Citations

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

Background: Estimates of ‘brain-predicted age’ quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. Methods: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A−) participants (18–89 years old). In independent samples of 144 CN/A−, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite. Results: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A−. In CI participants only, elevated S-BAG and S+FC BAG were associated with more advanced AD pathology and lower cognitive performance. Conclusions: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences. Funding: This work was supported by the National Institutes of Health (P01-AG026276, P01- AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, and U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimer’s Association (SG-20-690363-DIAN).

OBJECTIVE Paroxysmal sympathetic hyperactivity (PSH) is a complication of severe traumatic or hypoxic brain injury characterized by transient episodes of tachycardia, tachypnea, hypertension, hyperthermia, diaphoresis, and/or dystonic posturing. Posttraumatic "sympathetic storms" are associated with poor outcomes. PSH rarely occurs after brain tumor resection in pediatric patients; only 4 cases have been published since 1929. Thus, the authors sought to report their experience with postcraniotomy PSH in pediatric brain tumor patients. METHODS A retrospective study of patients younger than 18 years of age who underwent craniotomy for brain tumor resection at a single center by a single surgeon over a 7-year period was performed. A clinical diagnosis of postoperative PSH was recorded. Recorded outcomes included the interval between surgery and initiation of cytotoxic therapy, need for long-term CSF diversion, length of hospital stay, and survival. RESULTS Of the 150 patients who were included for analysis, 4 patients were diagnosed with postoperative PSH for an overall occurrence of 2.7%. PSH patients were younger than non-PSH patients (1.8 ± 0.4 years vs 9.2 ± 5.3 years, p = 0.010) and tended to have intraventricular tumors close to the thalamus, basal ganglia, and/or brainstem. PSH patients experienced longer hospital admissions (44.3 ± 23.4 days vs 6.8 ± 9.4 days, p = 0.001), a shorter interval between surgery and initiation of cytotoxic cancer-directed therapy (14.3 ± 8.0 days vs 90.7 days ± 232.9 days, p = 0.011), and increased need for long-term CSF diversion compared with non-PSH patients (75% vs 25%, p = 0.005). At the last follow-up, 50% of PSH patients had died compared with 13% of non-PSH patients (p = 0.094). CONCLUSIONS PSH is a rare postoperative complication that may affect young children with periventricular tumors and is associated with poorer clinical outcomes. Increasing awareness of this condition is vital to improving patient outcomes.

Abstract Background: Smoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. An emerging area of interest for risk reduction is immunoprevention. MUC1 glycoprotein is aberrantly expressed in adenocarcinomas, including lung cancer and their premalignant lesions. MUC1 vaccine in the premalignant or high-risk setting may be effective in halting neoplastic development and progression. Trial design: Through the NCI-funded Cancer Prevention Network (CPN), we conducted a two-center pilot trial to evaluate immunogenicity of the MUC1 vaccine (assessed at 12 weeks), and safety (assessed at up to 24 weeks) in current and former heavy smokers. 87 participants were screened in order to have at least 40 evaluable for baseline and 12-week immunogenicity assessments. Smoking history of ≥30 pack-years and either current (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria were standard for lung cancer screening. Methods: MUC1 peptide plus polyICLC adjuvant (Hiltonol) vaccine was given at week 0, 2 and 10. Blood was collected for safety tests and immune assays pre and 2 weeks post each vaccine, and at week 24. Anti-MUC1 IgG titer was evaluated by ELISA. Based on previous studies of this vaccine, 40 evaluable participants would provide 96% power to detect immune response rate of 15% versus 40%, using a 2-sided test of proportions with type I error rate of 0.05. PBMC were assayed for the presence of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) (secondary endpoint). Circulating levels of inflammatory cytokines and hsCRP were evaluated using commercially available tests (exploratory endpoint). AEs and toxicities were monitored for up to 24 weeks from the first vaccine. Results: 87 individuals were screened and 50 registered. 45 completed the study, 26 current and 19 former smokers (time since last smoked: average 7.8 years; 11 months -13 years). The vaccine was well-tolerated with injection site reactions being the most common AE. Immune response to the vaccine was lower than expected, with 2 current and 2 former smokers developing anti-MUC1 IgG titers ≥2 fold higher at week 12 over baseline (10%). We found high circulating levels of MDSCs in PBMC of both current and former smokers and very low or no serum cytokines. Conclusions: A preventative vaccine trial was feasible in individuals at high risk for lung cancer. However, we discovered a high level of immune suppression, previously documented only in advanced lung cancer. Mitigating the development of lung cancer in heavy smokers through vaccine administration may be limited by related immunosuppression. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Samantha Fatis, John McKolanis, Jia Xue, Pamela Beatty, Camille Jacqueline, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Liz S. Ambulay, Nathan Foster, Ryan McMurray, Carrie Strand, Andres M. Salazar, Lisa Bengtson, Eva Szabo, Paul Limburg, Malgorzata Wojtowicz, David E. Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR002.

Abstract Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. We and others have shown that gut microbiota play an important role in disease pathogenesis of MS as there is an enrichment or depletion of specific gut bacteria compared to healthy controls (HC). Thus the specific human gut bacteria found depleted or showing lower abundance in MS patients can be used as potential drug to treat MS. Further, we and others have shown that patients with MS have either lower abundance of Prevotella compared to HC or an increased level of Prevotella in patients receiving disease modifying therapies such as Copaxone and/or Interferon beta (IFN-β). We have previously identified a specific strain Prevotella histicola within Prevotella genus which can suppress disease in experimental autoimmune encephalomyelitis (EAE) animal model of MS. In this present study we compared disease suppressing ability of P. histicola to Copaxone or IFN-β in HLA-DR3.DQ8 transgenic mouse model of MS. We observed that P. histicola suppresses EAE as efficiently as Copaxone and IFN-β. P. histicola treated mice showed higher level of CD4+FoxP3+ regulatory T cell frequencies and decreased levels of pro-inflammatory cytokines IFNγ and IL17 suggesting that P. histicola suppresses disease through immunomodulation. Fecal microbiota analysis of different groups showed that group receiving Prevotella histicola had a distinct gut microbiota than the control group suggesting that P. histicola as might suppresses disease through modulation of gut microbiota. In conclusion, our study suggests that human gut commensal Prevotella histicola can provide an alternate treatment option for MS patients.

AbstractBackgroundPrevious studies have demonstrated low first‐time donor return rates (DRR) following catastrophic events. Little is known, however, about the influence of demographic factors on the DRR of first‐time donors during the COVID‐19 pandemic, including the unique motivation of COVID‐19 convalescent plasma (CCP) donors as compared to non‐CCP donors.Study Design and MethodsThirteen blood collection organizations submitted deidentified data from first‐time CCP and non‐CCP donors returning for regular (non‐CCP) donations during the pandemic. DRR was calculated as frequencies. Demographic factors associated with returning donors: race/ethnicity, gender, and generation (Gen Z: 19–24, Millennial: 25–40, Gen X: 41–56, and Boomer: ≥57 years old), within the CCP and non‐CCP first‐time cohorts were compared using chi‐square test at p < .05 statistical significance.ResultsFrom March 2020 through December 2021, there were a total of 44,274 first‐time CCP and 980,201 first‐time non‐CCP donors. DRR were 14.6% (range 11.9%–43.3%) and 46.6% (range 10.0%–76.9%) for CCP and non‐CCP cohorts, respectively. Age over 40 years (Gen X and Boomers), female gender, and White race were each associated with higher return in both donor cohorts (p < .001). For the non‐CCP return donor cohort, the Millennial and Boomers were comparable.ConclusionThe findings demonstrate differences in returning donor trends between the two donor cohorts. The motivation of a first‐time CCP donor may be different than that of a non‐CCP donor. Further study to improve first‐time donor engagement would be worthwhile to expand the donor base with a focus on blood donor diversity emphasizing engagement of underrepresented minorities and younger donors.

Abstract Background Fungal infections following pancreas transplantation carry significant morbidity and mortality with an estimated incidence of 3 to 28%. The American Society of Transplantation (AST) suggests considering fluconazole prophylaxis in pancreas transplant recipients (PTR) at high-risk of invasive candidiasis (IC). However, optimal dosage and duration of prophylaxis is unclear. Weekly fluconazole for prevention of IC has been previously reported in liver and bone marrow transplant recipients. We analyzed outcomes of once weekly fluconazole prophylaxis in PTR. Methods We retrospectively reviewed all pancreas transplants performed at our institution from January 2017 through September 2021. PTR at high-risk for IC were defined per AST criteria as those with enteric drainage, vascular thrombosis, and post-perfusion pancreatitis. Patients received once weekly oral fluconazole 200 mg for 12 weeks post-transplant for IC prophylaxis. We analyzed incidence of breakthrough IC within the first 6 months post-transplant. Results We identified a total of 22 PTR, all of whom received simultaneous kidney transplantation from deceased donors. Of these, 12/22 (55%) were male and 11/22 (50%) were African American. Median age at the time of transplantation was 39 years (IQR 34-46). The most common indication for transplantation was type 1 diabetes mellitus (17/22, 21%) with associated nephropathy. No donor organ cultures were positive for fungi and all pancreas transplants were performed using enteric drainage. Notably, one patient developed pancreas allograft thrombosis while another developed pancreatitis. No patients required early discontinuation of fluconazole due to intolerance or side effects and none developed breakthrough IC within 6 months post-transplant (Table 1). Table 1. Conclusion Weekly fluconazole prophylaxis has not been previously studied in PTR. In our cohort, this approach was well tolerated, with no cases of IC at 6 months post-transplantation in patients at high-risk. Randomized controlled clinical trials are needed to define the optimal strategy in this population. Disclosures M. Rizwan Sohail, MD, Aziyo Biologics: Honoraria|Boston Scientific Corporation: Honoraria|Medtronic: Grant/Research Support|TRYX: Grant/Research Support.