INTRODUCTION: Most individuals with isolated rapid eye movement sleep behavior disorder (iRBD) develop dementia with Lewy bodies (DLB) or Parkinson's disease (PD). Brain biomarkers predicting specific phenoconversion trajectories are lacking. METHODS: In this multicenter diffusion magnetic resonance imaging study (261 iRBD, 177 controls), free water (FW) was measured in the nucleus basalis of Meynert (NBM) and posterior substantia nigra (SN). Among 230 iRBD patients with follow-up, 64 converted (16 DLB, 38 PD). Time-to-event analyses were performed to assess differential phenoconversion. RESULTS: Phenoconverters had higher FW in the NBM and posterior SN. Only FW in the NBM predicted conversion to DLB over PD. NBM volume predicted DLB conversion, but only FW remained significant when both were modeled. FW in the NBM correlated with lower MoCA scores in iRBD. DISCUSSION: FW in the NBM is a sensitive biomarker of cognitive decline and DLB progression in iRBD, outperforming volume and supporting its use in early stratification. HIGHLIGHTS: FW in the NBM specifically identifies conversion to DLB. Increased FW in the NBM is associated with lower global cognition in iRBD. FW in the SN in iRBD does not relate more to DLB than PD. FW in the NBM is a biomarker of differential phenoconversion in iRBD.

• Keywords
• Parkinson's disease, REM sleep behavior disorder, biomarker, dementia with Lewy bodies, diffusion magnetic resonance imaging, free water, prognosis,
• MeSH
• Biomarkers MeSH
• Lewy Body Disease * diagnostic imaging   diagnosis   MeSH
• Diffusion Magnetic Resonance Imaging MeSH
• Middle Aged MeSH
• Humans MeSH
• Parkinson Disease diagnostic imaging   MeSH
• REM Sleep Behavior Disorder * complications   diagnostic imaging   MeSH
• Disease Progression MeSH
• Aged MeSH
• Water * MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Names of Substances
• Biomarkers MeSH
• Water * MeSH

OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.

• MeSH
• Lewy Body Disease * diagnostic imaging   MeSH
• Dopamine * metabolism   MeSH
• Tomography, Emission-Computed, Single-Photon MeSH
• Middle Aged MeSH
• Humans MeSH
• Parkinson Disease * diagnostic imaging   complications   MeSH
• REM Sleep Behavior Disorder * diagnostic imaging   MeSH
• Presynaptic Terminals metabolism   MeSH
• Aged MeSH
• Machine Learning * MeSH
• Synucleinopathies * diagnostic imaging   MeSH
• Dopaminergic Imaging MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

Isolated REM sleep behavior disorder (iRBD) is an early stage of synucleinopathy with most patients progressing to Parkinson's disease (PD) or related conditions. Quantitative susceptibility mapping (QSM) in PD has identified pathological iron accumulation in the substantia nigra (SN) and variably also in basal ganglia and cortex. Analyzing whole-brain QSM across iRBD, PD, and healthy controls (HC) may help to ascertain the extent of neurodegeneration in prodromal synucleinopathy. 70 de novo PD patients, 70 iRBD patients, and 60 HCs underwent 3 T MRI. T1 and susceptibility-weighted images were acquired and processed to space standardized QSM. Voxel-based analyses of grey matter magnetic susceptibility differences comparing all groups were performed on the whole brain and upper brainstem levels with the statistical threshold set at family-wise error-corrected p-values <.05. Whole-brain analysis showed increased susceptibility in the bilateral fronto-parietal cortex of iRBD patients compared to both PD and HC. This was not associated with cortical thinning according to the cortical thickness analysis. Compared to iRBD, PD patients had increased susceptibility in the left amygdala and hippocampal region. Upper brainstem analysis revealed increased susceptibility within the bilateral SN for both PD and iRBD compared to HC; changes were located predominantly in nigrosome 1 in the former and nigrosome 2 in the latter group. In the iRBD group, abnormal dopamine transporter SPECT was associated with increased susceptibility in nigrosome 1. iRBD patients display greater fronto-parietal cortex involvement than incidental early-stage PD cohort indicating more widespread subclinical neuropathology. Dopaminergic degeneration in the substantia nigra is paralleled by susceptibility increase, mainly in nigrosome 1.

• Keywords
• Parkinson disease, QSM, REM sleep behavioral disorder, iron, whole brain,
• MeSH
• Humans MeSH
• Brain diagnostic imaging   pathology   MeSH
• Parkinson Disease * complications   MeSH
• REM Sleep Behavior Disorder * diagnostic imaging   MeSH
• Substantia Nigra diagnostic imaging   pathology   MeSH
• Synucleinopathies * complications   pathology   MeSH
• Iron MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Iron MeSH

BACKGROUND: Sialic acid-protein interactions are involved in regulating central nervous system immunity; therefore, derangements in sialylation could be involved in neurodegeneration. OBJECTIVES: We evaluate the differences in serum transferrin sialylation in prodromal and early-stage Parkinson's disease (PD), its relation to substantia nigra degeneration, and the risk of phenoconversion to manifest disease. METHODS: Sixty treatment-naive PD patients; 72 polysomnography-confirmed isolated rapid eye movement sleep behavior disorder (iRBD) patients, that is, patients with prodromal synucleinopathy; and 46 healthy volunteers aged ≥45 years and drinking ≤60 standard drinks per month were included. The proportion of serum low-sialylated, carbohydrate-deficient transferrin (CDT) isoforms was assessed using high-performance liquid chromatography, and the values were adjusted for alcohol intake (CDTadj ). Dopamine transporter single-photon emission computed tomography (DaT-SPECT) imaging was performed. In iRBD, phenoconversion risk of DaT-SPECT and CDTadj was evaluated using Cox regression adjusted for age and sex. RESULTS: Median CDTadj was lower in PD (1.1 [interquartile range: 1.0-1.3]%) compared to controls (1.2 [1.1-1.6]%) (P = 0.001). In iRBD, median CDTadj was lower in subjects with abnormal (1.1 [0.9-1.3]%) than normal (1.3 [1.2-1.6]%) DaT-SPECT (P = 0.005). After a median 44-month follow-up, 20% of iRBD patients progressed to a manifest disease. Although iRBD converters and nonconverters did not significantly differ in CDTadj levels (P = 0.189), low CDTadj increased the risk of phenoconversion with hazard ratio 3.2 (P = 0.045) but did not refine the phenoconversion risk associated with abnormal DaT-SPECT yielding hazard ratio 15.8 (P < 0.001). CONCLUSIONS: Decreased serum CDTadj is associated with substantia nigra degeneration in synucleinopathies. iRBD patients with low CDTadj are more likely to phenoconvert to manifest disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

• Keywords
• Parkinson's disease, phenoconversion, rapid eye movement sleep behavior disorder, sialylation, transferrin,
• MeSH
• Tomography, Emission-Computed, Single-Photon methods   MeSH
• Humans MeSH
• Parkinson Disease * complications   diagnostic imaging   MeSH
• REM Sleep Behavior Disorder * complications   diagnostic imaging   MeSH
• Synucleinopathies * MeSH
• Transferrin MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Transferrin MeSH

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.

• MeSH
• alpha-Synuclein MeSH
• Biomarkers * MeSH
• Humans MeSH
• REM Sleep Behavior Disorder complications   diagnosis   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Synucleinopathies diagnosis   etiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• alpha-Synuclein MeSH
• Biomarkers * MeSH