Plasma neurofilament light chain is increased in Niemann-Pick Type C but glial fibrillary acidic protein remains normal.

OBJECTIVE: Niemann-Pick Type C (NPC) is a genetic neurodegenerative lysosomal storage disorder commonly associated with psychiatric symptoms and delays to accurate diagnosis and treatment. This study investigated biomarker levels and diagnostic utility of plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in NPC compared to healthy controls. METHODS: Patients with NPC were recruited from a specialist assessment and management service. Data was available from an age and sex-matched healthy control group. NfL and GFAP were measured on Quanterix Simoa HD-X analysers and groups compared using generalised linear models. NfL levels were compared to, and percentiles derived from, recently developed NfL reference ranges. RESULTS: Plasma NfL was significantly elevated in 11 patients with NPC compared to 25 controls (mean 17.1 vs. 7.4 pg/ml, p < 0.001), and reference ranges (all >98th percentile). NfL distinguished NPC from controls with high accuracy. GFAP levels were not elevated in NPC (66.6 vs. 75.1 pg/ml). DISCUSSION: The study adds important evidence on the potential diagnostic utility of plasma NfL in NPC, extends the literature of NfL as a diagnostic tool to differentiate neurodegenerative from primary psychiatric disorders, and adds support to the pathology in NPC primarily involving neuronal, particularly axonal, degeneration.

Ontogeny of the Cytochrome P450 Superfamily in the Ornate Spiny Lobster (Panulirus ornatus).

Cytochrome P450s (CYP450s) are a versatile superfamily of enzymes known to undergo rapid evolution. They have important roles across growth and development pathways in crustaceans, although it is difficult to characterise orthologs between species due to their sequence diversity. Conserved CYP450s enzymes in crustaceans are those associated with ecdysteroidogenesis: synthesising and breaking down the active moult hormone, 20-hydroxyecdysone. The complex life cycle of the ornate spiny lobster, Panulirus ornatus, relies on moulting in order to grow and develop. Many of these diverse life stages have been analysed to establish a comprehensive transcriptomic database for this species. The transcripts putatively encoding for CYP450s were mapped using transcriptomic analysis and identified across growth and development stages. With the aid of phylogeny, 28 transcripts of 42 putative P. ornatus CYP450s were annotated, including the well conserved Halloween genes, which are involved in ecdysteroidogenesis. Expression patterns across the life stages determined that only a subset of the CYP450s can be detected in each life stage or tissue. Four Shed transcripts show overlapping expression between metamorphosis and adult tissues, suggesting pleotropic functions of the multiple Shed orthologs within P. ornatus.

Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders.

OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders.

OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.

Single position robot-assisted pedicle screw placement with S2-alar-iliac fixation in lateral decubitus: cadaveric feasibility study and early clinical experience.

OBJECTIVES: Single position lateral fusion with robotic assistance eliminates the need for surgical staging while harnessing the precision of robotic adjuncts. We expand on this technique by demonstrating the technical feasibility of placing bilateral pedicle screws with S2-alar-iliac (S2AI) fixation while in the lateral position. METHODS: A cadaveric study was performed using 12 human specimens. A retrospective clinical series was also performed for patients who had undergone robot-assisted placement of S2AI screws in lateral decubitus between June 2020 and June 2022. Case demographics, implant placement time, implant size, screw accuracy, and complications were recorded. Early postoperative radiographic outcomes were reported. RESULTS: In the cadaveric series, a total of 126 screws were placed with robotic assistance in 12 cadavers of which 24 screws were S2AI. There were four breaches from pedicle screws and none with S2AI screws for an overall accuracy rate of 96.8%. In the clinical series, four patients (all male, mean age 65.8 years) underwent single position lateral surgery with S2AI distal fixation. Mean BMI was 33.6 and mean follow-up was 20.5 months. Mean radiographic improvements were lumbar lordosis 12.3 ± 4.7°, sagittal vertical axis 1.5 ± 2.1 cm, pelvic tilt 8.5 ± 10.0°, and pelvic incidence-lumbar lordosis mismatch 12.3 ± 4.7°. A total of 42 screws were placed of which eight screws were S2AI. There were two breaches from pedicle screws and none from S2AI screws for an overall accuracy rate of 95.2%. No repositioning or salvage techniques were required for the S2AI screws. CONCLUSIONS: We demonstrate here the technical feasibility of single position robot-assisted placement of S2-alar-iliac screws in the lateral decubitus position for single position surgery.

Optoelectronic and Optomechanical Properties of Few-Atomic-Layer Black Phosphorus Nanoflakes as Revealed by In Situ TEM.

The optoelectronic signatures of free-standing few-atomic-layer black phosphorus nanoflakes are analyzed by in situ transmission electron microscopy (TEM). As compared to other 2D materials, the band gap of black phosphorus (BP) is related directly to multiple thicknesses and can be tuned by nanoflake thickness and strain. The photocurrent measurements with the TEM show a stable response to infrared light illumination and change of nanoflakes band gap with deformation while pressing them between two electrodes assembled in the microscope. The photocurrent spectra of an 8- and a 6-layer BP nanoflake samples are comparatively measured. Density functional theory (DFT) calculations are performed to identify the band structure changes of BP during deformations. The results should help to find the best pathways for BP smart band gap engineering via tuning the number of material atomic layers and programmed deformations to promote future optoelectronic applications.

Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from non-progressors.

BACKGROUND: Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative 'non-progressor' mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. METHODS: Cerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow-up information, patients were categorised as Progressors or Non-Progressors: further subtyped into Non-Progressor Revised (non-neurological/neurodegenerative final diagnosis), and Non-Progressor Static (static deficits, not fully explained by non-neurological/neurodegenerative causes). RESULTS: Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Non-Progressor Revised, 8 Non-Progressor Static), and 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M = 554 pg/mL, 95%CI:[461, 675], Non-Progressor Revised M = 459 pg/mL, 95%CI:[385, 539], and Non-Progressor Static M = 730 pg/mL, 95%CI:[516, 940]), compared to Progressors (M = 2397 pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Non-Progressor Static tended to have higher T-tau and P-tau levels compared to Non-Progressor Revised Diagnoses. CONCLUSION: This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL.

Series of virtual light therapy interventions for fatigue: a feasibility pilot study protocol for a series of personalised (N-of-1) trials.

INTRODUCTION: Fatigue is one of the most commonly recorded patient symptoms that can result in deficits in aspects of psychomotor functioning, cognition, work performance and mood. Research shows that bright light and dim light therapy may be an efficacious way to reduce symptoms of fatigue. Still, the feasibility, scalability, individual treatment effects and adverse event heterogeneity of these treatments are unknown. METHODS AND ANALYSIS: The current study evaluates the feasibility, acceptability and effectiveness of a series of personalised (N-of-1) interventions for virtual delivery of bright light therapy and dim light therapy versus usual care treatment for fatigue in 60 participants. We hypothesise that this study will provide valuable information about implementing virtual, N-of-1 randomised controlled trials (RCTs) for fatigue. It will also offer results about determining participants' ratings of usability and satisfaction with the virtual, personalised intervention delivery system; evaluating participants' improvement of fatigue symptoms; and, in the long term, identify ways to integrate N-of-1 light therapy trials into patient care. ETHICS AND DISSEMINATION: This trial was approved by the Northwell Health Institutional Review Board. The trial results will be published in a peer-reviewed journal. All publications resulting from this series of personalised trials will follow the Consolidated Standards of Reporting Trials extension for N-of-1 trials CENT 2015 reporting guidelines. REGISTRATION DETAILS: This trial is registered in www. CLINICALTRIALS: gov (number NCT04707846). TRIAL REGISTRATION NUMBER: NCT04707846.

Plasma Neurofilament Light Chain and Clinical Diagnosis in Frontotemporal Dementia Syndromes.

BACKGROUND: Frontotemporal dementia (FTD) syndromes, mimics, phenocopy (phFTD), and slowly progressive behavioral variant FTD (bvFTD) can be difficult to distinguish clinically. Biomarkers such as neurofilament light chain (NfL) may be helpful. OBJECTIVE: To study plasma NfL levels in people with FTD syndromes and determine if plasma NfL can distinguish between FTD syndromes and phFTD. METHODS: Plasma NfL levels were estimated using both Simoa® Quanterix HD-X™ and SR-X™ machines grouped via final diagnosis after investigation and review. RESULTS: Fifty participants were studied: bvFTD = 20, semantic variant FTD (svFTD) = 11, non-fluent variant FTD (nfvFTD) = 9, FTD with motor neuron disease (MND) = 4, phFTD = 2, slow progressors = 3, FTD mimic = 1, mean age 67.2 (SD 8.4) years. NfL levels were significantly higher in the FTD group compared to phenocopy group (p = 0.003). Median NfL (IQR) pg/mL was comparable in the FTD syndromes: bvFTD 41.10 (50.72), svFTD 44.38 (16.61), and nfvFTD 42.61 (22.93), highest in FTD with MND 79.67 (45.32) and lowest in both phFTD 13.99 (0.79) and slow progressors 17.97 (3.62). CONCLUSION: Plasma NfL appears to differentiate FTD syndromes and mimics. However, a lower NfL may predict a slower, but not necessarily absence of neurodegeneration, and therefore appears limited in distinguishing slow progressors from FTD phenocopies. Larger numbers of patients from all clinical groups are required to strengthen diagnostic utility.

Optomechanical Properties of MoSe2 Nanosheets as Revealed by In Situ Transmission Electron Microscopy.

Free-standing few-layered MoSe2 nanosheet stacks optoelectronic signatures are analyzed by using light compatible in situ transmission electron microscopy (TEM) utilizing an optical TEM holder allowing for the simultaneous mechanical deformation, electrical probing and light illumination of a sample. Two types of deformation, namely, (i) bending of nanosheets perpendicular to their basal atomic planes and (ii) edge deformation parallel to the basal atomic planes, lead to two distinctly different optomechanical performances of the nanosheet stacks. The former deformation induces a stable but rather marginal increase in photocurrent, whereas the latter mode is prone to unstable nonsystematic photocurrent value changes and a red-shifted photocurrent spectrum. The experimental results are verified by ab initio calculations using density functional theory (DFT).

Characterization of Dysphagia and Longitudinal Changes in Swallowing Function in Adults with Niemann-Pick Disease Type C Treated with Miglustat.

Niemann-Pick disease type C (NPC) is a rare, autosomal recessive neurodegenerative disease, characterized by progressive psychiatric and neurological deficits. Neurological symptoms include cognitive decline and dysphagia. Aspiration pneumonia secondary to dysphagia is a leading cause of death in NPC. Miglustat is currently the only approved disease-specific treatment shown to be effective in stabilizing neurological symptoms. Miglustat has previously been reported to halt or improve early dysphagia and cognitive symptoms. Here we examine the characteristics of dysphagia, the relationship between dysphagia and the presence of cognitive impairment, and longitudinal changes in swallowing function during miglustat treatment in adult-and-adolescent-onset NPC. Retrospective analysis of videofluoroscopic swallow studies (VFSS) was completed for ten adults with NPC (mean age 28.44 years ± 9.34 years). Participants were recruited through the Royal Melbourne Hospital in Australia between 2008 and 2015. The Bethlehem Swallowing Scale and the Penetration-Aspiration Scale were used to quantify VFSS data. Dysphagia was present in 90% of participants at baseline with reduced lingual function and a delayed swallowing reflex as the most common symptoms. Swallow impairment appeared to stabilize during miglustat therapy for periods up to 66 months, with no significant changes in scores (p > 0.05). Data were in accordance with the literature and support the use of miglustat as an efficacious treatment for reducing swallowing impairment and stabilizing cognitive function. Findings provide detailed information on the impairments experienced by patients, give context to events leading to aspiration in NPC and, importantly, inform how management of dysphagia can complement pharmaceutical treatment.

Effects of face masks on acoustic analysis and speech perception: Implications for peri-pandemic protocols.

Wearing face masks (alongside physical distancing) provides some protection against infection from COVID-19. Face masks can also change how people communicate and subsequently affect speech signal quality. This study investigated how three common face mask types (N95, surgical, and cloth) affected acoustic analysis of speech and perceived intelligibility in healthy subjects. Acoustic measures of timing, frequency, perturbation, and power spectral density were measured. Speech intelligibility and word and sentence accuracy were also examined using the Assessment of Intelligibility of Dysarthric Speech. Mask type impacted the power distribution in frequencies above 3 kHz for the N95 mask, and above 5 kHz in surgical and cloth masks. Measures of timing and spectral tilt mainly differed with N95 mask use. Cepstral and harmonics to noise ratios remained unchanged across mask type. No differences were observed across conditions for word or sentence intelligibility measures; however, accuracy of word and sentence translations were affected by all masks. Data presented in this study show that face masks change the speech signal, but some specific acoustic features remain largely unaffected (e.g., measures of voice quality) irrespective of mask type. Outcomes have bearing on how future speech studies are run when personal protective equipment is worn.

Massive Acute Spinal Subdural Hematoma Causing Sudden Onset Paraplegia in a Patient on Anticoagulation.

Spinal subdural hematoma (SSDH) is a rare but known entity that can cause severe and irreversible motor, sensory, and autonomic dysfunction if not decompressed in a timely manner. We present here a 74-year-old female on anticoagulation who developed sudden onset back pain with rapidly progressive paraplegia. On neurologic exam, she was completely flaccid in the bilateral lower extremities with absent sensation from the umbilicus down. Imaging demonstrated a massive extra-axial spinal hematoma from T12 to S1 that initially was believed to be epidural in origin. She was taken emergently to the operating room for a T11-L5 decompressive laminectomy, and dural opening demonstrated a thick subdural clot encasing the conus and cauda equina confirming the subdural pathology. Despite decompression and partial evacuation of the subdural hematoma, she did not recover neurologic function.

Management of Giant Sacral Pseudomeningocele in Revision Spine Surgery.

BACKGROUND: Giant pseudomeningoceles are an uncommon complication of spine surgery. Surgical management and extirpation can be difficult, and guidelines remain unclear. METHODS: Here, we present a 56-year-old female patient with a history of grade III L5-S1 spondylolisthesis who was treated with 2 prior spine surgeries. The patient was treated with bone grafting for pseudarthrosis and instrumentation from L4 to ilium. After unsuccessful intraoperative and postoperative cerebrospinal fluid drainage and dural repair, the patient presented to the emergency room with debilitating positional headaches. RESULTS: The patient underwent dural repair with bovine pericardial patch inlay sutured with 7-0 prolene, blood patch, and a dural sealant. Plastic surgery performed a layered closure, using acellular dermal matrix over the dural closure. The bilateral paraspinal flaps were advanced medially to cover the entirety of the acellular dermal matrix, and the fasciocutaneous flaps were then advanced to the midline for a watertight closure. At 3-month follow-up, the patient was headache free and had returned to her activities of daily living. CONCLUSIONS: We conclude that early consultation with plastic surgery can be greatly beneficial to effectively extirpate dead space and resolve giant sacral pseudomeningoceles, especially if there is concern of persistent cerebrospinal fluid leakage due to relatively immobile avascular soft tissue as a result of prior revision surgery.

Engorged venous plexus mimicking adjacent segment disease: Case report and review of the literature.

BACKGROUND: An engorged venous plexus may mimic nerve compression from a herniated disk on the magnetic resonance (MR) studies as they both have similar signal intensities. During a laminectomy, if an engorged venous plexus is encountered instead of a disk herniation, there may be marked unanticipated bleeding. CASE DESCRIPTION: A 58-year-old female who had a prior anterior lumbar interbody fusion later returned with recurrent radiculopathy. Adjacent segment disease from a spinal disk herniation was suspected based on the surgical history, physical examination, and imaging (MRI) findings. Rather than a disk, an engorged venous plexuses (EVP) was encountered intraoperatively. CONCLUSION: Here, we discussed our findings regarding a lumbar EVP rather than a herniated disk and reviewed the current literature. Although rare, a higher index of suspicion for these vascular malformations based on combined historical information and MRI studies should allow one to better detect and/or anticipate an EVP rather than a routine disk.

Associations of Alpha and Beta Interhemispheric EEG Coherences with Indices of Attentional Control and Academic Performance.

Introduction. Heretofore, research on optimizing academic performance has suffered from an inability to translate what is known about an individual's learning behaviors to how effectively they are able to use the critical nodes and hubs in their cerebral cortex for learning. A previous study from our laboratory suggests that lower theta-beta ratios (TBRs) measured by EEG may be associated with higher academic performance in a medical school curriculum. METHODS: In this study, we tested the hypothesis that TBR and academic performance may be correlated with EEG coherence, a measure of brain connectivity. We analyzed the interhemispheric coherences of the subjects involved in our prior study. TBR and coherence measurements were made at 19 scalp electrode recording sites and 171 electrode combinations with eyes open and closed (EO, EC). Control data were acquired during a session of acclimation to the research protocol 3 d before an initial examination in anatomy-physiology (control exam) and were repeated five weeks later, 3 d before a second exam covering different anatomy-physiology topics (comparison exam). RESULTS: Between the control and comparison exams, beta coherences increased significantly at the frontal pole, frontal, parietal, midtemporal, posterior temporal, and occipital recording sites under the EO condition and at the inferior frontal, central, midtemporal, and posterior temporal sites under the EC condition. Alpha coherences increased significantly at the same sites and under the same EO/EC conditions as found for the beta coherences. The beta coherences were negatively correlated with the TBR and were positively correlated with the comparison exam score at the midfrontal electrode site (F3-F4) but only under the EO condition. Beta and alpha coherences at the midfrontal, inferior frontal midtemporal, posterior temporal, and occipital sites were also negatively correlated with the average TBR under the EO condition. CONCLUSIONS: Lower TBR, an indicator of attentional control, was associated with higher alpha and beta interhemispheric coherences measured with eyes open at sites overlying the frontal, temporal, and occipital cortices. Changes in EEG coherences and TBRs might be useful as neurophysiological measures of neuroplasticity and the efficacy of strategies for preventing academic underachievement and treatments for improving academic performance.

Decompression Surgery versus Interspinous Devices for Lumbar Spinal Stenosis: A Systematic Review of the Literature.

In this retrospective review study, the authors systematically reviewed the literature to elucidate the efficacy and complications associated with decompression and interspinous devices (ISDs) used in surgeries for lumbar spinal stenosis (LSS). LSS is a debilitating condition that affects the lumbar spinal cord and spinal nerve roots. However, a comprehensive report on the relative efficacy and complication rate of ISDs as they compare to traditional decompression procedures is currently lacking. The PubMed database was queried to identify clinical studies that exclusively investigated decompression, those that exclusively investigated ISDs, and those that compared decompression with ISDs. Only prospective cohort studies, case series, and randomized controlled trials that evaluated outcomes using the Visual Analog Scale (VAS), Oswestry Disability Index, or Japanese Orthopedic Association scores were included. A random-effects model was established to assess the difference between preoperative and the 1-2-year postoperative VAS scores between ISD surgery and lumbar decompression. This study included 40 papers that matched our criteria. Twenty-five decompression-exclusive clinical trials with 3,386 patients and a mean age of 68.7 years (range, 31-88 years) reported a 2.2% incidence rate of dural tears and a 2.6% incidence rate of postoperative infections. Eight ISD-exclusive clinical trials with 1,496 patients and a mean age of 65.1 (range, 19-89 years) reported a 5.3% incidence rate of postoperative leg pain and a 3.7% incidence rate of spinous process fractures. Seven studies that compared ISDs and decompression in 624 patients found a reoperation rate of 8.3% in ISD patients vs. 3.9% in decompression patients; they also reported dural tears in 0.32% of ISD patients vs. 5.2% in decompression patients. A meta-analysis of the randomized controlled trials found that the differences in preoperative and postoperative VAS scores between the two groups were not significant. Both decompression and ISD interventions are unique surgical interventions with different therapeutic efficacies and complications. The collected studies do not consistently demonstrate superiority of either procedure over the other but understanding the differences between the two techniques can help tailor treatment regimens for patients with LSS.