Effect of spaceflight experience on human brain structure, microstructure, and function: systematic review of neuroimaging studies.

Spaceflight-induced brain changes have been commonly reported in astronauts. The role of microgravity in the alteration of the brain structure, microstructure, and function can be tested with magnetic resonance imaging (MRI) techniques. Here, we aim to provide a comprehensive overview of Spaceflight studies exploring the potential role of brain alterations identified by MRI in astronauts. We conducted a search on PubMed, Web of Science, and Scopus to find neuroimaging correlates of spaceflight experience using MRI. A total of 20 studies (structural MRI n = 8, diffusion-based MRI n = 2, functional MRI n = 1, structural MRI and diffusion-weighted MRI n = 6, structural MRI and functional MRI n = 3) met our inclusion criteria. Overall, the studies showed that regardless of the MRI techniques, mission duration significantly impacts the human brain, prompting the inclusion of various brain regions as features in the analyses. After spaceflight, notable alterations were also observed in the superior occipital gyrus and the precentral gyrus which show alterations in connectivity and activation during spaceflight. The results provided highlight the alterations in brain structure after spaceflight, the unique patterns of brain remodeling, the challenges in drawing unified conclusions, and the impact of microgravity on intracranial cerebrospinal fluid volume.

Behavioral and dysexecutive variant of Alzheimer's disease: Insights from structural and molecular imaging studies.

Frontal variant Alzheimer's disease (AD) manifests with either behavioral or dysexecutive syndromes. Recent efforts to gain a deeper understanding of this phenotype have led to a re-conceptualization of frontal AD. Behavioral (bAD) and dysexecutive (dAD) phenotypes could be considered subtypes, as suggested by both clinical and neuroimaging studies. In this review, we focused on imaging studies to highlight specific brain patterns in these two uncommon clinical AD phenotypes. Although studies did not compare directly these two variants, a common epicenter located in the frontal cortex could be inferred. On the contrary, 18F-FDG-PET findings suggested differing metabolic patterns, with bAD showing specific involvement of frontal regions and dAD exhibiting widespread alterations. Structural MRI findings confirmed this pattern, suggesting that degeneration might involve neural circuits associated with behavioral control in bAD and attentional networks in dAD. Furthermore, molecular imaging has identified different neocortical tau distribution in bAD and dAD patients compared to typical AD patients, although the distribution is remarkably heterogeneous. In contrast, Aß deposition patterns are less differentiated between these atypical variants and typical AD. Although preliminary, these findings underscore the complexity of AD frontal phenotypes and suggest that they represent distinct entities. Further research is essential to refine our understanding of the pathophysiological mechanisms in frontal AD.

White matter alterations in affective and non-affective early psychosis: A diffusion MRI study.

BACKGROUND: The early years after the onset of psychotic disorders, known as "early psychosis" (EP) are critical to determining the path of psychosis trajectory. We used a Diffusion Magnetic Resonance Imaging (DMRI) connectometry approach to assess the microstructural changes of white matter (WM) associated with EP. METHODS: We used the Human Connectome Project in Early Psychosis (HCP-EP) dataset to collect DMRI data from patients with EP. The imaging data were processed in the Montreal Neuroimaging Initiative space and transformed into quantitative anisotropy (QA). The QA value was translated into the WM connectivity of each tract and used in the subsequent analysis. RESULTS: 121 patients with EP (94 non-affective/27 affective) and 56 healthy controls were recruited. EP was associated with increased QA in the body and tapetum of corpus callosum (CC) and decreased QA in the bilateral cerebellum, and middle cerebellar peduncle. Compared to non-affective psychosis, affective psychosis showed increased QA in the bilateral cerebellum and vermis and decreased QA in the forceps minor, body of CC, right cingulum, and bilateral inferior fronto-occipital fasciculus. Furthermore, QA changes in several WM tracts were correlated with positive and negative symptom scale scores. LIMITATIONS: DMRI intrinsic limitations, limited sample size, and neurobiological effects of psychotropic treatment. CONCLUSIONS: EP is associated with alterations in WM connectivity primarily in the CC and cerebellar regions. Also, affective and non-affective psychosis have distinct alterations in WM connectivity. These results can be used for the early diagnosis and differentiation of psychotic disorders.

Functional and structural lesion network mapping in neurological and psychiatric disorders: a systematic review.

Background: The traditional approach to studying the neurobiological mechanisms of brain disorders and localizing brain function involves identifying brain abnormalities and comparing them to matched controls. This method has been instrumental in clinical neurology, providing insight into the functional roles of different brain regions. However, it becomes challenging when lesions in diverse regions produce similar symptoms. To address this, researchers have begun mapping brain lesions to functional or structural networks, a process known as lesion network mapping (LNM). This approach seeks to identify common brain circuits associated with lesions in various areas. In this review, we focus on recent studies that have utilized LNM to map neurological and psychiatric symptoms, shedding light on how this method enhances our understanding of brain network functions. Methods: We conducted a systematic search of four databases: PubMed, Scopus, and Web of Science, using the term "Lesion network mapping." Our focus was on observational studies that applied lesion network mapping in the context of neurological and psychiatric disorders. Results: Following our screening process, we included 52 studies, comprising a total of 6,814 subjects, in our systematic review. These studies, which utilized functional connectivity, revealed several regions and network overlaps across various movement and psychiatric disorders. For instance, the cerebellum was found to be part of a common network for conditions such as essential tremor relief, parkinsonism, Holmes tremor, freezing of gait, cervical dystonia, infantile spasms, and tics. Additionally, the thalamus was identified as part of a common network for essential tremor relief, Holmes tremor, and executive function deficits. The dorsal attention network was significantly associated with fall risk in elderly individuals and parkinsonism. Conclusion: LNM has proven to be a powerful tool in localizing a broad range of neuropsychiatric, behavioral, and movement disorders. It holds promise in identifying new treatment targets through symptom mapping. Nonetheless, the validity of these approaches should be confirmed by more comprehensive prospective studies.

Deep Learning Methods for Identification of White Matter Fiber Tracts: Review of State-of-the-Art and Future Prospective.

Quantitative analysis of white matter fiber tracts from diffusion Magnetic Resonance Imaging (dMRI) data is of great significance in health and disease. For example, analysis of fiber tracts related to anatomically meaningful fiber bundles is highly demanded in pre-surgical and treatment planning, and the surgery outcome depends on accurate segmentation of the desired tracts. Currently, this process is mainly done through time-consuming manual identification performed by neuro-anatomical experts. However, there is a broad interest in automating the pipeline such that it is fast, accurate, and easy to apply in clinical settings and also eliminates the intra-reader variabilities. Following the advancements in medical image analysis using deep learning techniques, there has been a growing interest in using these techniques for the task of tract identification as well. Recent reports on this application show that deep learning-based tract identification approaches outperform existing state-of-the-art methods. This paper presents a review of current tract identification approaches based on deep neural networks. First, we review the recent deep learning methods for tract identification. Next, we compare them with respect to their performance, training process, and network properties. Finally, we end with a critical discussion of open challenges and possible directions for future works.

Graph theoretical approach to brain remodeling in multiple sclerosis.

Multiple sclerosis (MS) is a neuroinflammatory disorder damaging structural connectivity. Natural remodeling processes of the nervous system can, to some extent, restore the damage caused. However, there is a lack of biomarkers to evaluate remodeling in MS. Our objective is to evaluate graph theory metrics (especially modularity) as a biomarker of remodeling and cognition in MS. We recruited 60 relapsing-remitting MS and 26 healthy controls. Structural and diffusion MRI, plus cognitive and disability evaluations, were done. We calculated modularity and global efficiency from the tractography-derived connectivity matrices. Association of graph metrics with T2 lesion load, cognition, and disability was evaluated using general linear models adjusting for age, gender, and disease duration wherever applicable. We showed that MS subjects had higher modularity and lower global efficiency compared with controls. In the MS group, modularity was inversely associated with cognitive performance but positively associated with T2 lesion load. Our results indicate that modularity increase is due to the disruption of intermodular connections in MS because of the lesions, with no improvement or preserving of cognitive functions.

Neurite Orientation Dispersion and Density Imaging in Multiple Sclerosis: A Systematic Review.

Diffusion-weighted imaging has been applied to investigate alterations in multiple sclerosis (MS). In the last years, advanced diffusion models were used to identify subtle changes and early lesions in MS. Among these models, neurite orientation dispersion and density imaging (NODDI) is an emerging approach, quantifying specific neurite morphology in both grey (GM) and white matter (WM) tissue and increasing the specificity of diffusion imaging. In this systematic review, we summarized the NODDI findings in MS. A search was conducted on PubMed, Scopus, and Embase, which yielded a total number of 24 eligible studies. Compared to healthy tissue, these studies identified consistent alterations in NODDI metrics involving WM (neurite density index), and GM lesions (neurite density index), or normal-appearing WM tissue (isotropic volume fraction and neurite density index). Despite some limitations, we pointed out the potential of NODDI in MS to unravel microstructural alterations. These results might pave the way to a deeper understanding of the pathophysiological mechanism of MS. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 3.

Central nervous system microstructural alterations in Type 1 diabetes mellitus: A systematic review of diffusion Tensor imaging studies.

AIMS: Type 1 diabetes mellitus (T1DM) is a chronic childhood disease with potentially persistent CNS disruptions. In this study, we aimed to systematically review diffusion tensor imaging studies in patients with T1DM to understand the microstructural effects of this entity on individuals' brains METHODS: We performed a systematic search and reviewed the studies to include the DTI studies in individuals with T1DM. The data for the relevant studies were extracted and a qualitative synthesis was performed. RESULTS: A total of 19 studies were included, most of which showed reduced FA widespread in optic radiation, corona radiate, and corpus callosum, as well as other frontal, parietal, and temporal regions in the adult population, while most of the studies in the juvenile patients showed non-significant differences or a non-persistent pattern of changes. Also, reduced AD and MD in individuals with T1DM compared to controls and non-significant differences in RD were noted in the majority of studies. Microstructural alterations were associated with clinical profile, including age, hyperglycemia, diabetic ketoacidosis and cognitive performance. CONCLUSION: T1DM is associated with microstructural brain alterations including reduced FA, MD, and AD in widespread brain regions, especially in association with glycemic fluctuations and in adult age.

Cingulum and Uncinate Fasciculus Microstructural Abnormalities in Parkinson's Disease: A Systematic Review of Diffusion Tensor Imaging Studies.

Diffusion tensor imaging (DTI) is gaining traction in neuroscience research as a tool for evaluating neural fibers. The technique can be used to assess white matter (WM) microstructure in neurodegenerative disorders, including Parkinson disease (PD). There is evidence that the uncinate fasciculus and the cingulum bundle are involved in the pathogenesis of PD. These fasciculus and bundle alterations correlate with the symptoms and stages of PD. PRISMA 2022 was used to search PubMed and Scopus for relevant articles. Our search revealed 759 articles. Following screening of titles and abstracts, a full-text review, and implementing the inclusion criteria, 62 papers were selected for synthesis. According to the review of selected studies, WM integrity in the uncinate fasciculus and cingulum bundles can vary according to symptoms and stages of Parkinson disease. This article provides structural insight into the heterogeneous PD subtypes according to their cingulate bundle and uncinate fasciculus changes. It also examines if there is any correlation between these brain structures' structural changes with cognitive impairment or depression scales like Geriatric Depression Scale-Short (GDS). The results showed significantly lower fractional anisotropy values in the cingulum bundle compared to healthy controls as well as significant correlations between FA and GDS scores for both left and right uncinate fasciculus regions suggesting that structural damage from disease progression may be linked to cognitive impairments seen in advanced PD patients. This review help in developing more targeted treatments for different types of Parkinson's disease, as well as providing a better understanding of how cognitive impairments may be related to these structural changes. Additionally, using DTI scans can provide clinicians with valuable information about white matter tracts which is useful for diagnosing and monitoring disease progression over time.

White matter tracts alterations underpinning reward and conflict processing.

BACKGROUND: Reinforcement sensitivity theory (RST) is proposed as a neurobiological system that eventually led to emotion and motivation-based constructs of personality. Traditionally segmented into the behavioral activation system (BAS) and the behavioral inhibition system (BIS), RST is commonly used to describe personality and behavior. Although there have been studies linking gray matter alterations with BIS/BAS subscales, the role of white matter (WM) alterations is yet controversial. We aimed to investigate the specific WM tracts associated with BIS/BAS scores. METHODS: 220 healthy participants (mean age = 39.14 ± 20.23, 80 (35.7 %) females) were evaluated using the BIS/BAS questionnaire from the LEMON database. Diffusion MRI connectometry (DMRI) was used to investigate the WM correlates of BIS/BAS subscales in each gender group. Multiple regression models with the covariates of age, handedness, and education were fitted to address the correlation of local connectomes with BIS/BAS components. RESULTS: DMRI connectometry revealed that the quantitative anisotropy (QA) value of the splenium of the corpus callosum, right cerebellum, middle cerebellar peduncle, and superior cerebellar peduncle, had a significant negative correlation with each BIS/BAS subscale. In contrast, the QA value in the body of the corpus callosum and bilateral cingulum showed a positive correlation with BIS/BAS subscales. CONCLUSION: The integrity of WM in certain tracts is associated with behavioral activation and inhibition. This finding expands our knowledge of the neural networks associated with risk-taking and reward-seeking behaviors.

Trait anger representation in microstructural white matter tracts: A diffusion MRI study.

BACKGROUND: Understanding the microstructure of the brain that underlies emotions is of pivotal importance for psychology and psychiatry. Herein, we investigated white matter (WM) tracts associated with anger using the diffusion magnetic resonance imaging (DMRI) connectometry approach while exploring potential sex differences. METHODS: 225 healthy participants from the LEMON database were evaluated using the State-Trait Anger Expression Inventory (STAXI). WM images were prepared and analyzed with DMRI. Multiple regression models were fitted to address the correlation of local connectomes with STAXI components with age and handedness as covariates. RESULTS: There were no statistically significant differences in state anger and trait anger between males and females (p = 0.55 and 0.30, respectively). DMRI connectometry revealed that quantitative anisotropy (QA) values in the bilateral corticospinal tract (CST), splenium of corpus callosum (SCC), middle cerebellar peduncle, left inferior cerebellar peduncle, left cingulum, and left fornix were negatively correlated with trait anger and trait anger temperament (TAT) in males. In contrast, the QA values in the bilateral CST and SCC showed a positive correlation with trait anger and TAT in females, which, however, did not reach statistical significance. LIMITATIONS: The cross-sectional design and self-reported measures of anger limit the generalizability of our results. CONCLUSIONS: This is the first DMRI connectometry study to investigate WM circuits involved in anger. We found that the pathways associated with the limbic system and movement-related regions were involved in trait anger and anger expression in men, while no brain pathways showed a significant relationship with anger in women.

White Matter Microstructure Associated with the Antidepressant Effects of Deep Brain Stimulation in Treatment-Resistant Depression: A Review of Diffusion Tensor Imaging Studies.

Treatment-resistant depression (TRD) is a severe disorder characterized by high relapse rates and decreased quality of life. An effective strategy in the management of TRD is deep brain stimulation (DBS), a technique consisting of the implantation of electrodes that receive a stimulation via a pacemaker-like stimulator into specific brain areas, detected through neuroimaging investigations, which include the subgenual cingulate cortex (sgCC), basal ganglia, and forebrain bundles. In this context, to improve our understanding of the mechanism underlying the antidepressant effects of DBS in TRD, we collected the results of diffusion tensor imaging (DTI) studies exploring how WM microstructure is associated with the therapeutic effects of DBS in TRD. A search on PubMed, Web of Science, and Scopus identified 11 investigations assessing WM microstructure in responders and non-responders to DBS. Altered WM microstructure, particularly in the sgCC, medial forebrain bundle, cingulum bundle, forceps minor, and uncinate fasciculus, was associated with the antidepressant effect of DBS in TRD. Overall, the results show that DBS targeting selective brain regions, including the sgCC, forebrain bundle, cingulum bundle, rectus gyrus, anterior limb of the internal capsule, forceps minor, and uncinate fasciculus, seem to be effective for the treatment of TRD.

White matter tracts associated with alexithymia and emotion regulation: A diffusion MRI study.

BACKGROUND: Alexithymia is a cognitive-affective impairment, suggested to be associated with emotion regulation. Herein, we investigated white matter (WM) tracts with Diffusion Magnetic Resonance Imaging (DMRI) connectometry approach using quantitative anisotropy (QA) tractography to discover possible associations between the emotion identification and regulation patterns and WM tracts. METHODS: DMRI data were acquired from 218 healthy subjects aging 39.15 ± 20.19 who filled the Toronto Alexithymia Scale (TAS) and emotion regulation questionnaire (ERQ) from the LEMON dataset. Connectometry analysis was applied on WM tracts in DMRI images. RESULTS: DMRI connectometry analysis revealed a significant correlation between TAS identification score and increased microstructural connectivity in WM pathways, including the body of corpus callosum (CC), bilateral fornix, and left arcuate fasciculus (AF) in males (FDR = 0.028), and corticospinal and cingulum tracts in females (FDR = 0.026). Furthermore, we found a significant positive correlation between overall TAS score and fornix properties in men (FDR = 0.026) and corticospinal tracts in women (FDR = 0.028). Middle cerebellar peduncle negatively correlated with describing emotion (FDR = 0.025) and the splenium of the CC and corticospinal tracts negatively correlated with this subscale (FDR = 0.049) in male group. However, the splenium of the CC, corticospinal tracts, and left AF positively associated with this subscale (FDR = 0.029). The splenium of the CC was negatively related to externally-oriented thinking among men (FDR = 0.038). Our results showed marginally associations between ERQ and similar WM tracts. CONCLUSION: Certain WM microstructures significantly correlate with emotion identification and regulation. These tracts are associated with specific somatosensory areas, language processing areas, and limbic area.

Microstructural white matter alterations associated with migraine headaches: a systematic review of diffusion tensor imaging studies.

The pathophysiology of migraine as a headache disorder is still undetermined. Diffusion tensor imaging (DTI) has significantly improved our knowledge about brain microstructure in this disease. Here, we aimed to systematically review DTI studies in migraine and survey the sources of heterogeneity by investigating diffusion parameter changes associated with clinical characteristics and migraine subtypes. Microstructural changes, as revealed by widespread alteration of diffusion metrics in white matter (WM) tracts, subcortical and cortical regions, were reported by several migraine DTI studies. Specifically, we reported changes in the corpus callosum, thalamic radiations, corona radiata, and brain stem. These alterations showed high variability across migraine cycle phases. Additionally, migraine associated with depressive/anxiety symptoms revealed significant changes in the corpus callosum, internal capsule, and superior longitudinal fasciculus. No significant WM microstructural differences were observed between migraine patients with and without aura. Overall, differences between chronic and episodic migraine showed inconsistency across studies. Migraine is associated with microstructural changes in widespread regions including thalamic radiations, corpus callosum, and brain stem. These alterations can highlight neuronal damage and neuronal plasticity mechanisms either following pain stimulations occurring in migraine cycle or as a compensatory response to pain in chronic migraine. Longitudinal studies applying advanced modalities may shed new light on the underlying microstructural changes in migraine subtypes.

The forgotten tract of vision in multiple sclerosis: vertical occipital fasciculus, its fiber properties, and visuospatial memory.

Visual disturbances are a common disease manifestation in multiple sclerosis (MS) due to lesions damaging white matter tracts involved in vision. Vertical occipital fasciculus (VOF), a tract located vertically in the occipital lobe, was neglected for more than a century. We hypothesize that VOF is involved in integrating information between dorsal and ventral visual streams. Thus, its damage in MS, as well as its probable role in visual processing (by using MS as a VOF damage model) needs to be clarified. To study fiber characteristics of VOF in MS, and their clinical and visual learning associations, 57 relapsing-remitting MS (RRMS) and 25 healthy controls (HC) were recruited. We acquired MS Functional Composite, Expanded Disability Status Scale (EDSS), and Brief Visuospatial Memory Test-Revised (BVMT-R), and diffusion MRI scans. Tractography of VOF and optic radiation (OR) was done. VOF's metrics were statistically tested for between-group differences and clinical and visual tests associations. Along-tract analysis and laterality were also tested. RRMS patients had higher mean, axial, and radial diffusivity (nearly in all fiber points), and lower fractional anisotropy in bilateral VOFs compared to HC. No laterality was noted. These were associated with poor clinical outcomes, poor visual scores in EDSS, and lower total immediate and delayed recall in BVMT-R in RRMS, after adjusting for age, gender, and fiber metrics of OR. VOF damage is present in RRMS and is associated with visual symptoms and visuospatial learning impairments. It seems VOF is involved in integrating information between visual streams.

Cerebellar Microstructural Abnormalities in Parkinson's Disease: a Systematic Review of Diffusion Tensor Imaging Studies.

Diffusion tensor imaging (DTI) is now having a strong momentum in research to evaluate the neural fibers of the CNS. This technique can study white matter (WM) microstructure in neurodegenerative disorders, including Parkinson's disease (PD). Previous neuroimaging studies have suggested cerebellar involvement in the pathogenesis of PD, and these cerebellum alterations can correlate with PD symptoms and stages. Using the PRISMA 2020 framework, PubMed and EMBASE were searched to retrieve relevant articles. Our search revealed 472 articles. After screening titles and abstracts, and full-text review, and implementing the inclusion criteria, 68 papers were selected for synthesis. Reviewing the selected studies revealed that the patterns of reduction in cerebellum WM integrity, assessed by fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity measures can differ symptoms and stages of PD. Cerebellar diffusion tensor imaging (DTI) changes in PD patients with "postural instability and gait difficulty" are significantly different from "tremor dominant" PD patients. Freezing of the gate is strongly related to cerebellar involvement depicted by DTI. The "reduced cognition," "visual disturbances," "sleep disorders," "depression," and "olfactory dysfunction" are not related to cerebellum microstructural changes on DTI, while "impulsive-compulsive behavior" can be linked to cerebellar WM alteration. Finally, higher PD stages and longer disease duration are associated with cerebellum white matter alteration depicted by DTI. Depiction of cerebellar white matter involvement in PD is feasible by DTI. There is an association with disease duration and severity and several clinical presentations with DTI findings. This clinical-imaging association may eventually improve disease management.

A systematic review of resting-state and task-based fmri in juvenile myoclonic epilepsy.

Functional neuroimaging modalities have enhanced our understanding of juvenile myoclonic epilepsy (JME) underlying neural mechanisms. Due to its non-invasive, sensitive and analytical nature, functional magnetic resonance imaging (fMRI) provides valuable insights into relevant functional brain networks and their segregation and integration properties. We systematically reviewed the contribution of resting-state and task-based fMRI to the current understanding of the pathophysiology and the patterns of seizure propagation in JME Altogether, despite some discrepancies, functional findings suggest that corticothalamo-striato-cerebellar network along with default-mode network and salience network are the most affected networks in patients with JME. However, further studies are required to investigate the association between JME's main deficiencies, e.g., motor and cognitive deficiencies and fMRI findings. Moreover, simultaneous electroencephalography-fMRI (EEG-fMRI) studies indicate that alterations of these networks play a role in seizure modulation but fall short of identifying a causal relationship between altered functional properties and seizure propagation. This review highlights the complex pathophysiology of JME, which necessitates the design of more personalized diagnostic and therapeutic strategies in this group.

White matter changes in drug-naïve Parkinson's disease patients with impulse control & probable REM sleep behavior disorders.

BACKGROUND: According to epidemiological studies, Parkinson's disease (PD) patients with probable REM sleep behavior disorder (pRBD) are more prone to develop impulse control disorders (ICDs), which is shown to be present in drug-naïve PD patients, and vice versa. OBJECTIVES: To investigate white-matter integrity differences, with and without comorbid pRBD and ICDs. METHODS: 149 de-novo PD patients and 30 age- and gender-matched controls from the Parkinson's Progression Markers Initiative were studied. PD subjects were categorized into four groups with and without these comorbidities. We investigated the white matter integrity differences between these groups. RESULTS: PDs with only ICDs manifested greater fractional anisotropy (FA) and lower mean diffusivity (MD) in ipsilateral cerebellar connections when compared to controls and to Parkinson's with both comorbid disorders. In contrast, significantly lower FA and higher MD in the ipsilateral fornix-stria-terminalis was observed in PDs with only pRBD compared to controls and to PDs without either comorbid disorder. Also, PDs with only pRBD manifested greater FA in contralateral putamen when compared to controls. CONCLUSIONS: Our results suggest the presence of an underlying neural network in PDs with ICDs, particularly involving cerebellar connections, which makes the subjects susceptible to pRBD. Lower white-matter integrity in the fornix of PDs with only pRBD suggests a neuropathological pathway specific to sleep behavior disorder, independent of impulse control disorders. Greater white-matter integrity observed in PDs without comorbid ICDs, regardless of their comorbid pRBD status, might reflect compensatory mechanisms. Targeted therapies for this particular neuropathology may help prevent these comorbidities.