The economic benefit of timely, adequate, and adherence to Parkinson's disease treatment: the Value of Treatment Project 2.

BACKGROUND: Parkinson's disease (PD) is a chronic progressive neurological disorder with a high psychosocial and economic burden. As part of the European Brain Council (EBC)-led Value of Treatment project, this study aimed to capture the economic benefit of timely, adequate, and adherence to PD treatment. METHODS: The EBC Value of Treatment Initiative combined different stakeholders to identify unmet needs in the patients' journey according to Rotterdam methodology. The economic evaluation focused on three major topics identified as major gaps: start of treatment; best treatment for advanced disease; and adherence to treatment. Two separate healthcare systems (Germany and the UK) were chosen. Cost-effectiveness was determined by using decision-analytical modelling approaches. Effectiveness was expressed as quality-adjusted life-years (QALYs) gained and incremental cost-effectiveness ratio (ICER). RESULTS: Treatment intervention in PD was found to be cost-effective regardless of the initial health state of the patient receiving the treatment. Cost savings were between -€1000 and -€5400 with 0.10 QALY gain and -€1800 and -€7600 with 0.10 QALY gain for Germany and the UK, respectively. Treatment remains cost-effective within the National Institute for Health and Care Excellence thresholds. Availability of adequate treatment to more patients was also found to be cost-effective, with an ICER of €15,000-€32,600 across country settings. Achieving the target adherence to treatment would generate cost-savings of €239,000-€576,000 (Germany) and €917,000-€2,980.000 (UK) for every 1,000 patients treated adequately. CONCLUSIONS: The analyses confirmed that timely, adequate, and adherence to PD treatment will not only improve care of the patients but is also cost-effective across healthcare systems. Further studies with a distinct identification of gaps in care are necessary to develop better and affordable care.

[Dementia: relevant aspects for otorhinolaryngologists]. / Demenzerkrankungen: Relevantes für den HNO-Arzt.

The aging of society observed during the past century in industrialized countries has not only led to a longer life expectancy, but also an increased frequency of age-related diseases and multimorbidity. In addition to dysphagia and vertigo, sensory deficits such as olfaction and hearing disorders are common in elderly persons and have a significant influence on quality of life. Alzheimer's disease is the most common form of dementia. Epidemiological studies have recently shown that disorders of olfaction and hearing are not only associated with dementia, but also represent specific risk factors for development and progression of the disease. Recognition and adequate treatment, e.g., of hearing loss, by otorhinolaryngologists is thus assuming an increasingly important role, not only to preserve patients' quality of life, but also to reduce the risk of developing dementia in the future.

Pre-fracture quality of life predicts 1-year survival in elderly patients with hip fracture-development of a new scoring system.

UNLABELLED: Hip fractures are common in elderly people. Despite great progress in surgical care, the outcome of patients with hip fracture remains disappointing. This study determined four prognostic factors (lower ASA score, higher pre-fracture EQ-5D index, higher MMSE score, and female gender) to predict 1-year survival in patients with hip fracture. INTRODUCTION: This study determined the prognostic factors for 1-year survival in patients with hip fracture. Based on these predictors, a scoring system was developed for use upon patients' admission to the hospital. METHODS: Hip fracture patients, aged ≥60 years, were prospectively enrolled. Upon admission, patients' sociodemographic data, type of fracture, American Society of Anesthesiologists (ASA) score, health-related quality of life scores (EQ-5D index) and Mini-Mental State Examination (MMSE) scores were recorded, among other parameters. Correlational analysis was performed on all potential variables to identify relevant predictor variables of 1-year survival. Univariate regression analysis was performed on all selected variables, followed by a multivariate analysis for variables that were significant in the univariate analysis. The final score was developed by converting the ß-coefficients of each variable from the multivariate analysis into a scoring system. RESULTS: For 391 hip fracture patients, complete data were available at the time of the 1-year follow-up. In multivariate regression analysis, independent predictors of 1-year survival were lower ASA score, higher pre-fracture EQ-5D index, higher MMSE score, and female gender. The different variables were weighted according to their ß-coefficient to build the prognostic score, which ranged from 0 to 10 points. The ROC curve for 1-year mortality after hip fracture showed an area under the curve of 0.74 (R (2) = 0.272; 95 % CI 0.68-0.79; p < 0.001). CONCLUSIONS: With only four instruments, the new score represents a useful tool for estimating 1-year survival in elderly patients with hip fractures. At present, the score is limited due to a lack of validation. A validation study is currently underway to prove its reliability.

Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.

BACKGROUND: Data on gender-specific profiles of cognitive functions in patients with Parkinson's disease (PD) are rare and inconsistent, and possible disease-confounding factors have been insufficiently considered. METHOD: The LANDSCAPE study on cognition in PD enrolled 656 PD patients (267 without cognitive impairment, 66% male; 292 with mild cognitive impairment, 69% male; 97 with PD dementia, 69% male). Raw values and age-, education-, and gender-corrected Z scores of a neuropsychological test battery (CERAD-Plus) were compared between genders. Motor symptoms, disease duration, l-dopa equivalent daily dose, depression - and additionally age and education for the raw value analysis - were taken as covariates. RESULTS: Raw-score analysis replicated results of previous studies in that female PD patients were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.03), while men outperformed women in visuoconstruction (p = 0.002) and figural memory (p = 0.005). In contrast, gender-corrected Z scores showed that men were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.02; recognition, p = 0.04), while no difference was found for visuospatial tests. This picture could be observed both in the overall analysis of PD patients as well as in a differentiated group analysis. CONCLUSIONS: Normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is stronger in women than in men with PD. Future studies are needed to replicate these findings, examine the progression of gender-specific cognitive decline in PD and define different underlying mechanisms of this dysfunction.

What determines health-related quality of life in hip fracture patients at the end of acute care?--a prospective observational study.

UNLABELLED: Hip fractures are associated with reduced health-related quality of life (HrQoL). We found pre-existing need of care or limited function, cognitive impairment, and depression to be independent factors associated with lower HrQoL during the postsurgical period. In contrast, joint replacement was associated with better HrQoL compared to internal fixation. Patients' treatment should be focused on functional recovery and treatment of depression. INTRODUCTION: The aim of the study was to identify independent factors that were correlated with health-related quality of life (HrQoL) after hip fracture. METHODS: A total of 402 patients with a mean age of 81 years suffering from a hip fracture were included in this prospective, observational cohort study. HrQoL (determined by the EuroQol instrument) was measured at admission and at discharge from an acute care hospital. Independent factors correlated with HrQoL at discharge and changes from pre-fracture to discharge were determined using multivariate analyses. The influence of antidepressants was evaluated by an ANOVA with repeated measurements. RESULTS: Need of care prior to fracture was the most important determinant of EQ-5D index at discharge (ß = -0.359, p = 0.003). Additionally, low Mini Mental Status Examination (MMSE) was associated with a lower EQ-5D index at discharge (MMSE 0-9: ß = -0.238, p <0.001; MMSE 10-19: ß = -0.294, p <0.001) and a greater decrease in EQ-5D during hospitalisation (MMSE 10-19: ß = 0.281, p <0.001), while joint replacement (compared to internal fixation) was associated with a higher EQ-5D index (ß = 0.188, p = 0.002) and a lower decrease in the index (ß = -0.216, p = 0.003). EQ VAS values at discharge were correlated with pre-fracture Barthel Index (ß = 0.253, p <0.001) and Geriatric Depression Scale scores (ß = -0.135, p = 0.026). Depressive patients on antidepressants demonstrated less of a decrease in the EQ-5D index compared to patients not receiving medication (F = 2.907, p = 0.090). CONCLUSIONS: Acute care of hip fracture patients should be focused on functional recovery and treatment of depression. When the preferred surgical strategy is unclear, joint replacement should be considered.

[Multimorbidity: concept, epidemiology and treatment]. / Multimorbidität: Konzept, Epidemiologie, Versorgung.

Multimorbidity is defined as the simultaneous presence of several diseases or health conditions (at least two or more) in one person. In contrast, comorbidity indicates the occurrence of additional diseases to a main or index disease. The probability for the occurrence of multimorbidity increases with advancing age and is a growing problem for affected patients, relatives, and also for the healthcare system, as multimorbid patients have a decreased quality of life, often requiring high levels of care and may increase the resource use at all levels of healthcare. The prevalence of multimorbidity is difficult to estimate due to the different conceptualizations and the age-related accumulation. Thus, the numbers vary greatly in the different studies and are estimated to be between 3 % and 50 %, in some studies numbers are even higher. The treatment of patients is often difficult and results in a variety of medications and drugs that are often not coordinated with each other and so may increase the risk for adverse drug effects, especially in a fragile population. The aim of this article is to give a brief overview on the concept of multimorbidity and comorbidity, to present epidemiological data and to describe the care of patients with multiple illnesses in the German context.

[Prediction of Alzheimer's dementia]. / Prädiktion der Alzheimer-Demenz.

The prediction of Alzheimer's dementia is relevant for the development and design of prevention trials but also for individual counselling of patients. There are two key characteristics which determine the level of prediction that can be achieved. Firstly, the prevalence of Alzheimer's dementia in the respective setting is important. In low prevalence settings, such as primary care populations, it is probably impossible to achieve positive predictive values above 50%. In high prevalence settings, such as memory clinics, the positive predictive value of Alzheimer's dementia can be much higher. The second major characteristic is the level of cognitive impairment of an individual. The predictive power for Alzheimer's dementia increases from the cognitively healthy status to the status of progressive mild cognitive impairment. Prediction can further be increased by the use of cerebral spinal fluid and brain imaging biomarkers of Alzheimer's disease. The combination of different biomarkers may increase prediction even further. The present article reviews studies and outlines the principles of prediction of Alzheimer's dementia.

[Anticoagulation medication for proximal femoral fractures: prospective validation study of new institutional guidelines]. / Gerinnungshemmende Medikation bei proximaler Femurfraktur: Prospektive Validierungsstudie einer neuen institutionellen Leitlinie.

BACKGROUND: Under current guidelines surgical care of hip fractures has to be initiated within 48 h which is a challenge for the management of patients on medical anticoagulation. The aim of this study was to evaluate the in-house standard operation procedure (SOP) concerning these patients. METHODS: All geriatric hip fracture patients were included in this prospective study. Data concerning medical anticoagulation and hemoglobin levels on admission and at discharge, the start and duration of surgery, transfusion rates and postoperative complications were collected RESULTS: A total of 154 (62%) out of 247 patients were on anticoagulants. Patients on acetylsalicylic acid (ASA) demonstrated a significant increase in the rate of transfusion (62%, 95% CI, range 53%-72%, p<0.05) but lost significantly less hemoglobin during hospitalization (1.25 g/dl, 95% CI 0.62-1.88g/dl, p<0.05) in comparison to the control group (40% transfused, hemoglobin loss 3.00 g/dl). Patients on phenprocoumon were operated on later (26 h versus 20 h,95% CI 22-30, p<0.001). There were no significant differences concerning complications. CONCLUSION: Under this SOP anticoagulation has no impact on complication rates after hip fracture. The increased transfusion rates under ASS can be attributed to early blood transfusions. Antagonization of coumarin with vitamin K delays surgery but seems adequate. An analysis of more patients over a longer period of time should be conducted.

[Parkinson's disease: cost-of-illness in an outpatient cohort]. / Morbus Parkinson: Krankheitskosten einer ambulanten Patientenkohorte.

OBJECTIVE: The aim of this study was to evaluate the direct and indirect costs in a cohort of German outpatients with Parkinson's disease (PD) and to identify major cost drivers in PD. METHODS: 91 PD patients were consecutively enrolled in the outpatient department of the neurological clinic at the University of Marburg, Germany. Patients had to fill out a standardised questionnaire at baseline and at a 3-month follow-up and report their health service resource utilisation for the past three months, retrospectively. In addition, information on clinical parameters of PD (UPDRS, Hoehn and Yahr stage) were assessed. For 86 patients, the direct and indirect cost data were analysed. Indirect costs were calculated by the human capital approach. RESULTS: Total costs per patient and 6-month period amounted to € 8,400 [95%CI 6,768-10,302]. Of these, 30% were indirect costs (€ 2,505 [95%CI 1,541-4,047]) and 70% were direct costs (€ 5,895 [95%CI 4,846-7,376]). The major parts of the direct costs were triggered by antiparkinsonian medication (€ 2,889 [95%CI 2,392-3,655]) and inpatient stays (hospital und rehabilitation, € 1,556 [95%CI 865-2,892]). A linear multivariate model with disease severity, disease duration, sleep disorders, psychosis and dystonia explained 24% of the variance of total costs and 33% of variance of direct costs, respectively. CONCLUSION: Parkinson's disease imposes a high financial burden on both patient and society. A reduced health-related quality of life reflects the individual patient's impairment by PD.

[Dementia and depression determine care dependency in Parkinson's disease: analysis of 1,449 outpatients receiving nursing care in Germany]. / Demenz und Depression determinieren Pflegebedürftigkeit bei M. Parkinson : Untersuchung an 1449 Patienten im ambulanten Versorgungssektor in Deutschland.

BACKGROUND: Parkinson's disease (PD) is frequently accompanied by dementia or depression which can aggravate the clinical picture of the disease and increase the risk of care dependency (CD). Little is known about the associations between PD, these neuropsychiatric comorbidities and CD in outpatients. PATIENTS AND METHODS: A nationwide sample of outpatients (n=1,449) was examined by office-based neurologists (n=315) comprising the documentation of the general, neurological status and the degree of CD. The dementia status was clinically rated according to the established DSM-IV criteria. Depression was screened with the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Overall, 18.3% of all patients were care dependent. Even after adjustment for PD severity, patients with depression (OR=2.8; 95% CI 1.8-4.3), dementia (OR=2.7; 95% CI 1.8-4.1) or both (OR=3.9; 95% CI 2.5-60,0) were at higher risk for CD than patients without dementia or depression. Patients aged ≥76 years were fourfold more likely to be care dependent than patients aged ≤65 years (OR=3.5; 95% CI 2.3-5.5). Across all age groups, patients with depression featured the highest increments (from 11.9 to 42.0%). CONCLUSION: The risk for CD is substantially elevated in outpatients with PD when further neuropsychiatric symptoms are present. The data suggest that depression contributes equally to disability as does dementia.

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. METHODS AND PATIENTS: Patients with PD (n = 145) were recruited from two clinical departments, two office-based neurologists and 12 GPs. Clinical evaluations were performed at baseline, 3, 6 and 12 months. Disease severity was measured using the Unified Parkinson's Disease Rating Scale (UPDRS). Cost data were assessed based on a patient diary and via personal structured interviews at the respective time-points. Costs were calculated from the societal perspective (2009 euro). Cost-driving factors were identified by multivariate regression analysis. RESULTS: Mean annual costs totalled euro20 095 per patient. Amongst direct costs, the highest expenditures (euro13 158) were for drugs (euro3526) and inpatient care including nursing homes (euro3789). Indirect costs accounted for 34.5% (euro6937) of total costs. Costs of home care provided by family accounted for 20% of direct costs. Cost-driving factors were identified for total costs (UPDRS, fluctuations, dyskinesia and younger age), direct costs (UPDRS, fluctuations), patient expenditures (UPDRS, depression) and drug costs (younger age). CONCLUSION: Parkinson's disease has a chronic course with growing disability and considerable socioeconomic burden. Disease progression leads to an increasing number of patients who require costly institutionalized care. Home care is a major factor influencing patients' families. Healthcare programmes aimed at reducing the burden of PD on society and individuals should consider cost-driving factors of PD.

[The German Study on the Epidemiology of Parkinson's Disease with Dementia (GEPAD): more than Parkinson]. / Die "German study on the epidemiology of Parkinson's disease with dementia" (GEPAD): mehr als nur Parkinson.

UNLABELLED: It is unknown, how frequently Parkinson's disease (PD) is complicated by dementia, depression and other neuropsychiatric conditions. An epidemiologic characterisation of the situation in specialised neurologic settings is lacking. The Geman Study on the Epidemiology of Parkinson's Disease with Dementia (GEPAD) isa national representative epidemiological study of n=1449 PD patients in n=315 office-based neurological settings, designed to estimate the prevalence of dementia, depression and other neuropsychiatric conditions in patients with PD of all stages by using standardized clinical assessments. RESULTS: 28.6% met DSM-IV criteria for dementia. 33.6% met criteria for depression and 61% additionally had other clinically significant psychopathological syndromes. Only 29.4% had no neuropsychiatric conditions. GEPAD reveals for the first time comprehensively that the neuropsychiatric burden of PD patients in all stages and even early stages is considerable, posing challenging questions for research and clinical management.

The late stage of Parkinson's -results of a large multinational study on motor and non-motor complications.

INTRODUCTION: There is little information on the late stages of parkinsonism. METHODS: We conducted a multicentre study in 692 patients with late stage parkinsonism in six European countries. Inclusion criteria were disease duration of ≥7 years and either Hoehn and Yahr stage ≥4 or Schwab and England score of 50 or less. RESULTS: Average disease duration was 15.4 (SD 7.7) years and mean total UPDRS score was 82.7 (SD 22.4). Dementia according to MDS-criteria was present in 37% of patients. Mean levodopa equivalence dose was 874.1 (SD 591.1) mg/d. Eighty two percent of patients reported falls, related to freezing (16%) or unrelated to freezing (21% of patients) or occurring both related and unrelated to freezing (45%), and were frequent in 26%. Moderate-severe difficulties were reported for turning in bed by 51%, speech by 43%, swallowing by 16% and tremor by 11%. Off-periods occurred in 68% and were present at least 50% of the day in 13%, with morning dystonia occurring in 35%. Dyskinesias were reported by 45% but were moderate or severe only in 7%. Moderate-severe fatigue, constipation, urinary symptoms and nocturia, concentration and memory problems were encountered by more than half of participants. Hallucinations (44%) or delusions (25%) were present in 63% and were moderate-severe in 15%. The association with overall disability was strongest for severity of falls/postural instability, bradykinesia, cognitive score and speech impairment. CONCLUSION: These data suggest that current treatment of late stage parkinsonism in the community remains insufficiently effective to alleviate disabling symptoms in many patients.

[Direct costs for Parkinson's treatment in private neurology practices in Berlin]. / Direkte Kosten der Parkinson-Behandlung : Eine Erhebung in neurologischen Schwerpunktpraxen in Berlin.

BACKGROUND: Aim of this study was to assess the direct costs of Parkinson's disease (PD) within a 3-month period (i.e. the accounting period for the German statutory health insurance) in 12 neurological outpatient practices in Berlin during 2006. MATERIAL AND METHODS: A total of 425 patients (age 69.1+/-9.3 years, 185 females) were recruited, and sociodemographic and clinical data were obtained by a specific questionnaire. The distribution of costs was analyzed based on several clinical and patient parameters. The costs were calculated with different approaches: (1) prospectively, with the practices' accounting according to German uniform scales (GoA, EbM) and (2) retrospectively, with questionnaires for the Parkinson's patients. Costs were calculated according to current German guidelines of the statutory health insurance. Clinical parameters were assessed with a questionnaire for physicians. RESULTS: The direct medical costs totaled 1,667 EUR (range 1,436-1,995 EUR, CI 95%) per patient per 3 months. Charges by physicians were 42 EUR (39-45 EUR, CI 95%) for patients with statutory health insurance and 135 EUR (106-177 EUR, CI 95%) for those with private insurance. Disease severity and disease duration correlated with higher direct medical costs. Motor fluctuations and depression also were major factors influencing cost. CONCLUSION: Our study emphasizes the large economic burden caused mainly by PD medication and hospitalization. For the first time a direct comparison between costs and actual physicians' reimbursement was possible. In combination with further economic studies, this comparison will help to define shortcomings and excesses in PD health care services.

Caffeic acid phenethyl ester prevents cerebellar granule neurons (CGNs) against glutamate-induced neurotoxicity.

Caffeic acid phenethyl ester (CAPE) is an active component of propolis obtained from honeybee hives and is found to have the following properties: anti-mitogenic, anti-carcinogenic, anti-inflammatory, immunomodulatory, and antioxidant. Recent reports suggest that CAPE also has a neuronal protective property against ischemic injury. Since excitotoxicity may play an important role in ischemia, in this study, we investigated whether CAPE could directly protect neurons against excitotoxic insult. We treated cultured rat cerebellar granule neurons (CGNs) with excitotoxic concentrations of glutamate in the presence or absence of CAPE and found that CAPE markedly protected neurons against glutamate-induced neuronal death in a concentration-dependent fashion. Glutamate-induced CGNs death is associated with time-dependent activation of caspase-3 and phosphorylation of p38, both events of which can be blocked by CAPE. Treating CGNs with specific inhibitors of these two enzymes together exerts a synergistic neuroprotective effect, similar to the neuroprotective effect of CAPE exposure. These results suggest that CAPE is able to block glutamate-induced excitotoxicity by inhibiting phosphorylation of p38 and caspase-3 activation. This finding may further help understanding of the mechanism of glutamate-induced neuronal death and CAPE-induced neuroprotection against excitotoxicity.

Quality of life in a German cohort of Parkinson's patients assessed with three different measures.

BACKGROUND: Parkinson's disease (PD) is characterized by severe motor and non-motor symptoms reducing patients' quality of life (QoL). Instruments have been well established for QoL assessments in PD, including the EuroQol (EQ-5D), the Parkinson's disease questionnaire (PDQ-39), or rather uncommon, like the WHOQOL-100. So far, the impact of variables has been investigated for each of these measures separately in different study populations, limiting the comparability of the results. Thus, this study compared the EQ-5D, PDQ-39, and the WHOQOL-100 (with its short-form WHOQOL-BREF) in the same study population. METHODS: Seventy-five PD outpatients were assessed in a prospective study, including disease severity according to Hoehn and Yahr stage (HY) and Unified Parkinson Disease Rating Scale (UPDRS). The Geriatric Depression Scale (GDS-15) screened for depression. RESULTS: Decreased QoL was found with all three instruments. In multivariate models, sex and treatment complications had an impact on QoL according to all three measures, while duration of PD and HY was not associated with QoL in any of them. Depression was relevant for the WHOQOL-100/WHOQOL-BREF and the PDQ-39, but not for the EQ-5D. The total variances explained by the WHOQOL-100, WHOQOL-BREF, PDQ-39, and the EQ-5D were 0.27, 0.34, 0.70, and 0.50, respectively. CONCLUSIONS: The associations between clinical aspects of PD and QoL vary substantially among all three measures. Importantly, depression as a frequent comorbidity in PD is underestimated by the EQ-5D, but not by the PDQ-39 and the WHOQOL-100/WHOQOL-BREF. In turn, motor impairments are underestimated by the latter and associated strongest with QoL in the EQ-5D.

Assessing health-related quality of life in patients with Parkinson's disease in a prospective longitudinal study.

OBJECTIVE: To prospectively assess the health-related quality of life (HrQoL) in Parkinson's disease (PD) during 12 months. METHODS: HrQoL was assessed in 145 PD patients using the PD-specific PDQ-39, PDQL and the generic EQ-5D. In addition, clinical rating-scales were used. RESULTS: All scales showed a pronounced effect of PD. In comparison to an age-matched population the EQ-5D was considerably affected. In comparison to baseline, however, there was no significant change in the generic scale but a significant change in the sum-score of disease-specific HrQoL-scales. CONCLUSIONS: Only disease-specific scales were sensitive to change. Further studies are necessary to evaluate the time-dependent change in HrQoL.

Activation of SK2 channels preserves ER Ca²âº homeostasis and protects against ER stress-induced cell death.

Alteration of endoplasmic reticulum (ER) Ca(2+) homeostasis leads to excessive cytosolic Ca(2+) accumulation and delayed neuronal cell death in acute and chronic neurodegenerative disorders. While our recent studies established a protective role for SK channels against excessive intracellular Ca(2+) accumulation, their functional role in the ER has not been elucidated yet. We show here that SK2 channels are present in ER membranes of neuronal HT-22 cells, and that positive pharmacological modulation of SK2 channels with CyPPA protects against cell death induced by the ER stressors brefeldin A and tunicamycin. Calcium imaging of HT-22 neurons revealed that elevated cytosolic Ca(2+) levels and decreased ER Ca(2+) load during sustained ER stress could be largely prevented by SK2 channel activation. Interestingly, SK2 channel activation reduced the amount of the unfolded protein response transcription factor ATF4, but further enhanced the induction of CHOP. Using siRNA approaches we confirmed a detrimental role for ATF4 in ER stress, whereas CHOP regulation was dispensable for both, brefeldin A toxicity and CyPPA-mediated protection. Cell death induced by blocking Ca(2+) influx into the ER with the SERCA inhibitor thapsigargin was not prevented by CyPPA. Blocking the K(+) efflux via K(+)/H(+) exchangers with quinine inhibited CyPPA-mediated neuroprotection, suggesting an essential role of proton uptake and K(+) release in the SK channel-mediated neuroprotection. Our data demonstrate that ER SK2 channel activation preserves ER Ca(2+) uptake and retention which determines cell survival in conditions where sustained ER stress contributes to progressive neuronal death.