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Novel Imaging Method Could Help Screen Subjects, Select Drug Doses for ALS Trials

Key findings

  • Uptake of a positron emission tomography radiotracer called the radiotracer was increased in disease-relevant regions in people with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS)
  • The radiotracer uptake co-localized with cortical thinning in ALS
  • Clinical measures of functional status were correlated with the radiotracer uptake
  • The new imaging method could guide dose selection in early trials of ALS treatments and help researchers select likely responders

Early trials of investigational drugs for amyotrophic lateral sclerosis (ALS) have a spectacular failure rate. A principal reason is that researchers have no way to know whether the drug is having the desired effect in the brain.

Nazem Atassi, MD, associate director of the Neurological Clinical Research Institute at Massachusetts General Hospital, and neurology research fellow Mohamad J Alshikho, MD, and colleagues have developed a molecular imaging tool that distinguishes ALS patients from healthy control subjects, which correlates with clinical findings. It could be invaluable in guiding dose selection in ALS clinical trials and selecting likely responders, the researchers explain in Annals of Neurology.

The research team is studying a positron emission tomography (PET) radiotracer called [11C]-PBR28. It binds to the translocator protein encoded by the TSPO gene, which is expressed throughout the brain, including the activated microglia found in the motor cortex, brainstem and spinal cord in ALS patients.

In a previous study, the team found increased [11C]-PBR28 uptake in the precentral gyrus in a small group of ALS patients.

To explore this finding further, the researchers studied patients with ALS or primary lateral sclerosis (PLS) and healthy control subjects recruited between May 22, 2012 and May 24, 2017. All participants were genotyped for a TSPO gene polymorphism that predicts binding affinity to [11C]-PBR28. Participants who were either mixed or high TSPO binders underwent imaging using a scanner that integrates PET and magnetic resonance imaging (MRI). The final sample included 85 patients: 53 ALS, 11 PLS and 21 controls.

Whole Brain Voxelwise Analyses

The researchers found significantly increased [11C]-PBR28 uptake in the cortical and subcortical regions of the motor cortices in ALS patients compared with controls. Patients with PLS showed a distinct pattern of even higher [11C]-PBR28 uptake that was located predominantly in the subcortical white matter.

The latter finding might simply reflect the fact that PLS patients in this study had longer disease duration and worse functional status than ALS patients, the researchers note. However, they raise the possibility that PLS might be fundamentally a different disease than ALS, with more white matter involvement.

Surface-based Analyses

Confirming the research group's earlier finding, ALS patients had significantly higher [11C]-PBR28 uptake bilaterally in the precentral and paracentral gyri compared with controls. The increase was largely co-localized with cortical thinning in the same anatomic regions.

No difference in [11C]-PBR28 uptake was detected between ALS and PLS on the cortical surfaces, but cortical thickness was significantly reduced in PLS compared with ALS.

Whole Brain Voxelwise Correlation Analyses

[11C]-PBR28 uptake in the motor cortices was correlated strongly with patient scores on the Upper Motor Neuron Burden (UMNB) scale and, more weakly, with scores on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS–R).

There was a significant inverse correlation between [11C]-PBR28 uptake and fractional anisotropy, an MRI diffusion parameter. This relationship suggests, the researchers say, that neuronal damage in ALS and PLS may be caused directly by the inflammatory products of activated glial cells. Alternatively, the reverse might be true: the injured tissues might trigger activation of microglia and astrocytes.

Region of Interest Analyses

Pearson correlation analyses of [11C]-PBR28 uptake within combined white and gray matter revealed significant correlations with the UMNB, the fine motor domain of the ALSFRS-R and fractional anisotropy.

Longitudinal Findings

Ten of the ALS patients were re-imaged six months after baseline. No significant changes were detected in [11C]-PBR28 uptake, cortical thickness or fractional anisotropy. The team comments that the stability in [11C]-PBR28 uptake suggests a plateau shortly after symptom onset. However, in this study, the ALS progression rate was only 0.5 points on the ALSFRS-R per month, almost 50% slower than average in ALS clinical trials. The selection of slow progressors may have obscured an increase in [11C]-PBR28 over six months.

Dr. Atassi and his colleagues conclude that [11C]-PBR28 PET–MRI is a promising tool for phase 1 and phase 2 clinical trials in ALS. They say it can be used to select participants with high levels of brain inflammation who are more likely to respond to a specific treatment. In addition, this imaging tool can provide proof of the biological activity of investigational drugs, which can help with dose selection in phase 1b trials.

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