Engelstalige samenvatting van het proefschrift sonja de jongx

Engelstalige samenvatting van het proefschrift:
Amyotrophic lateral sclerosis: epidemiology, risk factors and treatment
Door Dr. Sonja de Jong, gepromoveerd op 12-10-2012.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons leading to progressive weakness of the limbs, the bulbar muscles and the respiratory muscles. Fifty percent of patients die within 3 years after onset of symptoms, mainly due to respiratory failure. Chapter 1 provides a general introduction to the epidemiology of ALS, the multifactorial pathogenesis, and possible treatment strategies of the disease. In a large, prospective, population-based study we calculated the incidence and prevalence of ALS in the Netherlands using the capture-recapture methodology (Chapter 2). The annual incidence rate was 2.77 per 100,000 person years. The reliable age- and gender specific incidence rates offered by this study method provide evidence that the rapid decrease of ALS incidence after 74 years of age is real, and may not be caused solely by under-ascertainment in the elderly. This implies that the ALS incidence peak in the 70 to 74-year age group reflects a time period with maximal susceptibility, and that ALS is not merely the result of aging. Furthermore, no clear evidence was found for a postmenopausal drop in the male: female ratio. ALS is considered to be a multifactorial disease. Several molecular mechanisms have been described to mediate motor neuron death. In chapter 3 through 7 we described several possible risk factors in ALS, studied in a large prospective, population-based case-control study in the Netherlands between 2006 and 2010. Cigarette smoke could increase the risk of developing ALS through several mechanisms, including inflammation, oxidative stress, and neurotoxicity caused by heavy metals and other chemical compounds present in cigarette smoke. In addition, other confounding lifestyle factors could be involved—for example, alcohol consumption. Our study showed that cigarette smoking was, indeed, independently associated with an increased risk of ALS and alcohol consumption is independently associated with a reduced risk of ALS (Chapter 3). Current smoking was also associated with a worse prognosis. This study also emphasizes the relevance of performing studies in incident patients to identify susceptibility or disease-modifying factors (environmental or genetic), particularly for diseases such as ALS, which is associated with shortened survival. Several epidemiological studies, including our study described in chapter 2, showed a lower incidence of ALS in women than in men. This suggests a possible protective effect of female reproductive hormones. In Chapter 4 we concluded that a longer reproductive time-span, which may be a proxy for longer exposure to female productive hormones, was found to be independently associated with a decreased risk of ALS and with a prolonged survival of ALS patients, adjusted for known prognostic factors. Similar results were found for the lifetime estrogen exposure, unopposed by progesterone (calculated by subtracting the duration of pregnancies and oral contraceptive use, and the number of post-ovulatory weeks from the menarche-menopause interval): a longer lifetime estrogen exposure seemed to be associated with a decreased risk of ALS, although not statistically significant. Also patients with a relatively long estrogen exposure survived, on average, more than a year longer than patients with a relatively short lifetime estrogen exposure, adjusted for known prognostic factors. Our results may indicate that higher exposure to female reproductive hormones has a beneficial effect on susceptibility to ALS and survival rate, suggesting a neuroprotective effect on motor neurons. Sporadic ALS is a multifactorial disease for which there are probably multiple genetic risk factors. An association with increased parental age might suggest there is a role for specific (epi)genetic changes. However, in our large study, parental age was not associated with an increased risk of ALS, and therefore these specific (epi)genetic alterations are not likely to contribute to the aetiology of sporadic ALS (Chapter 5). Familial aggregation of ALS with neurodegenerative diseases such as Parkinson’s disease or dementia, could suggest shared genetic or environmental risk factors. However, in our study no familial aggregation of ALS with other neurodegenerative diseases could be established (Chapter 6). On the other hand, a lowered risk of vascular diseases in relatives of ALS patients was found. Also, a higher level of leisure time physical activity was found in our study (Chapter 7). These results support the hypothesis ALS is associated with a beneficial vascular risk profile (lower occurrence of vascular diseases in relatives, lower premorbid body mass index, favorable lipid profile, higher leisure time physical activity). Diagnosing ALS remains difficult because of the lack of a reference test with a high positive predictive value. The aim of the revisions of the different sets of diagnostic criteria was to enhance clinical research, therapeutic trials and molecular genetic studies. Inclusion in clinical trials, early in the course of the disease, is important because therapeutic agents probably have the best effect when motor neuron damage is as limited as possible. Our study showed that the revised El Escorial criteria as well as the Awaji algorithm, still exclude a large percentage of the patients for clinical trials at time of diagnosis (Chapter 8). A higher copy number of the SMN2 gene is associated with a more favorable disease course in ALS patients. Increasing the survival motor neuron (SMN) protein expression by enhancing SMN2 transcription by valproic acid could therefore modify the disease course in ALS patients. In our randomized, placebo-controlled, double-blind, clinical trial, valproic acid, at a dose used in epilepsy, as an adjunct to riluzole, did not improve survival in ALS, and did not attenuate disease progression as measured by a functional rating scale (Chapter 9).

Source: http://www.alsonderzoek.nl/files/Engelstalige%20samenvatting%20van%20het%20proefschrift%20Sonja%20de%20Jongx(1).pdf