Heckman, Michael G.

Abstract Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in the overall sample and among non-Hispanic whites. The results show that among non-Hispanic whites, presence of rare functional variants in ABCC2 was associated with 7-fold higher risk of metabolic HCC (OR = 6.92, 95% CI: 2.38–20.15, P = 0.0004), and this association remained significant when analyses were restricted to functional rare variants observed in ≥2 participants (cases 3.2% versus controls 0.0%, P = 1.02 × 10−5). In the overall multiethnic sample, presence of rare functional variants in ABCC2 was nominally associated with metabolic HCC (OR = 3.60, 95% CI: 1.52–8.58, P = 0.004), with similar nominal association when analyses were restricted to functional rare variants observed in ≥2 participants (cases 2.9% versus controls 0.2%, P = 0.006). A common variant in PNPLA3 (rs738409[G]) was associated with higher HCC risk in the overall sample (P = 6.36 × 10−6) and in non-Hispanic whites (P = 0.0002). Our findings indicate that rare functional variants in ABCC2 are associated with susceptibility to metabolic HCC in non-Hispanic whites. PNPLA3-rs738409 is also associated with metabolic HCC risk.

We previously demonstrated that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in Alzheimer’s disease (AD) brains. SERPINA5 was further demonstrated to be a novel tau-binding partner that colocalizes within neurofibrillary tangles. Our goal was to determine whether genetic variants in the SERPINA5 gene contributed to clinicopathologic phenotypes in AD. To screen for SERPINA5 variants, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. To further assess the frequency of a rare missense variant, SERPINA5 p.E228Q, we screened an additional 1114 neuropathologically diagnosed AD cases. To provide neuropathologic context in AD, we immunohistochemically evaluated SERPINA5 and tau in a SERPINA5 p.E228Q variant carrier and a matched noncarrier. In the initial SERPINA5 screen, we observed 1 individual with a rare missense variant (rs140138746) that resulted in an amino acid change (p.E228Q). In our AD validation cohort, we identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.0021. There was no significant difference between SERPINA5 p.E228Q carriers and noncarriers in terms of demographic or clinicopathologic characteristics. Although not significant, on average SERPINA5 p.E228Q carriers were 5 years younger at age of disease onset than noncarriers (median: 66 [60–73] vs 71 [63–77] years, P = .351). In addition, SERPINA5 p.E228Q carriers exhibited a longer disease duration than noncarriers that approached significance (median: 12 [10–15]) vs 9 [6–12] years, P = .079). More severe neuronal loss was observed in the locus coeruleus, hippocampus, and amygdala of the SERPINA5 p.E228Q carrier compared to noncarrier, although no significant difference in SERPINA5-immunopositive lesions was observed. Throughout the AD brain in either carrier or noncarrier, areas with early pretangle pathology or burnt-out ghost tangle accumulation did not reveal SERPINA5-immunopositive neurons. Mature tangles and newly formed ghost tangles appeared to correspond well with SERPINA5-immunopositive tangle-bearing neurons. SERPINA5 gene expression was previously associated with disease phenotype; however, our findings suggest that SERPINA5 genetic variants may not be a contributing factor to clinicopathologic differences in AD. SERPINA5-immunopositive neurons appear to undergo a pathologic process that corresponded with specific levels of tangle maturity.

AbstractBackgroundThere is an unmet need for the treatment of colony‐stimulating factor‐1 receptor (CSF1R)‐related leukoencephalopathy.ObjectivesTo evaluate the association of glucocorticoids (GCs) with disease onset and progression in CSF1R variant carriers.MethodsRetrospective cohort study on CSF1R variants carriers (n = 41) whose medical records were collected at Mayo Clinic Florida from 2003 to 2023. We retrieved information on sex, ethnicity, family history, medications, disease onset, course and duration, neuroimaging features, and activities of daily living (ADL).ResultsRisk of developing symptoms was significantly lower for individuals who used GCs (n = 8) compared to individuals who did not (n = 33) (12.5% vs. 81.8%, hazard ratio [HR] = 0.10, P = 0.036). The risk of becoming dependent in ADL was markedly lower for the GCs group (0.0% vs. 43.8%, P = 0.006). White matter lesions and corpus callosum involvement were less common in the GCs group (62.5% vs. 96.6%, P = 0.026; 37.5% vs. 84.6%, P = 0.017; respectively).ConclusionsWe found a protective association of GCs in CSF1R variant carriers against developing CSF1R‐related leukoencephalopathy. We call for further studies to validate our findings and investigate the potential application of GCs in CSF1R‐related leukoencephalopathy. © 2023 International Parkinson and Movement Disorder Society.

AbstractIntraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson’s disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer’s disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity.Using summary statistics from Parkinson’s disease and Alzheimer’s disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson’s disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer’s disease co-pathology.In an ordinal logistic regression model, the Alzheimer’s disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson’s disease risk score and specific to the subset of samples without significant concomitant Alzheimer’s disease related neuropathology.Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson’s and Alzheimer’s disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer’s disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.

Background: Mayo Clinic’s Care Hotel is a virtual hybrid care model which allows postoperative patients to recover in a comfortable environment after a low-risk procedure. Hospitals need to understand the key patient factors that promote acceptance of the Care Hotel if they are to benefit from this innovative care model. This study aims to identify factors that can predict whether a patient will stay at Care Hotel. Materials and methods: This retrospective chart review of 1065 patients was conducted between 23 July 2020, and 31 December 2021. Variables examined included patient age, sex, race, ethnicity, Charlson comorbidity index, distance patient travelled to hospital, length of surgery, day of the week of surgery, and surgical service. Associations of patient and surgery characteristics with the primary outcome of staying at the Care Hotel were assessed using unadjusted and multivariable logistic regression models. Results: Of the 1065 patients who met criteria for admission to the Care Hotel during the study period, 717 (67.3%) chose to stay at the Care Hotel while 328 (32.7%) choose to be admitted to the hospital. In multivariable analysis, there was a significant association between surgical service and staying at the Care Hotel (P<0.001). Specifically, there was a higher likelihood of staying at the Care Hotel for patients from Neurosurgery [odds rato (OR)=1.86, P=0.004], Otorhinolaryngology (OR=2.70, P<0.001), and General Surgery (OR=2.75, P=0.002). Additionally, there was a higher likelihood of staying at the Care Hotel with distance travelled over 110 miles [OR (per each doubling)=1.10, P=0.007]. Conclusion: When developing a post-surgical care model for patients following outpatient procedures, the referring surgical service is a primary factor to consider in order to ensure patient acceptance, along with patient distance. This study can assist other healthcare organizations considering this model, as it provides guidance on which factors are most indicative of acceptance.

Background: Survey studies have found an increased prevalence of migraine in patients with inflammatory bowel disease (IBD). However, the clinical characteristics of migraines in this population are unknown. We conducted a retrospective medical record review study to characterize migraines in the IBD population. Methods: Six hundred seventy-five migraine patients (280 with IBD, 395 without IBD) who were evaluated at Mayo Clinic Rochester, Mayo Clinic Arizona, or Mayo Clinic Florida between July 2009 and March 2021 were included. Patients with ICD codes for migraine and either Crohn’s disease (CD) or ulcerative colitis (UC) were selected. Electronic health care records were reviewed. Patients confirmed to have IBD and migraine were included. Demographic, IBD, and migraine characteristics were collected. Statistical analysis was completed using SAS. Results: Patients with IBD were less often male (8.6% vs 21.3%, P < .001) and had a higher Charlson Comorbidity Index (>2: 24.6% vs 15.7%, P = .003); 54.6% had CD and 39.3% had UC. Patients with IBD had migraine with aura and without aura more frequently ( OR 2.20, P < .001 and OR 2.79, P < .001, respectively) than non-IBD patients. Additionally, those with IBD less commonly had chronic migraine (OR 0.23, P < .001) and less commonly had chronic migraine or treatment for migraine (ORs 0.23-0.55, P ≤ .002). Conclusions: Migraine with and without aura have increased prevalence in IBD patients. Further study of this topic will be helpful to clarify the prevalence of migraine, establish this population’s response to treatment, and better understand the reason(s) for a low rate of treatment.

Objective We sought to determine the prevalence and possible features associated with symptoms in adult patients diagnosed with an aberrant right subclavian artery (ARSA). Methods In this single-center retrospective study, 386 adult patients were diagnosed with ARSA on chest CT scans performed between June 2016 and April 2021. Patients were grouped by the presence of symptoms, which included dysphagia, shortness of breath, cough, and upper airway wheezing. Four cardiothoracic radiologists reviewed the chest CT scans to assess features of ARSA. Agreement and multivariable logistic regression analyses were performed to determine interobserver variability and features associated with the presence of symptoms, respectively. Results The prevalence of ARSA was 1.02% and 81.3% of patients were asymptomatic. Shortness of breath (74.6%) was the most common symptom. Interobserver agreement was acceptable with most variables having an interclass correlation coefficient or κ >0.80. A patient's height > 158 cm (OR: 2.50, P = 0.03), cross-sectional area > 60 mm2 of ARSA at the level of the esophagus (OR: 2.39, P = 0.046), and angle >108 degrees formed with the aortic arch (OR: 1.99, P = 0.03) were associated with the presence of symptoms on multivariable logistic regression. A distance increase per 1 mm between ARSA and trachea (OR: 0.85, P = 0.02) was associated with decreased odds of symptoms. Conclusions Aberrant right subclavian artery is an incidental finding in most adult patients. The cross-sectional area at the level of the esophagus, angle formed with the medial wall of the aortic arch, distance between the ARSA and the trachea, and a patient's height were features associated with the presence of symptoms.

18 Background: Studies have shown that African Americans (AA) are at increased risk for Colorectal Cancer (CRC) compared to other groups. Despite advancements in CRC screening modalities, few studies have investigated disparities in CRC screening among this vulnerable population. Methods: We performed a retrospective review of patients of age 45 or older who were seen in Family Medicine (FM), Internal Medicine (IM), or Gastroenterology (GI) between January 1, 2015 and December 31, 2021 at the Mayo Clinic. Information was collected regarding patient characteristics (age, sex, Charlson comorbidity score, race), and outcomes (whether a Cologuard test was ordered on the same day as the initial appointment, and whether the patient underwent a colonoscopy within 1 year after the initial appointment). Categorical variables were summarized with number and percentage of patients. Outcomes were compared between race groups (Caucasian, AA, Asian, Other) using unadjusted and multivariable logistic regression models. Multivariable models were adjusted for age, sex, and Charlson comorbidity score. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. P-values <0.05 were considered as statistically significant, and all statistical tests were two-sided. Results: Overall, 558,078 were included for analysis and 14,607 (2.6%) were AA. Overall, AA patients for less likely to have Cologuard ordered compared to Caucasians (OR=0.62, p<0.001), notably driven by patient seen in the FM group (OR=0.54, p<0.001) and no statistically significant difference was observed in the IM and GI groups (p=0.055 and p=0.43, respectively). Notably, compared to Caucasian patients, Asian patients were overall more likely to have Cologuard ordered (OR=1.23, p=0.003). In multivariable analysis assessing the likelihood of having a colonoscopy performed within 1 year of the initial appointment, the likelihood of a colonoscopy within 1 year of initial clinic visit was significantly lower for AA compared to Caucasian patients (OR=0.50, p=0.028). This difference was strongest in FM patients (OR=0.26, p=0.022) and was not significant for IM (OR=0.67, p=0.37) or GI (OR=2.31, p=0.25). Conclusions: In this study, we found that AA ethnicity is associated with reduced likelihood of having Cologuard ordered compared to Caucasian patients. Furthermore, AA patients were less likely to have colonoscopy ordered within 1 year of initial visit clinic visit among the overall cohort, highlighting important disparities in CRC screening among this vulnerable patient population notably for those seen in the FM group. Future studies are needed to assess other barriers for CRC screening in this population.