Faculty Bibliography

BACKGROUND:C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS:F]-FBB identified 8 amyloid PET positive (Aβ+) and 16 Aβ- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS:LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aβ+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION/CONCLUSIONS:The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Cannabis has been used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized controlled clinical trials that led to US Food and Drug Administration approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.

The purpose of this paper is to confirm previous reports that identified magnetization transfer (MT) as an inherent driver of longitudinal relaxation in brain tissue by asserting a substantial difference between the $T_1$ relaxation times of the free and the semi-solid spin pools. Further, we aim to identify an avenue towards the quantification of these relaxation processes on a voxel-by-voxel basis in a clinical imaging setting, i.e. with a nominal resolution of 1mm isotropic and full brain coverage in 12min. To this end, we optimized a hybrid-state pulse sequence for mapping the parameters of an unconstrained MT model. We scanned 4 people with relapsing-remitting multiple sclerosis (MS) and 4 healthy controls with this pulse sequence and estimated $T_1^f \approx 1.90$s and $T_1^s \approx 0.327$s for the free and semi-solid spin pool of healthy WM, respectively, confirming previous reports and questioning the commonly used assumptions $T_1^s = T_1^f$ or $T_1^s = 1$s. Further, we estimated a fractional size of the semi-solid spin pool of $m_0^s \approx 0.202$, which is larger than previously assumed. An analysis of $T_1^f$ in normal appearing white matter revealed statistically significant differences between individuals with MS and controls. In conclusion, we confirm that longitudinal spin relaxation in brain tissue is dominated by MT and that the hybrid state facilitates a voxel-wise fit of the unconstrained MT model, which enables the analysis of subtle neurodegeneration.

Few studies examining the patient outcomes of concurrent neurological manifestations during acute COVID-19 leveraged multinational cohorts of adults and children or distinguished between central and peripheral nervous system (CNS vs. PNS) involvement. Using a federated multinational network in which local clinicians and informatics experts curated the electronic health records data, we evaluated the risk of prolonged hospitalization and mortality in hospitalized COVID-19 patients from 21 healthcare systems across 7 countries. For adults, we used a federated learning approach whereby we ran Cox proportional hazard models locally at each healthcare system and performed a meta-analysis on the aggregated results to estimate the overall risk of adverse outcomes across our geographically diverse populations. For children, we reported descriptive statistics separately due to their low frequency of neurological involvement and poor outcomes. Among the 106,229 hospitalized COVID-19 patients (104,031 patients ≥18 years; 2,198 patients <18 years, January 2020-October 2021), 15,101 (14%) had at least one CNS diagnosis, while 2,788 (3%) had at least one PNS diagnosis. After controlling for demographics and pre-existing conditions, adults with CNS involvement had longer hospital stay (11 versus 6 days) and greater risk of (Hazard Ratio = 1.78) and faster time to death (12 versus 24 days) than patients with no neurological condition (NNC) during acute COVID-19 hospitalization. Adults with PNS involvement also had longer hospital stay but lower risk of mortality than the NNC group. Although children had a low frequency of neurological involvement during COVID-19 hospitalization, a substantially higher proportion of children with CNS involvement died compared to those with NNC (6% vs 1%). Overall, patients with concurrent CNS manifestation during acute COVID-19 hospitalization faced greater risks for adverse clinical outcomes than patients without any neurological diagnosis. Our global informatics framework using a federated approach (versus a centralized data collection approach) has utility for clinical discovery beyond COVID-19.

BACKGROUND:We examined drivers of self and study partner reports of memory loss in mild cognitive impairment (MCI) from Alzheimer (AD-MCI) and vascular disease (Va-MCI). METHODS:We performed retrospective cross-sectional analyses of participants with AD-MCI (n=2874) and Va-MCI (n=376) from the National Alzheimer's Coordinating Center data set. Statistical analysis utilized 2-sided t test or the Fisher exact test. RESULTS:Compared with AD-MCI, Va-MCI subjects (24.5% vs. 19.7%, P=0.031) and study partners (31.4% vs. 21.6%, P<0.0001) were more likely to deny memory loss. Black/African Americans were disproportionately represented in the group denying memory loss in AD-MCI (20.0% vs. 13.2%, P<0.0001) and Va-MCI (33.7% vs. 18.0%, P=0.0022). Study partners of participants with these features also disproportionately denied memory loss: female (AD-MCI: 60.1% vs. 51.7%, P=0.0002; Va-MCI: 70.3% vs. 52.3%, P=0.0011), Black/African American (AD-MCI: 23.5% vs. 11.98%, P<0.0001; Va-MCI: 48.8% vs. 26.5%, P=0.0002), and <16 years of education (AD-MCI only: 33.9% vs. 16.3%, P=0.0262). In AD-MCI and Va-MCI, participants with anxiety were disproportionately represented in the group endorsing memory loss (AD: 28.2% vs. 17.4%, P<0.0001; Va: 31.5% vs. 16.1%, P=0.0071), with analogous results with depression. CONCLUSION/CONCLUSIONS:The findings would suggest extra vigilance in interview-based MCI detection of persons at-risk for self-based or informant-based misreport.

The field of epilepsy has undergone substantial advances as we develop novel drugs and devices. Yet considerable challenges remain in developing broadly effective, well-tolerated treatments, but also precision treatments for rare epilepsies and seizure-monitoring devices. We summarize major recent and ongoing innovations in diagnostic and therapeutic products presented at the seventeenth Epilepsy Therapies & Diagnostics Development (ETDD) conference, which occurred May 31 to June 2, 2023, in Aventura, Florida. Therapeutics under development are targeting genetics, ion channels and other neurotransmitters, and many other potentially first-in-class interventions such as stem cells, glycogen metabolism, cholesterol, the gut microbiome, and novel modalities for delivering electrical neuromodulation.