Faculty Bibliography

INTRODUCTION/BACKGROUND:Alzheimer's disease (AD), primary age-related tauopathy (PART), and chronic traumatic encephalopathy (CTE) all feature hyperphosphorylated tau (p-tau)-immunoreactive neurofibrillary degeneration, but differ in neuroanatomical distribution and progression of neurofibrillary degeneration and amyloid beta (Aβ) deposition. METHODS:We used Nanostring GeoMx Digital Spatial Profiling to compare the expression of 70 proteins in neurofibrillary tangle (NFT)-bearing and non-NFT-bearing neurons in hippocampal CA1, CA2, and CA4 subregions and entorhinal cortex of cases with autopsy-confirmed AD (n = 8), PART (n = 7), and CTE (n = 5). RESULTS:There were numerous subregion-specific differences related to Aβ processing, autophagy/proteostasis, inflammation, gliosis, oxidative stress, neuronal/synaptic integrity, and p-tau epitopes among these different disorders. DISCUSSION/CONCLUSIONS:These results suggest that there are subregion-specific proteomic differences among the neurons of these disorders, which appear to be influenced to a large degree by the presence of hippocampal Aβ. These proteomic differences may play a role in the differing hippocampal p-tau distribution and pathogenesis of these disorders. HIGHLIGHTS/CONCLUSIONS:Alzheimer's disease neuropathologic change (ADNC), possible primary age-related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) can be differentiated based on the proteomic composition of their neurofibrillary tangle (NFT)- and non-NFT-bearing neurons. The proteome of these NFT- and non-NFT-bearing neurons is largely correlated with the presence or absence of amyloid beta (Aβ). Neurons in CTE and definite PART (Aβ-independent pathologies) share numerous proteomic similarities that distinguish them from ADNC and possible PART (Aβ-positive pathologies).

BACKGROUND/UNASSIGNED:In the DISCOMS (DISCOntinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS)) randomized clinical trial, we could not demonstrate that discontinuing MS DMTs in older, stable adults was not inferior to continuing DMTs. Relapses were rare in both groups, and most new disease activity was one to two new brain magnetic resonance imaging (MRI) lesions unassociated with clinical changes. OBJECTIVE/AIMS/UNASSIGNED:Describe results of the DISCOMS extension study. METHODS/UNASSIGNED:Among 10/19 of the original sites, we enrolled patients who completed DISCOMS; did not reach the primary endpoint during the original trial; and retained original randomized assignment. Participants completed one study visit and brain MRI at least 30 months after original enrollment in DISCOMS. Primary endpoint was time from entry into the primary study to relapse or new brain MRI activity. RESULTS/UNASSIGNED:= 0.043 from log-rank test). CONCLUSIONS/UNASSIGNED:From entry into DISCOMS extension study, time to new MS activity remained shorter in discontinuers, but relapses were absent and new brain MRI lesions were rare.

Paired vagus nerve stimulation (VNS) has emerged as a promising strategy to potentiate recovery after neurological injury. This approach, which combines short bursts of electrical stimulation of the vagus nerve with rehabilitation exercises, received approval from the US Food and Drug Aministration in 2021 as the first neuromodulation-based therapy for chronic stroke. Because this treatment is increasingly implemented in clinical practice, there is a need to take stock of what we know about this approach and what we have yet to learn. Here, we provide a survey on the foundational basis of VNS therapy for stroke and offer insight into the mechanisms that underlie potentiated recovery, focusing on the principles of neuromodulatory reinforcement. We discuss the current state of observations regarding synaptic reorganization in motor networks that are enhanced by VNS, and we propose other prospective loci of neuromodulation that should be evaluated in the future. Finally, we highlight the future opportunities and challenges to be faced as this approach is increasingly translated to clinical use. Collectively, a clearer understanding of the mechanistic basis of VNS therapy may reveal ways to maximize its benefits.

OBJECTIVE:Randomized controlled trials (RCTs) are necessary to evaluate the efficacy of novel treatments for epilepsy. However, there have been concerning increases in the placebo responder rate over time. To understand these trends, we evaluated features associated with increased placebo responder rate. METHODS:Using individual-level data from 20 focal-onset seizure trials provided by seven pharmaceutical companies, we evaluated associations with change in seizure frequency in participants randomized to placebo. We used multivariable logistic regression to evaluate participant and study factors associated with differing rates of 50% reduction in seizure frequency during blinded placebo treatment, as compared to pre-randomization baseline seizure frequency. In addition, we focused on the association of placebo responder rate with pre-randomization baseline seizure frequency and country of recruitment. RESULTS:). In addition, there was a significantly higher 50RR in participants with a baseline seizure frequency of six or fewer seizures per 28 days (29% vs 21%, p = .00018). SIGNIFICANCE/CONCLUSIONS:These results can assist future RCTs in estimating the expected placebo responder rate, which may lead to more reliable power estimates. Higher placebo responder rate was associated with markers of less-refractory epilepsy. There were concerning significant differences in placebo responder rate by country and geographic region as well as an elevated placebo responder rate in participants with baseline seizure frequency close to the minimum eligibility criteria.

OBJECTIVE:This study examines the American Headache Society First Contact-Headache in Primary Care program metrics to date in order to assess the program's reach and provide direction for future initiatives. BACKGROUND:Approximately 4 million primary care office visits annually are headache-specific encounters. Therefore, it is important that primary care providers are knowledgeable about headache management. Recognizing the need, the American Headache Society First Contact designed the comprehensive First Contact-Headache in Primary Care program with input from an advisory board comprised of a diverse group of physicians and advanced practice providers with backgrounds in family and internal medicine, pediatrics, obstetrics and gynecology, and neurology. This is the first study to assess the reach of the program and critically examine how to best meet the needs of clinicians and patients going forward. METHODS:We report descriptive statistics for the First Contact website metrics from October 2020 to June 2023 and grand rounds program data from May 2020 to December 2023. We also conducted a cross-sectional analysis of survey data from presentations conducted at two large national family medicine symposia, as well as a thematic analysis of the question: "Please indicate what areas of your practice could be enhanced or improved with additional education?" RESULTS:The First Contact program homepage was the second most visited page on the American Headache Society website (>100,000 views). A total of 20 podcast episodes were created for the program (>3500 plays). The First Contact program held 99 events (72 institutional grand rounds, 22 State-level meetings, and five national meetings), reaching >7000 clinicians. The institutional grand rounds and state-level meetings were held across 27 States and Washington D.C. Only 31.9% (30/94) of First Contact program events (excluding national meetings) occurred in the West census region, which has the fewest headache subspecialists and lowest headache subspecialist density in the United States. When examining survey data of participants who attended the two virtual national family medicine symposia (39.3% response rate, N = 636/1620), 85.7% (544/635) reported being "completely confident" or "very confident" in their ability to recognize and accurately diagnose patients presenting with a primary complaint of headache and 81.5% (517/634) reported being "completely confident" or "very confident" in their ability to develop evidence-based treatment plans that are tailored to the needs of individual patients. The use of diagnostic tools to recognize patients with migraine (60.4%, 384/636) and translating standards of care to the practice setting (42.5%, 270/636) were the most reported intended changes by participants. Most participants reported that program content was of clinical relevance and would improve their patients' outcomes (90.5% [571/631] and 90.6% [572/631], respectively). Over three-quarters (77.8%, 495/636) of participants reported areas of their practice that can be improved by additional education specifically regarding workflow, diagnosis, and management. CONCLUSION/CONCLUSIONS:This study evaluates one of the first national initiatives for primary care education. Data from the two First Contact Family Medicine national symposia indicate the program is generally well received with most participants reporting improved confidence and intention to implement key changes in practice to improve care for patients with headache; however, there remain areas of exploration for education that could further enhance participant experience and expand the reach of the initiatives. Areas for future programming include continued education on multifactorial approaches to headache treatment and suggestions for addressing cost, insurance, and time constraints. Also, future work may examine where the First Contact program might focus initiatives based on specific areas of need in headache care, such as geographic "desert" areas, racial and ethnic disparities, and uninsured/underinsured populations.

The α-synuclein seed amplification assay (αSyn-SAA) sensitively detects Lewy pathology, the amyloid state of α-synuclein, in the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD). The αSyn-SAA harnesses the physics of seeding, whereby a superconcentrated solution of recombinant α-synuclein lowers the thermodynamic threshold (nucleation barrier) for aggregated α-synuclein to act as a nucleation catalyst ("seed") to trigger the precipitation (nucleation) of monomeric α-synuclein into pathology. This laboratory setup increases the signal for identifying a catalyst if one is present in the tissue examined. The result is binary: positive, meaning precipitation occurred, and a catalyst is present, or negative, meaning no precipitation, therefore no catalyst. Since protein precipitation via seeding can only occur at a concentration many-fold higher than the human brain, laboratory-elicited seeding does not mean human brain seeding. We suggest that a positive αSyn-SAA reveals the presence of pathological α-synuclein but not the underlying etiology for the precipitation of monomeric α-synuclein into its pathological form. Thus, a positive αSyn-SAA supports a clinical diagnosis of PD but cannot inform disease pathogenesis, ascertain severity, predict the rate of progression, define biology or biological subtypes, or monitor treatment response.

BACKGROUND:α-Synuclein seed amplification assay on cerebrospinal fluid (CSF-αSyn-SAA) has shown high accuracy for Parkinson's disease (PD) diagnosis. The analysis of CSF-αSyn-SAA parameters may provide useful insight to dissect the heterogeneity of synucleinopathies. OBJECTIVE:To assess differences in CSF-αSyn-SAA amplification parameters in participants with PD stratified by rapid eye movement (REM) sleep behavior disorder (RBD), dysautonomia, GBA, and LRRK2 variants. METHODS:(T50), time to threshold (TTT), slope, and area under the curve (AUC). Sporadic PD (n = 371) was stratified according to RBD and dysautonomia (DysA) symptoms. Genetic PD included carriers of pathogenic variants of GBA (GBA-PD, n = 52) and LRRK2 (LRRK2-PD, n = 124) gene. RESULTS:CSF-αSyn-SAA was positive in 77% of LRRK2-PD, 92.3% of GBA-PD, and 93.8% of sporadic PD. The LRRK2-PD cohort showed longer T50 and TTT, and smaller AUC than GBA-PD (P = 0.029, P = 0.029, P = 0.016, respectively) and sporadic PD (P = 0.034, P = 0.033, P = 0.014, respectively). In the sporadic cohort, CSF-αSyn-SAA parameters were similar between PD with (n = 157) and without (n = 190) RBD, whereas participants with DysA (n = 193) presented shorter T50 (P = 0.026) and larger AUC (P = 0.029) than those without (n = 150). CONCLUSION/CONCLUSIONS:CSF-αSyn-SAA parameters vary across genetic and non-genetic PD subtypes at the group level. These differences are mostly driven by the presence of LRRK2 variants and DysA. Significant overlaps in the amplification parameter values exist between groups and limit their use at the individual level. Further studies are necessary to understand the mechanisms of CSF-αSyn-SAA parameter differences. © 2024 International Parkinson and Movement Disorder Society.

Cerebral accumulation of alpha-synuclein (αSyn) aggregates is the hallmark event in a group of neurodegenerative diseases-collectively called synucleinopathies-which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Currently, these are diagnosed by their clinical symptoms and definitively confirmed postmortem by the presence of αSyn deposits in the brain. Here, we summarize the drawbacks of the current clinical definition of synucleinopathies and outline the rationale for moving toward an earlier, biology-anchored definition of these disorders, with or without the presence of clinical symptoms. We underscore the utility of the αSyn seed amplification assay to detect aggregated αSyn in living patients and to differentiate between neuronal or glial αSyn pathology. We anticipate that a biological definition of synucleinopathies, if well-integrated with the current clinical classifications, will enable further understanding of the disease pathogenesis and contribute to the development of effective, disease-modifying therapies.