Amyotrophic Lateral Sclerosis

ALS is a progressive neurodegenerative disease defined by loss of both upper motor neurons (motor cortex/corticospinal tracts) and lower motor neurons (brainstem and spinal anterior horn cells). In most cases, it is also a TDP-43 proteinopathy.

Core pathology

• Degeneration and death of upper and lower motor neurons cause combined spasticity/weakness and denervation-related muscle atrophy.
• Approximately 97% of ALS cases show abnormal loss of nuclear TDP-43 with cytoplasmic accumulation of phosphorylated, ubiquitinated TDP-43 aggregates in neurons and glia.
• The minority of cases without TDP-43 pathology typically have SOD1- or FUS-associated aggregates. C9orf72-associated ALS additionally has RNA foci and dipeptide-repeat protein inclusions.

Gross findings

• Atrophy of skeletal muscle, often affecting the tongue, bulbar/oropharyngeal muscles, and limb musculature from denervation.
• Atrophy of the motor cortex, especially the precentral gyrus.
• Pallor and sclerosis of the corticospinal and corticobulbar tracts due to axonal and myelin loss; this lateral-column sclerosis underlies the term lateral sclerosis.
• Thinning of ventral spinal roots and hypoglossal nerves, reflecting lower motor neuron loss.

Microscopic findings

• Marked loss of anterior horn α-motor neurons in the spinal cord, motor nuclei in the brainstem, and Betz cells in the primary motor cortex.
• Reactive astrocytosis and microglial activation in both gray and white matter.
• Axonal loss and myelin pallor in corticospinal tracts.
• Surviving motor neurons may contain:
  • Bunina bodies: small eosinophilic, cystatin C–positive intracytoplasmic inclusions.
  • Ubiquitinated/TDP-43–positive cytoplasmic inclusions.
• Skeletal muscle shows chronic neurogenic atrophy: grouped angular atrophic fibers with fiber-type grouping from repeated denervation and collateral reinnervation.

Selective neuronal vulnerability

Oculomotor neurons and Onuf’s nucleus are relatively spared until late in disease. This explains the usual early preservation of extraocular movements and bladder/sphincter function despite extensive motor neuron degeneration elsewhere.

Disease mechanisms

Although ALS has heterogeneous genetic causes, its biology converges on several interconnected processes:

• Abnormal RNA processing and TDP-43 dysfunction.
• Failure of protein quality control, ubiquitin-proteasome activity, and autophagy.
• Cytoskeletal disruption and impaired axonal transport.
• Mitochondrial dysfunction, oxidative stress, and excitotoxic vulnerability.
• Neuroinflammation, impaired nucleocytoplasmic transport, and defective DNA-damage responses.

TDP-43 pathology often follows a staged anatomic distribution, beginning in motor-system structures and extending to frontal, basal ganglia, and temporal regions as disease progresses. This pattern supports the concept of network-based, potentially prion-like propagation of abnormal protein pathology.

ALS comprises 80-90% of motor neuron disease cases but has a 10% diagnostic error rate; accurate early diagnosis is critical as delayed diagnosis by average of 12 months (up to 13.1 months) leads to worse outcomes.

The pathophysiology of ALS involves prion-like protein dysregulation affecting RNA, with additional contributing factors including oxidative stress, glutamate excitotoxicity, and mitochondrial dysregulation; loss of Betz cells and CD68 macrophage aggregation are pathologic hallmarks.

Average survival is 3-5 years post-diagnosis with respiratory failure as most common cause of mortality; respiratory symptom management is mainstay of treatment.

Riluzole (sodium channel blocker) and Edaravone (antioxidant free radical scavenger) are FDA-approved agents that provide modest improvement in motor function and slow disease progression; combination therapy shows promise.

Neuroimaging plays crucial role in diagnosis by excluding other mimics and confirming ALS; conventional MRI is most useful while advanced techniques (DTI, MRS, PET) have promise but currently have low sensitivity/specificity and are not routine clinically.

Male predominance and peak incidence in sixth decade are characteristic epidemiologic features; younger patients (under 45) experience more delayed diagnosis.