Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Disturbances in brain catecholamine activity may be associated with symptoms after exposure to repetitive head impacts (RHIs) or related chronic traumatic encephalopathy (CTE). In this article, we studied CSF catecholamines in former professional and college American football players and examined the relationship with football proxies of RHI exposure, CTE probability, cognitive performance, neuropsychiatric symptoms, and parkinsonism. METHODS:In this observational cross-sectional study, we examined male former American football players, professional ("PRO") or college ("COL") level, and asymptomatic unexposed male ("UE") individuals from the DIAGNOSE CTE Research Project. Catecholamines-norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), and dopamine (DA) and its precursor, 3,4-dihydroxyphenylalanine (l-DOPA), and metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC)-were measured in CSF with high-performance liquid chromatography and compared across groups with analysis of covariance. Multivariable linear regression models tested the relationship between CSF catecholamines and proxies of RHI exposure (e.g., total years of playing American football), factor scores for cognition, and neurobehavioral dysregulation (explosivity, emotional dyscontrol, impulsivity, affective lability), as well as depressive/anxiety symptoms, measured with the Beck Depression/Anxiety Inventories. CTE probability and parkinsonism were assessed using the National Institute of Neurological Disorders and Stroke consensus diagnostic criteria for traumatic encephalopathy syndrome (TES), and biomarkers were compared among different diagnostic groups. RESULTS:The cohort consisted of 120 former American football players (85 PRO players, 35 COL players) and 35 UE participants (age 45-75). Former players had significantly lower levels of NE (mean difference = -0.114, 95% CI -0.190 to -0.038), l-DOPA (-0.121, 95% CI -0.109 to -0.027), and DOPAC (-0.116, 95% CI -0.177 to -0.054) than UE participants. For NE and DOPAC, these overall group differences were primarily due to differences between the PRO and UE cohorts. No significant differences were found across TES-CTE probability subgroups or TES-parkinsonism diagnostic groups. Within the COL cohort, tested as post hoc analyses, higher CSF NE and l-DOPA were associated with higher neurobehavioral dysregulation factor scores, BAI total score, and worse executive functioning and processing speed. CSF DHPG and DOPAC were associated with impulsivity only in this subgroup. DISCUSSION/CONCLUSIONS:We observed reduced CSF catecholamine concentrations in former elite American football players, although the relationship with degree of RHI exposure and the clinical impact needs further study.

More than half of individuals with multiple sclerosis (MS) use cannabis, with up to 20 % at risk of cannabis use disorder (CUD). While some individuals with MS report symptom relief from cannabis use, particularly for pain, sleep, and mood, there is limited support for its evidence-based therapeutic use. In contrast, long-term use has been associated with poorer cognitive and emotional functioning, fatigue, and reduced quality of life. Although reducing or stopping cannabis use has shown benefits, there is a lack of accessible interventions. We recruited nationally for a pilot study of a remotely supervised home-based intervention to reduce cannabis use among women with MS and CUD. The trial response provided critical insights into cannabis use patterns and the significant demand for accessible, effective interventions, highlighting an urgent unmet need within the MS community.

BACKGROUND:Cerebral arteriovenous malformations (AVMs) are complex vascular lesions that pose a risk for hemorrhagic stroke. The number of draining veins has recently emerged as a significant predictor of rupture risk. This multicenter study aimed to evaluate the outcomes in adult AVM patients with single versus multiple draining veins. METHODS:We conducted a retrospective analysis of 735 AVM patients from the Multicenter International Study for Treatment of Brain AVMs (MISTA) database. Patients were categorized into single draining vein (n = 430) and multiple draining veins (n = 305) groups. Logistic and linear regression models were used to assess outcomes, adjusting for baseline characteristics, including age, rupture status, Spetzler-Martin grade, and other relevant factors. RESULTS:After adjustment, no significant differences were observed in complete AVM obliteration at last follow-up between the multiple and single draining veins groups (OR: 1.1; 95 % CI: 0.72-1.93, p = 0.49) after any treatment type. Good functional outcomes at last follow-up (mRS 0-2) were similar between the two groups (OR: 1.00; 95 % CI: 0.48-2.09, p = 0.98), as were retreatment rates (OR: 1.68; 95 % CI: 0.74-3.83, p = 0.21). Ruptured AVMs were more common in the single draining vein group (52.0 % vs. 35.4 %, p < 0.001). Patients in the multiple draining vein group had lower odds of hemorrhagic complications compared to the single vein group (OR: 0.38; 95 % CI: 0.14-1.02, p = 0.05). CONCLUSION/CONCLUSIONS:Single draining vein AVMs were more likely to present with rupture, but no significant differences in obliteration rates, functional outcomes, or retreatment rates were found between the groups after adjustment. These findings suggest that while venous drainage patterns may influence initial presentation, they do not appear to affect overall treatment success or patient prognosis after any treatment type. Further studies are needed to confirm.

Curbs serve as vital borders that delineate safe pedestrian zones from potential vehicular traffic hazards. Curbs also represent a primary spatial hazard during dynamic navigation with significant stumbling potential. Such vulnerabilities are particularly exacerbated for persons with blindness and low vision (PBLV). Accurate visual-based discrimination of curbs is paramount for assistive technologies that aid PBLV with safe navigation in urban environments. Herein, we investigate the efficacy of curb segmentation for foundation models. We introduce the largest curb segmentation dataset to date to benchmark leading foundation models. Our results show that state-of-the-art foundation models face significant challenges in curb segmentation. This is due to their low precision and recall with poor performance distinguishing curbs from curb-like objects or non-curb areas, such as sidewalks. In addition, the best-performing model averaged a 3.70-s inference time, underscoring problems in providing real-time assistance. In response, we propose solutions including filtered bounding box selections to achieve more accurate curb segmentation. Overall, despite the immediate flexibility of foundation models, their application for practical assistive technology applications still requires refinement. This research highlights the critical need for specialized datasets and tailored model training to address navigation challenges for PBLV and underscores implicit weaknesses in foundation models.

BACKGROUND AND PURPOSE/OBJECTIVE:Cerebrovascular reactivity (CVR) is a widely studied biomarker of cerebral hemodynamics, commonly used in risk stratification and treatment planning in patients with steno-occlusive disease (SOD). Conventional use relies on normalization of estimates to contralateral hemisphere reference values, which is unsuitable for bilateral or indeterminate distributions of disease. We report upon a custom data-driven approach leveraging random forest classifiers (RFc) to identify candidate voxels for normalization in order to facilitate interrogation outside conditions of known unilateral SOD MATERIALS AND METHODS: We retrospectively analyzed 16 patients with unilateral SOD who underwent acetazolamide-augmented BOLD-MRI and DSC perfusion. Three RFc models were trained using leave-one-out cross-validation (LOOCV) to identify candidate voxels brain-wide whose CVR were within 10% of the normal hemispheric median: i. all voxels; ii. gray matter only; and iii. white matter only. Model input features included time-to-maximum (Tmax), mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV) from contemporaneous DSC. The median model-predicted reference CVR (CVRref) was compared to ground-truth medians in LOOCV, and its impact on threshold-based volumetric classification of CVR reduction assessed. RESULTS:RFc models effectively predicted ground-truth CVR voxels, achieving median absolute percent differences of 12.8% (IQR: 5.0%-18.9%) using all voxels, 11.3% (IQR: 9.3%-16.1%) for gray matter, and 9.8% (IQR: 4.4%-16.9%) for white matter. Volumetric estimates of CVR reduction across thresholds for the models revealed excellent agreement between ground-truth and model estimates without statistically significant differences (p>0.01), excepting lowest white matter CVR thresholds. Model use in a small pilot deployment of bilateral SOD cases demonstrated the potential utility, enabling voxel-wise CVR assessment without reliance on contralateral reference. CONCLUSIONS:We present a novel data-driven approach for normalizing CVR maps in patients with bilateral or indeterminate SOD. Using an RFc, our method provides an individualized, brain-wide reference CVR, expanding the utility of CVR estimates beyond the typical constraints of unilateral disease, and with potential application to other, similarly constrained scenarios such as for SPECT or PET hemodynamic studies. ABBREVIATIONS/BACKGROUND:CVR = cerebrovascular reactivity; RFc = random forest classifier; SOD = steno-occlusive disease.

INTRODUCTION/BACKGROUND:This study investigates whether midlife cortisol levels predict Alzheimer's disease (AD) biomarker burden 15 years later, with particular attention to sex differences and menopausal status. METHODS:F]Flortaucipir) positron emission tomography (PET) imaging conducted 15 years later. We performed multivariable regression analyses adjusted for confounders including, apolipoprotein E4 (APOE4) status. RESULTS:Elevated midlife cortisol correlated with increased amyloid deposition, specifically in post-menopausal women, predominantly in posterior cingulate, precuneus, and frontal-lateral regions (p < 0.05). No significant associations were observed with tau burden or in males. DISCUSSION/CONCLUSIONS:These findings reveal post-menopausal women with high midlife cortisol are at increased risk of AD. Results highlight the importance of identifying early risk factors when biomarkers are detectable but cognitive impairment is absent. HIGHLIGHTS/CONCLUSIONS:High midlife cortisol is linked to increased amyloid deposition in post-menopausal women. Cortisol showed no association with tau pathology. Post-menopausal hormone changes may amplify cortisol's effects on amyloid.

Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma, where desmosomes are mutated in more than 70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations in desmosome genes is associated with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics and protein immunofluorescence suggests that these decreases in expression occur in keratinocytes in the microenvironment rather than in primary melanoma cells. In further support of a microenvironmental origin, we find that desmosome gene knockdown in keratinocytes yields markedly increased proliferation of adjacent melanoma cells in keratinocyte and melanoma cocultures. Similar increases in melanoma proliferation are observed in media preconditioned with desmosome-deficient keratinocytes. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanoma cells for neoplastic transformation.

Presence of focal to bilateral tonic-clonic seizures (FBTCS) in focal epilepsy is associated with increased morbidity and mortality. Risk factors for FBTCS are poorly understood, and little is known regarding FBTCS recurrence after treatment initiation. This study aimed to investigate factors related to FBTCS in newly diagnosed focal epilepsy and their recurrence after starting antiseizure medications (ASMs) in the Human Epilepsy Project (HEP) cohort. HEP was an international, prospective cohort study that enrolled people with newly diagnosed focal epilepsy within 4 months of treatment initiation and followed them for up to 6 years. Baseline characteristics, treatment choices, and seizure outcomes were collected. Descriptive and inferential statistical analysis was conducted to assess the differences between study participants who had FBTCS and those who never experienced FBTCS. A total of 443 participants were included in this analysis; 77% (n = 342) had FBTCS at some point prior to or within the study period. In participants with FBTCS, regardless of initial seizure type, diagnosis was mostly made after FBTCS (335/342, 98%). After treatment initiation, FBTCS did not recur in 57% (n = 194/342) of cases. A higher number of total pretreatment seizures (median = 16 vs. 11, p = .048, Mann-Whitney U-test), predominantly focal aware seizures (FAS) or focal impaired awareness seizures (FIAS; median = 15 vs. 10, p = .049, Mann Whitney U-test), was associated with no recurrence in FBTCS after treatment initiation. Of 108 participants without FBTCS prior to treatment, only seven (6%) developed FBTCS after treatment initiation. There was no significant difference in choice of initial ASM class (levetiracetam vs. sodium channel blockers) between participants who experienced FBTCS and those who did not. This study highlights the significance of FBTCS among individuals with newly diagnosed focal epilepsy. The majority of participants who experienced FBTCS were diagnosed with epilepsy after experiencing their first FBTCS despite preceding FAS/FIAS. The more frequent FAS/FIAS in participants whose FBTCS resolved may be a characteristic of their epilepsy.