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Burman, J., Tolf, A., Hägglund, H. & Askmark, H. (2018). Autologous haematopoietic stem cell transplantation for neurological diseases. Journal of Neurology, Neurosurgery and Psychiatry, 89(2), 147-155
Open this publication in new window or tab >>Autologous haematopoietic stem cell transplantation for neurological diseases
2018 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 89, no 2, p. 147-155Article, review/survey (Refereed) Published
Abstract [en]

Neuroinflammatory diseases such as multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis are leading causes of physical disability in people of working age. In the last decades significant therapeutic advances have been made that can ameliorate the disease course. Nevertheless, many affected will continue to deteriorate despite treatment, and the costs associated with disease-modifying drugs constitute a significant fiscal burden on healthcare in developed countries. Autologous haematopoietic stem cell transplantation is a treatment approach that aims to ameliorate and to terminate disease activity. The erroneous immune system is eradicated using cytotoxic drugs, and with the aid of haematopoietic stem cells a new immune system is rebuilt. As of today, more than 1000 patients with multiple sclerosis have been treated with this procedure. Available data suggest that autologous haematopoietic stem cell transplantation is superior to conventional treatment in terms of efficacy with an acceptable safety profile. A smaller number of patients with other neuroinflammatory conditions have been treated with promising results. Herein, current data on clinical effect and safety of autologous haematopoietic stem cell transplantation for neurological disease are reviewed.

Keywords
clinical neurology, haematology, multiple sclerosis, myasthenia, neuropathy
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-336956 (URN)10.1136/jnnp-2017-316271 (DOI)000424004400007 ()28866625 (PubMedID)
Available from: 2017-12-19 Created: 2017-12-19 Last updated: 2019-01-25Bibliographically approved
Jonasson, M., Appel, L., Danfors, T., Nyholm, D., Askmark, H., Frick, A., . . . Lubberink, M. (2017). Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.. American Journal of Nuclear Medicine and Molecular Imaging, 7(6), 263-274
Open this publication in new window or tab >>Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.
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2017 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 7, no 6, p. 263-274Article in journal (Refereed) Published
Abstract [en]

[11C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [11C]PE2I scans, showing dopamine transporter availability (BPND) and relative cerebral blood flow (R1), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clinical application. Twelve subjects with parkinsonism and seventeen healthy controls underwent 80 min dynamic [11C]PE2I PET scans. BPND and R1 images were generated using cerebellum reference region defined on a co-registered MRI, as well as a supervised cluster analysis (SVCA)-based reference. Initial 20, 30 and 40 min of the scans were extracted and images of standardized uptake value ratio (SUVR) and R1 were computed using MRI- and SVCA-based reference. Correlation was high between striatal 80 min MRI-based BPND and 40 min SVCA-based SUVR-1 (R2=0.95). High correlation was also found between R1 values in striatal and limbic regions (R2≥0.91) whereas correlation was moderate for cortical regions (R2=0.71). The results indicate that dynamic [11C]PE2I scans can be restricted to 40 min and that SVCA can be used for automatic extraction of a reference region. These outcomes will support routine applications of [11C]PE2I PET in clinical settings.

Keywords
PET, [11C]PE2I, parametric images, parkinsonism, supervised clustering
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-340790 (URN)000419593300003 ()29348981 (PubMedID)
Funder
Swedish Research CouncilSwedish Society for Medical Research (SSMF)
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-02-21Bibliographically approved
Senek, M., Aquilonius, S.-M., Askmark, H., Bergquist, F., Constantinescu, R., Ericsson, A., . . . Nyholm, D. (2017). Levodopa/carbidopa microtablets in Parkinson’s disease: A study of pharmacokinetics and blinded motor assessment. European Journal of Clinical Pharmacology, 73(5), 563-571
Open this publication in new window or tab >>Levodopa/carbidopa microtablets in Parkinson’s disease: A study of pharmacokinetics and blinded motor assessment
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2017 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 73, no 5, p. 563-571Article in journal (Refereed) Published
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-320487 (URN)10.1007/s00228-017-2196-4 (DOI)000399175100006 ()28101657 (PubMedID)
Funder
VINNOVA
Available from: 2017-01-18 Created: 2017-04-20 Last updated: 2018-02-28Bibliographically approved
Appel, L., Jonasson, M., Danfors, T., Nyholm, D., Askmark, H., Lubberink, M. & Sörensen, J. (2015). Use of C-11-PE2I PET in Differential Diagnosis of Parkinsonian Disorders. Journal of Nuclear Medicine, 56(2), 234-242
Open this publication in new window or tab >>Use of C-11-PE2I PET in Differential Diagnosis of Parkinsonian Disorders
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2015 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 56, no 2, p. 234-242Article in journal (Refereed) Published
Abstract [en]

In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clinical diagnosis. A dual examination using I-123-FP-CIT (I-123-N-omega-fluoropropyl- 2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane, or I-123-ioflupane) SPECT and F-18-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, respectively. Parametric images based on a single, dynamic C-11-PE2I (N-(3-iodoprop-2E-enyl)-2 beta-carbomethoxy-3 beta-(4-methyl-phenyl) nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R-1]) at voxel level. This study aimed to evaluate the validity of C-11-PE2I PET against the dual-modality approach using I-123-FP-CIT SPECT and F-18-FDG PET.

Methods: Sixteen patients with parkinsonian disorders had a dual examination with F-18-FDG PET and I-123-FP-CIT SPECT following clinical routines and additionally an experimental C-11-PE2I PET scan. Parametric BPND and R-1 images were generated using receptor parametric mapping with the cerebellum as a reference. T1-weighted MR imaging was used for automated definition of volumes of interest (VOI). The DAT VOIs included the basal ganglia, whereas the overall brain functional activity was examined using VOIs across the brain. BPND and R-1 values were compared with normalized I-123-FP-CIT and F-18-FDG uptake values, respectively, using Pearson correlations and regression analyses. In addition, 2 masked interpreters evaluated the images visually, in both the routine and the experimental datasets, for comparison of patient diagnoses.

Results: Parametric C-11-PE2I BPND and R-1 images showed high consistency with I-123-FP-CIT SPECT and F-18-FDG PET images. Correlations between C-11-PE2I BPND and I-123-FP-CIT uptake ratios were 0.97 and 0.76 in the putamen and caudate nucleus, respectively. Regional C-11-PE2I R-1 values were moderately to highly correlated with normalized F-18-FDG values (range, 0.61-0.94). Visual assessment of DAT availability showed a high consistency between C-11-PE2I BPND and I-123-FP-CIT images, whereas the consistency was somewhat lower for appraisal of overall brain functional activity using I-123-FP-CIT and F-18-FDG images. Substantial differences were found between clinical diagnosis and both neuro-imaging diagnoses.

Conclusion: A single, dynamic C-11-PE2I PET investigation is a powerful alternative to a dual examination with I-123-FP-CIT SPECT and F-18-FDG PET for differential diagnosis of parkinsonian disorders. A large-scale patient study is, however, needed to further investigate distinct pathologic patterns in overall brain functional activity for various parkinsonian disorders.

Keywords
parkinsonism, dopamine transporter, DAT, overall brain functional activity, PET, SPECT
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-247403 (URN)10.2967/jnumed.114.148619 (DOI)000349324300024 ()25593112 (PubMedID)
Available from: 2015-03-20 Created: 2015-03-18 Last updated: 2018-02-15Bibliographically approved
Elf, K., Shevchenko, G., Nygren, I., Larsson, L., Bergquist, J., Askmark, H. & Artemenko, K. (2014). Alterations in muscle proteome of patients diagnosed with amyotrophic lateral sclerosis. Journal of Proteomics, 108, 55-64
Open this publication in new window or tab >>Alterations in muscle proteome of patients diagnosed with amyotrophic lateral sclerosis
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2014 (English)In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 108, p. 55-64Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle paralysis. Currently clinical tools for ALS diagnostics do not perform well enough and their improvement is needed. The objective of this study was to identify specific protein alterations related to the development of ALS using tiny muscle biopsies. We applied a shotgun proteomics and quantitative dimethyl labeling in order to analyze the global changes in human skeletal muscle proteome of ALS versus healthy subjects for the first time. 235 proteins were quantified and 11 proteins were found significantly regulated in ALS muscles. These proteins are involved in muscle development and contraction, metabolic processes, enzyme activity, regulation of apoptosis and transport activity. In order to eliminate a risk to confuse ALS with other denervations, muscle biopsies of patients with postpolio syndrome and Charcot Marie Tooth disease (negative controls) were compared to those of ALS and controls. Only few proteins significantly regulated in ALS patients compared to controls were affected differently in negative controls. These proteins (BTB and kelch domain-containing protein 10, myosin light chain 3, glycogen debranching enzyme, transitional endoplasmic reticulum ATPase), individually or as a panel, could be selected for estimation of ALS diagnosis and development. Biological significance ALS is a devastating neurodegenerative disease, and luckily, very rare: only one to two people out of 100,000 develop ALS yearly. This fact, however, makes studies of ALS very challenging since it is very difficult to collect the representative set of clinical samples and this may take up to several years. In this study we collected the muscle biopsies from 12 ALS patients and compared the ALS muscle proteome against the one from control subjects. We suggested the efficient method for such comprehensive quantitative analysis by LC-MS and performed it for the first time using human ALS material. This gel- and antibody-free method can be widely applied for muscle proteome studies and has been used by us for revealing of the specific protein alterations associated with ALS.

Keywords
Amyotrophic lateral sclerosis (ALS), Dimethyl labeling quantitative proteomics, Mass spectrometry (MS), Muscle biopsy
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-230939 (URN)10.1016/j.jprot.2014.05.004 (DOI)000340315400004 ()
Available from: 2014-09-04 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
Press, R., Askmark, H., Svenningsson, A., Andersen, O., Axelson, H. W., Strömberg, U., . . . Hägglund, H. (2014). Autologous haematopoietic stem cell transplantation: a viable treatment option for CIDP. Journal of Neurology, Neurosurgery and Psychiatry, 85(6), 618-624
Open this publication in new window or tab >>Autologous haematopoietic stem cell transplantation: a viable treatment option for CIDP
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2014 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, no 6, p. 618-624Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Only 70-80% of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) respond satisfactorily to the established first-line immunomodulatory treatments. Autologous haematopoietic stem cell transplantation (AHSCT) has been performed as a last treatment resort in a few therapy-refractory cases with CIDP. We describe the results of AHSCT in 11 consecutive Swedish patients with therapy-refractory CIDP with a median follow-up time of 28 months.

METHOD: Case data were gathered retrospectively for AHSCT treatments in 11 patients with CIDP refractory to the first-line immunomodulatory treatments, intravenous high-dose immunoglobulin, corticosteroids and plasma exchange and to one or more second-line treatments used in 10 of the 11 patients.

RESULTS: The median Inflammatory Neuropathy Cause and Treatment (INCAT) score within 1 month prior to AHSCT was 6 and the Rankin score 4. Total INCAT and Rankin scores improved significantly within 2-6 months after AHSCT and continued to do so at last follow-up. The motor action potential amplitudes (CMAP) improved already within 4 months (median) after AHSCT. Three of the 11 patients relapsed during the follow-up period, requiring retransplantation with AHSCT in one. Eight of the 11 patients maintained drug-free remission upon last follow-up. AHSCT was safe but on the short term associated with a risk of cytomegalovirus (CMV) and Epstein-Barr virus reactivation, CMV disease, haemorrhagic cystitis and pancreatitis.

CONCLUSIONS: Our results though hampered by the limited number of patients and the lack of a control group suggest AHSCT to be efficacious in therapy-refractory CIDP, with a manageable complication profile. Confirmation of these results is necessary through randomised controlled trials.

National Category
Medical and Health Sciences Neurology
Identifiers
urn:nbn:se:uu:diva-223064 (URN)10.1136/jnnp-2013-306014 (DOI)000336124400009 ()24262917 (PubMedID)
Available from: 2014-04-16 Created: 2014-04-16 Last updated: 2017-12-05Bibliographically approved
Jakobsson Larsson, B., Nordin, K., Askmark, H. & Nygren, I. (2014). Coping strategies among patients with newly diagnosed amyotrophic lateral sclerosis. Journal of Clinical Nursing, 23(21-22), 3148-3155
Open this publication in new window or tab >>Coping strategies among patients with newly diagnosed amyotrophic lateral sclerosis
2014 (English)In: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 23, no 21-22, p. 3148-3155Article in journal (Refereed) Published
Abstract [en]

AIMS AND OBJECTIVES: To prospectively identify different coping strategies among newly diagnosed amyotrophic lateral sclerosis patients and whether they change over time and to determine whether physical function, psychological well-being, age and gender correlated with the use of different coping strategies.

BACKGROUND: Amyotrophic lateral sclerosis is a fatal disease with impact on both physical function and psychological well-being. Different coping strategies are used to manage symptoms and disease progression, but knowledge about coping in newly diagnosed amyotrophic lateral sclerosis patients is scarce.

DESIGN: This was a prospective study with a longitudinal and descriptive design.

METHODS: A total of 33 patients were included and evaluation was made at two time points, one to three months and six months after diagnosis. Patients were asked to complete the Motor Neuron Disease Coping Scale and the Hospital Anxiety and Depression Scale. Physical function was estimated using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale.

RESULTS: The most commonly used strategies were support and independence. Avoidance/venting and information seeking were seldom used at both time points. The use of information seeking decreased between the two time points. Men did not differ from women, but patients ≤64 years used positive action more often than older patients. Amyotrophic Lateral Sclerosis Functional Rating Scale was positively correlated with positive action at time point 1, but not at time point 2. Patients' psychological well-being was correlated with the use of different coping strategies.

CONCLUSIONS: Support and independence were the most used coping strategies, and the use of different strategies changed over time. Psychological well-being was correlated with different coping strategies in newly diagnosed amyotrophic lateral sclerosis patients.

RELEVANCE TO CLINICAL PRACTICE: The knowledge about coping strategies in early stage of the disease may help the nurses to improve and develop the care and support for these patients.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-219767 (URN)10.1111/jocn.12557 (DOI)000343835300016 ()24476534 (PubMedID)
Available from: 2014-03-11 Created: 2014-03-05 Last updated: 2017-12-05Bibliographically approved
Elf, K., Askmark, H., Nygren, I. & Punga, A. R. (2014). Vitamin D deficiency in patients with primary immune-mediated peripheral neuropathies. Journal of the Neurological Sciences, 345(1-2), 184-188
Open this publication in new window or tab >>Vitamin D deficiency in patients with primary immune-mediated peripheral neuropathies
2014 (English)In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 345, no 1-2, p. 184-188Article in journal (Refereed) Published
Abstract [en]

PURPOSE: T cells are important in the immunopathology of immune-mediated peripheral neuropathies (PNP) and activated vitamin D regulates the immune response through increasing the amount of regulatory T cells. An association between vitamin D deficiency and polyneuropathy has been stipulated; hence we assessed whether patients with primary immune-mediated PNP have low vitamin D [25(OH)D] levels.

METHODS: Plasma levels of 25(OH)D were analyzed in 26 patients with primary immune-mediated PNP, 50 healthy matched blood donors and 24 patients with motor neuron disease (MND). INCAT score was assessed in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. ALSFRS-R score was applied to MND patients and the modified Rankin (mRankin) scale compared disability among patient groups.

RESULTS: Mean 25(OH)D value in PNP patients was 40±16nmol/l, compared to 69±21nmol/l in healthy blood donors (p<0.001). MND patients had a higher mean 25(OH)D than PNP patients (59±26nmol/L; p=0.006) and comparable levels to healthy blood donors (p=0.15). Mean 25(OH)D value was not higher in PNP patients with pre-existing vitamin D3 supplementation of 800IU/day (N=6; 35±18nmol/L) than in unsupplemented PNP patients (42±16nmol). INCAT score ranged from 0 to 10 (mean 3.5) and ALSFRS-R ranged from 11 to 44 (mean 31). mRankin score was more severe in MND patients (mean 3.5) compared to PNP patients (mean 2.1).

CONCLUSIONS: All patients with primary immune-mediated PNP were diagnosed with vitamin D deficiency and they had significantly lower 25(OH)D values than healthy control persons and MND patients. We suggest monitoring of vitamin D status in patients with autoimmune PNP, since immune cells are responsive to the ameliorative effects of vitamin D.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-230891 (URN)10.1016/j.jns.2014.07.040 (DOI)000343689600030 ()25115500 (PubMedID)
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
Hagglund, H., Askmark, H., Strömberg, U., Axelsson, H., Svenningsson, A., Isaksson, C., . . . Press, R. (2013). Autologous haematopoietic stem cell transplantation: a viable treatment option for chronic inflammatory demyelinating polyneuropathy. Paper presented at 39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT), APR 07-10, 2013, London, ENGLAND. Bone Marrow Transplantation, 48(Suppl. 2), S336-S336
Open this publication in new window or tab >>Autologous haematopoietic stem cell transplantation: a viable treatment option for chronic inflammatory demyelinating polyneuropathy
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2013 (English)In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 48, no Suppl. 2, p. S336-S336Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-203022 (URN)000319025201130 ()
Conference
39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT), APR 07-10, 2013, London, ENGLAND
Available from: 2013-07-02 Created: 2013-07-01 Last updated: 2017-12-06Bibliographically approved
Jonasson, M., Appel, L., Engman, J., Frick, A., Nyholm, D., Askmark, H., . . . Lubberink, M. (2013). Validation of parametric methods for [(11)C]PE2I positron emission tomography. NeuroImage, 74, 172-178
Open this publication in new window or tab >>Validation of parametric methods for [(11)C]PE2I positron emission tomography
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2013 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 74, p. 172-178Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES

The radioligand [(11)C]PE2I is highly selective for dopamine transporter (DAT) and can be used in vivo for investigation of changes in DAT concentration, progression of disease and validation of treatment using positron emission tomography (PET). DAT is an important protein for regulation of central dopamine concentration and DAT deficiency has been associated with several neurodegenerative and neuropsychiatric disorders. Accurate parametric images are a prerequisite for clinical application of [(11)C]PE2I. The purpose of this study was to evaluate different methods for producing [(11)C]PE2I parametric images, showing binding potential (BPND) and relative delivery (R1) at the voxel level, using clinical data as well as simulations.

METHODS

Investigations were made in twelve subjects either with social anxiety disorder (n=6) or parkinsonian syndrome (n=6), each receiving an 80min dynamic PET scan. All subjects underwent a T1-weighted MRI scan which was co-registered to the PET images and used for definition of regions of interest using a probabilistic template (PVElab). Two basis function implementations (receptor parametric mapping: RPM, RPM2) of the simplified reference tissue model (SRTM) and three multilinear reference tissue models (MRTMo, MRTM and MRTM2) were used for computation of parametric BPND and R1 images. In addition, reference Logan and standard uptake value ratio (SUVr) were investigated. Evaluations of BPND and R1 images were performed using linear regression to compare the parametric methods to region-based analyses with SRTM and cerebellar gray matter as reference region. Accuracy and precision of each method were assessed by simulations.

RESULTS

Correlation and slope of linear regression between parametric and region-based BPND and R1 values in both striatum and extra-striatal regions were optimal for RPM (R(2)=0.99 for both BPND and R1; slopes 0.99 and 0.98 for BPND and R1, respectively, in striatum). In addition, accuracy and precision were best for RPM and RPM2.

CONCLUSION

The basis function methods provided more robust estimations of the parameters compared to the other models and performed best in simulations. RPM, a basis function implementation of SRTM, is the preferred method for voxel level analysis of [(11)C]PE2I PET studies.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-197228 (URN)10.1016/j.neuroimage.2013.02.022 (DOI)000317441300018 ()23435214 (PubMedID)
Available from: 2013-03-22 Created: 2013-03-19 Last updated: 2018-02-15Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7636-4722

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