PET imaging of glucose metabolism, neuroinflammation and synaptic density in amyotrophic lateral sclerosis

ALS is a neurodegenerative disease with progressive muscle loss and an average survival of 2 to 5 years after symptom onset. Until now, no curative treatment is available. The general aim of this PhD was to investigate a triad of interrelated in-vivo imaging biomarkers that may be used for diagnosis and prognosis and the study of their physiopathological significance in ALS: glucose metabolism, neuroinflammation and synaptic density. GLUCOSE METABOLISM In early diagnostic stages it can be difficult to discriminate between ALS and diseases mimicking ALS symptoms, also named ALS mimics. We demonstrated that glucose metabolism may increase clinical accuracy in this differential diagnosis by assessing a disease specific [18F]FDG signature in ALS. The combination of brain and spinal cord metabolism could discriminate between ALS and ALS mimics with an accuracy of 81.5% in early disease stages. The observed glucose metabolic pattern in ALS can be reproduced across different centers with similar clinical diagnostic criteria. Using glucose metabolism, patients can be subdivided in 4 different metabolic stadia, which may be useful to create more homogeneous subgroups for therapeutic trials. Altogether, our results show that glucose metabolism is a promising and clinically useful diagnostic biomarker and stratification aid for multicenter studies. (chapter 1) NEUROINFLAMMATION The mitochondrial TSPO receptor is upregulated in neuroinflammation and over the last twenty years several TSPO radioligands have been developed. Currently, all second generation TSPO radioligands still have a relatively low signal-to-noise ratio and require genotyping. Therefore, we investigated a theoretically more specific target for neuroinflammation, the P2X7 receptor. Although, P2X7R radioligands seemed promising to quantify neuroinflammation, we demonstrated no significant differences in ALS vs. HV, so thus far TSPO tracers remain the best option to measure neuroinflammation in symptomatic ALS patients. We proposed a clinically practical imaging protocol and confirmed that (multicentric) pooling of data obtained with different second-generation TSPO tracers is achievable. The latter will facilitate the use and practical feasibility for clinical implementation and in future therapeutic studies. (chapter 2) SYNAPTIC DENSITY Since the FDG signal is, amongst others, determined by (glutamatergic) synaptic activity as well as neuroinflammation, we investigated [11C]UCB-J PET as a biomarker for synaptic density changes in ALS. In our pilot study (n = 11), no significant difference in cerebral synaptic density was observed between ALS patients and HV. (chapter 3) Therefore, this suggests that cerebral synaptic density imaging is probably not valuable as biomarker for use in ALS, in contrast to manifest changes found in other neurodegenerative diseases such as AD (predominantly hippocampal) and PD (predominantly in the substantia nigra). INTERACTION BETWEEN GLUCOSE METABOLISM, NEUROINFLAMMATION AND SYNAPTIC DENSITY In a pilot study, we examined the triad of glucose metabolism, synaptic density and neuroinflammation simultaneously in a subset of ALS patients. Whereas synaptic density was not significantly correlated with TSPO signal or glucose metabolism, a relation between hypermetabolism and neuroinflammation was found, indicating that hypermetabolism in ALS can be - at least partly - attributed to neuroinflammation. (chapter 3) Overall, this PhD thesis demonstrates the utility of [18F]FDG and TSPO PET imaging in the context of early diagnosis, prognosis and patient stratification for (multicentric) therapeutic trials.

Publication year:2020

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