Faculty Bibliography
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school:SOM
Department/Unit:Neurology
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23001
Author Correction: Global dietary quality in 185 countries from 1990 to 2018 show wide differences by nation, age, education, and urbanicity (Nature Food, (2022), 3, 9, (694-702), 10.1038/s43016-022-00594-9)
EMBASE:2021228968
ISSN: 2662-1355
CID: 5513812
Phase II study of TAS-OX (TAS-102 and oxaliplatin) plus bevacizumab for late-line colorectal cancer [Meeting Abstract]
Background: TAS-102 (trifluridine/tipiracil) is a novel oral antimetabolite for late line metastatic colorectal cancer (CRC) approved in 2018. Many patients are treated early in their course with oxaliplatin (OX), particularly adjuvant, and may benefit from re-treatment. In this trial we combine the typical late line use of TAS with OX (BEV [bevacizumab] added at investigator discretion) with goal of improved response.
Method(s): Eligibility included measurable CRC previously treated with all approved drugs per TAS package insert (irinotecan, oxaliplatin, 5FU, anti-VEGF, anti-EGF) as appropriate, PS = 0-1, labs within usual range, neuropathy < grade 2, ability to take oral meds, appropriate contraception. If no contraindication to BEV, this could be added at patient. TAS was dosed at 35 mg/m2 days 1-5 with OX 85/m2 d1 every 14 days (and BEV 5 mg/kg, if given). All supportive care was allowed including growth factors.
Result(s): 47 patients (pts, median age 55) were enrolled in a Simon mini-max design, including 45% female, 21% black, 11% Asian, 11% Hispanic and 5% mixed. 26 pts received BEV. For the first 40 pts, 385 cycles were given (mean = 7 cycles, median 8) with 18 pts (45%) requiring dose reductions (1 dose reduction = 9 pts, 2 = 6, 3 = 3), and 9 receiving (peg)/filgrastim. Toxicities leading to SAEs included gr 3 heme (2), heart failure, abd pain/n/v (6), sepsis (2), urinary (4); and related gr 3 included one gr 3 vomiting and one gr 3 neutropenia. Independently reviewed RECIST Response (N = 32) included PR 2(6%), SD 23 (72%), PD 7 (22%). Mean TTP was 4.5 m (median 4, range 1 - 18) with 9 (28%) pts more than 6 months.
Conclusion(s): In patients with late-line CRC and candidates for TAS (trifluridine/tipiracil), treatment with TAS plus OX is both well tolerated and active. RR is higher than single agent and 78% (95% CI, 60-91%) of patients had stable disease or response, with 60% receiving 8 or more cycles. Randomized trials comparing to single agent TAS are warranted in this setting
Method(s): Eligibility included measurable CRC previously treated with all approved drugs per TAS package insert (irinotecan, oxaliplatin, 5FU, anti-VEGF, anti-EGF) as appropriate, PS = 0-1, labs within usual range, neuropathy < grade 2, ability to take oral meds, appropriate contraception. If no contraindication to BEV, this could be added at patient. TAS was dosed at 35 mg/m2 days 1-5 with OX 85/m2 d1 every 14 days (and BEV 5 mg/kg, if given). All supportive care was allowed including growth factors.
Result(s): 47 patients (pts, median age 55) were enrolled in a Simon mini-max design, including 45% female, 21% black, 11% Asian, 11% Hispanic and 5% mixed. 26 pts received BEV. For the first 40 pts, 385 cycles were given (mean = 7 cycles, median 8) with 18 pts (45%) requiring dose reductions (1 dose reduction = 9 pts, 2 = 6, 3 = 3), and 9 receiving (peg)/filgrastim. Toxicities leading to SAEs included gr 3 heme (2), heart failure, abd pain/n/v (6), sepsis (2), urinary (4); and related gr 3 included one gr 3 vomiting and one gr 3 neutropenia. Independently reviewed RECIST Response (N = 32) included PR 2(6%), SD 23 (72%), PD 7 (22%). Mean TTP was 4.5 m (median 4, range 1 - 18) with 9 (28%) pts more than 6 months.
Conclusion(s): In patients with late-line CRC and candidates for TAS (trifluridine/tipiracil), treatment with TAS plus OX is both well tolerated and active. RR is higher than single agent and 78% (95% CI, 60-91%) of patients had stable disease or response, with 60% receiving 8 or more cycles. Randomized trials comparing to single agent TAS are warranted in this setting
EMBASE:640368484
ISSN: 1527-7755
CID: 5512342
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
COVID-19 in people with neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis
PURPOSE/OBJECTIVE:People with pre-existing conditions may be more susceptible to severe COVID-19 when infected by SARS-CoV-2. The relative risk and severity of SARS-CoV-2 infection in people with rare diseases such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), or schwannomatosis (SWN) is unknown. METHODS:We investigated the proportions of people with NF1, NF2, or SWN in the National COVID Cohort Collaborative (N3C) electronic health record data set who had a positive test result for SARS-CoV-2 or COVID-19. RESULTS:The cohort sizes in N3C were 2501 (NF1), 665 (NF2), and 762 (SWN). We compared these with N3C cohorts of patients with other rare diseases (98-9844 individuals) and the general non-NF population of 5.6 million. The site- and age-adjusted proportion of people with NF1, NF2, or SWN who had a positive test result for SARS-CoV-2 or COVID-19 (collectively termed positive cases) was not significantly higher than in individuals without NF or other selected rare diseases. There were no severe outcomes reported in the NF2 or SWN cohorts. The proportion of patients experiencing severe outcomes was no greater for people with NF1 than in cohorts with other rare diseases or the general population. CONCLUSION/CONCLUSIONS:Having NF1, NF2, or SWN does not appear to increase the risk of being SARS-CoV-2 positive or of being a patient with COVID-19 or of developing severe complications from SARS-CoV-2.
PMCID:9579183
PMID: 36565307
ISSN: 1530-0366
CID: 5418922
Journal of clinical & experimental neuropsychology. 2023:45(1):1-11.DOI: 10.1080/13803395.2023.2203464
Does comorbid depression impact executive functioning (EF) in adults diagnosed with ADHD?: a comparison of EF across diagnoses in clinically-referred individuals
INTRODUCTION:Executive functioning (EF) is a salient factor in both ADHD as well as depressive disorders. However, sparse literature has examined whether depression severity impacts EF concurrently among adults with ADHD. The goal of this study was to examine differences in EF between adult patients diagnosed with ADHD and those diagnosed with a non-ADHD primary psychopathological condition, as a function of both ADHD presentation and depression severity in a diverse clinical sample. METHOD:This crosssectional study included 404 adult patients clinically referred for neuropsychological evaluation to assist with differential diagnosis and/or treatment planning related to known or suspected ADHD. Various EF tasks and a measure of depression severity were administered. One-way MANOVA analyses were conducted to compare EF performance between individuals diagnosed with ADHD or a non-ADHD primary psychopathological condition, with additional analyses examining group differences based on ADHD presentation and depression severity. Regression analyses also examined the potential contribution of depression severity to each EF measure within each group. RESULTS:No significant EF performance differences were found when comparing individuals diagnosed with ADHD and those with a non-ADHD primary psychopathological condition, nor based on ADHD presentation. When comparing across groups using cut-offs for high or low depression, only one EF measure showed significant differences between groups. Further, depression severity generally did not predict reduced EF performances with the exception of verbal fluency and working memory performances in select groups. CONCLUSIONS:This study demonstrated that individuals with ADHD generally perform comparably on EF measures regardless of the presence or absence of comorbid depression. These results suggest further examination of EF deficits when they emerge for adults with ADHD, especially beyond comorbid depression severity.
PMID: 37083506
ISSN: 1744-411x
CID: 5592332
Where's the Vision? The Importance of Visual Outcomes in Neurologic Disorders: The 2021 H. Houston Merritt Lecture
Neurologists have long-recognized the importance of the visual system in the diagnosis and monitoring of neurological disorders. This is particularly true since approximately 50% of the brain's pathways subserve afferent and efferent aspects of vision. During the past 30 years, researchers and clinicians have further refined this concept to include investigation of the visual system for patients with specific neurologic diagnoses, including multiple sclerosis (MS), concussion, Parkinson's disease (PD) and conditions along the spectrum of Alzheimer's disease (AD, mild cognitive impairment [MCI] and subjective cognitive decline [SCD]). This review, highlights the visual "toolbox" that has been developed over the past three decades and beyond to capture both structural and functional aspects of vision in neurologic disease. While the efforts to accelerate the emphasis on structure-function relationships in neurological disorders began with MS during the early 2000's, such investigations have broadened to recognize the need for outcomes of visual pathway structure, function and quality of life for clinical trials of therapies across the spectrum of neurological disorders. This review begins with a patient case study highlighting the importance utilizing the most modern technologies for visual pathway assessment, including optical coherence tomography (OCT). We emphasize that both structural and functional tools for vision testing can be used in parallel to detect what might otherwise be sub-clinical events or markers of visual and, perhaps, more global neurological, decline. Such measures will be critical as clinical trials and therapies become more available across the neurological disease spectrum.
PMID: 36522160
ISSN: 1526-632x
CID: 5382402
Author Correction: Federated learning enables big data for rare cancer boundary detection
PMID: 36702828
ISSN: 2041-1723
CID: 5426632
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
Assessment of learning and memory impairments in adults with predominately inattentive versus combined presentation attention-deficit/hyperactivity disorder
This cross-sectional study compared adults diagnosed with Attention-Deficit/Hyperactivity Disorder-Inattentive (ADHD-I) and ADHD-Combined (ADHD-C) presentations with a non-ADHD group on verbal and visual learning and delayed recall using the Rey Auditory Verbal Learning Test (RAVLT) and Brief Visuospatial Memory Test-Revised (BVMT-R), respectively. Data from 380 predominately college student adult outpatients were used, with 155 who met criteria for ADHD-I, 165 who met criteria for ADHD-C, and 60 who did not meet criteria for ADHD but were diagnosed with a primary depressive or anxiety disorder or received no diagnosis. Each patient was administered the RAVLT and BVMT-R as part of a comprehensive neuropsychological evaluation. Significant main effects of study group were found, such that patients with ADHD-C demonstrated worse learning and delayed recall of both verbal and visual information than patients with ADHD-I and the non-ADHD group. Patients with ADHD-I performed comparably to the non-ADHD group, apart from visual learning and delayed recall. Notably, more patients in the ADHD groups had possible or probable learning and memory impairment compared to the non-ADHD group. Findings were consistent with previous research indicating that those with ADHD exhibit poorer verbal and visual learning and delayed recall than those without ADHD.
PMID: 36697387
ISSN: 2327-9109
CID: 5592762
The SMN Complex at the Crossroad between RNA Metabolism and Neurodegeneration
In the cell, RNA exists and functions in a complex with RNA binding proteins (RBPs) that regulate each step of the RNA life cycle from transcription to degradation. Central to this regulation is the role of several molecular chaperones that ensure the correct interactions between RNA and proteins, while aiding the biogenesis of large RNA-protein complexes (ribonucleoproteins or RNPs). Accurate formation of RNPs is fundamentally important to cellular development and function, and its impairment often leads to disease. The survival motor neuron (SMN) protein exemplifies this biological paradigm. SMN is part of a multi-protein complex essential for the biogenesis of various RNPs that function in RNA metabolism. Mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy (SMA). A fundamental question in SMA biology is how selective motor system dysfunction results from reduced levels of the ubiquitously expressed SMN protein. Recent clarification of the central role of the SMN complex in RNA metabolism and a thorough characterization of animal models of SMA have significantly advanced our knowledge of the molecular basis of the disease. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP biogenesis. We discuss developments in our understanding of SMN activity as a molecular chaperone of RNPs and how disruption of SMN-dependent RNA pathways can contribute to the SMA phenotype.
PMCID:9917330
PMID: 36768569
ISSN: 1422-0067
CID: 5421062
