Claudia Bartels

Recombinant Human Erythropoietin in the Treatment of Acute Ischemic Stroke

Background and Purpose— Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. Methods— This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40 000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for. Results— Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke. Conclusions— Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

Reduced oxidative damage in ALS by high‐dose enteral melatonin treatment

Abstract:  Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects not conveyed by classical antioxidants. In preparation of a possible future clinical trial, we explored the potential of melatonin as neuroprotective compound and antioxidant in: (1) cultured motoneuronal cells (NSC‐34), (2) a genetic mouse model of ALS (SOD1G93A‐transgenic mice), and (3) a group of 31 patients with sporadic ALS. We found that melatonin attenuates glutamate‐induced cell death of cultured motoneurons. In SOD1G93A‐transgenic mice, high‐dose oral melatonin delayed disease progression and extended survival. In a clinical safety study, chronic high‐dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high‐dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.

Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system

SummaryThe growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulated in the adult brain after injury. Peripherally administered EPO, and at least some of its variants, cross the blood-brain barrier, stimulate neurogenesis, neuronal differentiation, and activate brain neurotrophic, anti-apoptotic, anti-oxidant and anti-inflammatory signaling. These mechanisms underlie their tissue protective effects in nervous system disorders. As the tissue protective functions of EPO can be separated from its stimulatory action on hematopoiesis, novel EPO derivatives and mimetics, such as asialo-EPO and carbamoylated EPO have been developed. While the therapeutic potential of the novel EPO derivatives continues to be characterized in preclinical studies, the experimental findings in support for the use of recombinant human (rh)EPO in human brain disease have already been translated to clinical studies in acute ischemic stroke, chronic schizophrenia, and chronic progressive multiple sclerosis. In this review article, we assess the studies on EPO and, in particular, on its structural or functional variants in experimental models of nervous system disorders, and we provide a short overview of the completed and ongoing clinical studies testing EPO as neuroprotective/neuroregenerative treatment option in neuropsychiatric disease.

Practice effects in healthy adults: a longitudinal study on frequent repetitive cognitive testing

BackgroundCognitive deterioration is a core symptom of many neuropsychiatric disorders and target of increasing significance for novel treatment strategies. Hence, its reliable capture in long-term follow-up studies is prerequisite for recording the natural course of diseases and for estimating potential benefits of therapeutic interventions. Since repeated neuropsychological testing is required for respective longitudinal study designs, occurrence, time pattern and magnitude of practice effects on cognition have to be understood first under healthy good-performance conditions to enable design optimization and result interpretation in disease trials.MethodsHealthy adults (N = 36; 47.3 ± 12.0 years; mean IQ 127.0 ± 14.1; 58% males) completed 7 testing sessions, distributed asymmetrically from high to low frequency, over 1 year (baseline, weeks 2-3, 6, 9, months 3, 6, 12). The neuropsychological test battery covered 6 major cognitive domains by several well-established tests each.ResultsMost tests exhibited a similar pattern upon repetition: (1) Clinically relevant practice effects during high-frequency testing until month 3 (Cohens d 0.36-1.19), most pronounced early on, and (2) a performance plateau thereafter upon low-frequency testing. Few tests were non-susceptible to practice or limited by ceiling effects. Influence of confounding variables (age, IQ, personality) was minor.ConclusionsPractice effects are prominent particularly in the early phase of high-frequency repetitive cognitive testing of healthy well-performing subjects. An optimal combination and timing of tests, as extractable from this study, will aid in controlling their impact. Moreover, normative data for serial testing may now be collected to assess normal learning curves as important comparative readout of pathological cognitive processes.

Induction of α-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies

Stuendl et al. show that CSF exosomes of patients with Parkinson’s disease or dementia with Lewy bodies contain α-synuclein and induce α-synuclein aggregation in a reporter cell line. Thus, exosomes may support inter-neuronal transmission of α-synuclein pathology. CSF exosomal α-synuclein may serve as a biomarker in α-synuclein-related neurodegeneration.

Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia

Neurodevelopmental abnormalities together with neurodegenerative processes contribute to schizophrenia, an etiologically heterogeneous, complex disease phenotype that has been difficult to model in animals. The neurodegenerative component of schizophrenia is best documented by magnetic resonance imaging (MRI), demonstrating progressive cortical gray matter loss over time. No treatment exists to counteract this slowly proceeding atrophy. The hematopoietic growth factor erythropoietin (EPO) is neuroprotective in animals. Here, we show by voxel-based morphometry in 32 human subjects in a placebo-controlled study that weekly high-dose EPO for as little as 3 months halts the progressive atrophy in brain areas typically affected in schizophrenia, including hippocampus, amygdala, nucleus accumbens, and several neocortical areas. Specifically, gray matter protection is highly associated with improvement in attention and memory functions. These findings suggest that a neuroprotective strategy is effective against common pathophysiological features of schizophrenic patients, and strongly encourage follow-up studies to optimize EPO treatment dose and duration.

Diagnostic accuracy of diffusion tensor imaging in amyotrophic lateral sclerosis: A systematic review and individual patient data meta-analysis

RATIONALE AND OBJECTIVES There have been a large number of case-control studies using diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS). The objective of this study was to perform an individual patient data (IPD) meta-analysis for the estimation of the diagnostic accuracy measures of DTI in the diagnosis of ALS using corticospinal tract data. MATERIALS AND METHODS MEDLINE, EMBASE, CINAHL, and Cochrane databases (1966-April 2011) were searched. Studies were included if they used DTI region of interest or tractography techniques to compare mean cerebral corticospinal tract fractional anisotropy values between ALS subjects and healthy controls. Corresponding authors from the identified articles were contacted to collect individual patient data. IPD meta-analysis and meta-regression were performed using Stata. Meta-regression covariate analysis included age, gender, disease duration, and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores. RESULTS Of 30 identified studies, 11 corresponding authors provided IPD and 221 ALS patients and 187 healthy control subjects were available for study. Pooled area under the receiver operating characteristic curve (AUC) was 0.75 (95% CI: 0.66-0.83), pooled sensitivity was 0.68 (95% CI: 0.62-0.75), and pooled specificity was 0.73 (95% CI: 0.66-0.80). Meta-regression showed no significant differences in pooled AUC for each of the covariates. There was moderate to high heterogeneity of pooled AUC estimates. Study quality was generally high. Data from 19 of the 30 eligible studies were not ascertained, raising possibility of selection bias. CONCLUSION Using corticospinal tract individual patient data, the diagnostic accuracy of DTI appears to lack sufficient discrimination in isolation. Additional research efforts and a multimodal approach that also includes ALS mimics will be required to make neuroimaging a critical component in the workup of ALS.

Callosal dysfunction in amyotrophic lateral sclerosis correlates with diffusion tensor imaging of the central motor system

We investigated the frequency and functional relevance of corpus callosum degeneration in amyotrophic lateral sclerosis (ALS). A total of 22 ALS patients and 29 healthy controls performed the newly developed Contralateral Co-Movement Test as indicator of callosal dysfunction. Diffusion tensor imaging was applied to determine fractional anisotropy values in the callosal area containing the crossing motor fibers and in the pyramidal tracts in 13 subjects of each group. ALS patients had more than twice the amount of co-movements as compared to healthy subjects. Contralateral co-movements correlated with fractional anisotropy values of the corpus callosum motor region as did ALS Functional Rating Scale as measure of disease progression. In both groups, contralateral co-movements correlated with the central motor index (ratio of the mean of fractional anisotropy values of both pyramidal tracts and corpus callosum motor region). Neuropsychological test results failed to show correlations with functional or morphological parameters. Combining Contralateral Co-Movement Test and diffusion tensor imaging in ALS revealed the close relation between functional and morphological impairment in the degenerating central motor-neuronal network. The Contralateral Co-Movement Test delivers simple means of symptom quantification, independent of ALS Functional Rating Scale, for future neuroprotective trials.

Recombinant Human Erythropoietin: Novel Strategies for Neuroprotective/Neuro-regenerative Treatment of Multiple Sclerosis

Treatment of multiple sclerosis (MS) is still unsatisfactory and essentially non-existing for the progressive course of the disease. Recombinant human erythropoietin (EPO) may be a promising neuroprotective/neuroregenerative treatment of MS. In the nervous system, EPO acts anti-apoptotic, antioxidative, anti-inflammatory, neurotrophic and plasticity-modulating. Beneficial effects have been shown in animal models of various neurological and psychiatric diseases, including different models of experimental autoimmune encephalomyelitis. EPO is also effective in human brain disease, as shown in double-blind placebo-controlled clinical studies on ischemic stroke and chronic schizophrenia. An exploratory study on chronic progressive MS yielded lasting improvement in motor and cognitive performance upon high-dose long-term EPO treatment.

The influence of personality factors on disease progression and health‐related quality of life in people with ALS

We aimed to perform a prospective long‐term follow‐up of health‐related quality of life (QOL) in ALS and to investigate the relationship of personality factors with changes in QOL and disease progression. Data on QOL were collected prospectively for 12 months from 31 ALS patients. Personality factors were studied using the NEO‐FFI (NEO Five Factor Inventory). Monthly self‐ratings of global QOL, and seven health‐related QOL functions, as well as ALSFRS (ALS Functional Rating Scale) scores were analyzed using a linear mixed model approach. QOL and ALSFRS scores decreased during follow‐up. Patients who scored higher on the agreeableness personality dimension, despite similar total duration of disease, had higher QOL at the beginning of the follow‐up period but the reduction of QOL over time was significantly steeper than in patients who scored lower on agreeableness, associated with faster disease progression. These findings suggest that being less agreeable might serve as a protective factor with respect to QOL and disease progression in ALS.