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Medicine Apr 2024Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant form of non-Hodgkin lymphoma categorized under the diffuse large B-cell type. It accounts for...
RATIONALE
Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant form of non-Hodgkin lymphoma categorized under the diffuse large B-cell type. It accounts for merely 1% of all non-Hodgkin lymphoma cases and comprises approximately 3% of all brain tumors. The involvement of the cerebellum is observed in only 9% of these cases. Recently, we came across an unusual instance: a young man presenting with multiple lesions located specifically within the cerebellum.
PATIENT CONCERNS
A 26-year-old male was admitted to the hospital due to severe headaches. He has a medical history of sporadic headaches, accompanied by dizziness, nausea, and vomiting persisting for a month. Over the last 10 days, his headaches have intensified, coupled with decreased vision and protrusion of the eyeballs. Magnetic resonance imaging (MRI) revealed abnormal signals in both cerebellar hemispheres.
DIAGNOSES, INTERVENTIONS, AND OUTCOMES
Diagnostic procedures included cerebellar biopsy, posterior fossa decompression, and lateral ventricle drainage. Histopathological examination identified diffuse large B-cell lymphoma (DLBCL) with high proliferative activity. To minimize neurotoxicity, chemotherapy involved intrathecal methotrexate (MTX) injections combined with the CHOP program. The patient has shown good tolerance to the treatment so far.
LESSONS
While the definitive optimal treatment approach remains elusive, current chemotherapy centered on high-dose MTX stands as the standard induction therapy. Integrating surgery with radiotherapy and chemotherapy significantly extends patient survival.
Topics: Humans; Male; Adult; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Combined Chemotherapy Protocols; Cerebellar Neoplasms; Cyclophosphamide; Vincristine; Doxorubicin; Methotrexate; Prednisone; Combined Modality Therapy; Magnetic Resonance Imaging; Cerebellum
PubMed: 38669361
DOI: 10.1097/MD.0000000000037923 -
Science Advances Apr 2024The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role...
The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, we establish that noradrenergic neurons of the locus coeruleus (LC) are essential for supraspinal opioid antinociception. While much previous work has emphasized the role of descending serotonergic pathways, we find that opioid antinociception is primarily driven by excitatory output from the ventrolateral periaqueductal gray (vlPAG) to the LC. Furthermore, we identify a previously unknown opioid-sensitive inhibitory input from the rostroventromedial medulla (RVM), the suppression of which disinhibits LC neurons to drive spinal noradrenergic antinociception. We describe pain-related activity throughout this circuit and report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings substantially revise current models of the DPMS and establish a supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation.
Topics: Locus Coeruleus; Periaqueductal Gray; Animals; Medulla Oblongata; Pain; Analgesics, Opioid; Male; Adrenergic Neurons; Mice; Neural Pathways
PubMed: 38669335
DOI: 10.1126/sciadv.adj9581 -
Science Advances Apr 2024While the kinesin-2 motors KIF3A and KIF3B have essential roles in ciliogenesis and Hedgehog (HH) signal transduction, potential role(s) for another kinesin-2 motor,...
While the kinesin-2 motors KIF3A and KIF3B have essential roles in ciliogenesis and Hedgehog (HH) signal transduction, potential role(s) for another kinesin-2 motor, KIF17, in HH signaling have yet to be explored. Here, we investigated the contribution of KIF17 to HH-dependent cerebellar development, where is expressed in both HH-producing Purkinje cells and HH-responding cerebellar granule neuron progenitors (CGNPs). Germline deletion in mice results in cerebellar hypoplasia due to reduced CGNP proliferation, a consequence of decreased HH pathway activity mediated through decreased Sonic HH (SHH) protein. Notably, Purkinje cell-specific deletion partially phenocopies germline mutants. Unexpectedly, CGNP-specific deletion results in the opposite phenotype-increased CGNP proliferation and HH target gene expression due to altered GLI transcription factor processing. Together, these data identify KIF17 as a key regulator of HH-dependent cerebellar development, with dual and opposing roles in HH-producing Purkinje cells and HH-responding CGNPs.
Topics: Animals; Kinesins; Cerebellum; Hedgehog Proteins; Mice; Purkinje Cells; Signal Transduction; Cell Proliferation; Mice, Knockout; Gene Expression Regulation, Developmental; Neural Stem Cells; Zinc Finger Protein GLI1; Developmental Disabilities; Nervous System Malformations
PubMed: 38669326
DOI: 10.1126/sciadv.ade1650 -
Nature Aging May 2024Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer's disease. By combining in vivo...
Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer's disease. By combining in vivo longitudinal magnetic resonance imaging measures of LC integrity, tau positron emission tomography imaging and cognition with autopsy data and transcriptomic information, we examined whether LC changes precede allocortical tau deposition and whether specific genetic features underlie LC's selective vulnerability to tau. We found that LC integrity changes preceded medial temporal lobe tau accumulation, and together these processes were associated with lower cognitive performance. Common gene expression profiles between LC-medial temporal lobe-limbic regions map to biological functions in protein transport regulation. These findings advance our understanding of the spatiotemporal patterns of initial tau spreading from the LC and LC's selective vulnerability to Alzheimer's disease pathology. LC integrity measures can be a promising indicator for identifying the time window when individuals are at risk of disease progression and underscore the importance of interventions mitigating initial tau spread.
Topics: Locus Coeruleus; Humans; tau Proteins; Alzheimer Disease; Cognition; Positron-Emission Tomography; Male; Female; Aged; Magnetic Resonance Imaging; Aged, 80 and over; Temporal Lobe
PubMed: 38664576
DOI: 10.1038/s43587-024-00626-y -
Scientific Reports Apr 2024In this work we endeavor to further understand the genetic architecture of the cerebellum by examining the genetic underpinnings of the different cerebellar lob(ul)es,...
In this work we endeavor to further understand the genetic architecture of the cerebellum by examining the genetic underpinnings of the different cerebellar lob(ul)es, identifying their genetic relation to cortical and subcortical regions, as well as to psychiatric disorders, as well as traces of their evolutionary trajectories. We confirm the moderate heritability of cerebellar volumes, and reveal genetic clustering and variability across their different substructures, which warranted a detailed analysis using this higher structural resolution. We replicated known genetic correlations with several subcortical volumes, and report new cortico-cerebellar genetic correlations, including negative genetic correlations between anterior cerebellar lobules and cingulate, and positive ones between lateral Crus I and lobule VI with cortical measures in the fusiform region. Heritability partitioning for evolutionary annotations highlighted that the vermis of Crus II has depleted heritability in genomic regions of "archaic introgression deserts", but no enrichment/depletion of heritability in any other cerebellar regions. Taken together, these findings reveal novel insights into the genetic underpinnings of the different cerebellar lobules.
Topics: Aged; Female; Humans; Male; Middle Aged; Cerebellum; Magnetic Resonance Imaging; UK Biobank; United Kingdom
PubMed: 38664414
DOI: 10.1038/s41598-024-59699-9 -
Nature Communications Apr 2024Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle that serves as a signaling hub for the cell. Using proximity labeling and quantitative...
Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle that serves as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identify Numb as a ciliary protein that positively regulates Hh signaling. Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, thereby promoting Ptch1 exit from the cilium, a key step in Hh signaling activation. Numb loss impedes Sonic hedgehog (Shh)-induced Ptch1 exit from the cilium, resulting in reduced Hh signaling. Numb loss in spinal neural progenitors reduces Shh-induced differentiation into cell fates reliant on high Hh activity. Genetic ablation of Numb in the developing cerebellum impairs the proliferation of granule cell precursors, a Hh-dependent process, resulting in reduced cerebellar size. This study highlights Numb as a regulator of ciliary Ptch1 levels during Hh signal activation and demonstrates the key role of ciliary pocket-mediated endocytosis in cell signaling.
Topics: Hedgehog Proteins; Cilia; Animals; Signal Transduction; Patched-1 Receptor; Mice; Nerve Tissue Proteins; Cerebellum; Membrane Proteins; Humans; Endocytosis; Cell Differentiation; Cell Proliferation; Neural Stem Cells; Mice, Knockout
PubMed: 38664376
DOI: 10.1038/s41467-024-47244-1 -
Brazilian Journal of Medical and... 2024We aimed to develop a prognostic model for primary pontine hemorrhage (PPH) patients and validate the predictive value of the model for a good prognosis at 90 days. A...
We aimed to develop a prognostic model for primary pontine hemorrhage (PPH) patients and validate the predictive value of the model for a good prognosis at 90 days. A total of 254 PPH patients were included for screening of the independent predictors of prognosis, and data were analyzed by univariate and multivariable logistic regression tests. The cases were then divided into training cohort (n=219) and validation cohort (n=35) based on the two centers. A nomogram was developed using independent predictors from the training cohort to predict the 90-day good outcome and was validated from the validation cohort. Glasgow Coma Scale score, normalized pixels (used to describe bleeding volume), and mechanical ventilation were significant predictors of a good outcome of PPH at 90 days in the training cohort (all P<0.05). The U test showed no statistical difference (P=0.892) between the training cohort and the validation cohort, suggesting the model fitted well. The new model showed good discrimination (area under the curve=0.833). The decision curve analysis of the nomogram of the training cohort indicated a great net benefit. The PPH nomogram comprising the Glasgow Coma Scale score, normalized pixels, and mechanical ventilation may facilitate predicting a 90-day good outcome.
Topics: Humans; Female; Male; Prognosis; Glasgow Coma Scale; Nomograms; Middle Aged; Adult; Respiration, Artificial; Pons; Predictive Value of Tests; Aged; Reproducibility of Results; Intracranial Hemorrhages; Retrospective Studies
PubMed: 38656075
DOI: 10.1590/1414-431X2024e13359 -
ENeuro Apr 2024Attending to salient sensory attributes of food, such as tastes that are new, displeasing, or unexpected, allows the procurement of nutrients without food poisoning....
Attending to salient sensory attributes of food, such as tastes that are new, displeasing, or unexpected, allows the procurement of nutrients without food poisoning. Exposure to new tastes is known to increase norepinephrine (NE) release in taste processing forebrain areas, yet the central source for this release is unknown. Locus ceruleus norepinephrine neurons (LC-NE) emerge as a candidate in signaling salient information about taste, as other salient sensory stimuli (e.g., visual, auditory, somatosensation) are known to activate LC neurons. To determine if LC neurons are sensitive to features of taste novelty, we used fiber photometry to record LC-NE activity in water-restricted mice that voluntarily licked either novel or familiar substances of differential palatability (saccharine, citric acid). We observed that LC-NE activity was suppressed during lick bursts and transiently activated upon the termination of licking and that these dynamics were independent of the familiarity of the substance consumed. We next recorded LC dynamics during brief and unexpected consumption of tastants and found no increase in LC-NE activity, despite their responsiveness to visual and auditory stimuli, revealing selectivity in LC's responses to salient sensory information. Our findings suggest that LC activity during licking is not influenced by taste novelty, implicating a possible role for non-LC noradrenergic nuclei in signaling critical information about taste.
Topics: Animals; Locus Coeruleus; Male; Mice, Inbred C57BL; Norepinephrine; Taste; Mice; Taste Perception; Citric Acid; Saccharin; Neurons; Female; Behavior, Animal
PubMed: 38649278
DOI: 10.1523/ENEURO.0535-23.2024 -
Annals of Clinical and Translational... Jun 2024Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain...
OBJECTIVE
Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs.
METHODS
Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples.
RESULTS
Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web-based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis.
INTERPRETATION
These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem.
Topics: Humans; Essential Tremor; Aged; Female; Male; Cerebellum; Middle Aged; Aged, 80 and over; Algorithms; Cerebellar Cortex
PubMed: 38644741
DOI: 10.1002/acn3.52068 -
Acta Neuropathologica Apr 2024The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72....
The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.
Topics: Humans; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Cerebellum; DNA Repeat Expansion; Frontotemporal Lobar Degeneration; Gene Expression Profiling; Transcriptome
PubMed: 38641715
DOI: 10.1007/s00401-024-02720-2