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Regulation of poly(ADP-ribose) (PAR) synthesis and turnover is critical to determining cell fate after genotoxic stress. Hyperactivation of PAR synthesis by poly(ADP-ribose) polymerase-1 (PARP-1) occurs when cells deficient in DNA repair are exposed to genotoxic agents; however, the function of this hyperactivation has not been adequately explained. Here, we examine PAR synthesis in mouse fibroblasts deficient in the base excision repair enzyme DNA polymerase β (pol β). The extent and duration of PARP-1 activation was measured after exposure to either the DNA alkylating agent, methyl methanesulfonate (MMS), or to low energy laser-induced DNA damage. There was strong DNA damage-induced hyperactivation of PARP-1 in pol β nullcells, but not in wild-type cells. In the case of MMS treatment, PAR synthesis did not lead to cell death in the pol β null cells, but instead resulted in increased PARylation of the nonhomologous end-joining (NHEJ) protein Ku70 and increased association of Ku70 with PARP-1. Inhibition of the NHEJ factor DNA-PK, under conditions of MMS-induced PARP-1 hyperactivation, enhanced necrotic cell death. These data suggest that PARP-1 hyperactivation is a protective mechanism triggering the classical-NHEJ DNA repair pathway when the primary alkylated base damage repair pathway is compromised.

Base excision repair (BER) is a DNA repair pathway designed to correct small base lesions in genomic DNA. While DNA polymerase beta (pol beta) is known to be the main polymerase in the BER pathway, various studies have implicated other DNA polymerases in back-up roles. One such polymerase, DNA polymerase lambda (pol lambda), was shown to be important in BER of oxidative DNA damage. To further explore roles of the X-family DNA polymerases lambda and beta in BER, we prepared a mouse embryonic fibroblast cell line with deletions in the genes for both pol beta and pol lambda. Neutral red viability assays demonstrated that pol lambda and pol beta double null cells were hypersensitive to alkylating and oxidizing DNA damaging agents. In vitro BER assays revealed a modest contribution of pol lambda to single-nucleotide BER of base lesions. Additionally, using co-immunoprecipitation experiments with purified enzymes and whole cell extracts, we found that both pol lambda and pol beta interact with the upstream DNA glycosylases for repair of alkylated and oxidized DNA bases. Such interactions could be important in coordinating roles of these polymerases during BER.

Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an artificial intelligence (AI) model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a microaveraged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the microaveraged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in clinical settings and drug trials. Further prospective studies are needed to confirm its ability to improve patient care., (© 2024. The Author(s).)

Background: Increasing incidence of idiopathic intracranial hypertension (IIH), overreported radiologic signs of intracranial hypertension, difficult access to outpatient neuro-ophthalmology services, poor insurance coverage, and medicolegal concerns have lowered the threshold for emergency department (ED) visits for "papilledema." Our objective was to examine referral patterns and outcomes of neuro-ophthalmology ED and inpatient consultations for concern for papilledema., Methods: At one university-based quaternary care center, all adults referred for "papilledema" over one year underwent a standardized ED "papilledema protocol." We collected patient demographics, final diagnoses, and referral patterns., Results: Over 1 year, 153 consecutive patients were referred for concern for papilledema. After papilledema protocol, 89 of 153 patients (58%) had bilateral optic disc edema, among whom 89% (79/89) had papilledema (intracranial hypertension). Of the 38 of 153 (25%) consultations for suspected disorder of intracranial pressure without previous fundus examination (Group 1), 74% (28/38) did not have optic disc edema, 21% (8/38) had papilledema, and 5% (2/38) had other causes of bilateral disc edema. Of the 89 of 153 (58%) consultations for presumed papilledema seen on fundus examination (Group 2), 58% (66/89) had confirmed papilledema, 17% (15/89) had pseudopapilledema, and 9% (8/89) had other causes of bilateral optic disc edema. Of the 26 of 153 (17%) patients with known IIH (Group 3), 5 had papilledema and 4 required urgent intervention. The most common diagnosis was IIH (58/79). Compared with IIH, patients with secondary causes of intracranial hypertension were older (P = 0.002), men (P < 0.001), not obese (P < 0.001), and more likely to have neurologic symptoms (P = 0.002)., Conclusion: Inpatient and ED consultations for "papilledema" are increasing. Of the 153 ED and inpatient neuro-ophthalmology consultations seen for "papilledema" over 1 year, one-third of patients with optic disc edema of unknown cause before presentation to our ED had new vision- or life-threatening disease, supporting the need for prompt identification and evaluation of optic disc edema in the ED. In the face of limited access to neuro-ophthalmologists, this study supports the need for emergency department access to expert eye-care evaluation or ocular fundus camera for prompt identification of optic disc edema and standardized evaluation for neurologic emergencies., Competing Interests: V. Biousse is a consultant for GenSight Biologics and Neurophoenix and receives research support from GenSight Biologics. N. J. Newman is a consultant for GenSight Biologics, Chiesi, Stoke, Neurophth, Avidity and Neurophoenix; receives research support from GenSight Biologics and Santhera/Chiesi; is a participant in educational webinars sponsored by WebMD-Global Medscape and First Class. The remaining authors report no conflicts of interest., (Copyright © 2024 North American Neuro-Ophthalmology Society.)

Purpose of Review: In this review, we will describe current methods for visual field testing in neuro-ophthalmic clinical practice and research, develop terminology that accurately describes patterns of field deficits, and discuss recent advances such as augmented or virtual reality-based perimetry and the use of artificial intelligence in visual field interpretation., Recent Findings: New testing strategies that reduce testing times, improve patient comfort, and increase sensitivity for detecting small central or paracentral scotomas have been developed for static automated perimetry. Various forms of machine learning-based tools such as archetypal analysis are being tested to quantitatively depict and monitor visual field abnormalities in optic neuropathies. Studies show that the combined use of optical coherence tomography and standard automated perimetry to determine the structure-function relationship improves clinical care in neuro-ophthalmic disorders. Visual field assessment must be performed in all patients with neuro-ophthalmic disorders affecting the afferent visual pathway. Quantitative visual field analysis using standard automated perimetry is critical in initial diagnosis, monitoring disease progression, and guidance of therapeutic plans. Visual field defects can adversely impact activities of daily living such as reading, navigation, and driving and thus impact quality of life. Visual field testing can direct appropriate occupational low vision rehabilitation in affected individuals., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To describe the clinical characteristics, outcomes, and management of a large cohort of patients with concomitant malignant arterial hypertension and intracranial hypertension., Methods: Design: Retrospective case series., Subjects: Patients aged ≥ 18 years with bilateral optic disc oedema (ODE), malignant arterial hypertension and intracranial hypertension at five academic institutions. Patient demographics, clinical characteristics, diagnostic studies, and management were collected., Results: Nineteen patients (58% female, 63% Black) were included. Median age was 35 years; body mass index (BMI) was 30 kg/m 2 . Fourteen (74%) patients had pre-existing hypertension. The most common presenting symptom was blurred vision (89%). Median blood pressure (BP) was 220 mmHg systolic (IQR 199-231.5 mmHg) and 130 mmHg diastolic (IQR 116-136 mmHg) mmHg), and median lumbar puncture opening pressure was 36.5 cmH 2 O. All patients received treatment for arterial hypertension. Seventeen (89%) patients received medical treatment for raised intracranial pressure, while six (30%) patients underwent a surgical intervention. There was significant improvement in ODE, peripapillary retinal nerve fibre layer thickness, and visual field in the worst eye (p < 0.05). Considering the worst eye, 9 (47%) presented with acuity ≥ 20/25, while 5 (26%) presented with ≤ 20/200. Overall, 7 patients maintained ≥ 20/25 acuity or better, 6 demonstrated improvement, and 5 demonstrated worsening., Conclusions: Papilloedema and malignant arterial hypertension can occur simultaneously with potentially greater risk for severe visual loss. Clinicians should consider a workup for papilloedema among patients with significantly elevated blood pressure and bilateral optic disc oedema., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Purpose: Prompt neuro-ophthalmology consultation prevents diagnostic errors and improves patient outcomes. The scarcity of neuro-ophthalmologists means that the increasing outpatient demand cannot be met, prompting many emergency department (ED) referrals by non-neuro-ophthalmologists. We describe our quaternary care institution's ED and inpatient neuro-ophthalmology consultation patterns and patient outcomes., Design: Prospective observational study., Participants: Consecutive neuro-ophthalmology ED and inpatient consultation requests over 1 year., Methods: We collected patient demographics, distance traveled, insurance status, referring provider details, consultation question, final diagnosis, complexity of consultation, time of consultation, and need for outpatient follow-up., Main Outcome Measures: Consultation patterns and diagnoses, complexity, and follow-up., Results: Of 494 consecutive adult ED and inpatient neuro-ophthalmology consultations requested over 1 year, 241 of 494 consultations (49%) occurred at night or during weekends. Of ED consultations (322 of 494 [65%]), 127 of 322 consultations (39%) occurred during weekdays, 126 of 322 consultations (39%) occurred on weeknights, and 69 of 322 consultations (22%) occurred on weekends or holidays. Of 322 ED consultations, 225 of 322 consultations (70%) were patients who initially sought treatment in the ED with a neuro-ophthalmic chief symptom. Of the 196 patients sent to the ED by a health care professional, 148 patients (148/196 [76%]) were referred by eye care specialists (74 optometrists and 74 ophthalmologists). The most common ED referral questions were for papilledema (75 of 322 [23%]) and vision loss (72 of 322 [22%]). A total of 219 of 322 patients (68%) received a final active neuro-ophthalmic diagnosis, 222 of 322 patients (69%) were cases of high or very high complexity, and 143 of 322 patients (44%) required admission. Inpatient consultations (n = 172) were requested most frequently by hospitalists, including neurologists (71 of 172 [41%]) and oncologists (20 of 172 [12%]) for vision loss (43 of 172 [25%]) and eye movement disorders (36 of 172 [21%]) and by neurosurgeons (58 of 172 [33%]) for examination for mass or a preoperative evaluation (19 of 172 [11%]). An active neuro-ophthalmic diagnosis was confirmed in 67% of patients (116 of 172). Outpatient neuro-ophthalmology follow-up was required for 291 of 494 patients (59%)., Conclusions: Neuro-ophthalmology consultations are critical to the diagnosis and management in the hospital setting. In the face of a critical shortage of neuro-ophthalmologists, this study highlights the need for technological and diagnostic aids for greater outpatient access., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Visual snow (VS) is a rare but distressing phenomenon of persistent granular or pixelated visual distortions that may occur in isolation or as a component of visual snow syndrome (VSS). The current understanding of VS pathogenesis, including the role of retinal involvement structurally and functionally, is limited. The objective of this study is to investigate retinal structural and electrophysiological abnormalities in VS., Methods: This retrospective case series included 8 subjects (7 with VSS and 1 with isolated VS). Patients with other ocular and neurologic diseases were excluded. Data were assessed from automated perimetry, optical coherence tomography (OCT), visual evoked potential (VEP), and full-field electroretinography (ffERG) testing. The VEP and ffERG data of visual snow subjects were compared with age- and sex-matched control subjects for statistical significance., Results: The mean age of the cohort was 29.4 years (SD = ±5.3) with 50% gender split. The mean age of VS onset was 24.2 years (SD = ±3.8). All subjects had normal visual acuity, color vision, brain MRI, automated perimetry, OCT parameters (peripapillary retinal nerve fiber layer and macular ganglion cell layer thickness), and P100 and N135 wave pattern on VEP. Compared with controls, VS subjects had a greater mean b-wave amplitude in response to light-adapted 3.0 stimuli ( t test; P = 0.035 right eye and P = 0.072 left eye), greater mean light-adapted 3.0 flicker amplitude ( t test; P = 0.028 right eye P = 0.166 left eye) and greater b-wave amplitude in response to dark-adapted 10.0 stimuli ( t test; P = 0.102 right eye; P = 0.017 left eye) on ERG., Conclusions: Patients with VS and VSS have normal retinal structure, but abnormal electrophysiology compared with control subjects. The increased b-wave and flicker amplitudes observed with ffERG suggest increased responsiveness of the rod and cone photoreceptors and may contribute to VS pathophysiology., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by North American Neuro-Ophthalmology Society.)

Background: Radiologic findings of intracranial hypertension (RAD-IH) are common in idiopathic intracranial hypertension (IIH) patients. Paralleling the increasing rates of obesity, the burden of IIH is growing. Urgent neuro-ophthalmology consultations for possible IIH in patients with incidentally detected RAD-IH are increasing, with many patients receiving unnecessary lumbar punctures (LPs) and treatments. This retrospective observational study aimed to determine the prevalence of neuro-ophthalmology consultations for RAD-IH, rate of funduscopic examination by referring providers, prevalence of papilledema, outcomes after neuro-ophthalmic evaluation, and rates of misdiagnosis., Methods: Records of 1,262 consecutive new patients seen in one neuro-ophthalmology clinic from January 2019 to January 2020 were reviewed. We identified patients who were: 1) referred with concern for IIH because of findings of RAD-IH; 2) referred for "papilledema"; 3) referred with a diagnosis of IIH; and 4) referred for spontaneous cranial cerebrospinal fluid (CSF) leaks. In addition to basic demographic profiles for all groups, detailed information was collected for patients referred solely for RAD-IH, including referral patterns, prior history of IIH, previous LPs, prior medical or surgical treatment(s), risk factors for increased intracranial pressure (ICP), presenting symptoms, radiologic features observed on neuroimaging, and final disposition. When available, the neuroimaging was reviewed by an expert neuroradiologist., Results: Of 1,262 consecutive new patients, 66 (5%) were referred specifically for RAD-IH; most referrals came from neurologists (58%); 8/66 (12%) patients had papilledema; 16/66 (24%) patients had prior LP and 13/66 (20%) were already treated based on MRI findings; and 22/66 (33%) patients had ≤2 RAD-IH. Only 34/66 (52%) of patients referred for RAD-IH had prior funduscopic examinations. We confirmed papilledema in 26/82 (32%) patients referred for "papilledema." Only 29/83 (35%) patients referred with a diagnosis of IIH had active papilledema, and 3/16 (19%) patients with spontaneous CSF leaks had papilledema. In total, 247/1,262 (20%) new patients were referred to our clinic over 1 year with concern for IIH, among whom only 66 (27%) were confirmed to have active IIH with papilledema., Conclusions: One in 5 new patient referrals seen in our neuro-ophthalmology clinic were referred because of concern for increased ICP, but only 1/4 had active papilledema. Most patients referred for isolated RAD-IH do not have papilledema, many having undergone unnecessary LPs and treatments. The burden of these "rule-out IIH" consultations is overwhelming and will only continue to increase with the concurrent rise of obesity and IIH, straining the already limited neuro-ophthalmologic resources available in the US., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by North American Neuro-Ophthalmology Society.)

Purpose of Review: The practice of neurology is undergoing a paradigm shift because of advances in the field of data science, artificial intelligence, and machine learning. To ensure a smooth transition, physicians must have the knowledge and competence to apply these technologies in clinical practice. In this review, we describe physician perception and preparedness, as well as current state for clinical applications of artificial intelligence and machine learning in neurology., Recent Findings: Digital health including artificial intelligence-based/machine learning-based technology has made significant inroads into various aspects of healthcare including neurological care. Surveys of physicians and healthcare stakeholders suggests an overall positive perception about the benefits of artificial intelligence/machine learning in clinical practice. This positive perception is tempered by concerns for lack of knowledge and limited opportunities to build competence in artificial intelligence/machine learning technology. Literature about neurologist's perception and preparedness towards artificial intelligence/machine learning-based technology is scant. There are very few opportunities for physicians particularly neurologists to learn about artificial intelligence/machine learning-based technology., Summary: Neurologists have not been surveyed about their perception and preparedness to adopt artificial intelligence/machine learning-based technology in clinical practice. We propose development of a practical artificial intelligence/machine learning curriculum to enhance neurologists' competence in these newer technologies., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Compression of the anterior visual pathways by sellar and parasellar masses can produce irreversible and devastating visual loss. Optical coherence tomography (OCT) is a noninvasive high-resolution ocular imaging modality routinely used in ophthalmology clinics for qualitative and quantitative analysis of optic nerve and retinal structures, including the retinal ganglion cells. By demonstrating structural loss of the retinal ganglion cells whose axons form the optic nerve before decussating in the optic chiasm, OCT imaging of the optic nerve and retina provides an excellent tool for detection and monitoring of compressive optic neuropathies and chiasmopathies due to sellar and parasellar masses. Recent studies have highlighted the role of OCT imaging in the diagnosis, follow-up, and prognostication of the visual outcomes in patients with chiasmal compression. OCT parameters of optic nerve and macular scans such as peripapillary retinal nerve fiber layer thickness and macular ganglion cell thickness are correlated with the degree of visual loss; additionally, OCT can detect clinically significant optic nerve and chiasmal compression before visual field loss is revealed on automated perimetry. Preoperative values of OCT optic nerve and macular parameters represent a prognostic tool for postoperative visual outcome. This review provides a qualitative analysis of the current applications of OCT imaging of the retina and optic nerve in patients with anterior visual pathway compression from sellar and parasellar masses. We also review the role of new technologies such as OCT-angiography, which could improve the prognostic ability of OCT to predict postoperative visual function., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Interior exploration using Seismic Investigations, Geodesy and Heat Transport's (InSight) seismometer package Seismic Experiment for Interior Structure (SEIS) was placed on the surface of Mars at about 1.2 m distance from the thermal properties instrument Heat flow and Physical Properties Package (HP 3 ) that includes a self-hammering probe. Recording the hammering noise with SEIS provided a unique opportunity to estimate the seismic wave velocities of the shallow regolith at the landing site. However, the value of studying the seismic signals of the hammering was only realized after critical hardware decisions were already taken. Furthermore, the design and nominal operation of both SEIS and HP 3 are nonideal for such high-resolution seismic measurements. Therefore, a series of adaptations had to be implemented to operate the self-hammering probe as a controlled seismic source and SEIS as a high-frequency seismic receiver including the design of a high-precision timing and an innovative high-frequency sampling workflow. By interpreting the first-arriving seismic waves as a P-wave and identifying first-arriving S-waves by polarization analysis, we determined effective P- and S-wave velocities of v P = 11 9 - 21 + 45  m/s and v S = 6 3 - 7 + 11  m/s, respectively, from around 2,000 hammer stroke recordings. These velocities likely represent bulk estimates for the uppermost several 10s of cm of regolith. An analysis of the P-wave incidence angles provided an independent v P / v S ratio estimate of 1.8 4 - 0.35 + 0.89 that compares well with the traveltime based estimate of 1.8 6 - 0.25 + 0.42 . The low seismic velocities are consistent with those observed for low-density unconsolidated sands and are in agreement with estimates obtained by other methods., (© 2022. The Authors.)

Worldwide, there are nearly 10 million new cases of dementia annually, of which Alzheimer's disease (AD) is the most common. New measures are needed to improve the diagnosis of individuals with cognitive impairment due to various etiologies. Here, we report a deep learning framework that accomplishes multiple diagnostic steps in successive fashion to identify persons with normal cognition (NC), mild cognitive impairment (MCI), AD, and non-AD dementias (nADD). We demonstrate a range of models capable of accepting flexible combinations of routinely collected clinical information, including demographics, medical history, neuropsychological testing, neuroimaging, and functional assessments. We then show that these frameworks compare favorably with the diagnostic accuracy of practicing neurologists and neuroradiologists. Lastly, we apply interpretability methods in computer vision to show that disease-specific patterns detected by our models track distinct patterns of degenerative changes throughout the brain and correspond closely with the presence of neuropathological lesions on autopsy. Our work demonstrates methodologies for validating computational predictions with established standards of medical diagnosis., (© 2022. The Author(s).)

Purpose: Glaucoma patients with peripheral vision loss have in the past subjectively described their field loss as 'blurred' or 'no vision compromise'. We developed an iPad app for patients to self-characterise perception within areas of glaucomatous visual field loss., Methods: Twelve glaucoma patients with visual acuity ≥20/40 in each eye, stable and reliable Humphrey Visual Field (HVF) over 2 years were enrolled. An iPad app (held at 33 cm) allowed subjects to modify 'blur' or 'dimness' to match their perception of a 2×2 m wall-mounted poster at 1 m distance. Subjects fixated at the centre of the poster (spanning 45° of field from centre). The output was degree of blur/dim: normal, mild and severe noted on the iPad image at the 54 retinal loci tested by the HVF 24-2 and was compared to threshold sensitivity values at these loci. Monocular (Right eye (OD), left eye (OS)) HVF responses were used to calculate an integrated binocular (OU) visual field index (VFI). All three data sets were analysed separately., Results: 36 HVF and iPad responses from 12 subjects (mean age 71±8.2y) were analysed. The mean VFI was 77% OD, 76% OS, 83% OU. The most common iPad response reported was normal followed by blur. No subject reported dim response. The mean HVF sensitivity threshold was significantly associated with the iPad response at the corresponding retinal loci (For OD, OS and OU, respectively (dB): normal: 23, 25, 27; mild blur: 18, 16, 22; severe blur: 9, 9, 11). On receiver operative characteristic (ROC) curve analysis, the HVF retinal sensitivity cut-off at which subjects reported blur was 23.4 OD, 23 OS and 23.3 OU (dB)., Conclusions: Glaucoma subjects self-pictorialised their field defects as blur; never dim or black. Our innovation allows translation of HVF data to quantitatively characterise visual perception in patients with glaucomatous field defects., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)