

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

Treponema denticola Has the Potential to Cause Neurodegeneration in the Midbrain via the Periodontal Route of Infection-Narrative Review.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common example of dementia. The neuropathological features of AD are the abnormal deposition of extracellular amyloid-ß (Aß) and intraneuronal neurofibrillary tangles with hyperphosphorylated tau protein. It is recognized that AD starts in the frontal cerebral cortex, and then it progresses to the entorhinal cortex, the hippocampus, and the rest of the brain. However, some studies on animals suggest that AD could also progress in the reverse order starting from the midbrain and then spreading to the frontal cortex. Spirochetes are neurotrophic: From a peripheral route of infection, they can reach the brain via the midbrain. Their direct and indirect effect via the interaction of their virulence factors and the microglia potentially leads to the host peripheral nerve, the midbrain (especially the locus coeruleus), and cortical damage. On this basis, this review aims to discuss the hypothesis of the ability of Treponema denticola to damage the peripheral axons in the periodontal ligament, to evade the complemental pathway and microglial immune response, to determine the cytoskeletal impairment and therefore causing the axonal transport disruption, an altered mitochondrial migration and the consequent neuronal apoptosis. Further insights about the central neurodegeneration mechanism and Treponema denticola's resistance to the immune response when aggregated in biofilm and its quorum sensing are suggested as a pathogenetic model for the advanced stages of AD.

The Pesticide Chlordecone Promotes Parkinsonism-like Neurodegeneration with Tau Lesions in Midbrain Cultures and C. elegans Worms.

Chlordecone (CLD) is an organochlorine pesticide (OCP) that is currently banned but still contaminates ecosystems in the French Caribbean. Because OCPs are known to increase the risk of Parkinson's disease (PD), we tested whether chronic low-level intoxication with CLD could reproduce certain key characteristics of Parkinsonism-like neurodegeneration. For that, we used culture systems of mouse midbrain dopamine (DA) neurons and glial cells, together with the nematode C. elegans as an in vivo model organism. We established that CLD kills cultured DA neurons in a concentration- and time-dependent manner while exerting no direct proinflammatory effects on glial cells. DA cell loss was not impacted by the degree of maturation of the culture. The use of fluorogenic probes revealed that CLD neurotoxicity was the consequence of oxidative stress-mediated insults and mitochondrial disturbances. In C. elegans worms, CLD exposure caused a progressive loss of DA neurons associated with locomotor deficits secondary to alterations in food perception. L-DOPA, a molecule used for PD treatment, corrected these deficits. Cholinergic and serotoninergic neuronal cells were also affected by CLD in C. elegans, although to a lesser extent than DA neurons. Noticeably, CLD also promoted the phosphorylation of the aggregation-prone protein tau (but not of α-synuclein) both in midbrain cell cultures and in a transgenic C. elegans strain expressing a human form of tau in neurons. In summary, our data suggest that CLD is more likely to promote atypical forms of Parkinsonism characterized by tau pathology than classical synucleinopathy-associated PD.

[Abnormal changes of static and dynamic functional connectivity of dopaminergic midbrain in patients with first-episode schizophrenia and their correlations with clinical symptoms].

Objective: To investigate the abnormal changes of static functional connectivity (sFC) and dynamic functional connectivity (dFC) in the dopaminergic midbrain (ventral dorsal tegmental area and bilateral substantia nigra compacta, VTA/SNc) in patients with first-episode schizophrenia(SCH), and their correlation with the Positive and Negative Symptom Scale (PANSS). Methods: The data of 198 first-episode untreated schizophrenia patients and 199 healthy controls (HC) matched by age, sex and years of education who were admitted to the First Affiliated Hospital of Zhengzhou University from January 2019 to May 2022 were prospectively collected. All subjects underwent high resolution structural MRI and resting state functional magnetic resonance imaging (rs-fMRI) scanning. The dopaminergic midbrain (VTA/SNc) was defined as three regions of interest (ROI). The sFC and dFC analyses with VTA/SNc as seeds were performed to produce a whole-brain diagram initially, which subsequently were compared between schizophrenia group and HC group. Finally, the correlation analysis of sFC and dFC values with the PANSS scores were performed, including the positive scale score, negative scale score, general psychopathology scale score, total score and symptom scores. Results: There were 86 males and 112 females in SCH group, and aged (23±9) years. Meanwhile, there were 95 males and 104 females in HC group, and aged (22±5) years. In the SCH group, the positive (P), the negative (N) and the general psychopathology (G) scale scores and the total score (T) of the PANSS scale was 20±7, 21±7, 41±11 and 82±22, respectively. Compared with the HC group, the VTA showed decreased sFC with four clusters including cerebellar vermis 7/9, left putamen, right thalamus and left middle cingulate gyrus in the schizophrenia group (peak center, t=-4.35, -4.81, -4.35 and -4.65; voxel P<0.005; cluster P<0.05), the right SNc showed decreased sFC with four clusters including left cerebellar hemisphere 4/5/8, right putamen, right medial orbitofrontal gyrus and the left putamen in the schizophrenia group (peak center, t=-4.91, -5.15, -4.77 and -5.21; voxel P<0.005; cluster P<0.05), and the left SNc showed decreased sFC with four clusters including the left putamen, right putamen, right medial orbitofrontal gyrus and left middle cingulate gyrus in the schizophrenia group (peak center, t=-5.82, -4.83 and -4.65; voxel P<0.005; cluster P<0.05). Compared with the HC group, the VTA showed decreased dFC with the right inferior parietal gyrus, right angular gyrus and right superior parietal gyrus in schizophrenia group (t=-4.17). In the schizophrenia group, the sFC value of cluster 2 (left putamen) with VTA as seed and cluster 4 (left putamen) with right SNc as seed were positively correlated with the positive scale scores in PANSS (r=0.141, 0.169, both P<0.05). The sFC and dFC values of significant regions were also correlated with hallucination, delusion, suspicion, hostility, communication disorder, passivity/indifference, lack of communication, stereotyped thinking, depression, non-cooperation, lack of judgment and insight, impulse control disorder, active social avoidance (all P<0.05). Conclusion: The static and dynamic functional connectivity (stability) of VTA/SNc to cerebellum, thalamus, striatum, prefrontal lobe and cingulate gyrus in first-episode schizophrenia patients were decreased, which were closely related to the positive and negative symptoms of schizophrenia.

Human iPSC-derived midbrain organoids functionally integrate into striatum circuits and restore motor function in a mouse model of Parkinson's disease.

Rationale: Parkinson's disease (PD) is a prevalent neurodegenerative disorder that is characterized by degeneration of dopaminergic neurons (DA) at the substantia nigra pas compacta (SNpc). Cell therapy has been proposed as a potential treatment option for PD, with the aim of replenishing the lost DA neurons and restoring motor function. Fetal ventral mesencephalon tissues (fVM) and stem cell-derived DA precursors cultured in 2-dimentional (2-D) culture conditions have shown promising therapeutic outcomes in animal models and clinical trials. Recently, human induced pluripotent stem cells (hiPSC)-derived human midbrain organoids (hMOs) cultured in 3-dimentional (3-D) culture conditions have emerged as a novel source of graft that combines the strengths of fVM tissues and 2-D DA cells. Methods: 3-D hMOs were induced from three distinct hiPSC lines. hMOs at various stages of differentiation were transplanted as tissue pieces into the striatum of naïve immunodeficient mouse brains, with the aim of identifying the most suitable stage of hMOs for cellular therapy. The hMOs at Day 15 were determined to be the most appropriate stage and were transplanted into a PD mouse model to assess cell survival, differentiation, and axonal innervation in vivo. Behavioral tests were conducted to evaluate functional restoration following hMO treatment and to compare the therapeutic effects between 2-D and 3-D cultures. Rabies virus were introduced to identify the host presynaptic input onto the transplanted cells. Results: hMOs showed a relatively homogeneous cell composition, mostly consisting of dopaminergic cells of midbrain lineage. Analysis conducted 12 weeks post-transplantation of day 15 hMOs revealed that 14.11% of the engrafted cells expressed TH+ and over 90% of these cells were co-labeled with GIRK2+, indicating the survival and maturation of A9 mDA neurons in the striatum of PD mice. Transplantation of hMOs led to a reversal of motor function and establishment of bidirectional connections with natural brain target regions, without any incidence of tumor formation or graft overgrowth. Conclusion: The findings of this study highlight the potential of hMOs as safe and efficacious donor graft sources for cell therapy to treat PD.

Primary midbrain germinomas: Report of a rare case with an updated review of the literature.

Intracranial germinomas are most commonly extra-axial germ cell tumors that are predominantly found in the pineal and suprasellar regions. Primary intra-axial midbrain germinomas are extremely rare, with only eight reported cases. Here we present a 30-year-old man who presented with severe neurological deficits, with an MRI that showed a heterogeneously enhancing mass with ill-defined margins in the midbrain, and with surrounding vasogenic edema extending to the thalamus. The presumptive preoperative differential diagnosis included glial tumors and lymphoma. The patient underwent a right paramedian suboccipital craniotomy and biopsy obtained through the supracerebellar infratentorial transcollicular approach. The histopathological diagnosis was reported as pure germinoma. After patient discharge, he received chemotherapy with carboplatin and etoposide, followed by radiotherapy. Follow-up MRI at up to 26 months showed no contrast-enhancing lesions but a mild T2 FLAIR hyperintensity adjacent to the resection cavity. Differential diagnosis of midbrain lesions can be challenging and should include glial tumors, primary central nervous system lymphoma, germ cell tumors, and metastasis. Accurate diagnosis requires adequate tissue sampling. In this report, we present a very rare case of a primary intra-axial germinoma of the midbrain which is biopsied via a transcollicular approach. This report is also unique as it provides the first surgical video of an open biopsy and the microscopic appearance of an intra-axial primary midbrain germinoma via a transcollicular approach.

Palatal myoclonus and hypertrophic olivary degeneration following wernekinck commissure syndrome: a case report.

BACKGROUND: Hypertrophic olivary degeneration (HOD), a rare form of transsynaptic degeneration, is secondary to dentato-rubro-olivary pathway injuries in some cases. We describe a unique case of an HOD patient who presented with palatal myoclonus secondary to Wernekinck commissure syndrome caused by a rare bilateral "heart-shaped" infarct lesion in the midbrain. CASE PRESENTATION: A 49-year-old man presented with progressive gait instability in the past 7 months. The patient had a history of posterior circulation ischemic stroke presenting with diplopia, slurred speech, and difficulty in swallowing and walking 3 years prior to admission. The symptoms improved after treatment. The feeling of imbalance appeared and was aggravated gradually in the past 7 months. Neurological examination demonstrated dysarthria, horizontal nystagmus, bilateral cerebellar ataxia, and 2-3 Hz rhythmic contractions of the soft palate and upper larynx. Magnetic resonance imaging (MRI) of the brain performed 3 years prior to this admission showed an acute midline lesion in the midbrain exhibiting a remarkable "heart appearance" on diffusion weighted imaging. MRI after this admission revealed T2 and FLAIR hyperintensity with hypertrophy of the bilateral inferior olivary nucleus. We considered a diagnosis of HOD resulting from a midbrain heart-shaped infarction, which caused Wernekinck commissure syndrome 3 years prior to admission and later HOD. Adamantanamine and B vitamins were administered for neurotrophic treatment. Rehabilitation training was also performed. One year later, the symptoms of this patient were neither improved nor aggravated. CONCLUSION: This case report suggests that patients with a history of midbrain injury, especially Wernekinck commissure injury, should be alert to the possibility of delayed bilateral HOD when new symptoms occur or original symptoms are aggravated.