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Narcolepsy is mainly associated with excessive daytime sleepiness, but the characteristic feature is abnormal rapid eye movement (REM) sleep phenomena. REM sleep disturbances can manifest as cataplexy (in narcolepsy type 1), sleep paralysis, sleep-related hallucinations, REM sleep behavior disorder, abnormal dreams, polysomnographic evidence of REM sleep disruption with sleep-onset REM periods, and fragmented REM sleep. Characterization of REM sleep and related symptoms facilitates the differentiation of narcolepsy from other central hypersomnolence disorders and aids in distinguishing between narcolepsy types 1 and 2. A circuit comprising regions within the brainstem, forebrain, and hypothalamus is involved in generating and regulating REM sleep, which is influenced by changes in monoamines, acetylcholine, and neuropeptides. REM sleep is associated with brainstem functions, including autonomic control, and REM sleep disturbances may be associated with increased cardiovascular risk. Medications used to treat narcolepsy (and REM-related symptoms of narcolepsy) include stimulants/wake-promoting agents, pitolisant, oxybates, and antidepressants; hypocretin agonists are a potential new class of therapeutics. The role of REM sleep disturbances in narcolepsy remains an area of active research in pathophysiology, symptom management, and treatment. This review summarizes the current understanding of the role of REM sleep and its dysfunction in narcolepsy.

BACKGROUND AND OBJECTIVE: Parkinsonian disorders, including Parkinsons disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), exhibit overlapping early-stage symptoms, complicating definitive diagnosis despite heterogeneous cellular and regional pathophysiology. Additionally, the progression and the eventual conversion of prodromal conditions such as REM behavior disorder (RBD) to PD, MSA, or DLB remain challenging to predict. Extracellular vesicles (EVs) are small, membrane-enclosed structures released by cells, playing a vital role in communicating cell-state-specific messages. Due to their ability to cross the blood-brain barrier into the peripheral circulation, measuring biomarkers in blood-isolated speculative CNS enriched EVs has become a popular diagnostic approach. However, replication and independent validation remain challenging in this field. Here, we aimed to evaluate the diagnostic accuracy of speculative CNS-enriched EVs for parkinsonian disorders. METHODS: We conducted a PRISMA-guided systematic review and meta-analysis, covering 18 studies with a total of 1695 patients with PD, 253 with MSA, 21 with DLB, 172 with PSP, 152 with CBS, 189 with RBD, and 1288 HCs, employing either hierarchical bivariate models or univariate models based on study size. RESULTS: Diagnostic accuracy was moderate for differentiating patients with PD from HCs, but revealed high heterogeneity and significant publication bias, suggesting an inflation of the perceived diagnostic effectiveness. The bias observed indicates that studies with non-significant or lower effect sizes were less likely to be published. Although results for differentiating patients with PD from those with MSA or PSP and CBS appeared promising, their validity is limited due to the small number of involved studies coming from the same research group. Despite initial reports, our analyses suggest that using speculative CNS-enriched EV biomarkers may not reliably differentiate patients with MSA from HCs or patients with RBD from HCs, due to their lesser accuracy and substantial variability among the studies, further complicated by substantial publication bias. CONCLUSION: Our findings underscore the moderate, yet unreliable diagnostic accuracy of biomarkers in speculative CNS-enriched EVs in differentiating parkinsonian disorders, highlighting the presence of substantial heterogeneity and significant publication bias. These observations reinforce the need for larger, more standardized, and unbiased studies to validate the utility of these biomarkers but also call for the development of better biomarkers for parkinsonian disorders.

COVID-19 infection has resulted in a high prevalence of a post-infectious syndrome, known as post-acute sequelae of SARS-CoV-2 (PASC) or "Long COVID". PASC is a heterogeneous disease with a high prevalence of sleep disturbances, varying from an insomnia disorder to excessive daytime sleepiness. Patients seen in the Covid Survivorship Program at the Beth Israel Deaconess Medical Center Boston, USA, were screened for sleep disorders as part of a comprehensive multi-system evaluation. Those who screened positive were referred for a comprehensive sleep evaluation in a dedicated COVID-19-Sleep clinic, followed by diagnostic sleep testing and treatment. This report summarizes patients who completed an American Academy of Sleep Medicine (AASM) accredited facility-based diagnostic evaluation. International Classification of Sleep Disorders 3rd Edition-Revised criteria were met for all diagnoses. In 42 patients with PASC, five categories of sleep disorder syndromes were observed following a sleep clinic evaluation, including obstructive sleep apnea, chronic insomnia disorder, primary hypersomnia, REM behavior disorder (RBD), and new onset circadian phase delay. Seven patients met criteria for idiopathic hypersomnia, and two had narcolepsy type 2. RBD patients were infected in three different waves; circadian disturbance patients were all infected in the winter wave of 2020/21, and the primary hypersomnolence group occurred during all waves, predominantly the initial wave of 2020. A peculiar form of insomnia was a persistent loss of sleep regularity. Specific sleep symptoms/syndromes are reported in this select group of patients with PASC/Long Covid. As new onset sleep complaints are prevalent in PASC, we recommend a complete clinical and investigative sleep evaluation for persistent severe sleep symptoms following COVID-19 infection. • Sleep complaints in PASC are frequent, varying from insomnia to excessive daytime sleepiness. • Noted syndromes: sleep apnea, insomnia, primary hypersomnia, REM behavior disorder, and circadian phase delay. • All circadian disturbances patients were infected in the Winter 20/21 wave. • The response to therapy for hypersomnia and narcolepsy has so far been unremarkable. • Vaccination could have influenced the incidence of PACS patients and their sleep syndromes. [ABSTRACT FROM AUTHOR]

Identifying the properties of the rapid eye movement (REM) sleep circuitry and its relation to diseases has been challenging due to the neuronal heterogeneity of the brainstem. Here, we show in mice that neurons in the pontine sublaterodorsal tegmentum (SubLDT) that express corticotropin-releasing hormone-binding protein (Crhbp + neurons) and project to the medulla promote REM sleep. Within the medullary area receiving projections from Crhbp + neurons, neurons expressing nitric oxide synthase 1 (Nos1 + neurons) project to the SubLDT and promote REM sleep, suggesting a positively interacting loop between the pons and the medulla operating as a core REM sleep circuit. Nos1 + neurons also project to areas that control wide forebrain activity. Ablating Crhbp + neurons reduces sleep and impairs REM sleep atonia. In Parkinson's disease patients with REM sleep behavior disorders, CRHBP-immunoreactive neurons are largely reduced and contain pathologic α-synuclein, providing insight into the mechanisms underlying the sleep deficits characterizing this disease. [Display omitted] • Crhbp + SubLDT→Gi neurons promote REM sleep and muscle atonia • Nos1 + DPGi,Pr neurons promote REM sleep and project to areas regulating forebrain activity • The above 2 neuronal populations constitute a pontine-medullary loop circuit • CRHBP+ SubLDT neurons are lost in human patients with Parkinson's disease and RBD A neuronal circuit originating in the brainstem pons and medulla strongly induces REM sleep, even in awake mice. Moreover, a subpopulation of neurons within this circuit is lost in patients with Parkinson's disease, a neurodegenerative disease characterized by severe REM sleep abnormalities. [ABSTRACT FROM AUTHOR]

Objective: Multiple system atrophy (MSA) is commonly associated with rapid eye movement sleep behavior disorder (RBD). Research on the prevalence of RBD in MSA and its effects on MSA patients has yielded inconsistent results. Currently, there is only one meta-analysis discussing the prevalence of RBD in MSA, but no meta-analysis discussing the impact of RBD on MSA. Methods: A systematic review and meta-analysis was conducted by searching studies related to MSA and RBD in PubMed, Web of Science, Embase, and Cochrane databases. Data were pooled as necessary to calculate prevalence of RBD, odds ratio (OR), weighted mean differences (WMD) with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic. Results: The prevalence of polysomnography confirmed-RBD in MSA was 79.9% (95% CI, 68.8-89.3%) in a pooled sample of 598 subjects. Patients with MSA who had RBD were notably younger at examination than those without RBD (WMD -3.26 years, 95% CI -4.99 to -1.53), and the age of disease onset in MSA patients with RBD was significantly lower than in those without RBD (WMD -3.27, 95% CI -5.06 to -1.48). Additionally, RBD was more common among male patients with MSA compared to female patients (OR 2.11, 95% CI 1.31 to 3.39). MSA patients with RBD also exhibited significantly higher Unified Multiple System Atrophy Rating Scale (UMSARS) I and IV scores than those without RBD (WMD 2.99, 95% CI 0.10 to 4.88, and WMD 0.23, 95% CI 0.03 to 0.43). Conclusion: The prevalence of polysomnography-confirmed RBD in MSA is 79.9%. The prevalence in Asian population was lower than in Europe and America, which might be related to an underestimation in Asian populations. Additionally, patients with MSA and RBD tend to be younger at examination, have an earlier age of onset, and exhibit more severe disease manifestations compared to MSA patients without RBD. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusions Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) progress to a parkinsonian alpha‐synucleinopathy. However, time to phenoconversion shows great variation. The aim of this study was to investigate whether cholinergic and dopaminergic dysfunction in iRBD patients was associated with impending phenoconversion.Twenty‐one polysomnography‐confirmed iRBD patients underwent baseline 11C‐donepezil and 6‐Fluoro‐(18F)‐l‐3,4‐dihydroxyphenylalanine (18F‐DOPA) positron emission tomography (PET). Potential phenoconversion was monitored for up to 8 years. PET images were analysed according to patients' diagnoses after 3 and 8 years using linear regression. Time‐to‐event analysis was made with Cox regression, dividing patients into low and high tracer uptake groups.Follow‐up was accomplished in 17 patients. Eight patients progressed to either Parkinson's disease (n = 4) or dementia with Lewy bodies (n = 4), while nine remained non‐phenoconverters. Compared with non‐phenoconverters, 8‐year phenoconverters had lower mean 11C‐donepezil uptake in the parietal (p = 0.032) and frontal cortex (p = 0.042), whereas mean 11C‐donepezil uptake in 3‐year phenoconverters was lower in the parietal cortex (p = 0.005), frontal cortex (p = 0.025), thalamus (p = 0.043) and putamen (p = 0.049). Phenoconverters within 3 years and 8 years had lower 18F‐DOPA uptake in the putamen (p < 0.001). iRBD patients with low parietal 11C‐donepezil uptake had a 13.46 (95% confidence interval 1.42;127.21) times higher rate of phenoconversion compared with those with higher uptake (p = 0.023). iRBD patients with low 18F‐DOPA uptake in the most affected putamen were all phenoconverters with higher rate of phenoconversion (p = 0.0002).These findings suggest that cortical cholinergic dysfunction, particularly within the parietal cortex, could be a biomarker candidate for predicting short‐term phenoconversion in iRBD patients. This study aligns with previous reports suggesting dopaminergic dysfunction is associated with forthcoming phenoconversion. [ABSTRACT FROM AUTHOR]

• EEG patterns during RBD movements resemble those of voluntary movements during wakefulness. • EEG patterns preceding RBD movements show no differences regarding the presence or absence of PD. • Results suggest a main involvement of the cortex in the generation of the movements during REM sleep. Motor symptoms of Parkinson's disease improve during REM sleep behavior disorder movement episodes. Our aim was to study cortical activity during these movement episodes, in patients with and without Parkinson's disease, in order to investigate the cortical involvement in the generation of its electromyographic activity and its potential relationship with Parkinson's disease. We looked retrospectively in our polysomnography database for patients with REM sleep behavior disorder, analyzing fifteen patients in total, seven with idiopathic REM sleep behavior disorder and eight associated with Parkinson's disease. We selected segments of REM sleep with the presence of movements (evidenced by electromyographic activation), and studied movement-related changes in cortical activity by averaging the electroencephalographic signal (premotor potential) and by means of time/frequency transforms. We found a premotor potential and an energy decrease of alpha–beta oscillatory activity preceding the onset of electromyographic activity, together with an increase of gamma activity for the duration of the movement. All these changes were similarly present in REM sleep behavior disorder patients with and without Parkinson's disease. Movement-related changes in electroencephalographic activity observed in REM sleep behavior disorder are similar to those observed during voluntary movements, regardless of the presence of Parkinson's disease motor symptoms. These results suggest a main involvement of the cortex in the generation of the movements during REM sleep. [ABSTRACT FROM AUTHOR]

• Investigated the characteristics of EEG activity before dream enactment behaviors during REM sleep in patients with iRBD. • Before the behaviors, delta/gamma power increases and wide-range beta-band connectivity increases were observed. • These findings suggest distinct cortical activity patterns during dream enactment in iRBD. This study aimed to identify electroencephalogram correlates of dream enactment behaviors (DEBs) and elucidate their cortical dynamics in patients with isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). This cross-sectional study included 15 patients with iRBD. Two REM sleep periods in routine polysomnography were compared: the 60 s preceding the DEBs ("pre-representative behavior" [preR]), and the 60 s with the least submental electromyogram activity ("background" [BG]). Six EEG frequency bands and electrooculogram were analyzed; power spectra, coherence and phase-locking values in four 15-s periods were examined to assess trends. These indices were also compared between preR and BG. Compared with BG, significantly higher delta power in the F3 channel and gamma power in the F4 and O2 channels were observed during preR. For functional connectivity, the widespread beta-band connectivity was significantly increased during preR than BG. Before notable REM sleep behaviors, uneven distributed higher EEG spectral power in both very low and high frequencies, and increased wide-range beta band functional connectivity, were observed over 60 s, suggesting cortical correlates to subsequent DEBs. This study may shed light on the pathological mechanisms underlies RBD through the routine vPSG analysis, leading to detection of DEBs. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusions Lower urinary tract symptoms (LUTS) are frequently observed in patients with Parkinson's disease (PD), but the underlying mechanism remains elusive. The concept of “body‐first” and “brain‐first” subtypes in PD has been proposed, but the correlation of PD subtype with LUTS remains unclear. We aimed to investigate the disparities in urological dysfunctions between body‐first and brain‐first subtypes of PD using urodynamic studies (UDS).We reviewed patients with PD (disease duration <3 years) who had undergone UDS and completed urological questionnaires (Overactive Bladder Symptom Score [OABSS] and International Prostate Symptom Score [IPSS]) and a voiding diary. Patients were categorized as having body‐first or brain‐first PD based on cardiac sympathetic denervation (CSD) using cardiac meta‐iodobenzylguanidine (MIBG) uptake and the presence of rapid eye movement sleep behavior disorder (RBD), assessed using a questionnaire (PD with CSD and RBD indicating the body‐first subtype).A total of 55 patients with PD were categorized into body‐first PD (n = 37) and brain‐first PD (n = 18) groups. The body‐first PD group exhibited smaller voiding volume and first desire volume (FDV) than the brain‐first PD group (p < 0.05 in both). Also, the body‐first PD group had higher OABSS and IPSS scores, and higher prevalence of overactive bladder diagnosed by OABSS, compared to the brain‐first PD group. In multiple linear regression, cardiac MIBG uptake was positively correlated with FDV and voiding volume and negatively correlated with OABSS and IPSS (p < 0.05 in all).Patients with the body‐first PD subtype exhibited more pronounced overactive bladder symptoms and impaired storage function in the early stage of disease. Additionally, cardiac MIBG was significantly associated with urological dysfunction. [ABSTRACT FROM AUTHOR]

For decades the greatest goal of Parkinson’s disease (PD) research has often been distilled to the discovery of treatments that prevent the disease or its progression. However, until recently only the latter has been realistically pursued through randomized clinical trials of candidate disease-modifying therapy (DMT) conducted on individuals after they received traditional clinical diagnosis of PD (i.e., tertiary prevention trials). Now, in light of major advances in our understanding of the prodromal stages of PD, as well as its genetics and biomarkers, the first secondary prevention trials for PD are beginning. In this review, we take stock of DMT trials to date, summarize the breakthroughs that allow the identification of cohorts at high risk of developing a traditional diagnosis of PD, and describe key design elements of secondary prevention trials and how they depend on the prodromal stage being targeted. These elements address whom to enroll, what interventions to test, and how to measure secondary prevention (i.e., slowed progression during the prodromal stages of PD). Although these design strategies, along with the biological definition, subtype classification, and staging of the disease are evolving, all are driven by continued progress in the underlying science and integrated by a broad motivated community of stakeholders. While considerable methodological challenges remain, opportunities to move clinical trials of DMT to earlier points in the disease process than ever before have begun to unfold, and the prospects for PD prevention are nowtangible. [ABSTRACT FROM AUTHOR]

Parkinson's Disease (PD) body-first subtype is characterized by prodromal autonomic symptoms and REM sleep behavior disorder (RBD), symmetric dopaminergic degeneration, and increased risk of dementia. On the other hand, the PD brain-first subtype has fewer non-motor symptoms and a milder motor phenotype. The temporal relationship between RBD onset and motor symptoms onset may differentiate these two subtypes. We aimed to investigate electrocortical differences between brain-first and body-first PD patients. PD patients with an available routinely collected EEG were retrospectively selected. RBD was diagnosed using the RBD screening questionnaire (≥ 6). According to the onset of RBD patients were classified into PD-RBDpre (RBD onset before motor symptoms) and PD-RBDpost (RBD onset after motor symptoms). Patients without RBD were classified as PD-RBD-. Presence of Mild Cognitive Impairment (MCI) was diagnosed according to the MDS criteria. EEG Spectral analysis was performed in resting state by computing the Power Spectral Density (PSD) of site-specific signal epochs for the common frequency bands (delta, theta, alpha, beta). Thirty-eight PD-RBD-, 14 PD-RBDpre and 31 PD-RBDpost patients were recruited. Comparing both global and site-specific absolute values, we found a significant trend toward beta band reduction going from PD-RBD-, PD-RBDpost and PD-RBDpre. No significant differences were found between PD-RBDpost and PD-RBD- patients. PD-RBDpre patients may represent a different subset of patients as compared to patients without RBD, while patients with later onset have intermediate EEG spectral features. Quantitative EEG may provide new hints in PD subtyping. [ABSTRACT FROM AUTHOR]

An individual's quality of life is greatly affected by Parkinson's disease (PD), a prevalent neurological degenerative condition. Rapid eye movement (REM) sleep behavior disorder (RBD) is a prominent non-motor symptom commonly associated with PD. Previous studies have shown a close relationship between PD and RBD. In addition to being a prodromal symptom of PD, RBD has a major negative impact on the prognosis of PD patients. This intrinsic connection indicates that there is a bidirectional relationship between PD and RBD. This paper provides a comprehensive review of the pathological mechanism related to PD and RBD, including the α-synuclein pathological deposition, abnormal iron metabolism, neuroinflammation, glymphatic system dysfunction and dysbiosis of the gut microbiota. Increasing evidence has shown that RBD patients have the same pathogenic mechanisms that underlie PD, but relatively little research has been done on how RBD contributes to PD progression. Therefore, a more thorough investigation is warranted to characterise how RBD affects the course of PD, in order to prepare for future therapeutic trials. [ABSTRACT FROM AUTHOR]

Background: Using 11C‐(R)‐PK11195‐PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. Objectives: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. Methods: Fifteen iRBD patients previously scanned with 11C‐(R)‐PK11195 and 18F‐DOPA‐PET underwent repeat 18F‐DOPA‐PET after 3 years. 18F‐DOPA Ki changes from baseline were evaluated with volumes‐of‐interest and voxel‐based analyses. Results: Significant 18F‐DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11C‐(R)‐PK11195 binding at baseline was a predictor of 18F‐DOPA Ki reduction in left caudate (coef = −0.0426, P = 0.016). Conclusions: Subjects with increased baseline 11C‐(R)‐PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Gait disturbance is a vital characteristic of motor manifestation in α– synucleinopathies, especially Parkinson's disease. Subtle gait alterations are present in isolated rapid eye movement sleep behavior disorder (iRBD) patients before phenoconversion; it is yet unclear, if gait analysis may predict phenoconversion. Objective: To investigate subtle gait alterations and explore whether gait analysis using wearable sensors is associated with phenoconversion of iRBD to α-synucleinopathies. Methods: Thirty-one polysomnography-confirmed iRBD patients and 33 healthy controls (HCs) were enrolled at baseline. All participants walked for a minute while wearing 6 inertial sensors on bilateral wrists, ankles, and the trunk (sternal and lumbar region). Three conditions were tested: (i) normal walking, (ii) fast walking, and (iii) dual-task walking. Results: Decreased arm range of motion and increased gait variation (stride length, stride time and stride velocity) discriminate converters from HCs at baseline. After an average of 5.40 years of follow-up, 10 patients converted to neurodegenerative diseases (converters). Cox regression analysis showed higher value of stride length asymmetry under normal walking condition to be associated with an early conversion of iRBD to α– synucleinopathies (adjusted HR 4.468, 95% CI 1.088– 18.349, p = 0.038). Conclusions: Stride length asymmetry is associated with progression to α– synucleinopathies in patients with iRBD. Gait analysis with wearable sensors may be useful for screening, monitoring, and risk stratification for disease-modifying therapy trials in patients with iRBD. [ABSTRACT FROM AUTHOR]

Background: Rapid eye movement sleep behavior disorder (RBD) may precede or follow motor symptoms in Parkinson's disease (PD). While over 70% of idiopathic RBD cases phenoconvert within a decade, a small subset develops PD after a more extended period or remains nonconverted. These heterogeneous manifestations of RBD in PD prompt subtype investigations. Premotor RBD may signify "body-first" PD with bottom-up, symmetric synucleinopathy propagation. Objective: Explore brainstem and nigrostriatal monoaminergic degeneration pattern differences based on premotor RBD presence and duration in de novo PD patients. Methods: In a cross-sectional analysis of de novo PD patients (n = 150) undergoing FP-CIT PET and RBD Single-Question Screen, the cohort was categorized into groups with and without premotor RBD (PDRBD +/–), with further classification of PDRBD + based on a 10-year duration of premotor RBD. Analysis of FP-CIT binding in the striatum and pons, striatal asymmetry, and striatum-to-pons ratios compared patterns of nigrostriatal and brainstem monoaminergic degeneration. Results: PDRBD + exhibited more severe and symmetrical striatal dopaminergic denervation compared to PDRBD–, with the difference in severity accentuated in the least-affected hemisphere. The PDRBD +<10Y subgroup displayed the most prominent striatal symmetry, supporting a more homogeneous "body-first" subtype. Pontine uptakes remained lower in PDRBD + even after adjusting for striatal uptake, suggesting early degeneration of pontine monoaminergic nuclei. Conclusions: Premotor RBD in PD is associated with severe, symmetrical nigrostriatal and brainstem monoaminergic degeneration, especially in cases with PD onset within 10 years of RBD. This supports the concept of a "widespread, bottom-up" pathophysiological mechanism associated with premotor RBD in PD. [ABSTRACT FROM AUTHOR]

Background: Isolated Rapid Eye Movement (REM) sleep Behavior Disorder (iRBD) requires quantitative tools to detect incipient Parkinson's disease (PD). Methods: A motor battery was designed and compared with the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale part III (MDS‐UPDRS‐III) in people with iRBD and controls. This included two keyboard‐based tests (BRadykinesia Akinesia INcoordination tap test and Distal Finger Tapping) and two dual tasking tests (walking and finger tapping). Results: We included 33 iRBD patients and 29 controls. The iRBD group performed both keyboard‐based tapping tests more slowly (P < 0.001, P = 0.020) and less rhythmically (P < 0.001, P = 0.006) than controls. Unlike controls, the iRBD group increased their walking duration (P < 0.001) and had a smaller amplitude (P = 0.001) and slower (P = 0.007) finger tapping with dual task. The combination of the most salient motor markers showed 90.3% sensitivity for 89.3% specificity (area under the ROC curve [AUC], 0.94), which was higher than the MDS‐UPDRS‐III (minus action tremor) (69.7% sensitivity, 72.4% specificity; AUC, 0.81) for detecting motor dysfunction. Conclusion: Speed, rhythm, and dual task motor deterioration might be accurate indicators of incipient PD in iRBD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: This study aims to identify distinct microbial and functional biomarkers characteristic of body-first or brain-first subtypes of Parkinson's disease (PD). This could illuminate the unique pathogenic mechanisms within these subtypes. Methods: In this cross-sectional study, we classified 36 well-characterized PD patients into body-first, brain-first, or undetermined subtypes based on the presence of premotor REM sleep behavior disorder (RBD) and cardiac meta-iodobenzylguanidine (MIBG) uptake. We then conducted an in-depth shotgun metagenomic analysis of the gut microbiome for each subtype and compared the results with those from age- and sex-matched healthy controls. Results: Significant differences were found in the gut microbiome of body-first PD patients (n = 15) compared to both brain-first PD patients (n = 9) and healthy controls. The gut microbiome in body-first PD showed a distinct profile, characterized by an increased presence of Escherichia coli and Akkermansia muciniphila, and a decreased abundance of short-chain fatty acid-producing commensal bacteria. These shifts were accompanied by a higher abundance of microbial genes associated with curli protein biosynthesis and a lower abundance of genes involved in putrescine and spermidine biosynthesis. Furthermore, the combined use of premotor RBD and MIBG criteria was more strongly correlated with these microbiome differences than the use of each criterion independently. Conclusions: Our findings highlight the significant role of dysbiotic and pathogenic gut microbial alterations in body-first PD, supporting the body-first versus brain-first hypothesis. These insights not only reinforce the gut microbiome's potential as a therapeutic target in PD but also suggest the possibility of developing subtype-specific treatment strategies.