Faculty Bibliography
Searched for:
Department/Unit:Neurology
Total Results:
24330
Disease detection and classification in temporal lobe epilepsy: step-wise versus simultaneous AI decision models in a multisite neuroimaging study
Diagnostic MRI evaluation of temporal lobe epilepsy (TLE) depends on the subjective visual interpretation of MRI images. These interpretations could be enhanced by quantitative artificial intelligence (AI) support tools. Humans often make sequential and conditional decisions during their radiological interpretations, such as whether an abnormality is present and, if present, characterizing the abnormality. It is not known whether it is superior to train AI to treat every decision separately in a similar step-wise manner or to train a model holistically on all decisions simultaneously. Here, we analysed three large epilepsy MRI datasets [n = 3676, 2320 people with epilepsy and 1356 healthy controls (HC)] to perform two tasks: (i) establish the presence of a TLE pattern on MRI and (ii) determine TLE pattern lateralization. We compared Step-wise models that independently classify TLE versus HC and lateralize patients as left TLE (L-TLE) or right TLE (R-TLE), against a simultaneous model trained to distinguish all three classes in a single step. To do this, 3D volumetric T1-weighted images were input into an EfficientNetV2 model multiple times to ensure reproducibility of results. Class prediction, model classification confidence and saliency maps were output for interpretability. Step-wise models outperformed the Simultaneous model on both tasks (both Ps < 0.001), with an average ∼2.8% accuracy increase for discriminating HC from TLE and an average 12.7% accuracy increase for distinguishing L-TLE from R-TLE. For both the Step-wise and Simultaneous models, important features discriminating TLE from HC included the known TLE limbic pattern involving the hippocampus, parahippocampal cortical regions, cingulate cortex and lateral temporal regions. However, there was less concordance between the Step-wise and Simultaneous models for the L-TLE versus R-TLE task (all Fisher's Zs > 10.5, Ps < 0.001); the Step-wise model focused less on subcortical regions such as the thalamus and hippocampus and focused more on distributed cortical pathology. Across the two Step-wise models, 95.1% of TLE patients had accurate classifications in either HC versus TLE and/or L-TLE versus R-TLE tasks. These results included 69.6% of patients being both correctly labelled as TLE and lateralized, 13.9% being correctly labelled TLE but lateralized incorrectly and 11.6% being lateralized correctly but not detected as TLE. These findings provide evidence that diagnostic tasks with simpler, Step-wise AI models may enhance diagnostic performance and interpretability in clinical workflows. Future AI clinical support tools can leverage this step-wise approach in the early identification of TLE-related structural patterns, supporting timely diagnosis and treatment decisions.
PMCID:13421366
PMID: 42534493
ISSN: 2632-1297
CID: 6070473
Integrated Interactomics Reveals Novel Protein Associations: The FOXA1-PBX1 Complex as a Case Study
Protein-protein interactions (PPIs) are fundamental to cellular signaling networks, yet many remain undetected due to technical limitations of individual affinity purification approaches. To address this, we systematically mapped the interaction landscapes of six regulatory proteins involved in cell proliferation, immunity, and inflammation, including three transcription factors (TFs) and three kinases. We implemented an integrated proteomics workflow that combined four complementary affinity purification strategies: native immunoprecipitation, two crosslinking-assisted capture methods, and proximity labeling. Combining these approaches revealed distinct yet overlapping interaction profiles, uncovered numerous previously unreported interactors not reliably detected by individual methods, and robustly recovered known interactions while substantially extending PPI networks. Despite method-specific differences at the protein level, functional enrichment analyses showed strong convergence on coherent biological pathways. Biochemical approaches validated most of the previously unreported interactions, including putative weak and transient complexes stabilized by crosslinking. Functional assays revealed a previously unrecognized physical interaction between FOXA1 and PBX1 TFs and demonstrated their cooperative regulation of transcriptional programs and cell fitness in estrogen receptor (ER) positive breast cells. We propose that the FOXA1-PBX1 complex could represent a higher-order regulatory node integrating chromatin accessibility and ER-driven transcriptional output.
PMCID:13404648
PMID: 42523200
ISSN: 2692-8205
CID: 6070441
Perceived comfort with migraine treatments and control of migraine symptoms: Results from the Headache Assessment via Digital Platform in United States study
OBJECTIVE:This study was conducted to identify patient characteristics and medication factors associated with perceived comfort with migraine treatments and control of migraine symptoms. BACKGROUND:Patient perceptions of migraine treatment influence adherence and outcomes, yet little is known about their underlying drivers. Our study objective was to identify clinical features of migraine associated with comfort and perceived control of symptoms, and medication classes associated with higher patient comfort and efficacy. METHODS:Participants in the Headache Assessment via Digital Platform in United States (HeAD-US) study completed a cross-sectional survey on demographics, migraine burden, mood, disability, and medication use between September and November 2023. Comfort and control were defined using corresponding items from the Migraine Treatment Optimization Questionnaire and categorized as "high" or "low." We compared patient characteristics, clinical features, and medication classes by reported comfort and control. RESULTS:Among 5717 participants (mean age, 41.7 ± 13.0 years; 92.1% female), 58.5% reported high comfort with migraine treatments, whereas only 27.5% reported high control of migraine symptoms. High comfort was associated with fewer monthly headache days (mean, 9.9 vs. 14.2; p < 0.001), lower migraine symptom severity (median Migraine Symptom Severity Score 18 vs. 19; p < 0.001), and lower disability (Migraine Disability Assessment Score, severe: 72.7% vs. 91.2%; p < 0.001) and mood symptom scores (Patient Health Questionnaire-4 severe: 9.5% vs. 21.0%; p < 0.001), as well as income, education, and employment status. High perceived control showed similar associations with monthly headache days (mean, 9.0 vs. 12.7; p < 0.001), migraine severity (median Migraine Symptom Severity Score, 18 vs. 19; p < 0.001), disability (severe: 66.0 vs. 85.8; p < 0.001), and mood symptoms (severe: 7.6 vs. 16.9; p < 0.001), and was associated with employment status but not income or education. Among those on monotherapy, gepants and triptans were associated with higher comfort and efficacy than over the counter medications or opioids/barbiturates/ergots. For preventive therapy, β blockers and botulinum toxin were associated with the lowest perceived comfort and efficacy. CONCLUSION/CONCLUSIONS:Perceived comfort and control were linked to headache frequency, severity and disability, and mood symptoms. Medication class use influenced perceptions, with gepants and triptans rated most favorably. These findings underscore the importance of incorporating patient perspectives into treatment planning, with particular attention to mood, disability, and choice of medication.
PMID: 42517716
ISSN: 1526-4610
CID: 6070410
Rethinking Lipid Burden and the Role of Non-LDL Biomarkers in Stroke Risk Stratification
PURPOSE OF REVIEW/OBJECTIVE:This article reviews the existing literature on non-LDL biomarkers in atherosclerotic cardiovascular disease (ACSVD), atherogenesis, and ischemic stroke risk, including a discussion of potential future applications for secondary prevention of stroke. RECENT FINDINGS/RESULTS:Although foundational studies established the strong link between elevated low-density lipoprotein-cholesterol (LDL-C) with the development of atherosclerosis and increased cardiovascular risk, a growing number of recent studies have shown that more precise cerebrovascular disease (CVD) risk stratification can be achieved by using other components of the traditional lipid panel along with additional lipoprotein assays. The specific relationship between these non-traditional markers of atherosclerosis and ischemic stroke risk remains incompletely defined. Lipid measures beyond LDL-C including updated interpretations of the standard lipid panel, such as the triglyceride-to-high density lipoprotein ratio (TG:HDL) as well as testing for lipoprotein (a) (Lp(a)) and apolipoprotein B (ApoB), play a important respective roles in estimating metabolic health as well as atherogenic particle burden. These measures should therefore be considered in the context of stroke risk assessment, monitoring, and secondary prevention.
PMID: 42501146
ISSN: 1534-6242
CID: 6070546
Convulsions, Palsy, and the Spanish Inquisition: Neurologic Cases in an Overlooked Historical Archive [Historical Article]
A largely unrecognized feature of the Spanish Inquisition (1478-1834) was the mandatory medical evaluation of all defendants, generating a vast archive of clinical documentation that remains almost entirely unexplored by historians of neurology. The institutional need to distinguish genuine illness from malingering and demonic affliction prompted physicians to evaluate neurologic conditions including convulsions, palsy, and behavioral changes. Drawing on published scholarship and targeted searches of the Spanish national archives, we identified over 80 cases related to neurology and neuropsychiatric content. In this article, we analyze 7 of them, for illustrative purposes, involving convulsions (termed aferecía or gota coral), palsy and paralysis (perlesía), and miscellaneous brain pathology (leso de la cabeza, cerebro débil y flaco), documented between 1562 and 1700. These records reveal a tripartite diagnostic framework (physician, surgeon, and exorcist) that evolved over 2 centuries and often favored naturalistic medical explanations. Cases analyzed include the convulsive episodes of King Carlos II, whose symptoms the Suprema (the supreme governing body of the Inquisition) ruled to be natural disease rather than bewitchment, and the case of Fray Mateo de la Puebla, who was absolved on neurologic grounds after his behavioral changes were attributed to acquired CNS disease. The Inquisition archives merit further investigation as a potential source for the history of clinical neurology in the early modern period.
PMID: 42479990
ISSN: 1526-632x
CID: 6070528
Global Burden of Elevated LDL-C: Findings From the Global Burden of Disease Study 2023
IMPORTANCE/UNASSIGNED:Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C-related burden is critical for guiding prevention and treatment strategies. OBJECTIVES/UNASSIGNED:To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. DESIGN, SETTING, AND POPULATION/UNASSIGNED:This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. EXPOSURE/UNASSIGNED:Population-level LDL-C concentrations. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C-attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. RESULTS/UNASSIGNED:In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C-attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.
PMID: 42525403
ISSN: 1538-3598
CID: 6070510
Proteomic comparison of hippocampal neurofibrillary tangles in PART, intermediate Alzheimer's disease and advanced Alzheimer's disease
Alzheimer's disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the hippocampal formation is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as "primary age-related tauopathy" (PART). Here, we applied an unbiased proteomic approach to determine how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by dissecting Tau pSer202/pThr205 "AT8" immunopositive neuronal profiles, combining chromogenic immunohistochemistry with laser capture microdissection, from hippocampal sections of 17 post-mortem brains spanning three groups: PART (n = 5; A0, B1-2, C0 scores), intermediate AD (n = 6; A1-2, B2-3, C1-2 scores) and advanced AD (n = 6; A3, B3, C3 scores). A label-free quantitative liquid chromatography-mass spectrometry based proteomic analysis, using data independent acquisition (DIA) on a Bruker timsTOF, was performed. A conserved core of 63 proteins was identified as enriched in tangles across all groups, mostly associated with "RNA binding" and "regulation of mRNA metabolic process", based on the Gene Ontology database. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to "structural molecule activity", whereas Aβ-positive cases showed specific enrichment of "RNA binding" and "cytoplasmic translation" pathways-with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.
PMID: 42542447
ISSN: 1432-0533
CID: 6070502
Predictive acoustical processing in human cortical layers
In our dynamic environments, predictive processing is vital for auditory perception and its associated behaviors. Predictive coding formalizes inferential processes by implementing them as information exchange across cortical layers and areas. With laminar-specific blood oxygenation level-dependent imaging we measured responses to a cascading oddball paradigm, to ground predictive auditory processes on the mesoscopic human cortical architecture. Using a modeling approach, we derive putative changes in neural dynamics while accounting for draining effects. We show that the violations of predictions are potentially hierarchically organized and associated with responses in superficial layers of the planum polare and middle layers of the lateral temporal cortex. Moreover, we relate the updating of the brain's internal model to changes in deep layers. Our results support the role of temporal cortical architecture in the implementation of predictive coding and highlight the ability of laminar fMRI to investigate mesoscopic processes in a large extent of temporal areas.
PMID: 42191715
ISSN: 2041-1723
CID: 6070515
Beyond Anakinra and Tocilizumab: Additional Adjunctive Therapies in Pediatric New Onset Refractory Status Epilepticus and Febrile Infection-Related Epilepsy Syndrome - A Narrative Review
New onset refractory status epilepticus and febrile infection-related epilepsy syndrome are rare and devastating entities in the pediatric population. While no known therapies have formally been established as the "gold standard" for management of the acute phase, consensus guidelines do establish interleukin therapies such as anakinra and tocilizumab as safe and effective second-line immunotherapeutic options. Despite the use of interleukin therapies, many patients continue to have super refractory status epilepticus. A number of publications (mainly case reports and case series) have described various adjunctive therapies in the management of new onset refractory status epilepticus/febrile infection-related epilepsy syndrome, including neuromodulatory therapies (such as vagal nerve stimulation, deep brain stimulation, and electroconvulsive therapy), surgical resection, noninterleukin immunotherapies (such as intrathecal dexamethasone, intravenous rituximab, and cyclophosphamide), infusions (such as lidocaine and magnesium), and anesthetic agents (such as sevoflurane). Utilizing a modified Preferred Reporting Items for Systematic reviews and Meta-Analyses approach, this narrative review summarizes the effectiveness and safety of second-line immunotherapies such as tocilizumab and anakinra, as well as the various adjunctive third-line therapies that aim to abort seizures and mitigate comorbidities within an intensive care setting, such as prolonged sedation and secondary systemic complications.
PMID: 41265024
ISSN: 1873-5150
CID: 6070578
Late-window reperfusion in imaging-selected ischemic stroke: interpreting thrombolysis and mechanical thrombectomy trials
Mechanical thrombectomy (MT) is superior to medical therapy for anterior circulation proximal large-vessel occlusion (LVO) stroke, including in imaging-selected patients treated 6 to 24 h after their last known well (LKW) time. Beyond 4.5 h, the role of intravenous thrombolysis (IVT) has become more relevant because many health systems lack the ability to provide timely thrombectomy access for eligible late-window patients. Recent late-window IVT trials, including TRACE-III and HOPE, have demonstrated benefit in imaging-selected patients in whom thrombectomy was not planned or not effectively deliverable, addressing a critical systems-of-care gap. We review these trials alongside emerging evidence and situate each within a systems-of-care framework, distinguishing bridging scenarios from settings where MT is unavailable or substantially delayed. However, we argue that their results should not be taken to imply therapeutic equivalence with MT, a comparison that is misleading on methodological grounds. No randomized, head-to-head late-window trial of IVT versus MT exists. Comparing treated-arm outcomes across these separate trials as a proxy for therapeutic equivalence is vulnerable to differences in baseline prognosis, occlusion site, imaging selection, access to rescue therapy, and control-group outcomes. In this Perspective, we argue that these trials should be read one at a time. Each treated arm should be judged against its own control group and against the clinical and angiographic profile of the patients enrolled, not against treated arms from trials that enrolled very different strokes.
PMCID:13407094
PMID: 42523499
ISSN: 1664-2295
CID: 6070444
