Faculty Bibliography

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.

BACKGROUND:Early neurological deterioration (END) and recurrence of vessel blockage frequently complicate intravenous thrombolysis (IVT) for acute ischemic stroke (AIS). Several studies have indicated the potential effectiveness of the early initiation (within < 24 h) of antiplatelet therapy (APT) after IVT. However, conflicting results have been reported by other studies. We aimed to offer a thorough overview of the current literature through a systematic review and meta-analysis. METHODS:Our systematic review and meta-analysis were prospectively registered on PROSPERO (ID: CRD42023488173) following the PRISMA guidelines. We systematically searched Web of Science, SCOPUS, PubMed, and Cochrane Library until May 5, 2024. Rayyan. ai facilitated the screening process. The R statistical programming language was used to calculate the odds ratios and conduct a meta-analysis. Our primary outcomes were excellent functional recovery (modified Rankin Scale score 0-1), symptomatic intracranial hemorrhage (sICH), and mortality. RESULTS:Eight studies involving 2,134 participants were included in the meta-analysis. Early APT showed statistically significant increased odds of excellent functional recovery (mRS 0-1) compared to the standard APT group (OR, 1.81; [95% CI: 1.10, 2.98], p = 0.02). However, we found no differences between the early and standard APT groups regarding sICH (OR, 1.74; [95% CI: 0.91, 3.33], p = 0.10) and mortality (OR, 0.88; [95% CI: 0.62, 1.24]; p = 0.47). CONCLUSION/CONCLUSIONS:Early APT within 24 h of IVT in stroke patients is safe, with no increase in bleeding risk, and has a positive effect on excellent functional recovery. However, there was a statistically insignificant trend of increased sICH with early APT, and the current evidence is based on highly heterogeneous studies. Further large-scale RCTs are warranted.

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.

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.

BACKGROUND:Spetzler-Martin (SM) Grade III brain arteriovenous malformations (BAVMs) represent a transitional risk zone between low- and high-grade BAVMs, characterized by diverse angioarchitecture. The primary treatment options are endovascular embolization, microsurgical resection (MS), and stereotactic radiosurgery (SRS). This study compares the efficacy and outcomes of MS and SRS. METHODS:We conducted a multicenter, retrospective study involving patients from the MISTA database with SM Grade III BAVMs treated with MS or SRS between 2010 and 2023. Propensity matching was based on age, favorable modified Rankin Score (mRS) at presentation, nidus size, rupture status, location depth, and eloquence. RESULTS:, p = 0.6) were similar. MS showed higher obliteration rates (93.3 %) compared to SRS (46.7 %) at the last follow-up (p < 0.001). The median time to obliteration post-SRS was 31.5 months (IQR: 15.3-60.0). SRS obliteration rates were 19 %, 29 %, and 59 % at 24, 36, and 60 months, respectively. Overall complication rates (MS: 30 % vs. SRS: 20 %, p = 0.4) and permanent complications (MS: 10 % vs. SRS: 13.3 %, p > 0.9) were similar. Hemorrhage occurred once in the MS group and none in the SRS (p > 0.9). Favorable outcomes (mRS 0-2) were higher with SRS than MS (93.3 % vs 80.0 %, p = 0.3), with one AVM-related mortality in the MS group. CONCLUSION/CONCLUSIONS:MS and SRS are viable treatments for SM Grade III BAVMs. Treatment choice should be individualized by a multidisciplinary team, considering patient goals.

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).

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:The goal of precision oncology is to find effective therapeutics for every patient. Through the inclusion of emerging therapeutics in a high-throughput drug screening platform, our functional genomics pipeline inverts the common paradigm to identify patient populations that are likely to benefit from novel therapeutic strategies. APPROACH/METHODS:Utilizing drug screening data across a panel of 46 cancer cell lines from 11 tumor lineages, we identified an ovarian cancer-specific sensitivity to the first-in-class CRL4 inhibitors KH-4-43 and 33-11. CRL4 (i.e., Cullin-4 RING E3 ubiquitin ligase) is known to be dysregulated in a variety of cancer contexts, making it an attractive therapeutic target. Unlike proteasome inhibitors that are associated with broad toxicity, CRL4 inhibition offers the potential for tumor-specific effects. RESULTS:We observed that CRL4 inhibition negatively regulates core gene signatures that are upregulated in ovarian tumors and significantly slowed tumor growth as compared to the standard of care, cisplatin, in OVCAR8 xenografts. Building on this, we performed combination drug screening in conjunction with proteomic and transcriptomic profiling to identify ways to improve the antitumor effects of CRL4 inhibition in ovarian cancer models. CRL4 inhibition consistently resulted in activation of the mitogen-activated protein kinase (MAPK) signaling cascade at both the transcriptomic and protein levels, suggesting that survival signaling is induced in response to CRL4 inhibition. These observations were concordant with the results of the combination drug screens in seven ovarian cancer cell lines that showed CRL4 inhibition cooperates with MEK inhibition. Preclinical studies in OVCAR8 and A2780 xenografts confirmed the therapeutic potential of the combination of KH-4-43 and trametinib, which extended overall survival and slowed tumor progression relative to either single agent or the standard of care. CONCLUSIONS:Together, these data demonstrate the prospective utility of functional modeling pipelines for therapeutic development and underscore the clinical potential of CRL4 inhibition in the ovarian cancer context. HIGHLIGHTS/CONCLUSIONS:A precision medicine pipeline identifies ovarian cancer sensitivity to CRL4 inhibitors. CRL4 inhibition induces activation of MAPK signalling as identified by RNA sequencing, proteomics, and phosphoproteomics. Inhibitor combinations that target both CRL4 and this CRL4 inhibitor-induced survival signalling enhance ovarian cancer sensitivity to treatment.

BACKGROUND:This study primarily aimed to explore the etiology of the phenotypic relationships between personality traits and executive functions. We assessed common genetic and environmental sources of variance in these phenomena by examining different dimensions of the Five Factor Model (FFM) and executive function factors. An additional research question focused on whether specific facets within the FFM share a greater genetic overlap with executive functions compared to broader personality dimensions. METHODS:The NEO-PI-R, the Wisconsin Card Sorting Test, the Trail Making Test, and verbal fluency tests were applied to a sample of 468 twins from the Serbian Twin Advanced Registry (153 monozygotic twin pairs). RESULTS:Several facets from all domains had significant genetic associations with executive functions, with Ideas and Values showing the highest positive correlations, and Order and Vulnerability showing the highest negative genetic correlations. Most phenotypic associations between the two domains of individual differences were almost entirely explained by shared genetic influences. CONCLUSIONS:These findings underscore the importance of examining personality traits at the facet level, as facet-level analysis provides more detailed insights into the relationship between personality and executive functions than broader personality dimensions. The results emphasize the role of shared genetic influences in shaping both personality and executive abilities, suggesting that future research should investigate the underlying neural mechanisms driving these associations.