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PurposeTo evaluate and compare structural connectivity using graph theoretical analysis in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and healthy subjects.MethodsTen consecutive patients with iRBD were recruited from a single tertiary hospital. All patients had normal brain magnetic resonance imaging results on visual inspection. They did not have any other neurological disorder. Control subjects were also enrolled. All subjects underwent three-dimensional volumetric T1-weighted imaging. Absolute structural volumes were calculated using FreeSurfer image analysis software. Structural volume and connectivity analyses were performed with Brain Analysis using Graph Theory.ResultsCompared to healthy controls, patients with iRBD showed significant alterations in cortical and subcortical volumes, showing increased volumes of frontal cortex, thalamus, and caudate nucleus. In addition, patients with iRBD exhibited significantly different structural connectivity compared to healthy controls. In measures of global network, average degree, global efficiency, and local efficiency were decreased whereas characteristic path length was increased in iRBD patients. In measures of local network, there was significant hub reorganization in patients with iRBD. Betweenness centrality of caudate nucleus and frontal cortex was increased in patients with iRBD.ConclusionsThis is the first study to report that structural volume and connectivity in patients with iRBD are significantly different from those in healthy controls. iRBD patients exhibited disrupted topological disorganization of the global brain network and hub reorganization. These alterations are implicated in the pathogenesis of iRBD. They might be potential biomarkers of iRBD.

Abstract Study Objectives REM sleep behavior disorder (RBD) is a parasomnia affecting 33% to 46% of patients with Parkinson’s disease (PD). The existence of a unique and specific impaired cognitive profile in PD patients with RBD is still controversial. We extensively assessed cognitive functions to identify whether RBD is associated with more severe cognitive deficits in nondemented patients with PD. Methods One hundred sixty-two participants, including 53 PD patients with RBD, 40 PD patients without RBD, and 69 healthy subjects, underwent polysomnography, a neurological assessment and an extensive neuropsychological exam to assess attention, executive functions, episodic learning and memory, visuospatial abilities, and language. Results PD patients with RBD had poorer and clinically impaired performance in several cognitive tests compared to PD patients without RBD and healthy subjects. These two latter groups were similar on all cognitive measures. Mild cognitive impairment (MCI) diagnosis frequency was almost threefold higher in PD patients with RBD compared to PD patients without RBD (66% vs. 23%, p < .001). Moreover, subjective cognitive decline was reported in 89% of PD patients with RBD compared to 58% of PD patients without RBD (p = .024). Conclusions RBD in PD is associated with a more impaired cognitive profile and higher MCI diagnosis frequency, suggesting more severe and widespread neurodegeneration. This patient subgroup and their caregivers should receive targeted medical attention to better detect and monitor impairment and to enable the development of management interventions for cognitive decline and its consequences.

To estimate the risk for developing a defined neurodegenerative syndrome in a large cohort of idiopathic REM sleep behavior disorder (IRBD) patients with long follow-up. Using the Kaplan-Meier method, we estimated the disease-free survival rate from defined neurodegenerative syndromes in all the consecutive IRBD patients diagnosed and followed-up in our tertiary referal sleep center between November 1991 and July 2013. The cohort comprises 174 patients with a median age at diagnosis of IRBD of 69 years and a median follow-up of four years. The risk of a defined neurodegenerative syndrome from the time of IRBD diagnosis was 33.1% at five years, 75.7% at ten years, and 90.9% at 14 years. The median conversion time was 7.5 years. Emerging diagnoses (37.4%) were dementia with Lewy bodies (DLB) in 29 subjects, Parkinson disease (PD) in 22, multiple system atrophy (MSA) in two, and mild cognitive impairment (MCI) in 12. In six cases, in whom postmortem was performed, neuropathological examination disclosed neuronal loss and widespread Lewy-type pathology in the brain in each case. In a large IRBD cohort diagnosed in a tertiary referal sleep center, prolonged follow-up indicated that the majority of patients are eventually diagnosed with the synucleinopathies PD, DLB and less frequently MSA. IRBD represented the prodromal period of these conditions. Our findings in IRBD have important implications in clinical practice, in the investigation of the early pathological events occurring in the synucleinopathies, and for the design of interventions with potential disease-modifying agents.

Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson’s disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls. Skin biopsy was taken at C7, Th10, and the upper and lower leg. Presynaptic dopamine transporter imaging using FP-CIT-SPECT was performed in all patients with RBD and in 11 patients with PD. All RBD patients underwent olfactory function testing. The likelihood ratio (LR) for prodromal PD was calculated for each patient based on published research criteria. Skin serial sections were assessed by double-immunofluorescence labelling with antibodies to pSer129-alpha-syn under blinded conditions. P-alpha-syn was visualized in 10/18 patients with RBD (sensitivity of 55.6%) and in 20/25 early PD patients (sensitivity of 80%) but in none of the controls (specificity of 100%). The percentage of dermal structures innervated by p-alpha-syn-positive fibres was negatively correlated with dopamine transporter binding in the FP-CIT-SPECT ( ρ  = −0.377, p  = 0.048), with olfactory function ( ρ  = −0.668, p  = 0.002), and positively correlated with the total LR for RBD to present prodromal PD ( ρ  = 0.531, p  = 0.023). Dermal p-alpha-syn can be considered a peripheral histopathological marker of synucleinopathy and can be detected in a subgroup of RBD patients presumably representing prodromal PD. Dermal p-alpha-syn is detectable in RBD patients without PD motor symptoms, thereby stratifying a patient group that is of great interest for clinical trials testing disease-modifying drugs.

Accumulating evidence suggests that α-synuclein aggregates—a defining pathology of Parkinson's disease—display cell-to-cell transmission. α-synuclein aggregation is hypothesised to start in autonomic nerve terminals years before the appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. To assess this hypothesis, we investigated sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder, a prodromal phenotype of Parkinson's disease. In this prospective, case-control study, we recruited patients with idiopathic REM sleep behaviour disorder, confirmed by polysomnography, without clinical signs of parkinsonism or dementia, via advertisement and through sleep clinics in Denmark. We used 11C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, 11C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and 18F-dihydroxyphenylalanine (DOPA) PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, we compared patients with idiopathic REM sleep behaviour disorder with previously published reference data of controls without neurological disorders or cognitive impairment and with symptomatic patients with Parkinson's disease. We assessed imaging data using one-way ANOVA corrected for multiple comparisons. Between June 3, 2016, and Dec 19, 2017, we recruited 22 consecutive patients with idiopathic REM sleep behaviour disorder to the study. Compared with controls, patients with idiopathic REM sleep behaviour disorder had decreased colonic 11C-donepezil uptake (−0·322, 95% CI −0·112 to −0·531; p=0·0020), 123I-MIBG heart:mediastinum ratio (−0·508, −0·353 to −0·664; p<0·0001), neuromelanin-sensitive MRI locus coeruleus:pons ratio (−0·059, −0·019 to −0·099; p=0·0028), and putaminal 18F-DOPA uptake (Ki; −0·0023, −0·0009 to −0·0037; p=0·0013). No between-group differences were detected between idiopathic REM sleep behaviour disorder and Parkinson's disease groups with respect to 11C-donepezil (p=0·39), 123I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and 11C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had 18F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased 18F-DOPA Ki values when compared with patients with idiopathic REM sleep behaviour disorder (p<0·0001). Patients with idiopathic REM sleep behaviour disorder had fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed Parkinson's disease. These patients also showed noradrenergic thalamic denervation, but most had normal putaminal dopaminergic storage capacity. This caudorostral gradient of dysfunction supports the hypothesis that α-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem. Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation.

We postulated that idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) represents the prodromal phase of a Lewy body disorder and that, with sufficient follow-up, most cases would eventually be diagnosed with a clinical defined Lewy body disorder, such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB). Patients from an IRBD cohort recruited between 1991 and 2003, and previously assessed in 2005, were followed up during an additional period of 7 years. In this original cohort, we sought to identify the nature and frequency of emerging defined neurodegenerative syndromes diagnosed by standard clinical criteria. We estimated rates of survival free from defined neurodegenerative disease by means of the Kaplan-Meier method. We further characterised individuals who remained diagnosed as having only IRBD, through dopamine transporter (DAT) imaging, transcranial sonography (TCS), and olfactory testing. We did a neuropathological assessment in three patients who died during follow-up and who had the antemortem diagnosis of PD or DLB. Of the 44 participants from the original cohort, 36 (82%) had developed a defined neurodegenerative syndrome by the 2012 assessment (16 patients were diagnosed with PD, 14 with DLB, one with multiple system atrophy, and five with mild cognitive impairment). The rates of neurological-disease-free survival from time of IRBD diagnosis were 65·2% (95% CI 50·9 to 79·5) at 5 years, 26·6% (12·7 to 40·5) at 10 years, and 7·5% (−1·9 to 16·9) at 14 years. Of the four remaining neurological-disease-free individuals who underwent neuroimaging and olfactory tests, all four had decreased striatal DAT uptake, one had substantia nigra hyperechogenicity on TCS, and two had impaired olfaction. In three patients, the antemortem diagnoses of PD and DLB were confirmed by neuropathological examination showing widespread Lewy bodies in the brain, and α-synuclein aggregates in the peripheral autonomic nervous system in one case. In these three patients, neuronal loss and Lewy pathology (α-synuclein-containing Lewy bodies and Lewy neurites) were found in the brainstem nuclei that regulate REM sleep atonia. Most IRBD individuals from our cohort developed a Lewy body disorder with time. Patients who remained disease-free at follow-up showed markers of increased short-term risk for developing PD and DLB in IRBD, such as decreased striatal DAT binding. Our findings indicate that in most patients diagnosed with IRBD this parasomnia represents the prodromal phase of a Lewy body disorder. IRBD is a candidate for the study of early events and progression of this prodromal phase, and to test disease-modifying strategies to slow or stop the neurodegenerative process. None.

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P  = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P  = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P  = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P  = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P  = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P  = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.

Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) is thought to be an early stage of α-synuclein-related neurodegenerative diseases. Nevertheless, the definitive identification of its biological substrate can be determined only by post-mortem neuropathology. We aimed to describe the post-mortem neuropathology of individuals with IRBD who developed or did not develop a neurodegenerative disease before death. In this case series at the Hospital Clinic de Barcelona, Barcelona, Spain, we examined post-mortem brain tissue and spinal cords from individuals diagnosed with IRBD by video polysomnography who became donors to the Neurological Tissue Bank between May 28, 2005, and March 23, 2023. We performed post-mortem neuropathology to assess the presence and distribution of neuronal loss, gliosis, and protein aggregates using antibodies against α-synuclein, amyloid β, phosphorylated tau, three-repeat and four-repeat tau isoforms, and TDP-43. Comparative statistical analyses were not done because of the small sample size, but differences observed across the nuclei and brain structures were described. The brains and spinal cords of 20 individuals with IRBD were examined (19 [95%] men, one [5%] woman). Their clinical antemortem diagnoses were of IRBD without any other neurological disorder in three (15%), Parkinson's disease without dementia in two (10%), Parkinson's disease dementia (PDD) in three (15%), and dementia with Lewy bodies (DLB) in 12 (60%) individuals. Post-mortem neuropathological diagnoses were Lewy body disease in 19 (95%) and multiple system atrophy (MSA) in one (5%). All participants with Lewy body disease and MSA showed neuronal loss, gliosis, and α-synuclein deposits in neurons and astrocytes. In all participants, α-synuclein was found in the structures that regulate REM sleep atonia (eg, subcoeruleus nucleus, gigantocellular reticular nucleus, laterodorsal tegmentum, and amygdala). Coexistent pathologies were found in all participants, including Alzheimer's disease pathology (amyloid β plaques and neurofibrillary tangles) in 14 (70%), ageing-related tau astrogliopathy in 12 (60%), cerebral amyloid angiopathy in 11 (55%), argyrophilic grain disease in four (20%), limbic-predominant age-related TDP-43 encephalopathy in four (20%), and early changes indicative of progressive supranuclear palsy in three (15%). In individuals with IRBD without any other neurological disorder and in those who developed Parkinson's disease without dementia, α-synuclein was found in the brainstem and limbic system and rarely in the cortex, whereas coexisting proteinopathies were few and showed mild pathological burden. In contrast, in individuals who developed PDD or DLB, α-synuclein had diffuse distribution in the brainstem, limbic system, and cortex, and multiple comorbid pathologies were common, particularly those related to Alzheimer's disease. Although limited by a relatively small sample size, our observations provide strong neuropathological evidence that IRBD is an early stage of α-synuclein-related neurodegenerative disease. Concomitant pathologies are frequent and their role remains to be clarified: some might have contributed to the development of dementia, but some might be age-related changes. Our findings could inform the design of clinical trials of compounds that target specific pathological proteins (eg, α-synuclein and amyloid β) in people with IRBD. Fundación BBVA–Hospital Clínic de Barcelona.

Isolated REM sleep behavior disorder, characterized by dream-enacting movements during REM sleep, is a male-predominant parasomnia and the strongest prodromal marker of synucleinopathies. Individuals with this disorder show cortical atrophy whose regional distribution covaries with gene expression patterns measured in the healthy human brain. However, the effect of sex on these brain changes remains unknown. The study objective is to comprehensively assess sex differences in cortical morphology and to characterize the healthy-brain gene expression correlates of brain abnormalities using the largest international multicentric MRI dataset of polysomnography-confirmed patients. Males have significantly more extensive and severe cortical thinning compared to females, despite similar age and clinical features. Imaging transcriptomics analyses indicate that regions affected in female patients map onto areas with higher expression of estrogen-related receptor genes, particularly ESRRG and ESRRA , in the healthy brain. These findings support  potential sex-specific neuroprotection in the prodromal stages of synucleinopathies and may inform personalized and targeted therapeutic strategies. This study reveals that females with isolated REM sleep behavior disorder show less neurodegeneration than males. The least affected regions in females are regions that overexpress estrogen-related genes, suggesting potential sex-specific neuroprotection.

Parkinson’s disease (PD) is an age-related neurodegenerative disorder, diagnosed on the basis of typical motor disturbances, but also characterized by the presence of non-motor symptoms, such as rapid eye movement (REM)-sleep behavior disorders, olfactory impairment, and constipation, which are often prodromal to the onset of the disease. PD is often associated with the presence of oxidative brain injury and chronic neuroinflammation, with infiltration and accumulation of peripheral immune cells that have been found in affected brain regions of PD patients. Recently, the role of the gut-brain axis in the pathogenesis of PD is getting more and more attention, and several pieces of evidence indicate alterations in the gut microbiota of PD-affected patients. Diet exerts a central role in defining the microbiota composition and different dietetic patterns can result in a higher or lower abundance of specific bacteria that, in turn, can affect gut permeability and express anti- or pro-inflammatory metabolites. In the present review, the effects of the Mediterranean diet in modulating both PD onset and its progression will be considered with a special focus on the antioxidant and anti-inflammatory properties of this dietetic regimen as well as on its effects on the microbiota composition.