Disease onset and disease progression are thought to have a different mechanism. Because the motor symptoms of ALS are usually initiated in one or two highly localised sites, the motor symptoms and the responsible lesions always spread regionally as the disease progresses. Many neurologists have thought that regional spread of the symptoms is just one aspect of disease progression in ALS because ALS is a systemic disease that eventually involves the entire UMN and LMN systems, and every motor neuron in ALS ubiquitously has a cause of disease. The most easily understood example is familial ALS with mutations in SOD1 or TDP-43, in which every motor neuron and glial cell has a chromosomal genetic defect that causes motoneuronal cell death (). For the initial onset, in sporadic as well as familial ALS, molecular change most likely predates clinical onset. A motor neuron becomes symptomatic when the accumulated molecular pathology, including increased pathogenic protein aggregates, exceeds a certain threshold. In sporadic cases, the multifocal hit hypothesis has a different mechanism but represents a similar phenotype in which an acquired defect in chromatin, DNA, RNA or proteins (such as epigenetic alternation, a somatic DNA mutation, RNA editing error or misfolding of proteins possibly due to ageing effects or various environmental stressors) occurs randomly in each cell, and these defects accumulate and converge to initiate the pathogenic process (). The multifocal hit hypothesis () is different from the ubiquitous change mechanism () in that the molecular change occurs in individual cells, and unaffected cells do not have any molecular defect. In both mechanisms, the region of initiation may be determined by a stochastic hit but there is a vulnerability among the motoneurons resulting in more frequent focal involvement of the tongue and distal limb muscles in the early stage. These two schemas shown in are a possible onset mechanism of ALS but the regional spread of the motor symptoms as a disease progression can also be explained by just summation of the increased number of symptomatic or hit neurons by the same mechanism without following propagative pathology.
Figure 1 Onset and regional spread mechanisms of amyotrophic lateral sclerosis (ALS) lesion. Symptom is initiated by focal neuronal change, the onset mechanism of which exists in every motor neuron (A–a), or is limited to the affected neuron (A–b). (more ...)
The concept of ‘prion-like propagation’ is the intercellular transmission of the disease phenotype, typically considered to be mediated by an aggregate of pathogenic proteins. Local contiguous spread could occur through cell to cell ‘domino-like’ propagation between neighbouring neurons in a cell autonomous or non-cell autonomous manner (). In the case of spinal motor neurons, this local and contiguous spread has two vectors in the three-dimensional anatomy of motoneurons determined by its anatomical structure: one is radial, leading to rostral or caudal spread in the motor neuron column beyond the spinal segment, and the other is lateral/horizontal, leading to lateral to medial spread on one side of the anterior horn showing progression from distal to axial muscles, and contralateral spread within the same spinal segment showing progression to the contralateral limb ().4
If the spread is non-contiguous, there are two possible mechanisms: (1) anterograde trans-synaptic spread (dying forward) or retrograde degeneration (dying back) of neural networks (, left); and (2) non-synaptic and remote spread of a misfolded protein or toxic molecule through the blood or CSF via exosomes, similar to the metastasis of cancer cells (, right).5
Before regional propagation can occur, there must be a focal lesion that develops with a molecular mechanism that is different from that of propagation. This initiation mechanism should include ubiquitous (figure 1A–a) or local and multiple hit (figure 1A–b) pathology. The contiguous and non-contiguous propagation mechanisms are not independent but can coexist with each other, and therefore the final clinical picture appears to be a complex combination of single or multiple hits, with or without contiguous or non-contiguous propagation.
Disease progression in ALS consists of regional spread of motor symptoms and exacerbation of local motor symptoms, such as a decrease in grip strength and progression of thenar muscle atrophy. We suppose that such an exacerbation of focal motor symptoms is also explained by the contiguous propagation mechanism. For example, the severity of hand muscle atrophy is determined by the remaining number of motor neurons in the lateral nuclear group of the spinal anterior horn innervating the hand muscle after neuronal degeneration and reinnervation of the denervated muscle fibres. In this motor neuron pool of the lateral nuclear group, neuronal degeneration might be mediated by local cell to cell propagation of the disease property between spinal motor neurons proximate to each other after the seeding to a single motor neuron (). This indicates that the concept of ‘propagation’ can include exacerbation of the focal symptom as well as its regional spread.
Figure 2 The severity of the focal symptom can be explained by local propagation. Exacerbation of hand muscle atrophy is caused by loss of α-motor neurons in the motor neuron pool in the spinal anterior horn innervating the hand muscle. Such a severity (more ...)