Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-40/42, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights 7 core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data.. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking.

Stable, chronic in-vivo recordings from a fully wireless subdural-contained 65,536-electrode brain-computer interface device.

Minimally invasive, high-bandwidth brain-computer-interface (BCI) devices can revolutionize human applications. With orders-of-magnitude improvements in volumetric efficiency over other BCI technologies, we developed a 50-µm-thick, mechanically flexible micro-electrocorticography (µECoG) BCI, integrating 256×256 electrodes, signal processing, data telemetry, and wireless powering on a single complementary metal-oxide-semiconductor (CMOS) substrate containing 65,536 recording and 16,384 stimulation channels, from which we can simultaneously record up to 1024 channels at a given time. Fully implanted below the dura, our chip is wirelessly powered, communicating bi-directionally with an external relay station outside the body. We demonstrated chronic, reliable recordings for up to two weeks in pigs and up to two months in behaving non-human primates from somatosensory, motor, and visual cortices, decoding brain signals at high spatiotemporal resolution.

Progressive microvascular failure in acute ischemic stroke: A systematic review, meta-analysis, and time-course analysis.

This systematic review, meta-analysis, and novel time course analysis examines microvascular failure in the treatment of acute ischemic stroke (AIS) patients undergoing endovascular therapy (EVT) and/or thrombolytic administration for stroke management. A systematic review and meta-analysis following PRIMSA-2020 guidelines was conducted along with a novel curve-of-best fit analysis to elucidate the time-course of microvascular failure. Scopus and PubMed were searched using relevant keywords to identify studies that examine recanalization and reperfusion assessment of AIS patients following large vessel occlusion. Meta-analysis was conducted using a random-effects model. Curve-of-best-fit analysis of microvascular failure rate was performed with a negative exponential model. Twenty-seven studies with 1151 patients were included. Fourteen studies evaluated patients within a standard stroke onset-to-treatment time window (≤6 hours after last known normal) and thirteen studies had an extended time window (>6 hours). Our analysis yields a 22% event rate of microvascular failure following successful recanalization (95% CI: 16-30%). A negative exponential curve modeled a microvascular failure rate asymptote of 28.5% for standard time window studies, with no convergence of the model for extended time window studies. Progressive microvascular failure is a phenomenon that is increasingly identified in clinical studies of AIS patients undergoing revascularization treatment.

A Wireless, Mechanically Flexible, 25µm-Thick, 65,536-Channel Subdural Surface Recording and Stimulating Microelectrode Array with Integrated Antennas.

This paper presents a fully wireless microelectrode array (MEA) system-on-chip (SoC) with 65,536 electrodes for non-penetrative cortical recording and stimulation, featuring a total sensing area of 6.8mm×7.4mm with a 26.5µm×29µm electrode pitch. Sensing, data telemetry, and powering are monolithically integrated on a single chip, which is made mechanically flexible to conform to the surface of the brain by substrate removal to a total thickness of 25µm allowing it to be contained entirely in the subdural space under the skull.

No-Reflow Post-Recanalization in Acute Ischemic Stroke: Mechanisms, Measurements, and Molecular Markers.

Acute ischemic stroke remains the primary cause of disability worldwide. For patients with large vessel occlusions, intravenous thrombolysis followed by mechanical thrombectomy remains the standard of care. Revascularization of the large vessel is typically successful. However, despite reopening of the occluded vessel, many patients fail to return to independence. Functional failure, despite macrovascular recanalization, is often referred to as the no-reflow phenomenon. Even with an extensive characterization of reperfusion in animal models, numerous mechanisms may explain no-reflow. Further, uniform measurements of this microvascular dysfunction and prognostic markers associated with no-reflow are lacking. In this review, we highlight a number of mechanisms that may explain no-reflow, characterize current multimodal measurements, and assess its molecular markers.

Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial.

BACKGROUND: Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma. METHODS: We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 µM topotecan 200 µL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996. FINDINGS: Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients. INTERPRETATION: In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes. FUNDING: US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

The Sledgehammer in Precision Medicine: Dexamethasone and Immunotherapeutic Treatment of Glioma.

Understanding dexamethasone's effect on the immune microenvironment in glioma patients is of key importance. We performed a comprehensive literature review using the NCBI PubMed database for all articles meeting the following search criteria. ((dexamethasone[All Fields]) AND (glioma or glioblastoma)[Title/Abstract]) AND (immune or T cell or B cell or monocyte or neutrophil or macrophage). Forty-three manuscripts were deemed relevant to the topic at hand. Multiple clinical studies have linked dexamethasone use to decreased overall survival while preclinical studies in murine glioma models have demonstrated decreased tumor-infiltrating lymphocytes after dexamethasone administration.

An immune response characterizes early Alzheimer's disease pathology and subjective cognitive impairment in hydrocephalus biopsies.

Early Alzheimer's disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. This represents an opportunity to study early AD pathology in living patients. Here we report RNA-seq data on 106 cortical biopsies from this patient population. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of biopsy ß-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Taken together, these findings highlight a restricted set of microglial and non-microglial genes that correlate with early AD pathology in the setting of subjective cognitive decline.

Deconvolution of cell type-specific drug responses in human tumor tissue with single-cell RNA-seq.

BACKGROUND: Preclinical studies require models that recapitulate the cellular diversity of human tumors and provide insight into the drug sensitivities of specific cellular populations. The ideal platform would enable rapid screening of cell type-specific drug sensitivities directly in patient tumor tissue and reveal strategies to overcome intratumoral heterogeneity. METHODS: We combine multiplexed drug perturbation in acute slice culture from freshly resected tumors with single-cell RNA sequencing (scRNA-seq) to profile transcriptome-wide drug responses in individual patients. We applied this approach to drug perturbations on slices derived from six glioblastoma (GBM) resections to identify conserved drug responses and to one additional GBM resection to identify patient-specific responses. RESULTS: We used scRNA-seq to demonstrate that acute slice cultures recapitulate the cellular and molecular features of the originating tumor tissue and the feasibility of drug screening from an individual tumor. Detailed investigation of etoposide, a topoisomerase poison, and the histone deacetylase (HDAC) inhibitor panobinostat in acute slice cultures revealed cell type-specific responses across multiple patients. Etoposide has a conserved impact on proliferating tumor cells, while panobinostat treatment affects both tumor and non-tumor populations, including unexpected effects on the immune microenvironment. CONCLUSIONS: Acute slice cultures recapitulate the major cellular and molecular features of GBM at the single-cell level. In combination with scRNA-seq, this approach enables cell type-specific analysis of sensitivity to multiple drugs in individual tumors. We anticipate that this approach will facilitate pre-clinical studies that identify effective therapies for solid tumors.

Convection Enhanced Delivery of Topotecan for Gliomas: A Single-Center Experience.

A key limitation to glioma treatment involves the blood brain barrier (BBB). Convection enhanced delivery (CED) is a technique that uses a catheter placed directly into the brain parenchyma to infuse treatments using a pressure gradient. In this manuscript, we describe the physical principles behind CED along with the common pitfalls and methods for optimizing convection. Finally, we highlight our institutional experience using topotecan CED for the treatment of malignant glioma.

Impact of venous thromboembolism during admission for meningioma surgery on hospital charges and postoperative complications.

Surgical resection of meningiomas has been associated with high rates of venous thromboembolic events (VTE) as compared with all other intracranial tumors. There is a paucity of data regarding the clinical complications and comorbidities associated with this cohort yet the underlying pathophysiological mechanism for this tumor-specific finding remains unclear. Our goal was to determine the various impacts of VTE on meningioma surgery in a large cohort of inpatient admissions. This retrospective analysis utilized discharge data from the National Inpatient Sample (NIS) from 2002 to 2010. Patient demographics, comorbidities, length of stay, hospital charges, and postoperative complications were compared between patients with and without VTE. Of 20,259 patients, 426 (2.1%) experienced a VTE. Compared to the non-VTE cohort, patients that experienced a VTE were older (62.7 ±â€¯13.7 vs. 57.2 ±â€¯14.7; p < 0.001), were more commonly male (38.0% vs 30.1%; p = 0.001), had longer hospitalizations (18.8 vs 6.6 days; p < 0.001), and incurred significantly greater hospital charges ($195,837 vs $74,434; p < 0.001). VTE patients experienced significantly higher rates of acute postoperative complications including shock, hemorrhage, wound dehiscence, infection, intracerebral hemorrhage, hemiparesis/hemiplegia, stroke, and death during admission. Odds ratio of aforementioned postsurgical complications remained significantly higher both before and after adjusting for age and sex (all p < 0.01). Occurrence of VTE in patients undergoing meningioma resection portends greater hospital charges, most likely attributed to longer lengths of admission. Increased postoperative complications and mortality in the VTE group warrants further investigation and wariness of the surgeon when treating surgical candidates of meningioma.

High-frequency spinal cord stimulation causing cardiac paresthesias after lead migration: a case report.

INTRODUCTION: High-frequency (HF) spinal cord stimulation (SCS), a relatively new form of spinal cord stimulation, provides stimulation frequencies of up to 10 kHz and allows for paresthesia-free pain relief, an advantage that distinguishes it from traditional stimulation therapy. Without paresthesias, patients with HF SCS do not experience position-dependent painful stimulation and do not have to experience treatment interruption during sleep. Lead migration is a well-known complication of conventional spinal cord stimulation and usually results in a loss of efficacy along with other unpleasant sensory symptoms. In this case report, we present an incidence of lead migration in HF SCS that resulted in paresthesias, a symptom not expected to occur in this novel therapy. CASE: The patient, a 60-year-old female with post-laminectomy syndrome, underwent a trial of HF SCS with standard lead placement at T8-T9. She initially had pain relief, but returned to the office on post-operative day 2 complaining of left chest wall and cardiac paresthesias, without frank pain or palpitations, in addition to loss of efficacy for her back and leg pain. Imaging showed that the leads had migrated, with one lead reaching the levels of T1-T3. CONCLUSION: While HF SCS has emerged as an effective paresthesia-free means of reducing back and leg pain, we provide the first report of paresthesias occurring with the HF SCS system as a result of cephalad lead migration. As HF SCS is only now being utilized as a treatment modality, we must remain cautious of potential adverse outcomes in patients, in particular above T8.

Laryngeal adenocarcinoma not otherwise specified: A population-based perspective.

OBJECTIVES/HYPOTHESIS: Laryngeal adenocarcinoma not otherwise specified (LAdC NOS) is a category to which variants of minor salivary gland tumors of the larynx that do not fit other well-characterized histological subtypes are assigned. Its rare nature and inconsistency in available reports has hindered the investigation and further understanding of this malignancy. In this study, a national population-based resource was used to evaluate the epidemiology and survival of this rare entity. STUDY DESIGN: Retrospective population-based analysis. METHODS: The Surveillance, Epidemiology, and End Results database was searched for patients diagnosed with LAdC NOS between 1973 and 2012. Patient demographics, tumor location, TNM stage, grade, incidence, and survival trends were collected and analyzed. RESULTS: One hundred eleven patients met criteria for diagnosis of LAdC NOS, of which the majority were male (80.2%), white (84.7%), with a mean age of 65 years. The supraglottis was the most common site at presentation (38.7%). The majority presented with grade II tumor (45.7%). TNM staging revealed T2 (36.8%), N0 (72.2%), and M0 (88.9%) to be the most common classification. The overall incidence between the years of 2000 and 2012 was 0.008/100,000 individuals. The overall 5-year disease-specific survival (DSS) was 60.1%, compared to 85.7% in patients treated with combination surgery and radiotherapy. CONCLUSIONS: LAdC NOS is an uncommon malignancy. It most commonly affects men in their mid-60s, indiscriminate of race. Lesions most commonly present in the supraglottis and are more often low grade histologically. DSS is highest in patient treated with combination surgery and radiotherapy. LEVEL OF EVIDENCE: 4 Laryngoscope, 2016 127:424-429, 2017.

Laryngeal Verrucous Carcinoma.

Objective Laryngeal verrucous carcinoma (LVC) is a rare, locally invasive neoplasm comprising 1% to 3.4% of laryngeal carcinomas. Management strategies are a topic of ongoing conversation, and no definitive treatment protocol based on T stage and presentation exists. This review examines characteristics, treatment modalities, and patient outcomes of LVC. Data Sources PubMed, MEDLINE, EMBASE, and Web of Science. Methods Databases were searched through October 29, 2015, for literature detailing individual patient cases of LVC. Variables analyzed included patient demographics, tumor characteristics, tumor size, treatment, and outcomes. Results Thirty-seven articles with 369 cases were included. LVC was found more commonly in males (13.8:1), at an average age of 58.7 years, and located in the glottis (74.0%). Most patients had local disease at presentation (94.9%). The most common presenting symptom was hoarseness (92.3%). The most common primary treatment was surgery alone (72.3%), with local excision as the most common technique (56.8%). In patients with data available on both surgical modality and T stage, most patients who presented as T1 and were managed surgically underwent local excision (79.2%). Surgical treatment alone led to high rates of disease-free survival at follow-up (86.8%). A large number of patients presenting with T1 disease were disease free at follow-up (88.6%). Overall survival was 80.3%. Conclusion LVC is most often managed surgically. The extent of surgical resection may be guided by T stage, with smaller tumors resected via local excision and larger tumors via partial or total laryngectomy. Regardless of T stage or therapy, LVC has a good posttreatment prognosis.

Impact of Diabetes Mellitus on Head and Neck Cancer Patients Undergoing Surgery.

OBJECTIVE: The impact of diabetes mellitus (DM) on surgical outcomes and cost of care for patients undergoing surgery for head and neck cancer (HNCA) is not well established. We used the Nationwide Inpatient Sample to analyze the postoperative impact of DM on HNCA patients. STUDY DESIGN: Population-based inpatient registry analysis. SETTING: Academic medical center. SUBJECTS AND METHODS: Discharge data from the Nationwide Inpatient Sample were analyzed for patients undergoing HNCA surgery from 2002 to 2010. Patient demographics, comorbidities, length of stay, hospital charges, and postoperative complications were compared between HNCA patients with and without DM. RESULTS: Of 31,075 patients, 4029 patients (13.0%) had a DM diagnosis. DM patients were older (65.7 ± 10.8 vs 61.1 ± 14.1 years old; P < .001), had more preexisting comorbidities, had longer hospitalizations, and incurred greater hospital charges. Compared with the non-DM cohort, DM patients experienced significantly higher rates of postoperative infections (2.6% vs 2.1%, P = .025), cardiac events (9.0% vs 4.3%, P < .001), pulmonary edema/failure (6.6% vs 5.7%, P = .023), acute renal failure (3.3% vs 1.5%, P < .001), and urinary tract infections (2.8 % vs 2.1%, P = .005). No differences in surgical wound healing rates were observed (0.1 vs 0.1, P = .794). On multivariate logistic regression corrected for age and race, DM patients had greater odds of postoperative infections (1.382, P = .007), cardiac events (1.893, P < .001), and acute renal failure (2.023, P < .001). CONCLUSIONS: DM is associated with greater length of stay and hospital charges among HNCA patients. DM patients have significantly greater rates of postoperative complications, including postoperative infections, cardiac events, and acute renal failure.

Injury in aged animals robustly activates quiescent olfactory neural stem cells.

While the capacity of the olfactory epithelium (OE) to generate sensory neurons continues into middle age in mice, it is presumed that this regenerative potential is present throughout all developmental stages. However, little experimental evidence exists to support the idea that this regenerative capacity remains in late adulthood, and questions about the functionality of neurons born at these late stages remain unanswered. Here, we extend our previous work in the VNO to investigate basal rates of proliferation in the OE, as well as after olfactory bulbectomy (OBX), a commonly used surgical lesion. In addition, we show that the neural stem cell retains its capacity to generate mature olfactory sensory neurons in aged animals. Finally, we demonstrate that regardless of age, a stem cell in the OE, the horizontal basal cell (HBC), exhibits a morphological switch from a flattened, quiescent phenotype to a pyramidal, proliferative phenotype following chemical lesion in aged animals. These findings provide new insights into determining whether an HBC is active or quiescent based on a structural feature as opposed to a biochemical one. More importantly, it suggests that neural stem cells in aged mice are responsive to the same signals triggering proliferation as those observed in young mice.

Lateral skull base Inflammatory pseudotumor: A systematic review.

OBJECTIVE: Inflammatory pseudotumor (IPT) of the lateral skull base is a rare nonneoplastic inflammatory process of unknown cause often mistaken for malignancy or infection. This systematic review aims to analyze all reported cases of lateral skull base IPT to date in order to provide insight into the management of this uncommon lesion. DATA SOURCES: MEDLINE/PubMed database. REVIEW METHODS: The MEDLINE/PubMed databases were searched for articles related to lateral skull base IPT. A bibliography review of the search results was then performed for additional articles. Demographics, presentation, radiographic findings, treatment, follow-up, and outcome were analyzed. RESULTS: Thirty articles describing 39 patients were reviewed. The most common presenting symptom was hearing loss (53.8%). The mastoid bone had the highest incidence of IPT (61.5%). Computed tomography (CT) was the most utilized imaging modality. The lesion appeared isointense on T1-weighted magnetic resonance imaging (MRI) (75.0%) and hypointense on T2-weighted MRI (62.5%). Histopathological analysis showed fibrosis (96.9%) with inflammatory cell infiltration (100.0%). Surgical resection (alone or in combination with other treatments) was the most common treatment modality (92.3%), producing the greatest number of disease-free patients overall (96.0%). The mean follow-up time was 21.6 months, at which point 34.4% of patients showed improvement and 31.3% were completely disease-free. CONCLUSION: This review is the most comprehensive analysis of lateral skull base IPT to date. A thorough workup including clinical exam, imaging, and biopsy is essential for diagnosis. Surgical excision is the most common and most successful treatment modality, followed by surgery with corticosteroids.

Impact and cost of care of venous thromboembolism following pituitary surgery.

OBJECTIVES/HYPOTHESIS: In 2008, the Centers for Medicare and Medicaid Services discontinued reimbursement for postoperative venous thromboembolism (VTE) events such as deep venous thrombosis and pulmonary embolism, citing them as preventable postoperative complications. We examined the impact of postoperative VTE on patients undergoing pituitary surgery. METHODS: The Nationwide Inpatient Sample (NIS) was evaluated for patients undergoing pituitary resection from 2002 to 2010. Patient demographics, comorbidities, length of stay, hospital charges, and postoperative complications were analyzed. RESULTS: Eighty-seven patients who underwent pituitary surgery developed a VTE. Patients who underwent pituitary surgery that developed VTE were older (55.9 ± 15.2 years) than those who did not develop VTE (50.1 ± 17.2 years) (P = 0.002). VTE occurred at a significantly higher rate in patients with coagulopathy, peripheral vascular disorder, and weight loss (P < 0.05). VTE was associated with increased rates of postoperative neurological, pulmonary, cardiac, urinary, renal, hemorrhage, fluid and electrolytes, diabetes insipidus, and cerebrospinal fluid rhinorrhea complications (P < 0.01)-as well as increased mortality rate (P < 0.001), length of stay (P < 0.001), and cost of care (P < 0.001). CONCLUSIONS: Analysis of the data from the NIS database showed that risk factors for the development of VTE following pituitary surgery include older age, preexisting coagulopathy, peripheral vascular disorder, and weight loss. Patients who developed postoperative VTE had a longer length of hospital stay, higher hospital charges, and increased morbidity and mortality.