Motor Neuron Disease

Patients were diagnosed with definite, probable, and probable lab-supported ALS according to the revised El Escorial Criteria [17 (link)]. For the pilot analyses presented here, all patients were seen by neurologists specialized in motor neuron diseases at the University Medical Center Utrecht and Academic Medical Center (Amsterdam, The Netherlands). The samples were all included in the Prospective ALS study in the Netherlands (PAN), an incidence-based registry of ALS cases [18 (link)]. Controls were population-based controls that were matched for age, sex, and geographical region. As is true for all contributing cohorts to Project MinE, cases and controls were ascertained in a roughly 2:1 ratio; the 2:1 case-control ratio was selected to improve detection of variants in cases and with the plan to include publicly-available sequenced controls in future analyses.

The Institute for Health Metrics and Evaluation produces annual updates of the GBD study and includes a growing collaboration of scientists. Reported estimates span the period from 1990 to 2016. Annual updates allow incorporation of new data and methodological improvements to ensure that the most up-to-date information is available to policy makers to help make resource allocation decisions. In this analysis, we have aggregated results from GBD 2016 for 15 disease and injury outcomes that are generally cared for by neurological services. These include infectious conditions (tetanus, meningitis, and encephalitis), stroke, brain and other CNS cancers, TBI, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category of other less common neurological disorders. Compared to a previous analysis based on GBD 2015,² (link) we added non-fatal outcomes of TBI and spinal cord injury. Medication overuse headache is no longer included as a separate cause but quantified as a consequence of the underlying headache types. For all neurological disorders combined we report here estimates of deaths and DALYs because aggregate incidence and prevalence estimates of combined neurological disorders are not useful for policy making.
In the methods section of this overview paper, we present a summary of the general methods of the GBD as they apply to neurological disorders. In the ten accompanying disease-specific papers, we have concentrated on methods that are specific to each disorder. Details on the methods of estimates for tetanus, encephalitis, and the residual category of other neurological disorders are provided in the appendix. The guiding principle of GBD is to assess health loss due to mortality and disability comprehensively, defining disability as any departure from full health. In GBD 2016, estimates were made for 195 countries and territories and 579 subnational locations, for 27 years starting from 1990, for 23 age groups, and for both sexes. Deaths were estimated for 264 diseases and injuries, whereas prevalence and incidence were estimated for 328 diseases and injuries. To allow meaningful comparisons between deaths and non-fatal disease outcomes as well as between diseases, data for deaths from and prevalence of neurological disorders are summarised in a single indicator, the DALY. DALYs are the sum of YLLs and YLDs. YLLs are estimated as the product of counts of deaths and a standard ideal remaining life expectancy at the age of death. The standard life expectancy is derived from the lowest observed mortality rates by age in any population in the world larger than 5 million people.¹³ (link) YLDs are estimated as the product of prevalence of individual consequences of disease (or sequelae) multiplied by their corresponding disability weights, which quantify the relative severity of sequelae as a number between 0 (representing full health) and 1 (representing death). Disability weights have been estimated in nine population surveys and an open-access internet survey in which respondents were asked to choose the healthier option between random pairs of health states that were presented with short descriptions of their main features.¹⁴ (link)

We conducted the systematic search in 4 literature databases: PubMed, EMBASE, DARE, and the Cochrane Library; the study protocol for the systematic review is presented in the supplementary material (eAppendix 1: Systematic Review Protocol,, links.lww.com/WNL/C516). Additional forms or information, such as data collection forms, can be provided on request. The primary purpose of the meta-analyses was to provide an explanatory summary of the current literature. All databases were last searched in June 2022. Search terms included the MeSH terms: “Amyotrophic Lateral Sclerosis”; “Motor Neuron Disease”; “Cholesterol”; “Cholesterol, LDL”; “Cholesterol, HDL”; “Triglyceride”; “Lipid”; “Prognosis”; “Survival”; “Mortality”; “Kaplan-Meier estimate”; and “Proportional Hazard Models.” Studies were selected on the basis of the following inclusion criteria: (1) participants diagnosed with ALS according to the revised El Escorial criteria (EEC)¹⁷ ; (2) reporting of at least one of the following measurements: TC, HDL-C, LDL-C, or TG, obtained after symptom onset; (3) reporting of survival time and hazard ratio (HR); and (4) written in English or Dutch. Study eligibility was not based on sample size. All articles were screened independently by 2 reviewers for title and abstract (M.J.v.M. and A.H.). Included and excluded articles were discussed; if no consensus was reached, a third reviewer was consulted (R.P.A.v.E.).

Community-dwelling older adults aged 70–90 years, living in the Eastern Suburbs of Sydney, Australia, were selected via the electoral roll and invited to participate in the Sydney Memory and Ageing Study (MAS) in 2005. Of the 8,914 individuals invited to participate, 1,037 participants were included in the baseline sample. Inclusion criteria were the ability to speak and write English sufficiently well to complete a psychometric assessment and self-report questionnaires. Exclusion criteria included any major psychiatric diagnoses, acute psychotic symptoms, or a current diagnosis of multiple sclerosis, motor neuron disease, developmental disability, progressive malignancy, or dementia. More detailed methods of recruitment and baseline demographics have been previously described by Sachdev et al. (2010) (link). For the current study, participants were further excluded if they were not able to speak English at a basic conversational level by the age of 9 (N = 164) because of the questionable validity of using normative data based on persons of English-speaking background to determine cognitive impairment in these individuals (Kochan et al., 2010 (link)).
Of the 873 participants included in the present study, 849 (97.3%) had an informant at baseline. Informants were nominated by the participants and answered questions relating to the participant’s memory, thinking, and daily functioning at each study wave. Informants were required to have at least 1 h of contact with the participant per week and were composed of spouses, children, family members, and close friends or contacts.
Comprehensive assessments consisting of medical history, medical examination, neuropsychological testing, and subjective cognitive complaints were conducted by trained research assistants at two-yearly intervals (called waves). At each wave, informants completed comprehensive telephone interviews and questionnaire packets about themselves and the participants. All participants and informants provided written consent to participate in this study, which was approved by the University of New South Wales Human Ethics Review Committee (HC: 05037, 09382, 14327). A study flowchart outlining participant and informant sample size, dementia incidence and participants’ reason for attrition at each wave is presented in Figure 1.