Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive disease of the motor system involving both upper motor neurons in the brain and lower motor neurons in the spinal cord. Patients suffer from progressive wasting and weakness of limb, bulbar and respiratory muscles. Onset and disease course in ALS is heterogeneous as each patient has its unique combination of upper and lower motor neuron involvement, site of onset and symptom development. In The Netherlands, 400 to 500 persons are diagnosed each year with this destructive disease. ALS can occur at any age during adulthood with a median age of onset of 63 years and a median survival of three years. This thesis consists of three parts 1) disease spread, 2) biomarkers and 3) clinical trials.
1) Up until now, little is known about how ALS progressively affects the motor system. We assessed spread of disease in ALS both clinically as by examining the changes in the brain. Symptom development was found to be not random, but with preferred spread to the opposite limb. Using MRI techniques, mainly DTI, we reconstructed the brain network. Comparing patients with healthy controls, we found a subnetwork of impaired connectivity in ALS. This impaired subnetwork shows large overlap with the motor network in healthy controls. Over time, we found this impaired subnetwork was expanding including more and more brain regions. Our findings in the first part of this thesis are in support of disease spread guided by the brain’s network structure. These findings might provide new targets for disease modifying treatments.
2) Upper motor neuron involvement is currently assessed on clinical examination only, while it is known that patients can have subclinical involvement as well. An objective marker for upper motor neuron involvement would facilitate and improve diagnosis. We used several MRI techniques to assess the integrity of the upper motor neuron in ALS. The main finding from these studies was a significantly reduced cortical thickness in primary motor regions (precentral gyrus) in ALS, suggesting this measure might be an objective marker for upper motor neuron involvement.
3) Only one drug – riluzole – has proved effective in extending the lifespan of patients with ALS, and it does so by only 3–6 months. A better treatment is urgently needed. In 2008 a pilot study showed a favourable effect of lithium in a transgenic mouse model of ALS and in an open-label study in 44 patients. To examine the true efficacy and safety of lithium in ALS, we performed a randomised, placebo controlled, clinical trial with sequential analysis. Unfortunately our results did not lend support for a beneficial effect of lithium on survival, nor disease progression.
Original language | English |
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Qualification | Doctor of Philosophy |
Awarding Institution |
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Supervisors/Advisors |
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Award date | 18 Dec 2012 |
Publisher | |
Print ISBNs | 978-90-9027183-5 |
Publication status | Published - 18 Dec 2012 |
Keywords
- Econometric and Statistical Methods: General
- Geneeskunde(GENK)
- Medical sciences
- Bescherming en bevordering van de menselijke gezondheid