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Observational Study
. 2023 Jun 1;146(6):2512-2523.
doi: 10.1093/brain/awac439.

Metabolic patterns in brain 18F-fluorodeoxyglucose PET relate to aetiology in paediatric dystonia

Stavros Tsagkaris  1   2 , Eric K C Yau  3 , Verity McClelland  1   4 , Apostolos Papandreou  1   5 , Ata Siddiqui  6 , Daniel E Lumsden  1   7 , Margaret Kaminska  1 , Eric Guedj  8 , Alexander Hammers  2 , Jean-Pierre Lin  1   9
Affiliations
Observational Study

Metabolic patterns in brain 18F-fluorodeoxyglucose PET relate to aetiology in paediatric dystonia

Stavros Tsagkaris et al. Brain. .

Abstract

There is a lack of imaging markers revealing the functional characteristics of different brain regions in paediatric dystonia. In this observational study, we assessed the utility of [18F]2-fluoro-2-deoxy-D-glucose (FDG)-PET in understanding dystonia pathophysiology by revealing specific resting awake brain glucose metabolism patterns in different childhood dystonia subgroups. PET scans from 267 children with dystonia being evaluated for possible deep brain stimulation surgery between September 2007 and February 2018 at Evelina London Children's Hospital (ELCH), UK, were examined. Scans without gross anatomical abnormality (e.g. large cysts, significant ventriculomegaly; n = 240) were analysed with Statistical Parametric Mapping (SPM12). Glucose metabolism patterns were examined in the 144/240 (60%) cases with the 10 commonest childhood-onset dystonias, focusing on nine anatomical regions. A group of 39 adult controls was used for comparisons. The genetic dystonias were associated with the following genes: TOR1A, THAP1, SGCE, KMT2B, HPRT1 (Lesch Nyhan disease), PANK2 and GCDH (Glutaric Aciduria type 1). The acquired cerebral palsy (CP) cases were divided into those related to prematurity (CP-Preterm), neonatal jaundice/kernicterus (CP-Kernicterus) and hypoxic-ischaemic encephalopathy (CP-Term). Each dystonia subgroup had distinct patterns of altered FDG-PET uptake. Focal glucose hypometabolism of the pallidi, putamina or both, was the commonest finding, except in PANK2, where basal ganglia metabolism appeared normal. HPRT1 uniquely showed glucose hypometabolism across all nine cerebral regions. Temporal lobe glucose hypometabolism was found in KMT2B, HPRT1 and CP-Kernicterus. Frontal lobe hypometabolism was found in SGCE, HPRT1 and PANK2. Thalamic and brainstem hypometabolism were seen only in HPRT1, CP-Preterm and CP-term dystonia cases. The combination of frontal and parietal lobe hypermetabolism was uniquely found in CP-term cases. PANK2 cases showed a distinct combination of parietal hypermetabolism with cerebellar hypometabolism but intact putaminal-pallidal glucose metabolism. HPRT1, PANK2, CP-kernicterus and CP-preterm cases had cerebellar and insula glucose hypometabolism as well as parietal glucose hypermetabolism. The study findings offer insights into the pathophysiology of dystonia and support the network theory for dystonia pathogenesis. 'Signature' patterns for each dystonia subgroup could be a useful biomarker to guide differential diagnosis and inform personalized management strategies.

Keywords: PET functional imaging; dystonic cerebral palsy; inherited childhood dystonia.

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Conflict of interest statement

S.T. and J.-P.L. received support from the GSTT charity research and education fund A13. J.-P.L. has received support from the Guy’s and St Thomas Charity New Services and Innovation Grant G060708; the Dystonia Society UK Grants 01/2011 and 07/2013 and Action Medical Research GN2097 for work in childhood dystonia and deep brain stimulation neuromodulation and unrestricted educational grants from Medtronic Ltd. A.H. receives institutional infrastructure support from the Wellcome EPSRC Centre for Medical Engineering at King’s College London (WT 203148/Z/16/Z) and also from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. He also receives royalties for commercial use of Hammers Atlas databases (academic use as in this paper is free). V.M. is currently supported by a Clinician Scientist Fellowship from the Medical Research Council UK (MRP0068681) and by the Rosetrees Trust (CF-2021-2-112) and was previously supported by a post-doctoral clinical research training fellowship from the Medical Research Council UK (MRP0068681) and by a project grant from the Rosetrees Trust (A1598). D.E.L. is supported by MRC Clinical Academic Research Partnership (Grant Number MR/T005424/1). He is a Chair of the Movement Disorder Specialist Interest Group of the British Paediatric Neurology Association and an associate editor for the ‘Archives of Disease in Childhood’ Journal. A.P. is supported by a National Institute for Health Research GOSH BRC Catalyst Fellowship (NIHR GOSH BRC 20DD06—BRC Catalyst Fellowship [9]). The European Paediatric Neurology Society supported V.M., D.E.L. and A.H. attendance and presentation at the Specialist Symposium on Neuromodulation in Children (Athens, Sept 2019).

Figures

Figure 1
Figure 1
Patient ascertainment flowchart.
Figure 2
Figure 2
FDG uptake compared to controls in inherited dystonias that only showed hypometabolism (excluding PANK2). Areas of relative regional hypometabolism are displayed in a blue-scale with brighter tones indicating higher t-scores. (A) TOR1A (n = 7): Putamen-frontal hypometabolism. (B) THAP1 (n = 3): Caudate-putaminal and right fronto-parietal hypometabolism. (C) SGCE (n = 6): Head of caudate, globus pallidus, inferior frontal lobe hypometabolism. (D) KMT2B (n = 7): Marked caudate-putaminal (striatal) and bi-frontal and bi-parietal hypometabolism. (E) HPRT1 (n = 5). Extreme caudate-putaminal-pallidal, medial thalamic, and pan-hemispheric and antero-superior cerebellar hypometabolism. (F) GCDH (n = 9). Relative regional hypometabolism in the posterior putamina and globi pallidi. All results are displayed on the 97-region version of the maximum probability atlas derived from the Hammers Atlas Database (www.brain-development.org/brain-atlases), which is a 3D maximum probability atlas of the human brain.
Figure 3
Figure 3
PANK2. FDG uptake in pantothenate kinase associated neurodegeneration cases (n = 14) compared to controls. Left: Areas of regional relative hypermetabolism seen in the superior parietal lobes and displayed in a yellow-scale with brighter tones indicating higher t-scores. Middle and right: Hypometabolic areas noted in the peri-insular cortex, cerebellar dentate nuclei and posterior inferior cerebellar cortex and displayed in a blue-scale with brighter tones indicating higher t-scores.
Figure 4
Figure 4
FDG uptake in CP-kernicterus cases (n = 13) compared to controls. Left: Relative hypermetabolism in superior parietal lobes displayed in a yellow-scale with brighter tones indicating higher t-scores. Middle and right: Areas of relative hypometabolism, including the antero-medial temporal cortex, globi pallidi, thalami, midbrain, pons, dentate-cortical cerebellum and peri-insular cortex, displayed in a blue-scale with brighter tones indicating higher t-scores.
Figure 5
Figure 5
FDG uptake in CP-preterm cases (n = 35) compared to controls. Left: Relative hypermetabolism in the superior parietal lobes displayed in a yellow-scale with brighter tones indicating higher t-scores. Middle and right: Areas of relative hypometabolism, involving the superior-medial temporal lobes, peri-insular cortex, globi pallidi, thalami and brainstem, displayed in a blue-scale with brighter tones indicating higher t-scores.
Figure 6
Figure 6
FDG uptake in CP-term cases (n = 45) compared to controls. Left: Regionally increased uptake in the superior anterior frontal and superior parietal lobules respectively, displayed in a yellow-scale with brighter tones indicating higher t-scores. Right: Regionally reduced uptake in the posterior putamina, globi pallidi and lateral parts of the thalami displayed in a blue-scale with brighter tones indicating higher t-scores.
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