Interplay between spinal cord and cerebral cortex metabolism in amyotrophic lateral sclerosis

Marini, Cecilia; Morbelli, Silvia; Cistaro, Angelina; Campi, Cristina; Caponnetto, Claudia; Bauckneht, Matteo; Bellini, A.; Buschiazzo, Ambra; Calamia, Iolanda; Beltrametti, Mauro C.; Margotti, Simone; Fania, Piercarlo; Poggi, Ilaria; Cabona, Corrado; Capitanio, Selene; Piva, Roberto; Calvo, Andrea; Moglia, Cristina; Canosa, Antonio; Massone, Anna Maria; Nobili, Flavio; Mancardi, Gianluigi; Chiò, Adriano; Piana, Michele; Sambuceti, Gianmario

doi:10.1093/brain/awy152

Cited by 40 publications

(44 citation statements)

References 27 publications

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“…Accordingly, the SUVmax of the [12,13]. While a pattern of decreased or increased [ 18 F]FDG uptake was observed in in ammatory myelopathies and neurosarcoidosis, presumably re ecting varying delay between disease onset and time of PET and possible interference with steroid therapy [12,13], in case of amyotrophic lateral sclerosis elevated [ 18 F]FDG uptake values were reported [24]. Additional potential diseases suitable to be evaluated with PET of the spinal cord include trauma, post-radiation myelopathy, Vitamin B12 de ciency myelopathy and some neurodegenerative diseases which primarily affect the spinal cord as Friedreich's ataxia and hereditary spastic paraplegia.…”

Section: Resultsmentioning

confidence: 99%

[18F]FDG uptake of the normal spinal cord in PET/MR imaging: Comparison with PET/CT imaging

Aiello

Alfano

Salvatore

et al. 2020

Preprint

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Background The lack of visualization of the spinal cord hinders the evaluation of [18F]Fluoro-deoxy-glucose (FDG) uptake of the spinal cord in PET/CT. By exploiting the capability of MRI to precisely outline the spinal cord, we performed a retrospective study aimed to define normal pattern of spinal cord [18F]FDG uptake in PET/MRI.Methods Forty-one patients with lymphoma without clinical or MRI signs of spinal cord or bone marrow involvement underwent simultaneous PET and MRI acquisition using Siemens Biograph mMR after injection of 3.5 MBq/kg body weight of [18F]FDG for staging purposes. Using a custom-made software, we placed ROIs of 3 and 9 mm in diameter in spinal cord, lumbar CSF and vertebral marrow that were identified on MRI at 5 levels (C2, C5, T6, T12 and L3). The SUVmax, SUVmean and the SUVmax and SUVmean normalized (NSUVmax and NSUVmean) to the liver were measured. For comparison, the same ROIs were placed in PET-CT images obtained immediately before the PET-MRI acquisition following the same tracer injection.Results On PET/MRI using the 3 mm ROI the following average (all level excluding L3) spinal cord median (1st and 3rd quartile) values were measured:SUVmean1.68 (1.39 and 1.83), SUVmax1.92(1.60 and 2.14), NSUVmean1.18(0.93 and 1.36), NSUVmax1.27(1.01 and 1.33). Using the 9 mm ROI the corresponding values were: SUVmean1.41 (1.25-1.55), SUVmax2.41(2.08 and 2.61), NSUVmean0.93 (0.79 and 1.04), NSUVmax1.28(1.02 and 1.39).Using the 3 mm ROI the highest values of PET-MRI SUVmax, SUVmean, NSUVmax and NSUVmean were consistently observed at C5 and the lowest at T6. Using a 9 mm ROI the highest values were consistently observed at C5 and the lowest at T12 or T6. The spinal cord [18F]FDG-uptake values correlated with bone marrow uptake at the same level, especially in case of NSUVmax. Comparison with PET-CT data revealed that the average SUVmax and SUVmean of the spinal cord were similar in PET-MRI and PET-CT. However, the average NSUVmax and NSUVmean of the spinal cord were higher (range 21% - 47%) in PET-MRI than in PET-CT. Conclusions Using a whole-body protocol we defined the maximum and mean [18F]FDG uptake of the normal spinal cord in PET/MRI. While the observed values show the expected longitudinal distribution, they appear to be higher than those measured in PET/CT. Normalization of the SUVmax and SUVmean of the spinal cord to the liver radiotracer uptake could help in multi-institutional comparisons and studies.

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Section: Resultsmentioning

confidence: 99%

[18F]FDG uptake of the normal spinal cord in PET/MR imaging: Comparison with PET/CT imaging

Aiello

Alfano

Salvatore

et al. 2020

Preprint

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“…We previously reported a predictive power of spinal cord [18F]-uorodeoxyglucose (FDG) uptake computationally extracted from PET/CT images of ALS patients [7]. The apparent metabolic activation of this nervous district faced an opposite pattern in the brain cortex that showed a generalized reduction in tracer uptake [8]. By contrast, it extended to the psoas muscles of the same patients, suggesting a link between the metabolic pattern of the second motoneuron and its effector [9].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in Amyotrophic Lateral Sclerosis

Marini

Cossu

Bonifacino

et al. 2020

Preprint

Self Cite

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Background. We recently reported that enhanced [18F]-fluorodeoxyglucose (FDG) uptake in skeletal muscles predicts disease aggressiveness in patients with amyotrophic lateral sclerosis (ALS). The present experimental study aimed to assess whether this predictive potential reflects the link between FDG uptake and redox stress that has been previously reported in different tissues and disease models. Methods. The study included 15 SOD1G93A mice (as experimental ALS model) and 15 wildtype mice (around 120-days-old). Mice were submitted to micro-PET imaging. Enzymatic pathways and response to oxidative stress were evaluated in harvested quadriceps and hearts by biochemical, immunohistochemical and immunofluorescence analysis. Colocalization between the endoplasmic reticulum (ER) and the fluorescent FDG analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was performed in fresh skeletal muscle sections. Finally, mitochondrial ultrastructure and bioenergetics were evaluated in harvested quadriceps and hearts.Results. FDG retention was significantly higher in hindlimb skeletal muscles of symptomatic SOD1G93A mice with respect to control ones. This difference was not explained by any acceleration in glucose degradation through glycolysis or cytosolic pentose phosphate pathway (PPP). Similarly, it was independent of inflammatory infiltration. Rather, the high FDG retention in SOD1G93A skeletal muscle was associated with an accelerated generation of reactive oxygen species. This redox stress selectively involved the ER and the local PPP triggered by hexose-6P-dehydrogenase. ER involvement was confirmed by the colocalization of the 2-NBDG with a vital ER tracker. The oxidative damage in transgenic skeletal muscle was associated with a severe impairment in the crosstalk between ER and mitochondria combined with alterations in mitochondrial ultrastructure and fusion/fission balance. The expected respiratory damage was confirmed by a deceleration in ATP synthesis and oxygen consumption rate. These same abnormalities were represented to a markedly lower degree in the myocardium, as a sample of non-voluntary striated muscle.Conclusion. Skeletal muscle of SOD1G93A mice reproduces the increased FDG uptake observed in ALS patients. This finding reflects the selective activation of the ER-PPP in response to significant redox stress associated with alterations of mitochondrial ultrastructure, networking, and connection with the ER itself. This scenario is less severe in cardiomyocytes suggesting a relevant role for either communication with synaptic plaque or contraction dynamics.

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“…Thirdly, evidence points to a defective carbohydrate metabolism in ALS. Studies using [ 18 F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (PET) reported that cortical glucose uptake is reduced in ALS patients while local glucose uptake seems to be increased in both the cervical and dorsal spinal cord [38][39][40]. Furthermore, cortical hypometabolism is suggested to be an early diagnostic event that can be linked to the severity of the disease [38,41].…”

Section: Introductionmentioning

confidence: 99%

Existing and Emerging Metabolomic Tools for ALS Research

Germeys

Vandoorne

Bercier

et al. 2019

Genes

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Growing evidence suggests that aberrant energy metabolism could play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, studies applying advanced technologies to investigate energy metabolism in ALS remain scarce. The rapidly growing field of metabolomics offers exciting new possibilities for ALS research. Here, we review existing and emerging metabolomic tools that could be used to further investigate the role of metabolism in ALS. A better understanding of the metabolic state of motor neurons and their surrounding cells could hopefully result in novel therapeutic strategies.

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Interplay between spinal cord and cerebral cortex metabolism in amyotrophic lateral sclerosis

Cited by 40 publications

References 27 publications

[18F]FDG uptake of the normal spinal cord in PET/MR imaging: Comparison with PET/CT imaging

[18F]FDG uptake of the normal spinal cord in PET/MR imaging: Comparison with PET/CT imaging

Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in Amyotrophic Lateral Sclerosis

Existing and Emerging Metabolomic Tools for ALS Research

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