als

Amyotrophic Lateral Sclerosis (ALS) Overview

  • Presenter: Abdallah Hayar

  • Institution: University of Arkansas for Medical Sciences
      - Department of Neurobiology & Developmental Sciences
      - Center for Translational Neuroscience

Definition of Amyotrophic Lateral Sclerosis (ALS)

  • Etymology:
      - A-myo-trophic: no muscle nourishment
      - Lateral Sclerosis: refers to the involvement of lateral corticospinal tracts.

  • Nature of the Disease:
      - ALS is characterized by degeneration of somatic motor neurons that run from the upper motor cortical pyramidal neurons to lower motor neurons located in the brainstem and spinal cord.

Notable Individuals Affected by ALS

  • Lou Gehrig (1903 –1941)
      - An American baseball first baseman, known as "the Iron Horse", played for the New York Yankees throughout his career.

  • Stephen Hawking (1942 –2018)
      - An English theoretical physicist and cosmologist renowned for his work in black hole physics and authoring books like "A Brief History of Time".

Ice Bucket Challenge

  • Description: An activity where a bucket of ice water is poured over someone's head, known for raising awareness and funds for ALS research.

  • Viral Popularity: Gained immense traction on social media from July to August 2014.

  • Process: Participants recorded the event and were encouraged to nominate others, with a stipulation of 24 hours to comply or make a charitable donation.

  • Criticism: Noted by Steve-O, many videos focused more on the stunt rather than encouraging donations. Notably, only a few individuals like Charlie Sheen and Bill Gates mentioned making actual donations.

  • Concerns: Raised issues about the waste of water amid drought and environmental criticisms.

Epidemiology of ALS

  • Incidence:
      - Estimated incidence of 2/100,000 person-years.
      - Slightly higher incidence observed in males.

  • Lifetime Risk:
      - 1 in 350 for men
      - 1 in 400 for women

  • Peak Age of Onset:
      - Sporadic cases: 58-63 years
      - Familial cases: 47-52 years

  • Genetic Basis:
      - Approximately 90-95% of cases are sporadic.
      - Familial Cases: Represent around 5-10% of the total.

Historical Context

  • 1869: First clinical description of ALS by Dr. Jean-Martin Charcot.

  • Timeline of Discoveries:
      - 1993: Identification of SOD1 mutation.
      - 1997: Further revelations in ALS genetics.
      - 2012: PFN1 mutation discovered affecting ALS.
      - 2013: About 102,000 papers published on ALS over the last 20 years, reflecting ongoing research and interest in the disorder.

  • Current Status: Despite substantial research over 146 years, no cure is available yet.

Pathology of ALS

  • Neuronal Loss: Involves loss of both upper and lower motor neurons.

  • Common Symptoms:
      - Muscle twitches, cramping, or stiffness.
      - Weakness in arms or legs.
      - Slurred, nasal speech, or difficulties in chewing and swallowing.

  • Prevalence:
      - 90-95% of cases are sporadic; 5-10% are familial.

  • Etiology:
      - Overall cause remains unknown; likely involves a combination of genetic and environmental factors.

Reasons for Vulnerability of Motor Neurons

  • Unique Characteristics:
      - Large cell size and high metabolic activity.
      - Sensitivity to mitochondrial dysfunction.
      - High content of neurofilaments.
      - Limited ability to buffer calcium.

  • Clinical Observations:
      - Sensory Abnormalities: A study (Hammad et al., 2007) indicated about one-third of ALS patients report sensory symptoms.
      - Reduced sensory response amplitudes were observed in many patients during evaluations of sural nerve biopsies (91% incidence).

Variants of ALS

  • Primary Lateral Sclerosis (PLS):
      - Affects only upper motor neurons, leading to spasticity that affects speech, swallowing, and walking abilities.

  • Progressive Muscular Atrophy (PMA):
      - Affects only lower motor neurons, causing muscle weakness and atrophy.

  • Disease Progression: PLS and PMA may evolve into classic ALS.

  • Common Presentations:
      - Limb-onset ALS: 70% - Most common form.
      - Bulbar-onset ALS: 25% - Characterized by difficulties in speech and swallowing.

Internal Capsule Structure and Function

  • Description: A white matter structure in the inferomedial part of cerebral hemispheres.

  • Function: Carries information past the basal ganglia, separating the caudate nucleus and thalamus from the putamen and globus pallidus.

  • Corticospinal Tract: Responsible for motor information transmission from primary motor cortex to spinal cord’s lower motor neurons.

  • Imaging:
      - Control subjects represented specific isointensities in brain scans (FLAIR, T1-weighted SE MTC images).
      - An ALS patient displayed hyperintensity in the cortical and subcortical regions.

Proposed Pathogenic Mechanisms in ALS

  • Mechanisms Identified:
      - Oxidative stress
      - Excitotoxicity
      - Abnormal protein aggregation
      - Cytoskeletal defects
      - Impaired axonal transport
      - Neuroinflammation
      - Abnormalities in hypoxia-regulated genes
      - Absence of growth factors
      - Apoptosis

Pathological Findings in ALS

  • Ventral Horn Analysis:
      - Evident loss of motor nerve cells, some surviving neurons can be identified.   - Presence of Bunina bodies (BB) in surviving neurons, indicating characteristic inclusions specific to ALS.
      - BB are eosinophilic, hyaline (glass-like) and may vary in shape.

  • Lewy bodies-like inclusions:
      - Found in some motor neurons exhibiting eosinophilic inclusions with surrounding halos, significant for diagnosis of ALS.

  • Skein-like inclusions:
      - Nearly 100% prevalence in ALS patients, linked to ubiquitination.

Genetic Aspects and Discoveries in ALS

  • Genetic Trends Over Time:
      - Explosion of gene discovery linked to ALS, correlated with advancements in high-throughput DNA sequencing technology.

  • Familial vs Sporadic Forms:
      - The relationship has blurred due to discoveries of genes like C9orf72, equally found in familial and sporadic cases.

  • Recent Advances:
      - Profilin 1 gene (PFN1) mutations shown to cause familial ALS.
      - Testing of subjects showed mutations lead to cellular aggregates that interfere with normal motor neuron function.

Models of ALS for Research

  • Animal Models:
      - Mice: Transgenic models using the SOD1 gene (mutations: G93A, G85R, etc.).
      - Other organisms: Drosophila, C. elegans, and zebrafish used for further studies of ALS mechanisms.

  • Initial Changes:
      - Early signs of changes in cell bodies, with evidence of neuromuscular junctions degeneration in mouse models.

Inflammatory Response in ALS

  • Post-mortem Findings: Elevated levels of pro-inflammatory cytokines (FAS ligand, TNF-alpha) found in ALS spinal cords.

Management and Care for ALS Patients

  • Diagnosis Communication: Should be in-person, with ample discussion time, reassuring patients of continued support.

  • Multidisciplinary Care Team: Collaboration between various specialists including physicians, nurses, therapists, and social workers.

  • Therapeutic Approaches:
      - Emphasis on palliative and symptomatic treatments aimed at improving quality of life.
      - Riluzole: The only proven disease-modifying agent:
        - Extends survival by 3-6 months.
        - It works by blocking sodium channels associated with damaged neurons and influencing glutamate levels.

  • Ventilation Strategies: Non-invasive ventilation and tracheostomy are essentials for respiratory support.

Research Innovations

  • Stem Cell Trials: Exploration of using stem cells harvested from patients’ adipose tissue to potentially reverse ALS damage by providing neuroprotective factors.

  • FDA-approved Trials: Investigating use of stem-cell methods to replace lost neurons in ALS patients.