Abstract An evidence-based review was undertaken of the literature published between 2002 and 2006 about sports, trauma and ALS in order to see if there were new data to modify the conclusions of a ...previous review (2003). The new data support the previous conclusions that physical activity and trauma are probably (“more likely than not”) not risk factors for ALS (Level II conclusions). This review concludes also that the reports of an apparent excess of ALS in Italian soccer players likely reflect incorrect analysis of the data. The appearance of excess relies on accepting as valid estimation methods resulting in improbably low numbers of expected cases. A different method is proposed: it generates more plausible numbers of expected cases, compared to which there is no excess of total cases (Level C conclusion). A theoretical framework is developed to analyze the possible influence of a “healthy worker effect” on incidence of neurodegenerative diseases in cohorts of employed or formerly employed individuals. In lieu of theoretical speculations, data are needed to measure this effect, while controlling for known lifestyle factors and accounting for the effect of loss of competing causes of mortality.
Parental lineage has been shown to increase the risk of Alzheimer’s disease (AD) in the offspring, with greater risk attributed to maternal lineage. While 40 genes/loci have been linked to the risk ...of developing AD, none has been found on the X chromosome. We propose a new method to estimate the risk for developing AD mediated by the X chromosome in a subgroup of late-onset AD (LOAD) patients with amnestic mild cognitive impairment (aMCI) or early AD and unilateral ancestral history of AD or dementia, and pilot-test it on our clinic data. Records of patients aged 55–80 years presenting to our Memory Disorders Clinic with aMCI or early AD between May 2015 and September 2020, were reviewed, counting patients with a family history of AD or dementia and unilateral ancestral lineage. The X chromosome-attributable relative risk was estimated by calculating the following odds ratio (OR): (women with paternal lineage:women with maternal lineage)/(men with paternal lineage:men with maternal lineage). The proportion of genetic risk borne by the X chromosome is equal to (OR-1)/OR. 40 women aged 66.1 ± 5.1 years (mean ± standard deviation) and 31 men aged 68.1 ± 6.5 were identified. The OR was (18:22)/(6:25) = 3.4 (95% confidence interval 1.1–10.1;
p
= 0.027). The estimated proportion of genetic risk borne by the X chromosome in this population is 70% (95% CI 12–90%). This paper presents the first application of a new method. The numbers are small, the confidence intervals wide. The findings need to be replicated. The method may be generalizable to other diseases.
A 2003 evidence-based review of exogenous risk factors for sporadic amyotrophic lateral sclerosis (ALS) identified smoking as the only risk factor that attained "probable" (more likely than not) ...status, based on 2 class II studies. The purpose of the current, evidence-based, update was to see if the conclusion of the previous review needed to be modified, based on studies published since.
A Medline literature search was conducted for the period between 2003 and April 2009 using the search terms smoking and (ALS or "amyotrophic lateral sclerosis" or MND or "motor neuron disease"). The references of primary articles and reviews were checked to assure completeness of the search. Primary articles published since the previous review were classified as before.
Twenty-eight titles were identified, but only 7 articles met inclusion criteria. Of these, 1 provided class II evidence, and 1 class III evidence: both showed increased risk of ALS with smoking. The class II study showed a dose-response effect, and risk decreasing with number of years since quitting smoking. Five articles provided class IV or V evidence, which may not be relied upon to draw conclusions.
Smoking may be considered an established risk factor for sporadic amyotrophic lateral sclerosis (ALS) (level A rating; 3 class II studies, 1 class III study). Evidence-based analysis of epidemiologic data shows concordance among results of better-designed studies linking smoking to ALS, and lets those results drive the conclusions.
Establishing mechanisms of disease causation in neurodegenerative diseases has long seemed to be beyond the pale of traditional epidemiological tools. Establishing a plausible mechanism for ...initiation of amyotrophic lateral sclerosis (ALS) has appeared a particularly elusive goal. This review shows that a likely mechanism for ALS initiation may be inferred by applying classical methods of epidemiological inference.
Advances in characterizing the biology of ALS suggest that most cases of ALS are cortically-generated, part of the ALS-FTD spectrum, with focal onset and spread by contiguity within the motor super-network. Evidence-based methods identified the most credible exogenous risk factor – smoking. AB Hill's nine viewpoints to inferring causation from association were invoked. The most likely mechanism consistent with smoking being a risk factor for ALS was inferred: cumulative DNA damage, akin to cumulative somatic mutations in carcinogenesis. Focal onset supports the concept that these changes, occurring in a single cell, may trigger the cascade leading to clinical ALS. The plausibility of this mechanism was affirmed by its coherence/consistency with other observations in sporadic, familial and western Pacific ALS.
Application of traditional epidemiological reasoning suggests that cumulative DNA damage may contribute to disease onset in ALS.
•A likely mechanism for ALS initiation may be inferred by applying classical methods of epidemiological inference, such as AB Hill's nine “viewpoints.”•Most cases of ALS are cortically-generated, part of the ALS-FTD spectrum, with focal onset and spread by contiguity within the motor super-network.•The most credible exogenous risk factor for ALS is smoking. The most likely mechanism consistent with smoking being a risk factor for ALS is cumulative DNA damage, akin to cumulative somatic mutations in carcinogenesis.•Focal onset supports the concept that these changes, occurring in a single cell, may trigger the cascade leading to clinical ALS.•The plausibility of this mechanism is affirmed by its coherence/consistency with observations in sporadic, familial and western Pacific ALS.
ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a multilevel disease of the motor neuron system. The mechanisms triggering disease onset should be considered separately from those facilitating its ...spread and motor neuron death. In 2005, I brought together clinical and epidemiological evidence to support the hypothesis that acquired nucleic acid changes may trigger sporadic ALS. Since 2005, the conceptual foundations for this hypothesis have been strengthened. The journal Amyotrophic Lateral Sclerosis was renamed Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. The focal onset, with simultaneous initial maximal upper and lower motor neuron involvement in the region of onset, and patterns of spread, were characterized further. Clues from the epidemiology of sporadic ALS were affirmed by quantitative analysis, including the increase in disease incidence with age, suggesting accrual of time‐dependent changes, and the confirmation of smoking as an established risk factor. Additional observations support the conclusion that accrued somatic mutations trigger onset of ALS. Muscle Nerve 53: 842–849, 2016
Theme 1 Epidemiology and informatics Armon, Carmel
Amyotrophic lateral sclerosis and frontotemporal degeneration,
11/2019, Letnik:
20, Številka:
sup1
Journal Article
Recenzirano
Identifying mechanisms of neurodegenerative disease causation has for long seemed to be beyond the pale of traditional epidemiological tools. Elucidating a plausible mechanism for initiation of ...amyotrophic lateral sclerosis (ALS) has appeared particularly elusive (1). The impression, that environmental risk factors for ALS were not providing consistent direction, meant there was no sturdy epidemiologically-based "handle" to grasp when trying to envisage a biological mechanism for triggering sporadic ALS (2). There have been challenges with interpreting the data. At times, generic concerns over potential limitations of traditional epidemiological studies have appeared to overshadow the findings in circumstances where these limitations had been overcome largely. At other times, studies with different degrees of methodological limitations have been lumped together, thereby obscuring the results of the studies with less limitations. On occasion, methodological limitations have been downplayed or ignored entirely.Emergence of Mendelian Randomization (MR) methods has offered the promise of overcoming some of the potential limitations of epidemiological studies that used traditional methods. MR methods apply concepts developed in the field of economics to infer causality in the presence of unmeasured confounding (3). The principal idea is: 1) a genetic pattern is identified that predicts a suspected risk factor - a laboratory value in patients' blood, or a particular behavior; 2) that pattern is sought in patients and controls; 3) excess presence of the pattern in patients suggests that the risk factor plays a causal role in producing the disease.However, application of MR methods requires that several underlying assumptions, specific to these methods, have been satisfied (3). Moreover, epidemiological analyses using MR methods need to adhere to core epidemiological and statistical principles. Finally, findings from MR studies need to be interpreted critically, with close attention to the context from which they arise, and with utilization of internal and external comparators (4,5).This presentation will discuss the assumptions that need to be met to apply MR methods in general and how they relate to studies in patients with ALS, drawing on recently published reports.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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