Endovascular stroke treatment does not preclude high thrombolysis rates.

BACKGROUND AND PURPOSE: In 1995 intravenous recombinant tissue plasminogen activator (IVRTPA) was the first reperfusion therapy to be approved in patients with acute ischaemic stroke (AIS). The significance and impact of IVRTPA in times of modern endovascular stroke treatment (EST) were analysed in a German academic stroke centre. METHODS: A retrospective observational cohort analysis of 1034 patients with suspected AIS presenting at the emergency department in 2014 was performed. Patients were evaluated for baseline characteristics, reperfusion procedures, IVRTPA eligibility, clinical outcome, symptomatic intracranial haemorrhage (sICH) and mortality. Data acquisition was part of an investigator-initiated, prospective and blinded end-point registry. RESULTS: In 718 (69%) patients the diagnosis of symptomatic AIS was confirmed. 419 (58%) patients presented within 4.5 h of symptom onset and of those 260 (62%) received reperfusion therapy (IVRTPA alone, n = 183; combination or bridging therapy, n = 60; EST alone, n = 17). Subtracting cases with absolute contraindications for IVRTPA resulted in an effective thrombolysis rate of 82%. sICH occurred in two patients treated with IVRTPA alone (1.1%). The median door-to-needle interval was 30 min. Fifty (17%) non-EST eligible AIS patients presenting within 4.5 h without absolute contraindications did not receive IVRTPA mainly due to mild or regressive symptoms. Most of these untreated IVRTPA eligible patients (82%) were discharged with a good clinical outcome (modified Rankin Scale ≤ 2). CONCLUSIONS: Intravenous recombinant tissue plasminogen activator remains the most frequently applied reperfusion therapy in AIS patients presenting within 4.5 h of onset in a tertiary stroke centre. An effective thrombolysis rate of over 80% can be achieved without increased rates of sICH.

Comprehensive pharmaceutical care to prevent drug-related readmissions of dependent-living elderly patients: a randomized controlled trial.

BACKGROUND: Elderly patients are vulnerable to adverse drug reactions (ADRs). Drug-related readmissions (DRRs) can be a major consequence of ADR. Therefore, this study aimed to investigate the effects of a ward-based, comprehensive pharmaceutical care service on the occurrence of DRRs as the endpoint in dependent-living elderly patients. METHODS: A randomized, controlled trial was performed at a German University Hospital. Patients fulfilling the following criteria were eligible: admission to a cooperating ward, existing drug therapy at admission, 65 years of age and older, home-care or nursing home residents in ambulatory care, and a minimum hospital stay of three days. Patients received either standard care (control group) or pharmaceutical care (intervention group). Follow-up consultations were conducted for each patient at 1, 8, 26, and 52 weeks after discharge. The time to DRR was defined as the primary outcome measure and was analysed using the log-rank test. The Cox-proportional hazard model was used for risk factor analysis. RESULTS: Sixty patients (n = 31 intervention group, n = 29 control group) participated in the study. For patients in the intervention group, the median time to DRR was prolonged; however, the level of statistical significance was not reached (log-rank test P = 0.068; HR = 3.28, P = 0.086). When the risk factors 'age' or 'length of stay on the ward' were added to the Cox proportional hazard model, patients in the control group exhibited a significantly higher risk of experiencing a DRR than patients of the intervention group (HR = 4.62; P = 0.028 including age and HR = 5.76; P = 0.033 including length of stay on the ward). CONCLUSIONS: Our findings demonstrate the successful implementation of ward-based, comprehensive pharmaceutical care for dependent-living elderly. Despite a low participation rate, which led to an underpowered study, the results provide a preliminary efficacy signal and effect size estimates to power a definitive trial. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01578525 , prospectively registered April 13, 2012.

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.

Neurothrombectomy in acute ischaemic stroke: a prospective single-centre study and comparison with randomized controlled trials.

BACKGROUND AND PURPOSE: In the last few months five multicentre, randomized controlled trials (RCTs) unequivocally showed the superiority of mechanical thrombectomy in large vessel occlusion acute ischaemic stroke compared to systemic thrombolysis. Despite varying inclusion criteria and time intervals from onset to revascularization overall increases of good functional outcome between 55% and 81% were reported. However, only a minority of screened patients (approximately 1%) were eligible for intra-arterial (IA) therapy. METHODS: An investigator-initiated, single-centre, prospective and blinded end-point analysis was performed of 3123 consecutive patients with acute ischaemic stroke presenting between February 2010 and December 2014. RESULTS: One hundred and fifty-four patients [4.9%, age (years) mean (SD), median (interquartile range) 71.2 (±14), 74.7 (65.9-81.4)] met the inclusion criteria of sparse early ischaemic signs on initial standard cranial computed tomography (CT) (ASPECT score ≥7), large vessel occlusion in the anterior circulation on CT angiography and start of treatment within 6 h of onset of symptoms. After consensual interdisciplinary treatment decisions 130 patients (4.2%) received IA treatment - in the majority stent-assisted thrombectomy in combination with intravenous (IV) recombinant tissue plasminogen activator - and 24 patients (0.7%) standard IV thrombolysis. On 3 months' follow-up an overall significant improvement of disability (P = 0.05) as measured by the modified Rankin Scale was shown in favour of the IA treatment group. Good functional outcome was achieved in about twice as many patients (IA vs. IV, 41.2% vs. 21.2%; P = 0.078). CONCLUSION: By choosing pragmatic inclusion criteria state-of-the-art IA therapy of a specialized tertiary stroke centre can be safely applied under real-world conditions to a higher percentage of patients with similar success to the recently published RCTs.

Elevation of plasma 1-deoxy-sphingolipids in type 2 diabetes mellitus: a susceptibility to neuropathy?

BACKGROUND AND PURPOSE: Diabetic distal sensorimotor polyneuropathy (DSPN) is a frequent, disabling complication of diabetes mellitus. There is increasing evidence that sphingolipids play a role in insulin resistance and type 2 diabetes (T2DM). Whether neurotoxic 1-deoxy-sphingolipids are elevated in DSPN patients' plasma and whether levels correlate to the DSPN stage were examined. METHODS: The plasma profile of 12 sphingoid bases in patients with DSPN and T2DM(n = 39) were cross-sectionally compared to other nerve disorders including chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 13), transthyretin-related familial amyloid polyneuropathy (FAP) (n = 10), amyotrophic lateral sclerosis (ALS) (n = 13) and small fibre neuropathy (n = 12) by liquid chromatography mass spectrometry. Correlations to the DSPN stage were additionally performed. Furthermore, the sphingoid base distribution in sural nerve specimens was measured in patients with DSPN (n = 6) compared to CIDP (n = 3). RESULTS: A significantly increased amount of 1-deoxy-sphingolipids [1-deoxy-sphinganine (0.11 ± 0.06 µmol/l), 1-deoxy-sphingosine (0.24 ± 0.16 µmol/l)] in patients with DSPN was observed compared to age-matched healthy controls (0.06 ± 0.03 µmol/l; 0.12 ± 0.05 µmol/l) and to the other groups. (Para)clinical parameters including sensory loss, neuropathic pain, weakness, vibration perception, nerve conduction velocity, sensory nerve action potentials (sural nerve) and duration of T2DM did not correlate with plasma 1-deoxy-sphingolipid levels, neither did the clinical stage according to the Dyck classification for DSPN. Sphingolipid levels in sural nerve biopsies showed no differences between DSPN and CIDP. Contrarily, patients with a small fibre neuropathy had decreased C20-sphingosine plasma levels. CONCLUSION: 1-deoxy-sphingolipid plasma levels are significantly elevated in DSPN. They are already detectable in early disease stages but do not correlate with the clinical course. Further knowledge on 1-deoxy-sphingolipids might lead to a better pathophysiological understanding and future treatment options in DSPN.

[Influence of lifestyle on neurodegenerative diseases]. / Einfluss des Lebensstils auf neurodegenerative Erkrankungen.

Lifestyle factors in midlife have an important influence on the risk of developing a neurodegenerative disease during later life. Data on lifestyle factors exist for Alzheimer's disease and Parkinson's disease. Continuous physical and cognitive activity, a balanced or Mediterranean diet with a high proportion of unsaturated fatty acids, the pharmacological treatment of arterial hypertension, sufficient and unfragmented sleep and possibly treatment with lipophilic statins reduce the risk of developing dementia later in life. Several studies in recent years have provided evidence that during the last decades the age-adjusted incidence of dementia has decreased. This is probably due to a healthier lifestyle and the treatment of risk factors. Continuous physical activity also decreases the likelihood of developing Parkinson's disease. Whether lifestyle factors also have an influence on the course and the progression of Alzheimer's and Parkinson's diseases in the symptomatic stages is unknown.

Rating disease progression of Friedreich's ataxia by the International Cooperative Ataxia Rating Scale: analysis of a 603-patient database.

The aim of this cross-sectional study was to analyse disease progression in Friedreich's ataxia as measured by the International Cooperative Ataxia Rating Scale. Single ratings from 603 patients with Friedreich's ataxia were analysed as a function of disease duration, age of onset and GAA repeat lengths. The relative contribution of items and subscales to the total score was studied as a function of disease progression. In addition, the scaling properties were assessed using standard statistical measures. Average total scale progression per year depends on the age of disease onset, the time since diagnosis and the GAA repeat length. The age of onset inversely correlates with increased GAA repeat length. For patients with an age of onset ≤14 years associated with a longer repeat length, the average yearly rate of decline was 2.5 ± 0.18 points in the total International Cooperative Ataxia Rating Scale for the first 20 years of disease duration, whereas patients with a later onset progress more slowly (1.8 ± 0.27 points/year). Ceiling effects in posture, gait and lower limb scale items lead to a reduced sensitivity of the scale in the severely affected population with a total score of >60 points. Psychometric scaling analysis shows generally favourable properties for the total scale, but the subscale grouping could be improved. This cross-sectional study provides a detailed characterization of the International Cooperative Ataxia Rating Scale. The analysis further provides rates of change separated for patients with early and late disease onset, which is driven by the GAA repeat length. Differences in the subscale dynamics merit consideration in the design of future clinical trials applying this scale as a neurological assessment instrument in Friedreich's ataxia.

Gait improvement by high-frequency stimulation of the subthalamic nucleus in Parkinsonian mice is not associated with changes of the cholinergic system in the pedunculopontine nucleus.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is standard care for severe motor symptoms of Parkinson's disease (PD). However, a challenge of DBS remains improving gait. Gait has been associated with the cholinergic system in the pedunculopontine nucleus (PPN). In this study, we investigated the effects of long-term intermittent bilateral STN-DBS on PPN cholinergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonian mouse model. Motor behavior, previously assessed by the automated Catwalk gait analysis, demonstrated a parkinsonian-like motor phenotype with static and dynamic gait impairments, which were reversed by STN-DBS. In this study, a subset of brains was further immunohistochemically processed for choline acetyltransferase (ChAT) and the neuronal activation marker c-Fos. MPTP treatment resulted in a significant reduction of PPN ChAT expressing neurons compared to saline treatment. STN-DBS did not alter the number of ChAT expressing neurons, nor the number of double-labelled PPN neurons for ChAT and c-Fos. Although STN-DBS improved gait in our model this was not associated with an altered expression or activation of PPN acetylcholine neurons. Motor and gait effects of STN-DBS are therefore less likely to be mediated by the STN-PPN connection and PPN cholinergic system.

Modelling neural correlates of working memory: a coordinate-based meta-analysis.

Working memory subsumes the capability to memorize, retrieve and utilize information for a limited period of time which is essential to many human behaviours. Moreover, impairments of working memory functions may be found in nearly all neurological and psychiatric diseases. To examine what brain regions are commonly and differently active during various working memory tasks, we performed a coordinate-based meta-analysis over 189 fMRI experiments on healthy subjects. The main effect yielded a widespread bilateral fronto-parietal network. Further meta-analyses revealed that several regions were sensitive to specific task components, e.g. Broca's region was selectively active during verbal tasks or ventral and dorsal premotor cortex were preferentially involved in memory for object identity and location, respectively. Moreover, the lateral prefrontal cortex showed a division in a rostral and a caudal part based on differential involvement in task set and load effects. Nevertheless, a consistent but more restricted "core" network emerged from conjunctions across analyses of specific task designs and contrasts. This "core" network appears to comprise the quintessence of regions, which are necessary during working memory tasks. It may be argued that the core regions form a distributed executive network with potentially generalized functions for focussing on competing representations in the brain. The present study demonstrates that meta-analyses are a powerful tool to integrate the data of functional imaging studies on a (broader) psychological construct, probing the consistency across various paradigms as well as the differential effects of different experimental implementations.

[ZSE-DUO - dual guidance structure at the centre for rare diseases]. / ZSE-DUO ­ duale Lotsenstruktur im Zentrum für Seltene Erkrankungen.

BACKGROUND: Patients with an unclear diagnosis and suspected rare disease pose special challenges to physicians, among others. AIM OF THE STUDY (RESEARCH QUESTION): The ZSE-DUO project aims to establish whether patient care under the joint supervision of a somatic expert and a mental health expert can improve diagnostic efficacy and precision, as well as shorten the time to diagnosis. MATERIAL AND METHODS: ZSE-DUO has successfully recruited more than 1000 patients at eleven national centres for rare diseases in a control and an intervention group. The findings are being analysed by three evaluating institutions. RESULTS AND DISCUSSION: The study is currently in its final phase. The results will be published in further papers.

Causes of Death in Endovascularly Treated Patients with Acute Stroke.

BACKGROUND AND PURPOSE: Because stroke therapy has changed with the introduction of endovascular stroke treatment as a standard approach, studies on intrahospital causes of death from stroke are no longer up-to-date. The purpose of this observational study was to present the causes of death during hospitalization of patients with ischemic stroke who received endovascular stroke treatment, with the focus on a differentiation of curative and secondary palliative treatment. MATERIALS AND METHODS: We studied a total cohort of 1342 patients who received endovascular stroke treatment in a tertiary stroke center (Aachen, Germany) between 2010 and 2020 and analyzed the causes of death in all 326 consecutive deceased patients. We distinguished between curative treatment and a secondary palliative approach and analyzed causes of death and treatment numbers across the years. RESULTS: In the entire cohort of 326 deceased patients, the most common cause of death was of a cerebrovascular nature (51.5%), followed by pneumonia and sepsis (25.8%) and cardiovascular causes (8.3%). Neurovascular causes constituted 75.8% of reasons for palliation. In the group with a secondary palliative approach, causes of death were neurovascular in 54.0% of patients and pneumonia and sepsis in 26.0% of patients. CONCLUSIONS: Cerebrovascular causes in patients with stroke play a major role in the intrahospital causes of death and reasons for palliation. Considering the large proportion of secondarily palliative-treated patients, reasons for palliation should be considered instead of causes of death to avoid concealment by, for example, life-terminating measures.

[On the role of MAO B inhibitors and NMDA antagonists in the therapy of Parkinson's disease]. / Stellenwert von MAO-B-Inhibitoren und NMDA-Antagonisten in der Therapie des Morbus Parkinson.

In this workshop report, the N-methyl-D-aspartate (NMDA) receptor antagonists and the monoamine oxidase (MAO) type B inhibitors are discussed with respect to their role in the pharmacotherapy of Parkinson's Disease (PD). For the NMDA antagonist amantadine, studies demonstrated beneficial effects in various symptoms of the PD complex, while memantine seems to be beneficial in the treatment of cognitive deficits in PD-associated dementia. The MAO B inhibitors selegiline and rasagiline are in use for PD pharmacotherapy; for rasagiline, studies have demonstrated a possible disease-modifying effect. Although not supported by specific controlled studies, a "triple" early therapy is discussed which consists of a dopamine agonist, a MAO B inhibitor and amantadine, in order to try to delay the start of levodopa therapy.

Bilateral changes in neuronal activity of the basal ganglia in the unilateral 6-hydroxydopamine rat model.

The functional significance of the interhemispheric projections on the basal ganglia level is poorly understood. Insofar as the anatomical evidence for crossing projections between basal ganglia nuclei is sparse, whereas tracing studies demonstrated important crossing projections from the pedunculopontine nucleus (PPN) to the basal ganglia, it is suggested that the PPN might play a key role in interhemispheric regulation of basal ganglia activity. The present study was performed to assess changes in neuronal activity of ipsilateral and contralateral subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and PPN in the unilateral 6-hydroxydopamine (6-OHDA) rat model of advanced PD under urethane anesthesia. After unilateral lesioning of the SNc, the firing rate of contralateral STN neurons significantly increased from 10.9 +/- 1.0 spikes/sec (mean +/- SEM) to 16.3 +/- 1.5 spikes/sec. Similarly, the firing rate of contralateral SNr neurons significantly increased from 19.4 +/- 1.2 to 25.7 +/- 1.9 spikes/sec, and the firing rate of contralateral PPN neurons significantly increased from 10.6 +/- 0.8 to 13.9 +/- 1.1 spikes/sec. The observed activity changes in contralateral STN, SNr, and PPN are similar to those induced in the corresponding nuclei of the hemisphere ipsilateral to the nigrostriatal degeneration. Based on previous, predominantly anatomical data, the results of the present study suggest that the PPN on the lesioned side is at the origin of changes in the activity of STN and SNr on the contralateral hemisphere, because of its crossing efferent projections.

Long-term EMG recordings differentiate between parkinsonian and essential tremor.

The differential diagnosis of tremor is mainly based on clinical criteria.Nevertheless, these criteria are in some cases not sufficient to differentiate between different tremor forms. Long-term EMG has proven to be a valid and reliable method for the quantification of pathological tremors. The aim of the study was to develop a long-term EMG-based automated analysis procedure that separates parkinsonian tremor from essential tremor. Using longterm EMG tremor was recorded in 45 consecutive patients, 26 with Parkinson's disease (PD) and 19 with essential tremor (ET). Eight tremor parameters were generated automatically. By stepwise backward regression a subset of these criteria was extracted to achieve an automated classification of the tremor by a mathematical model. The obtained model was then tested on a new group of 13 patients in early stages of the disease. Significant differences between groups were found for tremor occurrence, tremor asymmetry, mean tremor frequency and standard deviation of phase of antagonistic muscles. Due to data overlap a classification of the two tremor forms was not possible based on a single tremor parameter. Using logistic regression, a linear formula based on the three parameters tremor occurrence, mean tremor frequency and standard deviation of phase was established and predicted the correct diagnosis in 93% of patients. The validation of the model on the new group of patients in early stages of the tremor disease yielded a correct diagnosis in 100% of cases. We conclude that long-term EMG recording allows a rater-independent classification of parkinsonian versus essential tremor.

The discriminative value of blood gas analysis parameters in the differential diagnosis of transient disorders of consciousness.

AIM: The differentiation between epileptic and non-epileptic episodes can be challenging. Our aim was to compare lactate, anion gap (AG), bicarbonate and the Denver Seizure Score (DSS) as point-of-care test (POCT) markers for episodes of transient alterations of consciousness. METHODS: The blood serum parameters were drawn at arrival in the emergency department (ED) within 2 h of the episode. After calculating AG and DSS values, the four parameters were compared retrospectively between patients with generalized tonic-clonic seizures (GTCS) (n = 165) and patients with other disorders of consciousness [syncopes (n = 43), and psychogenic non-epileptic seizures (n = 15)]. Additionally, we compared all values among men and women. RESULTS: In GTCS patients, all four parameters differed significantly compared to non-epileptic episode patients (p < 0.001). Serum lactate showed significant additional benefit over the remaining values, with an AUC of 0.947 (95% CI 0.92-0.975) and a high sensitivity and specificity for an optimal cut-off value of 2.45 mmol/l. For DSS, the AUC was 0.857 (95% CI 0.808-0.906; cut-off: 0.35), and for AG 0.836 (95% CI 0.783-0.889; cut-off: 12.45 mmol/l). In the case of serum bicarbonate, the AUC was 0.831 (95% CI 0.775-0.886; cut-off: 22.75 mmol/l). In the sex-dependent comparison, the results were similar. Men showed more significant differences in the compared values than women. CONCLUSIONS: Serum lactate is best suited as POCT marker in the differential diagnosis of epileptic and non-epileptic episodes and is superior to AG, DSS and bicarbonate. The differences among sexes may pose a challenge in their implementation and interpretation.

Exogenous administration of gangliosides displaces GPI-anchored proteins from lipid microdomains in living cells.

Exogenous application of gangliosides to cells affects many cellular functions. We asked whether these effects could be attributed to the influence of gangliosides on the properties of sphingolipid-cholesterol microdomains on the plasma membrane, also termed rafts. The latter are envisaged as lateral assemblies of sphingolipids (including gangliosides), cholesterol, and a specific set of proteins. Rafts have been implicated in processes such as membrane trafficking, signal transduction, and cell adhesion. Recently, using a chemical cross-linking approach with Madin-Darby canine kidney (MDCK) cells permanently expressing a GPI-anchored form of growth hormone decay accelerating factor (GH-DAF) as a model system, we could show that GPI-anchored proteins are clustered in rafts in living cells. Moreover, this clustering was dependent on the level of cholesterol in the cell. Here we show that incubation of MDCK cells with gangliosides abolished subsequent chemical cross-linking of GH-DAF. Furthermore, insertion of gangliosides into the plasma membrane of MDCK GH-DAF cells renders GH-DAF soluble when subjected to extraction with Triton X-114 at 4 degrees C. Our data suggest that exogenous application of gangliosides displaces GPI-anchored proteins from sphingolipid-cholesterol microdomains in living cells.

Anti-apoptotic gene therapy in Parkinson's disease.

Apoptosis, whether caspase-dependent or caspase-independent, has been implicated as one of the important mechanisms leading to the death of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Major advances of our understanding of apoptosis have been achieved in studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice and monkeys and 6-hydroxydopamine (6-OHDA) toxicity in rats and monkeys. The use of viral vectors to either express anti-apoptotic proteins or to downregulate pro-apoptotic proteins has the major advantage of addressing selective molecular targets, bypassing the blood-brain-barrier to specifically target the nigrostriatal pathway by their stereotaxic application and by the choice of the appropriate virus and promotor. Used thus far have been virus-mediated overexpression of inhibitor of apoptosis proteins, inhibitors of the c-jun-N-terminal kinase (JNK) pathway, inhibitors of calpains and dominant negative inhibitors of the protease activating factor (APAF)-1 and cdk5. Most studies implicate the endogenous, mitochondrial pathway in the apoptosis of dopaminergic neurons. The results suggest that only an inhibition of this pathway upstream of caspase activation will also result in the protection of nigrostriatal dopaminergic terminals and behavioral benefit, whereas an inhibition of caspases alone may not be sufficient to prevent the degeneration of terminals, although it may promote the survival of neuronal cell bodies for some time.

Limitations of cellular models in Parkinson's disease research.

Cell cultures for Parkinson's disease research have the advantage of virtually unlimited access, they allow rapid screening for disease pathogenesis and drug candidates, and they restrict the necessary number of animal experiments. Limitations of cell cultures, include that the survival of neurons is dependent upon the culture conditions; that the cells do not develop their natural neuronal networks. In most cases, neurons are deprived from the physiological afferent and efferent connections. In Parkinson's disease research, mesencephalic slice cultures, primary immature dopaminergic neurons and immortalized cell lines--either in a proliferating state or in a differentiated state--are used. Neuronal cultures may be plated in the presence or absence of glial cells and serum. These different culture conditions as well as the selection of outcome parameters (morphological evaluation, viability assays, biochemical assays, metabolic assays) have a strong influence on the results of the experiments and the conclusions drawn from them. A primary example is the question of whether L-Dopa is toxic to dopaminergic neurons or whether it provides neurotrophic effects: In pure, neuronal-like cultures, L-Dopa provides toxicity, whereas in the presence of glial cells, it provides trophic effects when applied. The multitude of factors that influence the data generated from cell culture experiments indicates that in order to obtain clear-cut and unambiguous results, investigators need to choose their model carefully and are encouraged to verify their main results with different models.