Citations

Abstract Normal pressure hydrocephalus is typically defined by the triad of gait disturbance, cognitive impairment, and urinary incontinence, and is characterized on MRI by disproportionately enlarged subarachnoid-space. Gait disturbance is also a commonly reported symptom in Parkinsonian disorders, especially progressive supranuclear palsy, although the frequency, clinical significance and mechanisms of hydrocephalus in these disorders are unclear. We aimed to assess the prevalence of hydrocephalic MRI parameters in a large cohort of Parkinsonian disorders and evaluate associations with clinical features and abnormalities on MRI and PET. Two hundred and thirty-eight participants with a Parkinsonian disorder, including 181 progressive supranuclear palsy, 36 corticobasal syndrome and 21 Parkinson’s disease, were enrolled from Mayo Clinic by the Neurodegenerative Research Group between September 2009 to October 2023. Automated detection of disproportionately enlarged subarachnoid-space hydrocephalus (D) was applied and using Evans’ index (E) cut-off point >0.3, participants were classified based on both measures as imaging-suggestive of hydrocephalus (D+E+), enlarged subarachnoid-space only (D+E−), large Evans’ index only (D−E+) and no imaging evidence of hydrocephalus (D−E−). Demographic, clinical and imaging features, including magnetic resonance parkinsonism index, cortical and subcortical volumes, white matter hyperintensities, diffusion tractography metrics, and metabolism on PET, were compared across groups. Among the 238 participants, 24 had borderline subarachnoid space scores and were excluded. The remaining 214 participants were classified as: D+E+ (n = 20, 9%); D+E− (n = 8, 4%); D−E+ (n = 71, 33%) and D−E− (n = 115, 54%). Among the progressive supranuclear palsy participants, 11% were D+E+, 4% D+E−, 34% D−E+ and 51% D−E−. Most cases (n = 18) in the imaging-suggestive of hydrocephalus D+E+ group had progressive supranuclear palsy. The D+E+ participants were older, had more disorientation, more downgaze palsy, greater midbrain and cortical atrophy, lower striatal metabolism, greater degeneration of long-range white matter tracts, larger cistern areas and more periventricular and deep white matter hyperintensities compared to the D−E− participants without imaging evidence of hydrocephalus. The D+E− participants had the highest metabolism in the paracentral lobule and superior parietal gyrus. The D−E+ participants showed worse disease severity and greater midbrain and cortical atrophy compared to the D−E− participants. These findings demonstrate that disproportionately enlarged subarachnoid-space hydrocephalus occurs in ∼15% of progressive supranuclear palsy participants, and is associated with worse clinical and imaging outcomes, as well as white matter hyperintensities. We hypothesize that disproportionately enlarged subarachnoid-space may be a mechanistic byproduct of degeneration and subsequent cerebrospinal fluid flow re-distribution in progressive supranuclear palsy.

Background: High-grade gliomas (HGGs), particularly glioblastoma (GBM), are associated with exceptionally high mortality and inevitable recurrence. In considering novel treatment options for these devastating diseases, immunotherapies represent promising candidates. Immunotherapies have demonstrated efficacy for several advanced tumors outside the central nervous system, highlighting a potential role for these agents in treating HGGs. However, multiple challenges to immunotherapy efficacy have tempered therapeutic benefit in practice, including local and systemic immunosuppression, intratumoral heterogeneity, and various mechanisms of intrinsic and acquired resistance. In the past 30 years, diverse immunotherapeutic subclasses have been assessed for benefit against HGGs. Methods: We performed a PubMed search for randomized clinical trials performed within the last 30 years evaluating the following immunotherapy agents for high-grade gliomas: immune checkpoint inhibitors, vaccines, oncologic viruses, cytokines, and CAR T-cells. The present review offers a critical analysis of key pre-clinical and clinical trials that have shaped the immunotherapy landscape for high-grade gliomas over the past two decades. Results/Conclusions: Across the different immunotherapeutic methods and modalities explored thus far, a recurring theme emerges: while therapeutic strategies with a compelling conceptual basis are continually under development and even demonstrate a benefit in preclinical and early-phase trials, larger and later-phase trials consistently fail to produce concordantly significant outcomes. To date, no large-scale clinical trial has demonstrated a benefit of sufficient consequence to change practice. Continued critical appraisal of the strengths and pitfalls of prior investigative work, optimization of treatment development and delivery, and innovative approaches to combination therapy design will collectively be integral to future therapeutic advancement.

ABSTRACT Background Mitral transcatheter edge‐to‐edge repair (TEER) is approved for patients with severe functional mitral regurgitation (FMR) beyond optimal medical therapy (OMT). Aims We aimed to assess TEER's efficacy beyond OMT in patients with severe FMR. Methods A systematic review and meta‐analysis were conducted, including randomized controlled trials from PubMed, Cochrane, Scopus, and EMBASE up to September 2024. Primary outcome: heart failure hospitalization (HFH); secondary outcomes: cardiovascular (CV) mortality, all‐cause mortality, and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Time‐to‐event data from Kaplan−Meier curves were reconstructed for individual patient data. Results Three studies (1423 patients) were included. TEER significantly reduced HFH (RR 0.73, 95% CI 0.58−0.92, p < 0.01) and CV mortality (RR 0.79, 95% CI 0.66−0.95, p = 0.01), and improved KCCQ scores (mean difference 14.32, 95% CI 10.85−17.80, p < 0.01) compared to OMT. No significant difference was found for all‐cause mortality (RR 0.80, 95% CI 0.63−1.02, p = 0.07). Prognostic meta‐analysis showed a 34% reduced risk of HFH (HR 0.66, 95% CI 0.45−0.96, p = 0.03), but no effect on all‐cause or CV mortality. Reconstructed Kaplan−Meier analysis confirmed a 34% reduced risk of HFH (HR 0.65, p < 0.001), with effect attenuation after 15 months in landmark analysis (HR 0.64, p = 0.07). RMST analysis showed a 2.9‐month longer HFH‐free survival with TEER ( p < 0.01). Conclusion In patients with FMR, TEER significantly reduces HFH, improves functional status, and lowers CV mortality at 24 months but does not significantly affect all‐cause mortality. The device group experienced a modest, but significant, 2.9‐month longer HFH‐free survival compared to the control group. However, the reduction in HFH showed attenuation beyond 15 months.

Background Accurate and timely prehospital detection of large vessel occlusion (LVO) is critical for optimizing patient triage and initiating appropriate reperfusion therapies. Recent advances in portable stroke detection technologies, such as electroencephalography (EEG) and transcranial Doppler (TCD) ultrasound, offer potential solutions but their diagnostic performance remains unclear. Methods We searched PubMed, Scopus, Embase, and Web of Science, following the PRISMA guidelines. Studies were included if they assessed the diagnostic performance of non-invasive prehospital LVO detection tools compared to CT or MR angiography. Risk of bias was assessed using the QUADAS-2 tool. Results A total of 13 studies were included, examining various portable detection tools including EEG or neurophysiological monitoring, ultrasound-based techniques including TCD or TCCD, portable Openwater optical blood flow monitor and cranial accelerometry. The pooled diagnostic odds ratio (DOR) was 52.7 (95% CI: 28.3–97.8), indicating strong diagnostic performance, with significant heterogeneity among studies (I 2 = 67.3%, P < 0.001). Subgroup analysis revealed that TCD-based methods had the highest DOR (120.4, 95% CI: 76.9–188.7), followed by other tools (26.8, 95% CI: 13.7–52.6), and EEG (18.2, 95% CI: 9.1–36.3). The pooled sensitivity was 87.4% (95% CI: 82.5–91.0) and specificity was 89.39% (95% CI: 83.0–93.5) across all methods. TCD-based methods showed the highest specificity (95.0%, 95% CI: 91.8–97.0). Conclusion Non-invasive prehospital LVO detection tools show promising diagnostic performance, particularly TCD-based methods. Future studies should focus on validating these tools in larger, diverse populations to enhance prehospital stroke triage and improve patient outcomes.

Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from an RNA-Seq (DaPars) tool to ALS/FTD transcriptome datasets and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional relevance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3′ UTRs, corresponding with a change in the subcellular distribution of MARK3 and increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously understudied feature of TDP-43–driven disease pathology in ALS/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.

OBJECTIVE The purpose of this study was to evaluate the risks and benefits of removing painful pelvic/iliac screws in spine fusion surgery patients. METHODS A retrospective review identified patients who had traditional iliac and S2-alar-iliac (S2AI) screws removed for pain. The minimum follow-up was 24 months. RESULTS Fifty-two patients (75% women) were included with a mean age of 63 years, BMI of 28, and follow-up of 65 months. Most of the removed screws were S2AI (83%) compared with traditional iliac screws (17%). Forty-three patients (83%) had improvement in their pelvic screw related–pain following removal. Eight patients (15%) experienced lumbosacral mechanical complications following pelvic screw removal including sacral fracture (n = 3, 6%) and/or L4–5 or L5–S1 rod fracture (n = 7, 13%). On multivariable analysis, risk factors for mechanical complications following pelvic screw removal included a longer fusion construct (OR 1.34, p = 0.035), greater postoperative L4–S1 lordosis (OR 1.14, p = 0.04, ideal cutoff > 40°), and lack of bone morphogenetic protein (BMP; OR 0.03, p = 0.02). Ten patients (19%) underwent subsequent SI joint fusion following pelvic screw removal, and higher standing pelvic incidence (OR 1.10, p = 0.03) was the only independent predictor of SI fusion. CONCLUSIONS Removal of painful pelvic screws resulted in a high rate of postoperative pain relief, albeit with a risk of lumbosacral mechanical complications and subsequent SI joint fusion. Patients at risk for lumbosacral mechanical complications following pelvic screw removal included those with longer fusion constructs, more lordosis from L4 to S1 (> 40°), and lack of BMP. Patients at risk for receiving an instrumented SI joint fusion following pelvic screw removal included those with a higher pelvic incidence.

OBJECTIVE While traditional literature in adult spinal deformity (ASD) examining mechanical complications has focused on proximal junctional kyphosis and failure, distal junctional failure (DJF) of constructs ending at the sacrum with or without spinopelvic fixation remains less explored. The current study sought to 1) propose a new DJF classification with a panel of experienced deformity surgeons, and 2) analyze intra- and interreliability of the novel classification. METHODS A prior review study was completed that identified all types of distal complications for lumbosacral fusions. A panel of 25 experienced spinal deformity surgeons used a modified Delphi approach with three rounds of review to create a classification system. Ten deformity surgeons then reviewed a representative series of 14 de-identified cases to assess the interrater reliability of the classification system using the intraclass correlation coefficient (ICC). A second round of review was conducted by each investigator to determine intrarater reliability using Cohen’s kappa coefficient. RESULTS Complications were classified as acute (< 90 days from the date of surgery) or chronic (≥ 3 months from the date of surgery). Acute failures included mechanical failure of the screws or screw-rod interface, such as pelvic set plug dissociation, tulip head dissociation, and fracture of the pelvic screw at any point along its trajectory. Fractures of the rod (proximal vs distal to S1) and distal bony anatomy (sacrum vs pelvis) were included, as was failure of the offset connector. Chronic failures also consisted of pseudarthrosis at distal levels, sacroiliac joint (SIJ) pain, screw halo formation, and painful screw prominence. The intrarater and interrater reliability were both high with Cohen’s kappa of 0.91 and an ICC of 0.98, respectively. CONCLUSIONS These data provide a comprehensive and systematic classification scheme of distal complications following long-segment ASD fusion to the sacrum. This new paradigm will allow for more detailed and consistent reporting of distal junctional complications following spinopelvic fusion, with or without supplemental pelvic fixation and/or concomitant SIJ fusion. This classification scheme resulted in high intra- and interrater reliability.