Novel PET Tracer Can Detect In Vivo Synaptic Density in Patients With ALS

The use of ¹⁸F-SynVesT-1 positron emission tomography (PET) has provided unparalleled evidence of relatively low uptake distribution in the right temporal lobe, bilateral frontal lobe, and hippocampus-insula region in patients with amyotrophic lateral sclerosis (ALS) compared with healthy control individuals. These are the findings of a study published in the European Journal of Neurology.

Researchers sought to evaluate the possible discriminant diagnostic value of ¹⁸F-SynVesT-1 PET as a marker of ALS pathology and to explore whether specific synaptic density signatures are present in different subtypes of ALS. They conducted a cohort study among patients with ALS from the department of neurology, Xiangya Hospital, Central South University, located in mainland China. The current analysis appears to be the first study of in vivo synaptic vesicle glycoprotein 2A (SV2A) PET imaging to quantitatively evaluate synaptic density with the use of ¹⁸F-SynVesT-1 in patients with ALS. SVA2 is an essential vesicle membrane protein of all synapses that is ubiquitous, exhibiting expression in every structure in the brain at varying levels. The protein is found in both excitatory and inhibitory synapses.

The researchers recruited a total of 21 sporadic patients with ALS between
December 18, 2019, and April 21, 2021. All of the participants were diagnosed with clinically definite, probable, or probably laboratory-supported ALS by at least 2 experienced neurologists. All of the individuals with ALS had been treated with riluzole and edaravone since their diagnosis. A total of 25 age- and sex-matched healthy individuals with normal cognitive function from the department of nuclear medicine at Xiangya Hospital served as the healthy control individuals.

Among the patients with ALS, demographic and clinical data, including sex, age, family history, age at onset (AAO), disease duration, site of onset, and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores, were obtained by specialists. The Chinese version of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used for cognitive profiling.

The researchers found that the mean AAO in participants with ALS was 51.05±
10.87 years, the mean time from ALS onset to undergoing a PET scan was 19.10±
15.12 months, and the mean ALSFRS-R score was 36.33±5.80. There were 15 slow progressors and 6 fast progressors with ALS. Overall, 16 individuals with ALS completed the ECAS, with a mean ECAS score of 77.81±18.80. The additional 5 patients with ALS did not complete the ECAS because of severe bulbar and hand dysfunction.

Based on the ECAS score cutoff values, 10 of the patients with ALS were classified as having ALS with cognitive impairment (ALSci) and 6 were classified as having ALS with normal cognitive function. All patients tolerated the ¹⁸F-SynVesT-1 injection well, with no objective or subjective adverse effects reported.

Low uptake distribution was revealed in the 21 patients with ALS compared with the healthy control individuals — in the right temporal lobe and the bilateral inferior frontal gyrus, the anterior cingulate, and the hippocampus-insula region. Further, low uptake was also detected in the bilateral superior temporal gyrus, the hippocampus-insula, the anterior cingulate, and the left inferior frontal gyrus in patients with ALSci compared with healthy control individuals. The height threshold was set at P <.001 (P <.05 familywise error [FEW] corrected at cluster).

Additionally, compared with individuals with spinal-onset ALS, those with bulbar-onset ALS demonstrated low uptake in the bilateral cingulate gyrus, along with high uptake in the bilateral superior temporal gyrus and the left occipital lobe.

Several limitations of the study should be noted. The results of more sophisticated diagnostic tests, including magnetic resonance imaging (MRI) neuroimaging, were not evaluated in the study participants. Subsequent studies should combine the use of ¹⁸F-SynVesT-1 PET with high-resolution MRI analyses. Additionally, the sample size of 21 patients with ALS and 25 healthy controls was relatively small.

The use of ¹⁸F-SynVesT-1 PET is “presently not justified as a routine investigation to detect evidence of brain dysfunction leading to progression in ALS,” the researchers noted. However, they do believe that “This approach may provide a direct measure of synaptic density, and it therefore might represent a potentially useful biomarker for ALS diagnosis, as well as for estimating the cognitive decline and site of onset in ALS.”