Improving Early Recognition of Treatment-Responsive Causes of Rapidly Progressive Dementia: The STAM3 P Score.

OBJECTIVE: To improve the timely recognition of patients with treatment-responsive causes of rapidly progressive dementia (RPD). METHODS: A total of 226 adult patients with suspected RPD were enrolled in a prospective observational study and followed for up to 2 years. Diseases associated with RPD were characterized as potentially treatment-responsive or non-responsive, referencing clinical literature. Disease progression was measured using Clinical Dementia Rating® Sum-of-Box scores. Clinical and paraclinical features associated with treatment responsiveness were assessed using multivariable logistic regression. Findings informed the development of a clinical criterion optimized to recognize patients with potentially treatment-responsive causes of RPD early in the diagnostic evaluation. RESULTS: A total of 155 patients met defined RPD criteria, of whom 86 patients (55.5%) had potentially treatment-responsive causes. The median (range) age-at-symptom onset in patients with RPD was 68.9 years (range 22.0-90.7 years), with a similar number of men and women. Seizures, tumor (disease-associated), magnetic resonance imaging suggestive of autoimmune encephalitis, mania, movement abnormalities, and pleocytosis (≥10 cells/mm3 ) in cerebrospinal fluid at presentation were independently associated with treatment-responsive causes of RPD after controlling for age and sex. Those features at presentation, as well as age-at-symptom onset <50 years (ie, STAM3 P), captured 82 of 86 (95.3%) cases of treatment-responsive RPD. The presence of ≥3 STAM3 P features had a positive predictive value of 100%. INTERPRETATION: Selected features at presentation reliably identified patients with potentially treatment-responsive causes of RPD. Adaptation of the STAM3 P screening score in clinical practice may minimize diagnostic delays and missed opportunities for treatment in patients with suspected RPD. ANN NEUROL 2024;95:237-248.

Diagnostic Utility of Cerebrospinal Fluid Biomarkers in Patients with Rapidly Progressive Dementia.

OBJECTIVE: This study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment-responsive causes of RPD. METHODS: Biomarkers of Alzheimer disease neuropathology (amyloid-ß 42/40 ratio, phosphorylated tau [p-tau181, p-tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin-like protein-1 [VILIP-1], total tau), neuroinflammation (chitinase-3-like protein [YKL-40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein-1 [MCP-1]), and synaptic dysfunction (synaptosomal-associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age- and sex-matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease. RESULTS: Alzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL-40 and low VILIP-1 identified patients with autoimmune/inflammatory diseases. MCP-1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP-1, p-tau181, and sTREM2 identified the 44 patients with treatment-responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease. INTERPRETATION: Selected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross-sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2024;95:299-313.

Anticholinergic Burden in Patients Treated for Overactive Bladder: Second-Line Therapy with Tibial Nerve Stimulation as a Solution.

Overactive bladder (OAB) is a highly prevalent condition with significant associated comorbidities. Current management guidelines suggest the utilization of anticholinergic medication as a second line after nonpharmacological treatment. Tibial nerve stimulation (TNS), which has previously been thought to have been expensive and inaccessible, was relegated to a third-line therapy. However, given the recently discovered association between anticholinergic medication use and dementia as well as the recent FDA approval of transcutaneous tibial nerve stimulation (TTNS), there may be a need to revisit management guidelines. In this commentary, we identify the two types of TNS, percutaneous tibial nerve stimulation (PTNS) and TTNS and compare them with anticholinergics. By considering their respective efficacies, side-effects profiles, and associated costs, we make the case in this commentary for an update to guidelines that includes TNS as second-line OAB management ahead of anticholinergic medication.

Long term rescue of Alzheimer's deficits in vivo by one-time gene-editing of App C-terminus.

Gene-editing technologies promise to create a new class of therapeutics that can achieve permanent correction with a single intervention. Besides eliminating mutant alleles in familial disease, gene-editing can also be used to favorably manipulate upstream pathophysiologic events and alter disease-course in wider patient populations, but few such feasible therapeutic avenues have been reported. Here we use CRISPR-Cas9 to edit the last exon of amyloid precursor protein (App), relevant for Alzheimer's disease (AD). Our strategy effectively eliminates an endocytic (YENPTY) motif at APP C-terminus, while preserving the N-terminus and compensatory APP-homologues. This manipulation favorably alters events along the amyloid-pathway - inhibiting toxic APP-ß-cleavage fragments (including Aß) and upregulating neuroprotective APP-α-cleavage products. AAV-driven editing ameliorates neuropathologic, electrophysiologic, and behavioral deficits in an AD knockin mouse model. Effects persist for many months, and no abnormalities are seen in WT mice even after germline App-editing; underlining overall efficacy and safety. Pathologic alterations in the glial-transcriptome of App-KI mice, as seen by single nuclei RNA-sequencing (sNuc-Seq), are also normalized by App C-terminus editing. Our strategy takes advantage of innate transcriptional rules that render terminal exons insensitive to nonsense-decay, and the upstream manipulation is expected to be effective for all forms of AD. These studies offer a path for a one-time disease-modifying treatment for AD.

Exosomes as biomarkers and therapy in type 2 diabetes mellitus and associated complications.

Type 2 diabetes mellitus (T2DM) is one of the most prevalent metabolic disorders worldwide. However, T2DM still remains underdiagnosed and undertreated resulting in poor quality of life and increased morbidity and mortality. Given this ongoing burden, researchers have attempted to locate new therapeutic targets as well as methodologies to identify the disease and its associated complications at an earlier stage. Several studies over the last few decades have identified exosomes, small extracellular vesicles that are released by cells, as pivotal contributors to the pathogenesis of T2DM and its complications. These discoveries suggest the possibility of novel detection and treatment methods. This review provides a comprehensive presentation of exosomes that hold potential as novel biomarkers and therapeutic targets. Additional focus is given to characterizing the role of exosomes in T2DM complications, including diabetic angiopathy, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, and diabetic wound healing. This study reveals that the utilization of exosomes as diagnostic markers and therapies is a realistic possibility for both T2DM and its complications. However, the majority of the current research is limited to animal models, warranting further investigation of exosomes in clinical trials. This review represents the most extensive and up-to-date exploration of exosomes in relation to T2DM and its complications.

Intramedullary Spinal Cord Abscess Management: Case Series, Operative Video, and Systematic Review.

BACKGROUND: Intramedullary spinal cord abscess (ISCA) is an extremely rare disease, which has had fewer than 250 reported cases since its initial description in 1830. The condition is limited to level V evidence, limiting the ability for surgeons to characterize and treat it. OBJECTIVE: To report the cases of 2 patients with ISCA and their surgical management: a 59-year-old woman who presented with progressive right hemiparesis and a 69-old man who presented with acute gait instability and significant bilateral shoulder pain. In addition, to report findings from a systematic literature review and associated logistic regression analysis. METHODS: A MEDLINE and Embase search was conducted using the keywords "intramedullary," "spinal cord," "abscess," and "tuberculoma" and the results were screened for case reports. A logistic regression model was fit 100 times on data to retrieve predictor odds ratios. RESULTS: Two hundred case reports of ISCA were identified between 1965 and 2022. Logistic regression determined that the only variables of significance were age (P < 0.01) and antibiotics (P < 0.05). CONCLUSIONS: Treatment of ISCAs has significantly improved over the years. However, ISCAs are still poorly understood. Our recommendations can be used to guide diagnosis and treatment.

A Rare Presentation of a Complex Mixed Autoimmune Encephalitis Diagnosis: A Case Report and Literature Review.

This case report presents a unique case of a difficult differential diagnosis of autoimmune encephalitis (AE) in the setting of Mycoplasma pneumoniae. A 40-year-old female with a history of Hashimoto thyroiditis, polycystic ovarian syndrome, and a lower respiratory infection presented to the emergency department with new-onset progressive neurological symptoms. These included generalized tonic-clonic seizure and worsening respiratory status that required intubation and tracheostomy. Blood cultures returned positive for M. pneumoniae. We concluded this to be a mixed diagnosis case of anti-glutamic acid decarboxylase 65 (anti-GAD65), Bickerstaff's brainstem encephalitis (BBE), Hashimoto's encephalopathy (HE), and Miller Fisher Syndrome (MFS) concurrently in the setting of M. pneumoniae. Initial treatment with intravenous immunoglobulin showed minimal improvement; however, subsequent treatment with plasmapheresis proved to be beneficial for the patient. Over the course of the plasma exchange therapy (PLEX), the patient slowly became more alert, attentive, and verbal. She was able to answer simple questions and follow commands. Common trends of age, gender, presenting symptoms, associated antibodies, and sessions of PLEX in different AE diseases were identified through a literature review. Only 69.7% of the cases implemented PLEX or plasmapheresis. Currently, there is no standard protocol for the treatment of AE. Our case report aims to present a clinically complicated example of AE and to provide further evidence to support PLEX as an important therapeutic option.

Machine Learning for Predicting In-Hospital Mortality After Traumatic Brain Injury in Both High-Income and Low- and Middle-Income Countries.

BACKGROUND: Machine learning (ML) holds promise as a tool to guide clinical decision making by predicting in-hospital mortality for patients with traumatic brain injury (TBI). Previous models such as the international mission for prognosis and clinical trials in TBI (IMPACT) and the corticosteroid randomization after significant head injury (CRASH) prognosis calculators can potentially be improved with expanded clinical features and newer ML approaches. OBJECTIVE: To develop ML models to predict in-hospital mortality for both the high-income country (HIC) and the low- and middle-income country (LMIC) settings. METHODS: We used the Duke University Medical Center National Trauma Data Bank and Mulago National Referral Hospital (MNRH) registry to predict in-hospital mortality for the HIC and LMIC settings, respectively. Six ML models were built on each data set, and the best model was chosen through nested cross-validation. The CRASH and IMPACT models were externally validated on the MNRH database. RESULTS: ML models built on National Trauma Data Bank (n = 5393, 84 predictors) demonstrated an area under the receiver operating curve (AUROC) of 0.91 (95% CI: 0.85-0.97) while models constructed on MNRH (n = 877, 31 predictors) demonstrated an AUROC of 0.89 (95% CI: 0.81-0.97). Direct comparison with CRASH and IMPACT models showed significant improvement of the proposed LMIC models regarding AUROC (P = .038). CONCLUSION: We developed high-performing well-calibrated ML models for predicting in-hospital mortality for both the HIC and LMIC settings that have the potential to influence clinical management and traumatic brain injury patient trajectories.

Machine Learning for Predicting Discharge Disposition After Traumatic Brain Injury.

BACKGROUND: Current traumatic brain injury (TBI) prognostic calculators are commonly used to predict the mortality and Glasgow Outcome Scale, but these outcomes are most relevant for severe TBI. Because mild and moderate TBI rarely reaches severe outcomes, there is a need for novel prognostic endpoints. OBJECTIVE: To generate machine learning (ML) models with a strong predictive capacity for trichotomized discharge disposition, an outcome not previously used in TBI prognostic models. The outcome can serve as a proxy for patients' functional status, even in mild and moderate patients with TBI. METHODS: Using a large data set (n = 5292) of patients with TBI from a quaternary care center and 84 predictors, including vitals, demographics, mechanism of injury, initial Glasgow Coma Scale, and comorbidities, we trained 6 different ML algorithms using a nested-stratified-cross-validation protocol. After optimizing hyperparameters and performing model selection, isotonic regression was applied to calibrate models. RESULTS: When maximizing the microaveraged area under the receiver operating characteristic curve during hyperparameter optimization, a random forest model exhibited top performance. A random forest model was also selected when maximizing the microaveraged area under the precision-recall curve. For both models, the weighted average area under the receiver operating characteristic curves was 0.84 (95% CI 0.81-0.87) and the weighted average area under the precision-recall curves was 0.85 (95% CI 0.82-0.88). CONCLUSION: Our group presents high-performing ML models to predict trichotomized discharge disposition. These models can assist in optimization of patient triage and treatment, especially in cases of mild and moderate TBI.

Perspectives into the possible effects of the B.1.1.7 variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on spermatogenesis.

B.1.1.7 is a recently discovered variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated with increased transmissibility. Recent findings indicate that this variant has a propensity to infect adolescents and children at higher rates than adults. The virus gains entry into various body cells utilizing angiotensin-converting enzyme 2 (ACE-2) and basigin (CD147) as receptors. The virus mainly affects type II pneumocytes of lungs, endothelial cells, enterocytes, and renal tubular cells. It is reported to affect testes, causing testicular pain, and producing histopathological changes, as observed in some autopsies. The B.1.1.7 variant can also affect various cells in the testes. This raises a major concern regarding the long-term effects of the viral infection on spermatogenesis and highlights the pressing need for a robust database of serum samples from infected male children.

Comparison of Minimally Invasive Total versus Subtotal Resection of Spinal Tumors: A Systematic Review and Meta-Analysis.

OBJECTIVE: With the advent of minimally invasive techniques, minimally invasive spine surgery (MISS) has become a realistic option for many spine cases. This study aims to evaluate the operative and clinical outcomes of MISS for total versus subtotal tumor resection from current evidence. METHODS: A literature search was performed using the search term (Minimally invasive surgery OR MIS) AND (spine tumor OR spinal tumor). Studies including both minimally invasive total and subtotal resection cases with operative or clinical data were included. RESULTS: Seven studies describing 159 spinal tumor cases were included. Compared with total resection, subtotal resection showed no significant differences in surgical time (mean difference (MD), 9.44 minutes; 95% confidence interval [CI], -47.66 to 66.55 minutes; P = 0.37), surgical blood loss (MD, -84.72 mL; 95% CI, -342.82 to 173.39 mL; P = 0.34), length of stay (MD, 1.38 days; 95% CI, -0.95 to 3.71 days; P = 0.17), and complication rate (odds ratio, 9.47; 95% CI, 0.34-263.56; P = 0.12). Pooled analyses with the random-effects model showed that neurologic function improved in 89% of patients undergoing total resection, whereas neurologic function improved in 61% of patients undergoing subtotal resection. CONCLUSIONS: Our analyses show that there is no significant difference in operative outcomes between total and subtotal resection. Patients undergoing total resection showed slightly better improvement in neurologic outcomes compared with patients undergoing subtotal resection. Overall, this study suggests that both total and subtotal resection may result in comparable outcomes for patients with spinal tumors. However, maximal safe resection remains the ideal treatment because it provides the greatest chance of long-term benefit.

Malignant sublingual gland tumors: demographics, prognostic factors, and treatment outcomes.

OBJECTIVE: To determine the demographic characteristics, prognostic factors, and optimal treatment modalities of patients diagnosed with malignant primary tumors of the sublingual gland. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry contains 210 patients diagnosed with sublingual gland tumors in the SEER database. Kaplan-Meier and multivariate Cox regression analysis were performed on age, sex, race, histologic subtype, stage, and treatment modality. RESULTS: Kaplan-Meier analysis found an overall survival and disease-specific survival at 5 years of 69% and 83%, respectively. Multivariate analysis demonstrated that age, sex, stage, and surgery were predictors of overall survival, whereas stage was a predictor of disease-specific survival. CONCLUSIONS: Here we report, to our knowledge, the largest study to date investigating demographic characteristics, prognostic factors, and treatment modalities of patients diagnosed with primary malignant tumors of the sublingual gland. Increased age and stage correlated with decreased survival, whereas female gender and surgical therapy correlated with increased survival in the overall population. Radiation therapy for patients diagnosed with adenoid cystic carcinoma in the sublingual gland was correlated with increased survival.

Epidemiology, Prognostic Factors, and Treatment of Malignant Submandibular Gland Tumors: A Population-Based Cohort Analysis.

IMPORTANCE: Malignant tumors of the submandibular gland are uncommon, leading to limited information regarding prognostic factors and difficulty in evaluating treatment modalities. OBJECTIVE: To investigate the correlates of survival in patients with primary malignant tumors of the submandibular gland. DESIGN, SETTING, AND PARTICIPANTS: Data from 2626 patients with a diagnosis of primary tumors of the submandibular gland between 1973 and 2011 in the Surveillance, Epidemiology, and End Results database were used in a retrospective population-based cohort analysis. Kaplan-Meier analysis along with multivariate Cox regression analysis was performed to determine prognostic factors in overall survival (OS) and disease-specific survival (DSS). INTERVENTIONS: Patients were treated with surgery, radiation therapy, both, or neither. MAIN OUTCOMES AND MEASURES: Overall and disease-specific survival. RESULTS: We identified 2626 patients with a diagnosis of primary malignant tumors of the submandibular gland, 52.9% male and 47.1% female, with a mean (range) age of 61.3 (7-101) years. Adenoid cystic carcinoma (36.0%) was the most prevalent histologic subtype, followed by squamous cell carcinoma (18.1%), mucoepidermoid carcinoma (16.9%), and adenocarcinoma (13.7%). Kaplan-Meier analysis demonstrated an OS and DSS of 65% and 74%at 2 years, 54% and 67% at 5 years, and 40% and 60% at 10 years, respectively. Multivariate Cox regression analysis revealed independent predictors of OS and DSS to be age (HR, 1.04 [95% CI, 1.03-1.04], P < .001; HR, 1.02 [95% CI, 1.01-1.03], P < .001), sex (HR, 0.69 [95% CI, 0.57-0.84], P < .001; HR, 0.73 [95% CI, 0.56-0.96], P = .02), tumor grade (HR, 1.47 [95% CI, 1.19-1.81], P < .001; HR, 1.67 [95% CI, 1.25-2.25], P = .001), stage at presentation (HR, 1.56 [95% CI, 1.41-1.72], P < .001; HR, 1.96 [95% CI, 1.69-2.28], P < .001), and surgical resection (HR, 0.55 [95% CI, 0.41-0.74], P < .001; HR, 0.51 [95% CI, 0.35-0.75], P = .001). CONCLUSIONS AND RELEVANCE: We report, to our knowledge, the largest study to date focused on correlates of survival in submandibular gland malignant neoplasms. Multivariate analysis found that older age at diagnosis, high tumor grade, and later stage at presentation were correlated with decreased survival whereas female sex and surgical resection were correlated with increased survival. In addition, a 3-cm tumor cutoff size was demonstrated above which was associated with a significantly less favorable prognosis. Radiation therapy had mixed association with survival, dependent on tumor size and subtype.