Amyotrophic lateral sclerosis (ALS) is usually considered to beginwhen the first symptomsdevelop; anexample is theonset ofdistalweakness andatrophy inanupper limb,oftenwith fasciculation in amorewidespread distribution.1 This definition of disease onset follows an understanding of the pattern of onset in other acquired neurological diseases and is rooted in the history of neurology. However, neurodegenerative disorders as a group seem characteristically to begin gradually and subclinically without a clearly definedmoment of onset. Obvious examples are Alzheimer-type dementia, Huntington disease, Parkinson disease, and many peripheral neuropathies,whether genetic or acquired, suchas diabeticneuropathy.Evenmonogeneticdisorders suchasHuntington disease or the Charcot-Marie-Tooth syndromes exhibit gradual and indefinable onset patterns. Because the onset of ALS, as distinct from its diagnostic clinical features, cannot be defined, the question ariseswhether there is a long preclinical phase of accumulation of pathology or toxic metabolites in the cytosol. This concept is presently undefined and virtually unstudied, at least in human ALS,2 although it may be possible to address it in transgenic rodent models. In sporadicALS, there is accumulationof cytosolic TDP43 (transactive response DNA binding protein 43 kDa), a protein derived fromRNAmetabolism; this protein is also found inother recognized formsofmutation-relatedALS, althoughnot in superoxide dismutase–related ALS. The variation in age at onset and clinical phenotype of ALS suggests a possible analogy with the inverse relationshipbetweenbirthweight and the risk of cerebrovascular disease and type2diabetesmellitus,which is sometimes termed the metabolic syndrome X.3 Therefore, in ALS, as in other neurodegenerative disorders inwhich there is a genetic susceptibility, there is increasing suspicionof anearly life factor involved in causationof the later development of the overt disease syndrome. Certainly, ALS must begin long before clinical presentation, perhaps as protein misfolding builds in the cytoplasm of motor neurons or other toxic metabolites such as reactive oxygen species accumulate.4,5 The evidence for a glial disorder is especially strong.6While genetic factors such asmutations that expand hexanucleotide repeats atC9orf72 seemtopredispose toALS,7 these and other currently recognized genetic associations are not causative in the sense that theynecessarily predict thedevelopment of ALS. Indeed, the penetrance of ALS among individualswithC9orf72mutations is only 50%at age60years.8 Despite suspicions of environmental or polygenic traits conferring increased susceptibility, in addition to the monogenic traitsalreadyrecognized, little isknownabout these putative factors.9 Indeed, there is controversy as to whether the 90% of cases of ALS presently recognized as not genetic in origin are truly sporadic.1 Nonetheless, despite much well-conducted epidemiological work, the search for environmental factors in ALS causation has generally been disappointing.9,10 Amyotrophic lateral sclerosis is a malepredominant disorder in all societies and is weakly associatedwithsmoking9; inaddition there isa strongsuspicion,only weakly supported by statistical evidence, that athleticism or overuse of certainmuscle groups (eg, the split-handphenomenon)may be a risk factor.2,11 Wartime experience as a causation, especially in theGulfWar, remains controversial anddifficult to understand. There is loss of large and small motor neurons and interneurons in themotor cortex and spinal cord with increased excitation, leading to fasciculation anddegeneration of themotor system. The excitatory state observed in physiological studies of the motor cortex in human ALS12 remains incompletelyunderstood in termsofphysiologyandbiochemistry, although increased cerebrospinal fluid and tissue glutamate levels may perhaps be correlated with this physiological abnormality.13Magnetic resonance connectivity studies in the brain demonstrate marked early changes but these studies are only available after clinical disease onset and are relatively gross. In this issue of JAMA Neurology, Fitzgerald et al14 describe a greater dietary intakeofω-3polyunsaturated fatty acids (PUFAs) associatedwithamarkedly reduced risk for thedevelopment of ALS. This effect is attributed to consumption of both α-linolenic acid (relative risk = 0.73; 95% CI, 0.59-0.89) and marine ω-3 PUFAs (relative risk = 0.84; 95 % CI, 0.651.08) but notwithdietary intake ofω-6PUFA. Total energy intakeorpercentageofenergy intake fromtotal fatorother types of dietary fat was not associated with ALS risk. These results arederived fromstudyof 1 002 082participants in the following 5 prospective US cohort studies: theNational Institutes of Health-AARP Diet and Health Study (1995-1996), the Cancer Prevention Study (1992), the Health Professionals Follow-up Study (1986), the Multiethnic Cohort Study (1993-1996), and theNurses’ Health Study (1976). A total of 995ALS caseswere identified in these cohorts based on the National Death Index, a certification of cause of death in relation to notificationofALS, previously validatedby the authors.Withpermissionfromthepatientor family, inquirywasmadeof the treating neurologist regarding certainty of diagnosis using the El Escorial criteria as a benchmark and using certification of death Related article page 1102 Opinion
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Nov 28, 2021
Andre Dik + 19
Open Access
