ALS is a progressive neurodegenerative disorder that targets the motor neurons controlling voluntary muscles. The disease leads to muscle weakness, atrophy, and eventually paralysis. Currently, a standard, routine blood test cannot definitively diagnose ALS, as there is no single marker that confirms its presence. Diagnosis remains a complex process of clinical evaluation and the systematic exclusion of other conditions that mimic ALS symptoms.
The Role of Routine Blood Work in Ruling Out Other Conditions
Since no single blood test confirms ALS, doctors rely on a comprehensive panel of standard blood work to perform a differential diagnosis. This crucial step involves ruling out other treatable diseases that present with similar neurological symptoms, such as muscle weakness and atrophy. These conditions, often referred to as “ALS mimics,” must be excluded before an ALS diagnosis can be established.
Routine testing often includes a complete blood count and comprehensive metabolic panels to check for general health issues, infection, or organ dysfunction. Thyroid function tests are common because both overactive and underactive thyroid conditions can cause muscle weakness. Doctors also check for specific vitamin deficiencies, such as low levels of Vitamin B12, which can cause neuropathy resembling initial ALS symptoms.
A detailed blood workup also involves screening for infectious diseases like HIV or hepatitis, which can affect the nervous system, and for autoimmune disorders causing inflammation. Creatine kinase (CK) levels are measured because this enzyme is released when muscle tissue is damaged. Elevated CK levels are often seen in ALS patients but are not exclusive to the disease. A 24-hour urine collection may also be ordered to test for heavy metals, such as lead or mercury, as toxicity from these substances can cause motor neuron damage.
Emerging Blood Biomarkers for Early Detection and Progression
While routine blood work serves an exclusionary purpose, scientific research focuses on identifying specific blood-based biomarkers that could offer a definitive diagnostic tool. These emerging markers are molecules released into the bloodstream when motor neurons are damaged, offering a window into the disease process. The most widely studied example is Neurofilament Light Chain (NfL), a structural protein within neurons.
When neurons are injured, NfL is shed, and its concentration elevates in both the cerebrospinal fluid and the blood. Higher levels of plasma NfL are consistently observed in people with ALS compared to healthy controls. This elevation can be detected in presymptomatic individuals who carry ALS-related genetic mutations, sometimes years before symptoms begin. Although NfL is not specific to ALS—it can be elevated in other neurological conditions like multiple sclerosis—its level is strongly associated with the rate of disease progression and survival in ALS patients.
Researchers are exploring other markers, including specific proteins like TDP-43, which misfolds and aggregates in the motor neurons of most ALS patients. Measuring TDP-43 and other proteins in tiny lipid sacs called vesicles in the blood shows promise in distinguishing ALS from other neurological disorders. Recent studies have identified a panel of proteins that can distinguish ALS with high accuracy, suggesting the possibility of a definitive blood test. These findings are currently used primarily in research and clinical trials to monitor treatment effectiveness, but they represent a significant step toward an earlier and less invasive diagnosis.
The Definitive Diagnostic Process for Amyotrophic Lateral Sclerosis
Because a single blood test cannot yet confirm ALS, the definitive diagnosis relies on a comprehensive process centered on clinical presentation and specialized neurophysiological tests. The process begins with a detailed neurological examination to assess a patient’s reflexes, muscle strength, tone, and coordination. Diagnosis requires evidence of both upper motor neuron involvement (spasticity and overactive reflexes) and lower motor neuron involvement (muscle weakness, wasting, and twitching).
To confirm motor neuron damage, doctors rely on electrodiagnostic tests, primarily Electromyography (EMG) and Nerve Conduction Studies (NCS). NCS uses small electrical shocks to measure how fast nerves transmit impulses, helping to rule out conditions like multifocal motor neuropathy. Needle EMG involves inserting a fine electrode into various muscles to record their electrical activity at rest and during contraction, revealing characteristic signs of chronic nerve damage and reinnervation indicative of ALS.
Magnetic Resonance Imaging (MRI) of the brain and spinal cord is a standard tool used to exclude structural problems that could mimic ALS symptoms, such as spinal cord tumors or herniated disks. The neurologist uses established criteria, such as the El Escorial criteria, to formally classify the disease based on the combination of clinical signs and electrophysiological findings across different body regions. Establishing a diagnosis often takes a year or more from the onset of symptoms due to the necessity of ruling out all other potential causes.