Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. It causes loss of muscle control, paralysis, and eventually respiratory failure. There is currently no cure for ALS and no definitive diagnostic test. However, blood tests can provide important clues and help rule out other conditions.
What is ALS?
ALS is characterized by the progressive degeneration of motor neurons, which are nerve cells that control voluntary muscle movement. As motor neurons die, the brain loses the ability to initiate and control muscle movement. Early symptoms of ALS often include muscle weakness, twitching, and cramping, or slurred speech.
The disease progresses to cause difficulties walking, loss of hand function, and trouble swallowing and breathing. Eventually most people with ALS lose the ability to stand, walk, use their hands and arms, and breathe without assistance. While ALS does not directly affect thinking or sensation, roughly 50% of people with ALS will experience mild changes in cognition or behavior.
ALS usually strikes in mid-adulthood, between the ages of 40 and 70. It affects slightly more men than women globally, although in some populations the incidence is equal between sexes. Most cases of ALS occur sporadically with no clearly associated risk factors. About 5-10% of cases are familial, meaning they are inherited from a person’s parents.
What causes ALS?
The exact causes of ALS are not fully understood. Research points to a combination of genetic and environmental factors that lead to oxidative damage, protein misfolding, glutamate excitotoxicity, impaired axonal transport, inflammation, and other cellular processes. This results in the progressive degeneration and death of motor neurons.
A number of genes have been linked to ALS, including C9ORF72, SOD1, TARDBP, and FUS. Mutations in these genes can cause familial ALS and account for 60-70% of inherited cases. The abnormal protein products from these genetic mutations contribute to damaging motor neurons through various mechanisms.
However, most ALS cases do not have a clear genetic cause. Potential environmental risk factors for sporadic ALS include exposure to toxins, smoking, military service, strenuous physical activity, and viral infections. But more research is needed to establish definite environmental triggers.
Ultimately ALS arises from a confluence of multiple genetic susceptibilities and environmental exposures that damage motor neurons over time. The variability in onset and progression indicates that ALS has a complex multifactorial origin.
What are common ALS symptoms?
Some of the initial symptoms of ALS include:
- Muscle weakness in the arms, legs, face or throat
- Twitching (fasciculation) of muscles
- Cramping and tightness of muscles
- Trouble using the arms or hands to grip objects, write, open jars, or turn keys
- Tripping or stumbling due to foot drop
- Slurred, nasal speech or slowed voice
- Difficulty swallowing (dysphagia)
As ALS advances, additional symptoms emerge:
- Impaired walking due to leg weakness
- Unable to stand or rise from a seated position
- Weakness in the face, jaw, and neck
- Shortness of breath, shallow breathing
- Fatigue from muscle degeneration
- Uncontrolled emotional reactions (pseudobulbar affect)
- Cognitive changes such as forgetfulness, confusion
Symptoms typically start in one area such as the arm or leg, before spreading to other parts of the body as disease progresses. Eventually this results in paralysis and the inability to move, speak, swallow, and breathe without assistance.
How is ALS diagnosed?
ALS is generally diagnosed based on a person’s symptoms, a series of tests to rule out other conditions, and by tracking the progression of symptoms. Steps in the diagnosis process include:
- Physical exam: Checking for muscle weakness, atrophy, twitches, and evaluating speech, coordination, and mental status.
- Electromyography (EMG): Measuring electrical activity of muscles and nerves. Can detect abnormal nerve function.
- Nerve conduction studies: Assess signals along peripheral nerves. Low amplitudes indicate nerve damage.
- MRI: Provides images of the brain and spinal cord to rule out tumors, myelitis, or cervical spondylosis.
- Blood and urine tests: Help exclude other mimicking disorders such as thyroid disease, vitamin deficiencies, or autoimmune disorders.
- Muscle or nerve biopsy: Examines nerve and muscle tissue under a microscope. Can show nerve fiber degeneration.
- Genetic testing: Screens for known ALS-causing gene mutations in familial cases.
There is no single definitive test for ALS. Doctors assemble findings from the workup to conclusively diagnose ALS based on established criteria. They also track progression of worsening symptoms over time.
What blood tests may be done for ALS?
While there are no blood-based biomarkers to conclusively diagnose ALS, certain blood tests are very helpful to rule out mimicking disorders and identify potential causes. Common blood tests done during an ALS diagnostic workup include:
Complete blood count (CBC)
A CBC checks levels of red cells, white cells, hemoglobin, and platelets. It helps identify anemia, infection, or blood disorders associated with muscle weakness.
Electrolytes
Electrolytes like sodium, potassium, chloride, and bicarbonate are essential for nerve conduction. Abnormal electrolyte levels can cause muscle problems.
Erythrocyte sedimentation rate (ESR)
An elevated ESR indicates inflammation. It helps rule out autoimmune disorders with similar symptoms as ALS.
Thyroid function tests
These check levels of thyroid hormones T3 and T4. An over or underactive thyroid can cause muscle weakness.
Creatine kinase (CK)
CK is an enzyme present in muscles. High CK suggests muscle breakdown that can occur due to ALS, inflammation, or injury.
Lead test
Exposure to heavy metals like lead has been linked to increased risk of ALS. A blood lead test checks for levels of this neurotoxic metal.
Genetic testing
Genetic panels look for known familial ALS mutations in genes like SOD1, C9ORF72, and FUS. This is done for inherited cases of ALS.
Immunologic tests
These test for autoantibodies and immunoglobulin levels to exclude disorders like multiple sclerosis, myasthenia gravis, or rheumatoid arthritis.
Metabolic panel
This evaluates kidney function, blood sugar, proteins, and electrolytes. Helps uncover issues that can contribute to neuromuscular symptoms.
HIV test
Rarely ALS-like symptoms can result from HIV infection. An HIV blood test should be performed to exclude this possibility.
Are there ALS blood biomarkers?
Currently there are no validated blood-based biomarkers that reliably diagnose ALS in clinical practice. Scientists are actively researching blood biomarkers that may one day allow earlier diagnosis or tracking disease progression in ALS. Some potential blood biomarkers under investigation include:
Neurofilaments
Neurofilaments are structural proteins specific to nerve cells. Elevated levels of neurofilaments (NF-L, pNF-H) seem to correlate with nerve damage in ALS patients. May help monitor disease status.
TAR DNA-binding protein
TDP-43 regulates DNA transcription and is mutated in some ALS cases. Measuring TDP-43 levels may help diagnose and monitor ALS progression.
Cytokines and chemokines
These are immune signaling proteins involved in inflammation. Certain cytokines like IL-6, IL-1β, and MCP-1 appear dysregulated in ALS patients.
Metabolites
Metabolic profiling of blood samples revealed metabolites related to lipid, energy, and muscle metabolism are altered in ALS patients.
Exosomes
These extracellular vesicles transport molecular cargo. Exosomes derived from ALS patients show differences in proteins, lipids, and microRNAs compared to controls.
Oxidative stress markers
Since oxidative damage contributes to ALS, markers like protein carbonyls, nitric oxide, and malondialdehyde may provide clues to disease mechanisms.
However, more research is needed to validate these candidate biomarkers in large ALS patient cohorts. Developing reliable blood-based assays could improve ALS diagnosis, monitoring, and personalized treatment.
Can blood tests rule out ALS mimics?
While no single blood test can confirm ALS, blood work is very helpful to exclude “ALS mimic” disorders that have comparable symptoms. Testing can identify alternative diagnoses so the proper treatment can be initiated. Examples of conditions that blood work may rule out include:
- Polymyositis: Inflammation of muscle fibers, seen in autoimmune disorders like lupus. Elevated muscle enzymes like CK, plus antibodies help diagnose.
- Multiple sclerosis (MS): Nerve damage from autoimmunity. Blood may show high white cell count, immunoglobulin bands, and antibodies.
- Spinal muscular atrophy (SMA): Inherited motor neuron disorder. Genetic test detects disease-causing SMN1 gene mutation.
- Multifocal motor neuropathy: Autoimmune disorder affecting motor nerves to limbs. Elevated immunoglobulin M (IgM) antibodies are detectable.
- Myasthenia gravis: Autoimmune neuromuscular junction disorder. Blood can reveal acetylcholine receptor antibodies.
- Inclusion body myositis (IBM): Inflammatory muscle disease. Tests show increased CK, signs of autoimmunity, and muscle biopsy changes.
- Lyme disease: Tick-borne bacterial infection that can affect nerves. Blood tests check for Lyme antibodies to confirm diagnosis.
Appropriate blood testing helps physicians rule out these and other alternative causes of muscle weakness and nerve problems, allowing proper treatment. While ALS has no blood test, mimics can often be excluded through blood analysis.
Can blood tests predict ALS progression?
Currently there are no established blood biomarkers that are clinically useful to predict how rapidly ALS will progress in a given patient. Research is ongoing to identify prognostic biomarkers that can forecast an individual’s disease course. Some potential prognostic biomarkers being investigated include:
Creatine Kinase (CK)
Higher baseline CK seems to correlate with faster disease progression in ALS patients, indicating more extensive muscle damage at diagnosis predicts more rapid decline.
Ferritin
Low blood ferritin, which stores iron, is associated with shorter survival in ALS patients. This points to iron regulation playing a role in disease mechanisms.
Inflammatory cytokines
Certain cytokines like IL-6 and IL-18 appear elevated in rapidly progressing ALS cases, linking inflammation to more aggressive disease.
Neurofilaments (pNF-H, NF-L)
Rising levels of neurofilaments over time may reflect faster motor neuron breakdown and more rapid progression.
Excitatory amino acids
Increased glutamate and aspartate in the blood correlate to quicker progression rates in ALS patients.
Metabolic markers
Changes in metabolites related to lipids, cellular energetics, and muscle function associate with faster progression.
However, more validation is required to develop prognostic multimarker blood profiles that can predict the course of ALS for individual patients. This could guide prognosis and treatment decisions in the future.
Conclusion
While there are currently no definitive blood biomarkers to diagnose ALS, blood tests play an important supporting role in the diagnostic process. Blood work helps identify or exclude many ALS mimic conditions, points to inherited causes, and provides clues about disease mechanisms. Ongoing research aims to uncover reliable prognostic biomarkers in blood that can predict disease progression rate for ALS patients. For now, physicians must use blood tests in conjunction with clinical findings, neuroimaging, and other modalities to ultimately confirm a diagnosis of ALS. Continued progress in biomarkers research offers much promise to improve all aspects of ALS management.