Idiopathic REM Sleep Behavior Disorder Research Articles

Automatic quantification of REM sleep without atonia reliably identifies patients with REM sleep behavior disorder: a possible screening tool?

REM Sleep Behavior Disorder (RBD) is characterized by absence of physiological muscle atonia during REM sleep (REM sleep without atonia, RWA). Nigro-striatal dopaminergic impairment is a feature of Parkinson disease (PD) and can be identified in prodromal stages as well, such as idiopathic RBD (iRBD). Aims of this study are to explore the efficacy of an automatic RWA quantification in identifying RBD patients and the correlation between RWA and nigro-striatal dopaminergic function. Forty-five iRBD, 46 PD with RBD, 24 PD without RBD patients and 11 healthy controls were enrolled in the Genoa Center (group A) and 25 patients with iRBD (group B) were enrolled in the Danish Center. Group A underwent brain [123I]FP-CIT-SPECT and group B underwent brain [18F]PE2I-PET as measures of nigro-striatal dopaminergic function. Chin muscle activity was recorded in all subjects and analyzed by applying a published automatic algorithm. Correlations between RWA and nigro-striatal dopaminergic function were explored. The automatic quantification of RWA significantly differentiated RBD from non-RBD subjects (AUC = 0.86), although with lower accuracy compared with conventional visual scoring (AUC = 0.99). No significant correlation was found between RWA and nigro-striatal dopaminergic function. The automatic quantification of RWA is a reliable tool to identify subjects with RBD and may be used as a first-line screening tool, but without correlations with nigro-striatal dopaminergic functioning.

Cortical activation in REM behavior disorder mimics voluntary movement. An electroencephalography study

ObjectivesMotor 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. MethodsWe 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. ResultsWe 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. ConclusionsMovement-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. SignificanceThese results suggest a main involvement of the cortex in the generation of the movements during REM sleep.

The relationship between rapid eye movement electromyogram activity and sleep stability in rapid eye movement sleep behavior disorder

Objective: To investigate the relationship between the types of electromyogram (EMG) activity and sleep stability during rapid eye movement (REM) in patients with rapid eye movement sleep behavior disorder(RBD). Methods: One hundred and three patients with RBD who met the inclusion and exclusion criteria at the Second Affiliated Hospital of Air Force Military Medical University from January 2017 to December 2019 were retrospectively analyzed. The general situation, clinical symptoms, sleep and emotion questionnaires and nocturnal PSG data were collected. According to the different proportions of tonic and phasic EMG activity, the group with a higher proportion of tonic EMG than phasic EMG was defined as the tonic dominant group, and the group with a higher proportion of phasic EMG than tonic was defined as the phasic dominant group. The sleep instability index was calculated according to the ratio of the number of transitions from sleep to wakefulness to the total sleep time of each sleep stage. Multiple linear regression was used to explore the relationship between REM EMG activity and sleep instability index. Results: A total of 35 idiopathic RBD (iRBD) patients were included, aged(54.5±18.2)years, with 17 males and 18 females. There were 27 RBD with Parkinson's disease (PD), with an average age of (59.4±7.9)years, including 17 males and 10 females. Additionally, there were 41 RBD patients with narcolepsy, aged (21.2±13.2)years, consisting of 22 males and 19 females. Both iRBD and RBD patients with PD had lower objective total sleep time, sleep latency, sleep efficiency, wake time after sleep onset and the percentage of N3 sleep compared to RBD with episodic sleep disorder (all P<0.05). N1-W index[M(Q1, Q3),10.6 (6.5, 16.9)/h vs 7.3 (4.7, 10.5)/h], N2-W index [4.0 (2.2, 5.6)/h vs 2.3 (1.5, 3.9)/h], NREM-W index [ (5.8±2.9)/h vs (4.5±3.2)/h] and REM-W index[ 3.9 (1.9, 7.3)/h vs 2.7 (1.0, 4.0)/h] in the phasic dominant group were higher than those in the tonic dominant group. After adjusting for confounding factors, the effect of phasic EMG dominant group on REM-W was higher than that in the tonic dominant group (β=2.05, 95%CI: 0.09-3.26, P=0.012). Conclusion: In RBD patients, the phasic EMG activity has a significant impact on sleep stability, especially on REM sleep stability.

Developing disease-modifying interventions in idiopathic REM sleep behavior disorder and early synucleinopathy

Alpha-synucleinopathies are prevalent neurological disorders that cause significant disability, leading to progressive clinical deterioration that is currently managed solely through symptomatic treatment. Efforts to evaluate disease-modifying therapies during the established stage of the disease have not yielded positive outcomes in terms of clinical or imaging efficacy endpoints. However, alpha-synucleinopathies have a long prodromal phase that presents a promising opportunity for intervention with disease-modifying therapies. The presence of polysomnography-confirmed REM sleep behavior disorder (RBD) is the most reliable risk factor for identifying individuals in the prodromal stage of alpha-synucleinopathy. This paper discusses the rationale behind targeting idiopathic/isolated RBD in disease-modifying trials and outlines possible study designs, including strategies for patient stratification, selection of biomarkers to assess disease progression and patient eligibility, as well as the identification of suitable endpoints. Additionally, the potential targets for disease-modifying treatment in alpha-synucleinopathies are summarized.

Symmetric and Profound Monoaminergic Degeneration in Parkinson's Disease with Premotor REM Sleep Behavior Disorder.

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. Explore brainstem and nigrostriatal monoaminergic degeneration pattern differences based on premotor RBD presence and duration in de novo PD patients. 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. 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. 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.

Free-Water Imaging of the Nucleus Basalis of Meynert in Patients With Idiopathic REM Sleep Behavior Disorder and Parkinson Disease.

Cognitive impairments are common in idiopathic REM sleep behavior disorder (iRBD), in which the cholinergic degeneration of nucleus basalis of Meynert (NBM) may play an important role. However, the progressive changes of NBM, the relationship between progressive NBM degeneration and progression of cognitive impairments, and whether degeneration of the NBM can predict cognitive decline in patients with iRBD remain unclear. This study aimed to investigate the cross-sectional and longitudinal microstructural alterations in the NBM of patients with iRBD using free-water imaging and whether free water in the NBM is related to cognitive, mood, and autonomic function. We compared the baseline free-water values in the NBM between 59 healthy controls (HCs), 57 patients with iRBD, 57 patients with Parkinson disease (PD) with normal cognition (PD-NC), and 64 patients with PD with cognitive impairment (PD-CI). Thirty patients with iRBD and 40 HCs had one longitudinal data. In patients with iRBD, we explored the associations between baseline and longitudinal changes of free-water values in the NBM and clinical characteristics and whether baseline free-water values in the NBM could predict cognitive decline. IRBD, PD-NC, and PD-CI groups had significantly increased free-water values in the NBM compared with HCs, whereas PD-CI had higher free-water values compared with iRBD and PD-NC. In patients with iRBD, free-water values in the NBM were progressively elevated over follow-up and correlated with the progression of cognitive impairment and depression. Free-water values in the NBM could predict cognitive decline in the iRBD group. Furthermore, we found that patients with iRBD with cognitive impairment had higher relative change of free-water value in the NBM compared with patients with iRBD with normal cognition over follow-up. This study proves that free-water values in the NBM are elevated cross-sectionally and longitudinally and are associated with the progression of cognitive impairment and depression in patients with iRBD. Moreover, the free-water value in the NBM can predict cognitive decline in patients with iRBD. Whether free-water imaging of the NBM has the potential to be a marker for monitoring progressive cognitive impairment and predicting the conversion to dementia in synucleinopathies needs further investigation.

Cognitive Deficits are Similar Among Patients with Serotonergic-induced REM Sleep Behavior Disorder (5-HT RBD) Compared to Idiopathic RBD (iRBD) (P8-9.012)

Cognitive Deficits are Similar Among Patients with Serotonergic-induced REM Sleep Behavior Disorder (5-HT RBD) Compared to Idiopathic RBD (iRBD) (P8-9.012)

Turning alterations detected by mobile health technology in idiopathic REM sleep behavior disorder

Idiopathic REM sleep Behavior Disorder (iRBD) is a condition at high risk of developing Parkinson’s disease (PD) and other alpha-synucleinopathies. The aim of the study was to evaluate subtle turning alterations by using Mobile health technology in iRBD individuals without subthreshold parkinsonism. A total of 148 participants (23 persons with polysomnography-confirmed iRBD without subthreshold parkinsonism, 60 drug-naïve PD patients, and 65 age-matched controls were included in this prospective cross-sectional study. All underwent a multidimensional assessment including cognitive and non-motor symptoms assessment. Then a Timed-Up-and-Go test (TUG) at normal and fast speed was performed using mobile health technology on the lower back (Rehagait®, Hasomed, Germany). Duration, mean, and peak angular velocities of the turns were compared using a multivariate model correcting for age and sex. Compared to controls, PD patients showed longer turn durations and lower mean and peak angular velocities of the turns in both TUGs (all p ≤ 0.001). iRBD participants also showed a longer turn duration and lower mean (p = 0.006) and peak angular velocities (p < 0.001) compared to controls, but only in the TUG at normal speed. Mobile health technology assessment identified subtle alterations of turning in subjects with iRBD in usual, but not fast speed. Longitudinal studies are warranted to evaluate the value of objective turning parameters in defining the risk of conversion to PD in iRBD and in tracking motor progression in prodromal PD.

EEG rhythmic and arrhythmic spectral components and functional connectivity at resting state may predict the development of synucleinopathies in idiopathic REM sleep behavior disorder.

Idiopathic/isolated REM-sleep behavior disorder (iRBD) often precedes the onset of synucleinopathies. Here, we investigated whether baseline resting-state EEG advanced spectral power and functional connectivity differ between iRBD patients who converted towards a synucleinopathy at follow-up and those who did not. Eighty-one participants with iRBD (66.89±6.91 years) underwent a baseline resting-state EEG recording, a neuropsychological assessment and a neurological examination. We estimated EEG power spectral density using standard analyses and derived spectral estimates of rhythmic and arrhythmic components. Global and pairwise EEG functional connectivity analyses were computed using the weighted phase-lag index (wPLI). Pixel-based permutation tests were used to compare groups. After a mean follow-up of 5.01±2.76 years, 34 patients were diagnosed with a synucleinopathy (67.81±7.34 years) and 47 remained disease-free (65.53±7.09 years). Among patients who converted, 22 were diagnosed with Parkinson's disease and 12 with dementia with Lewy bodies. As compared to patients who did not convert, patients who converted exhibited at baseline higher relative theta standard power, steeper slopes of the arrhythmic component and higher theta rhythmic power mostly in occipital regions. Furthermore, patients who converted showed higher beta global wPLI but lower alpha wPLI between left temporal and occipital regions. Analyses of resting-state EEG rhythmic and arrhythmic components and functional connectivity suggest an imbalanced excitatory-to-inhibitory activity within large-scale networks, which is associated with later development of a synucleinopathy in iRBD patients.

Mitochondrial DNA deletions in the cerebrospinal fluid of patients with idiopathic REM sleep behaviour disorder

Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) represents the prodromal stage of Lewy body disorders (Parkinson's disease (PD) and dementia with Lewy bodies (DLB)) which are linked to variations in circulating cell-free mitochondrial DNA (cf-mtDNA). Here, we assessed whether altered cf-mtDNA release and integrity are already present in IRBD. We used multiplex digital PCR (dPCR) to quantify cf-mtDNA copies and deletion ratio in cerebrospinal fluid (CSF) and serum in a cohort of 71 participants, including 1) 17 patients with IRBD who remained disease-free (non-converters), 2) 34 patients initially diagnosed with IRBD who later developed either PD or DLB (converters), and 3) 20 age-matched controls without IRBD or Parkinsonism. In addition, we investigated whether CD9-positive extracellular vesicles (CD9-EVs) from CSF and serum samples contained cf-mtDNA. Patients with IRBD, both converters and non-converters, exhibited more cf-mtDNA with deletions in the CSF than controls. This finding was confirmed in CD9-EVs. The high levels of deleted cf-mtDNA in CSF corresponded to a significant decrease in cf-mtDNA copies in CD9-EVs in both IRBD non-converters and converters. Conversely, a significant increase in cf-mtDNA copies was found in serum and CD9-EVs from the serum of patients with IRBD who later converted to a Lewy body disorder. Alterations in cf-mtDNA copy number and deletion ratio known to occur in Lewy body disorders are already present in IRBD and are not a consequence of Lewy body disease conversion. This suggests that mtDNA dysfunction is a primary molecular mechanism of the pathophysiological cascade that precedes the full clinical motor and cognitive manifestation of Lewy body disorders. Funded by Michael J. Fox Foundation research grant MJFF-001111. Funded by MICIU/AEI/10.13039/501100011033 "ERDF A way of making Europe", grants PID2020-115091RB-I00 (RT) and PID2022-143279OB-I00 (ACo). Funded by Instituto de Salud Carlos III and European Union NextGenerationEU/PRTR, grant PMP22/00100 (RT and ACo). Funded by AGAUR/Generalitat de Catalunya, grant SGR00490 (RT and ACo). MP has an FPI fellowship, PRE2018-083297, funded by MICIU/AEI/10.13039/501100011033 "ESF Investing in your future".

Dreaming Characteristics in Non-Rapid Eye Movement Parasomnia and Idiopathic Rapid Eye Movement Sleep Behaviour Disorder: Similarities and Differences.

Speech graph analysis (SGA) of dreams has recently shown promise as an objective and language-invariant diagnostic tool that can aid neuropsychiatric diagnosis. Whilst the notion that dreaming mentations reflect distinct physiologic processes is not new, such studies in patients with sleep disorders remain exceptionally scarce. Here, using SGA and other dream content analyses, we set to investigate structural and thematic differences in morning dream recalls of patients diagnosed with Non-Rapid Eye Movement Parasomnia (NREMP) and Idiopathic REM Sleep Behavior Disorder (iRBD). A retrospective cross-sectional study of morning dream recalls of iRBD and NREMP patients was undertaken. Traditional dream content analyses, such as Orlinsky and Hall and Van de Castle analyses, were initially conducted. Subsequently, SGA was performed in order to objectively quantify structural speech differences between the dream recalls of the two patient groups. Comparable rate of morning recall of dreams in the sleep laboratory was recorded; 25% of iRBD and 18.35% of NREMP patients. Aggression in dreams was recorded by 28.57% iRBD versus 20.00% in NREMP group. iRBD patients were more likely to recall dreams (iRBD vs NREMP; P = 0.007), but they also had more white dreams, ie having a feeling of having dreamt, but with no memory of it. Visual and quantitative graph speech analyses of iRBD dreams suggested stable sequential structure, reflecting the linearity of the chronological narrative. Conversely, NREMP dream reports displayed more recursive, less stable systems, with significantly higher scores of graph connectivity measures. The findings of our exploratory study suggest that iRBD and NREMP patients may not only differ on what is recalled in their dreams but also, perhaps more strikingly, on how dreams are recalled. It is hoped that future SGA-led dream investigations of larger groups of patients will help discern distinct mechanistic underpinnings and any associated clinical implications.

Periodic Leg Movements during Sleep Associated with REM Sleep Behavior Disorder: A Machine Learning Study.

Most patients with idiopathic REM sleep behavior disorder (iRBD) present peculiar repetitive leg jerks during sleep in their clinical spectrum, called periodic leg movements (PLMS). The clinical differentiation of iRBD patients with and without PLMS is challenging, without polysomnographic confirmation. The aim of this study is to develop a new Machine Learning (ML) approach to distinguish between iRBD phenotypes. Heart rate variability (HRV) data were acquired from forty-two consecutive iRBD patients (23 with PLMS and 19 without PLMS). All participants underwent video-polysomnography to confirm the clinical diagnosis. ML models based on Logistic Regression (LR), Support Vector Machine (SVM), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost) were trained on HRV data, and classification performances were assessed using Leave-One-Out cross-validation. No significant clinical differences emerged between the two groups. The RF model showed the best performance in differentiating between iRBD phenotypes with excellent accuracy (86%), sensitivity (96%), and specificity (74%); SVM and XGBoost had good accuracy (81% and 78%, respectively), sensitivity (83% for both), and specificity (79% and 72%, respectively). In contrast, LR had low performances (accuracy 71%). Our results demonstrate that ML algorithms accurately differentiate iRBD patients from those without PLMS, encouraging the use of Artificial Intelligence to support the diagnosis of clinically indistinguishable iRBD phenotypes.

[18F]FDG-PET as a biomarker for phenoconversion trajectories in idiopathic REM behavior disorder

[18F]FDG-PET as a biomarker for phenoconversion trajectories in idiopathic REM behavior disorder

Reading the mind in the eyes in patients with idiopathic REM sleep behavior disorder.

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by vocalizations, jerks, and motor behaviors during REM sleep, often associated with REM-related dream content, which is considered a prodromal stage of α-synucleinopathy. The results of the Reading the Mind in the Eyes (RME) reflecting affective Theory of Mind (ToM) are inconsistent in α-synucleinopathy. The present study tried to investigate the RME in patients with iRBD. A total of 35 patients with iRBD and 26 healthy controls were included in the study. All participants were administered the RME and the cognitive assessments according to a standard procedure. The patients with iRBD were further divided into two groups (high or low RME) according to the scores of the RME (> 21, or ≤ 20). The patients with iRBD had worse scores on cognitive tests compared with healthy controls involving global cognitive screening, memory, and visuospatial abilities (p < 0.05), but the scores of the RME were similar between the two groups (20.83 ± 3.38, 20.58 ± 3.43) (p ˃ 0.05). Patients with low RME had more obvious cognitive impairments than healthy controls. After applying Bonferroni correction for multiple tests, the low REM group only performed worse on the Sum of trials 1 to 5 and delayed recall of the RAVLT compared with the healthy control group (p < 0.001, = 0.002). The RME correlated with the scores of cognitive tests involving executive function, attention, memory, and visuospatial function. The changes in RME had a relationship with cognitive impairments, especially memory, in patients with iRBD.

Heart rate variability during sleep in synucleinopathies: a review.

Synucleinopathies are a group of neurodegenerative diseases characterized by abnormal accumulations of insoluble alpha-synuclein in neurons or glial cells. These consist of Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Moreover, idiopathic REM sleep behavior disorder (iRBD) is often the first manifestation of synucleinopathies, demonstrating a pathophysiological continuum. While these disorders vary in prevalence, symptom patterns, and severity, they can all include autonomic nervous system (ANS) dysfunction, which significantly reduces quality of life and worsens prognosis. Consequently, identifying abnormalities of the ANS can provide opportunities for improving quality of life through symptomatic treatments that are tailored to the individual's symptoms. An exciting development is using heart rate variability (HRV) as a non-invasive research tool for analyzing how the ANS regulates physiological processes. HRV during sleep, however, may provide a more accurate and reliable measure of ANS activity than during wakefulness, as during awake time, ANS activity is influenced by a variety of factors, including physical activity, stress, and emotions, which may mask or confound the underlying patterns of ANS activity. This review aims to provide an overview of the current knowledge regarding sleep-related HRV in synucleinopathies and to discuss contributing mechanisms. Evidence suggests that iRBD, PD, and MSA are associated with nocturnal ANS dysfunction. Further, comparative studies indicate that the presence of RBD could exacerbate this abnormality. In contrast, no studies have been conducted in patients with DLB. Overall, this review provides new insight into the complex interplay between the ANS and synucleinopathies and underscores the need for further research in this area to develop effective therapies to improve sleep and overall quality of life in patients with synucleinopathies.

Clinical correlates of pareidolias and color discrimination deficits in idiopathic REM sleep behavior disorder and Parkinson's disease.

Visuoperceptual dysfunction is common in Parkinson's disease (PD) and is also reported in its prodromal phase, isolated REM sleep behavior disorder (iRBD). We aimed to investigate color discrimination ability and complex visual illusions known as pareidolias in patients with iRBD and PD compared to healthy controls, and their associating clinical factors. 46 iRBD, 43 PD, and 64 healthy controls performed the Farnsworth-Munsell 100 hue test and noise pareidolia tests. Any relationship between those two visual functions and associations with prodromal motor and non-motor manifestations were evaluated, including MDS-UPDRS part I to III, Cross-Cultural Smell Identification Test, sleep questionnaires, and comprehensive neuropsychological assessment. iRBD and PD patients both performed worse on the Farnsworth-Munsell 100 hue test and had greater number of pareidolias compared to healthy controls. No correlations were found between the extent of impaired color discrimination and pareidolia scores in either group. In iRBD patients, pareidolias were associated with frontal executive dysfunction, while impaired color discrimination was associated with visuospatial dysfunction, hyposmia, and higher MDS-UPDRS-III scores. Pareidolias in PD patients correlated with worse global cognition, whereas color discrimination deficits were associated with frontal executive dysfunction. Color discrimination deficits and pareidolias are frequent but does not correlate with each other from prodromal to clinically established stage of PD. The different pattern of clinical associates with the two visual symptoms suggests that evaluation of both color and pareidolias may aid in revealing the course of neurodegeneration in iRBD and PD patients.

Diffusion MRI free water in hippocampal subfields CA3 and CA1 tracks progression in prodromal and overt synucleinopathy

AbstractBackgroundPostmortem study of the hippocampal subfields in the Lewy body dementias has revealed selective involvement of CA3 with synuclein pathology and CA1 with amyloid and tau, i.e., Alzheimer’s disease (AD) co‐pathology (Coughlin et al., 2020, PMID:32892355). However, new neuroimaging methods are needed to study the hippocampal subfields in vivo in synucleinopathies. Diffusion MRI free water (FW) measurement detects increased hippocampal FW in AD (Ofori et al., 2019, PMID:31470214). However, typical diffusion MRI protocols have voxels ≥ 2 mm3 making hippocampal subfield imaging infeasible due to volume averaging effects. To address this, we developed a high‐resolution diffusion MRI protocol capable of imaging the hippocampal subfields. We applied this approach to study a prodromal synucleinopathy group – idiopathic REM sleep behavior disorder (iRBD), as well as PD with normal cognition (PD‐NC), PD with cognitive impairment (PD‐CI), and dementia with Lewy bodies (DLB).MethodParticipants with PD‐NC, PD‐CI, DLB, and polysomnographically confirmed iRBD were recruited at Emory University. T1 MPRAGE (0.8mm3 voxels) and high‐resolution diffusion MRI (b = 0, 500mm2/sec; 30 diffusion directions; 1.1mm3 voxels) data were acquired with a Siemens 3T Prisma‐fit system. FreeSurfer v7 was used to segment hippocampal subfields. FW was measured as described in Ofori, et al (2017, PMID:28714593). Groups were compared using ANCOVA followed by post‐hoc tests, and clinical and MRI features were correlated.Result Table 1 shows group demographic and clinical characteristics. A progressive increase in CA3 and CA1 FW was observed from iRBD to PD‐NC to PD‐CI and DLB, and the ANCOVA model, controlling for age, found a statistically significant difference between groups for CA3 FW (Figure 1). Figure 2 shows statistically significant negative correlations between MoCA and hippocampal FW measures and between years of education and FW in CA3 and CA1.ConclusionCA3 and CA1 FW are significantly increased in advanced synucleinopathy (DLB, PD‐CI) as compared to iRBD, and PD‐NC has intermediate values. Strong negative correlations between CA3 and CA1 FW and cognition further indicate that these measures may track disease progression. The negative correlations between CA3 and CA1 FW and education also suggest that these measures may be biological correlates of cognitive reserve.

Diffusion MRI free water in hippocampal subfields CA3 and CA1 tracks progression in prodromal and overt synucleinopathy

AbstractBackgroundPostmortem study of the hippocampal subfields in the Lewy body dementias has revealed selective involvement of CA3 with synuclein pathology and CA1 with amyloid and tau, i.e., Alzheimer’s disease (AD) co‐pathology (Coughlin et al., 2020, PMID:32892355). However, new neuroimaging methods are needed to study the hippocampal subfields in vivo in synucleinopathies. Diffusion MRI free water (FW) measurement detects increased hippocampal FW in AD (Ofori et al., 2019, PMID:31470214). However, typical diffusion MRI protocols have voxels = 2 mm3 making hippocampal subfield imaging infeasible due to volume averaging effects. To address this, we developed a high‐resolution diffusion MRI protocol capable of imaging the hippocampal subfields. We applied this approach to study a prodromal synucleinopathy group – idiopathic REM sleep behavior disorder (iRBD), as well as PD with normal cognition (PD‐NC), PD with cognitive impairment (PD‐CI), and dementia with Lewy bodies (DLB).MethodParticipants with PD‐NC, PD‐CI, DLB, and polysomnographically confirmed iRBD were recruited at Emory University. T1 MPRAGE (0.8mm3 voxels) and high‐resolution diffusion MRI (b = 0, 500mm2/sec; 30 diffusion directions; 1.1mm3 voxels) data were acquired with a Siemens 3T Prisma‐fit system. FreeSurfer v7 was used to segment hippocampal subfields. FW was measured as described in Ofori, et al (2017, PMID:28714593). Groups were compared using ANCOVA followed by post‐hoc tests, and clinical and MRI features were correlated.ResultTable 1 shows group demographic and clinical characteristics. A progressive increase in CA3 and CA1 FW was observed from iRBD to PD‐NC to PD‐CI and DLB, and the ANCOVA model, controlling for age, found a statistically significant difference between groups for CA3 FW (Figure 1). Figure 2 shows statistically significant negative correlations between MoCA and hippocampal FW measures and between years of education and FW in CA3 and CA1.ConclusionCA3 and CA1 FW are significantly increased in advanced synucleinopathy (DLB, PD‐CI) as compared to iRBD, and PD‐NC has intermediate values. Strong negative correlations between CA3 and CA1 FW and cognition further indicate that these measures may track disease progression. The negative correlations between CA3 and CA1 FW and education also suggest that these measures may be biological correlates of cognitive reserve.

Predictive biomarkers for cognitive decline in patients with idiopathic REM sleep behavior disorder

AbstractBackgroundIdiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is regarded as an early stage of the synucleinopathy, which may precede the onset of cognitive impairment or parkinsonism. Biomarkers for cognitive decline in patients with iRBD would be helpful to early intervention. Our aim was to identify biomarkers for predicting the cognitive deterioration risk in patients with iRBD.MethodWe involved patients with polysomnographically confirmed iRBD who has at least 2 visits from the Parkinson’s Progression Markers Initiative (PPMI) database. Progression of cognitive state to MCI or dementia during follow‐up was defined as the endpoint. Baseline clinical features, biofluid and genetic biomarkers were compared between iRBD with or without progression of cognitive decline. Predictive biomarkers were identified with Kaplan‐Meier and Cox proportional hazards analysis, adjusting for age, sex, and years of education.ResultA total of 38 patients with iRBD were enrolled (average age: 69.53 ± 5.54, male: 84.21%) . During follow‐up (median 5.45, IQR 4.08‐7.1 years), Progression of cognitive decline occurred in 57.89% (22/38) patients with iRBD. Baseline clinical features including hallucinations and psychosis (HR = 13.783, p = 0.022) and higher confidence abnormalities consistent with a neurodegenerative parkinsonian syndrome (HR = 2.258, p = 0.017) increased the risk. Patients with a lower loge‐transformed the ratio of Aβ 1‐42 in cerebrospinal fluid (CSF) to ΝfL in serum (Aβ/NfL, HR = 0.375, p = 0.044) and t‐tau in CSF to ΝfL in serum (t‐tau/NfL, HR = 0.277, p = 0.044) had a higher risk of cognitive decline. Genetic biomarkers consisting of GBA rs75548401(HR = 13.783, p = 0.022), STK39 rs1955337 (HR = 11.882, p&lt;0.001), and COMT rs4680 (HR = 2.376, p = 0.021) variants increased the risk, while MCCC1 rs12637471 (HR = 0.408, p = 0.024), COMT rs165656 (HR = 0.451, p = 0.033), COMT rs4633 (HR = 0.421, p = 0.021), and COMT rs165599 (HR = 0.427, p = 0.023) variants decreased the risk. A model combining age and variables with p&lt;0.05 exhibited above presented the best predictive performance, with an AUC of 0.963 (95% CI 0.896–1.000, p&lt;0.001).ConclusionOur findings provide potential biomarkers to evaluate the risk of progression to MCI or dementia in patients with iRBD. Combination of clinical features, biofluid and genetic biomarkers performs optimal predicting accuracy.

Patients with idiopathic REM sleep behaviour disorder (iRBD) should be informed about the future risk of Parkinson disease

Patients with idiopathic REM sleep behaviour disorder (iRBD) should be informed about the future risk of Parkinson disease