Publications by authors named "Julia E Crook"

97 Publications

Mental Health and Chemical Dependency Services at US Cancer Centers.

J Natl Compr Canc Netw 2021 Mar 4:1-10. Epub 2021 Mar 4.

1Department of Psychiatry & Psychology.

Background: It is standard of care and an accreditation requirement to screen for and address distress and psychosocial needs in patients with cancer. This study assessed the availability of mental health (MH) and chemical dependency (CD) services at US cancer centers.

Methods: The 2017-2018 American Hospital Association (AHA) survey, Area Health Resource File, and Centers for Medicare & Medicaid Services Hospital Compare databases were used to assess availability of services and associations with hospital-level and health services area (HSA)-level characteristics.

Results: Of 1,144 cancer centers surveyed, 85.4% offered MH services and 45.5% offered CD services; only 44.1% provided both. Factors associated with increased adjusted odds of offering MH services were teaching status (odds ratio [OR], 1.76; 95% CI, 1.18-2.62), being a member of a hospital system (OR, 2.00; 95% CI, 1.31-3.07), and having more beds (OR, 1.04 per 10-bed increase; 95% CI, 1.02-1.05). Higher population estimate (OR, 0.98; 95% CI, 0.97-0.99), higher percentage uninsured (OR, 0.90; 95% CI, 0.86-0.95), and higher Mental Health Professional Shortage Area level in the HSA (OR, 0.99; 95% CI, 0.98-1.00) were associated with decreased odds of offering MH services. Government-run (OR, 2.85; 95% CI, 1.30-6.22) and nonprofit centers (OR, 3.48; 95% CI, 1.78-6.79) showed increased odds of offering CD services compared with for-profit centers. Those that were members of hospital systems (OR, 1.61; 95% CI, 1.14-2.29) and had more beds (OR, 1.02; 95% CI, 1.01-1.03) also showed increased odds of offering these services. A higher percentage of uninsured patients in the HSA (OR, 0.92; 95% CI, 0.88-0.97) was associated with decreased odds of offering CD services.

Conclusions: Patients' ability to pay, membership in a hospital system, and organization size may be drivers of decisions to co-locate services within cancer centers. Larger organizations may be better able to financially support offering these services despite poor reimbursement rates. Innovations in specialty payment models highlight opportunities to drive transformation in delivering MH and CD services for high-need patients with cancer.
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http://dx.doi.org/10.6004/jnccn.2020.7657DOI Listing
March 2021

Latent trait modeling of tau neuropathology in progressive supranuclear palsy.

Acta Neuropathol 2021 Feb 26. Epub 2021 Feb 26.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.
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http://dx.doi.org/10.1007/s00401-021-02289-0DOI Listing
February 2021

Plasma Biomarkers of Alzheimer's Disease in African Americans.

J Alzheimers Dis 2021 ;79(1):323-334

Mayo Clinic, Department of Neuroscience, Jacksonville, FL, USA.

Background/objective: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer's disease (AD) pathology and neuroinflammation are associated with disease status in African Americans.

Methods: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer's Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aβ42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations.

Results: Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOEɛ4 was associated with lower plasma Aβ42 and tau levels. Older age was associated with higher plasma Aβ42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aβ42.

Conclusion: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aβ42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.
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http://dx.doi.org/10.3233/JAD-200828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902984PMC
January 2021

Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressive supranuclear palsy.

Acta Neuropathol Commun 2020 10 22;8(1):172. Epub 2020 Oct 22.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.

Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer's disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (n = 2008, n = 1037, n = 971) and Thal phase amyloid plaque scores (n = 1786, n = 1018, n = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46-4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = - 0.822, 95% CI - 1.439 to - 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = - 0.995, 95% CI - 1.773 to - 0.218, p = 0.012) than LBD-NP patients (ß = - 0.292, 95% CI - 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = - 0.638, 95% CI - 1.139 to - 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.
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http://dx.doi.org/10.1186/s40478-020-01050-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579984PMC
October 2020

Correction to: Deciphering cellular transcriptional alterations in Alzheimer's disease brains.

Mol Neurodegener 2020 09 15;15(1):54. Epub 2020 Sep 15.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13024-020-00403-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490892PMC
September 2020

Association of Genetic Variants at With Chemotherapy-Related Heart Failure.

Front Cardiovasc Med 2020 13;7:142. Epub 2020 Aug 13.

Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States.

Our previous GWAS identified genetic variants at six novel loci that were associated with a decline in left ventricular ejection fraction (LVEF), < 1 × 10 in 1,191 early breast cancer patients from the N9831 clinical trial of chemotherapy plus trastuzumab. In this study we sought replication of these loci. We tested the top loci from the GWAS for association with chemotherapy-related heart failure (CRHF) using 26 CRHF cases from N9831 and 984 patients from the Mayo Clinic Biobank which included CRHF cases ( = 12) and control groups of patients treated with anthracycline +/- trastuzumab without HF ( = 282) and patients with HF that were never treated with anthracycline or trastuzumab ( = 690). We further examined associated loci in the context of gene expression and rare coding variants using a TWAS approach in heart left ventricle and Sanger sequencing, respectively. Doxorubicin-induced apoptosis and cardiomyopathy was modeled in human iPSC-derived cardiomyocytes and endothelial cells and a mouse model, respectively, that were pre-treated with GsMTx-4, an inhibitor of TRPC6. ' flanking variant rs57242572-T was significantly more frequent in cases compared to controls, = 0.031, and rs61918162-T showed a trend for association, = 0.065. The rs61918162 T-allele was associated with higher expression in the heart left ventricle. We identified a single rare missense variant (rs767086724, N338S, prevalence 0.0025% in GnomAD) in one of 38 patients (2.6%) with CRHF. Pre-treatment of cardiomyocytes and endothelial cells with GsMTx4 significantly reduced doxorubicin-induced apoptosis. Similarly, mice treated with GsMTx4 had significantly improved doxorubicin-induced cardiac dysfunction. Genetic variants that are associated with increased expression in the heart and rare missense variants may be clinically useful as risk factors for CRHF. GsMTx-4 may be a cardioprotective agent in patients with risk variants. Replication of the genetic associations in larger well-characterized samples and functional studies are required.
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http://dx.doi.org/10.3389/fcvm.2020.00142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438395PMC
August 2020

Comparison of endoscopic ultrasound-guided fine-needle biopsy versus fine-needle aspiration for genomic profiling and DNA yield in pancreatic cancer: a randomized crossover trial.

Endoscopy 2021 Apr 6;53(4):376-382. Epub 2020 Aug 6.

Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA.

Background:  National guidelines recommend genomic profiling of tumor tissue to guide precision therapy. We compared the specimen adequacy for genomic profiling and yield of DNA between endoscopic ultrasound (EUS)-guided fine-needle biopsy (FNB) and EUS-guided fine-needle aspiration (FNA).

Methods:  In our tandem, randomized controlled trial, consecutive patients undergoing EUS for evaluation of pancreatic masses underwent both conventional EUS-FNA with a 25-gauge needle and paired EUS-FNB (19 or 22-gauge needle), with the order randomized (EUS-FNA first followed by EUS-FNB, or vice versa). A minimum of one pass with each needle was obtained for histology. Second and third passes were performed to collect DNA. Specimens were evaluated by a cytopathologist blinded to the needle type. Specimen adequacy for genomic profiling was calculated based on FoundationOne clinical diagnostic (CDx) adequacy requirements. We compared the adequacy for genomic profiling DNA (quantity) and histology yields with both needles.

Results:  Analysis included 50 patients (25 men; mean age 68 [standard deviation (SD) 13] years), with a mean lesion size of 38 (SD 17) mm; 37 lesions (74 %) were pancreatic ductal adenocarcinoma (PDAC). The mean DNA concentrations in PDAC by FNB and FNA needles were 5.930 (SD 0.881) µg/mL vs. 3.365 (SD 0.788) µg/mL, respectively ( = 0.01). The median standardized histology score per pass with EUS-FNB was 5 (sufficient for histology) and for EUS-FNA was 2 (enough for cytology). Specimen adequacy for genomic profiling and yield of DNA was significantly higher with FNB than with FNA needles.

Conclusions:  In this study, adequacy for genomic profiling, DNA, and histology yield were considerably superior using an EUS-FNB needle compared with an EUS-FNA needle.
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http://dx.doi.org/10.1055/a-1223-2171DOI Listing
April 2021

Deciphering cellular transcriptional alterations in Alzheimer's disease brains.

Mol Neurodegener 2020 07 13;15(1):38. Epub 2020 Jul 13.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.

Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer's disease (AD), however these findings can be confounded by cellular composition changes in bulk-tissue. To identify cell intrinsic gene expression alterations of individual cell types, we designed a bioinformatics pipeline and analyzed three AD and control bulk-RNAseq datasets of temporal and dorsolateral prefrontal cortex from 685 brain samples. We detected cell-proportion changes in AD brains that are robustly replicable across the three independently assessed cohorts. We applied three different algorithms including our in-house algorithm to identify cell intrinsic differentially expressed genes in individual cell types (CI-DEGs). We assessed the performance of all algorithms by comparison to single nucleus RNAseq data. We identified consensus CI-DEGs that are common to multiple brain regions. Despite significant overlap between consensus CI-DEGs and bulk-DEGs, many CI-DEGs were absent from bulk-DEGs. Consensus CI-DEGs and their enriched GO terms include genes and pathways previously implicated in AD or neurodegeneration, as well as novel ones. We demonstrated that the detection of CI-DEGs through computational deconvolution methods is promising and highlight remaining challenges. These findings provide novel insights into cell-intrinsic transcriptional changes of individual cell types in AD and may refine discovery and modeling of molecular targets that drive this complex disease.
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http://dx.doi.org/10.1186/s13024-020-00392-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359236PMC
July 2020

Linear vs volume measures of ventricle size: Relation to present and future gait and cognition.

Neurology 2020 02 20;94(5):e549-e556. Epub 2019 Nov 20.

From the Departments of Health Sciences Research (J.E.C., C.T.B.) and Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; and Departments of Radiology (J.L.G., C.R.J.) and Neurology (D.T.J., J.G.-R., D.S.K., B.F.B., R.C.P.), Mayo Clinic, Rochester, MN.

Objective: To compare the clinical utility of volume-based ratios with the standard linear ratio of Evans index (EI) by examining their associations with gait, cognition, and other patient and imaging variables.

Methods: From MRI scans of 1,774 participants in the Mayo Clinic Study of Aging, we calculated 3 ventricle size measures: Evan index (frontal horn width divided by widest width of skull inner table), total ventricular volume, and frontal horn volume as ratios of total intracranial volume. Gait was measured by a timed 25-foot walk and cognition by a composite of psychometric tests. We also evaluated variables associated with the measures of ventricular size. Further, we evaluated gait and cognition associations with MRI of extraventricular findings seen in normal-pressure hydrocephalus: disproportionate enlargement of subarachnoid space (DESH) and focal sulcal dilations (FSD).

Results: Ventricular volume measures had stronger association with gait and cognition measures than EI. In decreasing order of strength of association with ventricle size were DESH, FSD, white matter hyperintensity volume ratio, age, male sex, cortical thickness, and education. Modest evidence was observed that FSD was associated with future decline in gait and cognition.

Conclusion: Ventricular volume measures are clinically more useful than EI in indicating current and future gait and cognition. Multiple factors are associated with ventricle volume size, including FSD and DESH, suggesting that changes in CSF dynamics may go beyond simple ventriculomegaly.
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http://dx.doi.org/10.1212/WNL.0000000000008673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080290PMC
February 2020

Selective Vulnerability of the Nucleus Basalis of Meynert Among Neuropathologic Subtypes of Alzheimer Disease.

JAMA Neurol 2020 02;77(2):225-233

Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.

Importance: Corticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD.

Objective: To investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes.

Design, Setting, And Participants: In this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings.

Main Outcomes And Measures: Demographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation.

Results: In total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n = 163), lower in typical AD (10 [5-16]; n = 937), and lowest in limbic predominant AD (8 [5-11], n = 163) (P < .001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n = 148), higher in typical AD (25 [19-30]; n = 727), and highest in limbic predominant AD (26 [19-32]; n = 127) (P = .002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (β, -1.5; 95% CI, -2.9 to -0.15; P = .03) and typical AD (β, -3.2; 95% CI, -3.9 to -2.4; P < .001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (β, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (β, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (β, -1.8; 95% CI, -3.2 to -0.31; P = .02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases.

Conclusions And Relevance: These data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.
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http://dx.doi.org/10.1001/jamaneurol.2019.3606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820048PMC
February 2020

Comparative Effectiveness of Behavioral Interventions on Quality of Life for Older Adults With Mild Cognitive Impairment: A Randomized Clinical Trial.

JAMA Netw Open 2019 05 3;2(5):e193016. Epub 2019 May 3.

Department of Clinical and Health Psychology, University of Florida, Gainesville.

Importance: Recommendations to engage in behavioral strategies to combat clinically significant cognitive and behavioral symptoms are routinely given to persons with mild cognitive impairment (MCI). The comparative effectiveness of these behavioral interventions is not well understood.

Objective: To compare the incremental effects of combinations of 5 behavioral interventions on outcomes of highest importance to patients with MCI.

Design, Setting, And Participants: In this multisite, cluster randomized, multicomponent comparative effectiveness trial, 272 patients from 4 academic medical outpatient centers (Mayo Clinic, Rochester, Minnesota; Mayo Clinic, Scottsdale, Arizona; Mayo Clinic, Jacksonville, Florida; and University of Washington, Seattle) were recruited from September 1, 2014, to August 31, 2016, with last follow-up March 31, 2019. All participants met the National Institute on Aging-Alzheimer's Association criteria for MCI.

Interventions: The intervention program was modeled on the Mayo Clinic Healthy Action to Benefit Independence and Thinking (HABIT) program, a 50-hour group intervention conducted during 2 weeks, including memory compensation training, computerized cognitive training, yoga, patient and partner support groups, and wellness education. In our study, 1 of 5 interventions was randomly selected to be withheld for each intervention group. Participants and their partners had 1-day booster sessions at 6 and 12 months after intervention.

Main Outcomes And Measures: Quality-of-life measurement of participants with MCI at 12 months was the primary outcome, selected based on the preference rankings of previous program participants. Mood, self-efficacy, and memory-based activities of daily living were also highly ranked.

Results: A total of 272 participants (mean [SD] age, 75 [8] years; 160 [58.8%] male and 112 [41.2%] female) were enrolled in this study, with 56 randomized to the no yoga group, 54 to no computerized cognitive training, 52 to no wellness, 53 to no support, and 57 to no memory support system. The greatest effect size for quality of life was between the no computerized cognitive training and no wellness education groups at 0.34 (95% CI, 0.05-0.64). In secondary analyses, wellness education had a greater effect on mood than computerized cognitive training (effect size, 0.53; 95% CI, 0.21-0.86), and yoga had a greater effect on memory-related activities of daily living than support groups (effect size, 0.43; 95% CI, 0.13-0.72).

Conclusions And Relevance: These results provide further support for behavioral interventions for persons with MCI. Different outcomes were optimized by different combinations of interventions. These findings provide an initial exploration of the effect of behavioral interventions on patient-advocated outcomes in persons with MCI.

Trial Registration: ClinicalTrials.gov identifier: NCT02265757.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.3016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537922PMC
May 2019

Ethnoracial differences in Alzheimer's disease from the FLorida Autopsied Multi-Ethnic (FLAME) cohort.

Alzheimers Dement 2019 05 18;15(5):635-643. Epub 2019 Feb 18.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Introduction: Our primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy-confirmed cohort of Alzheimer's disease cases.

Methods: A retrospective study was conducted in the Florida Autopsied Multi-Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self-reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539).

Results: Hispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups.

Discussion: Despite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies.
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http://dx.doi.org/10.1016/j.jalz.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511501PMC
May 2019

Timeline and location of recurrence following successful ablation in Barrett's oesophagus: an international multicentre study.

Gut 2019 08 11;68(8):1379-1385. Epub 2019 Jan 11.

Barrett's Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Objective: Surveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett's oesophagus (BE) are currently empiric and not based on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines.

Design: Data on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies.

Results: 594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4-4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI -7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia).

Conclusions: BE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.
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http://dx.doi.org/10.1136/gutjnl-2018-317513DOI Listing
August 2019

Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy.

Acta Neuropathol 2018 11 22;136(5):709-727. Epub 2018 Aug 22.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP.
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http://dx.doi.org/10.1007/s00401-018-1900-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208732PMC
November 2018

ERAS protocol validation in a propensity-matched cohort of patients undergoing colorectal surgery.

Int J Colorectal Dis 2018 Nov 21;33(11):1543-1550. Epub 2018 Jul 21.

Section of Colon and Rectal Surgery, Mayo Clinic, Jacksonville, FL, USA.

Purpose: Enhanced recovery after surgery (ERAS) provides many benefits. However, important knowledge gaps with respect to specific components of enhanced recovery after surgery remain because of limited validation data. The aim of the study was to validate a mature ERAS protocol at a different hospital and in a similar population of patients.

Methods: This is a retrospective analysis of patients undergoing elective colorectal surgery from 2009 through 2016. Patients enrolled in ERAS are compared with those undergoing the standard of care. Patient demographic characteristics, length of stay, pain scores, and perioperative morbidity are described.

Results: Patients (1396) were propensity matched into two equal groups (ERAS vs non-ERAS). No significant difference was observed for age, Charlson Comorbidity Index, American Society of Anesthesiologists score, body mass index, sex, operative approach, and surgery duration. Median length of stay in ERAS and non-ERAS groups was 3 and 5 days (P < .001). Mean pain scores were lower in the ERAS group, measured at discharge from the postanesthesia unit (P < .001), on postoperative day 1 (P = .002) and postoperative day 2 (P = .02) but were identical on discharge.

Conclusions: This ERAS protocol was validated in a similar patient population but at a different hospital. ERAS implementation was associated with an improved length of stay and pain scores similar to the original study. Different than most retrospective studies, propensity score matching ensured that groups were evenly matched. To our knowledge, this study is the only ERAS validation study in a propensity-matched cohort of patients undergoing elective colorectal surgery.
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http://dx.doi.org/10.1007/s00384-018-3133-4DOI Listing
November 2018

Breast Cancer Clinical Trial of Chemotherapy and Trastuzumab: Potential Tool to Identify Cardiac Modifying Variants of Dilated Cardiomyopathy.

J Cardiovasc Dev Dis 2017 May 4;4(2). Epub 2017 May 4.

Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.

Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in ( = 0.0045-0.0009, MAF = 0.18-0.50) and two in (both = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (, , , , , and , = 0.042-0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for as well as , , , , and ( = 0.044-0.008). Our results suggest that rare and common variants in , as well as in other genes, could have modifying effects in cardiomyopathy.
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http://dx.doi.org/10.3390/jcdd4020006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715703PMC
May 2017

The limbic and neocortical contribution of α-synuclein, tau, and amyloid β to disease duration in dementia with Lewy bodies.

Alzheimers Dement 2018 03 31;14(3):330-339. Epub 2017 Oct 31.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Introduction: We sought to assess the individual and combined contribution of limbic and neocortical α-synuclein, tau, and amyloid β (Aβ) to duration of illness in dementia with Lewy bodies (DLB).

Methods: Quantitative digital pathology of limbic and neocortical α-synuclein, tau, and Aβ was assessed in 49 patients with clinically probable DLB. Regression modeling examined the unique and shared contribution of each pathology to the variance of illness duration.

Results: Patients with diffuse Lewy body disease had more severe pathology of each type and a shorter duration of illness than individuals with transitional Lewy body disease. The three pathologies accounted for 25% of the total variance of duration of illness, with 19% accounted for by α-synuclein alone or in combination with tau and Aβ. When the diffuse Lewy body disease group was examined separately, α-synuclein deposition significantly exceeded that of tau and Aβ. In this model, 20% of 24% total variance in the model for duration of illness was accounted for independently by α-synuclein.

Discussion: In DLB, α-synuclein is an important predictor of disease duration, both independently and synergistically with tau and Aβ.
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http://dx.doi.org/10.1016/j.jalz.2017.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899889PMC
March 2018

Development and validation of a prediction model for adenoma detection during screening and surveillance colonoscopy with comparison to actual adenoma detection rates.

PLoS One 2017 28;12(9):e0185560. Epub 2017 Sep 28.

Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, United States of America.

Objective: The adenoma detection rate (ADR) varies widely between physicians, possibly due to patient population differences, hampering direct ADR comparison. We developed and validated a prediction model for adenoma detection in an effort to determine if physicians' ADRs should be adjusted for patient-related factors.

Materials And Methods: Screening and surveillance colonoscopy data from the cross-sectional multicenter cluster-randomized Endoscopic Quality Improvement Program-3 (EQUIP-3) study (NCT02325635) was used. The dataset was split into two cohorts based on center. A prediction model for detection of ≥1 adenoma was developed using multivariable logistic regression and subsequently internally (bootstrap resampling) and geographically validated. We compared predicted to observed ADRs.

Results: The derivation (5 centers, 35 physicians, overall-ADR: 36%) and validation (4 centers, 31 physicians, overall-ADR: 40%) cohort included respectively 9934 and 10034 patients (both cohorts: 48% male, median age 60 years). Independent predictors for detection of ≥1 adenoma were: age (optimism-corrected odds ratio (OR): 1.02; 95%-confidence interval (CI): 1.02-1.03), male sex (OR: 1.73; 95%-CI: 1.60-1.88), body mass index (OR: 1.02; 95%-CI: 1.01-1.03), American Society of Anesthesiology physical status class (OR class II vs. I: 1.29; 95%-CI: 1.17-1.43, OR class ≥III vs. I: 1.57; 95%-CI: 1.32-1.86), surveillance versus screening (OR: 1.39; 95%-CI: 1.27-1.53), and Hispanic or Latino ethnicity (OR: 1.13; 95%-CI: 1.00-1.27). The model's discriminative ability was modest (C-statistic in the derivation: 0.63 and validation cohort: 0.60). The observed ADR was considerably lower than predicted for 12/66 (18.2%) physicians and 2/9 (22.2%) centers, and considerably higher than predicted for 18/66 (27.3%) physicians and 4/9 (44.4%) centers.

Conclusion: The substantial variation in ADRs could only partially be explained by patient-related factors. These data suggest that ADR variation could likely also be due to other factors, e.g. physician or technical issues.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185560PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619799PMC
November 2017

Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial.

Pharmacogenet Genomics 2017 Oct;27(10):378-385

aHealth Sciences Research Departments of bCancer Biology cCardiovascular Diseases dHematology/Oncology, Mayo Clinic, Jacksonville, Florida eHealth Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

Objectives: The major clinical side effect of the ERBB2-targeted breast cancer therapy, trastuzumab, is a decline in the left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity.

Methods: The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or concurrent paclitaxel and trastuzumab (arm C) in patients with HER2-positive breast cancer. A genome-wide association study was performed on all patients with available DNA (N=1446). We used linear regression to identify single nucleotide polymorphisms (SNPs) associated with decline in LVEF, adjusting for age, baseline LVEF, antihypertensive medications, and the first two principle components.

Results: In total, 618 863 SNPs passed quality control and DNA from 1191 patients passed genotyping quality control and were identified as Whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF (P=7.73×10 to 8.93×10), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6, and LINC01060, in patients who received chemotherapy plus trastuzumab (arms BC, N=800). None of these loci were significant in patients who received chemotherapy only (arm A, N=391) and did not increase in significance in the combined analysis of all patients. We did not observe association, P<0.05, with SNPs previously associated with trastuzumab-induced cardiotoxicity at ERBB2, I655V, and P1170A. We replicated association, P<0.05, with SNPs previously associated with anthracycline-induced cardiotoxicity at CBR3 and ABCB1.

Conclusion: Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity.
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http://dx.doi.org/10.1097/FPC.0000000000000302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581215PMC
October 2017

Timing interval from peri-prostatic block to biopsy impacts procedural pain.

Can J Urol 2017 Jun;24(3):8795-8801

Department of Urology, Mayo Clinic, Jacksonville, Florida, USA.

Introduction: To compare visual analog scale (VAS) pain scores between patients with a 2-minute versus 10-minute delay of peri-prostatic lidocaine injection prior to transrectal ultrasound-guided prostate biopsies (TRUS-bx).

Materials And Methods: Eighty patients who underwent standard 12-core TRUS-bx by a single surgeon were prospectively randomized into four different treatment arms: bibasilar injection with a 2-minute delay, bibasilar injection plus a single apical injection with a 2-minute delay, bibasilar injection with a 10-minute delay, and bibasilar injection plus a single apical injection with a 10-minute delay. Patients were asked to report their level of pain on the VAS (0-10, with 10 indicating unbearable pain) at the following intervals: probe insertion (baseline), after each core, and post-procedure. The primary outcome measure was mean VAS score across all 12 cores minus baseline VAS score, which we refer to baseline-adjusted mean VAS score.

Results: Baseline-adjusted mean VAS score was significantly higher for the 2-minute delay group compared to the 10-minute delay group (mean: -0.7 versus -1.6, p = 0.025). Subset analysis of biopsies 1-3, 4-6, 7-9 and 10-12 also demonstrated higher baseline-adjusted mean VAS scores in the 2-minute delay group (all p ≤ 0.043).

Conclusions: Lower TRUS-bx VAS scores can be achieved by extending the time from lidocaine injection to onset of prostate biopsy from 2 to 10 minutes.
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June 2017

Impact of an Endoscopic Quality Improvement Program Focused on Adenoma Detection on Sessile Serrated Adenoma/Polyp Detection.

Dig Dis Sci 2017 06 25;62(6):1464-1471. Epub 2017 Apr 25.

Division of Gastroenterology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Background: Sessile serrated adenomas/polyps (SSA/P) are an under-recognized disease with a unique malignant pathway. Improved endoscopic recognition and pathological interpretation is needed.

Aims: To determine whether an educational intervention that improved adenoma detection rate (ADR) could improve SSA/P detection rate after reclassification of previously termed "hyperplastic" polyps.

Methods: We reanalyzed data from a prospective randomized trial of an educational intervention aimed at increasing ADR. All hyperplastic polyps ≥6 mm reported in a previously published study were rereviewed and reclassified using standardized criteria for serrated lesions. Detection rates of sessile serrated adenomas/polyps and other clinically relevant serrated polyps were calculated in the baseline and post-training phases of the original study.

Results: Of 263 available for rereview, 33 (12.5%) were reclassified as SSA/P (N = 32) or traditional serrated adenoma (TSA) (N = 1). Reclassification was more common in the right colon (18 vs. 8%, p = 0.02). Baseline SSA/P detection rate was 0.7% in the untrained group and 1.3% in the trained group. Post-training, the SSA/P detection rate increased to 2.1 and 1.5%, respectively. The clinically relevant serrated polyp detection rate at baseline was 14.2% in the untrained group and 11.3% in the trained group. After the educational intervention, the clinically relevant serrated polyp detection rates increased to 16.5 and 14.8% in the untrained and trained groups, respectively. The estimated odds of an endoscopist detecting either a SSA/P or other clinically relevant serrated polyp during colonoscopy increased by only 3% with the educational intervention (OR 1.03, 95% CI 0.61-1.74, p = 0.91).

Conclusions: Pathological re-interpretation of larger serrated polyps resulted in the reclassification of 12.5% of lesions. Quality improvement methods focused on adenoma detection did not impact SSA/P detection, and thus specific methods for serrated polyp detection are needed.
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http://dx.doi.org/10.1007/s10620-017-4582-2DOI Listing
June 2017

A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression.

Alzheimers Dement 2017 Jun 8;13(6):663-673. Epub 2016 Dec 8.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA. Electronic address:

Introduction: We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression.

Methods: Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis.

Results: A variant within a DNase hypersensitive site 5' of TREM2, rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10 and 4.6 × 10, respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10 and 3.5 × 10, Bonferroni-corrected P = 6.7 × 10 and 7.1 × 10, respectively).

Discussion: Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.
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http://dx.doi.org/10.1016/j.jalz.2016.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462884PMC
June 2017

Effect of an endoscopic quality improvement program on adenoma detection rates: a multicenter cluster-randomized controlled trial in a clinical practice setting (EQUIP-3).

Gastrointest Endosc 2017 Mar 26;85(3):538-545.e4. Epub 2016 Jul 26.

Indiana University School of Medicine, Indianapolis, Indiana, USA.

Background: Colonoscopy is protective against colorectal cancer, but its quality and protective benefits can vary. Adenoma detection rate (ADR) is associated with quality and the degree of protection against colorectal cancer and death. In a previous, single academic center, randomized, controlled trial, we demonstrated that an endoscopic quality improvement program increased ADR (EQUIP-1) and that those increases were durable (EQUIP-2). We hypothesized that EQUIP training would increase ADR in a multicenter clinical practice setting.

Methods: Nine large clinical practice sites were recruited. After a baseline period (phase I), 5 sites were randomized to receive supplemental in-person EQUIP training with active feedback. After follow-up (phase II), the changes in ADRs at these sites were compared with the changes at 4 control sites that did not receive training or feedback until after study completion.

Results: Twenty-two thousand three hundred sixteen colonoscopies were included. There was a statistically significant increase in ADR at the training sites (odds ratio [OR], 1.28; P = .004) with a raw ADR of 31% in phase I and 42% in phase II after the intervention. However, raw ADRs also increased at the control sites (from 36% to 39%). As a result, there was limited evidence of a training effect (OR, 1.03; 95% confidence interval [CI], 0.84-1.25; P = .78).

Conclusions: ADRs increased at the sites participating in the endoscopic quality improvement program. However it is not clear to what extent the training program is responsible for the changes, because raw ADRs also increased at the control sites but to a lesser extent. (Clinical Trials Registration number: NCT02325635.).
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http://dx.doi.org/10.1016/j.gie.2016.07.042DOI Listing
March 2017

Prosaposin is a regulator of progranulin levels and oligomerization.

Nat Commun 2016 06 30;7:11992. Epub 2016 Jun 30.

Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.

Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimer's and Parkinson's disease; thus, increasing PGRN levels is a promising therapeutic for multiple disorders. To uncover novel PGRN regulators, we linked whole-genome sequence data from 920 individuals with plasma PGRN levels and identified the prosaposin (PSAP) locus as a new locus significantly associated with plasma PGRN levels. Here we show that both PSAP reduction and overexpression lead to significantly elevated extracellular PGRN levels. Intriguingly, PSAP knockdown increases PGRN monomers, whereas PSAP overexpression increases PGRN oligomers, partly through a protein-protein interaction. PSAP-induced changes in PGRN levels and oligomerization replicate in human-derived fibroblasts obtained from a GRN mutation carrier, further supporting PSAP as a potential PGRN-related therapeutic target. Future studies should focus on addressing the relevance and cellular mechanism by which PGRN oligomeric species provide neuroprotection.
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http://dx.doi.org/10.1038/ncomms11992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931318PMC
June 2016

Contrast-induced nephropathy in outpatients with preexisting renal impairment: a comparison between intravenous iohexol and iodixanol.

Clin Imaging 2016 Sep-Oct;40(5):902-6. Epub 2016 Apr 26.

Division of Epidemiology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224.

Background: Concern for contrast-induced nephropathy (CIN) may result in administration of more costly agents. We prospectively compared outpatient CIN incidence of iodixanol to iohexol.

Methods: Patients were randomized to receive 100ml of iohexol (n=47) or iodixanol (n=55). We compared patients who developed CIN using the Wilson score interval and also calculated an odds ratio for the development of CIN.

Results: CIN rate for iohexol was 2% compared to 9% for iodixanol. Those receiving iodixanol were almost 5 times more likely to experience CIN.

Conclusion: These results do not suggest a benefit of iodixanol over iohexol in the study population.
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http://dx.doi.org/10.1016/j.clinimag.2016.04.008DOI Listing
December 2016

Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease.

Acta Neuropathol 2016 08 14;132(2):225-234. Epub 2016 May 14.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-β (Aβ) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aβ40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aβ40/Aβ42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aβ40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aβ42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aβ40 and apoE.
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http://dx.doi.org/10.1007/s00401-016-1580-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947445PMC
August 2016

Neuropathologic differences by race from the National Alzheimer's Coordinating Center.

Alzheimers Dement 2016 06 16;12(6):669-77. Epub 2016 Apr 16.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Introduction: Compared to Caucasians, African Americans (AAs) have higher dementia prevalence, different genetic markers, and higher vascular risk factors. However, pathologic underpinnings are unknown.

Methods: We used neuropathologic and clinical data on 110 AA and 2500 Caucasians who were demented before death. The groups were compared regarding demographics, cognition, apolipoprotein E (APOE) genotype, comorbidities, and clinical and neuropathologic characteristics.

Results: AA and Caucasians differed in their demographics, cognition at the last visit before death, APOE genotype, presence of hypertension, primary clinical diagnoses, and AD, cerebrovascular disease (CVD), and other neuropathologies such as Lewy body disease (LBD).

Discussion: AD, LBD, and CVD pathology were more common and TDP and frontotemporal lobar degeneration-tau less common in AA than in Caucasians. APOE accounted for most of the AD neuropathologic differences. If replicated, the observed differences in underlying neuropathology by race will be important for public health policy and recruitment for and interpreting of clinical trials.
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http://dx.doi.org/10.1016/j.jalz.2016.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903907PMC
June 2016

Assessment of Tumor Heterogeneity, as Evidenced by Gene Expression Profiles, Pathway Activation, and Gene Copy Number, in Patients with Multifocal Invasive Lobular Breast Tumors.

PLoS One 2016 14;11(4):e0153411. Epub 2016 Apr 14.

Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, United States of America.

Background: Invasive lobular carcinoma (ILC) comprises approximately ~10-20% of breast cancers. In general, multifocal/multicentric (MF/MC) breast cancer has been associated with an increased rate of regional lymph node metastases. Tumor heterogeneity between foci represents a largely unstudied source of genomic variation in those rare patients with MF/MC ILC.

Methods: We characterized gene expression and copy number in 2 or more foci from 11 patients with MF/MC ILC (all ER+, HER2-) and adjacent normal tissue. RNA and DNA were extracted from 3x1.5 mm cores from all foci. Gene expression (730 genes) and copy number (80 genes) were measured using Nanostring PanCancer and Cancer CNV panels. Linear mixed models were employed to compare expression in tumor versus normal samples from the same patient, and to assess heterogeneity (variability) in expression among multiple ILC within an individual.

Results: 35 and 34 genes were upregulated (FC>2) and down-regulated (FC<0.5) respectively in ILC tumor relative to adjacent normal tissue, q<0.05. 9/34 down-regulated genes (FIGF, RELN, PROM1, SFRP1, MMP7, NTRK2, LAMB3, SPRY2, KIT) had changes larger than CDH1, a hallmark of ILC. Copy number changes in these patients were relatively few but consistent across foci within each patient. Amplification of three genes (CCND1, FADD, ORAOV1) at 11q13.3 was present in 2/11 patients in both foci. We observed significant evidence of within-patient between-foci variability (heterogeneity) in gene expression for 466 genes (p<0.05 with FDR 8%), including CDH1, FIGF, RELN, SFRP1, MMP7, NTRK2, LAMB3, SPRY2 and KIT.

Conclusions: There was substantial variation in gene expression between ILC foci within patients, including known markers of ILC, suggesting an additional level of complexity that should be addressed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153411PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831790PMC
August 2016

Use of endoscopic distal attachment cap to enhance image stabilization in probe-based confocal laser endomicroscopy in colorectal lesions.

Endosc Int Open 2015 Oct 21;3(5):E516-22. Epub 2015 Jul 21.

Mayo Clinic in Florida, Jacksonville, Florida, United States.

Background And Study Aims: Colorectal cancer can be prevented through the use of colonoscopy with polypectomy. Most colon polyps are benign or low grade adenomas. However, currently all lesions need histopathologic analysis, which increases diagnostic costs and delays the final diagnosis. Confocal laser endomicroscopy (CLE) is a new technology that enables real-time endomicroscopy. However, there are challenges to maintaining a stable image with currently available systems. We conducted a small study to obtain a preliminary assessment of whether the use of an endoscopic distal attachment cap may enhance image quality of CLE in comparison with images obtained with free-hand acquisition.

Patients And Methods: Forty outpatients underwent colonoscopy for evaluation of colon polyps in a single academic medical center. Patients were assigned randomly to 1 of 2 study arms on the basis of whether an endoscopic distal attachment cap was used (n = 21, Cap Used) or not used (n = 19, No Cap) in the procedure. The quality of confocal images and probe stabilization was summarized.

Results: A total of 81 polyps were identified. The proportion of polyps with images of high quality was 74 % (28/38) in the Cap Used group and 79 % (30/38) in the No Cap arm. Image stability was also similar with and without a cap. Diagnostic accuracy was estimated to be slightly higher in the Cap Used group for probe-based confocal laser endomicroscopy (pCLE; 78 % vs 70 %). This was also true for white-light and narrow-band imaging.

Conclusions: This preliminary study did not yield any evidence to support that the use of an endoscopic distal attachment cap improves the quality of images obtained during CLE.
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http://dx.doi.org/10.1055/s-0034-1392233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612228PMC
October 2015

Evaluating pathogenic dementia variants in posterior cortical atrophy.

Neurobiol Aging 2016 Jan 8;37:38-44. Epub 2015 Oct 8.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ∼ 4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688220PMC
January 2016