Brain glucose metabolism and nigrostriatal degeneration in isolated rapid eye movement sleep behaviour disorder

Patricia Diaz-Galvan, Toji Miyagawa, Scott A Przybelski, Timothy G Lesnick, Matthew L Senjem, Clifford R Jack Jr, Leah K Forsberg, Hoon-Ki Min, Erik K St Louis, Rodolfo Savica, Julie A Fields, Eduardo E Benarroch, Val Lowe, Ronald C Petersen, Bradley F Boeve, Kejal Kantarci, Patricia Diaz-Galvan, Toji Miyagawa, Scott A Przybelski, Timothy G Lesnick, Matthew L Senjem, Clifford R Jack Jr, Leah K Forsberg, Hoon-Ki Min, Erik K St Louis, Rodolfo Savica, Julie A Fields, Eduardo E Benarroch, Val Lowe, Ronald C Petersen, Bradley F Boeve, Kejal Kantarci

Abstract

Alterations of cerebral glucose metabolism can be detected in patients with isolated rapid eye movement sleep behaviour disorder, a prodromal feature of neurodegenerative diseases with α-synuclein pathology. However, metabolic characteristics that determine clinical progression in isolated rapid eye movement sleep behaviour disorder and their association with other biomarkers need to be elucidated. We investigated the pattern of cerebral glucose metabolism on 18F-fluorodeoxyglucose PET in patients with isolated rapid eye movement sleep behaviour disorder, differentiating between those who clinically progressed and those who remained stable over time. Second, we studied the association between 18F-fluorodeoxyglucose PET and lower dopamine transporter availability in the putamen, another hallmark of synucleinopathies. Patients with isolated rapid eye movement sleep behaviour disorder from the Mayo Clinic Alzheimer's Disease Research Center and Center for Sleep Medicine (n = 22) and age-and sex-matched clinically unimpaired controls (clinically unimpaired; n = 44) from the Mayo Clinic Study of Aging were included. All participants underwent 18F-fluorodeoxyglucose PET and dopamine transporter imaging with iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane on single-photon emission computerized tomography. A subset of patients with isolated rapid eye movement sleep behaviour disorder with follow-up evaluations (n = 17) was classified as isolated rapid eye movement sleep behaviour disorder progressors (n = 7) if they developed mild cognitive impairment or Parkinson's disease; or isolated rapid eye movement sleep behaviour disorder stables (n = 10) if they remained with a diagnosis of isolated rapid eye movement sleep behaviour disorder with no cognitive impairment. Glucose metabolic abnormalities in isolated rapid eye movement sleep behaviour disorder were determined by comparing atlas-based regional 18F-fluorodeoxyglucose PET uptake between isolated rapid eye movement sleep behaviour disorder and clinically unimpaired. Associations between 18F-fluorodeoxyglucose PET and dopamine transporter availability in the putamen were analyzed with Pearson's correlation within the nigrostriatal pathway structures and with voxel-based analysis in the cortex. Patients with isolated rapid eye movement sleep behaviour disorder had lower glucose metabolism in the substantia nigra, retrosplenial cortex, angular cortex, and thalamus, and higher metabolism in the amygdala and entorhinal cortex compared with clinically unimpaired. Patients with isolated rapid eye movement sleep behaviour disorder who clinically progressed over time were characterized by higher glucose metabolism in the amygdala and entorhinal cortex, and lower glucose metabolism in the cerebellum compared with clinically unimpaired. Lower dopamine transporter availability in the putamen was associated with higher glucose metabolism in the pallidum within the nigrostriatal pathway; and with higher 18F-fluorodeoxyglucose uptake in the amygdala, insula, and temporal pole on a voxel-based analysis, although these associations did not survive after correcting for multiple comparisons. Our findings suggest that cerebral glucose metabolism in isolated rapid eye movement sleep behaviour disorder is characterized by hypometabolism in regions frequently affected during the prodromal stage of synucleinopathies, potentially reflecting synaptic dysfunction. Hypermetabolism is also seen in isolated rapid eye movement sleep behaviour disorder, suggesting that synaptic metabolic disruptions may be leading to a lack of inhibition, compensatory mechanisms, or microglial activation, especially in regions associated with nigrostriatal degeneration.

Keywords: FDG; Lewy bodies disease; PET; SPECT; isolated REM sleep behaviour disorder.

© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Pattern of FDG PET glucose metabolism in iRBD. We used weighted two-stage parameter estimation approach accounting for matching on age and sex to calculate area under the receiver operation curves (AUROC). AUROC tested the ability of FDG SUVr in each atlas-based ROI (50 ROIs) to distinguish iRBD patients from CU controls. FDG, 18F-fluorodeoxyglucose; SUVr, standardized uptake value ratio.
Figure 2
Figure 2
Age-adjusted Pearson’s correlations between dopamine transporter availability in the putamen on 123I-FP-CIT SPECT (horizontal axis) and FDG uptake in each nigrostriatal nucleus (vertical axis). Scatterplots display data of the entire cohort of iRBD patients (n = 22). Patients with iRBD who progressed over time are coloured in red. FDG, 18F-fluorodeoxyglucose; SUVr , standardized uptake value ratio.
Figure 3
Figure 3
Voxel-based analysis of the association between the dopamine transporter availability in the putamen on 123I-FP-CIT SPECT and FDG PET SUVr in cortex. Maps of this association are displayed at the P < 0.001 level for the entire cohort of iRBD patients (n = 22). Colours towards red indicate higher FDG SUVr or hypermetabolism in association with lower dopamine transporter availability in the putamen. The voxel-based regional associations of putamen 123I-FP-CIT SPECT and FDG PET SUVr were corrected for multiple comparisons using family-wise error correction. Because there were no significant associations between putamen 123I-FP-CIT SPECT and FDG PET after correction for multiple comparisons, we display the uncorrected results.
Figure 4
Figure 4
Alterations of nigrostriatal pathway in iRBD. Image on the right illustrates a neuroanatomic representation of the nigrostriatal pathway as well as cortico-striatal and cortico-thalamic connections. Image on the left illustrates a zoomed scheme of the nigrostriatal pathway. Filled circles represent neuron nuclei in the subtantia nigra and cortex from which the striatum receives dopamine and glutamine input respectively. Lines ending with a V shape represent presynaptic neurons in the corresponding tracks. Lines starting with a hollow circle represent postsynaptic neurons in the tracks. Crosses illustrate the tracks that are disrupted because of a degeneration of the susbtantia nigra in iRBD. Briefly, the substantia nigra pars compacta sends dopaminergic input to the putamen to modulate its activity (in green). The putamen has a direct and indirect inhibitory GABAergic connection with the pallidum. When the putamen receives dopamine from the substantia nigra, it activates the release of GABA to the pallidum, which inhibit its activity (in blue). If there is neurodegeneration of the substantia nigra, there is a lack of dopamine input to the putamen, which leads to a lack of inhibition of the pallidum. Consequently, the pallidum will be over-activated, showing hypermetabolism that can be detected on FDG PET.

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