Multiple system atrophy (MSA) is a severe neurodegenerative disorder with various underlying pathophysiological features. Mitochondrial dysfunction has been implied as a viable treatment target in patients with MSA. Yet, there is a lack of in-vivo studies examining regional metabolic differences between the Parkinsonian (MSAp) and the cerebellar (MSAc) subtype of MSA. Twenty-four patients with MSA (12 patients with MSAp and 12 patients with MSAc), 24 patients with Parkinson's disease (PD), and 24 age- and sex-matched healthy controls (HCs) underwent clinical evaluations and multimodal neuroimaging, including 31P-MRSI targeting the basal ganglia and the cerebellum. Ratios of high-energy phosphorus-containing metabolites (HEPs) were compared between groups. Only patients with MSAc showed decreased HEP levels in the cerebellum. Conversely, no differences in basal ganglia HEP levels appeared between both MSA subtypes, patients with PD, or HCs. Our findings provide preliminary in-vivo evidence for regionally detectable bioenergetic alterations in the cerebellum of patients with MSAc, while basal ganglia results, particularly in MSAp, require cautious interpretation because of the spatial-resolution limits of the present 31P-MRSI approach.

ATP1A3-related neurological disorders display a broad clinical spectrum with three predominant phenotypes, including rapid-onset dystonia-parkinsonism (RDP).1 The ATP1A3 gene encoding the α-subunit (subtype 3) of the Na+/K+-ATPase enzyme maintains the neuronal electrochemical gradient by removing intracellular sodium in exchange for extracellular potassium ions, which is essential for regulating the excitability of neurons, cell volume, and neurotransmission.2, 3 This study used 23Na-MRI (magnetic resonance imaging) employing the nuclear magnetic resonance of sodium, with a combination of total sodium (tNa) and intracellular-weighted sodium imaging (inversion recovery 23Na-MRI [IR-Na]).4 The latter measurement is particularly interesting considering that decreased Na+/K+-ATPase activity is expected to lead to an accumulation of intracellular sodium, which might serve as a direct measure of the proposed disease mechanisms in ATP1A3-related disorders. A 45-year-old male patient with RDP harboring a heterozygous missense mutation in the ATP1A3 gene [NM_152296.5(ATP1A3):c.2788C>T(p.Arg930Trp)] and seven age/sex-matched (45.4 ± 2.4 years) control subjects were enrolled. Neuroimaging was performed on a 3T Siemens MAGNETOM Skyra MRI scanner using a 64-channel head/neck coil (Siemens) and a dual-tuned quadrature head coil 1H/23Na (RAPID Biomedical). Preprocessing of sodium images and voxel-based morphometry was done using the SPM12 software package and CAT12 toolbox. Volumes (T1) and the mean voxel intensities (tNa and IR-Na images) for caudate, putamen, pallidum, thalamus, supplementary motor area (SMA), precentral gyrus (PrecG), postcentral gyrus (PostcG), and the cerebellum were extracted using the Neuromorphometrics brain atlas. We selected the side-averaged regions of interest (ROIs) based on their involvement in the development of dystonia.5 In addition, the occipital lobe (OccL) served as a control ROI because it is not implicated in the pathophysiology of dystonia. Extracted ROI values were scaled to the total intracranial volume (TIV) and z-transformed. More details on the methods and the case description can be found in the Supporting Information Methods and Video S1. The volumetry values of our index patient were within the reference range of the control group (Supporting Information Fig. S1D). The assessment of tNa content demonstrated marked differences for most of the earlier-mentioned ROIs contrary to the control ROI (Fig. 1C). The cerebellum showed the highest tNa z-score (6.29) and also the highest IR-Na z-score (2.79) (Fig. 1D). Our study provides the first in-vivo evidence that sodium predominantly accumulates in the cerebellum of patients with RDP, which appears to be driven by intracellular accumulation. The measurement of a sodium disequilibrium is supported by previous reports showing pathophysiological involvement of the cerebellum in the development of ATP1A3-related disorders and other forms of dystonia.5, 6 In rodent models, cerebellar injection of ouabain (a pharmacological inhibitor of the Na+/K+-ATPase enzyme) or an ATP1A3-directed small hairpin RNA leads to the development of dystonia-like phenotypes.7 In addition, cerebellar pathologies either caused by structural lesions or consequent to inherited ataxias can result in dystonia in humans.5 Overall, these results indicate that tNa and IR-Na imaging may be suitable for studying ATP1A3-related disorders and should be applied once it becomes broadly available to future clinical trials. Future studies in patients with other forms of dystonia or parkinsonism are needed to evaluate the pathophysiological specificity of 23Na-MRI in ATP1A3-related neurological disorders. J.P. received funding from the Parkinson's Foundation, the Deutsche Parkinsongesellschaft, and the Deutsche Forschungsgemeinschaft via the Clinician Scientist School Lübeck (DFG- GEPRIS 413535489). N.B. received funding from the Deutsche Forschungs-Gemeinschaft (BR4328.2–1 [FOR2488], GRK1957). Open Access funding enabled and organized by Projekt DEAL. Open access funding enabled and organized by Projekt DEAL. 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript: A. Writing of the first draft, B. Review and Critique. J.P.: 1A, 1B, 1C, 2A, 2B, 3A M.G.: 1C, 2A, 2B, 2C, 3A S.S.G.: 1B, 1C, 2C, 3C K.R.: 1B, 1C, 2C, 3C B.E.: 1B, 1C, 2C, 3C A.M.: 1B, 1C, 2C, 3C A.M.N.: 1C, 2B, 2C, 3C N.B.: 1A, 1B, 1C, 2B, 2C, 3C J.P.—Stock Ownership in medically related fields – none; Intellectual Property Rights – none; Consultancies – none; Expert Testimony – none; Advisory Boards – none; Employment – University Medical Center Schleswig Holstein; Partnerships – none; Contracts – none; Honoraria – none; Royalties, − none; Grants – none; Other – none. M.G.—Stock Ownership in medically–related fields – none; Intellectual Property Rights – none; Consultancies – none; Expert Testimony – none; Advisory Boards – none; Employment – University Medical Center Schleswig Holstein; Partnerships – none; Contracts – none; Honoraria – none; Royalties, − none; Grants – none; Other – none. S.S.G.—Stock Ownership in medically related fields – none; Intellectual Property Rights – none; Consultancies – none; Expert Testimony – none; Advisory Boards – none; Employment – none; Partnerships – none; Contracts – none; Honoraria – none; Royalties, − none; Grants – none; Other – none. K.R.—Stock Ownership in medically related fields – none; Intellectual Property Rights Consultancies – none; Expert Testimony – none; Advisory Boards – none; Employment – none; Partnerships – none; Contracts – none; Honoraria – none; Royalties, − none; Grants – none; Other – none. B.E.—Stock Ownership in medically related fields – none; Intellectual Property Rights – none; Consultancies – none; Expert Testimony – none; Advisory Boards – none; Employment – none; Partnerships – none; Contracts – none; Honoraria – none; Royalties − none; Grants – none; Other – none. A.M.—Stock Ownership in medically related fields – none; Intellectual Property Rights – none; Consultancies – Desitin, Merz Pharmaceuticals, Admedicum, PTC Therapeutics; Expert Testimony – none; Advisory Boards – German Tourette Syndrome Association and Alliance of patients with chronic rare diseases; Employment – University Medical Center Schleswig Holstein; Partnerships – none; Contracts – none; Honoraria – Allergan, Ipsen, Merz Pharmaceuticals, Actelion, GlaxoSmithKline, Desitin, Teva, and Takeda; Royalties − none; Grants – Possehl-Stiftung (Lübeck, Germany), Margot und Jürgen Wessel Stiftung (Lübeck, Germany), Tourette Syndrome Association (Germany), Interessenverband Tourette Syndrom (Germany), CHDI, Damp-Stiftung (Kiel, Germany); Deutsche Forschungsgemeinschaft (DFG): projects 1692/3–1, 4–1, SFB 936, and FOR 2698 (project numbers 396,914,663, 396,577,296, 396,474,989); European Reference Network – Rare Neurological Diseases (ERN – RND; Project ID No 739510); Other – none. A.M.N.—Stock Ownership in medically related fields – none; Intellectual Property Rights Consultancies – none; Expert Testimony – none; Advisory Boards – none; Employment – University Hospital Erlangen; Partnerships – none; Contracts – none; Honoraria – none; Royalties, − none; Grants – none; Other – none. N.B.—Stock Ownership in medically related fields – none; Intellectual Property Rights Consultancies – Bridgebio, Centogene, Biogen, and AbbVie; Expert Testimony – none; Advisory Boards – Bridgebio, Biomarin, and Zambon; Employment – University Medical Center Schleswig Holstein; Partnerships – none; Contracts – none; Honoraria – Abbott, AbbVie, Biogen, Centogene, Bridgebio, Biomarin, and Zambon; Royalties − none; Grants – DFG (BR4328.2–1, GRK1957); Other – none. The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to containing information that could compromise the privacy of research participants. Appendix S1. Supporting Information. Fig. S1Structural neuroimaging of our index male patient with reference to the control group. Exemplary axial planes of the neuroimaging assessment of our index male patient are highlighted on the level of the basal ganglia and cerebellum. T1- (panel A), T2- (panel B), and FLAIR images (panel C) are shown. In panel D, the TIV-standardized ROI-volumes of the reference group (bars) are compared to our index patient (lines with respective z-scores). The control-ROI (the occipital lobe) is depicted hatched. Arb. units: arbitrary units. FLAIR: fluid-attenuated inversion recovery. SMA: supplementary motor area. TIV: total intracranial volume. Video S1 The video shows a slight dystonic posture of both hands while holding in front, which is most pronounced on the left side, together with a dystonic foot inversion on the left, hyperlordosis of the trunk, and a dystonic and shuffling gait of our patient. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUND AND OBJECTIVE:Bioenergetic disturbance, mainly caused by mitochondrial dysfunction, is an established pathophysiologic phenomenon in neurodegenerative movement disorders. The in vivo assessment of brain energy metabolism by 31phosphorus magnetic resonance spectroscopy imaging could provide pathophysiologic insights and serve in the differential diagnosis of parkinsonian disorders. In this study, we investigated such aspects of the underlying pathophysiology in patients with idiopathic Parkinson disease (PwPD) and progressive supranuclear palsy (PwPSP). METHODS:In total, 30 PwPD, 16 PwPSP, and 25 healthy control subjects (HCs) underwent a clinical examination, structural magnetic resonance imaging, and 31phosphorus magnetic resonance spectroscopy imaging of the forebrain and basal ganglia in a cross-sectional study. RESULTS:High-energy phosphate metabolites were remarkably decreased in PwPD, particularly in the basal ganglia (-42% compared with HCs and -43% compared with PwPSP, p < 0.0001). This result was not confounded by morphometric brain differences. By contrast, PwPSP had normal levels of high-energy energy metabolites. Thus, the combination of morphometric and metabolic neuroimaging was able to discriminate PwPD from PwPSP with an accuracy of up to 0.93 [95%-CI: 0.91-0.94]. DISCUSSION:Our study shows that mitochondrial dysfunction and bioenergetic depletion contribute to idiopathic Parkinson disease pathophysiology but not to progressive supranuclear palsy. Combined morphometric and metabolic imaging could serve as an accompanying diagnostic biomarker in the neuroimaging-guided differential diagnosis of these parkinsonian disorders. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that 31phosphorus magnetic resonance spectroscopy imaging combined with morphometric MRI can differentiate PwPD from PwPSP.

Progressive supranuclear palsy (PSP) is a debilitating neurodegenerative disease characterized by an aggressive disease course. Total and intracellular-weighted sodium imaging (23Na-MRI) is a promising method for investigating neurodegeneration in vivo. We enrolled 10 patients with PSP and 20 age- and gender-matched healthy control subjects; all study subjects underwent a neurological examination, whole-brain structural, and (total and intracellular-weighted) 23Na-MRI. Voxel-wise analyses revealed increased brainstem total sodium content in PSP that correlated with disease severity. The ROI-wise analysis highlighted additional sodium level changes in other regions implicated in the pathophysiology of PSP. 23Na-MRI yields substantial benefits for the diagnostic workup of patients with PSP and adds complementary information on the underlying neurodegenerative tissue changes in PSP.

Background The underlying pathophysiology of Parkinson's disease is complex, involving different molecular pathways, including brain iron deposition and mitochondrial dysfunction. At a molecular level, these disease mechanisms are likely interconnected. Therefore, they offer potential strategies for disease-modifying treatments. We aimed to investigate subcortical brain iron deposition as a potential predictor of the bioenergetic status in patients with idiopathic Parkinson’s disease. Methods Thirty patients with idiopathic Parkinson's disease underwent multimodal MR imaging (T1, susceptibility-weighted imaging, SWI) and 31 phosphorus magnetic resonance spectroscopy imaging. SWI contrast-to-noise ratios served as a measure for brain iron deposition in the putamen, caudate, globus pallidus, and thalamus and were used in a multiple linear regression model to predict in-vivo energy metabolite ratios. Results Subcortical brain iron deposition, particularly in the putamen and globus pallidus, was highly predictive of the region-specific amount of high-energy-containing phosphorus metabolites in our subjects. Conclusions Our study suggests that brain iron deposition but not the variability of individual volumetric measurements are highly predictive of mitochondrial impairment in vivo. These findings offer the opportunity, e.g., by using chelating therapies, to improve mitochondrial bioenergetics in patients with idiopathic Parkinson's disease.