Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics.

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD). KATNAL2, a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of Katnal2 (Katnal2Δ17) in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly. In both humans and mice, KATNAL2 is highly expressed in ciliated radial glia of the fetal ventricular-subventricular zone as well as in their postnatal ependymal and neuronal progeny. The ventriculomegaly observed in Katnal2Δ17 mice is associated with disrupted primary cilia and ependymal planar cell polarity that results in impaired cilia-generated CSF flow. Further, prefrontal pyramidal neurons in ventriculomegalic Katnal2Δ17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Consistent with these findings in mice, we identified rare, damaging heterozygous germline variants in KATNAL2 in five unrelated patients with neurosurgically treated CH and comorbid ASD or other neurodevelopmental disorders. Mice engineered with the orthologous ASD-associated KATNAL2 F244L missense variant recapitulated the ventriculomegaly found in human patients. Together, these data suggest KATNAL2 pathogenic variants alter intraventricular CSF homeostasis and parenchymal neuronal connectivity by disrupting microtubule dynamics in fetal radial glia and their postnatal ependymal and neuronal descendants. The results identify a molecular mechanism underlying the development of ventriculomegaly in a genetic subset of patients with ASD and may explain persistence of neurodevelopmental phenotypes in some patients with CH despite neurosurgical CSF shunting.

Biomechanical instability of the brain-CSF interface in hydrocephalus.

Hydrocephalus, characterized by progressive expansion of the cerebrospinal fluid (CSF)-filled ventricles (ventriculomegaly), is the most common reason for brain surgery. "Communicating" (i.e., non-obstructive) hydrocephalus is classically attributed to a primary derangement in CSF homeostasis, such as choroid plexus-dependent CSF hypersecretion, impaired cilia-mediated CSF flow currents, or decreased CSF reabsorption via the arachnoid granulations or other pathways. Emerging data suggest abnormal biomechanical properties of the brain parenchyma are an underappreciated driver of ventriculomegaly in multiple forms of communicating hydrocephalus across the lifespan. We discuss recent evidence from human and animal studies that suggests impaired neurodevelopment in congenital hydrocephalus, neurodegeneration in elderly normal pressure hydrocephalus, and, in all age groups, inflammation-related neural injury post-infectious and post-hemorrhagic hydrocephalus, can result in loss of stiffness and viscoelasticity of the brain parenchyma. Abnormal brain biomechanics creates barrier alterations at the brain-CSF interface that pathologically facilitates secondary enlargement of the ventricles, even at normal or low intracranial pressures. This "brain-centric" paradigm has implications for the diagnosis, treatment, and study of hydrocephalus from womb to tomb.

TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus.

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly, is one of the most common reasons for pediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate CH risk gene, however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated CH (totaling 2,697 parent-proband trios and 8,091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, CH, developmental delay, dysmorphic features, and other structural brain defects including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbor arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven additional patients with rare, damaging, unphased or transmitted variants of uncertain significance were also identified. NHL-domain variants of TRIM71 exhibited impaired binding to the canonical TRIM71 target CDKN1A; other variants failed to direct the subcellular localization of TRIM71 to processing bodies. Single-cell transcriptomic analysis of human embryos revealed expression of TRIM71 in early first-trimester neural stem cells of the brain. These data show TRIM71 is essential for human brain morphogenesis and that TRIM71 mutations cause a novel neurodevelopmental syndrome featuring ventriculomegaly and CH.

The "microcephalic hydrocephalus" paradox as a paradigm of altered neural stem cell biology.

Characterized by enlarged brain ventricles, hydrocephalus is a common neurological disorder classically attributed to a primary defect in cerebrospinal fluid (CSF) homeostasis. Microcephaly ("small head") and hydrocephalus are typically viewed as two mutually exclusive phenomenon, since hydrocephalus is thought of as a fluid "plumbing" disorder leading to CSF accumulation, ventricular dilatation, and resultant macrocephaly. However, some cases of hydrocephalus can be associated with microcephaly. Recent work in the genomics of congenital hydrocephalus (CH) and an improved understanding of the tropism of certain viruses such as Zika and cytomegalovirus are beginning to shed light into the paradox "microcephalic hydrocephalus" by defining prenatal neural stem cells (NSC) as the spatiotemporal "scene of the crime." In some forms of CH and viral brain infections, impaired fetal NSC proliferation leads to decreased neurogenesis, cortical hypoplasia and impaired biomechanical interactions at the CSF-brain interface that collectively engender ventriculomegaly despite an overall and often striking decrease in head circumference. The coexistence of microcephaly and hydrocephalus suggests that these two phenotypes may overlap more than previously appreciated. Continued study of both conditions may be unexpectedly fertile ground for providing new insights into human NSC biology and our understanding of neurodevelopmental disorders.

Utility of cortical tissue analysis in normal pressure hydrocephalus.

Clinical improvement following neurosurgical cerebrospinal fluid shunting for presumed idiopathic normal pressure hydrocephalus is variable. Idiopathic normal pressure hydrocephalus patients may have undetected Alzheimer's disease-related cortical pathology that confounds diagnosis and clinical outcomes. In this study, we sought to determine the utility of cortical tissue immuno-analysis in predicting shunting outcomes in idiopathic normal pressure hydrocephalus patients. We performed a pooled analysis using a systematic review as well as analysis of a new, original patient cohort. Of the 2707 screened studies, 3 studies with a total of 229 idiopathic normal pressure hydrocephalus patients were selected for inclusion in this meta-analysis alongside our original cohort. Pooled statistics of shunting outcomes for the 229 idiopathic normal pressure hydrocephalus patients and our new cohort of 36 idiopathic normal pressure hydrocephalus patients revealed that patients with Aß + pathology were significantly more likely to exhibit shunt nonresponsiveness than patients with negative pathology. Idiopathic normal pressure hydrocephalus patients with Alzheimer's disease -related cortical pathology may be at a higher risk of treatment facing unfavorable outcomes following cerebrospinal fluid shunting. Thus, cortical tissue analysis from living patients may be a useful diagnostic and prognostic adjunct for patients with presumed idiopathic normal pressure hydrocephalus and potentially other neurodegenerative conditions affecting the cerebral cortex.

Cases of familial idiopathic normal pressure hydrocephalus implicate genetic factors in disease pathogenesis.

Idiopathic normal pressure hydrocephalus is a disorder of unknown pathophysiology whose diagnosis is paradoxically made by a positive response to its proposed treatment with cerebrospinal fluid diversion. There are currently no idiopathic normal pressure hydrocephalus disease genes or biomarkers. A systematic analysis of familial idiopathic normal pressure hydrocephalus could aid in clinical diagnosis, prognosis, and treatment stratification, and elucidate disease patho-etiology. In this 2-part analysis, we review literature-based evidence for inheritance of idiopathic normal pressure hydrocephalus in 22 pedigrees, and then present a novel case series of 8 familial idiopathic normal pressure hydrocephalus patients. For the case series, demographics, familial history, pre- and post-operative symptoms, and cortical pathology were collected. All novel familial idiopathic normal pressure hydrocephalus patients exhibited improvement following shunt treatment and absence of neurodegenerative cortical pathology (amyloid-beta and hyperphosphorylated tau), in contrast to many sporadic cases of idiopathic normal pressure hydrocephalus with variable clinical responses. Analysis of the 30 total familial idiopathic normal pressure hydrocephalus cases reported herein is highly suggestive of an autosomal dominant mechanism of inheritance. This largest-ever presentation of multiply affected idiopathic normal pressure hydrocephalus pedigrees provides strong evidence for Mendelian inheritance and autosomal dominant transmission of an idiopathic normal pressure hydrocephalus trait in a subset of patients that positively respond to shunting and lack neurodegenerative pathology. Genomic investigation of these families may identify the first bona fide idiopathic normal pressure hydrocephalus disease gene.

Elevated risk of recurrence and retreatment for silent pituitary adenomas.

PURPOSE: Pituitary adenomas are the most common tumor of the pituitary gland and comprise nearly 15% of all intracranial masses. These tumors are stratified into functional or silent categories based on their pattern of hormone expression and secretion. Preliminary evidence supports differential clinical outcomes between some functional pituitary adenoma (FPA) subtypes and silent pituitary adenoma (SPA) subtypes. METHODS: We collected and analyzed the medical records of all patients undergoing resection of SPAs or FPAs from a single high-volume neurosurgeon between 2007 and 2018 at Brigham and Women's Hospital. Descriptive statistics and the Mantel-Cox log-rank test were used to identify differences in outcomes between these cohorts, and multivariate logistic regression was used to identify predictors of radiographic recurrence for SPAs. RESULTS: Our cohort included 88 SPAs and 200 FPAs. The majority of patients in both cohorts were female (48.9% of SPAs and 63.5% of FPAs). SPAs were larger in median diameter than FPAs (2.1 cm vs. 1.2 cm, p < 0.001). The most frequent subtypes of SPA were gonadotrophs (55.7%) and corticotrophs (30.7%). Gross total resection (GTR) was achieved in 70.1% of SPA resections and 86.0% of FPA resections (p < 0.001). SPAs had a higher likelihood of recurring (hazard ratio [HR] 3.2, 95% confidence interval [95%CI] 1.6-7.2) and a higher likelihood of requiring retreatment for recurrence (HR 2.5; 95%CI 1.0-6.1). Subset analyses revealed that recurrence and retreatment were more both likely for subtotally resected SPAs than subtotally resected FPAs, but this pattern was not observed in SPAs and FPAs after GTR. Among SPAs, recurrence was associated with STR (odds ratio [OR] 9.3; 95%CI 1.4-64.0) and younger age (OR 0.92 per year; 95%CI 0.88-0.98) in multivariable analysis. Of SPAs that recurred, 12 of 19 (63.2%) were retreated with repeat surgery (n = 11) or radiosurgery (n = 1), while the remainder were observed (n = 7).There were similar rates of recurrence across different SPA subtypes. CONCLUSION: Patients undergoing resection of SPAs should be closely monitored for disease recurrence through more frequent clinical follow-up and diagnostic imaging than other adenomas, particularly among patients with STR and younger patients. Several patients can be observed after radiographic recurrence, and the decision to retreat should be individualized. Longitudinal clinical follow-up of SPAs, including an assessment of symptoms, endocrine function, and imaging remains critical.

Quantifying cerebrospinal fluid dynamics: A review of human neuroimaging contributions to CSF physiology and neurodegenerative disease.

Cerebrospinal fluid (CSF), predominantly produced in the ventricles and circulating throughout the brain and spinal cord, is a key protective mechanism of the central nervous system (CNS). Physical cushioning, nutrient delivery, metabolic waste, including protein clearance, are key functions of the CSF in humans. CSF volume and flow dynamics regulate intracranial pressure and are fundamental to diagnosing disorders including normal pressure hydrocephalus, intracranial hypotension, CSF leaks, and possibly Alzheimer's disease (AD). The ability of CSF to clear normal and pathological proteins, such as amyloid-beta (Aß), tau, alpha synuclein and others, implicates it production, circulation, and composition, in many neuropathologies. Several neuroimaging modalities have been developed to probe CSF fluid dynamics and better relate CSF volume and flow to anatomy and clinical conditions. Approaches include 2-photon microscopic techniques, MRI (tracer-based, gadolinium contrast, endogenous phase-contrast), and dynamic positron emission tomography (PET) using existing approved radiotracers. Here, we discuss CSF flow neuroimaging, from animal models to recent clinical-research advances, summarizing current endeavors to quantify and map CSF flow with implications towards pathophysiology, new biomarkers, and treatments of neurological diseases.

Bioaccessibility and bioavailability of biofortified food and food products: Current evidence.

Biofortification increases micronutrient content in staple crops through conventional breeding, agronomic methods, or genetic engineering. Bioaccessibility is a prerequisite for a nutrient to fulfill a biological function, e.g., to be bioavailable. The objective of this systematic review is to examine the bioavailability (and bioaccessibility as a proxy via in vitro and animal models) of the target micronutrients enriched in conventionally biofortified crops that have undergone post-harvest storage and/or processing, which has not been systematically reviewed previously, to our knowledge. We searched for articles indexed in MEDLINE, Agricola, AgEcon, and Center for Agriculture and Biosciences International databases, organizational websites, and hand-searched studies' reference lists to identify 18 studies reporting on bioaccessibility and 58 studies on bioavailability. Conventionally bred biofortified crops overall had higher bioaccessibility and bioavailability than their conventional counterparts, which generally provide more absorbed micronutrient on a fixed ration basis. However, these estimates depended on exact cultivar, processing method, context (crop measured alone or as part of a composite meal), and experimental method used. Measuring bioaccessibility and bioavailability of target micronutrients in biofortified and conventional foods is critical to optimize nutrient availability and absorption, ultimately to improve programs targeting micronutrient deficiency.

Evaluation of the safety, accuracy, and helpfulness of the GPT-4.0 Large Language Model in neurosurgery.

BACKGROUND: Although prior work demonstrated the surprising accuracy of Large Language Models (LLMs) on neurosurgery board-style questions, their use in day-to-day clinical situations warrants further investigation. This study assessed GPT-4.0's responses to common clinical questions across various subspecialties of neurosurgery. METHODS: A panel of attending neurosurgeons formulated 35 general neurosurgical questions spanning neuro-oncology, spine, vascular, functional, pediatrics, and trauma. All questions were input into GPT-4.0 with a prespecified, standard prompt. Responses were evaluated by two attending neurosurgeons, each on a standardized scale for accuracy, safety, and helpfulness. Citations were indexed and evaluated against identifiable database references. RESULTS: GPT-4.0 responses were consistent with current medical guidelines and accounted for recent advances in the field 92.8 % and 78.6 % of the time respectively. Neurosurgeons reported GPT-4.0 responses providing unrealistic information or potentially risky information 14.3 % and 7.1 % of the time respectively. Assessed on 5-point scales, responses suggested that GPT-4.0 was clinically useful (4.0 ± 0.6), relevant (4.7 ± 0.3), and coherent (4.9 ± 0.2). The depth of clinical responses varied (3.7 ± 0.6), and "red flag" symptoms were missed 7.1 % of the time. Moreover, GPT-4.0 cited 86 references (2.46 citations per answer), of which only 50 % were deemed valid, and 77.1 % of responses contained at least one inappropriate citation. CONCLUSION: Current general LLM technology can offer generally accurate, safe, and helpful neurosurgical information, but may not fully evaluate medical literature or recent field advances. Citation generation and usage remains unreliable. As this technology becomes more ubiquitous, clinicians will need to exercise caution when dealing with it in practice.

Applications of Functional Magnetic Resonance Imaging to the Study of Functional Connectivity and Activation in Neurological Disease: A Scoping Review of the Literature.

BACKGROUND: Functional magnetic resonance imaging (fMRI) has transformed our understanding of brain's functional architecture, providing critical insights into neurological diseases. This scoping review synthesizes the current landscape of fMRI applications across various neurological domains, elucidating the evolving role of both task-based and resting-state fMRI in different settings. METHODS: We conducted a comprehensive scoping review following the Preferred Reporting Items for Systematic Review and Meta-Analyses Extension for Scoping Reviews guidelines. Extensive searches in Medline/PubMed, Embase, and Web of Science were performed, focusing on studies published between 2003 and 2023 that utilized fMRI to explore functional connectivity and regional activation in adult patients with neurological conditions. Studies were selected based on predefined inclusion and exclusion criteria, with data extracted. RESULTS: We identified 211 studies, covering a broad spectrum of neurological disorders including mental health, movement disorders, epilepsy, neurodegeneration, traumatic brain injury, cerebrovascular accidents, vascular abnormalities, neurorehabilitation, neuro-critical care, and brain tumors. The majority of studies utilized resting-state fMRI, underscoring its prominence in identifying disease-specific connectivity patterns. Results highlight the potential of fMRI to reveal the underlying pathophysiological mechanisms of various neurological conditions, facilitate diagnostic processes, and potentially guide therapeutic interventions. CONCLUSIONS: fMRI serves as a powerful tool for elucidating complex neural dynamics and pathologies associated with neurological diseases. Despite the breadth of applications, further research is required to standardize fMRI protocols, improve interpretative methodologies, and enhance the translation of imaging findings to clinical practice. Advances in fMRI technology and analytics hold promise for improving the precision of neurological assessments and interventions.

Potential Mechanisms of Precision Nutrition-Based Interventions for Managing Obesity.

Precision nutrition (PN) considers multiple individual-level and environmental characteristics or variables to better inform dietary strategies and interventions for optimizing health, including managing obesity and metabolic disorders. Here, we review the evidence on potential mechanisms-including ones to identify individuals most likely to respond-that can be leveraged in the development of PN interventions addressing obesity. We conducted a review of the literature and included laboratory, animal, and human studies evaluating biochemical and genetic data, completed and ongoing clinical trials, and public programs in this review. Our analysis describes the potential mechanisms related to 6 domains including genetic predisposition, circadian rhythms, physical activity and sedentary behavior, metabolomics, the gut microbiome, and behavioral and socioeconomic characteristics, i.e., the factors that can be leveraged to design PN-based interventions to prevent and treat obesity-related outcomes such as weight loss or metabolic health as laid out by the NIH 2030 Strategic Plan for Nutrition Research. For example, single nucleotide polymorphisms can modify responses to certain dietary interventions, and epigenetic modulation of obesity risk via physical activity patterns and macronutrient intake have also been demonstrated. Additionally, we identified limitations including questions of equitable implementation across a limited number of clinical trials. These include the limited ability of current PN interventions to address systemic influences such as supply chains and food distribution, healthcare systems, racial or cultural inequities, and economic disparities, particularly when designing and implementing PN interventions in low- and middle-income communities. PN has the potential to help manage obesity by addressing intra- and inter-individual variation as well as context, as opposed to "one-size fits all" approaches though there is limited clinical trial evidence to date.

Evaluating the impact of tubular retractors in glioma surgery: A systematic review and meta-analysis.

BACKGROUND: Achieving safe, maximal tumor resection in gliomas can be challenging due to the tumor's intricate relationship with surrounding structures. Tubular retractors offer a minimally invasive approach, preserving functional pathways and reducing complications. To assess their efficacy and safety, we conducted a systematic review and meta-analysis. METHODS: A search across databases identified 26 studies meeting inclusion criteria, encompassing 106 patients with various glioma types and tumor locations. RESULTS: Among 26 eligible studies, 15 provided sufficient data on 106 patients (median age: 50.5 years). Glioblastoma multiforme constituted 52.4 % of tumors, followed by IDH-mutant astrocytomas at 31.0 %. Tumor locations varied, with intraventricular and thalamic involvement in 16.3 % (16/98) of cases, followed by temporal (12.2 %), frontal and occipital (each 8.16 %), basal ganglia (8.16 %), parietal (7.14 %), optic pathway (2.04 %), and caudate nucleus (1.02 %) involvement. VyCor and Brainpath retractors were most used (22.6 % and 21.7 %, respectively). Tubular retractors were often combined with the exoscope (35.9 %). Gross total resection (GTR) was achieved in 69.4 % of cases, near-total resection (NTR) in 5.1 %, and subtotal resection/partial resection (STR/PR) in 25.5 %. Mean extent of resection (EOR) significantly differed between GTR and STR/NTR/PR groups (p<0.001). Postoperative complications included visual deficits (6.38 %), hemiparesis or weakness (2.13 %), multiple complications (1.06 %), and other unspecified complications (3.19 %). CONCLUSION: Tubular retractors are a valuable intraoperative adjunct and component of the surgical armamentarium for glioma surgery allowing bimanual operative techniques to manage hemostasis directly with excellent surgical outcomes and an acceptable complication profile.

Genetics and molecular pathophysiology of normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by dilation of the cerebral ventricles without increased cerebral pressure. Patients typically present with cognitive impairment, gait abnormalities, and urinary incontinence. Despite current guidelines for diagnosis and surgical intervention, there is little consensus on the pathophysiology of iNPH. Familial cases and genomic studies of iNPH have recently suggested an underappreciated role of genetics in disease pathogenesis, implicating mechanisms ranging from dysregulated CSF dynamics to underlying neurodegenerative or neuroinflammatory processes. In this paper, the authors provide a brief review of genetic insights and candidate genes for iNPH, highlighting the continued importance of integrated genetic analysis and clinical studies to advance iNPH management.

The Power of a Belief System: A Systematic Qualitative Synthesis of Spiritual Care for Patients with Brain Tumors.

Background: Diagnosis with a brain tumor is a critical event in the lives of patients and their families due to poor medical prognoses and complex clinical care. Spiritual care interventions have been known to have meaningful effects in morbid diagnoses and palliative medicine, but their role in the neuro-oncologic patient's experience is poorly understood. This systematic review explores the role of spirituality and its relevance to patient care in the diverse setting of brain tumors. Methods: A comprehensive systematic review was conducted following PRISMA-SR guidelines. PUBMED was queried for studies on spirituality and neuro-oncology. Identified studies included RCTs, interviews, surveys, and case reports that examined spirituality in neuro-oncological clinical care, quality of life, and patient experience. Of 214 articles identified, 21 studies met the inclusion criteria, and the results were narratively synthesized. Results: Spirituality may play a significant role in mental well-being by reconciling existential questions faced by both patients and caregivers, and can serve as a valuable resource to improve mental well-being and reduce rates of palliative caregiver burnout. However, the paucity of studies examining the education and integration of spiritual awareness within the clinical literature warrants further study. Conclusions: While spiritual care interventions may improve the quality of life and mental wellness of patients and their caregivers, it is unclear how spiritual awareness and education should best be implemented. Further research is needed to better understand how key components of spiritual awareness can be integrated into medical education to deepen the patient-physician relationship and improve clinical experiences.

[1-11C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects.

BACKGROUND: Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS: 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aß+) and 16 Aß- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS: LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aß+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION: The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Sonodynamic Therapy and Sonosensitizers for Glioma Treatment: A Systematic Qualitative Review.

Sonodynamic therapy (SDT) has emerged as an encouraging noninvasive technique that uses ultrasound to activate targeted agents to induce antitumor effects for the treatment of glioma. With extensive variation in the types of sonosensitizers, protocols for sonication, and model systems, a comprehensive overview of existing preclinical data on the efficacy of SDT in glioma treatment is warranted. Here, we conduct a systematic review of preclinical and early clinical literature on implementing SDT to treat in vitro and in vivo models of glioma. Our findings suggest that coupling sonosensitizers such as 5-aminolevulinic acid, hematoporphyrin monomethyl ether, and sinoporphyrin sodium with focused ultrasound induces robust cytotoxic activity in tumor cells (in vitro and in vivo). These effects are likely mediated by the oxidative stress induced by reactive oxygen species production, apoptotic signaling cascades, and intracellular calcium overload. Future research is needed to better understand the biochemical and mechanistic properties of SDT, and ongoing trials may help elucidate the clinical feasibility of glioma treatment with optimized sonically activated treatments.

The Efficacy of Endoscopic Third Ventriculostomy for Idiopathic Normal Pressure Hydrocephalus.

Recently, intervention with endoscopic third ventriculostomy (ETV) for patients with idiopathic normal pressure hydrocephalus (iNPH) has emerged as a potential minimally invasive alternative to traditional treatments (ventriculoperitoneal shunting). The clinical response to these interventions is variable and unclear. The objective of this review was to assess the efficacy of endoscopic third ventriculostomy in treating patients with iNPH. A systematic review of PubMed, Web of Science, and Google Scholar was conducted using search terms relevant to ETV and iNPH. Included studies met consistent, predetermined diagnostic criteria for iNPH, implemented ETV in subjects greater than 40 years of age, and assessed all 3 components of Hakim's triad (gait impairment, dementia, and incontinence). Data extraction included dichotomization of successful ETV clinical outcomes and a subgroup meta-analysis of ETV success rates across binarized age groups. Meta-analysis was conducted using a Mantel-Haenszel fixed-effects model. The outcomes presented include generalized ETV success rates across all 12 studies. Age-specific individual data was measured with odds ratios, with a pooled statistic measured using the Mantel-Haenszel test. Overall, 2294 studies were identified in this search, of which 12 were selected for inclusion in this systematic review. Of these, 3 studies were utilized for age-specific meta-analyses. Preliminary synthesis of ETV clinical outcomes across all 12 studies revealed a success rate of 60.2%. Additionally, meta-analysis revealed that iNPH patients younger than or equal to 65 years of age were significantly more likely to respond successfully to ETV intervention. Heterogeneity was inconsequential in this analysis.

Sonolucent cranioplasty: Is therapeutic FUS the next frontier?

Focused ultrasound (FUS) has emerged as a promising area of research in neuro-oncology. Preclinical and clinical investigation has demonstrated the utility of FUS in therapeutic applications including blood brain barrier disruption for therapeutic delivery, and high intensity FUS for tumor ablation. However, FUS as it exists today is relatively invasive as implantable devices are necessary to achieve adequate intracranial penetration. Sonolucent implants, composed of materials permeable to acoustic waves, have been used for cranioplasty and intracranial imaging with ultrasound. Given the overlap in ultrasound parameters with those used for intracranial imaging, and the demonstrated efficacy of sonolucent cranial implants, we believe that therapeutic FUS through sonolucent implants represents a promising avenue of future research. The potential applications of FUS and sonolucent cranial implants may confer the demonstrated therapeutic benefits of existing FUS applications, without the drawbacks and complications of invasive implantable devices. Here we briefly summarize existing evidence regarding sonolucent implants and describe applications for therapeutic FUS.

Molecular Diagnostic Yield of Exome Sequencing in Patients With Congenital Hydrocephalus: A Systematic Review and Meta-Analysis.

Importance: Exome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay and autism spectrum disorder; however, current recommendations are not specific to or inclusive of congenital hydrocephalus (CH). Objective: To determine the diagnostic yield of ES in CH and whether ES should be considered as a first line diagnostic test for CH. Data Sources: PubMed, Cochrane Library, and Google Scholar were used to identify studies published in English between January 1, 2010, and April 10, 2023. The following search terms were used to identify studies: congenital hydrocephalus, ventriculomegaly, cerebral ventriculomegaly, primary ventriculomegaly, fetal ventriculomegaly, prenatal ventriculomegaly, molecular analysis, genetic cause, genetic etiology, genetic testing, exome sequencing, whole exome sequencing, genome sequencing, microarray, microarray analysis, and copy number variants. Study Selection: Eligible studies included those with at least 10 probands with the defining feature of CH and/or severe cerebral ventriculomegaly that had undergone ES. Studies with fewer than 10 probands, studies of mild or moderate ventriculomegaly, and studies using genetic tests other than ES were excluded. A full-text review of 68 studies was conducted by 2 reviewers. Discrepancies were resolved by consensus. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-Analysis of Observational Studies in Epidemiology guidelines were used by 2 reviewers to extract data. Data were synthesized using a random-effects model of single proportions. Data analysis occurred in April 2023. Main Outcomes and Measures: The primary outcome was pooled diagnostic yield. Additional diagnostic yields were estimated for specific subgroups on the basis of clinical features, syndromic presentation, and parental consanguinity. For each outcome, a 95% CI and estimate of interstudy heterogeneity (I2 statistic) was reported. Results: From 498 deduplicated and screened records, 9 studies with a total of 538 CH probands were selected for final inclusion. The overall diagnostic yield was 37.9% (95% CI, 20.0%-57.4%; I2 = 90.1). The yield was lower for isolated and/or nonsyndromic cases (21.3%; 95% CI, 12.8%-31.0%; I2 = 55.7). The yield was higher for probands with reported consanguinity (76.3%; 95% CI, 65.1%-86.1%; I2 = 0) than those without (16.2%; 95% CI, 12.2%-20.5%; I2 = 0). Conclusions and Relevance: In this systematic review and meta-analysis of the diagnostic yield of ES in CH, the diagnostic yield was concordant with that of previous recommendations for other neurodevelopmental disorders, suggesting that ES should also be recommended as a routine diagnostic adjunct for patients with CH.