ALS Flashcards
What is ALS?
Amyotrophic Lateral Sclerosis (ALS) is characterized by the accumulation of TDP-43 (TAR DNA-binding protein 43) in neurons. This protein, which is normally involved in DNA and RNA regulation, becomes mislocalized and aggregates in the cytoplasm, leading to neuronal dysfunction and toxicity.
• TDP-43 is present in all neurons, but in ALS, it accumulates abnormally in motor neurons and other brain regions.
• This pathology is not exclusive to ALS—TDP-43 inclusions are also found in frontotemporal dementia (FTD).
• The degeneration extends beyond the corticospinal tract, affecting extra-motor cortical regions, leading to cognitive and behavioral impairments.
Consequences of TDP-43 mislocalization?
- Nuclear Dysfunction
• TDP-43 normally shuttles between the nucleus and cytoplasm for RNA processing.
• In ALS, TDP-43 is trapped in the cytoplasm, preventing its normal nuclear function. - Cytoplasmic Aggregation and Toxicity
• TDP-43 forms protein inclusions in the cytoplasm, which are toxic to neurons.
• The loss of nuclear TDP-43 function and gain of toxic function in the cytoplasm both contribute to neurodegeneration. - Widespread Brain Involvement
• ALS is not purely a motor disease.
• Autopsy findings reveal TDP-43 pathology in motor neurons as well as other brain regions, explaining the cognitive and behavioral symptoms in some ALS patients.
Two primary presentations:
• Motor-dominant ALS (affecting corticospinal neurons first).
• Frontal-dominant ALS/FTD variant (starting with cognitive and behavioral changes).
Clinical variability in ALS and FTD?
• While some patients develop ALS first, others start with frontotemporal dementia (FTD).
• The same TDP-43 pathology underlies both diseases, but the initial site of neurodegeneration determines the first symptoms.
• Implication for treatment: Future drugs targeting TDP-43 inclusions may work for both ALS and FTD.
Progression of ALS? Stages of TDP spread?
• The disease typically starts in the motor cortex, then spreads anteriorly (to the frontal lobe) and posteriorly (to the parietal and temporal lobes).
• This pattern follows a connectivity-based model, meaning regions that are functionally connected to the motor cortex are affected first.
Stage 1 —> Motor cortex, brainstem somatomotor neurons, spinal motor neurons affected leads to initial motor deficits (weakness, fasciculations, hyperreflexia).
Stage 2 —> Reticular formation, precerebellar nuclei, red nucleus, substantia nigra affected leads to progressive weakness, bulbar symptoms.
Stage 3 —> Prefrontal cortex, postcentral cortex, basal ganglia affected leads to cognitive impairment, executive dysfunction.
Stage 4 —> Temporal lobe, hippocampus affected leads to memory loss, emotional disturbances.
Prion like hypothesis for ALS?
• TDP-43 behaves like a prion, spreading misfolded proteins through synaptic connections.
• This “network-based spread” explains why connected brain regions are sequentially affected.
• Similar spreading mechanisms are seen in Alzheimer’s (Tau), Parkinson’s (α-synuclein), and FTD (TDP-43).
Genetics of ALS?
Amyotrophic Lateral Sclerosis (ALS) is one of the most genetically influenced neurodegenerative diseases. While 90% of cases are sporadic, about 10% are familial (inherited). However, even in sporadic ALS, genetic mutations can often be identified, making genetic screening an important part of the diagnostic process.
Key genetic findings in ALS : the two most important genes in ALS are SOD1, the first gene discovered, and C90RF72 whimsical is the most common genetic cause of ALS and FTD. Another worthy mention is TARDBP, which encoded for TDP-43.
SOD1 : found on chromosome 21 and encoded superoxide dismutase 1, an antioxidant enzyme that detoxifies harmful superoxide radicals.
1. Loss of function: Impaired antioxidant activity → increased oxidative stress → neuronal damage.
2. Gain of toxic function: Mutant SOD1 proteins aggregate in neurons, forming cytoplasmic inclusions.
C90RF72 : repeat expansion of GGGGCC hexanucleotide repeats.
1. Haploinsufficiency: Loss of normal C9ORF72 protein function.
2. Toxic RNA inclusions: Expanded repeat RNA accumulates, disrupting RNA metabolism.
3. Dipeptide Repeat Proteins (DPRs): Mutated C9ORF72 produces abnormal toxic proteins, further harming neurons.
TARDBP :
• Mutations cause TDP-43 mislocalization, leading to its cytoplasmic aggregation.
• This is a hallmark feature of almost all ALS cases except those caused by SOD1 mutations.
Clinical features of ALS?
Disease progression and onset : ALS is a rapidly progressive neurodegenerative disease, with a focal onset that later spreads to other regions of the body. Unlike Parkinson’s disease or Alzheimer’s disease, which progress over years, ALS worsens within weeks to months.
• The hallmark of ALS is the simultaneous involvement of both upper and lower motor neurons.
Any voluntary muscle can be affected except for the extraocular muscles (eye movements remain intact) and sphincter muscles (until very late in the disease).
• The disease commonly starts in the distal upper limb (hand atrophy is an early sign).
• Later, it spreads to bulbar muscles, affecting speech and swallowing.
Respiratory muscle involvement is the main cause of death : signs include orthopnea, dyspnea, disturbed sleep, fatigue.
Dysphagia and malnutrition : dysphagia is a major complication, aspiration pneumonia due to food entering the lungs is also a big cause of morbidity and mortality.
Traditionally, ALS was considered purely a motor disease, but up to 50% of patients develop cognitive impairment.
• Some patients develop full-blown frontotemporal dementia (FTD) before or during motor decline.
Variants of ALS?
Amyotrophic lateral sclerosis is a heterogeneous disease with different clinical presentations and progression patterns. While classical ALS involves both upper motor neurons and lower motor neurons, some variants may initially or selectively affect one of these systems.
Main variants :
1. Spinal-Onset ALS (70% of cases)
• Most common form of ALS, begins with asymmetric limb weakness, typically in the hands or legs.
• Progression: Starts focally, then spreads to other limbs and eventually bulbar muscles.
• UMN and LMN involvement in both upper and lower limbs.
• Prognosis: Better than bulbar-onset ALS, but eventually leads to bulbar dysfunction and respiratory failure.
- Bulbar-Onset ALS (30% of cases)
• Begins with dysarthria (slurred speech) and dysphagia (difficulty swallowing).
• Early involvement of the cranial nerves, leading to rapid speech and swallowing impairment.
• Patients develop limb weakness later in the disease course.
• Associated with a worse prognosis due to early involvement of respiratory muscles.
ALS spectrum disorders (atypical variants) :
1. Primary Lateral Sclerosis (PLS)
• Only upper motor neurons (UMN) are affected.
• Clinical signs: Spastic paralysis, hyperreflexia, babinski sign positive, no muscle atrophy or fasciculations (as LMNs are intact).
• EMG (electromyography) is normal (no LMN degeneration).
• Prognosis: Better than ALS—patients can survive 10–15 years or more. Slower progression than classical ALS.
- Progressive muscular atrophy (PMA)
• Only lower motor neurons (LMN) are affected so upper motor neurons remain intact.
• Clinical signs: Flaccid paralysis (no spasticity), hyporeflexia, muscle atrophy, fasciculations.
• EMG confirms LMN degeneration.
• Prognosis: Worse than PLS, but still better than classical ALS. Survival can be longer than typical ALS (~5–10 years).
If UMN or LMN signs remain isolated for 3–4 years, it is unlikely to progress into classical ALS.
• PLS or PMA should only be diagnosed after monitoring for at least 3–4 years.
Diagnosis of ALS?
To diagnose classical ALS there must be UMN signs and LMN signs in at least one region of the body.
UMN signs : spasticity, hyperreflexia and babinski sign.
LMN signs : muscle atrophy, weakness, fasciculations, hyporeflexia.
We must rule out conditions that mimick UMN and LMN lesions. The first might be mimicked by a stroke or by MS. The latter might be confused with peripheral neuropathies and myopathies.
Lab test to exclude other causes like CPK for myopathies, vitamin B levels for deficiencies and thyroid function test.
EMG is the key diagnostic test as it detects LMN dysfunction even if clinical signs are absent. Findings include active denervation where muscle fibers fire randomly (fasciculations), and chronic reinnervation as surviving LMN attempt to compensate lost neurons by innervating more fibers leading to larger motor unit action potentials.
El Escorial diagnostic criteria for ALS? Role of MRI in ALS diagnosis?
The El Escorial criteria provide a structured approach for diagnosing ALS and are widely used in clinical practice. They emphasize:
1. Progressive motor impairment as the primary clinical feature.
2. Upper Motor Neuron and Lower Motor Neuron involvement:
• Definite ALS: UMN + LMN signs in at least 3 regions.
• Probable ALS: UMN + LMN signs in 2 regions.
• Possible ALS: UMN + LMN signs in 1 region or UMN in 1 region + LMN in 2+ regions.
3. Exclusion of other conditions through lab tests and imaging.
4. EMG confirmation of LMN involvement when it is not clinically evident.
Brain and spinal cord MRI are primarily used to exclude mimicking conditions. Although MRI can be used to find supportive findings such as hyperintensity of the corticospinal tract indicating white matter lesions, hypo intense lesions in the motor cortex.
Monitoring the clinical progression of ALS?
ALS Functional Rating Scale (ALS-FRS)
• The ALS Functional Rating Scale (ALS-FRS) is the most commonly used clinical scale for ALS progression.
• Scores range from 0 (death) to 48 (normal function).
• The scale evaluates motor function, bulbar function, and respiratory function.
• Cognitive function is NOT included in this scale.
Cognitive Impairment in ALS
• The frontal and temporal lobes are commonly affected due to TDP-43 pathology.
• 50% of ALS patients show some level of cognitive dysfunction.
• 15% of ALS patients develop frontotemporal dementia (FTD), meaning the cognitive decline is severe enough to impact daily life.
Overlap Between ALS and Frontotemporal Dementia?
• TDP-43 pathology is the cause of both ALS and FTD.
• 45% of FTD cases are due to TDP-43 accumulation.
• Overlap between ALS and FTD is common, leading to: ALS with cognitive impairment → Progressing to ALS + FTD, FTD with mild motor signs → Progressing to FTD + ALS
• ALS + FTD has the worst prognosis.
Prognostic factors in ALS? Treatment?
Worse prognosis : Bulbar onset ALS, C9ORF72 mutation, early respiratory failure and dysphagia, environmental and lifestyle factors.
Better prognosis : SOD1 mutation as it has a more benign course.
Approved drugs :
1.Riluzole : The first drug approved for ALS.
• Blocks glutamate excitotoxicity to slow neuron degeneration.
• Extends survival by ~3–6 months.
2. Edaravone
• Antioxidant therapy.
• Reduces oxidative stress in neurons.
• May slow disease progression.
Experimental & Ongoing Research
• Tofersen (anti-SOD1 therapy), approved for SOD1 mutation ALS.
