Faculty Bibliography
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Department/Unit:Neurology
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24301
Author Correction: Federated learning enables big data for rare cancer boundary detection
PMID: 36702828
ISSN: 2041-1723
CID: 5426632
Exploring the combined effects of sleep apnea and APOE-e4 on biomarkers of Alzheimer's disease
Objective: We determined the interactive associations of apolipoprotein e4 (APOE-e4), and obstructive sleep apnea (OSA) on biomarkers of Alzheimer's disease and examined for racial/ethnic differences of this association. Methods: We used data from the National Alzheimer's Coordinating Center Uniform Dataset (NACC UDS). All participants undergo annual observations, including demographic survey, battery of neuropsychological tests, blood draw (with genotyping), and a clinical evaluation with medical and cognitive/dementia status assessment, while a subset of participants have cerebrospinal fluid (CSF) biomarkers and neuroimaging data. Biomarkers of AD were characterized as the presence of abnormally low amyloid in CSF, via validated Aβ42 cut off protocols, and total segmented hippocampal volume, and volume of white matter hyper intensities (WMH). While clinical markers (to preview cognitive relationships) were characterized via the Montreal Cognitive Assessment (MOCA). Results: Biomarker and clinical marker data were derived from 1,387 participants at baseline (mean age = 69.73 � 8.32; 58.6% female; 13.7% Black/African American), 18.4% of the sample had sleep apnea, and 37.9% were APOE-e4 carriers. Our results confirmed previous reports that OSA and APOE-e4 were independently associated with AD through abnormal levels of amyloid (F(1,306) = 4.27; p = 0.040; F(1,285) = 60.88; p < 0.000, respectively), WMH volume (F(1,306) = 4.27; p = 0.040; F(1,285) = 60.88; p < 0.000, respectively), and MOCA scores (F(1,306) = 4.27; p = 0.040; F(1,285) = 60.88; p < 0.000, respectively). No significant interaction between OSA and APOE-e4 relative to amyloid emerged, however, race stratified analyses indicated the interaction of OSA and APOE-e4 and was significantly associated with WMH and hippocampal volume in Black/African American, but not white participants. Conclusion: OSA and APOE-e4 are interactively associated with WHM in Black/African Americans. This interaction may partially explicate increased levels of risk in this population.
SCOPUS:85146747048
ISSN: 1663-4365
CID: 5423842
Why are spine surgeons sued, and with what outcomes?
Background: Why are spine surgeons sued, how successfully, and for how much? Typical bases for spinal medicolegal suits have included; the failure to timely diagnose and treat, surgical negligence, (i.e. especially resulting in significant neurological deficits), and the lack of informed consent. We reviewed 17 medicolegal spinal articles looking for additional reasons for suits, along with identifying other factors contributing to defense verdicts, plaintiffs' verdicts, or settlements. Methods: After confirming the same three most likely causes of medicolegal suits, other factors leading to such suits included; the lack of patient access to surgeons postoperatively, poor postoperative management (i.e. contributing to new postoperative neurological deficits), failure to communicate between specialists/surgeons perioperatively, and failure to brace. Results: Critical factors leading to more plaintiffs' verdicts and settlements along with higher payouts for both included new severe and/or catastrophic postoperative neurological deficits. Conversely, defense verdicts were more likely for those with less severe new and/or residual injuries. The total number of plaintiffs' verdicts ranged from 17-35.2%, settlements, from 8.3-37%, and defense verdicts from 27.7-75%. Conclusion: The three most frequent bases for spinal medicolegal suits continue to include; failure to timely diagnose/treat, surgical negligence, and lack of informed consent. Here, we identified the following additional causes of such suits; the lack of patient access to surgeons perioperatively, poor postoperative management, lack of specialist/surgeon communication, and failure to brace. Further, more plaintiffs' verdicts or settlements and greater respective payouts were observed for those with new and/or more severe/catastrophic deficits, while more defense verdicts were typically rendered for patients with lesser new neurological injuries.
SCOPUS:85147964251
ISSN: 2152-7806
CID: 5425642
Gastrointestinal bleeding in children with familial dysautonomia: a case-control study
OBJECTIVE:Familial dysautonomia (FD) is a rare inherited autosomal recessive disorder with abnormal somatosensory, enteric, and afferent autonomic neurons. We aimed to define the incidence of gastrointestinal bleeding and its associated risk factors in patients with FD. METHODS:In this retrospective case-control study, we identified all episodes of gastrointestinal bleeding in patients with FD, occurring over four decades (January 1980-December 2017), using the New York University FD registry. RESULTS:We identified 104 episodes of gastrointestinal bleeding occurring in 60 patients with FD. The estimated incidence rate of gastrointestinal bleeds in the FD population rate was 4.20 episodes per 1000 person-years. We compared the 60 cases with 94 age-matched controls. Bleeding in the upper gastrointestinal tract from gastric and duodenal ulcers occurred most frequently (64 bleeds, 75.6%). Patients were more likely to have a gastrostomy (G)-tube and a Nissen fundoplication [odds ratio (OR) 3.73, 95% confidence interval (CI) 1.303-13.565] than controls. The mean time from G-tube placement to first gastrointestinal bleed was 7.01 years. The mean time from Nissen fundoplication to bleed was 7.01 years. Cases and controls had similar frequency of intake of nonsteroidal antiinflammatory drugs (NSAID) and selective serotonin reuptake inhibitors (SSRI). CONCLUSION/CONCLUSIONS:The incidence of gastrointestinal bleeding in the pediatric FD population was estimated to be 4.20 per 1000 person-years, 21 times higher than in the general pediatric population (0.2 per 1000 person-years). Patients with FD with a G-tube and a Nissen fundoplication had a higher risk of a subsequent gastrointestinal bleeding.
PMID: 36735101
ISSN: 1619-1560
CID: 5426782
Correction to: Improvements in Cognitive Processing Speed, Disability, and Patient‑Reported Outcomes in Patients with Early Relapsing‑Remitting Multiple Sclerosis Treated with Natalizumab: Results of a 4‑year, Real‑World, Open‑Label Study
BACKGROUND:STRIVE was a prospective, 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative patients with early relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE:Study objectives examined the effects of natalizumab on cognitive processing speed, confirmed disability improvement (CDI), and patient-reported outcomes (PROs). METHODS:Clinical and PRO secondary endpoints were assessed annually over 4 years in STRIVE. The Symbol Digit Modalities Test (SDMT) was used as a measure of cognitive processing speed. PROs were assessed using the Multiple Sclerosis Impact Score (MSIS-29) and the Work Productivity and Activity Impairment Questionnaire (WPAI). RESULTS:At all four annual assessments, the proportion of patients in the intent-to-treat (ITT) population (N = 222) who exhibited clinically meaningful improvement in their SDMT score from baseline (i.e., change ≥ 4 points) ranged from 41.9 to 54.0%. The cumulative probability of CDI at 4 years in patients in the ITT population with a baseline Expanded Disability Status Scale score ≥ 2 (N = 133) was 43.9%. Statistically significant reductions in the mean change from screening in the MSIS-29 physical and psychological scores, indicating improved quality of life, were observed over all 4 years (P ≤ 0.0012 for all). A statistically significant decrease from screening in the impact of MS on regular activities, signifying an improvement in this WPAI measure, was also observed over all 4 years of the study. CONCLUSION/CONCLUSIONS:These results further extend our knowledge of the effectiveness, specifically regarding improvements in cognitive processing speed, disability and PROs, of long-term natalizumab treatment in early RRMS patients. CLINICALTRIALS/RESULTS:GOV: NCT01485003 (5 December 2011).
PMID: 36780107
ISSN: 1179-1934
CID: 5427042
Neural stem cells and oligodendrocyte progenitor cells compete for remyelination in the corpus callosum
A major therapeutic goal in demyelinating diseases, such as Multiple Sclerosis, is to improve remyelination, thereby restoring effective axon conduction and preventing neurodegeneration. In the adult central nervous system (CNS), parenchymal oligodendrocyte progenitor cells (pOPCs) and, to a lesser extent, pre-existing oligodendrocytes (OLs) and oligodendrocytes generated from neural stem cells (NSCs) in the sub-ventricular zone (SVZ) are capable of forming new myelin sheaths. Due to their self-renewal capabilities and the ability of their progeny to migrate widely within the CNS, NSCs represent an additional source of remyelinating cells that may be targeted to supplement repair by pOPCs. However, in demyelinating disorders and disease models, the NSC contribution to myelin repair is modest and most evident in regions close to the SVZ. We hypothesized that NSC-derived cells may compete with OPCs to remyelinate the same axons, with pOPCs serving as the primary remyelinating cells due to their widespread distribution within the adult CNS, thereby limiting the contribution of NSC-progeny. Here, we have used a dual reporter, genetic fate mapping strategy, to characterize the contribution of pOPCs and NSC-derived OLs to remyelination after cuprizone-induced demyelination. We confirmed that, while pOPCs are the main remyelinating cells in the corpus callosum, NSC-derived cells are also activated and recruited to demyelinating lesions. Blocking pOPC differentiation genetically, resulted in a significant increase in the recruitment NSC-derived cells into the demyelinated corpus callosum and their differentiation into OLs. These results strongly suggest that pOPCs and NSC-progeny compete to repair white matter lesions. They underscore the potential significance of targeting NSCs to improve repair when the contribution of pOPCs is insufficient to affect full remyelination.
SCOPUS:85147662714
ISSN: 1662-5102
CID: 5424962
Risk of sudden unexpected death in epilepsy (SUDEP) with lamotrigine and other sodium channel-modulating antiseizure medications
OBJECTIVE:In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti-seizure medication (NaM-ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. METHODS:This retrospective, nested case-control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM-ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. RESULTS:Proportions of cases and controls prescribed lamotrigine (P = 0.166), one NaM-ASM (P = 0.80), or ≥2NaM-ASMs (P = 0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR] = 0.56; P = 0.054), one NaM-ASM (aHR = 0.8; P = 0.588) or ≥2 NaM-ASMs (aHR = 0.49; P = 0.139) at EMU admission were not at increased SUDEP risk up to 16 years following admission. Active tonic-clonic seizures at EMU admission associated with >2-fold SUDEP risk, irrespective of lamotrigine (aHR = 2.24; P = 0.031) or NaM-ASM use (aHR = 2.25; P = 0.029). Sensitivity analyses accounting for incomplete ASM data at follow-up suggest undetected changes to ASM use are unlikely to alter our results. SIGNIFICANCE/CONCLUSIONS:This study provides additional evidence that lamotrigine and other NaM-ASMs are unlikely to be associated with an increased long-term risk of SUDEP, up to 16 years post-EMU admission.
PMID: 36648376
ISSN: 2470-9239
CID: 5426352
An adversarial collaboration protocol for testing contrasting predictions of global neuronal workspace and integrated information theory
The relationship between conscious experience and brain activity has intrigued scientists and philosophers for centuries. In the last decades, several theories have suggested different accounts for these relationships. These theories have developed in parallel, with little to no cross-talk among them. To advance research on consciousness, we established an adversarial collaboration between proponents of two of the major theories in the field, Global Neuronal Workspace and Integrated Information Theory. Together, we devised and preregistered two experiments that test contrasting predictions of these theories concerning the location and timing of correlates of visual consciousness, which have been endorsed by the theories' proponents. Predicted outcomes should either support, refute, or challenge these theories. Six theory-impartial laboratories will follow the study protocol specified here, using three complementary methods: Functional Magnetic Resonance Imaging (fMRI), Magneto-Electroencephalography (M-EEG), and intracranial electroencephalography (iEEG). The study protocol will include built-in replications, both between labs and within datasets. Through this ambitious undertaking, we hope to provide decisive evidence in favor or against the two theories and clarify the footprints of conscious visual perception in the human brain, while also providing an innovative model of large-scale, collaborative, and open science practice.
PMCID:9916582
PMID: 36763595
ISSN: 1932-6203
CID: 5426982
Replicability of proton MR spectroscopic imaging findings in mild traumatic brain injury: Implications for clinical applications
PURPOSE/OBJECTIVE:H MRS) offers biomarkers of metabolic damage after mild traumatic brain injury (mTBI), but a lack of replicability studies hampers clinical translation. In a conceptual replication study design, the results reported in four previous publications were used as the hypotheses (H1-H7), specifically: abnormalities in patients are diffuse (H1), confined to white matter (WM) (H2), comprise low N-acetyl-aspartate (NAA) levels and normal choline (Cho), creatine (Cr) and myo-inositol (mI) (H3), and correlate with clinical outcome (H4); additionally, a lack of findings in regional subcortical WM (H5) and deep gray matter (GM) structures (H6), except for higher mI in patients' putamen (H7). METHODS:26 mTBI patients (20 female, age 36.5 ± 12.5 [mean ± standard deviation] years), within two months from injury and 21 age-, sex-, and education-matched healthy controls were scanned at 3 Tesla with 3D echo-planar spectroscopic imaging. To test H1-H3, global analysis using linear regression was used to obtain metabolite levels of GM and WM in each brain lobe. For H4, patients were stratified into non-recovered and recovered subgroups using the Glasgow Outcome Scale Extended. To test H5-H7, regional analysis using spectral averaging estimated metabolite levels in four GM and six WM structures segmented from T1-weighted MRI. The Mann-Whitney U test and weighted least squares analysis of covariance were used to examine mean group differences in metabolite levels between all patients and all controls (H1-H3, H5-H7), and between recovered and non-recovered patients and their respectively matched controls (H4). Replicability was defined as the support or failure to support the null hypotheses in accordance with the content of H1-H7, and was further evaluated using percent differences, coefficients of variation, and effect size (Cohen's d). RESULTS:Patients' occipital lobe WM Cho and Cr levels were 6.0% and 4.6% higher than controls', respectively (Cho, d = 0.37, p = 0.04; Cr, d = 0.63, p = 0.03). The same findings, i.e., higher patients' occipital lobe WM Cho and Cr (both p = 0.01), but with larger percent differences (Cho, 8.6%; Cr, 6.3%) and effect sizes (Cho, d = 0.52; Cr, d = 0.88) were found in the comparison of non-recovered patients to their matched controls. For the lobar WM Cho and Cr comparisons without statistical significance (frontal, parietal, temporal), unidirectional effect sizes were observed (Cho, d = 0.07 - 0.37; Cr, d = 0.27 - 0.63). No differences were found in any metabolite in any lobe in the comparison between recovered patients and their matched controls. In the regional analyses, no differences in metabolite levels were found in any GM or WM region, but all WM regions (posterior, frontal, corona radiata, and the genu, body, and splenium of the corpus callosum) exhibited unidirectional effect sizes for Cho and Cr (Cho, d = 0.03 - 0.34; Cr, d = 0.16 - 0.51). CONCLUSIONS:H MRS biomarkers for mTBI may best be achieved by using high signal-to-noise-ratio single-voxels placed anywhere within WM. The biochemical signature of the injury, however, may differ and therefore absolute levels, rather than ratios may be preferred. Future replication efforts should further test the generalizability of these findings.
PMCID:9898311
PMID: 36724732
ISSN: 2213-1582
CID: 5426722
Enhanced cognitive interference during visuomotor tasks may cause eye-hand dyscoordination
In complex visuomotor tasks, such as cooking, people make many saccades to continuously search for items before and during reaching movements. These tasks require cognitive resources, such as short-term memory and task-switching. Cognitive load may impact limb motor performance by increasing demands on mental processes, but mechanisms remain unclear. The Trail-Making Tests, in which participants sequentially search for and make reaching movements to 25 targets, consist of a simple numeric variant (Trails-A) and a cognitively challenging variant that requires alphanumeric switching (Trails-B). We have previously shown that stroke survivors and age-matched controls make many more saccades in Trails-B, and those increases in saccades are associated with decreases in speed and smoothness of reaching movements. However, it remains unclear how patients with neurological injuries, e.g., stroke, manage progressive increases in cognitive load during visuomotor tasks, such as the Trail-Making Tests. As Trails-B trial progresses, switching between numbers and letters leads to progressive increases in cognitive load. Here, we show that stroke survivors with damage to frontoparietal areas and age-matched controls made more saccades and had longer fixations as they progressed through the 25 alphanumeric targets in Trails-B. Furthermore, when stroke survivors made saccades during reaching movements in Trails-B, their movement speed slowed down significantly. Thus, damage to frontoparietal areas serving cognitive motor functions may cause interference between oculomotor, visual, and limb motor functions, which could lead to significant disruptions in activities of daily living. These findings augment our understanding of the mechanisms that underpin cognitive-motor interference during complex visuomotor tasks.
PMID: 36625969
ISSN: 1432-1106
CID: 5419032
