Faculty Bibliography

Alzheimer disease neuropathologic change (ADNC) is considered to be the most common cause of cognitive decline and dementia worldwide. ADNC level is determined using the density of neuritic plaques in combination with the topographical distribution of β-amyloid (Aβ) plaques and hyperphosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs). While cognitive decline correlates with the level of ADNC, there remains a great deal of variation in cognitive outcomes between individuals that is unaccounted for by current neuropathologic evaluation metrics. We leveraged quantitative computer-assisted positive pixel assessments to establish the neocortical p-tau burden in the middle frontal and superior temporal gyri of 61 individuals with Braak NFT stage V who had a wide range of cognitive outcomes and trajectories. Frontal and temporal neocortical p-tau burden varied between 0.2% and 53.7%. Both frontal and temporal p-tau burden directly affected cognitive outcome and correlated with function of multiple cognitive domains, including measures of language/semantic memory and attention/working memory. In multivariable analysis, only p-tau burden and microinfarcts significantly impacted cognitive decline, while Aβ, limbic-predominant age-related TDP-43 encephalopathy, Lewy body pathology, and other measures of cerebrovascular disease did not. Additionally, individuals with low mean neocortical p-tau burden (≤ 13%) had significantly better longitudinal cognitive trajectories over the final 15 years of life compared to those with high burden (≥ 23.5%). These results suggest that while all individuals with Braak stage V have some degree of neurofibrillary degeneration in the neocortex, the significant variation in cognitive decline observed between these individuals can be partially understood as a reflection of the variation in quantitatively assessed neocortical p-tau burden, which had a greater impact on progression to dementia than common comorbid neuropathologies associated with dementia risk. This argues for the incorporation of the density of ADNC-related pathology, in addition to its regional location, as an adjunct to future staging systems for Alzheimer disease.

Bioconjugation reactions are indispensable for probing biomolecules in their native environments. Photoactivatable bioconjugation offers spatiotemporal control; however, current methods face significant limitations, including the requirement for noncanonical functional groups, cytotoxic heavy-metal catalysts, and high-energy UV or visible light (λ < 800 nm), which restrict tissue penetration and increase phototoxicity risks. In response, we introduce TagC-RED, a Retro-Ene type sigmatropic rearrangement of Diazonium compounds for Cysteine-specific bioconjugation activated by infrared light (λ > 1000 nm). TagC-RED is quantitative, rapid, and catalyst-free, with deep tissue penetration, enabling robust labeling intracellularly and in vivo. Mechanistic studies and DFT calculations show that TagC-RED activates through the formation of an electron donor-acceptor (EDA) complex that enables IR irradiation and undergoes a stepwise retro-ene reaction. TagC-RED holds significant potential as a platform for in vivo chemical biology and diagnostic innovation.

PURPOSE/OBJECTIVE:To develop a novel single-shot radial echo planar imaging (ss-rEPI) technique for rapid, distortion-free brain imaging in functional MRI experiments. METHODS:* mapping and QSM. Visual BOLD fMRI experiments were conducted and evaluated against Cartesian EPI measurements. RESULTS:* measurements. CONCLUSION/CONCLUSIONS:modeling is critical for ss-rEPI performance. Advanced reconstruction techniques and self-calibration methods could further enhance its speed, performance, and applicability across diverse MRI techniques.

Childhood is a period of peak developmental plasticity, involving drastic changes in the maturation of the neural circuitry underlying fear learning. Disruption and atypical development of fear learning are candidate mechanisms underlying child psychopathology. While there is a lack of understanding behind the maturation of fear learning systems in humans, rodent studies in this area delineate the normative development of fear learning systems early in life, and the effects of early threatening and fearful experiences on this developmental trajectory. Here, we review the rodent literature on developmental fear learning, as well as human studies that show translational convergence in typical development and children exposed to early life threat. We identify several gaps in research, including the role that caregivers play in regulating fear learning at different developmental stages and the intergenerational transmission of learned fear. Finally, we provide recommendations on how to address these gaps in a way that would improve our developmental frameworks of fear learning.

BACKGROUND:Although germline genetic testing can inform medical management for patients with prostate cancer (PCa), data are limited regarding patient-reported outcomes (PROs) after germline genetic testing for PCa. Recall and comprehension of germline genetic testing results, uptake of post-test clinical recommendations, and psychological impact of germline genetic testing among patients with PCa were evaluated. METHODS:This is a secondary analysis of data from the PROCLAIM trial. PROs were analyzed overall and by germline genetic testing results. Differences between groups were determined by two-tailed Fisher's exact test with significance set at p < 0.05. RESULTS:Among 494 patients with informative survey responses, 60% and 71% accurately recalled and interpreted their germline genetic testing results, respectively, with the highest rates among patients with negative results and the lowest among those with variant of uncertain significance-only (VUS) results. Among 42/55 (76%) patients with positive results for whom clinicians made germline genetic testing-informed recommendations, 39 (93%) completed or planned to complete >1 clinical recommendation. Conversely, no further recommendations were made for 160/221 (72%) and 211/218 (97%) patients with VUS and negative results, respectively. However, 57% (213/371) of these patients indicated that they or their family members intended to pursue clinical management strategies that were not recommended by their clinicians. Of the patients who responded to the survey, >90% of patients reported no post-germline genetic testing increase in their level of concern for themselves or their family members. CONCLUSION/CONCLUSIONS:germline genetic testing for patients with PCa did not cause appreciable psychological harm to the tested patients. Furthermore, patients with positive results had a high uptake of clinician-recommended management strategies. Of note, there were inconsistencies in the understanding of VUS results, with some clinicians making recommendations not warranted by personal/family history; conversely, some patients pursued management strategies not recommended by their clinicians. This suggests that educational efforts are needed in the communication of germline genetic testing results and clinical recommendations to patients.

PURPOSE/OBJECTIVE:Although the Woven EndoBridge (WEB) device is increasingly used for the treatment of wide-neck intracranial aneurysms, including in the acute rupture setting, comparative evidence assessing the impact of rupture status remains limited. This study compared angiographic, safety, and clinical outcomes between ruptured and unruptured intracranial aneurysms treated with WEB. METHODS:We conducted a retrospective analysis of prospectively collected data from the multicenter cohort registry WorldWideWEB, including consecutive adult patients with intracranial aneurysms treated with the WEB. Patients were stratified into groups of ruptured and unruptured aneurysms. Propensity score matching was used to balance baseline characteristics between both groups. Retreatment rate was the primary outcome. Secondary outcomes included mRS, safety events (thromboembolic complications) and angiographic outcomes (periprocedurally and last follow-up). RESULTS:Among 1,220 patients, 342 (28.0%) presented with ruptured aneurysms. Propensity-score-matched analyses revealed no significant difference in thromboembolic complications (11.8% vs. 5.9%, p = 0.056), similar periprocedural adequate occlusion (53.3% vs. 53.8%, p > 0.9), and similar retreatment rates (11.8% (95% CI 7.8-17.6%) vs. 7.1% (95% CI 4.1-12.0%), p = 0.14); however, adequate occlusion at follow-up was lower (82.2% vs. 93.3%, p = 0.002) and functional outcomes were worse (mRS ≥ 2 in 34.1% vs. 21.9%, p = 0.012) among patients with ruptured aneurysms. CONCLUSION/CONCLUSIONS:Ruptured aneurysms demonstrated expected inferior follow-up functional and angiographic outcomes when compared with unruptured aneurysms, but no difference in retreatment rate and procedural safety. These findings support WEB as a safe and effective treatment option for appropriately selected ruptured intracranial aneurysms in routine clinical practice.

BACKGROUND:The frequency of residual angina and its impact on health status and death following anatomic complete revascularization in symptomatic patients with chronic coronary disease are unknown. METHODS:Data were analyzed from ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial participants randomized to invasive management with baseline angina (Seattle Angina Questionnaire Angina Frequency score <100), no prior coronary artery bypass graft surgery, and anatomic complete revascularization within 90 days of randomization. The primary outcome was frequency of residual angina after revascularization, defined as a Seattle Angina Questionnaire Angina Frequency score <100 within 6 months of randomization. Secondary outcomes included 6-month health status and medication use and 5-year all-cause and cardiovascular death. RESULTS:=0.006). Five-year all-cause and cardiovascular death did not differ significantly between groups. CONCLUSIONS:Residual angina is common (>40%) following anatomic complete revascularization for chronic coronary disease and is associated with reduced quality of life and greater antianginal medication use but no increase in death. REGISTRATION/BACKGROUND:Unique Identifier: NCT01471522.

Primary graft dysfunction (PGD) is a proinflammatory syndrome occurring within the first days following lung transplantation. It is initiated by ischemia-reperfusion injury and perpetuated by donor and recipient immunologic factors, resulting in alveolar damage and progressive hypoxemic respiratory failure.¹ PGD is a known risk factor for both early allograft failure and chronic lung allograft dysfunction (CLAD).² Incidence of severe PGD remains high at 10-25%, though is variable; risk factors for PGD include center experience, underlying recipient disease type, size matching, donor lung storage conditions, operative time, and post-operative management.² Strategies to prevent PGD or mitigate the long -term consequences after it develops, are sorely needed. However, lack of specificity of the current PGD definition may hamper further progress in the field, especially as it pertains to the development of robust and relevant clinical trials. We propose that future modifications of the PGD definition incorporate more objective surrogates of allograft injury and subsequent diffuse alveolar damage, which may improve our ability to accurately study disease pathogenesis and improve outcomes.