Faculty Bibliography

Over 50% of persons living with dementia (PLWD) and their care partners (dyads) visit the emergency department (ED) every year. In the ED, healthcare professionals face complex challenges managing acute issues and symptoms of Alzheimer's disease and Alzheimer's disease-related dementias without provider training or in-ED structures to ensure a successful discharge. While many of these visits are for conditions more suitable for ambulatory care, as many as 50% of PLWD discharged from the ED return within 30 days, suggesting opportunities to improve ED care, and discharge processes. Emergency Care Redesign (ECR) includes intentional workflows where physicians, nurses, and social workers engage in a team-based approach with structured assessments to manage a myriad of potential psychosocial and behavioral issues contributing to the need for ED care. Three core components comprise this evidence-based, efficient pragmatic intervention for PLWD and their care partners: (1) problem identification, (2) problem prioritization, and (3) provision of non-pharmacologic solutions supported by community resources. Although these components are essential to provide optimal ED care and reduce revisits and other adverse outcomes, they require an embedded clinical decision support structure, focused training, and clear workflows. In this paper, we describe the ECR intervention as one of three being implemented in the cluster-randomized multifactorial pragmatic trial, Emergency Departments LEading Transformation of Alzheimer's and Dementia Care (ED-LEAD), designed to improve care for PLWD and their outcomes after discharge home within 15 health systems and 79 EDs across the United States.

Three-dimensional (3D) ex vivo imaging of cleared tissue from intact brains from animal models, human brain surgical specimens, and large postmortem human and non-human primate brain specimens is essential for understanding physiological neural connectivity and pathological alterations underlying neurological and neuropsychiatric disorders. Contemporary light-sheet microscopy enables rapid, high-resolution imaging of large, cleared samples but is limited by the orthogonal arrangement of illumination and detection optics, which constrains specimen size. Light-sheet theta microscopy (LSTM) overcomes this limitation by employing two oblique illumination paths while maintaining a perpendicular detection geometry. Here, we report the development of a next-generation, fully integrated and user-friendly LSTM system that enables uniform subcellular-resolution imaging (with subcellular resolution determined by the lateral performance of the system) throughout large specimens without constraining lateral (XY) dimensions. The system provides a seamless workflow encompassing image acquisition, data storage, pre- and post-processing, enhancement and quantitative analysis. Performance is demonstrated by high-resolution 3D imaging of intact mouse brains and human brain samples, including complete downstream analyses such as digital neuron tracing, vascular reconstruction and design-based stereological analysis. This enhanced and accessible LSTM implementation enables rapid quantitative mapping of molecular and cellular features in very large biological specimens.

OBJECTIVES/OBJECTIVE:Temporal lobe epilepsy (TLE) impacts multiple brain networks. Aberrant functional connectivity has been demonstrated in resting-state networks (RSNs) that mediate higher brain functions in TLE. This study aimed to identify the reproducible patterns of altered functional connectivity in TLE in a large, international cohort through ENIGMA-Epilepsy. METHODS:Resting-state functional MRI datasets from nine centers across North America, South America, Europe and South Africa, including 442 people with TLE and 387 healthy adults, were analyzed. We examined group differences in whole-brain connectivity in patients compared to controls in seven major RSNs. We also investigated whole-brain connectivity maps for key nodes within the default mode network (DMN). Furthermore, the associations between connectivity patterns and clinical variables were assessed. RESULTS:We found lower within-network connectivity scores (13.6% on average) and higher between-network connectivity scores (129% on average) in non-limbic RSN in TLE. This pattern was reproducible across all seven sites and most robust for DMN and visual networks. Patterns of connectivity were not associated with age of seizure onset or disease duration and were mostly similar in patients with left and right TLE with a few exceptions; isolated regions of high connectivity in left TLE and lower connectivity in right TLE compared to controls. SIGNIFICANCE/CONCLUSIONS:We show strong evidence of lower connectivity within most RSNs and higher connectivity outside of these networks that was highly consistent across geographically diverse sites, demonstrating the robustness and generalizability of our findings. The findings demonstrate a consistent disruption of network organization in TLE that may underlie cognitive co-morbidities and seizure propagation patterns observed in this patient population. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:In this international ENIGMA-Epilepsy study, resting-state fMRI data from 442 individuals with TLE showed reduced connectivity within major resting-state networks (about 14% lower) and markedly increased connectivity between networks (about 129% higher), compared to 387 healthy controls. These patterns were highly reproducible across sites. Connectivity alterations were not related to age of onset or disease duration and were largely similar across left and right TLE, aside from small, region-specific differences. Overall, the study demonstrates a robust, widespread reorganization of brain network connectivity in TLE, which may help explain associated cognitive difficulties and seizure spread.

OBJECTIVE:Cenobamate has been shown to be an effective antiseizure medication for some patients with drug-resistant focal epilepsy being considered for epilepsy surgery. This retrospective single-center study evaluated whether surgery was obtained within 12 months for patients who received cenobamate as a treatment during the presurgical evaluation and those who did not, comparing across years before and after cenobamate approval. METHODS:Patients undergoing surgical evaluation for drug-resistant focal epilepsy at the University of Colorado during 2018 and 2023 who had 12 months of follow-up data were analyzed. Comparison years were also chosen to avoid the confounding effect of the COVID-19 pandemic on surgical volume (2020-2021). This allowed for comparison times before and after cenobamate's US Food and Drug Administration approval. The primary outcome (surgery within 12 months) was modeled with potential explanatory variables using multiple logistic regression. A p-value of <.05 was considered significant. RESULTS:After controlling for potentially confounding clinical and demographic variables, cenobamate use during the presurgical evaluation period was associated with .13 lower odds of surgery within 12 months compared to not being prescribed this medication (95% confidence interval [CI] = .04-.42, p < .001). Being Hispanic or Latino was significantly associated with .23 lower odds of surgery within 12 months compared to patients who did not report being Hispanic or Latino (95% CI = .09-.61, p = .003). Year of evaluation (2023 vs. 2018), education level, age, and sex did not have significant associations with undergoing surgery within 12 months. SIGNIFICANCE/CONCLUSIONS:Patients with drug-resistant focal epilepsy undergoing evaluation for epilepsy surgery may benefit from cenobamate. In this study, patients who received cenobamate during the presurgical evaluation were less likely to undergo surgery within 12 months. The delay to surgery identified among Hispanic and Latino patients suggests potential barriers to care in this patient population warranting further investigation.

BackgroundMisalignment between actual and perceived balance ability provides relevant information to understand functional deficits and fall risk. However, few studies have provided a continuous quantification of misalignment in neurological populations such as people with Parkinson's disease (PD).ObjectiveDetermine whether a continuous quantification of misalignment between actual and perceived balance ability, discordance, relates to functional outcomes such as quality of life and cognition.MethodsActual (gait velocity), and perceived (Activities of Balance Confidence) balance, cognition (measured via a computer-based cognitive assessment), and mobility-related quality of life were captured in a clinical sample of 95 people with PD. Primary outcomes were quality of life and cognitive domains frequently altered in people with PD (global cognition & executive function). Secondary cognitive domains assessed were attention, memory, visuo-spatial, verbal function, and information processing. Linear and non-linear models assessed the relationship between discordance, quality of life, and cognition.ResultsDiscordance related to mobility-related quality of life, such that under-confidence was related to poorer quality of life. Non-linear (quadratic) models were shown to fit the discordance-Global cognition (p = 0.02) data better than linear models such that over- and under-confidence related to poorer cognition. Secondary cognitive domains were not robustly related to discordance.ConclusionsIn a clinical sample of people with PD, discordance was related to mobility-related quality of life and global cognition. Global cognition further exhibited a possible non-linear relationship to discordance indicating that over- or under-confidence may relate to poorer cognition. This work underscores the functional relevance of misalignment of actual and balance abilities.

Consumer wearable devices are commonly used by patients and consumers for several reasons with increasing application as new technologies are developed. Use of these devices is an emerging issue in Neurology because of increased adoption and the additional data reported to providers by patients. Understanding of possible functions, limitations, and effect on patients of non-US Food and Drug Administration (FDA)-cleared wearable technology to inform neurologic care is needed. A common theme in people with neurologic conditions regarding consumer wearables and associated tracking applications is that there is significant promise in these tools, but adherence (days per use/per week), continued engagement (attrition), and unintended consequences such as heightened anxiety remain important issues. Further understanding and validation of these devices is needed within the field of Neurology before full use and confidence can be achieved. Below, we provide examples of non-FDA-cleared wearable devices used in Neurology in the areas of epilepsy, headache, cardiac monitoring, and sleep.

BACKGROUND:The RESCUE-ICAS study (Registry of Emergent Large-Vessel Occlusion due to Intracranial Stenosis) demonstrated that patients undergoing acute stenting of intracranial atherosclerosis with large-vessel occlusion after mechanical thrombectomy had better outcomes than those undergoing mechanical thrombectomy alone. We present 2 secondary analyses of RESCUE-ICAS to evaluate intracranial stenting among patients who achieved successful reperfusion. METHODS:From a prospective observational cohort of 25 stroke centers (2022-2023), patients with acute intracranial occlusion, National Institutes of Health Stroke Scale score ≥6, and 50% to 99% residual stenosis or occlusion after endovascular thrombectomy were included. In the first analysis, we compared patients with stenting versus those without stenting from among those patients with a final modified Thrombolysis in Cerebral Infarction score of 2B-3. In the second analysis, we compared patients who underwent stenting with those who did not from among the patients with a Thrombolysis in Cerebral Infarction (TICI) score of 2B-3 before stenting. The odds of a favorable 90-day mRS (0-2) and 24-hour MRI infarct volume <30 mL were assessed using multivariable logistic regression. We also examined the rates of symptomatic ICH and death at 90 days in these cohorts. RESULTS:=0.480). CONCLUSIONS:Among both the cohort with final successful reperfusion and the cohort with initial successful reperfusion after mechanical thrombectomy alone, intracranial stenting was associated with better long-term clinical and radiographic outcomes, without higher morbidity and mortality. REGISTRATION/BACKGROUND:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05403593.

OBJECTIVES/OBJECTIVE:The practice of limiting life-sustaining therapy (LST) at end-of-life is widespread globally. The goal of this study was to evaluate whether patient's age influences end-of-life limitations overall and of various LST in ICUs worldwide. DESIGN/METHODS:Multinational, multicenter, prospective observational study. SETTING/METHODS:One hundred ninety-nine ICUs in 36 countries worldwide. PATIENTS/METHODS:Consecutive adult patients admitted to ICUs who died and/or had LST limitations (withholding, withdrawing, or active shortening of the dying process) were included during a 6-month period between September 2015 and September 2016. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Patients were grouped: younger than 65 years, 65-79 years old, and 80 years old or older. A total of 12,200 patients were included. In multivariate logistic regression analysis, odds ratio (OR) for any LST limitation in the 80 years old or older group was higher than in younger than the 65 years old group (OR 1.47 [95% CI, 1.22-1.76], p < 0.001). When stratified by region, this association was significant in Central and Southern Europe (OR 1.56 [95% CI, 1.11-2.20], p = 0.037 and OR 2.23 [95% CI, 1.58-3.17], p < 0.001, respectively), but not in the other regions. The proportion of withholding therapy of each LST was highest in the group of individuals 80 years or older, whereas the proportion of withdrawing therapy was highest in the group younger than 65 years. The 80-year-old or older group also had a shorter time from ICU admission to first limitation. The predominant reason for any LST limitation in all age groups was unresponsiveness to maximal therapy, followed by neurologic and chronic diseases. Patient age was rarely the primary reason for limitations for all groups. CONCLUSIONS:End-of-life limitations were higher in patients 80 years or older compared to those 65 years old or younger, with regional variations. The main reasons for limitations were comparable across age groups, with age not being the primary reason.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Severe hypoxemia after generalized convulsive seizures (GCSs) can trigger neural injury and is a potential biomarker for sudden unexpected death in epilepsy (SUDEP). Some degree of variability in interbreath interval is normal, but increased variability may suggest dysfunctional breathing control and may be associated with severe postictal hypoxemia. We evaluated the relationship between interictal breathing variability and severity and duration of hypoxemia after GCS. METHODS:nadir), and secondary outcome: occurrence of combined prolonged and pronounced hypoxemia. Univariable and multivariable models were created for primary outcomes, but only univariable analyses were performed for the secondary outcome. RESULTS:= 0.002) was the only variable significantly associated with hypoxemia severity after controlling for duration of postictal generalized EEG suppression, SD-2 of the awake interbreath interval, and body mass index. Univariable analyses for combined prolonged and pronounced hypoxemia showed SD-2 of the awake interbreath interval, temporal lobe epilepsy, ictal central apnea, and a shorter tonic phase duration were significantly associated. DISCUSSION/CONCLUSIONS:Measures of interictal respiratory variability are associated with severe and prolonged hypoxemia after GCS. Increased interictal respiratory variability suggests baseline respiratory dysregulation in some PWE and may be a surrogate for SUDEP risk.