REM and NREM Sleep Parasomnia in Anti-NMDA Receptor Encephalitis.

OBJECTIVES: Encephalitis with anti-N-methyl-d-aspartate receptor antibodies (anti-NMDARe) is a rare disorder characterized by cognitive impairment, psychosis, seizures, and abnormal movements. Abnormal behaviors during REM sleep have not been described in anti-NMDARe. METHODS: Patients were monitored by video-polysomnography on a first night followed by multiple sleep latency tests and 18 hours of bed rest. RESULTS: Two patients with anti-NMDARe developed during the acute and postacute phase parasomnias including REM sleep behavior disorder and continuous finalistic quiet gesturing during a mixed N2/R sleep. The parasomnia disorder was improved by gabapentin and clonazepam. DISCUSSION: Video-polysomnography avoids misdiagnosing these parasomnia behaviors for seizure or movement disorders and allows adequate treatment.

Whole brain pattern of iron accumulation in REM sleep behavior disorder.

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.

Glutamate Signaling in Patients With Parkinson Disease With REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Clinical heterogeneity of patients with Parkinson disease (PD) is well recognized. PD with REM sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher nonmotor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning imbalances in neurotransmitter systems remain elusive. METHODS: Combining magnetic resonance (MR) spectroscopy and [11C]ABP688 PET on a PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with PD. Patients were grouped according to their RBD status in overnight video-polysomnography and compared with age-matched and sex-matched healthy control (HC) participants. Total volumes of distribution (VT) of [11C]ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between 45 and 60 minutes of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single-voxel stimulated echo acquisition mode MR spectroscopy of the left basal ganglia. RESULTS: We measured globally elevated VT of [11C]ABP688 in 16 patients with PD and RBD compared with 17 patients without RBD and 15 HC participants (F(2,45) = 5.579, p = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VT of [11C]ABP688. VT of [11C]ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600, p = 0.023) and with dopaminergic treatment response in patients with PD (F(1,30) = 5.823, p = 0.022). DISCUSSION: Our results suggest that patients with PD and RBD exhibit altered glutamatergic signaling indicated by higher VT of [11C]ABP688 despite unaffected glutamate levels. The imbalance of glutamate receptors and MR spectroscopy glutamate metabolite levels indicates a novel mechanism contributing to the heterogeneity of PD and warrants further investigation of drugs targeting mGluR5.

Biomarkers of neurodegeneration in isolated and antidepressant-related rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: This study compared the features of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and antidepressant-related REM sleep behaviour disorder (RBD) with the aim of highlighting markers that might distinguish the two entities. METHODS: The observational cohort study included RBD patients with and without antidepressant use (antiD+ and antiD- patients, respectively), without cognitive impairment and parkinsonism. Clinical features of RBD, subtle motor and non-motor symptoms of parkinsonism, sleep architecture, REM atonia index, dopamine transporter-single photon emission computed tomography (DAT-SPECT) and skin biopsies for the intraneuronal alpha-synuclein (α-syn), were evaluated in the baseline work-up. RESULTS: Thirty-nine patients, 10 antiD+ and 29 antiD-, were included. AntiD+ patients (more frequently female) reported more psychiatric symptoms, less violent dream enactment, and less frequent hyposmia. Dermal α-syn was detected in 93.1% of antiD- versus 30% of antiD+ patients (p = 0.00024). No differences appeared in other motor and non-motor symptoms, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score, DAT-SPECT, or polysomnographic features. CONCLUSIONS: Patients with antidepressant-related RBD have clinical and neuropathological features suggesting a lower risk of evolution than those with iRBD.

α-synuclein antibody 5G4 identifies idiopathic REM-sleep behavior disorder in abdominal skin biopsies.

INTRODUCTION: Idiopathic REM-sleep behavior disorder (iRBD) is considered the most specific prodromal marker of Parkinson's disease (PD). With the need to improve early detection of prodromal α-synucleinopathies, several methods to identify peripheral α-synuclein (α-syn) pathology have been exploited in manifest and prodromal PD with varying diagnostic accuracy. Recently, a disease specific 5G4 antibody has been evaluated in skin biopsies of manifest PD patients. The aim of our study was to analyze the 5G4 α-syn immunoreactivity in skin biopsies of deeply phenotyped subjects with iRBD and controls. METHODS: The study cohort consisted of 28 patients with PD, 24 subjects with iRBD and 27 healthy controls, recruited from the CEGEMOD, PDBIOM and PARCAS cohorts. All subjects were deeply phenotyped and assessed for prodromal PD (pPD) probability based on MDS research criteria. Abdominal skin punch biopsies were processed and stained using a conformation specific 5G4 α-syn antibody as well as axonal markers SMI-31 and S100. RESULTS: 5G4-positivity was identified in 23/28 PD patients, 20/24 iRBD subjects and 8/27 healthy controls. Compared to healthy controls, sensitivity and specificity reached 83.33 % and 70.37 % for iRBD; and 82.14 % and 70.37 % for PD, respectively. 5G4-positivity rate in our study was irrespective of the calculated pPD probability of iRBD subjects. CONCLUSIONS: This work establishes the diagnostic yield of conformation specific 5G4 α-syn antibody testing in skin biopsies of subjects with pPD, specifically iRBD. The diagnostic accuracy for this method seems to be similar for both manifest and prodromal PD and is not dependent on the pPD probability ratios.

Impaired Mitochondrial Respiration in REM-Sleep Behavior Disorder: A Biomarker of Parkinson's Disease?

BACKGROUND: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is associated with prodromal Parkinson's disease (PD), but the mechanisms linking phenoconversion of iRBD to PD have not yet been clarified. Considering the association between mitochondrial dysfunction and sleep disturbances in PD, we explored mitochondrial activity in fibroblasts derived from iRBD patients to identify a biochemical profile that could mark the presence of impending neurodegeneration. METHODS: The study involved 28 participants, divided into three groups: patients diagnosed with iRBD, PD patients converted from iRBD (RBD-PD), and healthy controls. We performed a comprehensive assessment of mitochondrial function, including an examination of mitochondrial morphology, analysis of mitochondrial protein expression levels by western blot, and measurement of mitochondrial respiration using the Seahorse XFe24 analyzer. RESULTS: In basal conditions, mitochondrial respiration did not differ between iRBD and control fibroblasts, but when cells were challenged with a higher energy demand, iRBD fibroblasts exhibited a significant (P = 0.006) drop in maximal and spare respiration compared to controls. Interestingly, RBD-PD patients showed the same alterations with a further significant reduction in oxygen consumption linked to adenosine triphosphate production (P = 0.032). Moreover, RBD-PD patients exhibited a significant decrease in protein levels of complexes III (P = 0.02) and V (P = 0.002) compared to controls, along with fragmentation of the mitochondrial network. iRBD patients showed similar, but milder alterations. CONCLUSIONS: Altogether, these findings suggest that mitochondrial dysfunctions in individuals with iRBD might predispose to worsening of the bioenergetic profile observed in RBD-PD patients, highlighting these alterations as potential predictors of phenoconversion to PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Subregional analysis of striatum iron in Parkinson's disease and rapid eye movement sleep behaviour disorder.

The loss of dopamine in the striatum underlies motor symptoms of Parkinson's disease (PD). Rapid eye movement sleep behaviour disorder (RBD) is considered prodromal PD and has shown similar neural changes in the striatum. Alterations in brain iron suggest neurodegeneration; however, the literature on striatal iron has been inconsistent in PD and scant in RBD. Toward clarifying pathophysiological changes in PD and RBD, and uncovering possible biomarkers, we imaged 26 early-stage PD patients, 16 RBD patients, and 39 age-matched healthy controls with 3 T MRI. We compared mean susceptibility using quantitative susceptibility mapping (QSM) in the standard striatum (caudate, putamen, and nucleus accumbens) and tractography-parcellated striatum. Diffusion MRI permitted parcellation of the striatum into seven subregions based on the cortical areas of maximal connectivity from the Tziortzi atlas. No significant differences in mean susceptibility were found in the standard striatum anatomy. For the parcellated striatum, the caudal motor subregion, the most affected region in PD, showed lower iron levels compared to healthy controls. Receiver operating characteristic curves using mean susceptibility in the caudal motor striatum showed a good diagnostic accuracy of 0.80 when classifying early-stage PD from healthy controls. This study highlights that tractography-based parcellation of the striatum could enhance sensitivity to changes in iron levels, which have not been consistent in the PD literature. The decreased caudal motor striatum iron was sufficiently sensitive to PD, but not RBD. QSM in the striatum could contribute to development of a multivariate or multimodal biomarker of early-stage PD, but further work in larger datasets is needed to confirm its utility in prodromal groups.

Neurofilament Light Protein Predicts Disease Progression in Idiopathic REM Sleep Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is increasingly recognized as a manifestation preceding the α-synucleinopathies like Parkinson's disease (PD). Neurofilament light chain (NfL) have been reported to be higher in synucleinopathies as a sign of neurodegeneration. OBJECTIVE: To evaluate whether plasma NfL is valuable in reflecting cognitive and motor status in iRBD and PD with a premorbid history of RBD (PDRBD), and predicting disease progression in iRBD. METHODS: Thirty-one patients with iRBD, 30 with PDRBD, and 18 healthy controls were included in the cross-sectional and prospective study. Another cohort from the Parkinson's Progression Markers Initiative (PPMI) dataset was enrolled for verification analysis. All patients received evaluations of cognitive, motor, and autonomic function by a battery of clinical tests at baseline and follow-up. Blood NfL was measured by the Quanterix Simoa HD-1. RESULTS: In our cohort, 26 patients with iRBD completed the follow-up evaluations, among whom eight (30.8%) patients displayed phenoconversion. Baseline plasma NfL cutoff value of 22.93 pg/mL performed best in distinguishing the iRBD converters from non-converters (sensitivity: 75.0%, specificity: 83.3%, area under the curve: 0.84). Cognitive and motor function were significantly correlated with NfL levels in PDRBD (correlation coefficients: -0.379, 0.399; respectively). Higher baseline NfL levels in iRBD were significantly associated with higher risks for cognitive, motor, autonomic function progression, and phenoconversion at follow-up (hazard ratios: 1.069, 1.065, 1.170, 1.065; respectively). The findings were supported by the PPMI dataset. CONCLUSION: Plasma NfL is valuable in reflecting disease severity of PDRBD and predicting disease progression and phenoconversion in iRBD.

Misfolded α-Synuclein Assessment in the Skin and CSF by RT-QuIC in Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Real-time quaking-induced conversion (RT-QuIC) assay detects misfolded α-synuclein (AS) in the skin and CSF of patients with the synucleinopathies Parkinson disease and dementia with Lewy bodies. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of these synucleinopathies. We aimed to compare the ability of RT-QuIC to identify AS in the skin and CSF of patients with IRBD. METHODS: This was a cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. Three-millimeter skin punch biopsies were obtained bilaterally in the cervical region from dorsal C7 and C8 dermatomes and in distal legs. RT-QuIC assessed AS in these 6 skin sites and the CSF. RESULTS: We recruited 91 patients with IRBD and 41 controls. In the skin, sensitivity to detect AS was 76.9% (95% CI 66.9-85.1), specificity 97.6% (95% CI 87.1-99.9) positive predictive value 98.6% (95% CI 91.0-99.8), negative predictive value 65.6% (95% CI 56.6-73.6), and accuracy 83.3% (95% CI 75.9-89.3). In the CSF, the sensitivity was 75.0% (95% CI 64.6-83.6), the specificity was 97.5% (95% CI 86.8-99.9), the positive predictive value was 98.5% (95% CI 90.5-99.8), the negative predictive value was 63.9% (95% CI 55.2-71.9), and the accuracy was 82.0% (95% CI 74.3-88.3). Results in the skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC AS-positive patients had a higher likelihood ratio of prodromal Parkinson disease (p < 0.001) and showed more frequently hyposmia (p < 0.001), dopamine transporter imaging single-photon emission CT deficit (p = 0.002), and orthostatic hypotension (p = 0.014). No severe or moderate adverse effects were reported. There was no difference between the percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% vs 17.2%; p = 0.053). One hundred and ten (83%) and 104 (80%) participants, respectively, stated they would accept to undergo skin biopsy and lumbar puncture again for research purposes. DISCUSSION: Our study in IRBD shows that (1) RT-QuIC detects AS in the skin and CSF with similar high sensitivity, specificity, and agreement, (2) AS RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and (3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. RT-QuIC in the skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting AS in IRBD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that RT-QuIC-detected AS in the skin and CSF distinguishes patients with IRBD from controls.

Dermal Real-Time Quaking-Induced Conversion Is a Sensitive Marker to Confirm Isolated Rapid Eye Movement Sleep Behavior Disorder as an Early α-Synucleinopathy.

BACKGROUND: Skin biopsy is a potential tool for the premortem confirmation of an α-synucleinopathy. OBJECTIVE: The aim was to assess the aggregation assay real-time quaking-induced conversion (RT-QuIC) of skin biopsy lysates to confirm isolated rapid eye movement sleep behavior disorder (iRBD) as an α-synucleinopathy. METHODS: Skin biopsies of patients with iRBD, Parkinson's disease (PD), and controls were analyzed using RT-QuIC and immunohistochemical detection of phospho-α-synuclein. RESULTS: α-Synuclein aggregation was detected in 97.4% of iRBD patients (78.4% of iRBD biopsies), 87.2% of PD patients (70% of PD biopsies), and 13% of controls (7.9% of control biopsies), with a higher seeding activity in iRBD compared to PD. RT-QuIC was more sensitive but less specific than immunohistochemistry. CONCLUSIONS: Dermal RT-QuIC is a sensitive method to detect α-synuclein aggregation in iRBD, and high seeding activity may indicate a strong involvement of dermal nerve fibers in these patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Isolated dream-enactment behaviours as a prodromal hallmark of rapid eye movement sleep behaviour disorder.

Recurrent dream-enactment behaviours (DEB) and rapid eye movement (REM) sleep without atonia (RSWA) are two diagnostic hallmarks of REM sleep behaviour disorder (RBD), a specific prodrome of α-synucleinopathy. Whilst isolated RSWA (without DEB) was suggested as a prodrome of RBD, the implication of 'isolated' recurrent DEB remains under-investigated. In this cross-sectional study, we sought to investigate neurodegenerative markers amongst the first-degree relatives (FDRs, aged >40 years) of patients with RBD who underwent clinical assessment for DEB, neurodegenerative markers, and video-polysomnography assessment. Isolated recurrent DEB was defined as: (i) three or more episodes of DEB, (ii) had a DEB episode in the past 1 year, and (iii) subthreshold RSWA. We identified 29 FDRs (mean [SD] age 53.4 [8.3] years, 55.2% male) with isolated recurrent DEB and 98 age and sex-matched FDRs as controls. Isolated DEB was associated with nightmare (27.6% versus 11.2%, p = 0.02), and the DEB group had a higher rate of current smoking (27.6% versus 3.1%, p = 0.006), type 2 diabetes mellitus (24.1% versus 10.2%, p = 0.003), anxiety disorder (24.1% versus 11.2%, p = 0.02), and constipation (hard lump of stool, 31.0% versus 7.1%, p < 0.001) than the control group. The present findings revealed that family relatives of patients with RBD with isolated recurrent DEB have increased risk of RBD and neurodegenerative features, which adds to the emerging data that isolated DEB is a prodromal feature of RBD and α-synucleinopathy neurodegeneration.

Sleep disorders and polysomnography findings in patients with autoimmune encephalitis.

BACKGROUND: Sleep disorders in patients with autoimmune encephalitis (AE) are increasingly reported. Early recognition and treatment have significant importance regarding the potential of sleep disorders' effect on morbidity and even mortality. There are a limited number of studies related to polysomnography (PSG) in these patients. Here, we report the clinical and PSG data of patients with AE and sleep disorders, with a particular interest in sleep-related breathing disorders (SRBD). METHODS: Seventeen patients with diagnosed AE and acute or subacute onset sleep complaints who underwent video-electroencephalography-PSG recordings in our tertiary center were investigated. RESULTS: The mean age was 50, with eight females and nine males. The detected antibodies were against leucine-rich glioma-inactivated 1(LGI-1) in 6, anti-contactin-associated protein-2(CASPR2) in 3, voltage-gated potassium channel complex antigens(VGKC) in 1, anti-glycine in 1, dipeptidyl-peptidase-like protein-6(DPPX) in 1, anti-Hu in 1, and anti-amphiphysin in 1. All commercially available and known autoimmune encephalitis-related antibodies were negative in 3 of the patients. Final diagnosis after PSG was circadian rhythm sleep disorder (n = 3), periodic limb movement disorder (n = 3), insomnia (n = 5), central apnea with or without Cheyne-Stokes breathing (CSB) (n = 4), obstructive sleep apnea (OSA) (n = 4), non-rapid eye movement (NREM) and REM parasomnia (n = 8), faciobrachial dystonic seizures (n = 2), and subclinical seizures (n = 1). Sleep microstructure was disrupted in 9, REM periods without atonia occurred in 4, and brief sleep fragments consisting of theta activity interspersed with faster rhythms existed in 7 patients. Nearly half of our patients (47%) had SRBD, and the mean apnea-hypopnea index (AHI) was 14. CONCLUSIONS: Sleep disorders are frequent and essential components of AEs. Systematic clinical questionnaires and routine PSG assessments would significantly impact the correct diagnosis and proper treatment of SRBD and the overall prognosis of AE.

Dream-enactment behaviours during the COVID-19 pandemic: an international COVID-19 sleep study.

There has been increasing concern about the long-term impact of coronavirus disease 2019 (COVID-19) as evidenced by anecdotal case reports of acute-onset parkinsonism and the polysomnographic feature of increased rapid eye movement sleep electromyographic activity. This study aimed to determine the prevalence and correlates of dream-enactment behaviours, a hallmark of rapid eye movement sleep behaviour disorder, which is a prodrome of α-synucleinopathy. This online survey was conducted between May and August 2020 in 15 countries/regions targeting adult participants (aged ≥18 years) from the general population with a harmonised structured questionnaire on sleep patterns and disorders, COVID-19 diagnosis and symptoms. We assessed dream-enactment behaviours using the Rapid Eye Movement Sleep Behaviour Disorder Single-Question Screen with an additional question on their frequency. Among 26,539 respondents, 21,870 (82.2%) answered all items that were analysed in this study (mean [SD] age 41.6 [15.8] years; female sex 65.5%). The weighted prevalence of lifetime and weekly dream-enactment behaviours was 19.4% and 3.1% and were found to be 1.8- and 2.9-times higher in COVID-19-positive cases, respectively. Both lifetime and weekly dream-enactment behaviours were associated with young age, male sex, smoking, alcohol consumption, higher physical activity level, nightmares, COVID-19 diagnosis, olfactory impairment, obstructive sleep apnea symptoms, mood, and post-traumatic stress disorder features. Among COVID-19-positive cases, weekly dream-enactment behaviours were positively associated with the severity of COVID-19. Dream-enactment behaviours are common among the general population during the COVID-19 pandemic and further increase among patients with COVID-19. Further studies are needed to investigate the potential neurodegenerative effect of COVID-19.

Risk factors for rapid eye-movement sleep-related behavioral disorders (RBDs): A systematic review and a meta-analysis.

OBJECTIVE: The present study aimed to systematically analyze the risk factors for RBD. METHODS: A systematic review and meta-analysis of case-control studies, cohort studies, and cross-sectional studies derived from the articles published in eight electronic databases before December 1, 2021. The primary outcome was the odds ratio (OR) and 95% confidence interval (95% CI), and heterogeneity was quantified using I2. Subgroup analyses and meta-regression were used to explore sources of heterogeneity. Egger's test and sensitivity analysis were performed. The PROSPERO ID number of the present study is CRD42021293942. RESULTS: We identified 26 studies (44,230 subjects) among 2022 citations, and 13 factors were considered. Male sex (OR = 1.36, 95% CI = 1.13-1.64), smoking (OR = 1.37, 95% CI: 1.26-1.50), depression (OR = 2.06, 95% CI = 1.66-2.56), antidepressant use (OR = 2.36, 95% CI = 1.98-2.82), duration of neuropsychiatric disorders(OR = 1.43, 95% CI = 1.13-1.73), levodopa equivalent daily dose (LEDD, OR = 60.15, 95% CI = 23.95-96.35) and observable motor dysfunction (OR = 2.43, 95% CI = 0.65-4.22) were associated with a higher risk of RBD. Tertiary education and above (OR = 0.58, 95% CI = 0.35-0.96) was associated with a lower RBD risk. Men (OR = 1.40, 95% CI: 1.10-1.78, I2 = 0%, P = 0.005) and older individual (OR = 2.73, 95% CI: 1.03-4.43, I2 = 60%, P = 0.002) were more likely to have iRBD. CONCLUSION: Six modifiable risk factors and one protective factor were associated with RBD. Further research is required to understand the mechanisms and to develop preventative strategies.

Relationship between Substantia Nigra Neuromelanin Imaging and Dual Alpha-Synuclein Labeling of Labial Minor in Salivary Glands in Isolated Rapid Eye Movement Sleep Behavior Disorder and Parkinson's Disease.

We investigated the presence of misfolded alpha-Synuclein (α-Syn) in minor salivary gland biopsies in relation to substantia nigra pars compacta (SNc) damage measured using magnetic resonance imaging in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and Parkinson's disease (PD) as compared to healthy controls. Sixty-one participants (27 PD, 16 iRBD, and 18 controls) underwent a minor salivary gland biopsy and were scanned using a 3 Tesla MRI. Deposits of α-Syn were found in 15 (55.6%) PD, 7 (43.8%) iRBD, and 7 (38.9%) controls using the anti-aggregated α-Syn clone 5G4 antibody and in 4 (14.8%) PD, 3 (18.8%) iRBD and no control using the purified mouse anti-α-Syn clone 42 antibody. The SNc damages obtained using neuromelanin-sensitive imaging did not differ between the participants with versus without α-Syn deposits (irrespective of the antibodies and the disease group). Our study indicated that the α-Syn detection in minor salivary gland biopsies lacks sensitivity and specificity and does not correlate with the SNc damage, suggesting that it cannot be used as a predictive or effective biomarker for PD.

Inflammatory markers and depression in Parkinson's disease: a systematic review.

BACKGROUND: Parkinson's disease (PD) patients experience non-motor symptoms (NMS), which may appear before motor manifestations. The most common NMS is depression, affecting about 30-40% of PD patients. Both PD and depression are associated with an increased inflammatory burden, with studies showing elevation of diverse inflammatory markers in patients with both conditions. METHODS: A systematic review was conducted in PubMed and PsycINFO databases to investigate what inflammatory markers are associated with PD depression (PDD). Only studies in English that measured inflammatory markers and analyzed against depression scores in PD patients were included. RESULTS: A total of 1132 articles were retrieved, and 14 entries were found to be eligible. Twelve were cross-sectional studies, one was a cohort, and one was a non-randomized controlled trial. IL-17A was the only marker strongly associated with PDD, while studies assessing sIL-2R and serum amyloid A found a moderate correlation. C-reactive protein, IL-10, tumor necrosis factor-α, monocyte chemoattractant protein-1, and IL-6 yielded conflicting results. Their possible roles in PDD are discussed. PDD was also related to longer disease duration and other NMS, such as anxiety, fatigue, dementia, REM sleep behavior disorder, and autonomic dysfunction. CONCLUSION: We suggest that these markers may be used for distinguishing isolated depression from that related to neurodegeneration, especially in individuals that concurrently present with other known prodromal symptoms of PD and other α-synucleinopathies. However, future prospective studies are warranted to confirm this hypothesis.

Evaluation of iron overload in nigrosome 1 via quantitative susceptibility mapping as a progression biomarker in prodromal stages of synucleinopathies.

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies, such as Parkinson's disease (PD), which are characterized by the loss of dopaminergic neurons in substantia nigra, associated with abnormal iron load. The assessment of presymptomatic biomarkers predicting the onset of neurodegenerative disorders is critical for monitoring early signs, screening patients for neuroprotective clinical trials and understanding the causal relationship between iron accumulation processes and disease development. Here, we used Quantitative Susceptibility Mapping (QSM) and 7T MRI to quantify iron deposition in Nigrosome 1 (N1) in early PD (ePD) patients, iRBD patients and healthy controls and investigated group differences and correlation with disease progression. We evaluated the radiological appearance of N1 and analyzed its iron content in 35 ePD, 30 iRBD patients and 14 healthy controls via T2*-weighted sequences and susceptibility (χ) maps. N1 regions of interest (ROIs) were manually drawn on control subjects and warped onto a study-specific template to obtain probabilistic N1 ROIs. For each subject the N1 with the highest mean χ was considered for statistical analysis. The appearance of N1 was rated pathological in 45% of iRBD patients. ePD patients showed increased N1 χ compared to iRBD patients and HC but no correlation with disease duration, indicating that iron load remains stable during the early stages of disease progression. Although no difference was reported in iron content between iRBD and HC, N1 χ in the iRBD group increases as the disease evolves. QSM can reveal temporal changes in N1 iron content and its quantification may represent a valuable presymptomatic biomarker to assess neurodegeneration in the prodromal stages of PD.

Association between probable REM sleep behavior disorder and increased dermal alpha-synuclein deposition in Parkinson's disease.

INTRODUCTION: Many patients with Parkinson's disease suffer from REM sleep behavior disorder, potentially preceding the onset of motor symptoms. Phospho-alpha-synuclein is detectable in skin biopsies of patients with isolated REM sleep behavior disorder several years prior to the onset of manifest PD, but information on the association between dermal phospho-alpha-synuclein deposition and REM sleep behavior disorder in patients with manifest PD is limited. We therefore aimed to investigate the alpha-synuclein burden in dermal peripheral nerve fibers in patients with Parkinson's disease with and without REM sleep behavior disorder. METHODS: Patients with Parkinson's disease (n = 43) who had undergone skin biopsy for the immunohistochemical detection of phosphorylated alpha-synuclein were screened for REM sleep behavior disorder using RBDSQ and Mayo Sleep Questionnaire. Skin biopsies from 43 patients with isolated polysomnography-confirmed REM sleep behavior disorder were used as comparators. RESULTS: Dermal alpha-synuclein deposition was more frequently found (81.8% vs. 52.4%, p = 0.05) and was more abundant (p = 0.01) in patients with Parkinson's disease suffering from probable REM sleep behavior disorder compared to patients without REM sleep behavior disorder and was similar to patients with isolated REM sleep behavior disorder (79.1%). CONCLUSION: The phenotype of REM sleep behavior disorder is associated with high amounts of dermal alpha-synuclein deposition, demonstrating a strong involvement of peripheral nerves in patients with this non-motor symptom and may argue in favor of REM sleep behavior disorder as an indicator of a "body-predominant" subtype of Parkinson's disease.

REM sleep behavior disorder as a complex condition with heterogeneous underlying disorders: clinical management and prognostic implications [Commentary].

PURPOSE: To review how REM sleep behavior disorder (RBD) is a complex condition with heterogeneous underlying disorders; and to review clinical management issues and prognostic implications. METHODS: PubMed literature search and contents from the first textbook of RBD (2018). RESULTS: RBD, with its core objective diagnostic feature of REM-without-atonia (RWA) documented by video-polysomnography, can emerge during the entire lifespan, and can initially present as an idiopathic (isolated) condition (iRBD), or can be associated with a broad spectrum of disorders including narcolepsy, alpha-synuclein neurodegenerative disorders (esp. Parkinson's disease [PD] and dementia with Lewy bodies [DLB]), paraneoplastic neurological syndromes and autoimmune disorders, CNS lesions (e.g., tumors, stroke), other neurological disorders, psychiatric disorders (PTSD, mood disorders), can be triggered by antidepressant/other medications, and can emerge acutely with drug withdrawal states, toxic-metabolic states, etc. Important clinical issues include the evolution of iRBD to PD/DLB in most middle-aged and older patients over a period of years to several decades, with compelling prognostic implications, along with the hope of enrolling these patients in future clinical trials to test promising disease-modifying therapies. Also, the strong link of RBD with narcolepsy needs further investigation. Parasomnia overlap disorder involves RBD and NREM parasomnias that can be idiopathic or linked with a broad range of clinical disorders. RBD usually responds to therapy consisting mainly of melatonin and/or clonazepam at bedtime. The complex associations of RBD with OSA are being increasingly investigated. RBD mimics with dream-enactment need to be recognized for diagnostic and management purposes, including severe OSA, NREM parasomnias, PLMD, nocturnal seizures, and other conditions. CONCLUSIONS: The clinical and research RBD fields span across the disciplines of neurology, pulmonary, psychiatry, psychology, and pediatric sleep medicine, along with physical medicine and rehabilitation medicine, other allied disciplines, and the basic and clinical neurosciences.