Role of Dickkopf-3 in Blood Pressure Regulation in Mice and Hypertensive Rats.

BACKGROUND: Dkk3 (Dickkopf-3) is a secreted glycoprotein known for its proapoptotic and angiogenic activity. The role of Dkk3 in cardiovascular homeostasis is largely unknown. Remarkably, the Dkk3 gene maps within a chromosome segment linked to the hypertensive phenotype in spontaneously hypertensive rats (SHR). METHODS: We used Dkk3-/- mice or stroke-resistant (sr) and stroke-prone (sp) SHR to examine the role of Dkk3 in the central and peripheral regulation of blood pressure (BP). We used lentiviral expression vector to rescue Dkk3 in knockout mice or to induce Dkk3 overexpression or silencing in SHR. RESULTS: Genetic deletion of Dkk3 in mice enhanced BP and impaired endothelium-dependent acetylcholine-induced relaxation of resistance arteries. These alterations were rescued by restoring Dkk3 expression either in the periphery or in the central nervous system (CNS). Dkk3 was required for the constitutive expression of VEGF (vascular endothelium growth factor), and the action of Dkk3 on BP and endothelium-dependent vasorelaxation was mediated by VEGF-stimulated phosphatidylinositol-3-kinase pathway, leading to eNOS (endothelial NO synthase) activation both in resistance arteries and the CNS. The regulatory function of Dkk3 on BP was confirmed in SHR stroke-resistant and SHR stroke-prone in which was blunted in both resistance arteries and brainstem. In SHR stroke-resistant, lentiviral expression vector-induced Dkk3 expression in the CNS largely reduced BP, whereas Dkk3 knock-down further enhanced BP. In SHR stroke-prone challenged with a hypersodic diet, lentiviral expression vector-induced Dkk3 expression in the CNS displayed a substantial antihypertensive effect and delayed the occurrence of stroke. CONCLUSIONS: These findings demonstrate that Dkk3 acts as peripheral and central regulator of BP by promoting VEGF expression and activating a VEGF/Akt (protein kinase B)/eNOS hypotensive axis.

Development and Validation of a Supplementary Grading Scale for Outcomes of Brainstem Cavernous Malformations.

BACKGROUND: Surgical risk assessment is intriguing for clinical decision-making of brainstem cavernous malformation (BSCM) treatment. While the BSCM grading scale, encompassing size, developmental venous anomaly, crossing axial midpoint, age, and timing of intervention, is increasingly utilized, the clinical relevance of neurological fluctuation and recurrent hemorrhage has not been incorporated. This study aimed to propose a supplementary grading scale with enhanced predictive efficacy. METHODS: Using a retrospective nationwide registry of consecutive patients with BSCMs undergoing surgery in China from March 2011 to May 2023, a new supplementary BSCM grading scale was developed from a derivative cohort of 260 patients and validated in an independent concurrent cohort of 67 patients. The primary outcome was unfavorable neurological function (modified Rankin Scale score >2) at the latest follow-up. The performance of the supplementary grading system was evaluated for discrimination, calibration, and clinical utility and further compared with its original counterpart. RESULTS: Over a follow-up of at least 6 months after surgery, the unfavorable outcomes were 31% in the overall cohort (101/327 patients). A preoperative motor deficit (odds ratio, 3.13; P=0.001), recurrent hemorrhage (odds ratio, 3.05; P<0.001), timing of intervention (odds ratio, 7.08; P<0.001), and crossing the axial midpoint (odds ratio, 2.57; P=0.006) were associated with the unfavorable outcomes and composed the initial Huashan grading variables. A supplementary BSCM grading system was subsequently developed by incorporating the Huashan grading variables into the original BSCM grading scale. The predictive capability of the supplementary scale was consistently superior to the original counterpart in either the derivative cohort (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.68-0.80] for the supplementary versus 0.68 [95% CI, 0.61-0.74] for the original) or the validation cohort (0.75 [95% CI, 0.62-0.87] versus 0.64 [95% CI, 0.48-0.81]). CONCLUSIONS: This study highlights the neurological relevance of BSCM hemorrhage in surgical risk assessment. Via compositing preoperative motor function and recurrent hemorrhages, a supplementary grading scale may improve a dynamic risk assessment for clinical decisions in the management of BSCMs.

Treatment Modalities and Outcomes in Brainstem Cavernous Malformations: A Large Multicenter Observational Cohort Study.

BACKGROUND: Symptomatic brainstem cavernous malformations (BSCMs) pose a high risk of morbidity and mortality due to recurrent hemorrhage, warranting aggressive management. However, few studies have compared the effectiveness of different treatment modalities for BSCMs. We aimed to assess the association of treatment modalities with recurrent hemorrhage and neurological outcomes in patients with BSCM. METHODS: We conducted a retrospective cohort study using an observational registry database covering population of southwest and southeast China. Adult patients with BSCM were included and followed up between March 1, 2011, to March 31, 2023. We compared outcomes between microsurgery and stereotactic radiosurgery (SRS) in propensity score-matched case pairs, incorporating demographic, medical history, and lesion characteristics. The outcomes studied included recurrent hemorrhage and poor prognosis (defined as a Glasgow Outcome Scale score, <4). Absolute rate differences and hazard ratios (HRs) with 95% CIs were calculated using Cox models. RESULTS: Among 736 diagnosed patients with BSCM, 96 (48 matched pairs) were included after exclusions and propensity score matching (mean age, 43.1 [SD, 12.1] years; 50% women). During the median 5-year follow-up, no significant differences in recurrent hemorrhage (4.2% [microsurgery] versus 14.6% [SRS], HR, 3.90 [95% CI, 0.46-32.65]; P=0.21) and poor prognosis (12.5% [microsurgery] versus 8.3% [SRS], HR, 0.29 [95% CI, 0.08-1.08]; P=0.07) were observed between microsurgery and SRS recipients. Furthermore, either microsurgery or SRS correlated with fewer recurrent hemorrhage (HR, 0.09 [95% CI, 0.02-0.39]; P=0.001; HR, 0.21 [95% CI, 0.07-0.69]; P=0.01) compared with conservative treatment. CONCLUSIONS: In this study, both microsurgery and SRS were safe and effective for BSCM, demonstrated comparable outcomes in recurrent hemorrhage and poor prognosis. However, interpretation should be cautious due to the potential for residual confounding. REGISTRATION: URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2300070907.

Different descending pathways mediate early and late portions of lower limb responses to transcranial magnetic stimulation.

Although recent studies in nonhuman primates have provided evidence that transcranial magnetic stimulation (TMS) activates cells within the reticular formation, it remains unclear whether descending brain stem projections contribute to the generation of TMS-induced motor evoked potentials (MEPs) in skeletal muscles. We compared MEPs in muscles with extensive direct corticomotoneuronal input (first dorsal interosseous) versus a prominent role in postural control (gastrocnemius) to determine whether the amplitudes of early and late MEPs were differentially modulated by cortical suppression. Suprathreshold TMS was applied with and without a preceding suprathreshold TMS pulse at two interstimulus intervals (50 and 80 ms). H reflexes in target muscles were also tested with and without TMS conditioning. Early and late gastrocnemius MEPs were differentially modulated by cortical inhibition, the amplitude of the early MEP being significantly reduced by cortical suppression and the late MEP facilitated. The amplitude of H reflexes in the gastrocnemius was reduced within the cortical silent period. Early MEPs in the first dorsal interosseous were also reduced during the silent period, but late MEPs were unaffected. Independent modulation of early and late MEPs in the gastrocnemius muscle supports the idea that the MEP is generated by multiple descending pathways. Suppression of the early MEP is consistent with transmission along the fast-conducting corticospinal tract, whereas facilitation of the late MEP suggests transmission along a corticofugal, potentially cortico-reticulospinal, pathway. Accordingly, differences in late MEP modulation between the first dorsal interosseous and gastrocnemius reflect an increased role of corticofugal pathways in the control of postural muscles.NEW & NOTEWORTHY Early and late portions of the response to transcranial magnetic stimulation (TMS) in a lower limb postural muscle are modulated independently by cortical suppression, late motor evoked potentials (MEPs) being facilitated during cortical inhibition. These results suggest a cortico-brain stem transmission pathway for late portions of the TMS-induced MEP.

Echocardiographic surrogate of left ventricular stroke work in a model of brain stem death donors.

BACKGROUND: The commonest echocardiographic measurement, left ventricular ejection fraction, can not necessarily predict mortality of recipients following heart transplantation potentially due to afterload dependency. Afterload-independent left ventricular stroke work index (LVSWI) is alternatively recommended by the current guideline; however, pulmonary artery catheters are rarely inserted in organ donors in most jurisdictions. We propose a novel non-invasive echocardiographic parameter, Pressure-Strain Product (PSP), as a potential surrogate of catheter-based LVSWI. This study aimed to investigate if PSP could correlate with catheter-based LVSWI in an ovine model of brain stem death (BSD) donors. The association between PSP and myocardial mitochondrial function in the post-transplant hearts was also evaluated. METHODS: Thirty-one female sheep (weight 47 ± 5 kg) were divided into two groups; BSD (n = 15), and sham neurologic injury (n = 16). Echocardiographic parameters including global circumferential strain (GCS) and global radial strain (GRS) and pulmonary artery catheter-based LVSWI were simultaneously measured at 8-timepoints during 24-h observation. PSP was calculated as a product of GCS or GRS, and mean arterial pressure for PSPcirc or PSPrad, respectively. Myocardial mitochondrial function was evaluated following 6-h observation after heart transplantation. RESULTS: In BSD donor hearts, PSPcirc (n = 96, rho = .547, p < .001) showed the best correlation with LVSWI among other echocardiographic parameters. PSPcirc returned AUC of .825 to distinguish higher values of cardiomyocyte mitochondrial function (cut-off point; mean value of complex 1,2 O2 Flux) in post-transplant hearts, which was greater than other echocardiographic parameters. CONCLUSIONS: PSPcirc could be used as a surrogate of catheter-based LVSWI reflecting mitochondrial function.

Brain stem tumors in children less than 3 months: Clinical and radiologic findings of a rare disease.

PURPOSE: Brain stem tumors in children < 3 months at diagnosis are extremely rare. Our aim is to study a retrospective cohort to improve the understanding of the disease course and guide patient management. METHODS: This is a multicenter retrospective analysis across the European Society for Pediatric Oncology SIOP-E HGG/DIPG Working Group linked centers, including patients with a brainstem tumor diagnosed between 2009 and 2020 and aged < 3 months at diagnosis. Clinical data were collected, and imaging characteristics were analyzed blindly and independently by two neuroradiologists. RESULTS: Five cases were identified. No patient received any therapy. The epicenter of two tumors was in the medulla oblongata alone and in the medulla oblongata and the pons in three. For patients with tumor in equal parts in the medulla oblongata and the pons (n = 3), the extension at diagnosis involved the spinal cord; for the two patients with the tumor epicenter in the medulla oblongata alone (n = 2), the extension at diagnosis included the pons (n = 2) and the spinal cord (n = 1). Biopsy was performed in one patient identifying a pilocytic astrocytoma. Two patients died. In one patient, autopsy revealed a high-grade glioma (case 3). Three survivors showed either spontaneous tumor regression (n = 2) or stable disease (n = 1). Survivors were followed up for 10, 7, and 0.6 years, respectively. One case had the typical imaging characteristics of a dorsal exophytic low-grade glioma. CONCLUSIONS: No patient fulfilled the radiologic criteria defining a high-grade glioma. Central neuroradiological review and biopsy may provide useful information regarding the patient management.

The use of an anterior-posterior atrophy index to distinguish Alzheimer's disease from frontotemporal disorders: an automated volumetric MRI Study.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) require different treatments. Since clinical presentation can be nuanced, imaging biomarkers aid in diagnosis. Automated software such as Neuroreader (NR) provides volumetric imaging data, and indices between anterior and posterior brain areas have proven useful in distinguishing dementia subtypes in research cohorts. Existing indices are complex and require further validation in clinical settings. PURPOSE: To provide initial validation for a simplified anterior-posterior index (API) from NR in distinguishing FTD and AD in a clinical cohort. MATERIAL AND METHODS: A retrospective chart review was completed. We derived a simplified API: API = (logVA/VP-µ)/σ where VA is weighted volume of frontal and temporal lobes and VP of parietal and occipital lobes. µ and σ are the mean and standard deviation of logVA/VP computed for AD participants. Receiver operating characteristic (ROC) curves and regression analyses assessed the efficacy of the API versus brain areas in predicting diagnosis of AD versus FTD. RESULTS: A total of 39 participants with FTD and 78 participants with AD were included. The API had an excellent performance in distinguishing AD from FTD with an area under the ROC curve of 0.82 and a positive association with diagnostic classification on logistic regression analysis (B = 1.491, P < 0.001). CONCLUSION: The API successfully distinguished AD and FTD with excellent performance. The results provide preliminary validation of the API in a clinical setting.

The risk factors affecting the persistence of corpus callosum splenium lesions.

BACKGROUND: The most compact portion of the corpus callosum (CC) is the corpus splenium (CS). PURPOSE: To evaluate the connection between clinical and demographic features to determine whether neuroimaging findings will be permanent or temporary in CS patients. MATERIAL AND METHODS: We enrolled 93 patients (age range = 18-86 years) with CS lesions. Demographic and clinical information were recorded. We examined the lesions depending on the location. Group 1 (n = 20) had lesions limited to the CS (egg-shaped or round); group 2 (n = 15) had "boomerang sign" lesions; and group 3 (n = 58) had splenium involvement in conditions affecting the whole brain (Boomerang sign+ plus). RESULTS: Group 1 had a lower mean age, shorter disease duration, and fewer persistent lesions than others (P < 0.01, P < 0.001, and P < 0.001, respectively). The mean disease onset age (in years) in group 1 was higher than that of the other groups (P < 0.045). Group 2 had lower potassium (K) (P < 0.003) and red cell distribution width levels (P < 0.029) than the other groups. Age <41.5 years (P < 0.001), age at illness initiation <48.5 years (P < 0.002), disease duration <5.5 months (P < 0.001), and eosinophil level <0.29 uL (P 0.014) all point to temporary lesions. CONCLUSION: Cases with limited CS lesions have younger onset ages, lower disease onset ages, and shorter disease durations. Age, age of disease onset, disease duration, and eosinophil level are risk variables that affect whether CS lesions are permanent or temporary.

Trans-radial artery microcatheter angiography-assisted juvenile ruptured brainstem arteriovenous malformation resection.

BACKGROUND: Due to their crucial functional location, surgical treatment of brainstem arteriovenous malformations (AVMs) has always been challenging. For unruptured AVMs, we can determine whether radiological therapy, interventional treatment, or surgical resection is feasible based on the AVM structure. However, for ruptured AVMs, microsurgical resection and interventional embolization are effective methods to prevent further rupture. In the microsurgical resection of AVMs, we usually use a hybrid operation to confirm the AVM structure and determine if the AVM is completely resected during the surgery. METHOD: We report a case of juvenile ruptured brainstem AVM resection. The right lateral position and left suboccipital retrosigmoid approach were used. We established an interventional approach via left radial artery and set a microcatheter in the feeding artery. Methylene blue injection via a microcatheter showed the AVM structure, and we totally resected the brainstem AVM under electrophysiological monitoring and navigation. Intraoperative angiography was performed to ensure complete resection without residual nidus. CONCLUSION: This case demonstrates that the trans-radial approach is convenient and safe for special positions in hybrid operations. Methylene blue injection via a microcatheter in the feeding artery provides clearer visualization of the AVM structure under the microscope.

Comparative analysis of stereotactic soft-channel and hard-channel aspiration in the treatment of primary brainstem hemorrhage.

OBJECTIVE: To evaluate the efficacy of stereotactic soft-channel and hard-channel aspiration in the treatment of primary brainstem hemorrhage. METHODS: The clinical data of 146 patients with primary brainstem hemorrhage at the First Hospital of Hebei Medical University from August 2014 to August 2023 were analyzed. At admission, 146 patients were divided into soft-channel group or hard-channel group using a random number table method. Sixty-five patients were treated with stereotactic soft-channel aspiration, and 81 patients were treated with stereotactic hard-channel aspiration. The amount of residual hematoma was evaluated by head CT immediately after the operation, and the length of the indwelling drainage tube was recorded. Survival status at 30d after the operation and treatment outcome (mRS score and GOS score) at 90d after the operation were also recorded. The amount of residual hematoma immediately after the operation, the length of the indwelling drainage tube after the operation, the mortality rate and the treatment outcome were compared between the two groups. RESULTS: There was significant difference in the mortality rate 30d after the operation (41.5% vs. 14.8%, χ2 = 20.192, P = 0.035) between stereotactic soft-channel aspiration and stereotactic hard-channel aspiration for brainstem hemorrhage. The hard-channel group had a higher survival rate. There was significant difference in the treatment outcome at 90 days after treatment (18.5% vs. 32.1%, χ2 = 4.783, P = 0.047). The hard-channel group showed better treatment outcomes 90 days after surgery. CONCLUSION: Stereotactic hard-channel aspiration for primary brainstem hemorrhage has greater clearance efficiency than soft-channel aspiration and can significantly reduce patient mortality and improve treatment outcomes. Stereotactic hard-channel aspiration is a safe and effective method for treating primary brainstem hemorrhage.

The Relationship between Speech Sound Disorder and Cortical Auditory Evoked Potential.

INTRODUCTION: Speech sound disorder (SSD) is a speech and language disorder associated with difficulties in motor production, perception, and phonological representation of sounds and speech segments. Since auditory perception has a fundamental role in forming and organizing sound representation for its recognition, studies that evaluate the cortical processing of sounds are required. Thus, the present study aimed to verify the relation between SSD severity measured by the percentage of correct consonants (PCCs) with the cortical auditory evoked potentials (CAEPs) using speech stimulus. METHODS: Twenty-nine children with normal hearing participated in this research and were grouped into three groups by SSD level measured by the PCC index. In addition, the groups were subdivided according to the children's age group: between 60-71 months, 72-83 months, and 83-94 months. The CAEP with speech stimulus was carried out in all children. RESULTS: Older children had longer P1 and N1 latencies. In P2 latency, there was an interference of age only in the severe group. The N2 latency was affected by age, where older children had longer latency. CONCLUSION: The amplitude of CAEP has not suffered any interference with the age, or severity of SSD. For the latency, older children generally presented longer averages than younger ones.

Consensus guidelines for the management of brain stem and diffuse midline glioma for low- and middle-income countries.

The understanding of brainstem gliomas and diffuse midline gliomas has significantly increased in the last decade. However, the management paradigm remains a dilemma. The critical location is the foremost factor dictating the outcome. Recent advancements in the field of neuro-oncology are pushing the boundaries of optimal care in the developed world nevertheless, the strategies in low- and middle-income countries (LMICs) need to be tailored according to the resources to improve outcome. The objective of these guidelines is to provide an algorithm-based management plan to cater challenges for healthcare providers in LMICs.

An efficacy of protection the organs at risks comparison between the intensitymodulated radiotherapy therapy (IMRT) and the three-dimensional conformal radiotherapy (3DCRT).

OBJECTIVE: To compare the efficiency of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy techniques. Method: The cross-sectional study was conducted from February to August 2021 at Al-Amal National Hospital, Baghdad, Iraq, and comprised patients aged 19-45 years with cancerous head and neck tumours of size 2-7cm. All the patients underwent magnetic resonance imaging or computed tomography simulation scans. Treatment planning techniques used for each patient were three-dimensional conformal radiotherapy and intensitymodulated radiotherapy. After evaluating patterns, a better plan and treatment with an X-ray beam was chosen. Data was analysed using SPSS 24. Results: The study involved thirty participants, with 17(57%) females and 13(43%) males, aged 19-45, and 28 patients having chemotherapy. Six out of thirty had craniotomy surgery. The intensity-modulated radiation therapy had a safer radiation dose than the three-dimensional conformal radiotherapy for spinal cord (p=0.3203), brain stem (p= 0.17924), right parotid gland (p=0.8556) and left parotid gland (p=0.2193). The three-dimensional conformal radiotherapy protected the organs better than intensity-modulated radiation therapy for left optic nerve (p=0.1227), right optic nerve (p=0.0032), left eye (p=0.3859), right eye (p=0.1189), left lens (p=0.0004), right lens (p=0.0001), optic chiasm (p=0.0320) and pituitary gland (p=0.9162). CONCLUSIONS: The intensity-modulated radiation therapy technique protected the spinal cord, brain stem, and right and left parotid glands. The three-dimensional conformal radiotherapy was safe for left and right optic nerves, left and right eyes, left and right lenses, optic chiasm and pituitary glands.

Investigating the Effects of Level-Specific CE-Chirp on Auditory Brainstem Response Waves in Normal Hearing Infants.

Background: Auditory brainstem response (ABR) to the level-specific (LS) CE-Chirp has been reported to provide optimum neural synchrony along cochlear partitions, theoretically improving ABR waveform resolution. Despite this promising finding, limited studies have been conducted to contrast the results between LS CE-Chirp and Click stimuli. The current study aimed to compare the results of ABR between the two stimuli (Click and LS CE-Chirp). Method: Sixty-seven normal-hearing infants, both with and without risk factors, aged less than 7 months old, participated in this study. The ABR test was conducted at 70 dBnHL using 33.3 stimulus repetition rates with both Click and LS CE-Chirp stimuli. The signal averaging was stopped at a maximum fixed signal average of 2,500 sweeps. Data were statistically compared between the two stimuli using the Wilcoxon signed-rank test. Results: The waves I and V ABRs elicited by LS CE-Chirp exhibited significantly larger amplitudes than the Click stimulus. However, the amplitude of wave III and absolute latencies were similar in both stimuli at a supra-threshold level. Conclusion: LS CE-Chirp has the advantage of larger amplitudes than the ABR from Click at the supra-threshold level (70 dBnHL) in normal-hearing infants.

The substantia nigra modulates proximal colon tone and motility in a vagally-dependent manner in the rat.

A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric motility. It is not known, however, whether this nigro-vagal pathway also modulates the tone and motility of the proximal colon. In rats, microinjection of retrograde tracers in the proximal colon and of anterograde tracers in SNpc showed that bilaterally labelled colonic-projecting neurons in the DMV received inputs from SNpc neurons. Microinjections of the ionotropic glutamate receptor agonist, NMDA, in the SNpc increased proximal colonic motility and tone, as measured via a strain gauge aligned with the colonic circular smooth muscle; the motility increase was inhibited by acute subdiaphragmatic vagotomy. Upon transfection of SNpc with pAAV-hSyn-hM3D(Gq)-mCherry, chemogenetic activation of nigro-vagal nerve terminals by brainstem application of clozapine-N-oxide increased the firing rate of DMV neurons and proximal colon motility; both responses were abolished by brainstem pretreatment with the dopaminergic D1-like antagonist SCH23390. Chemogenetic inhibition of nigro-vagal nerve terminals following SNpc transfection with pAAV-hSyn-hM4D(Gi)-mCherry decreased the firing rate of DMV neurons and inhibited proximal colon motility. These data suggest that a nigro-vagal pathway modulates activity of the proximal colon motility tonically via a discrete dopaminergic synapse in a manner dependent on vagal efferent nerve activity. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed in both patients and animal models of parkinsonism. KEY POINTS: Substantia nigra pars compacta (SNpc) neurons are connected to the dorsal motor nucleus of the vagus (DMV) neurons via a presumed direct pathway. Brainstem neurons in the lateral DMV innervate the proximal colon. Colonic-projecting DMV neurons receive inputs from neurons of the SNpc. The nigro-vagal pathway modulates tone and motility of the proximal colon via D1-like receptors in the DMV. The present study provides the mechanistic basis for explaining how SNpc alterations may lead to a high rate of constipation in patients with Parkinson's Disease.

Locomotor pattern generation and descending control: a historical perspective.

The ability to generate and control locomotor movements depends on complex interactions between many areas of the nervous system, the musculoskeletal system, and the environment. How the nervous system manages to accomplish this task has been the subject of investigation for more than a century. In vertebrates, locomotion is generated by neural networks located in the spinal cord referred to as central pattern generators. Descending inputs from the brain stem initiate, maintain, and stop locomotion as well as control speed and direction. Sensory inputs adapt locomotor programs to the environmental conditions. This review presents a comparative and historical overview of some of the neural mechanisms underlying the control of locomotion in vertebrates. We have put an emphasis on spinal mechanisms and descending control.

A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4.

Malignant brain tumors, known as H3K27-altered diffuse midline glioma (DMG) and H3G34-mutant diffuse hemispheric glioma (DHG), can affect individuals of all ages and are classified as CNS WHO grade 4. We comprehensively characterized 390 H3F3A-mutant diffuse gliomas (201 females, 189 males) arising in pediatric patients (under 20 years old) and adults (20 years and older) evaluated by the CGP program at Foundation Medicine between 2013 and 2020. We assessed information from pathology reports, histopathology review, and clinical data. The cohort included 304 H3K27M-mutant DMG (156 females, 148 males) and 86 H3G34-mutant DHG (45 females, 41 males). Median patient age was 20 years (1-74 years). The frequency of H3K27M-mutant DMG was similar in both pediatric and adult patients in our cohort-48.6% of the patients were over 20 years old, 31.5% over 30, and 18% over 40 at initial diagnosis. FGFR1 hotspot point mutations (N546K and K656E) were exclusively identified in H3K27M-mutant DMG tumors (64/304, 21%; p = 0.0001); these tend to occur in older patients (median age: 32.5 years) and mainly arose in the diencephalon. H3K27M-mutant DMG had higher rates of mutations in NF1 (31.0 vs 8.1%; p = 0.0001) and PIK3CA/PIK3R1 (27.9% vs 15.1%; p = 0.016) compared to H3G34-mutant DHG. However, H3G34-mutant DHG had higher rates of targetable alterations in cell-cycle pathway genes (CDK4 and CDK6 amplification; CDKN2A/B deletion) (27.0 vs 9.0%). Potentially targetable PDGFRA alterations were identified in ~ 20% of both H3G34-mutant DHG and H3K27M-mutant DMG. Overall, in the present study H3K27M-mutant DMG occurred at similar rates in both adult and patient patients. Through our analysis, we were able to identify molecular features characteristic of DMG and DHG. By identifying the recurrent co-mutations including actionable FGFR1 point mutations found in nearly one-third of H3K27M-mutant DMG in young adults, our findings can inform clinical translational studies, patient diagnosis, and clinical trial design.

Diffusion MRI is valuable in brainstem glioma genotyping with quantitative measurements of white matter tracts.

OBJECTIVES: To investigate the value of diffusion MRI (dMRI) in H3K27M genotyping of brainstem glioma (BSG). METHODS: A primary cohort of BSG patients with dMRI data (b = 0, 1000 and 2000 s/mm2) and H3K27M mutation information were included. A total of 13 diffusion tensor and kurtosis imaging (DTI; DKI) metrics were calculated, then 17 whole-tumor histogram features and 29 along-tract white matter (WM) microstructural measurements were extracted from each metric and assessed within genotypes. After feature selection through univariate analysis and the least absolute shrinkage and selection operator method, multivariate logistic regression was used to build dMRI-derived genotyping models based on retained tumor and WM features separately and jointly. Model performances were tested using ROC curves and compared by the DeLong approach. A nomogram incorporating the best-performing dMRI model and clinical variables was generated by multivariate logistic regression and validated in an independent cohort of 27 BSG patients. RESULTS: At total of 117 patients (80 H3K27M-mutant) were included in the primary cohort. In total, 29 tumor histogram features and 41 WM tract measurements were selected for subsequent genotyping model construction. Incorporating WM tract measurements significantly improved diagnostic performances (p < 0.05). The model incorporating tumor and WM features from both DKI and DTI metrics showed the best performance (AUC = 0.9311). The nomogram combining this dMRI model and clinical variables achieved AUCs of 0.9321 and 0.8951 in the primary and validation cohort respectively. CONCLUSIONS: dMRI is valuable in BSG genotyping. Tumor diffusion histogram features are useful in genotyping, and WM tract measurements are more valuable in improving genotyping performance. CLINICAL RELEVANCE STATEMENT: This study found that diffusion MRI is valuable in predicting H3K27M mutation in brainstem gliomas, which is helpful to realize the noninvasive detection of brainstem glioma genotypes and improve the diagnosis of brainstem glioma. KEY POINTS: • Diffusion MRI has significant value in brainstem glioma H3K27M genotyping, and models with satisfactory performances were built. • Whole-tumor diffusion histogram features are useful in H3K27M genotyping, and quantitative measurements of white matter tracts are valuable as they have the potential to improve model performance. • The model combining the most discriminative diffusion MRI model and clinical variables can help make clinical decision.

Rostral-middle locus coeruleus integrity and subjective cognitive decline in early old age.

OBJECTIVES: Abnormal tau, a hallmark Alzheimer's disease (AD) pathology, may appear in the locus coeruleus (LC) decades before AD symptom onset. Reports of subjective cognitive decline are also often present prior to formal diagnosis. Yet, the relationship between LC structural integrity and subjective cognitive decline has remained unexplored. Here, we aimed to explore these potential associations. METHODS: We examined 381 community-dwelling men (mean age = 67.58; SD = 2.62) in the Vietnam Era Twin Study of Aging who underwent LC-sensitive magnetic resonance imaging and completed the Everyday Cognition scale to measure subjective cognitive decline along with their selected informants. Mixed models examined the associations between rostral-middle and caudal LC integrity and subjective cognitive decline after adjusting for depressive symptoms, physical morbidities, and family. Models also adjusted for current objective cognitive performance and objective cognitive decline to explore attenuation. RESULTS: For participant ratings, lower rostral-middle LC contrast to noise ratio (LCCNR) was associated with significantly greater subjective decline in memory, executive function, and visuospatial abilities. For informant ratings, lower rostral-middle LCCNR was associated with significantly greater subjective decline in memory only. Associations remained after adjusting for current objective cognition and objective cognitive decline in respective domains. CONCLUSIONS: Lower rostral-middle LC integrity is associated with greater subjective cognitive decline. Although not explained by objective cognitive performance, such a relationship may explain increased AD risk in people with subjective cognitive decline as the LC is an important neural substrate important for higher order cognitive processing, attention, and arousal and one of the first sites of AD pathology.

Pediatric Pineal Region Tumors: Special Reference to Posterior Interhemispheric Trans-Tentorial Approach.

Pediatric pineal region tumors consist of tumors of pineal gland origin and parapineal origin. The former are comprised of germ cell tumor (GCT) and pineal parenchymal tumor. The latter originate from the surrounding neural structures, such as the midbrain and thalamus; thus, they are often benign gliomas during childhood. Pineal region tumors often cause obstructive hydrocephalus, which is the main cause of presenting symptoms. Advanced imaging discloses precise location and extension of the tumor and associated anomalies such as hydrocephalous, dissemination, hemorrhage, etc. Hydrocephalus has been managed with CSF diversion, mostly using an endoscopic third ventriculostomy. Because of different treatment paradigms for each tumor type, histological confirmation is needed either through biopsy, tumor markers for GCTs, and/or surgical resection sampling. Radical resection of these tumors remains a challenge due to their deep-seated location and involvement of delicate neural and vascular structures. Comparison of common craniotomy approaches, occipital transtentorial (OT) and infratentorial supracerebellar (ITSC), is reviewed for their advantages and disadvantages. Surgical area exposure and blind spots are important factors for successful tumor removal. The surgical techniques and nuances that the author employs for tumor resection via a posterior interhemispheric transtentorial approach are presented.