Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, brain stem, and spinal cord.
Diagnosing ALS in the early stage of the disease can be difficult because of variable presentation, and common mimic disorders, according to Erik Pioro, MD, PhD, director of the section of amyotrophic lateral sclerosis and related disorders at Cleveland Clinic.
“While ways to identify lower motor neuron dysfunction in ALS (like electromyography) are easily accessible, we have limited means to assess upper motor neuron abnormalities in patients, and quickly rule out ALS mimics,” Pioro said.
With no established objective markers of upper motor neuron and extramotor involvement in ALS, diagnostic workup is very complex and currently based on “clinical presentation, progression of symptoms, and exclusion of other diseases, supported by neurophysiological and neuroimaging examinations.”
Much of the complexity stems from the phenotypic expression of ALS, which is highly heterogeneous and determined by four elements: body region of onset, upper and lower motor neuron involvement, rate of progression, and cognitive impairment.4
A definitive diagnosis depends on both lower and upper neuron involvement, which is often not clinically evident.4 About 10% of cases are classified as familial, and now more than half of these have an identified mutation. However, most patients have sporadic ALS with no obvious family history.3
A comprehensive diagnostic workup includes the following procedures:4
- Thorough neurological examination
- Blood and urine studies
- Electrodiagnostic tests
- Spinal tap
- Muscle and/or nerve biopsy
- Myelogram of cervical spine
All of these factors contribute to an average delay of one year from initial symptom onset to diagnosis, which hampers biomarker research as trial populations inevitably enroll patients with “atypical,” slowly progressive disease, leaving out those with more aggressive disease.5 More importantly, more than 40% of ALS patients undergo incorrect medical treatment, including surgical intervention, emphasizing the need for reliable diagnostic and prognostic biomarkers for ALS.6
The Role of Neuroimaging
Although ALS is a complex condition, neuroimaging could enable objective phenotypic classification of patients, provide information on the brain regions affected, and identify which brain alterations correspond to various symptom progression rates. Neuroimaging could also identify disease stage and monitor progressive degenerative changes.7
Currently, conventional MRI is used to rule out upper cervical cord lesions and other conditions that may mimic ALS.9 Efforts to develop accurate diagnostic biomarkers for ALS have concentrated on multimodal applications of advanced neuroimaging methods.
Michael Knopp, MD, PhD, vice chair of research at Ohio State University’s Wexner Medical Center said that the complexity of ALS means it is unlikely a single biomarker will give the reader confidence to make the right diagnosis. Instead, he sees a consensus emerging on a complex series of imaging studies.
“Part of what is currently driving the community is putting consensus guidelines or best practices together that can then serve as an integrated biomarker by tapping into morphometric imaging, functional imaging using diffusion tensor, and also the neural functioning imaging, and then combining the biochemical readout coming from spectroscopy,” Knopp said. “I think what the community has recognized is that this has to be done in a structured way, and that if we use it in a structured way, the different components allow us to achieve a more precise diagnosis and more precise assessment of what is happening.”