Effect of menopausal hormone therapy on proteins associated with senescence and inflammation.

BACKGROUND: Estrogen may inhibit cell senescence that contributes to age-related disorders. This study determined the effects of menopausal hormone treatments on circulating levels of markers of cell senescence. METHODS: Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum using multiplexed bead-based assays and compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17ß-estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization using the Wilcoxon rank sum test. RESULTS: Serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. The difference in levels between treatment and placebo for GDF15, TNFR1, and FAS were greater for oCEE [-108 pg/mL (p = .008), -234 pg/mL (p = .0006), and -1374 pg/mL (p < .0001), respectively] than for tE2 [-76 pg/mL (p = .072), -105 pg/mL (p = .076), and -695 pg/mL (p = .036), respectively]. Additionally, TNFR1 showed a positive association with time past menopause (correlation = 0.255, p = .019). CONCLUSIONS: Circulating levels of some markers of cell senescence were lower in menopausal women treated with oCEE and tE2 compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery. These data generate new hypotheses with regard to the effects of menopause on the biology of aging.

Identifying incident Parkinson's disease using administrative diagnostic codes: a validation study.

BACKGROUND: Administrative databases that capture diagnostic codes are increasingly being used worldwide for research because they can save time and reduce costs. However, assessing validity is necessary before defining diseases using only diagnostic codes in research applications. OBJECTIVE: Our objective was to assess the validity of using diagnostic codes to identify incident Parkinson's disease (PD) cases in Olmsted County, Minnesota using an established standard for comparison (1976-2005). METHODS: Cases were identified solely using computer programs applied to administrative diagnostic code indexes from the Rochester Epidemiology Project (REP). Two codes >30 days apart or one code on the death certificate constituted PD. The standard was a clinical diagnosis by movement disorders specialists based on medical record review. Validity was assessed using positive predictive value (PPV) and sensitivity. Numbers of incident cases and incidence rates were compared between the two ascertainment methods by sex. RESULTS: The codes only method over-counted the number of incident PD cases by 73% (804 versus 464), and this over-counting generally increased with calendar year. Sensitivity was 80% (95% CI [76%, 84%]) and PPV was 46% (95% CI [34%, 50%]). Disease status misclassification accounted for two-thirds of falsely identified cases, where individuals were found to not have PD (43%) or even parkinsonism (23%) after medical record review. The codes only method also over-estimated the incidence rate time trend for men and women by approximately two-fold. CONCLUSION: In our context, using administrative diagnostic codes only to identify incident PD cases is not recommended unless more accurate algorithms are developed.

Intracardiac ablation for atrioventricular nodal reentry tachycardia using a 6 mm distal electrode cryoablation catheter: Prospective, multicenter, North American study (ICY-AVNRT STUDY).

INTRODUCTION: Radiofrequency (RF) ablation is effective for slow pathway ablation, but carries a risk of inadvertent AV block requiring permanent pacing. By comparison, cryoablation with a 4-mm distal electrode catheter has not been reported to cause permanent AV block but has been shown to be less effective than RF ablation. We sought to define the safety and efficacy of a 6-mm distal electrode cryoablation catheter for slow pathway ablation in patients with atrioventricular nodal reentry tachycardia (AVNRT). METHODS AND RESULTS: Twenty-six U.S. and eight Canadian centers participated in the study. Patients with supraventricular tachycardia (SVT) thought likely to be AVNRT were enrolled. If AVNRT was inducible and confirmed to be the clinical SVT, then the slow pathway was targeted with a cryoablation catheter using a standardized protocol of best practices. Acute success was defined as inducibility of no more than one echo beat after cryoablation. Primary efficacy was defined as acute success and the absence of documented recurrent AVNRT over 6 months of follow-up. Primary safety was a composite of serious procedure-related adverse events and/or device-related complications. Note that 397 subjects met enrollment criteria after the EP study and received cryoablation. Mean ablation procedure duration (including a waiting period) was 89 ± 40 minutes, and mean fluoroscopy time was 4.8 ± 5.9 minutes. Isoproterenol was administered before cryoablation in 53% and after the last lesion in 85% of cases. Acute procedural success was realized in 95% (378 of 397) of subjects. No subject received a permanent pacemaker due to AV block. The slow pathway could not be ablated in 19 subjects, including: 12 due to inefficacy, 2 due to transient AV block, and 5 due to both inefficacy and transient AV block. RF ablation was used in the same procedure in 11 of 19 failed subjects, and was ineffective in 3 subjects. Among the group with acute success, 10 subjects (2.7%) had documented recurrent AVNRT over the 6-month follow-up period, and all occurred within 3 months of the index cryoablation. Serious procedure-related adverse events occurred in 4 subjects (1.0%), including one each: tamponade, pulmonary embolism, femoral vein hemorrhage, and diagnostic EP catheter knotting. None of these serious adverse events were related to use of the cryoablation catheter. Overall, 93% of subjects had successful slow pathway ablation at 6 months with the study cryoablation catheter. CONCLUSIONS: Cryoablation for AVNRT using a focal 6-mm catheter was safe and effective. It resulted in a low risk of recurrence over 6 months of follow-up with no incidence of AV block requiring permanent pacing.

Characterization of health care utilization in patients receiving implantable cardioverter-defibrillator therapies: An analysis of the managed ventricular pacing trial.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are effective in terminating lethal arrhythmias, but little is known about the degree of health care utilization (HCU) after ICD therapies. OBJECTIVE: Using data from the managed ventricular pacing trial, we sought to identify the incidence and types of HCU in ICD patients after receiving ICD therapy (shocks or antitachycardia pacing [ATP]). METHODS: We analyzed HCU events (ventricular tachyarrhythmia [VTA]-related, heart failure-related, ICD implant procedure-related, ICD system-related, or other) and their association with ICD therapies (shocked ventricular tachycardia episode, ATP-terminated ventricular tachycardia episode, and inappropriately shocked episode). RESULTS: A total of 1879 HCUs occurred in 695 of 1030 subjects (80% primary prevention) and were classified as follows: 133 (7%) VTA-related, 373 (20%) heart failure-related, 97 (5%) implant procedure-related, 115 (6%) system-related, and 1160 (62%) other. Of 2113 treated VTA episodes, 1680 (80%) received ATP only and 433 (20%) received shocks. Stratifying VTA-related HCUs on the basis of the type of ICD therapy delivered, there were 25 HCUs per 100 shocked VTA episodes compared with 1 HCU per 100 ATP-terminated episodes. Inappropriate ICD shocks occurred in 8.7% of the subjects and were associated with 115 HCUs. The majority of HCUs (52%) began in the emergency department, and 66% of all HCUs resulted in hospitalization. CONCLUSION: For VTA-related HCUs, shocks are associated with a 25-fold increase in HCUs compared to VTAs treated by ATP only. Application of evidence-based strategies and automated device-based algorithms to reduce ICD shocks (higher rate cutoffs, use of ATP, and arrhythmia detection) may help reduce HCUs.

Feedback to providers improves evidence-based implantable cardioverter-defibrillator programming and reduces shocks.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) shocks are associated with increased anxiety, health care utilization, and potentially mortality. OBJECTIVE: The purpose of the Shock-Less Study was to determine if providing feedback reports to physicians on their adherence to evidence-based shock reduction programming could improve their programming behavior and reduce shocks. METHODS: Shock-Less enrolled primary prevention (PP) and secondary prevention (SP) ICD patients between 2009 and 2012 at 118 study centers worldwide and followed patients longitudinally after their ICD implant. Center-specific therapy programming reports (TPRs) were delivered to each center 9 to 12 months after their first enrollment. The reports detailed adherence to evidence-based programming targets: number of intervals to detect ventricular fibrillation (VF NID), longest treatment interval (LTI), supraventricular tachycardia (SVT) discriminators (Wavelet, PR Logic), SVT limit, Lead Integrity Alert (LIA), and antitachycardia pacing (ATP). Clinicians programmed ICDs at their discretion. The primary outcome measure was the change in utilization of evidence-based shock reduction programming before (phase I, n = 2694 patients) and after initiation of the TPR (phase II, n = 1438 patients). RESULTS: Patients implanted after feedback reports (phase II) were up to 20% more likely to have their ICDs programmed in line with evidence-based shock reduction programming (eg, VF NID in PP patients 30/40 in 33.5% vs 18.6%, P < .0001). Patients implanted in phase II had a lower risk of all-cause shock (adjusted hazard ratio 0.72, 95% confidence interval 0.58-0.90, P = .003). CONCLUSION: Providing programming feedback reports improves adherence to evidence-based shock reduction programming and is associated with lower risk of ICD shocks.

Lack of current implantable cardioverter defibrillator guidelines application for primary prevention of sudden cardiac death in Latin American patients with heart failure: a cross-sectional study.

AIMS: This cross-sectional study evaluated the application of accepted international implantable cardioverter defibrillator (ICD) guidelines for primary prevention of sudden cardiac death in patients with heart failure. METHODS AND RESULTS: The PLASMA (Probabilidad de Sufrir Muerte Arritmica) study was designed to characterize management of cardiac patients in Latin America. Twelve centres included 1958 consecutively admitted patients in cardiology units in 2008 and 2009. Discharged patients were evaluated for primary prevention, ICD indication and prescription by general cardiologists. Of 1711 discharged patients, 1525 (89%) had data available for evaluating indication status. Class I indications for ICD therapy were met for 153 (10%) patients based on collected data. Only 20 (13%, 95% confidence interval: 7.7-18.4%) patients with indication were prescribed an ICD. Patients prescribed an ICD were younger than patients who were not prescribed an ICD (62 vs. 68 years, P < 0.01). The reasons given by cardiologists for not prescribing an ICD for 133 patients with an indication were: indication criteria not met (75%), life expectancy <1 year (9.7%), rejection by the patient (5.2%), no medical coverage paying for the device (3.7%), psychiatric patient (2.2%), and other reasons (4.2%). CONCLUSIONS: In Latin America, international guidelines for primary prevention ICD implantation are not well followed. The main reason is that cardiologists believe that patients do not meet indication criteria, even though study data confirm that criteria are met. This poses a significant challenge and underlines the importance of continuous and improved medical education.

Do baseline diastolic echocardiographic parameters predict outcome after resynchronization therapy? Results from the PROSPECT trial.

INTRODUCTION: Cardiac resynchronization therapy (CRT) can improve clinical and cardiac structural status in heart failure patients. The role of baseline diastolic echocardiographic parameters to characterize the likelihood of positive outcomes is not well known. We explored relationships between diastolic parameters and outcomes 6 months after CRT implant in the Predictors of Response to CRT (PROSPECT) Trial. HYPOTHESIS: We hypothesized that diastolic echocardiographic parameters were associated with clinical and structural outcomes in CRT patients. METHODS: For 426 patients in PROSPECT, a prospective observational trial of CRT, baseline E/A ratio, left atrial (LA) area, isovolumic relaxation time, left ventricular inflow deceleration time, E' velocity, and E/E' ratio were evaluated and related to 6-month clinical composite score (CCS) and left ventricular end-systolic volume (LVESV) reduction using Spearman rank-order correlations. Parameters associated with outcomes were analyzed further by discrete categorization. RESULTS: As continuous variables, only E/A ratio and LA area correlated with CCSs (P = 0.017, P = 0.045, respectively) and relative change in LVESV at 6 months (P < 0.0001, P = 0.001, respectively). As discrete variables, E/A ratio and LA area also correlated with CCSs and LVESV. CONCLUSION: Diastolic echo parameters E/A ratio and LA area were associated with clinical and structural outcomes in CRT patients at 6 months.

Paced left ventricular QRS width and ECG parameters predict outcomes after cardiac resynchronization therapy: PROSPECT-ECG substudy.

BACKGROUND: For patients with symptomatic New York Heart Association class III or IV, ejection fraction ≤ 35%, and QRS ≥ 130 ms, cardiac resynchronization therapy (CRT) has become an established treatment option. However, use of these implant criteria fails to result in clinical or echocardiographic improvement in 30% to 45% of CRT patients. METHODS AND RESULTS: The Predictors of Response to CRT (PROSPECT)-ECG is a substudy of the prospective observational PROSPECT trial. ECGs collected before, during, and after CRT implantation were analyzed. Primary outcomes were improvement in clinical composite score (CCS) and reduction of left ventricular end systolic volume (LVESV) of >15% after 6 months. Age, sex, cause of cardiomyopathy, myocardial infarction location, right ventricular function, mitral regurgitation, preimplantation QRS width, preimplantation PR interval, preimplantation right ventricular-paced QRS width, preimplantation axis categories, LV-paced QRS width, postimplantation axis categories, difference between biventricular (Bi-V) pacing and preimplantation QRS width, and QRS bundle branch morphological features were analyzed univariably in logistic regression models to predict outcomes. All significant predictors (α=0.1), age, and sex were used for multivariable analyses. Cardiomyopathy cause interaction and subanalyses were also performed. In multivariable analyses, only QRS left bundle branch morphological features predicted both CCS (odds ratio [OR]=2.46, P=0.02) and LVESV (OR=2.89, P=0.048) response. The difference between Bi-V and preimplantation QRS width predicted CCS improvement (OR=0.89, P=0.04). LV-paced QRS width predicted LVESV reduction (OR=0.86, P=0.01). Specifically, an LV-paced QRS width of ≤ 200 ms was predictive of nonischemic LVESV reduction (OR=5.12, P=0.01). CONCLUSIONS: Baseline left bundle branch QRS morphological features, LV-paced QRS width, and the difference between Bi-V and preimplantation QRS width can predict positive outcomes after CRT and may represent a novel intraprocedural method to optimize coronary sinus lead placement. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00253357.

Prognostic significance of atrial arrhythmias in a primary prevention ICD population.

INTRODUCTION: We investigated whether primary prevention implantable cardioverter defibrillator (ICD) patients with atrial arrhythmias are at higher risk for ICD shocks and mortality compared to patients without atrial arrhythmias in a subanalysis of the PREPARE study. METHODS AND RESULTS: Details of the PREPARE study design and results have been previously reported. We now included 537 of the 700 patients enrolled in PREPARE. These patients had a dual or biventricular device and at least one device follow-up after implantation. Continuously collected device diagnostics data were used to classify patients into two groups during follow-up: with (n = 133) or without (n = 404) atrial tachycardia/atrial fibrillation (AT/AF). The primary outcomes were ICD shocks and mortality. Subjects were followed for a mean of 333 ± 73 (range 5-365) days. During a follow-up of 1 year, ICD shocks occurred in 44 (8%) patients. Significantly, more patients with AT/AF received a shock (13.0% vs 6.9%, P = 0.03), with inappropriate shocks accounting for the majority of the difference (6.9% vs 2.6%, P = 0.02). There was no difference in prevalence of shocks between patients with and without a history of AF. Mortality was similar in patients with and without AT/AF, whether detected during the study or prior to the study. In addition, the 34 subjects with high average ventricular rate (≥110 beats per minute) during AT/AF had a higher risk of an inappropriate shock (21.0% vs 2.1%, P < 0.01). CONCLUSION: Primary prevention ICD patients with AT/AF are more likely to receive shocks, especially inappropriate shocks. Mortality was not higher in AT/AF patients. (PACE 2011; 34:1070-1079).

Cardiac resynchronization therapy may benefit patients with left ventricular ejection fraction >35%: a PROSPECT trial substudy.

AIMS: Cardiac resynchronization therapy (CRT) is currently limited to those with left ventricular ejection fraction (LVEF) < or =35%. To evaluate whether patients with LVEF >35% might benefit from CRT, we performed a retrospective analysis of the predictors of response to CRT (PROSPECT) database. METHODS AND RESULTS: PROSPECT was a prospective, multicentre study that enrolled CRT patients based on enrolling centre-evaluated LVEF <35%, but all echocardiograms were subsequently analysed by a core laboratory. Patients with core laboratory-measured LVEF >35% (OVER35) were compared with those whose LVEF was <35% (UNDER35). Clinical composite score (CCS) and change in LV end systolic volume (LVESV) were analysed from baseline to 6-month follow-up. Of 361 patients, 86 (24%) had LVEF >35%. At entry, OVER35 had smaller LV volumes, shorter QRS duration, shorter 6-min walk distance, and were more likely to have ischaemic aetiology than UNDER35. Outcomes were comparable between the groups, with 62.8% of OVER35 improved in CCS (70.2% in UNDER35) and 50.8% of OVER35 improved in LVESV (57.8% in UNDER35). CONCLUSION: Patients with LVEF >35%, New York heart association functional Class III-IV status, and QRS >130 ms appear to derive clinical and structural benefit from CRT. As CRT may offer a valuable option for these patients, this hypothesis should be formally tested in a prospective, randomized multicentre trial.

Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial.

OBJECTIVES: The purpose of this trial was to determine whether microvolt T-wave alternans (MTWA) predicts ventricular tachyarrhythmic events (VTEs) in post-myocardial infarction patients with left ventricular ejection fraction (LVEF) < or =30%. BACKGROUND: Previous studies have established MTWA as a predictor for total and arrhythmic mortality, but its ability to identify prophylactic implantable cardioverter-defibrillator (ICD) recipients most likely to experience VTEs remains uncertain. METHODS: This prospective trial was conducted at 50 U.S. centers. Patients were eligible if they met MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) indications for device implant. All patients underwent MTWA testing followed by ICD implantation, with pre-specified programming to minimize the likelihood of therapies for non-life-threatening VTE. Minimum follow-up was 2 years with annual MTWA testing. Initially indeterminate MTWA tests were repeated. RESULTS: Analyses were conducted on 575 patients (84% male; average age +/- SD = 65 +/- 11 years; average LVEF +/- SD = 0.24 +/- 0.05). The final distribution of MTWA results were: MTWA positive in 293 (51%), MTWA negative in 214 (37%), and indeterminate in 68 patients (12%). Over an average follow-up of 2.1 +/- 0.9 years, there were 70 VTEs. A VTE occurred in 48 of 361 (13%, 6.3%/year) MTWA non-negative and 22 of 214 (10%, 5.0%/year) MTWA negative patients. A non-negative MTWA test result was not associated with VTE (hazard ratio: 1.26; 95% confidence interval: 0.76 to 2.09; p = 0.37), although total mortality was significantly increased (hazard ratio: 2.04; 95% confidence interval: 1.10 to 3.78; p = 0.02). CONCLUSIONS: In MADIT-II-indicated ICD-treated patients, the risk of VTE does not differ according to MTWA classification, despite differences in total mortality. (MASTER I-Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients; NCT00305240).

Use of an intracardiac electrogram eliminates the need for a surface ECG during implantable cardioverter-defibrillator follow-up.

BACKGROUND: A surface electrocardiogram (SECG) for pacing threshold measurements during routine implantable cardioverter-defibrillator (ICD) follow-up can be cumbersome. This study evaluated the use of an intrathoracic far-field electrogram (EGM) derived between the Can and superior vena cava (SVC) electrode -- the Leadless electrocardiogram (LLECG), in dual chamber ICDs in performing pacing threshold tests. METHODS: The LLECG was evaluated prospectively during atrial and ventricular pacing threshold testing as a substudy of the Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter-Defibrillators trial (EMPIRIC) in which dual chamber ICDs were implanted in 888 patients. Threshold tests were conducted at 1 volt by decrementing the pulse width. Follow-up at three months compared pacing thresholds measured using LLECG with those using Lead I of the surface ECG (SECG). The timesaving afforded by LLECG was assessed by a questionnaire. RESULTS: The median threshold difference between LLECG and SECG measurements for both atrial (0.00 ms, P = 0.90) and ventricular (0.00 ms, P = 0.34) threshold tests were not significant. Ninety percent of atrial and ventricular threshold differences were bounded by +/- 0.10 ms and -0.10 to +0.04 ms, respectively. We found that 99% of atrial and ventricular thresholds tests at six and 12 months attempted using LLECG were successfully completed. The questionnaire indicated that 65% of healthcare professionals found LLECG to afford at least some timesaving during device follow-ups. CONCLUSION: Routine follow-up can be performed reliably and expeditiously in dual chamber Medtronic (Minneapolis, MN, USA) ICDs using LLECG alone, resulting in overall timesaving.

Chemical exposures and Parkinson's disease: a population-based case-control study.

The putative association between pesticide exposures and Parkinson's disease (PD) remains controversial. We identified all subjects who developed PD in Olmsted County, Minnesota, from 1976 through 1995, and matched them by age (+/- 1 year) and sex to general population controls. We assessed exposures to chemical products by means of telephone interview with cases, controls, or their proxies (149 cases; 129 controls). Exposure to pesticides related or unrelated to farming was associated with PD in men (odds ratio, 2.4; 95% confidence interval, 1.1-5.4; P = 0.04). The association remained significant after adjustment for education or smoking. Analyses for the other six categories of industrial and household chemicals were all nonsignificant. This population-based study suggests a link between pesticides use and PD that is restricted to men. Pesticides may interact with other genetic or nongenetic factors that are different in men and women.

The Mayo Clinic cohort study of personality and aging: design and sampling, reliability and validity of instruments, and baseline description.

We established a historical cohort of 7,216 subjects who completed the Minnesota Multiphasic Personality Inventory (MMPI) at the Mayo Clinic from 1962 through 1965 for research (not clinical indication), and who resided within a 120-mile radius centered in Rochester, Minnesota. We describe here the overall cohort design and sampling, we report results concerning reliability and validity, and we describe age and sex patterns at baseline for four MMPI scores of primary interest (depression, anxiety, social introversion, and negativity). Subjects excluded from the cohort because of missing data had MMPI scores similar to subjects included (after appropriate rescaling). A cut-off specific for age and sex at the 75th percentile of the distribution of raw scores was valid compared with the traditional clinical cut-off (T scores plus one standard deviation). Baseline scores for all four scales were higher in women than in men at all ages (all p < 0.0001). Depression and social introversion scores showed an increasing trend with age in both sexes (Spearman rank correlation, rho = 0.05 and 0.08, respectively, p < 0.0001 for both). Baseline scores on the anxiety scale showed a decreasing trend with age in both sexes (rho = -0.06, p < 0.0001). Negativity scores remained relatively stable with age in both sexes (rho = 0.03, p = 0.01). We found a high correlation between the anxiety score and the negativity score (rho = 0.90, p < 0.0001) even after the exclusion of overlapping items (rho = 0.68, p < 0.0001). This newly established historical cohort study provides opportunities to test hypotheses regarding the link between personality and aging, aging-related diseases, and overall mortality.

Risk of cancer after the diagnosis of Parkinson's disease: a historical cohort study.

We investigated the risk of cancer after the diagnosis of Parkinson's disease (PD) through a historical cohort study. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all incident cases of PD in Olmsted County, Minnesota from 1976 through 1995. Patients with PD were matched by age (+/- 1 year) and gender to referent subjects from the same population. For 196 patients and 185 referent subjects, we ascertained the incidence of cancer through medical records abstraction between the date of diagnosis (or index date) and death, loss to follow-up, or end of study. The risk of cancer was higher among patients than in referent subjects (relative risk [RR] = 1.64; 95% confidence interval [CI] = 1.15-2.35; P = 0.007). The RR did not change noticeably after adjustment for smoking. The increased risk was significant for nonmelanoma skin cancer (RR = 1.76; 95% CI = 1.07-2.89; P = 0.03), but not for other more severe types of cancer; therefore, we cannot exclude the occurrence of a surveillance bias. Among PD patients, there was no relation between the risk of cancer and the cumulative dose of levodopa received or the use of other PD medications.

The Mayo Clinic family study of Parkinson's disease: study design, instruments, and sample characteristics.

We describe here the Mayo Clinic Family Study of Parkinson's disease (PD), including the overall study design (historical cohort study of relatives from birth to onset of PD or censoring), the data collection instruments, the strategies implemented to prevent or measure biases, and the sample obtained. These methodological details may provide assistance to other investigators designing studies of the familial aggregation of PD or other aging-related chronic diseases. We investigated the incidence of PD and other neurodegenerative diseases among 1,001 first-degree relatives of 162 patients with PD and 851 relatives of 147 controls representative of the population of Olmsted County, Minn., USA. In addition, we studied 2,713 first-degree relatives of 411 patients with PD referred to the Mayo Clinic. Finally, we studied a group of 625 spouses of either cases or controls. Relatives with PD or other neurodegenerative diseases were ascertained using the family study method.

Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study.

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a twofold to threefold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Several putative loci identified by genetic linkage have been reported to exist on chromosomes 1 (HPC1, PCAP, and CAPB), X (HPCX), 17 (HPC2), and 20 (HPC20), with genes RNASEL (HPC1) and ELAC2 (HPC2) tentatively defined. In this study, we report our genome linkage scan in 160 prostate cancer families, using the ABI Prism Linkage Mapping Set Version 2 with 402 microsatellite markers. The most significant linkage was found for chromosome 20, with a recessive model heterogeneity LOD score (HLOD) of 4.77, and a model-free LOD score (LOD - ZLR) of 3.46 for the entire group of pedigrees. Linkage for chromosome 20 was most prominent among families with a late age of diagnosis (average age at diagnosis >/= 66 years; maximum LOD - ZLR = 2.82), with <5 affected family members (LOD - ZLR = 3.02), with presence of hereditary prostate cancer (LOD - ZLR = 2.81), or with no male-to-male transmission of disease (LOD - ZLR = 3.84). No other chromosome showed significant evidence for linkage. However, chromosomes 6 and X showed suggestive results, with maximum LOD - ZLR values of 1.38 and 1.36, respectively. Subset analyses suggest additional chromosomal regions worth further follow-up.

Survival study of Parkinson disease in Olmsted County, Minnesota.

OBJECTIVE: To compare survival in incident cases of Parkinson disease (PD) with survival in subjects free of PD from the general population. METHODS: We used the medical records linkage system of the Rochester Epidemiology Project to identify incident cases of PD in Olmsted County, Minnesota, for the period 1976-1995. Cases were matched by age and sex to referent subjects from the same population. For 196 cases and 185 referent subjects, we studied survival between the date of diagnosis of PD (or index date) and death, loss to follow-up, or end of the study (May 1, 2000). RESULTS: The median length of follow-up was 7.2 years for cases and 8.0 years for referent subjects; 110 patients with PD and 79 referent subjects died during follow-up. The median survival was 10.3 years in cases and 13.4 years in referent subjects. The relative risk (RR) of death was 1.60 (95% confidence interval [CI], 1.20-2.14; P =.002) overall, 1.81 (95% CI, 1.15-2.84; P =.01) in women, and 1.49 (95% CI, 1.01-2.20; P =.04) in men. There was a decreasing trend in the RR of death according to age at onset of PD (in tertiles): younger than 67 years, RR, 2.04 (95% CI, 0.99-4.19; P =.05); 67 to 76 years, RR, 1.76 (95% CI, 1.08-2.86; P =.02); and older than 76 years, RR, 1.48 (95% CI, 0.95-2.29; P =.08). Patients with PD who had both rest tremor and pronounced asymmetry had a better prognosis than patients with neither clinical characteristic. Patients with PD who smoked survived better than expected. CONCLUSIONS: Patients with PD face a higher risk of death compared with subjects free of PD from the general population. Certain clinical characteristics and smoking modify survival.

Mutations in CHEK2 associated with prostate cancer risk.

The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of which were unique) were found among 578 patients. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in nine families. These mutations included two frameshift and three missense mutations. Importantly, 16 of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathological effect of CHEK2 mutations in prostate cancer development. Analyses of the two frameshift mutations in Epstein Barr virus-transformed cell lines, using reverse-transcriptase polymerase chain reaction and western blot analysis, revealed abnormal splicing for one mutation and dramatic reduction of CHEK2 protein levels in both cases. Overall, our data suggest that mutations in CHEK2 may contribute to prostate cancer risk and that the DNA-damage-signaling pathway may play an important role in the development of prostate cancer.