Cerebrospinal fluid tau and amyloid-ß1-42 in patients with dementia.

Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-ß1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-ß1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set was into two clusters, with the majority of patients with early onset Alzheimer's disease (75%) and late onset Alzheimer's disease (73%) assigned to one cluster and the patients with vascular dementia (91%), frontotemporal dementia (94%), Parkinson's disease dementia (94%) and dementia with Lewy bodies (87%) to the other cluster. Frontotemporal dementia had the highest cerebrospinal fluid levels of amyloid-ß1-42 and the lowest levels of total tau and phosphorylated tau. The highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-ß1-42 and amyloid-ß1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-ß1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease. In Parkinson's disease dementia and vascular dementia low cerebrospinal fluid amyloid-ß1-42 was associated with low Mini-Mental State Examination score. In the vascular dementia, frontotemporal dementia, dementia with Lewy bodies and Parkinson's disease dementia groups 53%, 34%, 67% and 53% of the subjects, respectively had abnormal amyloid-ß1-42 levels, 41%, 41%, 28% and 28% had abnormal total tau levels, and 29%, 28%, 25% and 19% had abnormal phosphorylated tau levels. Cerebrospinal fluid biomarkers were strongly associated with specific clinical dementia diagnoses with Alzheimer's disease and frontotemporal dementia showing the greatest difference in biomarker levels. In addition, cerebrospinal fluid amyloid-ß1-42, total tau, phosphorylated tau and the amyloid-ß1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-ß1-42 in Parkinson's disease dementia and vascular dementia. The results support the use of cerebrospinal fluid biomarkers to differentiate between dementias in clinical practice, and to estimate disease severity.

Risk of severe knee and hip osteoarthritis in relation to level of physical exercise: a prospective cohort study of long-distance skiers in Sweden.

BACKGROUND: To complete long-distance ski races, regular physical exercise is required. This includes not only cross-country skiing but also endurance exercise during the snow-free seasons. The aim of this study was to determine whether the level of physical exercise is associated with future risk of severe osteoarthritis independent of previous diseases and injuries. METHODOLOGY/PRINCIPAL FINDINGS: We used a cohort that consisted of 48 574 men and 5 409 women who participated in the 90 km ski race Vasaloppet at least once between 1989 and 1998. Number of performed races and finishing time were used as estimates of exercise level. By matching to the National Patient Register we identified participants with severe osteoarthritis, defined as arthroplasty of knee or hip due to osteoarthritis. With an average follow-up of 10 years, we identified 528 men and 42 women with incident osteoarthritis. The crude rate was 1.1/1000 person-years for men and 0.8/1000 person-years for women. Compared with racing once, participation in ≥ 5 races was associated with a 70% higher rate of osteoarthritis (multivariable-adjusted hazard ratio (HR) 1.72, 95% confidence interval (CI) 1.33 to 2.22). The association was dose-dependent with an adjusted HR of 1.09, 95% CI 1.05 to 1.13 for each completed race. A faster finishing time, in comparison with a slow finishing time, was also associated with an increased rate (adjusted HR 1.51, 95% CI 1.14 to 2.01). Contrasting those with 5 or more ski races and a fast finish time to those who only participated once with a slow finish time, the adjusted HR of osteoarthritis was 2.73, 95% CI 1.78 to 4.18. CONCLUSIONS/SIGNIFICANCE: Participants with multiple and fast races have an increased risk of subsequent arthroplasty of knee and hip due to osteoarthritis, suggesting that intensive exercise may increase the risk.

Survival after hip fracture.

Although it is known that overall mortality is increased after hip fracture, the influence of hip fracture risk factors on the subsequent mortality and cause of death has not been well studied. The objective of this study was to establish the survival after hip fracture in women and to assess the impact of comorbidity on mortality. We identified a complete population-based set of 2,245 incident hip fracture cases and 4,035 randomly selected population-based controls among women 50-81 years old in Sweden and followed these subjects for an average of 5 years through the Swedish National Inpatient and Cause-of-Death Registers. Information on factors related to hip fracture was obtained through linkage to hospital discharge data and through a mailed questionnaire. We studied excess mortality of hip fracture patients compared to controls using survival curves and proportional hazard regression models. During follow-up, 896 hip fracture patients (40%) and 516 (13%) controls died. The relative risk (RR) of death, adjusted for age and previous hospitalization for serious disease, was 2.3 (95% CI 2.0-2.5). Although the highest mortality risks were in the 1st 6 months post-fracture, RRs for fractures versus controls were increased for at least 6 years. Increased mortality was apparent both in those with evidence of comorbidity and those without. Hip fracture patients have a substantially increased risk of death that persists for at least 6 years post-fracture. The relative excess mortality is independent of comorbidity and known hip fracture risk factors.

Effect of pregnancy on survival in women with cutaneous malignant melanoma.

PURPOSE: An adverse influence of pregnancy on the risk of death in women with cutaneous melanoma was suggested historically by anecdotal reports. Previous studies included small numbers of women observed for short periods. METHODS: Using data from the Swedish National and Regional Registries, we performed a retrospective cohort study of all Swedish women who were diagnosed with cutaneous melanoma during their reproductive period, from January 1, 1958, to December 31, 1999. The relationship between pregnancy status at the diagnosis of melanoma and overall survival was examined in multivariable proportional-hazards models. RESULTS: The cohort comprised 185 women (3.3%) diagnosed with melanoma during pregnancy and 5,348 (96.7%) women of the same childbearing age diagnosed with melanoma while not pregnant. There was no statistically significant difference in overall survival between pregnant and nonpregnant groups (log-rank chi(2)1[r] = 0.84, P = .361). Pregnancy status at the time of diagnosis of melanoma was not related to survival in a multivariable Cox model in the 2,101 women (hazard ratio for death in the pregnant group was 1.08; 95% CI, 0.60 to 1.93). In the multivariable analysis, pregnancy status after diagnosis of melanoma was not a significant predictor of survival (hazard ratio for death in women who had pregnancy subsequent to the diagnosis of melanoma was 0.58; 95% CI, 0.32 to 1.05). CONCLUSION: The survival of pregnant women with melanoma is not worse than the survival of nonpregnant women with melanoma. Pregnancy subsequent to the diagnosis of primary melanoma was not associated with an increased risk of death.

Mortality in a population-based cohort of epilepsy surgery patients.

PURPOSE: To investigate mortality and especially the incidence of sudden unexpected death in epilepsy (SUDEP) in a population-based cohort of epilepsy surgery patients. METHODS: All patients who underwent epilepsy surgery treatment between January 1990 and December 1998 (surgery patients) or whose presurgical evaluation started, although not leading to an operation, during the same period (nonsurgery patients) were identified through the Swedish National Epilepsy register. All subjects were followed up through the Cause of Death Register until December 1998. Standardized mortality ratios (SMRs) for all causes of death and incidence of SUDEP were calculated. RESULTS: During the study period, 651 surgical operations were carried out on 596 patients (316 male). Of those, 14 patients died (six in SUDEP), rendering a total SMR of 4.9 [95% confidence interval (CI), 2.7-8.3]. SUDEP incidence was 2.4 per 1,000 person years. No major differences were found in SMRs or SUDEP rates between subgroups when stratifying for type of operation and for seizure outcome 2 years after surgery. SMR and SUDEP rates were higher in right-sided temporal lobe resections for gliosis than in left-sided, but the number of deaths was small. Among 212 nonsurgery patients, five died (four in SUDEP). The SMR for all causes was 7.9 (2.6-18.4), and SUDEP incidence, 6.3 per 1,000 person years. CONCLUSIONS: In this large and strictly population-based cohort, SMR for all causes and SUDEP incidence among surgery patients were similar to those of other studies. No differences in overall mortality emerged by seizure outcome, but none of the SUDEP cases was seizure free at the time of death. Four of five deaths in the nonsurgery group occurred during the surgery evaluation period. Mortality appeared to be lower for surgery than for nonsurgery patients, and the interpretation of this finding is discussed.

Risk factors for suicide in epilepsy: a case control study.

PURPOSE: Suicide is considered to be one of the most important causes of death contributing to the increased mortality of persons with epilepsy. We investigated the association between the risk of suicide in persons with epilepsy and clinical factors that might increase or have been suggested to increase the risk of suicide. METHODS: A case-control study was nested within a cohort of 6,880 patients registered in the Stockholm County In-Patient Register with a diagnosis of epilepsy. The study population was followed up through the National Cause of Death Register. Twenty-six cases of suicide, 23 cases of suspected but not proven suicide, and 171 controls, living epilepsy patients, were selected from the cohort. Clinical data were collected through medical record review. RESULTS: There was a ninefold increase in risk of suicide with mental illness and a 10-fold increase in relative risk (RR) with the use of antipsychotic drugs. The estimated RR of suicide was 16.0 [95% confidence interval (CI), 4.4-58.3] for onset of epilepsy at younger than 18 years, compared with onset after 29 years. The risk of suicide seemed to increase with high seizure frequency and antiepileptic drug (AED) polytherapy, although the estimates were imprecise and the associations not statistically significant. Insufficient data on seizure frequency and changes in AED dosage due to incomplete case records were associated with high RRs. We found no association between risk of suicide and any particular AED, with type of epilepsy, or localization or lateralization of epileptogenic focus on EEG [RR = 0.3 (95% CI, 0.1-1.7)]. CONCLUSIONS: The profile of the epilepsy patient who commits suicide that emerges from our study is a patient with early onset (particularly onset during adolescence) but not necessarily severe epilepsy, psychiatric illness, and perhaps inadequate neurologic follow-up. Previous reports of an association with temporal lobe epilepsy could not be confirmed.