Citations

Abstract Studies assessing genetic associations with neuropathological features in Lewy body disease (LBD) have been limited to candidate gene investigations, and therefore, information is lacking regarding the genetic architecture of the neuropathology of LBD. In the current study, we examined a large series of neuropathologically confirmed LBD cases (n = 980 in the discovery series, n = 503 in the replication series) and performed genome-wide association studies of 11 different neuropathological outcome measures. The 11 neuropathological outcomes included Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, LBD subtype, Lewy body (LB) counts in five different brain regions, dorsolateral and ventromedial putaminal tyrosine hydroxylase immunoreactivity and neuronal loss in the ventrolateral part of the substantia nigra. Associations between variants and outcomes were assessed using regression models appropriate for the nature of the given neuropathological outcome and that were adjusted for age at death, sex and top principal components of genetic data. In the discovery series, APOE rs429358 (i.e. APOE ε4) was associated with a greater severity of each of Braak NFT stage [odds ratio (OR) = 3.07, P = 2.34 × 10−32], Thal amyloid phase (OR = 3.57, P = 3.28 × 10−29) and LBD subtype (OR = 1.78, P = 9.85 × 10−9), with similar findings observed in the independent replication series (Braak NFT stage, OR = 2.30, P = 2.70 × 10−11; Thal amyloid phase, OR = 3.17, P = 6.39 × 10−18; LBD subtype, OR = 2.68, P = 3.85 × 10−10). In the subgroup of cases with lower levels of Alzheimer's disease pathology (Braak NFT stage ≤ III and Thal amyloid phase ≤2), there was a strong association between APOE rs429358 and LBD subtype even when adjusting for Braak stage and Thal phase in the discovery series (n = 218, OR = 2.47, P = 0.007) and the replication series (n = 141, OR = 3.60, P = 0.006). Although additional genome-wide significant associations were identified in the discovery series between LINC01581/MCTP2 rs547411734 and lower middle frontal LB counts, between TLE3 rs3743309 and lower cingulate LB counts, and between GRIN2A/ATF7IP2 rs1097915 and lower parahippocampal LB counts, these findings were not observed in the replication series. Our results indicate that the APOE ε4 allele is the most prominent genetic determinant of severity of neuropathology in LBD. These findings represent a key step forward in our understanding of genetic drivers of neuropathological features in LBD. Future studies utilizing meta-analytical approaches will be important to more precisely assess other associations that were not quite genome-wide significant in the discovery series.

AbstractBackgroundThe immune system is substantially involved in the development and progression of age‐related cognitive decline and Alzheimer’s disease (AD).MethodAs genetic and environmental factors interactively impact these conditions, we investigated how risk factors such as APOE genotype, age, and sex influence immune activation markers and AD biomarkers in cerebrospinal fluid (CSF) in elderly individuals enrolled in the Mayo Clinic Study of Aging cohort. Among cognitively unimpaired individuals aged over 65 at the baseline visit (N=298), we measured 365 CSF immune activation markers using the proximity extension assay.ResultWe found that age, sex, and diabetes status are associated with altered CSF levels of immune activation markers independently of other factors. For CSF AD biomarkers, we observed significant positive correlations between age and total tau, phosphorylated tau‐181 (p‐tau181), neurofilament light (NfL), and YKL40. APOE4 was also associated with lower Aβ42 and higher SNAP25 in CSF. We further examined whether baseline visit variables can predict cognitive decline, represented by the conversion from CDR=0 to CDR>0. We found that age, Aβ42, NfL, and REG4 were independently correlated with CDR conversion risk. When the cohort was dichotomized by their median values, older participants with lower Aβ42, higher NfL, and higher REG4 at baseline developed cognitive impairment during the follow up with a c‐index of 0.762 while age alone had a c‐index of 0.699.ConclusionTogether, our results suggest that assessing CSF immune activation markers and AD biomarkers can improve the prediction of cognitive impairment risk in the elderly.

AbstractBackgroundThe immune system is substantially involved in the development and progression of age‐related cognitive decline and Alzheimer’s disease (AD).MethodAs genetic and environmental factors interactively impact these conditions, we investigated how risk factors such as APOE genotype, age, and sex influence immune activation markers and AD biomarkers in cerebrospinal fluid (CSF) in elderly individuals enrolled in the Mayo Clinic Study of Aging cohort. Among cognitively unimpaired individuals aged over 65 at the baseline visit (N=298), we measured 365 CSF immune activation markers using the proximity extension assay.ResultWe found that age, sex, and diabetes status are associated with altered CSF levels of immune activation markers independently of other factors. For CSF AD biomarkers, we observed significant positive correlations between age and total tau, phosphorylated tau‐181 (p‐tau181), neurofilament light (NfL), and YKL40. APOE4 was also associated with lower Aß42 and higher SNAP25 in CSF. We further examined whether baseline visit variables can predict cognitive decline, represented by the conversion from CDR=0 to CDR>0. We found that age, Aß42, NfL, and REG4 were independently correlated with CDR conversion risk. When the cohort was dichotomized by their median values, older participants with lower Aß42, higher NfL, and higher REG4 at baseline developed cognitive impairment during the follow up with a c‐index of 0.762 while age alone had a c‐index of 0.699.ConclusionTogether, our results suggest that assessing CSF immune activation markers and AD biomarkers can improve the prediction of cognitive impairment risk in the elderly.

Abstract Background Dermatological health-related quality of life (HRQoL) among solid organ transplant recipients (SOTRs) may be adversely affected by various factors, including skin cancer. However, there has been limited assessment of dermatological HRQoL in SOTRs. This study aimed to evaluate the impact of skin cancer on quality of life (QoL) in SOTRs and to compare HRQoL measures between SOTRs with and without skin cancer. Methods This cross-sectional study was conducted at the Mayo Clinic Florida from June 2023 to March 2024. Adult patients who underwent solid organ transplantation between June 1995 and December 2023 were assessed using the Dermatology Life Quality Index (DLQI) and Skindex-29 questionnaires. For SOTRs with keratinocyte carcinoma (KC), the Basal and Squamous Cell Carcinoma Quality of Life (BaSQoL) questionnaire was also administered. Results A total of 150 adult SOTRs were included, with 82 having developed post-transplant skin cancer, including melanoma and keratinocyte carcinomas (KC). SOTRs with skin cancer were older at first transplant (Median: 61.8 vs. 57.3 years, P = 0.0073) and had a higher proportion of males (76.8% vs. 55.9%, P = 0.0086). Fitzpatrick skin type III-VI was less prevalent (8.5% vs. 38.2%, P < 0.0001). The frequency of SCC and BCC was 92.7% and 41.5%, respectively. DLQI scores were higher in SOTRs with skin cancer, however, the difference was not statistically significant (P ≥ 0.065). SOTRs with skin cancer had higher total Skindex-29 scores (P = 0.012) and “emotion” subscale scores (P = 0.0049), indicating a negative impact on QoL. BaSQoL scores showed a moderate negative effect on QoL, with a higher number of KCs correlating with lower QoL (P < 0.05). Female gender had higher DLQI total score (P = 0.0042) and BaSQoL diagnosis and treatment (P = 0.031). Conclusions: SOTRs with skin cancer exhibited lower overall QoL, with a greater number of skin cancers linked to more pronounced negative impacts on QoL across all assessment instruments. Female gender was also associated with lower QoL scores. Recognizing the potential for reduced QoL in SOTRs is essential for developing tailored management strategies to support this population.

BACKGROUND Flap repair provides unique advantages in facial reconstruction but still carries the potential for undesirable postoperative cosmetic changes. OBJECTIVE The aims of this study were to describe postoperative vascular outcomes of patients undergoing flap repairs after Mohs micrographic surgery on facial tumors and to assess associations of baseline characteristics with outcomes. MATERIALS AND METHODS In this study, 7 dermatologists and 1 physician assistant in dermatology assessed preoperative and postoperative photographs of 57 patients who underwent facial Mohs micrographic surgery, evaluating vascular and pigment outcomes and number of telangiectasias. RESULTS There was a significant difference in number of telangiectasias according to body location (p = .002), where the number of telangiectasias was highest for nose surgery. CONCLUSION These data suggest that nasal flap repairs are associated with increased postoperative vascular changes. This highlights an opportunity for improved preoperative patient counseling and possible early laser treatment after nasal Mohs micrographic surgery.

Purpose: To identify demographic and clinical factors associated with delayed diagnosis in patients with primary vitreoretinal lymphoma (VRL). Methods: Retrospective, tertiary referral center-based cohort study of all patients at Mayo Clinic in Rochester, Minnesota, with a biopsy-proven diagnosis of VRL from January 1, 2000, to October 31, 2022. Results: There were 87 patients included during the 22-year study period with 73 patients (83.9%) diagnosed with VRL upon initial evaluation at the tertiary center, with the other 14 patients (16.1%) diagnosed later. The median referral time was 4.8 months (range: 0–113 months). Patients who received an initial diagnosis of inflammatory uveitis or another incorrect diagnosis elsewhere were referred slower than those initially diagnosed with VRL (P = 0.04). The most common incorrect initial diagnosis from an outside institution was inflammatory uveitis (n = 35, 40.2%). When patients were split into four groups based on referral time, prior use of corticosteroids was associated with a significant delay in referral (P = 0.03). Conclusion: Diagnosing VRL continues to be challenging, as months-long delays from initial evaluation to expert referral center evaluation are common. Prior use of corticosteroids was associated with delay in diagnosis and referral time, underscoring the need to increase awareness regarding differences between VRL and uveitis.

AbstractBackgroundSimultaneous liver kidney (SLK) transplant protects against acute cellular rejection. In 2017, UNOS implemented a “safety net” policy to allow patients with renal recovery to avoid renal transplantation. Whether kidney after liver transplantation (KALT) increases the risk of rejection is unknown.MethodsWe performed a retrospective analysis of the Organ Procurement and Transplantation Network (OPTN) database of adult patients who received liver transplant, SLK or KALT between 2010 and 2020. We examined rejection of the liver within 6 months and 1 year of the liver transplant, as well as rejection of the kidney within 6 months and 1 year of receiving the kidney, as well as patient and graft loss.ResultsSixty‐six thousand seventy‐nine patients were transplanted; 60 168 with liver transplant alone, 5627 with SLK, and 284 with KALT. Acute or chronic liver rejection rates within 6 or 12 months were statistically higher in the KALT group (10.0% and 10.9%) compared to the SLK group (6.1% and 7.5%), but comparable to the LTA group (9.3% and 11.1%). Kidney rejection and graft survival rates were not different. Liver graft survival was worse in KALT than SLK or LTA (Kaplan‐Meier estimates .61 vs. .89 and .90), but these patients were more ill at the time of transplantation. KDPI and LDRI scores were notably lower in the SLK than KALT group. Patient survival was not clinically different between the groups.ConclusionKALT does not increase the risk of acute or chronic kidney rejection. SLK has a lower risk of early liver rejection, but this effect diminishes by one year to being not clinically different compared to KALT. Given that KALT is immunologically safe, and potentially avoids unnecessary renal graft use, it should be preferred over SLK.Brief summaryPatients undergoing sequential kidney after liver transplant do not have an increased risk of liver or kidney rejection when compared to liver transplant alone or simultaneous liver and kidney transplant.

The immune system substantially influences age-related cognitive decline and Alzheimer’s disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 ( N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Objective The aims of this study were to assess whether a relationship between anti–SSA-52 and interstitial lung disease (ILD) can be further defined, and to enhance screening, detection, and potentially guide treatment. Methods A historical cohort study of 201 patients was conducted at a single tertiary care center between January 1, 2016 and December 31, 2020. All included patients were anti–SSA-52 antibody positive. Chart review was performed for laboratory values, symptoms, pulmonary function tests, treatment, and imaging. Chest computed tomographies were reviewed by chest radiologists. Results Among anti–SSA-52 antibody–positive patients, ILD was found in 125 (62.2%) compared with 76 (37.8%) with no ILD (p = 0.001). For those with ILD, 78 (62.4%) were diagnosed with connective tissue disease (CTD)–associated ILD, 28 (22.4%) were diagnosed ILD only, and 19 (15.2%) met the criteria for interstitial pneumonia with autoimmune features. In patients with CTD-ILD, 18 (23.0%) had their ILD diagnosis made over 6 months before a CTD diagnosis, and an additional 43 (55.1%) had their ILD and CTD diagnosed within 6 months of each other (p < 0.001). Common computed tomography patterns were nonspecific interstitial pneumonia/organizing pneumonia overlap in 44 (35.2%), 25 (20.0%) nonspecific interstitial pneumonia, and 15 (12%) usual interstitial pneumonia. Twenty-eight (35.9%) had antisynthetase syndrome, followed by 16 (20.5%) with dermatomyositis, 10 (12.8%) with CTD overlap, and 6 (7.7%) with systemic scleroderma. Conclusions There was a significant association between anti–SSA-52 antibodies and ILD across a wide spectrum of rheumatological diagnoses. A significant portion of patients were diagnosed with ILD either at the same time or before their CTD diagnosis. Further study will be needed to assess effective treatment and response.