The increasing number of MRI studies focused on prodromal Parkinson’s Disease (PD) demonstrates a strong interest in identifying early biomarkers capable of monitoring neurodegeneration. In this systematic review, we present the latest information regarding the most promising MRI markers of neurodegeneration in relation to the most specific prodromal symptoms of PD, namely isolated rapid eye movement (REM) sleep behavior disorder (iRBD). We reviewed structural, diffusion, functional, iron-sensitive, neuro-melanin-sensitive MRI, and proton magnetic resonance spectroscopy studies conducted between 2000 and 2023, which yielded a total of 77 relevant papers. Among these markers, iron and neuromelanin emerged as the most robust and promising indicators for early neurodegenerative processes in iRBD. Atrophy was observed in several regions, including the frontal and temporal cortices, limbic cortices, and basal ganglia, suggesting that neurodegenerative processes had been underway for some time. Diffusion and functional MRI produced heterogeneous yet intriguing results. Additionally, reduced glymphatic clearance function was reported. Technological advancements, such as the development of ultra-high field MRI, have enabled the exploration of minute anatomical structures and the detection of previously undetectable anomalies. The race to achieve early detection of neurodegeneration is well underway. Despite tremendous improvement in the diagnosis and management of patients with Parkinson’s disease (PD), this disease remains incurable. In an attempt to limit the progression of neurodegeneration, many innovative treatments are being developed and tested, such as immunotherapy, gene therapy, and drug repurposing . HoweverIt is therefore urgent to develop early biomarkers able to identify neurodegeneration before the onset of motor symptoms and offer premotor patients a dedicated treatment. Moreover, these biomarkers are expected to reflect the stability or worsening of neurodegeneration during the trial of innovative treatments.The onset of motor symptoms occurs many years after the commencement of the neurodegenerative process and about 30% of nigrostriatal synaptic activity is already lost . During Brain imaging showed promising results toward the goal of identifying early biomarkers of neurodegeneration in high-risk patients. For example, positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging of striatal membrane dopamine transporters (DAT) revealed a dopaminergic deficit in approximately 50% of patients with idiopathic/isolated RBD (iRBD) . MoreoveTo identify promising biomarkers reflecting neurodegeneration in the premotor stage of synucleinopathies, we conducted a systematic review of the literature regarding MRI abnormalities at prodromal disease stages, especially in patients without any sign of parkinsonism but having iRBD.To achieve this aim, we adopted the relevant criteria of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) . In JuneSpecifically, the following criteria were applied for inclusion in the review: (1) English full text available; (2) original articles or case–control studies that included patients with iRBD; (3) iRBD diagnosis confirmed by video-polysomnography; (4) MRI studies, and (5) absence of motor sign of parkinsonism or not meeting the criteria for PD diagnosis.To reduce the risk of omitting a report, the search was conducted twice at 6-month intervals and the bibliography was carefully evaluated by all authors. This study was not registered in PROSPERO .According to the International Classification of Sleep Disorders 3rd Edition, rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams accompanied by simple or complex motor behaviors during REM sleep . The diaiRBD is undoubtedly the most studied premotor manifestation of synucleinopathies. The most important MRI features found in iRBD patients are listed in In summary, in iRBD there was a volumetric reduction in the striatum and lenticular nucleus ,23 alongIn patients with iRBD, a brain-clinical pattern in patients was found and predicted conversion to Dementia with Lewy Body (DLB) ,31.There was a consistent loss of neuromelanin in the SN ,33 and lFunctional network iRBD studies showed heterogeneous results. The connectivity within the basal ganglia was mostly decreased ,41,42,43Finally, MRS results on iRBD showed changes in neuron function and metabolism ,46, yet As a result, measures of atrophy, iron, and NM-sensitive MRI might be the most regular and promising features for an early neurodegenerative diagnosis. Different methods were used to evaluate GM integrity such as voxel-based morphometry (VBM), deformation-based morphometry (DBM), cortical thickness, and segmentations.With regard to cortical GM, most of the studies reported decreased volume or thinning  in the fMore marginally, other regions were reported to be affected: anterior cingulate ,28,63 teTo better understand the clinical relevance of these findings, some authors evaluated whether GM damage was correlated with clinical symptoms. The progression of motor signs in iRBD was associated with cortical thinning primarily in frontal regions . Lower GPatients with iRBD and Mild Cognitive Impairment (MCI) had cortical thinning in the frontal, cingulate, temporal, and occipital cortices, and abnormal surface contraction in the lenticular nucleus and thalamus; whereas, those without any cognitive symptoms had cortical thinning restricted to the frontal cortex . No neurUsing DBM, individuals with iRBD and MCI exhibited a distinct pattern of local deformation and volume atrophy in both cortical  and subcortical regions  when compared to iRBD patients without MCI or control subjects. These findings were correlated with diminished performance in visuospatial abilities, attention, and executive functions, and increased severity of motor symptoms .Taking advantage of follow-up databases, several studies explored longitudinal changes in iRBD. Changes in cortical thickness were noticed in the bilateral superior parietal and precuneus, the right cuneus, the left occipital pole, and lateral orbitofrontal gyri compared to controls ,64.Also, some authors found brain patterns related to Dementia with Lewy Body (DLB) in patients with iRBD. More precisely, one study characterized DLB-related whole-brain cortical thickness spatial covariance pattern (DLB-pattern) from a group of DLB patients and repeated this measure during the follow-up in DLB, iRBD, and control groups, identifying phenoconverters to PD or DLB. The DLB-pattern was characterized by thinning of the temporal, orbitofrontal, and insular cortices and relative preservation of the precentral and inferior parietal cortices. In the iRBD group, the baseline DLB-pattern scores were significantly higher in dementia-first than in parkinsonism-first converters. In non-converters, their analysis showed that the DLB-cortical thickness pattern remained stable over time in the majority of the cases. However, individual patterns were heterogeneous .A second study identified a latent variable linking atrophy in the basal ganglia, thalamus, amygdala, and frontotemporal grey and white matter, and expansion in the cerebrospinal fluid (CSF)-filled spaces, to impairment in measures of motor, cognitive, and autonomic functions. They used a Deformation-Based Morphometry (DBM) analysis and the deformation score from this specific pattern foretold the progression to and not PD . FinallyWith regard to the basal ganglia and the brainstem, decreased local volume in the SN pars compacta (SNc) , caudatePoorer quality of life, as measured by a high Parkinson’s Disease Questionnaire 39 items (PDQ-39) score, was associated with reduced normalized putamen volumes. Similarly, slower performance on the timed gait task was associated with reduced normalized caudate and putamen volumes . In a study designed to investigate subcortical and cortical GM volume alterations associated with depressive and anxiety symptoms in iRBD patients , authorsRotating frame relaxation parameters  tended to be higher in iRBD patients than in controls in the amygdala, hippocampus, and thalamus .In some studies it was paradoxically an increase in the volume of GM of the frontal cortex, caudate ,70, cereFinally, only four studies have found no significant clusters of reduced GM volume between iRBD patients and controls ,43,71,72The results of the microstructural WM assessment of iRBD were quite heterogeneous.In the brainstem, decreases of Fractional Anisotropy (FA) in the SN , the tegMean free-water values (bi-tensor DTI) in the posterior SN for iRBD patients were reported to be higher and with a significant negative correlation with dopaminergic SPECT/CT activity . On the Further, significant decreases in the axial diffusivity were observed in the pons and the right SN, which were interpreted as altered axonal integrity .At the supratentorial level, FA increases were found in the internal capsule bilaterally , in the olfactory region, in right insula, right putamen  and cortHigher quantitative anisotropy in iRBD subjects compared with PD patients was found in bilateral middle cerebellar peduncles and right arcuate fasciculus thought as neural compensation  but moreIncreased MD in the iRBD compared to the PD group was found in the corpus callosum, the right limb of the internal and external capsule, the right superior and inferior longitudinal fasciculus, the right inferior frontal-occipital fasciculus, the right corticospinal tract , the rigCompared to controls, increased MD in the iRBD were found in left angular gyrus, left calcarine fissure and surrounding cortex, left and right caudate nucleus, left anterior and middle cingulate gyrus, left cuneus, right IFG pars orbitalis, left superior frontal gyrus medical orbital part, left fusiform gyrus, left hippocampus, left middle occipital gyrus, left rectus gyrus, left inferior and middle temporal gyrus, left thalamus, left lobule III of cerebellar hemisphere, left lobule VIIB of cerebellar hemisphere, and lobule X of vermis .Radial diffusivity (RD) increases were observed in the fornix, the right visual stream , and the left superior temporal lobe . In anotThese results were not consistent with other studies assessing axial, radial, or mean diffusivity and reporting no abnormalities ,32. Regarding structural connectivity data, several studies identified WM changes in iRBD. Using graph-theoretical analysis, a study demonstrated that individuals with iRBD exhibited notably increased small-worldness, clustering coefficient, and enhanced local connectivity among regions associated with olfactory, motor, and sleep functions when compared to control subjects. Betweenness centrality was also elevated in the left olfactory cortex, left precentral gyrus, left supramarginal gyrus, left temporal pole superior temporal part, lobule of X of vermis, and left crus II of cerebellar hemisphere , caudateMoreover, with network-based statistics (NBS), a study showed greater connectivity between the right SMA area and right putamen, and between the left parahippocampal gyrus and left cerebellum in iRBD subjects compared to controls . Here aln = 11)  had increased and more variable Unified Parkinson’s Disease Rating Scale Part III Motor score (UPDRS-III) and Hoehn and Yahr scale (H&Y) scores at 1 and 1.5-year follow-up than at baseline. On the contrary, subgroup 2 (n = 5)  had UPDRS-III and H&Y scores near 0 at 1 and 1.5 year follow-up, similar to the scores achieved at baseline [Using probabilistic tractography, another study evaluated longitudinal degenerative progression patterns in prodromal PD patients (iRBD and/or hyposmia). A progression pattern was numerically quantified with a longitudinal brain connectome progression score. A trend towards two patterns of evolution of the connectome in prodromal PD patients  was found. Subgroup 1  connectome and that it mapped onto specific networks involved in motor and planning functions .Further, in a third study using 7 Tesla MRI, was found impaired structural connectivity in 14 brainstem nuclei, including the connectivity between REM-on  and REM sleep muscle atonia  areas .The different methods of acquisition and post-processing of the signal are undoubtedly one of the reasons that can explain the differences observed between the reported studies. Further, as the prodromal phase of PD extends over many years, it is possible that there is some heterogeneity in the evaluated patients regarding their progression in neurodegeneration. Nevertheless, most of these studies showed that there was a microstructural alteration in the brainstem as well as in other brain regions. Efforts should be made to harmonize assessment techniques and obtain reliable markers.The most frequently evaluated feature in iRBD patients was the loss of dorso-nigral hyperintensity (DNH), mostly corresponding to nigrosome 1, in SWI sequences . HoweverEvaluation of brain iron content using quantitative magnetic resonance imaging showed various results. On the one hand, no difference was found in the transverse relaxation rate (R2*) ,72 in thQSM showed superior sensitivity for PD-related tissue changes in nigrostriatal dopaminergic pathways  but thisAll the studies found a concordant result, namely a reduction in the neuromelanin-sensitive volume and/or signal intensity in the whole SN ,33,74,81This anomaly appears to be the most consistent in the prodromal stage of PD.Interestingly, two studies ,84 foundOnly two studies were performed in iRBD in proton Magnetic resonance spectroscopy (MRS). A 3T MRI study showed a reduction of choline/creatine and N-acetylaspartate/Choline ratios in the pontine tegmentum  whereas In iRBD, the most reported resting state fMRI (rsfMRI) result was a reduced nigro-striato-thalamo-pallidal inter- and intra-hemispheric connectivity ,86,87,88This was especially the case for the connectivity of the caudate, putamen, and globus pallidus, bilaterally , as wellIn comparison to controls, individuals with iRBD exhibited diminished cortico-cortical functional connectivity strength, particularly in edges located within posterior regions  but alsoFinally, global functional dynamics and functional connectivity (FC) in iRBD were impaired within the resting-state network, particularly in the visual network and sensorimotor networks. FC parameters  were negatively associated with the clinical features, including UPDRS-I, II, Total, and RBD-Sleep Questionnaire . Reduced FC between the brainstem and the cerebellum posterior lobe, temporal lobe, and anterior cingulate correlated with autonomic functions in iRBD  .Comparing iRBD patients with and without MCI with controls, a study reported a lower FC strength between the left lateral occipital cortex and the nucleus basalis of Meynert (belonging to the cholinergic system) and the lingual gyrus in the iRBD group with MCI than in the iRBD with normal cognitive scores and healthy subjects. FC mean values positively correlated with the MoCA and memory test scores . AnotherIn patients with iRBD and impulse control disorders (ICDs), a functional hypoconnectivity between the limbic striatum and temporal occipital regions was also reported. Furthermore, the presence of ICDs correlates with hypoconnectivity between the limbic striatum and clusters located in the cuneus, lingual, and fusiform gyrus .On the contrary, a study reported increased functional connectivity between the putamen and brain regions responsible for executing motion and coordination  and for planning movement  . The autElevated connectivity between the right SN and the right cuneus/precuneus/superior occipital gyrus was reported  and incrUsing the dynamic functional connectivity (dFC) approach, a study found four recurring dFC states that were characterized by significantly different connectivity patterns. iRBD patients spent more time in the frequent, fewer positive, and sparsely connected state  than controls did while almost no time in the infrequent, more positive, and strongly connected state .In an fMRI task involving bilateral hand movements, and in which there were internally selected and externally guided movement conditions for each hand, iRBD patients showed stronger functional recruitment compared to controls, mainly in the dorsolateral prefrontal, left primary somatosensory, the right fronto-insular cortices, in absence of behavioral differences. In these patients, lower MoCA scores were associated with higher activation in the left superior medial frontal and medial orbital gyrus, middle cingulate cortex, precuneus, and right cerebellum (Crus II) during the tasks .Additionally, individuals with iRBD exhibited a decrease in BOLD signal change within the dorsal caudate nucleus and displayed notably distinct corticostriatal functional connectivity patterns compared to control subjects during a dual-task virtual reality gait paradigm that involved foot pedals .Finally, in a virtual reality gait paradigm where individuals with iRBD were compared to controls, it was observed that iRBD patients exhibited diminished BOLD signal changes in the left posterior putamen and right mesencephalic locomotor region. Additionally, there was reduced FC between the frontoparietal network and the motor network when these patients navigated narrow versus wide doorways .In a retrospective study , of the A study used arterial spin-labeled imaging to examine changes in cerebral blood flow (CBF) in individuals with iRBD, aiming to identify alterations in brain perfusion associated with the condition. The findings revealed that the iRBD group exhibited notably reduced CBF values in the right middle frontal gyrus, right inferior frontal gyrus, and right insula. It is important to know that the iRBD group had a lower MMSE score  than in controls .More recently, another study found profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. They applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow. In iRBD patients, the microvascular flow disturbances were seen in cortical areas associated with visual processing, recognition, and language comprehension and were associated with impaired cognitive performance .Moreover, iRBD patients had significantly higher enlarged perivascular spaces (EPVS) in centrum semiovale (CSO), basal ganglia, SN, and brainstem than healthy subjects and PD. Higher CSO-EPVS and SN-EPVS burdens were positively correlated with the severity of clinical symptoms in iRBD patients . Also, tLateralization of brain structures or connectivity impairment varied across the studies we examined. In cases of symptomatic RBD, such as post-pontine strokes, both left and right lesions have been documented . For neuHowever, a study indicated that cortical degeneration in PD differed between the cerebral hemispheres, with early left hemisphere involvement and late right hemisphere involvement, often associated with posterior cortical atrophy. This pattern was not contingent on handedness or affected by the predominant side of motor symptoms . Also, aThe cause of this predominantly left hemisphere atrophy across various neurodegenerative diseases remains uncertain, although there are multiple hypotheses involving genetics, lateralized vulnerability, and disease-specific factors .In most RBD studies, handedness was often not mentioned. Incorporating this information into subsequent clinical and imaging investigations could assist in elucidating the presence and importance of initial microstructural/connectivity lateralization impairment.The increasing number of MRI studies assessing brain alterations in patients with prodromal PD symptoms demonstrates a strong interest of the scientific community in identifying early biomarkers able to monitor neurodegeneration.n = 5246 identified; n = 77 included), which was also the strength of this article. To reduce the risk of omitting a report, the search was conducted twice at 6-month intervals and the bibliography was carefully evaluated by all authors. Compared with previous review articles on this topic, we included many more eligible articles. Those reviews chose either to discuss neuroimaging findings in iRBD in general  [For this review, the literature search was limited to PubMed (MEDLINE) and Google Scholar databases for several reasons. First, a huge number of references were found due to the wide scope of MRI methods considered  ,107,108 omalies) ,110. Secomalies) , which iomalies) . Thus, wSome biomarkers such as frontal cortical and basal ganglia atrophy, reduction of neuromelanin in the SN and locus coeruleus, or increase of iron in nigrosome 1 were the most consistent and could help clinicians in the early decision-making of a prodromal synucleinopathy-related disease diagnosis. However, these MRI features still need to be investigated in larger cohorts and to be more widely tested longitudinally. Nevertheless, we should keep in mind that performing any single of these studies is difficult because of the diagnostic complex procedures for iRBD (requiring video-polysomnography) and the scarcity of patients with iRBD visiting a doctor. It was therefore worthwhile to carry out a review of the literature to cross-check the results and extract the most consistent results. Another problem was the lack of reproducibility of some of the studies leading to inconsistent results. As an example, we can evoke specific technical shortcomings of some of the manuscripts that may have used now known to be methods fraught with lots of statistically significant artifacts—like lack of rigorous quality control for movement in many diffusion and BOLD imaging studies. Thus, results strongly depend on the decisions made in terms of MRI preprocessing although structural imaging assessed with T1-weighted sequences shows greater reproducibility .The field has matured over the course of 22 years making a lot of the earlier studies less convincing in retrospect.Finally, the quality of the clinical movement disorders evaluation of the participants in the studies was not consistent across the studies. Indeed, a lack of parkinsonism from a movement disorders clinician is far more convincing than from someone not so trained. Unfortunately, the background of those who performed the clinical evaluation was not systematically specified. Nevertheless, we were able to find a common set of results for most of the MRI methodologies, the most difficult was obviously for fMRI. Further research is warranted, with larger cohorts to highlight discrete but constant abnormalities.Technological advances in terms of image acquisition and processing allow higher imaging resolution. As an example, the development of the ultra-high field (7 Tesla) MRI, now makes it possible to explore very small anatomical structures and to reveal previously undetectable anomalies. This will undoubtedly enable to establish a more accurate correlation between certain brain regions that were previously difficult to segment  and clinical symptoms. Optimizing parameters for image acquisition and processing will help reduce some of the heterogeneity between studies. Furthermore, at this stage, none of the described MRI parameters has been consistently assessed from the perspective of predicting which synucleinopathy the patient will develop . This information is of the utmost importance to best adapt the care management. In the years to come, the combination of different imaging modalities (such as PET/SPECT and MRI) will certainly be of great help to support the hypothesis of the presence of brain lesions  and of the type of neurodegeneration . Then, diagnostic algorithms that include clinical, molecular, and imaging biomarkers in addition to genetic biomarkers may have a huge impact by identifying patients most at risk for neurodegenerative disease, and by allowing them to undergo the most appropriate therapeutic trial.