ALS treatment: start long before clinical symptoms

ALS (amyotrophic lateral sclerosis), a devastating autoimmune disease of the central nervous system, has a long presymptomatic period during which neuroprotective interventions can be applied according to an important paper published in the Journal of Neurology, Neurosurgery & Psychiatry. The authors state:

"We propose that, in common with other neurodegenerations, the pathogenic mechanisms culminating in ALS phenotypes begin much earlier in life. Animal models of genetically determined ALS exhibit pathological abnormalities long predating clinical deficits. The overt clinical ALS phenotype may develop when safety margins are exceeded subsequent to years of mitochondrial dysfunction, neuroinflammation or an imbalanced environment of excitation and inhibition in the neuropil. Somatic mutations, the epigenome and external environmental influences may interact to trigger a metabolic cascade that in the adult eventually exceeds functional threshold. A long preclinical and subsequent presymptomatic period pose a challenge for recognition, since it offers an opportunity for protective and perhaps even preventive therapeutic intervention to rescue dysfunctional neurons."

Biological changes starting decades earlier

The authors postulate a lengthy evolution in the development of ALS and other neurodegenerative diseases:

"Symptom onset in adult neurodegenerations, including ALS, typically occurs in mid-life to late life. In Alzheimer's disease (AD) and Parkinson's disease (PD), pathological changes precede clinical disease by years, if not decades...It has previously been suggested that ALS may have a prolonged preclinical period, but, generally, it is assumed that the clinical onset of ALS is coincident with, or starts shortly after, the onset of the pathological process underlying the disease...However, absence of detectable change found by these tests of lower motor neuron function does not necessarily equate with normal functioning of anterior horn cells; abnormality of upper motor neuron functioning has clearly been demonstrated to precede clinical deficit in ALS. More likely, there is bio-molecular dysfunction at a cellular level that cannot presently be detected, which is insufficient to cause clinical features, but potentially present and building for years or decades prior to onset of clinical disease. In SOD1 ALS mouse models, pathological changes are evident shortly after birth, predating the first clinical abnormalities by 2–3 months. In human genetically-linked ALS (FALS), expression of the disease-causative proteins, or other metabolic defect, must be evident even during embryonic life. Similarly, in sporadic ALS, biological abnormalities reflect a long-lasting morbid process progressing over years, or potentially even decades, before the first symptoms become apparent.

Early mutations in both hereditary and sporadic ALS

Both familial and acquired genetic mutations can start the process that becomes symptomatic years later.

"Inherited mutations, applicable to the 29 nuclear genes that have presently been identified to be associated with hereditary ALS, have the highest risk of disease, since all cells carry the mutant gene. However, spontaneous gene mutations associated with cell division during embryogenesis and early development are also potentially disease-inducing. Spontaneous mutations blur the difference between hereditary and sporadic ALS. In sporadic ALS, spontaneously arising ‘at risk mutations’, occurring early in development, would carry only a slightly lower risk relative to hereditary ALS...it is likely that mutations of only a few of the numerous genes guiding developmental programming and network formation and function will add to the overall burden of risk for developing ALS later in life."

Perinatal and rapid developmental periods are particularly vulnerable

These are phases of increased susceptibility to mitochondrial and genetic damage:

"Neural network development begins at conception, and continues into adolescence and young adulthood. However, it is the prenatal and perinatal periods that are associated with the greatest metabolic activity. This is required for neurogenesis, neuronal proliferation and neural differentiation and migration...The added metabolic demand increases oxidative stress and must be countered by antioxidant production and redox-sensing systems sufficient to control reactive oxygen species (ROS) production, and remove damaged mitochondria. During these periods, spontaneous mutations may cause subtle abnormalities in central nervous system (CNS) wiring, connectivity and network formation inducing vulnerability for late-in-life neurodegeneration, including ALS. Postnatally, the process of synaptic proliferation continues through middle childhood and is followed by programmed elimination of synapses. Substantial refinement of brain structure and function occurs during adolescence, again a period of potential susceptibility for disease in later life."

Even in hereditary ALS environmental factors play a large role

"Neurodegenerative diseases with Mendelian inheritance and diseases including familial ALS are associated with genetic variants present from the time of conception, even though they do not present clinically until mid to late adulthood. This implies either that these genes are not ‘switched on’ until later life, or that there are decades of progressive cellular compromise eventually culminating in the catastrophic decline manifesting as presentation of clinically overt ALS. Heritability studies suggest that about 60% of the risk of ALS is genetically determined, and the remaining 40% environmentally determined."

Modifiable risk factors years in advance

There are significant points for early intervention that can be targeted by appropriate tests:

"Environmental exposure to toxins, smoking, excessive physical activity, occupation, dietary factors and changes in immunity all increase the risk of developing sporadic ALS. These factors may drive epigenetic changes over many years, which then induce disease onset and progression. There is a significant association with smoking; prolonged exposure and current smoking increase ALS risk by twofold to threefold. Exposure to pollutants is one mechanism that may trigger and can chronically perpetuate neuroinflammation...Nevertheless, neuronal damage from oxidative stress may continue throughout life by accumulation of environmental, occupational, dietary and lifestyle exposures. Neuroepidemiological studies of risk factors for ALS suggest that exposure must occur several years before disease onset, implying that an environmental trigger may be active for years before clinical disease develops."

Neuroinflammation and male predominance in ALS

They note the fascinating observation that physical aggression in boys predicts reduced anti-inflammatory cytokines:

"During development, microglia contribute to the formation of the neural network by stimulating vascularisation and assisting in pruning excess neurons and synapses, as well as facilitating cell differentiation. Throughout life, there is a balance between microglia-derived protective anti-inflammatory cytokines, which are maximum in early development and childhood, versus pro-inflammatory cytokines, which accumulate with ageing and are associated with a chronic inflammatory state. A shift toward pro-inflammatory cytokines contributes to increased susceptibility and neurodegenerations. Physical aggression in boys during childhood is a predictor of reduced anti-inflammatory cytokines in early adulthood, raising the intriguing speculation that the male predominance of ALS might partly be related to reduction of anti-inflammatory cytokines early in life. This may tie in with the findings that patients with ALS have a lower second-to-fourth digit ratio, consistent with higher prenatal circulating levels of testosterone, and possibly a prenatal influence of testosterone on motor neuron vulnerability in later life."

Clinical note

Practitioners should make appropriate use of the array of laboratory tests already available to investigate early undifferentiated neuronal autoimmunity, excessive oxidative stress, dysregulated inflammation and its contributing causes, and defects in mitochondrial function along with deficiencies in key co-factors that can be targeted well in advance of clinical symptoms for both hereditary and sporadic ALS.The authors conclude:

"We postulate that ALS shares commonality with other neurodegenerative disorders in which there is a compelling body of evidence to indicate that the onset of clinical symptoms is preceded by a long presymptomatic period. Such a period may last for years or possibly decades, with downstream events that exceed the threshold for the emergence of clinical symptoms becoming evident only years after the pathobiological disease process commenced...We suggest that many different biomolecular events may impact normal development in such a way that the disease only becomes clinically apparent when intrinsic compensatory mechanisms break down, perhaps decades after their onset. The processes involved are complex, interactive and progressive. The clinical syndrome of ALS becomes evident when neuronal and also possibly astroglial metabolism is overwhelmed by the accumulation of biological abnormality, especially involving energy kinetics, until a ‘tipping point’ is reached."

Imperative to intervene early

"It therefore follows that the current failure of therapies to effectively modify ALS may largely reflect the long time elapsed between the onset of the pathological process and the onset of overt symptomatic disease. It therefore becomes imperative to identify the primary targets of disease-causing proteins in this preclinical stage...A lengthy presymptomatic period with compromised cellular and associated neural network dysfunction, possibly arising in the perinatal period, opens a potentially important window for neuroprotective intervention that might allow rescue of dysfunctional but not yet dead neurons. It is even possible that many of the agents previously trialled, which have failed to show benefit in overt ALS, if given very early, may have neuroprotective properties."