Yaroslav Winter

Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial

BACKGROUND Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimers disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimers disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimers disease.

Contribution of Obesity and Abdominal Fat Mass to Risk of Stroke and Transient Ischemic Attacks

Background and Purpose— Waist circumference has been shown to be a better predictor of cardiovascular risk than body mass index (BMI). Our case-control study aimed to evaluate the contribution of obesity and abdominal fat mass to the risk of stroke and transient ischemic attacks (TIA). Methods— We recruited 1137 participants: 379 cases with stroke/TIA and 758 regional controls matched for age and sex. Associations between different markers of obesity (BMI, waist-to-hip ratio, waist circumference and waist-to-stature ratio) and risk of stroke/TIA were assessed by using conditional logistic regression adjusted for other risk factors. Results— BMI showed a positive association with cerebrovascular risk which became nonsignificant after adjustment for physical inactivity, smoking, hypertension, and diabetes (odds ratio 1.18; 95% CI, 0.77 to 1.79, top tertile versus bottom tertile). Markers of abdominal adiposity were strongly associated with the risk of stroke/TIA. For the waist-to-hip ratio, adjusted odds ratios for every successive tertile were greater than that of the previous one (2nd tertile: 2.78, 1.57 to 4.91; 3rd tertile: 7.69, 4.53 to 13.03). Significant associations with the risk of stroke/TIA were also found for waist circumference and waist-to-stature ratio (odds ratio 4.25, 2.65 to 6.84 and odds ratio 4.67, 2.82 to 7.73, top versus bottom tertile after risk adjustment, respectively). Conclusions— Markers of abdominal adiposity showed a graded and significant association with risk of stroke/TIA, independent of other vascular risk factors. Waist circumference and related ratios can better predict cerebrovascular events than BMI.

Health-related quality of life and its determinants in Parkinson’s disease: Results of an Italian cohort study

Parkinsons disease (PD) is a common neurodegenerative disorder with a progressive disabling course. Health-related quality of life (HrQoL) in Italian patients with PD has not been evaluated. The objective of this study was to evaluate HrQol of an Italian cohort of PD patients and to provide a comprehensive analysis of HrQoL determinants. We performed a cross-sectional survey of 70 outpatients with idiopathic PD recruited in the department of Neurology, Napoli University, Italy. Clinical data included the Unified PD Rating Scale (UPDRS), motor and non-motor symptoms. The generic instrument EuroQol (EQ-5D and EQ-VAS) was used to evaluate HrQol. Factors influencing HrQol were assessed by multivariate regression analysis. Severe problems in at least one dimension of the EQ-5D were experienced by 60% of PD patients versus 4.7% in general Italian population. The dimensions most affected were mobility, pain/discomfort and anxiety/depression with only 17.4%, 18.8% and 17.4% of patients, respectively, reporting no problems in these dimensions. The mean EQ-VAS score was 54.20 ± 18.38. Independent determinants of reduced HrQoL were increased UPDRS scores, motor fluctuations, dyskinesias, depression and dementia. PD strongly affects HrQol in Italian patients. The results of this study should be considered in the development of national healthcare programmes aimed at improvement of the HrQoL in Italian patients with PD. In particular, these programmes should concentrate not only on motor but also on non-motor manifestations of PD.

Health-Related Quality of Life in Patients with Subarachnoid Haemorrhage

Background: Aneurysmal subarachnoid haemorrhage (SAH) is a devastating disease with high mortality and disability. The data from large longitudinal studies on health-related quality of life (HRQoL) in patients with SAH are limited. The objective was to investigate HRQoL in patients after SAH and to identify predictors of HRQoL. Methods: 113 patients with aneurysmal SAH were assigned to either neurosurgery (n = 57) or endovascular coiling (n = 56). Clinical assessments (Barthel Index, modified Rankin Scale) and evaluation of HRQoL [36-Item Short-Form Survey, EuroQol (EQ5D), EQ visual analogue scale (EQ VAS)] were performed at discharge, and at 6 and 12 months of follow-up. Independent predictors of HRQoL were determined using multiple regression analysis. Results: HRQoL in SAH patients was considerably reduced compared to the normal population. At discharge, 92.2% of the patients had moderate or severe problems on the EQ5D. The EQ VAS score was 57.8 ± 19.3. However, HRQoL still showed improvement from 3 months up to 1 year. At 12 months after SAH, the EQ VAS score was approximately 12–14% higher than at discharge. The independent predictors of decreased HRQoL included female gender, severe SAH, functional disability, depression, a lower level of education and the lack of a stable partnership. Conclusions: The long-term HRQoL outcome after SAH is unfavourable. HRQoL outcome measures should be included in future studies to provide better evidence of the long-term outcomes after SAH. In addition, the independent determinants of HRQoL identified in this study should be considered in the healthcare programmes aimed at increasing the HRQoL in SAH survivors.

Incidence of Parkinson's disease and atypical parkinsonism: Russian population-based study.

Data on the incidence of Parkinsons disease (PD) and atypical parkinsonian syndromes (APS) in East European countries and Asia are limited. The objective of this prospective population‐based study was to determine the incidence of PD and APS in the Russian population. The study area was a large district of Moscow with a population of 1,237,900 inhabitants. Multiple sources of case ascertainment were used to identify incident cases of PD and APS between July 2006 and December 2008. All incident cases were examined by a specialist and followed up prospectively to confirm the diagnosis. The age‐standardized incidence rates per 100,000/year were 9.03 [95% confidence interval (CI) 8.01–10.15] for PD, 0.11 (95% CI 0.03–0.23) for multiple system atrophy, 0.14 (95% CI 0.08–0.21) for progressive supranuclear palsy, and 0.02 (95% CI 0.01–0.12) for corticobasal degeneration. The age‐standardized male‐to‐female ratio of PD was 0.87 for all ages and 1.46 for those aged 60 and older. A high proportion of new cases with PD (34%) and APS (50%) had comorbid depressive symptoms. Given the rapid growth of the elderly population in Eastern Europe and Asia, the epidemiology of PD and APS in these regions should be investigated in greater depth. The incidence of PD in our study was slightly lower than in studies of Western populations and the male‐to‐female ratio was closer to those reported in studies from Asia. The clinical implication of our study is that it highlights the need for better diagnosis and treatment of depression in early stages of PD.

Costs of illness and care in Parkinson's disease: an evaluation in six countries.

We investigated the costs of Parkinsons Disease (PD) in 486 patients based on a survey conducted in six countries. Economic data were collected over a 6-month period and presented from the societal perspective. The total mean costs per patient ranged from EUR 2620 to EUR 9820. Direct costs totalled about 60% to 70% and indirect costs about 30% to 40% of total costs. The proportions of costs components of PD vary notably; variations were due to differences in country-specific health system characteristics, macro economic conditions, as well as frequencies of resource use and price differences. However, inpatient care, long-term care and medication were identified as the major expenditures in the investigated countries.

Longitudinal study of the socioeconomic burden of Parkinson’s disease in Germany

Objective:  To determine the health economic burden on patients with Parkinson’s disease (PD) in Germany over a 12‐month observation period and provide a comprehensive analysis of cost‐driving factors.

Depression in elderly patients with Alzheimer dementia or vascular dementia and its influence on their quality of life

Background: Alzheimer dementia (AD) and vascular dementia (VD) are the most common causes of dementia in the elderly. Depression is an important co-morbid disorder in these diseases, which is often challenging to recognize. We investigated the prevalence of depression in patients with AD and VD and estimated the influence of depression on the health-related quality of life (HrQoL) in these patients. Materials and Methods: We evaluated prevalence of depression in consecutively recruited patients with AD or VD (n= 98). Depression was diagnosed according to criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and scored using the Geriatric Depression Scale. The EuroQol (EQ-5D and visual analogue scale) was applied to evaluate HrQoL. The severity of cognitive impairment was measured by the Mini-Mental State Examination (MMSE). Multiple regression analysis was used to identify factors predicting severity of depression. Results: The prevalence of depression in AD/VD was 87%. In comparison to the general population, HrQoL measured on the visual analogue scale was reduced by 54% in patients with AD/VD. In the dimension “anxiety/depression” of the EQ-5D, 81% of patients with AD/VD had moderate or severe problems. Depression showed significant association with reduced HrQoL (P<0.01). Independent predictors of more severe depression were older age, male gender, better MMSE scores and being not married. Conclusions: Depression is a prevalent psychiatric co-morbidity in patients with AD/VD, which is often under-diagnosed being masked by cognitive impairment. Depression is a predictor of reduced HrQoL in elder people with AD/VD. Therefore, they should be screened for presence of depressive symptoms and receive adequate antidepressant treatment.

Cost of Illness in Subarachnoid Hemorrhage: A German Longitudinal Study

Background and Purpose— Aneurysmal subarachnoid hemorrhage (SAH) is a cerebrovascular disease with a high mortality rate and severe disability. Longitudinal studies investigating health-economic costs in SAH are scare and only one of them analyzed cost-driving factors. The objective was to evaluate first-year costs in German patients with aneurysmal SAH and to identify independent determinants of costs. Methods— One hundred thirteen incident cases of aneurysmal SAH treated in the Department of Neurosurgery and Neuroradiology at the University of Bonn (catchment area of 500 000 people) between January 2004 and December 2005 were eligible for the study. Cost data were collected using health-economic questionnaires applied at baseline and 6- and 12-month follow-up time. All costs are expressed in &OV0556; (year 2009 values). Clinical assessments were performed using Hunt and Hess scale, Barthel Index, and Rankin Scale. Independent cost-driving factors were determined using multiple regression analysis. Results— The total first-year costs were &OV0556;38 300 (95% CI, 34 490 to 43 100) per patient. Direct costs accounted for 58.7% of total costs and were mainly paid by the health insurance (92.0%). Inpatient costs were the main cost component of direct and total costs (42.8% of total costs). The major cost-driving factors of total costs were younger age and worse functional outcome at 12-month follow-up (Barthel Index). Conclusions— Aneurysmal SAH is a cerebrovascular disease with considerable health-economic burden. Healthcare programs aimed at reducing the burden of SAH on society and individuals should consider cost-driving factors of SAH. Further health-economic studies investigating cost-driving factors of SAH in different countries are needed.

Social and clinical determinants of quality of life in Parkinson's disease in a Russian cohort study

Parkinsons disease (PD) is a chronic neurodegenerative disorder that has a major impact on health and longevity in Eastern countries. Studies investigating health-related quality of life (HRQoL) in Eastern European and Asian countries are scarce. The objective of this cross-sectional survey was to assess HRQoL in Russian patients with PD and identify its social and clinical determinants. The study included 100 outpatients with idiopathic PD and 100 controls. Patients were consecutively recruited from the neurological department of the Russian Medical State University in Moscow between October 2004 and December 2005. Regional healthy controls were matched for age and sex. The evaluation of HRQoL was performed using the EuroQol instrument (EQ-5D and EQ VAS). Disease severity was assessed using the Unified Parkinsons Disease Rating Scale (UPDRS). Multivariate regression analyses were used to identify independent determinants of HRQoL. HRQoL was more notably decreased in PD patients than in controls (98% versus 74% of individuals with moderate or severe problems in at least one dimension of the EQ-5D (p < 0.001), respectively). As compared to patients, the controls reported a higher mean EQ VAS score (74.0 +/- 16.0 versus 47.7 +/- 16.7, p < 0.001). Social and clinical determinants of HRQoL were age, disease severity, dystonia, depression, dementia and social support. While the HRQoL of patients with PD in Western countries is predominately affected by clinical parameters, social factors play an important role in Eastern countries. Our data should be considered in the development of national healthcare programs that seek to provide better social services support for patients with PD.