Activation of the nociceptin/orphanin-FQ receptor promotes NREM sleep and EEG slow wave activity.

Sleep/wake control involves several neurotransmitter and neuromodulatory systems yet the coordination of the behavioral and physiological processes underlying sleep is incompletely understood. Previous studies have suggested that activation of the Nociceptin/orphanin FQ (N/OFQ) receptor (NOPR) reduces locomotor activity and produces a sedation-like effect in rodents. In the present study, we systematically evaluated the efficacy of two NOPR agonists, Ro64-6198 and SR16835, on sleep/wake in rats, mice, and Cynomolgus macaques. We found a profound, dose-related increase in non-Rapid Eye Movement (NREM) sleep and electroencephalogram (EEG) slow wave activity (SWA) and suppression of Rapid Eye Movement sleep (REM) sleep in all three species. At the highest dose tested in rats, the increase in NREM sleep and EEG SWA was accompanied by a prolonged inhibition of REM sleep, hypothermia, and reduced locomotor activity. However, even at the highest dose tested, rats were immediately arousable upon sensory stimulation, suggesting sleep rather than an anesthetic state. NOPR agonism also resulted in increased expression of c-Fos in the anterodorsal preoptic and parastrial nuclei, two GABAergic nuclei that are highly interconnected with brain regions involved in physiological regulation. These results suggest that the N/OFQ-NOPR system may have a previously unrecognized role in sleep/wake control and potential promise as a therapeutic target for the treatment of insomnia.

The temporal structure of REM sleep shows minute-scale fluctuations across brain and body in mice and humans.

Rapid eye movement sleep (REM) is believed to have a binary temporal structure with "phasic" and "tonic" microstates, characterized by motoric activity versus quiescence, respectively. However, we observed in mice that the frequency of theta activity (a marker of rodent REM) fluctuates in a nonbinary fashion, with the extremes of that fluctuation correlating with phasic-type and tonic-type facial motricity. Thus, phasic and tonic REM may instead represent ends of a continuum. These cycles of brain physiology and facial movement occurred at 0.01 to 0.06 Hz, or infraslow frequencies, and affected cross-frequency coupling and neuronal activity in the neocortex, suggesting network functional impact. We then analyzed human data and observed that humans also demonstrate nonbinary phasic/tonic microstates, with continuous 0.01 to 0.04-Hz respiratory rate cycles matching the incidence of eye movements. These fundamental properties of REM can yield insights into our understanding of sleep health.

Novel Electrophysiological Signatures of Learning and Forgetting in Human Rapid Eye Movement Sleep.

Despite the known behavioral benefits of rapid eye movement (REM) sleep, discrete neural oscillatory events in human scalp electroencephalography (EEG) linked with behavior have not been discovered. This knowledge gap hinders mechanistic understanding of the function of sleep, as well as the development of biophysical models and REM-based causal interventions. We designed a detection algorithm to identify bursts of activity in high-density, scalp EEG within theta (4-8 Hz) and alpha (8-13 Hz) bands during REM sleep. Across 38 nights of sleep, we characterized the burst events (i.e., count, duration, density, peak frequency, amplitude) in healthy, young male and female human participants (38; 21F) and investigated burst activity in relation to sleep-dependent memory tasks: hippocampal-dependent episodic verbal memory and nonhippocampal visual perceptual learning. We found greater burst count during the more REM-intensive second half of the night (p < 0.05), longer burst duration during the first half of the night (p < 0.05), but no differences across the night in density or power (p > 0.05). Moreover, increased alpha burst power was associated with increased overnight forgetting for episodic memory (p < 0.05). Furthermore, we show that increased REM theta burst activity in retinotopically specific regions was associated with better visual perceptual performance. Our work provides a critical bridge between discrete REM sleep events in human scalp EEG that support cognitive processes and the identification of similar activity patterns in animal models that allow for further mechanistic characterization.

Selective Enhancement of REM Sleep in Male Rats through Activation of Melatonin MT1 Receptors Located in the Locus Ceruleus Norepinephrine Neurons.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.

Thalamocortical Dynamics during Rapid Eye Movement Sleep in the Mouse Somatosensory Pathway.

Rapid eye movement (REM) sleep, also referred to as paradoxical sleep for the striking resemblance of its electroencephalogram (EEG) to the one observed in wakefulness, is characterized by the occurrence of transient events such as limb twitches or facial and rapid eye movements. Here, we investigated the local activity of the primary somatosensory or barrel cortex (S1) in naturally sleeping head-fixed male mice during REM. Through local field potential recordings, we uncovered local appearances of spindle waves in the barrel cortex during REM concomitant with strong delta power, challenging the view of a wakefulness-like activity in REM. We further performed extra- and intracellular recordings of thalamic cells in head-fixed mice. Our data show high-frequency thalamic bursts of spikes and subthreshold spindle oscillations in approximately half of the neurons of the ventral posterior medial nucleus which further confirmed the thalamic origin of local cortical spindles in S1 in REM. Cortical spindle oscillations were suppressed, while thalamus spike firing increased, associated with rapid mouse whisker movements and S1 cortical activity transitioned to an activated state. During REM, the sensory thalamus and barrel cortex therefore alternate between high (wake-like) and low (non-REM sleep-like) activation states, potentially providing a neuronal substrate for mnemonic processes occurring during this paradoxical sleep stage.

Gata2, Nkx2-2 and Skor2 form a transcription factor network regulating development of a midbrain GABAergic neuron subtype with characteristics of REM-sleep regulatory neurons.

The midbrain reticular formation (MRF) is a mosaic of diverse GABAergic and glutamatergic neurons that have been associated with a variety of functions, including sleep regulation. However, the molecular characteristics and development of MRF neurons are poorly understood. As the transcription factor, Gata2 is required for the development of all GABAergic neurons derived from the embryonic mouse midbrain, we hypothesized that the genes expressed downstream of Gata2 could contribute to the diversification of GABAergic neuron subtypes in this brain region. Here, we show that Gata2 is required for the expression of several GABAergic lineage-specific transcription factors, including Nkx2-2 and Skor2, which are co-expressed in a restricted group of post-mitotic GABAergic precursors in the MRF. Both Gata2 and Nkx2-2 function is required for Skor2 expression in GABAergic precursors. In the adult mouse and rat midbrain, Nkx2-2-and Skor2-expressing GABAergic neurons locate at the boundary of the ventrolateral periaqueductal gray and the MRF, an area containing REM-off neurons regulating REM sleep. In addition to the characteristic localization, Skor2+ cells increase their activity upon REM-sleep inhibition, send projections to the dorsolateral pons, a region associated with sleep control, and are responsive to orexins, consistent with the known properties of midbrain REM-off neurons.

Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

Emotional Memory Processing during REM Sleep with Implications for Post-Traumatic Stress Disorder.

REM sleep is important for the processing of emotional memories, including fear memories. Rhythmic interactions, especially in the theta band, between the medial prefrontal cortex (mPFC) and limbic structures are thought to play an important role, but the ways in which memory processing occurs at a mechanistic and circuits level are largely unknown. To investigate how rhythmic interactions lead to fear extinction during REM sleep, we used a biophysically based model that included the infralimbic cortex (IL), a part of the mPFC with a critical role in suppressing fear memories. Theta frequency (4-12 Hz) inputs to a given cell assembly in IL, representing an emotional memory, resulted in the strengthening of connections from the IL to the amygdala and the weakening of connections from the amygdala to the IL, resulting in the suppression of the activity of fear expression cells for the associated memory. Lower frequency (4 Hz) theta inputs effected these changes over a wider range of input strengths. In contrast, inputs at other frequencies were ineffective at causing these synaptic changes and did not suppress fear memories. Under post-traumatic stress disorder (PTSD) REM sleep conditions, rhythmic activity dissipated, and 4 Hz theta inputs to IL were ineffective, but higher-frequency (10 Hz) theta inputs to IL induced changes similar to those seen with 4 Hz inputs under normal REM sleep conditions, resulting in the suppression of fear expression cells. These results suggest why PTSD patients may repeatedly experience the same emotionally charged dreams and suggest potential neuromodulatory therapies for the amelioration of PTSD symptoms.SIGNIFICANCE STATEMENT Rhythmic interactions in the theta band between the mPFC and limbic structures are thought to play an important role in processing emotional memories, including fear memories, during REM sleep. The infralimbic cortex (IL) in the mPFC is thought to play a critical role in suppressing fear memories. We show that theta inputs to the IL, unlike other frequency inputs, are effective in producing synaptic changes that suppress the activity of fear expression cells associated with a given memory. Under PTSD REM sleep conditions, lower-frequency (4 Hz) theta inputs to the IL do not suppress the activity of fear expression cells associated with the given memory but, surprisingly, 10 Hz inputs do. These results suggest potential neuromodulatory therapies for PTSD.

Rule Abstraction Is Facilitated by Auditory Cuing in REM Sleep.

Sleep facilitates abstraction, but the exact mechanisms underpinning this are unknown. Here, we aimed to determine whether triggering reactivation in sleep could facilitate this process. We paired abstraction problems with sounds, then replayed these during either slow-wave sleep (SWS) or rapid eye movement (REM) sleep to trigger memory reactivation in 27 human participants (19 female). This revealed performance improvements on abstraction problems that were cued in REM, but not problems cued in SWS. Interestingly, the cue-related improvement was not significant until a follow-up retest 1 week after the manipulation, suggesting that REM may initiate a sequence of plasticity events that requires more time to be implemented. Furthermore, memory-linked trigger sounds evoked distinct neural responses in REM, but not SWS. Overall, our findings suggest that targeted memory reactivation in REM can facilitate visual rule abstraction, although this effect takes time to unfold.SIGNIFICANCE STATEMENT The ability to abstract rules from a corpus of experiences is a building block of human reasoning. Sleep is known to facilitate rule abstraction, but it remains unclear whether we can manipulate this process actively and which stage of sleep is most important. Targeted memory reactivation (TMR) is a technique that uses re-exposure to learning-related sensory cues during sleep to enhance memory consolidation. Here, we show that TMR, when applied during REM sleep, can facilitate the complex recombining of information needed for rule abstraction. Furthermore, we show that this qualitative REM-related benefit emerges over the course of a week after learning, suggesting that memory integration may require a slower form of plasticity.

The why and how of sleep-dependent synaptic down-selection.

Sleep requires that we disconnect from the environment, losing the ability to promptly respond to stimuli. There must be at least one essential function that justifies why we take this risk every day, and that function must depend on the brain being offline. We have proposed that this function is to renormalize synaptic weights after learning has led to a net increase in synaptic strength in many brain circuits. Without this renormalization, synaptic activity would become energetically too expensive and saturation would prevent new learning. There is converging evidence from molecular, electrophysiological, and ultrastructural experiments showing a net increase in synaptic strength after the major wake phase, and a net decline after sleep. The evidence also suggests that sleep-dependent renormalization is a smart process of synaptic down-selection, comprehensive and yet specific, which could explain the many beneficial effects of sleep on cognition. Recently, a key molecular mechanism that allows broad synaptic weakening during sleep was identified. Other mechanisms still being investigated should eventually explain how sleep can weaken most synapses but afford protection to some, including those directly activated by learning. That synaptic down-selection takes place during sleep is by now established; why it should take place during sleep has a plausible explanation; how it happens is still work in progress.

Noradrenaline enhances Na-K ATPase subunit expression by HuR-induced mRNA stabilization and their transportation to the cell surface through PLC and PKC mediated pathway: Implications with REMS-loss associated disorders.

Rapid eye movement sleep (REMS) maintains brain excitability at least by regulating Na-K ATPase activity. Although REMS deprivation (REMSD)-associated elevated noradrenaline (NA) increases Na-K ATPase protein expression, its mRNA transcription did not increase. We hypothesized and confirmed both in vivo as well as in vitro that elevated mRNA stability explains the apparent puzzle. The mRNA stability was measured in control and REMSD rat brain with or without in vivo treatment with α1-adrenoceptor (AR) antagonist, prazosin (PRZ). Upon REMSD, Na-K ATPase α1-, and α2-mRNA stability increased significantly, which was prevented by PRZ. To decipher the molecular mechanism of action, we estimated NA-induced Na-K ATPase mRNA stability in Neuro-2a cells under controlled conditions and by transcription blockage using Actinomycin D (Act-D). NA increased Na-K ATPase mRNA stability, which was prevented by PRZ and propranolol (PRP, ß-AR antagonist). The knockdown assay confirmed that the increased mRNA stabilization was induced by elevated cytoplasmic abundance of Human antigen R (HuR) and involving (Phospholipase C) PLC-mediated activation of Protein Kinase C (PKC). Additionally, using cell-impermeable Enz-link sulfo NHS-SS-Biotin, we observed that NA increased Na-K ATPase α1-subunits on the Neuro-2a cell surface. We conclude that REMSD-associated elevated NA, acting on α1- and ß-AR, increases nucleocytoplasmic translocation of HuR and increases Na-K ATPase mRNA stability, resulting in increased Na-K ATPase protein expression. The latter then gets translocated to the neuronal membrane surface involving both PKC and (Protein Kinase A) PKA-mediated pathways. These findings may be exploited for the amelioration of REMSD-associated chronic disorders and symptoms.

Effects of non-rapid eye movement sleep on the cortical synaptic expression of GluA1-containing AMPA receptors.

Converging electrophysiological, molecular and ultrastructural evidence supports the hypothesis that sleep promotes a net decrease in excitatory synaptic strength, counteracting the net synaptic potentiation caused by ongoing learning during waking. However, several outstanding questions about sleep-dependent synaptic weakening remain. Here, we address some of these questions by using two established molecular markers of synaptic strength, the levels of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors containing the GluA1 subunit and the phosphorylation of GluA1 at serine 845 (p-GluA1(845)). We previously found that, in the rat cortex and hippocampus, these markers are lower after 6-8 h of sleep than after the same time spent awake. Here, we measure GluA1 and p-GluA1(845) levels in synaptosomes of mouse cortex after 5 h of either sleep, sleep deprivation, recovery sleep after sleep deprivation or selective REM sleep deprivation (32 C57BL/B6 adult mice, 16 females). We find that relative to after sleep deprivation, these synaptic markers are lower after sleep independent of whether the mice were allowed to enter REM sleep. Moreover, 5 h of recovery sleep following acute sleep deprivation is enough to renormalize their expression. Thus, the renormalization of GluA1 and p-GluA1(845) expression crucially relies on NREM sleep and can occur in a few hours of sleep after acute sleep deprivation.

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.

Chronic rapid eye movement sleep deprivation aggravates the pathogenesis of Alzheimer's disease by decreasing brain O-GlcNAc cycling in mice.

This study investigated the role of O-GlcNAc cycling in Alzheimer's disease-related changes in brain pathophysiology induced by chronic REM sleep deprivation (CSD) in mice. CSD increased amyloid beta (Aß) and p-Tau accumulation and impaired learning and memory (L/M) function. CSD decreased dendritic length and spine density. CSD also increased the intensity of postsynaptic density protein-95 (PSD-95) staining. All of these Alzheimer's disease (AD) pathogenic changes were effectively reversed through glucosamine (GlcN) treatment by enhancing O-GlcNAcylation. Interestingly, the lelvel of O-GlcNAcylated-Tau (O-Tau) exhibited an opposite trend compared to p-Tau, as it was elevated by CSD and suppressed by GlcN treatment. CSD increased neuroinflammation, as indicated by elevated levels of glial fibrillary acidic protein and IBA-1-positive glial cells in the brain, which were suppressed by GlcN treatment. CSD promoted the phosphorylation of GSK3ß and led to an upregulation in the expression of endoplasmic reticulum (ER) stress regulatory proteins and genes. These alterations were effectively suppressed by GlcN treatment. Minocycline not only suppressed neuroinflammation induced by CSD, but it also rescued the decrease in O-GlcNAc levels caused by CSD. Minocycline also reduced AD neuropathy without affecting CSD-induced ER stress. Notably, overexpressing O-GlcNAc transferase in the dentate gyrus region of the mouse brain rescued CSD-induced cognitive dysfunction, neuropathy, neuroinflammation, and ER stress responses. Collectively, our findings reveal that dysregulation of O-GlcNAc cycling underlies CSD-induced AD pathology and demonstrate that restoration of OGlcNAcylation protects against CSD-induced neurodegeneration.

Sleep-stage-dependent alterations in cerebral oxygen metabolism quantified by magnetic resonance.

A key function of sleep is to provide a regular period of reduced brain metabolism, which is critical for maintenance of healthy brain function. The purpose of this work was to quantify the sleep-stage-dependent changes in brain energetics in terms of cerebral metabolic rate of oxygen (CMRO2 ) as a function of sleep stage using quantitative magnetic resonance imaging (MRI) with concurrent electroencephalography (EEG) during sleep in the scanner. Twenty-two young and older subjects with regular sleep hygiene and Pittsburgh Sleep Quality Index (PSQI) in the normal range were recruited for the study. Cerebral blood flow (CBF) and venous oxygen saturation (SvO2 ) were obtained simultaneously at 3 Tesla field strength and 2.7-s temporal resolution during an 80-min time series using OxFlow, an in-house developed imaging sequence. The method yields whole-brain CMRO2 in absolute physiologic units via Fick's Principle. Nineteen subjects yielded evaluable data free of subject motion artifacts. Among these subjects, 10 achieved slow-wave (N3) sleep, 16 achieved N2 sleep, and 19 achieved N1 sleep while undergoing the MRI protocol during scanning. Mean CMRO2 was 98 ± 7(µmol min-1 )/100 g awake, declining progressively toward deepest sleep stage: 94 ± 10.8 (N1), 91 ± 11.4 (N2), and 76 ± 9.0 µmol min-1 /100 g (N3), with each level differing significantly from the wake state. The technology described is able to quantify cerebral oxygen metabolism in absolute physiologic units along with non-REM sleep stage, indicating brain oxygen consumption to be closely associated with depth of sleep, with deeper sleep stages exhibiting progressively lower CMRO2 levels.

Neuropsychological Changes in Isolated REM Sleep Behavior Disorder: A Systematic Review and Meta-analysis of Cross-sectional and Longitudinal Studies.

The aim of this meta-analysis is twofold: (a) to assess cognitive impairments in isolated rapid eye movement (REM) sleep behavior disorder (iRBD) patients compared to healthy controls (HC); (b) to quantitatively estimate the risk of developing a neurodegenerative disease in iRBD patients according to baseline cognitive assessment. To address the first aim, cross-sectional studies including polysomnography-confirmed iRBD patients, HC, and reporting neuropsychological testing were included. To address the second aim, longitudinal studies including polysomnography-confirmed iRBD patients, reporting baseline neuropsychological testing for converted and still isolated patients separately were included. The literature search was conducted based on PRISMA guidelines and the protocol was registered at PROSPERO (CRD42021253427). Cross-sectional and longitudinal studies were searched from PubMed, Web of Science, Scopus, and Embase databases. Publication bias and statistical heterogeneity were assessed respectively by funnel plot asymmetry and using I2. Finally, a random-effect model was performed to pool the included studies. 75 cross-sectional (2,398 HC and 2,460 iRBD patients) and 11 longitudinal (495 iRBD patients) studies were selected. Cross-sectional studies showed that iRBD patients performed significantly worse in cognitive screening scores (random-effects (RE) model = -0.69), memory (RE model = -0.64), and executive function (RE model = -0.50) domains compared to HC. The survival analyses conducted for longitudinal studies revealed that lower executive function and language performance, as well as the presence of mild cognitive impairment (MCI), at baseline were associated with an increased risk of conversion at follow-up. Our study underlines the importance of a comprehensive neuropsychological assessment in the context of iRBD.

Understanding REM Sleep Behavior Disorder through Functional MRI: A Systematic Review.

Neuroimaging studies in rapid eye movement sleep behavior disorder (RBD) can inform fundamental questions about the pathogenesis of Parkinson's disease (PD). Across modalities, functional magnetic resonance imaging (fMRI) may be better suited to identify changes between neural networks in the earliest stages of Lewy body diseases when structural changes may be subtle or absent. This review synthesizes the findings from all fMRI studies of RBD to gain further insight into the pathophysiology and progression of Lewy body diseases. A total of 32 studies were identified using a systematic review conducted according to PRISMA guidelines between January 2000 to February 2024 for original fMRI studies in patients with either isolated RBD (iRBD) or RBD secondary to PD. Common functional alterations were detectable in iRBD patients compared with healthy controls across brainstem nuclei, basal ganglia, frontal and occipital lobes, and whole brain network measures. Patients with established PD and RBD demonstrated decreased functional connectivity across the whole brain and brainstem nuclei, but increased functional connectivity in the cerebellum and frontal lobe compared with those PD patients without RBD. Finally, longitudinal changes in resting state functional connectivity were found to track with disease progression. Currently, fMRI studies in RBD have demonstrated early signatures of neurodegeneration across both motor and non-motor pathways. Although more work is needed, such findings have the potential to inform our understanding of disease, help to distinguish between prodromal PD and prodromal dementia with Lewy bodies, and support the development of fMRI-based outcome measures of phenoconversion and progression in future disease modifying trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Motor Dysfunction Seen in Isolated REM Sleep Behavior Disorder.

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.

Microglial Activation and Progression of Nigrostriatal Dysfunction in Isolated REM Sleep Behavior Disorder.

BACKGROUND: Using 11 C-(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 11 C-(R)-PK11195 and 18 F-DOPA-PET underwent repeat 18 F-DOPA-PET after 3 years. 18 F-DOPA Ki changes from baseline were evaluated with volumes-of-interest and voxel-based analyses. RESULTS: Significant 18 F-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 11 C-(R)-PK11195 binding at baseline was a predictor of 18 F-DOPA Ki reduction in left caudate (coef = -0.0426, P = 0.016). CONCLUSIONS: Subjects with increased baseline 11 C-(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.

Charting Disease Trajectories from Isolated REM Sleep Behavior Disorder to Parkinson's Disease.

BACKGROUND: Clinical presentation and progression dynamics are variable in patients with Parkinson's disease (PD). Disease course mapping is an innovative disease modelling technique that summarizes the range of possible disease trajectories and estimates dimensions related to onset, sequence, and speed of progression of disease markers. OBJECTIVE: To propose a disease course map for PD and investigate progression profiles in patients with or without rapid eye movement sleep behavioral disorders (RBD). METHODS: Data of 919 PD patients and 88 isolated RBD patients from three independent longitudinal cohorts were analyzed (follow-up duration = 5.1; 95% confidence interval, 1.1-8.1] years). Disease course map was estimated by using eight clinical markers (motor and non-motor symptoms) and four imaging markers (dopaminergic denervation). RESULTS: PD course map showed that the first changes occurred in the contralateral putamen 13 years before diagnosis, followed by changes in motor symptoms, dysautonomia, sleep-all before diagnosis-and finally cognitive decline at the time of diagnosis. The model showed earlier disease onset, earlier non-motor and later motor symptoms, more rapid progression of cognitive decline in PD patients with RBD than PD patients without RBD. This pattern was even more pronounced in patients with isolated RBD with early changes in sleep, followed by cognition and non-motor symptoms and later changes in motor symptoms. CONCLUSIONS: Our findings are consistent with the presence of distinct patterns of progression between patients with and without RBD. Understanding heterogeneity of PD progression is key to decipher the underlying pathophysiology and select homogeneous subgroups of patients for precision medicine. © 2023 International Parkinson and Movement Disorder Society.