Nancy N. Diehl

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study

BACKGROUND Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinsons disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinsons Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012). INTERPRETATION The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING Michael J Fox Foundation and National Institutes of Health.

A prospective, randomized, double-blind, placebo-controlled trial of endoscopic steroid injection therapy for recalcitrant esophageal peptic strictures.

BACKGROUND AND AIMS:The aim of the study was to examine whether endoscopic intralesional corticosteroid injection into recalcitrant peptic esophageal strictures reduces the need for repeat stricture dilation.METHODS:Patients with a peptic esophageal stricture and recurrent dysphagia having had at least one dilation in the preceding 18 months were enrolled in a prospective randomized, double-blind study comparing steroid and sham injection. After endoscopic confirmation of recurrent stricture, patients were randomized to receive either 0.5 cc/quadrant triamcinolone (40 mg/cc) or sham injection into the stricture followed by balloon dilation of the stricture. Patients were stratified by the number of dilations required in the preceding 18 months, severity of dysphagia, the presence of esophagitis, stricture severity, and prior therapy with a proton-pump inhibitor. Patients and their physicians were blinded to the type of intervention received. Baseline dysphagia questionnaires were completed. Post-procedurally all patients were placed on a standardized proton-pump inhibitor regimen and standardized telephone follow-up questionnaires were completed at 1 wk and at 1, 3, 6, 9, and 12 months. The original sample-size calculation of 60 patients could not be met in a timely fashion because of a low incidence of recalcitrant peptic stricture patients.RESULTS:A total of 30 patients were enrolled, 15 in the steroid group (10 men, mean age 66 yr) and 15 in the sham group (11 M, mean age 67 yr). Patients were followed for 1 yr, unless they underwent an antireflux operation or died. Two patients, one per group, died of non-esophageal causes at 1 and 12 months. Four patients had fundoplication, two in each group, unrelated to stricture or dysphagia. Two patients in the steroid group (13%) and nine in the sham group (60%) required repeat dilation (p= 0.011).CONCLUSIONS:In patients with recalcitrant peptic esophageal stricture, steroid injection into the stricture combined with acid suppression significantly diminishes both the need for repeat dilation and the average time to repeat dilation compared to sham injection and acid suppression alone.

Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study

BACKGROUND Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are the most common known genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). We assessed whether expansion size is associated with disease severity or phenotype. METHODS We did a cross-sectional Southern blot characterisation study (Xpansize-72) in a cohort of individuals with FTD, MND, both these diseases, or no clinical phenotype. All participants had GGGGCC repeat expansions in C9ORF72, and high quality DNA was available from one or more of the frontal cortex, cerebellum, or blood. We used Southern blotting techniques and densitometry to estimate the repeat size of the most abundant expansion species. We compared repeat sizes between different tissues using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. We assessed the association of repeat size with age at onset and age at collection using a Spearmans test of correlation, and assessed the association between repeat size and survival after disease onset using Cox proportional hazards regression models. FINDINGS We included 84 individuals with C9ORF72 expansions: 35 had FTD, 16 had FTD and MND, 30 had MND, and three had no clinical phenotype. We focused our analysis on three major tissue subgroups: frontal cortex (available from 41 patients [21 with FTD, 11 with FTD and MND, and nine with MND]), cerebellum (40 patients [20 with FTD, 12 with FTD and MND, and eight with MND]), and blood (47 patients [15 with FTD, nine with FTD and MND, and 23 with MND] and three carriers who had no clinical phenotype). Repeat lengths in the cerebellum were smaller (median 12·3 kb [about 1667 repeat units], IQR 11·1-14·3) than those in the frontal cortex (33·8 kb [about 5250 repeat units], 23·5-44·9; p<0·0001) and those in blood (18·6 kb [about 2717 repeat units], 13·9-28·1; p=0·0002). Within these tissues, we detected no difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of patients with FTD, repeat length correlated with age at onset (r=0·63; p=0·003) and age at sample collection (r=0·58; p=0·006); we did not detect such a correlation in samples from the cerebellum or blood. When assessing cerebellum samples from the overall cohort, survival after disease onset was 4·8 years (IQR 3·0-7·4) in the group with expansions greater than 1467 repeat units (the 25th percentile of repeat lengths) versus 7·4 years (6·3-10·9) in the group with smaller expansions (HR 3·27, 95% CI 1·34-7·95; p=0·009). INTERPRETATION We detected substantial variation in repeat sizes between samples from the cerebellum, frontal cortex, and blood, and longer repeat sizes in the cerebellum seem to be associated with a survival disadvantage. Our findings indicate that expansion size does affect disease severity, which--if replicated in other cohorts--could be relevant for genetic counselling. FUNDING The ALS Therapy Alliance, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Arizona Department of Health Services, the Arizona Biomedical Research Commission, and the Michael J Fox Foundation for Parkinsons Research.

The Incidence of Central Serous Chorioretinopathy in Olmsted County, Minnesota, 1980–2002

PURPOSE To determine the incidence of central serous chorioretinopathy (CSC) in Olmsted County, Minnesota from 1980 to 2002, determine the associated risk factors for CSC based on previously reported risk factors, investigate for any new risk factors not previously reported, and determine a population-based recurrence rate. DESIGN Population-based retrospective cohort and case-control study. PARTICIPANTS Cases were all patients with newly diagnosed CSC in Olmsted County Minnesota, from January 1, 1980 through December 31, 2002. Controls were selected from the same general population. Control group 1 patients were matched for age, gender, length of medical follow-up, and index date (corresponding with date of diagnosis for cases). Control group 2 patients were matched for all the same criteria as control group 1, and they had documented normal eye examination results. METHODS Using the Rochester Epidemiology Project medical records linkage system, which captures virtually all medical care provided to residents of Olmsted County, Minnesota, we identified all cases of CSC in county residents between 1980 and 2002. We reviewed the entire medical record of cases and applied standardized criteria for CSC. The medical records of cases and controls were reviewed for the presence of risk factors as well. MAIN OUTCOME MEASURE Incidence of CSC. Secondary outcomes were also evaluated. RESULTS There were 74 cases (63 men, 11 women) of CSC. Mean annual age-adjusted incidences per 100 000 were 9.9 (95% confidence interval [CI], 7.4-12.4) for men and 1.7 (95% CI, 0.7-2.7) for women. The incidence of CSC was approximately 6 times higher in men than in women (P<0.001). There were no significant risk factors identified for CSC. Twenty-three (31%) of the 74 patients with CSC had recurrences. The mean number of recurrences was 1.5 (range, 1-4). Median time from diagnosis to recurrence was 1.3 years (range, 0.4-18.2). CONCLUSION The incidence of CSC has not previously been reported in a population-based study. In accordance with previous studies, we found that CSC occurs more frequently in men than in women.

An Endoscopic Quality Improvement Program Improves Detection of Colorectal Adenomas

OBJECTIVES:Adenoma detection rate (ADR) is a key measure of quality in colonoscopy. Low ADRs are associated with development of interval cancer after “negative” colonoscopy. Uncontrolled studies mandating longer withdrawal time, and other incentives, have not significantly improved ADR. We hypothesized that an endoscopist training program would increase ADRs.METHODS:Our Endoscopic Quality Improvement Program (EQUIP) was an educational intervention for staff endoscopists. We measured ADRs for a baseline period, then randomly assigned half of the 15 endoscopists to undergo EQUIP training. We then examined baseline and post-training study ADRs for all endoscopists (trained and un-trained) to evaluate the impact of training. A total of 1,200 procedures were completed in each of the two study phases.RESULTS:Patient characteristics were similar between randomization groups and between study phases. The overall ADR in baseline phase was 36% for both groups of endoscopists. In the post-training phase, the group of endoscopists randomized to EQUIP training had an increase in ADR to 47%, whereas the ADR for the group of endoscopists who were not trained remained unchanged at 35%. The effect of training on the endoscopist-specific ADRs was estimated with an odds ratio of 1.73 (95% confidence interval 1.24–2.41, P=0.0013).CONCLUSIONS:Our results indicate that ADRs can be improved considerably through simple educational efforts. Ultimately, a trial involving a larger number of endoscopists is needed to validate the utility of our training methods and determine whether improvements in ADRs lead to reduced colorectal cancer.

SALVAGE RADIOTHERAPY FOR RISING PROSTATE-SPECIFIC ANTIGEN LEVELS AFTER RADICAL PROSTATECTOMY FOR PROSTATE CANCER: DOSE-RESPONSE ANALYSIS

PURPOSE To investigate the association between external beam radiotherapy (EBRT) dose and biochemical failure (BcF) of prostate cancer in patients who received salvage prostate bed EBRT for a rising prostate-specific antigen (PSA) level after radical prostatectomy. METHODS AND MATERIALS We evaluated patients with a rising PSA level after prostatectomy who received salvage EBRT between July 1987 and October 2007. Patients receiving pre-EBRT androgen suppression were excluded. Cox proportional hazards models were used to investigate the association between EBRT dose and BcF. Dose was considered as a numeric variable and as a categoric variable (low, <64.8 Gy; moderate, 64.8-66.6 Gy; high, >66.6 Gy). RESULTS A total of 364 men met study selection criteria and were followed up for a median of 6.0 years (range, 0.1-19.3 years). Median pre-EBRT PSA level was 0.6 ng/mL. The estimated cumulative rate of BcF at 5 years after EBRT was 50% overall and 57%, 46%, and 39% for the low-, moderate-, and high-dose groups, respectively. In multivariable analysis adjusting for potentially confounding variables, there was evidence of a linear trend between dose and BcF, with risk of BcF decreasing as dose increased (relative risk [RR], 0.77 [5.0-Gy increase]; p = 0.05). Compared with the low-dose group, there was evidence of a decreased risk of BcF for the high-dose group (RR, 0.60; p = 0.04), but no difference for the moderate-dose group (RR, 0.85; p = 0.41). CONCLUSIONS Our results suggest a dose response for salvage EBRT. Doses higher than 66.6 Gy result in decreased risk of BcF.

LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease.

Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n = 95; PD, n = 96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n = 1,247; PD, n = 633) and controls (n = 642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR) = 0.63; P = 0.026) and PD (OR = 0.54; P = 0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P < 0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P < 0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.

Incidence of traumatic brain injury across the full disease spectrum: A population-based medical record review study

Background: Extremely few objective estimates of traumatic brain injury incidence include all ages, both sexes, all injury mechanisms, and the full spectrum from very mild to fatal events. Methods: We used unique Rochester Epidemiology Project medical records-linkage resources, including highly sensitive and specific diagnostic coding, to identify all Olmsted County, MN, residents with diagnoses suggestive of traumatic brain injury regardless of age, setting, insurance, or injury mechanism. Provider-linked medical records for a 16% random sample were reviewed for confirmation as definite, probable, possible (symptomatic), or no traumatic brain injury. We estimated incidence per 100,000 person-years for 1987–2000 and compared these record-review rates with rates obtained using Centers for Disease Control and Prevention (CDC) data-systems approach. For the latter, we identified all Olmsted County residents with any CDC-specified diagnosis codes recorded on hospital/emergency department administrative claims or death certificates during 1987–2000. Results: Of sampled individuals, 1257 met record-review criteria for incident traumatic brain injury; 56% were ages 16–64 years, 56% were male, and 53% were symptomatic. Mechanism, sex, and diagnostic certainty differed by age. The incidence rate per 100,000 person-years was 558 (95% confidence interval = 528–590) versus 341 (331–350) using the CDC data-system approach. The CDC approach captured only 40% of record-review cases. Seventy-four percent of missing cases presented to the hospital/emergency department; none had CDC-specified codes assigned on hospital/emergency department administrative claims or death certificates; and 66% were symptomatic. Conclusions: Capture of symptomatic traumatic brain injuries requires a wider range of diagnosis codes, plus sampling strategies to avoid high rates of false-positive events.

Changing trends in the incidence, stage, survival, and screen-detection of colorectal cancer: a population-based study.

BACKGROUND & AIMS Colorectal cancer (CRC) screening has been advocated increasingly during the past 2 decades, but there is little direct evidence that it has affected cancer incidence or presentation at the population level. This study assessed concurrent trends in CRC incidence, presentation, survival, mortality, and polypectomies in Olmsted County, Minnesota. METHODS Longitudinal observational study was conducted of all Olmsted County residents with colorectal adenocarcinoma first diagnosed in 1980-1999. RESULTS Altogether, 889 invasive CRCs were diagnosed among Olmsted County residents from 1980 through 1999. Annual age- and sex-adjusted CRC incidence rates decreased significantly during this period (P = .02) with a 23% decline from 60 per 100,000 in 1980-1984 to 46 per 100,000 in 1995-1999. This was primarily accounted for by a 40% reduction in left-sided CRC (P < .001). The incidence of right-sided CRC remained unchanged, but the proportion of right-sided CRC increased from 46% to 58%. Cancer stage shifted downward, and survival improved over time. The overall proportion of screen-detected CRC rose from 8% to 17%. Annual adjusted adenomatous polypectomy rates increased dramatically from 86 to 320 per 100,000 (P < .001). CONCLUSIONS The incidence of CRC in Olmsted County has declined in recent years. An impact of screening is suggested by the observed upward trend in screen-detected cases, a favorable stage shift, and a concurrent rise in polypectomy rates. However, the incidence of right-sided cancer remains unaltered and might be less affected by historically used screening interventions. Most CRCs still present symptomatically, and more effective population screening is needed.

Postoperative outcomes in children with intermittent exotropia from a population-based cohort.

PURPOSE To describe the long-term surgical outcomes in a population-based cohort of children with intermittent exotropia. METHODS The medical records of all children (<19 years) who were diagnosed with intermittent exotropia as residents of Olmsted County Minnesota, from January 1, 1975, through December 31, 1994, and managed with surgery were retrospectively reviewed. RESULTS Of 184 patients with intermittent exotropia, 61 (33%) underwent surgery at a mean age of 7.6 years (range, 3.2 to 23 years). Twelve of the 61 children (19.7%) underwent a second surgery (10 for recurrent exotropia and 2 for consecutive esotropia), and no patient received 3 or more surgeries during a mean follow-up of 10 years from the first surgery. The final postoperative measurements were recorded in 56 of 61 patients (92%) at a mean of 7.4 years (range, 0 to 18 years) after the first surgery: 31 of the 56 (55%) were within 9(Delta) of orthotropia at distance and 25 of 55 (45%) had better than 60 seconds of stereopsis. The Kaplan-Meier rate of developing >/=10(Delta) of misalignment after the first surgery was 54% by 5 years, 76% by 10 years, and 86% by 15 years. CONCLUSIONS In this population-based study of surgery in children with intermittent exotropia, although only 1 in 5 received a second surgery, after a mean follow-up of 8 years, approximately half were successfully aligned and 45% had high-grade stereopsis.