Niclas Sjögren

Identification of novel candidate protein biomarkers for the post-polio syndrome - implications for diagnosis, neurodegeneration and neuroinflammation.

Survivors of poliomyelitis often develop increased or new symptoms decades after the acute infection, a condition known as post-polio syndrome (PPS). The condition affects 20-60% of previous polio patients, making it one of the most common causes of neurological deficits worldwide. The underlying pathogenesis is not fully understood and accurate diagnosis is not feasible. Herein we investigated whether it was possible to identify proteomic profile aberrations in the cerebrospinal fluid (CSF) of PPS patients. CSF from 15 patients with well-defined PPS were analyzed for protein expression profiles. The results were compared to data obtained from nine healthy controls and 34 patients with other non-inflammatory diseases which served as negative controls. In addition, 17 samples from persons with secondary progressive multiple sclerosis (SPMS) were added as relevant age-matched references for the PPS samples. The CSF of persons with PPS displayed a disease-specific and highly predictive (p=0.0017) differential expression of five distinct proteins: gelsolin, hemopexin, peptidylglycine alpha-amidating monooxygenase, glutathione synthetase and kallikrein 6, respectively, in comparison with the control groups. An independent ELISA confirmed the increase of kallikrein 6. We suggest that these five proteins should be further evaluated as candidate biomarkers for the diagnosis and development of new therapies for PPS patients.

Structural and functional differences between neuropathy with and without pain

We aimed to find functional and structural differences in neuropathy between patients with and without chronic pain following nerve injury. We included 30 patients requiring hand surgery after a trauma, with 21 reporting chronic pain for more than one year after the injury, while 9 did not suffer from injury-related chronic pain. We assessed mechanical sensitivity, thermal thresholds, electrically induced pain and axon reflex erythema and cutaneous nerve fiber density in skin biopsies of the injured site and its contralateral control. Epidermal fiber density of the injured site was reduced similarly in both patient groups. Thresholds for cold and heat pain and axon reflex areas were reduced in the injured site, but did not differ between the patient groups. Only warmth thresholds were better preserved in the pain patients (35.2 vs. 38.4°C). Neuronal CGRP staining did not reveal any difference between pain and non-pain patients. Epidermal innervation density correlated best to warmth detection thresholds and deeper dermal innervation density to the area of the axon reflex erythema. No specific pattern of subjective, functional or structural parameters was detected that would separate the neuropathy patients into pain and non-pain patients. Specific staining of additional targets may help to improve our mechanistic understanding of pain development.

Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients

Neuropathy can lead not only to impaired function but also to sensory sensitization. We aimed to link reduced skin nerve fibre density in different levels to layer‐specific functional impairment in neuropathic pain patients and tried to identify pain‐specific functional and structural markers.

Psychometric evaluation of ADAS-Cog and NTB for measuring drug response

To conduct a psychometric analysis to determine the adequacy of instruments that measure cognition in Alzheimers disease trials.

Cortical responses to amphetamine exposure studied by pCASL MRI and pharmacokinetic/pharmacodynamic dose modeling

INTRODUCTION Perfusion measurement by arterial spin labeling (ASL) techniques is well suited for pharmaceutical magnetic resonance imaging (phMRI) studies to investigate how drugs change the cerebral perfusion status and further, neuronal activity. MATERIALS AND METHOD Twelve healthy normal male volunteers participated in the study which was based on a double blinded design. Six subjects were randomly selected to receive a single oral dose of 20mg d-amphetamine and six were given placebo. Perfusion measurements by pseudo-continuous ASL (pCASL) technique were repeatedly performed at 10 different time points with a 3T clinical MRI scanner during a 10 hour period after dose together with physiologic data and blood sample collections. The dynamic changes in cerebral perfusion in response to the plasma concentration variations of d-amphetamine were analyzed at voxel-level and for regions of interest. RESULTS Compared to the placebo group a 20% reduction in cerebral blood flow (CBF) was observed in gray matter for the subjects that received d-amphetamine. The most significant reduction of regional CBF (rCBF) was detected in the basal ganglia, frontal region and insular cortex using voxel based analysis. A relation between d-amphetamine exposure and CBF response was found using PK/PD modeling, which predicted on average a 15% decrease of the CBF in gray matter at a plasma concentration of 30 ng/ml. CONCLUSION In this study we have demonstrated that repeated perfusion measurements by pCASL technique was sufficiently robust to differentiate the neurological response between the groups that received d-amphetamine and placebo. Quantitative and repetitive CBF measurements can be used for PK/PD modeling of CNS drug responses in humans.

Effective visualization of integrated knowledge and data to enable informed decisions in drug development and translational medicine

Integrative understanding of preclinical and clinical data is imperative to enable informed decisions and reduce the attrition rate during drug development. The volume and variety of data generated during drug development have increased tremendously. A new information model and visualization tool was developed to effectively utilize all available data and current knowledge. The Knowledge Plot integrates preclinical, clinical, efficacy and safety data by adding two concepts: knowledge from the different disciplines and protein binding.Internal and public available data were gathered and processed to allow flexible and interactive visualizations. The exposure was expressed as the unbound concentration of the compound and the treatment effect was normalized and scaled by including expert opinion on what a biologically meaningful treatment effect would be.The Knowledge Plot has been applied both retrospectively and prospectively in project teams in a number of different therapeutic areas, resulting in closer collaboration between multiple disciplines discussing both preclinical and clinical data. The Plot allows head to head comparisons of compounds and was used to support Candidate Drug selections and differentiation from comparators and competitors, back translation of clinical data, understanding the predictability of preclinical models and assays, reviewing drift in primary endpoints over the years, and evaluate or benchmark compounds in due diligence comparing multiple attributes.The Knowledge Plot concept allows flexible integration and visualization of relevant data for interpretation in order to enable scientific and informed decision-making in various stages of drug development. The concept can be used for communication, decision-making, knowledge management, and as a forward and back translational tool, that will result in an improved understanding of the competitive edge for a particular project or disease area portfolio. In addition, it also builds up a knowledge and translational continuum, which in turn will reduce the attrition rate and costs of clinical development by identifying poor candidates early.

Tesaglitazar, a Dual PPAR-α/γ Agonist, Hamster Carcinogenicity, Investigative Animal and Clinical Studies

Tesaglitazar was developed as a dual peroxisome proliferator–activated receptor (PPARα/γ). To support the clinical program, a hamster carcinogenicity study was performed. The only neoplastic findings possibly related to treatment with tesaglitazar were low incidences of hemangioma and hemangiosarcoma in the liver of male animals. A high-power, two-year investigative study with interim necropsies was performed to further elucidate these findings. Treatment with tesaglitazar resulted in changes typical for exaggerated PPARα pharmacology in rodents, such as hepatocellular hypertrophy and hepatocellular carcinoma, but not an increased frequency of hemangiosarcomas. At the highest dose level, there was an increased incidence of sinusoidal dilatation and hemangiomas. No increased endothelial cell (EC) proliferation was detected in vivo, which was confirmed by in vitro administration to ECs. Immunohistochemistry and gene expression analyses indicated increased cellular stress and vascular endothelial growth factor (VEGF) expression in the liver, which may have contributed to the sinusoidal dilatation. A two-fold increase in the level of circulating VEGF was detected in the hamster at all dose levels, whereas no effect on VEGF was observed in patients treated with tesaglitazar. In conclusion, investigations have demonstrated that tesaglitazar does not produce hemangiosarcomas in hamster despite a slight effect on vascular morphology in the liver.

Psychometric features of the ADAS-Cog: Identifying a potential cognition endpoint for prodromal Alzheimer's disease

cognitive functioning for different stages of AD. Despite the popularity of the ADAS-Cog, few studies have examined its item properties among patients with Mild Cognitive Impairment (MCI) and moderate impairment, and further validation of the ADAS-Cog is needed to substantiate its use at different stages of AD. This study examined whether there are differences in response to a particular item as a function of respondent characteristics (Apolipoprotein E and Impairment level) in the ADAS-Cog.Methods: jMetrik was used to analyse the ADAS-Cog. AD data was obtained from the Critical Path Institute Online Data Repository (CODR). Separate Rasch analyses were conducted comparingApoE carriers (n1⁄4 505) vs non-carriers (n 1⁄4 507), and MCI (MMSE 1⁄4 21 to 26; n 1⁄4 1362) and Moderate impairment (MMSE 14 to 20; n 1⁄4 1211) to examine summary and individual model fit statistics, person separation index (PSI), response format, local dependency, targeting, item bias (or differential item functioning -DIF), and dimensionalityResults:Based on the results of Rasch analyses different approaches can be taken to account measurement bias in properties of the ADAS-Cog post-hoc.Lower item calibration (Delta) reflects items with bias, indicating whether subgroups respond to items differently. The average age of 74.08 years (SD1⁄4 8.15) with 55.7%male patients. Commands (Delta 1⁄4 0.23), Constant Praxis (0.26), Ideational Praxis (0.32), and Naming Objects (0.26) shows ’moderate’ DIF, favoring theModerately impaired group, indicating that this item functions better in this group. Orientation (Delta 1⁄4 1.34) shows ’Large’ DIF, favoring the Moderately impaired group, indicating that this item functions better in this group. Word Recognition (-1.38) and Word Recall (-1.20) shows ’Large’ DIF, favoring the MCI group, indicating that this item functions better in this group. Conclusions: The choices made during analysis will substantially affect the results, and we have described and illustrated that the subgroups may have different impact on different items affecting outcome.

Cortical thinning patterns in Alzheimer's patients and subjects with mild cognitive impairment from the AddNeuroMed study

Introduction: A prominent feature of Alzheimers disease (AD) is the accumulation of amyloid-β peptide (Aβ) derived from abnormal processing of amyloid precursor protein in senile plaques. Accordingly, reduction in the potentially toxic Aβ has emerged as one of the most important therapeutic goals in treating AD. One potential source of phytotherapeutic agents is berberine (BBR), an alkaloid from Coptis Chinensis.1 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada, 2 Department of Health Science and Technology, Aalborg University, Aalborg, Denmark, 3 Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, 4 ITHINK Research Lab, Lawson Health Research Institute, London, ON, Canada, 5 AstraZeneca R&D, AstraZeneca, Södertälje, 6 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden, 7 Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece, 8 Department of Neurology, University and University Hospital of Kuopio, Kuopio, Finland, 9 Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy, 10 Department of Old Age Psychiatry & Psychotic Disorders, Medical University of Lodz, Lodz, Poland, 11 Department of Internal and Geriatrics Medicine, Hôpitaux de Toulouse, Toulouse, France, 12 Institute of Psychiatry, Kings College London, 13 NIHR Biomedical Research Centre for Mental Health, London, UKAlzheimers disease is characterized by progressive impairment of brain plasticity Although senile plaques and neurofibrillary tangles in the brain are the pathological hallmarks, their presence seems not to be related to the severity of dementia. In contrast, altered synaptic communication and neuronal loss, caused by other tau or amyloid species represent a direct pathological cause for dementia. Among tau species we focus on tau fragment (26-230) or N-tau. Clevage of tau by apoptotic proteases plays a crucial role in neurodegeneration and in the development of the neurofibrillary tangles as AD progresses. We have found that N-tau adversely affects neurons. Indeed, its overexpression has marked toxic effects on neurons that can be inhibited by the NMDAR antagonist and by inhibitors of NMDAR-associated processes such as MAP kinase and calpain. We have used conditional transgenic mice for N-tau and primary neuronal cultures overexpressing N-tau for decoding the signal transduction pathway that link Ntau expression to NMDAR activity and their upstream and downstream effectors inducing plasticity failure. Data regarding the electrophysiological recording of NMDAR, morphological, qualitative and quantitative analysis of synapse number, dendritic spines and behavioral analysis of N-tau transgenic mice performed to give an accurate and global view of the molecular events involved in N-tau modulation of neuronal plasticity will be presented.

Cluster Analysis and Decision Trees of MR Imaging in Patients Suffering Alzheimer’s

The use of novel analytical techniques (such as data clustering and decision trees) that can model and predict patient disease outcomes has great potential for assessing disease process and progression in Alzheimer’s disease and mild cognitive impairment. For this study, 43 different variables (generated from image data, demographics and clinical data) have been compiled and analyzed using a modified clustering algorithm. Our aim was to determine the influence of these variables on the incidence of Alzheimer’s and mild cognitive impairment. Furthermore, we used a decision tree algorithm to model the level of “importance” of variants influencing this decision.