Faculty Bibliography

INTRODUCTION/BACKGROUND:Alzheimer's disease (AD) and primary age-related tauopathy (PART) both harbor 3R/4R hyperphosphorylated-tau (p-tau)-positive neurofibrillary tangles (NFTs) but differ in the spatial p-tau development in the hippocampus. METHODS:Using Nanostring GeoMx Digital Spatial Profiling, we compared protein expression within hippocampal subregions in NFT-bearing and non-NFT-bearing neurons in AD (n = 7) and PART (n = 7) subjects. RESULTS:Proteomic measures of synaptic health were inversely correlated with the subregional p-tau burden in AD and PART, and there were numerous differences in proteins involved in proteostasis, amyloid beta (Aβ) processing, inflammation, microglia, oxidative stress, and neuronal/synaptic health between AD and PART and between definite PART and possible PART. DISCUSSION/CONCLUSIONS:These results suggest subfield-specific proteome differences that may explain some of the differences in Aβ and p-tau distribution and apparent pathogenicity. In addition, hippocampal neurons in possible PART may have more in common with AD than with definite PART, highlighting the importance of Aβ in the pathologic process. HIGHLIGHTS/CONCLUSIONS:Synaptic health is inversely correlated with local p-tau burden. The proteome of NFT- and non-NFT-bearing neurons is influenced by the presence of Aβ in the hippocampus. Neurons in possible PART cases share more proteomic similarities with neurons in ADNC than they do with neurons in definite PART cases.

BACKGROUND:Middle meningeal artery (MMA) embolization is a promising intervention as a stand-alone or adjunct treatment to surgery in patients with chronic subdural hematomas. There are currently no large animal models for selective access and embolization of the MMA for preclinical evaluation of this endovascular modality. Our objective was to introduce a novel in vivo model of selective MMA embolization in swine. METHODS:Diagnostic cerebral angiography with selective microcatheter catheterization into the MMA was performed under general anesthesia in five swine. Anatomical variants in arterial meningeal supply were examined. In two animals, subsequent embolization of the MMA with a liquid embolic agent (Onyx-18) was performed, followed by brain tissue harvest and histological analysis. RESULTS:The MMA was consistently localized as a branch of the internal maxillary artery just distal to the origin of the ascending pharyngeal artery. Additional meningeal supply was observed from the external ophthalmic artery, although not present consistently. MMA embolization with Onyx was technically successful and feasible. Histological analysis showed Onyx material within the MMA lumen. CONCLUSIONS:Microcatheter access into the MMA in swine with liquid embolic agent delivery represents a reproducible model of MMA embolization. Anatomical variations in the distribution of arterial supply to the meninges exist. This model has a potential application for comparing therapeutic effects of various embolic agents in a preclinical setting that closely resembles the MMA embolization procedure in humans.

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.

Guidelines for brain death/death by neurologic criteria (BD/DNC) determination were revised to provide a consistent and updated approach to BD/DNC evaluation across all ages by the American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and Society of Critical Care Medicine. This article is intended to complement the guidelines and highlight aspects relevant to the critical care community; the actual guidelines should be used to update hospital protocols and dictate clinical practice. Because BD/DNC evaluations are conducted in the ICU, it is essential for members of the critical care community to familiarize themselves with these guidelines. The fundamental concept of BD/DNC has not changed; BD/DNC is permanent loss of function of the brain as a whole, including the brain stem, resulting in coma, brainstem areflexia, and apnea in the setting of an adequate stimulus. The BD/DNC evaluation requires a sufficient observation period to ensure there is no chance of recovery, followed by exclusion of potentially confounding conditions like hypothermia, hypotension, severe metabolic disturbances, or medication effects. Specific guidance is provided for patients who were treated with therapeutic hypothermia or medical or surgical interventions to manage intracranial hypertension. The guidelines outline a structured and meticulous neurologic examination and detail the responses consistent with BD/DNC. A protocol is provided for how to safely perform apnea testing, including modifications needed for patients on extracorporeal membrane oxygenation. Controversial issues such as consent, BD/DNC evaluation in pregnancy, preservation of neuroendocrine function, and primary posterior fossa injuries are addressed. The ultimate goal is to ensure a consistent and accurate approach to BD/DNC evaluation in patients of all ages, fostering public trust in the medical community's ability to determine death. By adhering to these guidelines, critical care clinicians can confidently navigate the challenging aspects of BD/DNC determination.

Biofeedback has Grade A evidence for the treatment of migraine, yet few studies have examined the factors associated with patients' decisions to pursue biofeedback treatment recommendations. We sought to examine reasons for adherence or non-adherence to referral to biofeedback therapy as treatment for migraine. Patients with migraine who had been referred for biofeedback by a headache specialist/behavioral neurologist were interviewed in person or via Webex. Patients completed an enrollment questionnaire addressing demographics and questions related to their headache histories. At one month, patients were sent a follow-up questionnaire via REDCap and asked if they had pursued the recommendation for biofeedback therapy, their reasons for their decision, and their impressions about biofeedback for those who pursued it. Nearly two-thirds (65%; 33/51) of patients responded at one month. Of these, fewer than half (45%, 15/33) had contacted biofeedback providers, and only 18% (6/33) completed a biofeedback session. Common themes emerged for patients who did not pursue biofeedback, including feeling that they did not have time, concern for financial obstacles (e.g., treatment cost and/or insurance coverage), and having difficulty scheduling an appointment due to limited provider availability. When asked about their preference between type of biofeedback provider (e.g., a physical therapist or psychologist), qualitative responses were mixed; many patients indicated no preference as long as they took insurance and/or were experienced, while others indicated a specific preference for a physical therapist or psychologist due to familiarity, or prior experiences with that kind of provider. Patients with migraine referred for biofeedback therapy face numerous obstacles to pursuing treatment.

OBJECTIVE:The aim of this study was to evaluate the diagnostic accuracy of common interview questions used to distinguish a diagnosis of epilepsy from seizure mimics including non-epileptic seizures (NES), migraine, and syncope. METHODS:200 outpatients were recruited with an established diagnosis of focal epilepsy (n = 50), NES (n = 50), migraine (n = 50), and syncope (n = 50). Patients completed an eight-item, yes-or-no online questionnaire about symptoms related to their events. Sensitivity and specificity were calculated. Using a weighted scoring for the questions alone with baseline characteristics, the overall questionnaire was tested for diagnostic accuracy. RESULTS:Of individual questions, the most sensitive one asked if events are sudden in onset (98 % sensitive for epilepsy (95 % CI: 89 %, 100 %)). The least sensitive question asked if events are stereotyped (46 % sensitive for epilepsy (95 % CI: 32 %, 60 %)). Overall, three of the eight questions showed an association with epilepsy as opposed to mimics. These included questions about "sudden onset" (OR 10.76, 95 % CI: (1.66, 449.21) p = 0.0047), "duration < 5 min" (OR 3.34, 95 % CI: (1.62, 6.89), p = 0.0008), and "duration not > 30 min" (OR 4.44, 95 % CI: (1.94, 11.05), p = <0.0001). When individual seizure mimics were compared to epilepsy, differences in responses were most notable between the epilepsy and migraine patients. Syncope and NES were most similar in responses to epilepsy. The overall weighted questionnaire incorporating patient age and sex produced an area under the ROC curve of 0.80 (95 % CI: 0.74, 0.87)). CONCLUSION/CONCLUSIONS:In this study, we examined the ability of common interview questions used by physicians to distinguish between epilepsy and prevalent epilepsy mimics, specifically NES, migraines, and syncope. Using a weighted scoring system for questions, and including age and sex, produced a sensitive and specific predictive model for the diagnosis of epilepsy. In contrast to many prior studies which evaluated either a large number of questions or used methods with difficult practical application, our study is unique in that we tested a small number of easy-to-understand "yes" or "no" questions that can be implemented in most clinical settings by non-specialists.

PURPOSE/OBJECTIVE:Validated measures capable of demonstrating meaningful interventional change in the CDKL5 deficiency disorder (CDD) are lacking. The study objective was to modify the Rett Syndrome Gross Motor Scale (RSGMS) and evaluate its psychometric properties for individuals with CDD. METHODS:Item and scoring categories of the RSGMS were modified. Caregivers registered with the International CDKL5 Clinical Research Network uploaded motor videos filmed at home to a protected server and completed a feedback questionnaire (n = 70). Rasch (n = 137), known groups (n = 109), and intra- and inter-rater reliability analyses (n = 50) were conducted. RESULTS:The age of individuals with CDD ranged from 1.5 to 34.1 years. The modified scale, Gross Motor-Complex Disability (GM-CD), comprised 17 items. There were no floor or ceiling effects and inter- and intra-rater reliability were good. Rasch analysis demonstrated that the items encompassed a large range of performance difficulty, although there was some item redundancy and some disordered categories. One item, Prone Head Position, was a poor fit. Caregiver-reported acceptability was positive. Scores differed by age and functional abilities. SUMMARY/CONCLUSIONS:GM-CD appears to be a suitable remotely administered measure and psychometrically sound for individuals with CDD. This study provides the foundation to propose the use of GM-CD in CDD clinical trials. Longitudinal evaluation is planned.

BACKGROUND:Although racial and ethnic differences in CPAP adherence for OSA are widely established, no studies have examined the influence of perceived racial discrimination on CPAP usage, to our knowledge. RESEARCH QUESTION/OBJECTIVE:(1) Do Black adults with OSA report experiencing greater amounts of discrimination than non-Hispanic White adults? (2) Is discrimination associated with poorer CPAP adherence over time, independent of self-identified race? (3) Does discrimination mediate the relationship between self-identified Black race and CPAP usage? STUDY DESIGN AND METHODS/METHODS:/Fisher exact test, as appropriate. A linear regression model was completed with self-identified Black race and EDS total score as the primary independent variables of interest and mean daily CPAP usage at 30 and 90 days serving as the dependent outcomes. This regression modeling was repeated after adjusting for psychosocial variables known to be associated with CPAP usage. EDS total score was explored as a potential mediator of the association between self-identified Black race and mean daily CPAP adherence at 30 and 90 days. RESULTS:The sample for this analysis consisted of 78 participants (31% female, 38% Black) with a mean age of 57 ± 14 years. Sixty percent of the Black adults reported they experienced racial discrimination at least a few times each year. Relative to White adults, Black adults were also more likely to indicate more than one reason for discrimination (27% vs 4%, P = .003). Adjusting for discrimination, self-identified Black race was associated with 1.4 (95% CI, -2.3 to -0.4 h; P = .006) and 1.6 (95% CI, -2.6 to -0.6 h; P = .003) fewer hours of mean daily CPAP usage at 30 and 90 days, respectively. In the fully adjusted model, a 1-unit change in the total discrimination score (more discrimination) was associated with a 0.08-h (95% CI, 0.01-0.15 h; P = .029) and 0.08-h (95% CI, 0.01-0.16 h; P = .045) change in mean daily CPAP usage at 30 and 90 days, respectively. INTERPRETATION/CONCLUSIONS:Adults with OSA who encountered racial discrimination experienced greater decrement in CPAP usage than those who did not experience racial discrimination.

BACKGROUND:There is practice heterogeneity in the use, type, and duration of prophylactic antiseizure medications (ASMs) in patients with moderate-severe traumatic brain injury (TBI). METHODS:We conducted a systematic review and meta-analysis of articles assessing ASM prophylaxis in adults with moderate-severe TBI (acute radiographic findings and requiring hospitalization). The population, intervention, comparator, and outcome (PICO) questions were as follows: (1) Should ASM versus no ASM be used in patients with moderate-severe TBI and no history of clinical or electrographic seizures? (2) If an ASM is used, should levetiracetam (LEV) or phenytoin/fosphenytoin (PHT/fPHT) be preferentially used? (3) If an ASM is used, should a long versus short (> 7 vs. ≤ 7 days) duration of prophylaxis be used? The main outcomes were early seizure, late seizure, adverse events, mortality, and functional outcomes. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to generate recommendations. RESULTS:The initial literature search yielded 1998 articles, of which 33 formed the basis of the recommendations: PICO 1: We did not detect any significant positive or negative effect of ASM compared to no ASM on the outcomes of early seizure, late seizure, adverse events, or mortality. PICO 2: We did not detect any significant positive or negative effect of PHT/fPHT compared to LEV for early seizures or mortality, though point estimates suggest fewer late seizures and fewer adverse events with LEV. PICO 3: There were no significant differences in early or late seizures with longer versus shorter ASM use, though cognitive outcomes and adverse events appear worse with protracted use. CONCLUSIONS:Based on GRADE criteria, we suggest that ASM or no ASM may be used in patients hospitalized with moderate-severe TBI (weak recommendation, low quality of evidence). If used, we suggest LEV over PHT/fPHT (weak recommendation, very low quality of evidence) for a short duration (≤ 7 days, weak recommendation, low quality of evidence).