ALS Pathophysiology
Core Pathological Process
ALS is fundamentally characterized by progressive degeneration and death of both upper motor neurons (in the motor cortex and brainstem) and lower motor neurons (in the anterior horn of the spinal cord), leading to relentless muscle weakness, paralysis, and typically death within 3-5 years of symptom onset. 1, 2
The disease involves degeneration along the entire corticospinal tract from the motor cortex through the brainstem to the spinal cord. 3, 1
Cellular and Molecular Mechanisms
The pathophysiology is multifactorial and involves several interconnected processes:
Oxidative stress - Increased reactive oxygen species damage motor neurons and contribute to cellular dysfunction 1, 4
Glutamate excitotoxicity - Excessive glutamate accumulation leads to overstimulation of motor neurons and subsequent cell death 1, 4
Mitochondrial dysfunction - Impaired energy production and increased oxidative damage within motor neurons 1, 4
Protein aggregation - Accumulation of misfolded proteins disrupts normal cellular function 4
Neuroinflammation - Inflammatory processes involving both motor neurons and surrounding glial cells contribute to disease progression 1, 4
Apoptosis - Programmed cell death pathways are activated, leading to motor neuron loss 1, 4
Pathological Findings
Neuroimaging Correlates
MRI demonstrates the pathological changes in living patients:
T2/FLAIR hyperintensity appears anywhere along the corticospinal tracts (most commonly in the posterior limb of internal capsule and cerebral peduncles), corresponding to underlying axonal degeneration, demyelination, and gliosis on histopathology 3
T2/susceptibility-weighted imaging* shows hypointensity in the precentral gyrus and gray matter, which is highly sensitive and specific for ALS 3
"Snake eyes" appearance on spinal MRI reflects abnormal T2 signal in the anterior horns, indicating lower motor neuron disease 1
Critical Distinction
ALS is primarily an axonal degenerative disease, NOT a demyelinating disease. 1 The primary pathological process is progressive degeneration and death of motor neurons and their axons, with any demyelination being secondary to the axonal loss. 1 This distinguishes ALS from true demyelinating diseases like multiple sclerosis, where myelin degradation is the primary insult. 1
Clinical Manifestations of Pathophysiology
Upper Motor Neuron Signs
Lower Motor Neuron Signs
Bulbar Involvement
- Approximately 80% of bulbar-onset ALS patients develop dysarthria and dysphagia due to degeneration of brainstem motor nuclei 1, 2
Disease Progression Pattern
The disease begins focally in one region of the central nervous system and then spreads relentlessly to other regions. 4 This propagation pattern is a current focus of research, as understanding how the disease spreads may reveal therapeutic targets. 4
Genetic and Environmental Factors
- 85-90% of cases are sporadic with multifactorial etiology 1, 2
- 10-15% are familial with autosomal dominant inheritance 7
- The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30-50% of familial ALS and 7% of sporadic ALS 7
- Environmental factors including age, tobacco use, and athleticism may contribute to sporadic cases 4
Overlap with Other Neurodegenerative Diseases
Up to 50% of ALS patients have extra-motor manifestations including behavioral changes, executive dysfunction, and language problems. 7 In 10-15% of patients, these cognitive and behavioral changes are severe enough to meet criteria for frontotemporal dementia (FTD), reflecting shared molecular pathways between ALS and FTD. 7, 1
Respiratory Pathophysiology
Respiratory failure due to respiratory muscle weakness is the most common cause of death in ALS. 1 Progressive loss of motor neurons innervating respiratory muscles leads to ventilatory failure, typically limiting survival to 2-5 years after disease onset. 7