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- Bergman, Joakim, 1989-
(författare)
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Studies of the Biology of Intrathecal Treatment in Progressive MS
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune disease, affecting the central nervous system (CNS). About 85% of afflicted present with a relapsing-remitting form of the disease (RRMS), for which a breakthrough in treatment was made in 2008 with rituximab, an antibody directed towards CD20, a surface antigen on B-cells. These findings also contributed to cementing the importance of the B-cell’s role in MS pathophysiology. However, MS also exist as a progressive phenotype, affecting most MS patients either from onset or after a transition from RRMS, and for progressive MS the same treatment effect of anti-CD20 has not been observed. Still, studies have found follicle-like structures containing B-cells in meninges and subarachnoid space of the cortex in progressive MS brains, supporting the involvement of B-cells. Evidence also support the existence of a chronic, low-grade inflammatory process compartmentalised within the CNS that correlates with the progressive phase of MS, which may present a treatment barrier towards anti-CD20. Peripherally administrated therapeutic antibodies cross the intact blood-brain barrier with low efficiency with only 0.1-0.5% of the plasma concentration occurring in the cerebrospinal fluid (CSF). Intrathecal (IT) administration circumvents the blood-brain barrier, presenting an opportunity to better target the CNS B-cells.Aims: To evaluate the safety and feasibility of intrathecal anti-CD20 therapy with rituximab in progressive MS, its effect on disease progression through clinical parameters, and impact on biomarkers in CSF. Furthermore, this thesis aimed to evaluate the effect on biomarkers representative of cell injury related to insertion of a ventricular catheter for drug administration and to examine the interstitial milieu in the brain through microdialysis (MD).Methods: The thesis is based on the open-label, phase IIb, multicentre clinical trial Intrathecal Treatment Trial in Progressive Multiple Sclerosis (ITT-PMS; EudraCT 2008-002626-11), in which 23 participants received IT treatment with rituximab, and the extended follow-up study, ITT-PMS extension (EudraCT 2012-000721-53). All participants received a ventricular catheter and an Ommaya reservoir for drug administration through a neurosurgical procedure, and 10 participants received a MD catheter in parallel to the ventricular catheter for 10 days. The treatment effect was evaluated by regular clinical evaluations and analyses of CSF. The clinical outcome was evaluated through walking and upper-limb function tests, and by clinical evaluation scales. Levels of selected CSF biomarkers were analysed from the same time-points as the clinical evaluations.Results: After the completion of the extension trial, one clinical parameter (cognitive performance) showed improvement but could most likely be explained by a learning effect. Worsening of walking speed was observed, while the remaining clinical parameters showed no change. Two severe adverse events occurred in the form of low-virulent bacterial meningitis caused by Propionibacterium, but both were treated effectively with antibiotics without residual symptoms. A ‘spike’ was noticed in the level of lumbar CSF neurofilament light (NFL) following surgery but returned to pre-surgery baseline within 6-12 months. No change was observed for any of the other lumbar CSF biomarkers. No meaningful correlation of protein levels was observed when comparing MD samples, ventricular CSF, and lumbar CSF.Conclusions: Intrathecal treatment through intraventricular administration was well tolerated but not without risks. A continued progression was observed in gait impairment. The insertion of the ventricular catheter caused white matter injury, measured through an increase in NFL in lumbar CSF, in direct association with the surgical procedure. No impact was observed on other CSF biomarkers. There was a poor correlation between different CNS compartments regarding protein levels, arguing for caution in drawing conclusions about brain pathophysiology from lumbar CSF samples.
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| 2. |
- Norrgård, Johnny R, 1976-
(författare)
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Migration and quality of landlocked Atlantic salmon smolt : Implications for conservation and management
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atlantic salmon Salmo salar has a complex life cycle, including long migrations and habitat shifts for both juveniles and adults. As such, salmon populations are vulnerable to habitat degradation and fragmentation along their migratory routes. This makes management and conservation a complex task requiring knowledge of salmon ecology at different temporal and spatial scales. In this thesis I highlight the use of a holistic life-history based approach in the conservation and management of wild and hatchery-reared salmon in regulated rivers and lakes.Small populations of wild-reproducing landlocked salmon and trout Salmo trutta exist in the regulated River Klarälven, Sweden. Since the 1930s, transportation of adult spawners upstream of eight dams has given the fish access to spawning grounds. The number of returning wild spawners became critically low in the 1960s, but stocking of hatchery smolts resulted in an increase in spawners that continues today. My data show that wild smolt may suffer high mortality due to multiple dam passages. To ensure viable populations of wild populations, future management should include both up- and downstream solutions that ensure connectivity in the system.The recreational and commercial salmonid fishery are maintained by compensatory stockings, yielding annual catches of about 75 tons, and a river return rate of hatchery fish of about 1%. As a large portion of the stocked smolts does not survive downstream migration to the lake, there has been discussion about the quality of the stocked smolt and about stocking strategies. Based on my studies, producing hatchery smolts more closely resembling wild-born conspecifics should result in reduced loss rates. I suggest changes in the hatchery and stocking procedures to increase the survival of stocked smolts. The results of my research should be applicable to other regulated systems, particularly those with mixed stocks of wild and hatchery salmonid populations.
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