Probable REM Sleep Behavior Disorder Research Articles

Cognition and Other Non-Motor Symptoms in an At-Risk Cohort for Parkinson's Disease Defined by REM-Sleep Behavior Disorder and Hyposmia.

REM-sleep behavior disorder (RBD) and other non-motor symptoms such as hyposmia were proposed by the Movement Disorder Society as research criteria for prodromal Parkinson's disease (P-PD). Global cognitive deficit was later added. To compare non-motor symptoms, focusing on cognition, between a P-PD group and a matched control group. In this cross-sectional, case-control study, in a first set of analyses, we performed extensive cognitive testing on people with (n = 76) and a control group without (n = 195) probable RBD and hyposmia. Furthermore, we assessed motor and non-motor symptoms related to Parkinson's Disease (PD). After propensity score matching, we compared 62 P-PD with 62 age- and sex-matched controls. In addition, we performed regression analyses on the total sample (n = 271). In a second set of analyses, we used, a.o., the CUPRO to evaluate retrograde procedural memory and visuo-constructive functions. People with P-PD showed significantly poorer performances in global cognition, visuo-constructive and executive functions, mainly in mental flexibility (p < 0.001; p = 0.004; p = 0.003), despite similar educational levels (p = 0.415). We observed significantly more motor and non-motor symptoms (p < 0.001; p = 0.004), higher scores for depression (p = 0.004) and apathy (p < 0.001) as well as lower quality of life (p < 0.001) in P-PD. Our findings confirm that global cognitive, executive, and visuo-constructive deficits define the P-PD group. In addition, depression, apathy, and lower quality of life were more prevalent in P-PD. If replicated in other samples, executive and visuo-constructive deficits should be considered in non-motor P-PD. Determining specific patterns will support early recognition of PD, secondary prevention of complications and the development of neuroprotective treatments.

Microstructural alterations of the hypothalamus in Parkinson's disease and probable REM sleep behavior disorder

BackgroundWhether there is hypothalamic degeneration in Parkinson's disease (PD) and its association with clinical symptoms and pathophysiological changes remains controversial. ObjectivesWe aimed to quantify microstructural changes in hypothalamus using a novel deep learning-based tool in patients with PD and those with probable rapid-eye-movement sleep behavior disorder (pRBD). We further assessed whether these microstructural changes associated with clinical symptoms and free thyroxine (FT4) levels. MethodsThis study included 186 PD, 67 pRBD, and 179 healthy controls. Multi-shell diffusion MRI were scanned and mean kurtosis (MK) in hypothalamic subunits were calculated. Participants were assessed using Unified Parkinson's Disease Rating Scale (UPDRS), RBD Questionnaire-Hong Kong (RBDQ-HK), Hamilton Depression Rating Scale (HAMD), and Activity of Daily Living (ADL) Scale. Additionally, a subgroup of PD (n = 31) underwent assessment of FT4. ResultsPD showed significant decreases of MK in anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tubular (supTub), and inferior tubular hypothalamus when compared with healthy controls. Similarly, pRBD exhibited decreases of MK in a-iHyp and supTub. In PD group, MK in above four subunits were significantly correlated with UPDRS-I, HAMD, and ADL. Moreover, MK in a-iHyp and a-sHyp were significantly correlated with FT4 level. In pRBD group, correlations were observed between MK in a-iHyp and UPDRS-I. ConclusionsOur study reveals that microstructural changes in the hypothalamus are already significant at the early neurodegenerative stage. These changes are associated with emotional alterations, daily activity levels, and thyroid hormone levels.

Longitudinal brain changes in Parkinson's disease with severe olfactory deficit

IntroductionOlfactory dysfunction and REM sleep behavior disorder (RBD) are associated with distinct cognitive trajectories in the course of Parkinson's disease (PD). The underlying neurobiology for this relationship remains unclear but may involve distinct patterns of neurodegeneration. This study aimed to examine longitudinal cortical atrophy and thinning in early-stage PD with severe olfactory deficit (anosmia) without and with concurrent probable RBD. MethodsLongitudinal MRI data over four years of 134 de novo PD and 49 healthy controls (HC) from the Parkinson Progression Marker Initiative (PPMI) cohort were analyzed using a linear mixed-effects model. Patients were categorized into those with anosmia by the University of Pennsylvania Smell Identification Test (UPSIT) score ≤ 18 (AO+) and those without (UPSIT score > 18, AO-). The AO+ group was further subdivided into AO+ with probable RBD (AO+RBD+) and without (AO+RBD-) for subanalysis. ResultsCompared to subjects without baseline anosmia, the AO+ group exhibited greater longitudinal declines in both volume and thickness in the bilateral parahippocampal gyri and right transverse temporal gyrus. Patients with concurrent anosmia and RBD showed more extensive longitudinal declines in cortical volume and thickness, involving additional brain regions including the bilateral precuneus, left inferior temporal gyrus, right paracentral gyrus, and right precentral gyrus. ConclusionsThe atrophy/thinning patterns in early-stage PD with severe olfactory dysfunction include regions that are critical for cognitive function and could provide a structural basis for previously reported associations between severe olfactory deficit and cognitive decline in PD. Concurrent RBD might enhance the dynamics of cortical changes.

Associations between the burdens of comorbid sleep problems, central sensitization, and headache-related disability in patients with migraine.

Sleep disturbances are common in migraine patients and affect quality of life. Central sensitization (CS) is likely to play a role in the increased severity and chronicity of migraine. We hypothesized that the number of comorbid sleep problems would affect headache-related disability through the effects of central sensitization (CS). We performed a cross-sectional study including 215 consecutive patients with migraine. Insomnia was defined as a Pittsburgh Sleep Quality Index (PSQI) global score greater than 5. Probable REM sleep behavior disorder (pRBD) was defined as an RBD screening score of 5 or greater. Excessive daytime sleepiness (EDS) was defined as an Epworth Sleepiness Scale score of 10 or higher. Suspected sleep apnea (SA) was defined as patients with snoring or sleep apnea witnessed 3 or more nights a week. CS was assessed by the Central Sensitization Inventory (CSI). Restless legs syndrome, insomnia, EDS, SA and pRBD were observed in 25.6%, 71.6%, 34.4%, 10.2%, and 21.4%, respectively, of the patients. At least one sleep problem was present in 87.0% of the patients. According to the results of the multinomial logistic regression analysis with no sleep problems as a reference, after we corrected for adjustment factors, the Migraine Disability Assessment (MIDAS) score significantly increased when three or more comorbid sleep problems were present. According to our mediation analysis, an increased number of sleep problems had a direct effect on the MIDAS score after we adjusted for other variables, and the CSI score was indirectly involved in this association. The present study showed an association between migraine-related disability and the burden of multiple sleep problems, which was partially mediated by CS.

Parkinson’s disease motor progression in relation to the timing of REM sleep behavior disorder presentation: an exploratory retrospective study

REM sleep behavior disorder (RBD) is a frequent non-motor symptom of Parkinson’s disease (PD), and the timing of its presentation might have a role in the underlying neurodegenerative process. Here, we aimed to define the potential impact of probable RBD (pRBD) on PD motor progression.We conducted a longitudinal retrospective study on 66 PD patients followed up at the University Hospital of Rome Tor Vergata. Patients were divided into three groups: with post-motor pRBD (pRBDpost, n = 25), without pRBD (pRBDwo, n = 20), and with pre-motor pRBD (pRBDpre, n = 21). Hoehn and Yahr (H&Y) scores, Unified PD Rating Scale (UPDRS) motor scores, and levodopa equivalent daily dose were collected at two follow-up visits conducted in a 5-year interval (T0 and T1). pRBDpost patients had a greater rate of motor progression in terms of the H&Y scale compared to pRBDpre and pRBDwo patients, without the influence of anti-parkinsonian treatment.These preliminary findings suggest that the post-motor occurrence of pRBD can be associated with an acceleration in PD motor progression.

Reorganization of intrinsic functional connectivity in early-stage Parkinson’s disease patients with probable REM sleep behavior disorder

REM sleep behavior disorder (RBD) symptoms in Parkinson’s disease (PD) suggest both a clinically and pathologically malignant subtype. However, whether RBD symptoms are associated with alterations in the organization of whole-brain intrinsic functional networks in PD, especially at early disease stages, remains unclear. Here we use resting-state functional MRI, coupled with graph-theoretical approaches and network-based statistics analyses, and validated with large-scale network analyses, to characterize functional brain networks and their relationship with clinical measures in early PD patients with probable RBD (PD+pRBD), early PD patients without probable RBD (PD-pRBD) and healthy controls. Thirty-six PD+pRBD, 57 PD-pRBD and 71 healthy controls were included in the final analyses. The PD+pRBD group demonstrated decreased global efficiency (t = -2.036, P = 0.0432) compared to PD-pRBD, and decreased network efficiency, as well as comprehensively disrupted nodal efficiency and whole-brain networks (all eight networks, but especially in the sensorimotor, default mode and visual networks) compared to healthy controls. The PD-pRBD group showed decreased nodal degree in right ventral frontal cortex and more affected edges in the frontoparietal and ventral attention networks compared to healthy controls. Furthermore, the assortativity coefficient was negatively correlated with Montreal cognitive assessment scores in the PD+pRBD group (r = -0.365, P = 0.026, d = 0.154). The observation of altered whole-brain functional networks and its correlation with cognitive function in PD+pRBD suggest reorganization of the intrinsic functional connectivity to maintain the brain function in the early stage of the disease. Future longitudinal studies following these alterations along disease progression are warranted.

Pathological associations with parkinsonism in chronic traumatic encephalopathy

AbstractBackgroundParkinsonism has been shown to be more frequent in those with a history of traumatic brain injury, repetitive head impacts (RHI), and chronic traumatic encephalopathy (CTE), a disease characterized by tau pathology. However, the underlying pathological associations with parkinsonism in this context are not well known.MethodsAutopsy participants with a history of RHI exposure through contact sports participation and neuropathologically diagnosed with CTE (n = 481) were examined for pathology in the substantia nigra. Based on review of next‐of‐kin interviews and medical records, expert clinicians judged whether symptoms of parkinsonism, including bradykinesia, resting tremor, rigidity, micrographia, and shuffling gait, were present. The total number of consecutive years of contact sports play was used as a proxy for RHI exposure. Neuropathological diagnoses were made using established criteria. Pathology in the substantia nigra was quantified for alpha‐synuclein‐positive Lewy bodies, neurofibrillary tangles (NFTs), and neuronal loss.ResultsOf a total of 481 male CTE participants, 119 (24.7%) had symptoms of parkinsonism during life. Comparison of clinical characteristics of CTE participants with (n = 119) and without (n = 362) parkinsonism showed those with parkinsonism had an older age of death, and a larger proportion had symptoms of dementia, probable REM sleep behavior disorder, and visual hallucinations than participants without parkinsonism (p’s &lt;0.00001). Of those with CTE and parkinsonism, the majority (70%) did not have Lewy bodies within the substantia nigra, suggesting other pathologies may also contribute to motor symptoms. In fact, those with parkinsonism were more likely to have nigral NFTs and neuronal loss (Figure), adjusting for age as well as when restricting to those age &gt;65 (p’s&lt;0.001). Years of contact sports play was associated with NFTs (p = 0.03) and neuronal loss (p = 0.016), but not Lewy bodies in the substantia nigra. Both nigral NFTs (p = 0.001) and Lewy bodies (p&lt;0.001) were associated with nigral neuronal loss. Parkinsonism was associated with neuronal loss (p&lt;0.001) and Lewy bodies (p = 0.027) in the substantia nigra.ConclusionOverall, these findings suggest that RHI contributes to tau pathology and neuronal loss in the substantia nigra. Those susceptible to Lewy body pathology may be further at risk for parkinsonism in CTE.

Reorganization of intrinsic functional connectivity in early-stage Parkinson's disease patients with probable REM sleep behavior disorder

Reorganization of intrinsic functional connectivity in early-stage Parkinson's disease patients with probable REM sleep behavior disorder

The risk factors for probable REM sleep behavior disorder: A case-control study

ObjectiveTo investigate the risk factors for REM sleep behavior disorder (RBD) in a case-control study. MethodsParticipants with probable RBD (pRBD) were defined using the RBD Questionnaire–Hong Kong (RBDQ-HK). Controls were collected by matching age and sex. Demographic information, lifestyle, comorbidity, prodromal symptoms of Parkinson's disease (PD), and blood biomarkers were assessed. The associations between these factors and pRBD were investigated by logistic regression. Partial correlation analysis was used to assess the association between the severity of RBD and depression. ResultsA total of 278 pRBD participants (age = 58.31 ± 15.82 years) and 556 controls (age = 58.16 ± 15.84 years) were enrolled in this study. Patients with pRBD were more likely to be current alcohol drinkers (OR 1.50, 95% CI 1.0–2.32). Participants with pRBD had a higher Hamilton Depression Rating Scale (HAMD-17) score (OR 1.17, 95% CI 1.11–1.22) than controls and were more likely to report arthritis (OR 1.53, 95% CI 1.08–2.16), constipation (OR 1.93, 95% CI 1.31–2.86), hyposmia (OR 1.71, 95% CI 1.10–2.67), and depression (OR 3.15, 95% CI 2.17–4.58). Higher levels of total cholesterol (OR 1.15, 95% CI 0.99–1.33) and low-density lipoprotein (OR 1.21, 95% CI 0.99–1.47) had borderline associations with pRBD. Additionally, the severity of pRBD was positively related to depression (r = 0.31, P < 0.01). ConclusionsWe determined several risk factors for pRBD in this case-control study. Future studies are needed to understand the mechanism underlying the association between these factors and pRBD.

The Genetic Basis of Probable REM Sleep Behavior Disorder in Parkinson's Disease.

Patients with Parkinson's Disease (PD) experience REM sleep behavior disorder (RBD) more frequently than healthy controls. RBD is associated with torpid disease evolution. To test the hypothesis that differential genetic signatures might contribute to the torpid disease evolution in PD patients with RBD we compared the rate of genetic mutations in PD patients with or without probable RBD. Patients with a clinical diagnosis of PD in the Parkinson's Progression Markers Initiative (PPMI) database entered the study. We excluded those with missing data, dementia, psychiatric conditions, or a diagnosis change over the first five years from the initial PD diagnosis. Probable RBD (pRBD) was confirmed by a REM Sleep Behavior Disorder Screening Questionnaire score > 5 points. Logistic regression and Machine Learning (ML) algorithms were used to relate Single Nucleotide Polymorphism (SNPs) in PD-related genes with pRBD. We included 330 PD patients fulfilling all inclusion and exclusion criteria. The final logistic multivariate model revealed that the following SNPs increased the risk of pRBD: GBA_N370S_rs76763715 (OR, 95% CI: 3.38, 1.45-7.93), SNCA_A53T_rs104893877 (8.21, 2.26-36.34), ANK2. CAMK2D_rs78738012 (2.12, 1.08-4.10), and ZNF184_rs9468199 (1.89, 1.08-3.33). Conversely, SNP COQ7. SYT17_rs11343 reduced pRBD risk (0.36, 0.15-0.78). The ML algorithms led to similar results. The predictive models were highly specific (95-99%) but lacked sensitivity (9-39%). We found a distinctive genetic signature for pRBD in PD. The high specificity and low sensitivity of the predictive models suggest that genetic mutations are necessary but not sufficient to develop pRBD in PD. Additional investigations are needed.

0899 Use of Artificial Intelligence for Early Characterization of Patients with RBD/RWA

Abstract Introduction The prevalence of polysomnography (PSG) confirmed REM sleep behavior disorder (RBD) has been estimated at 0.68% of the general population, and that of probable RBD at 5.65%. Isolated RBD is considered a pre-clinical marker of neurodegeneration with strong predictive value. Large longitudinal cohort studies demonstrate 81–91% of idiopathic RBD patients, followed for ≥14-years, will develop a definite neurodegenerative disease or mild cognitive impairment. Furthermore, high prevalence of sleep apnea (SA) exists in patients with RBD/REM without atonia (RWA), which can confound analysis of EMG tone and arousal activity. We demonstrate predictive AI models for RBD/RWA in subjects with and without SA. Methods Patients with known RBD/RWA who underwent PSG were divided into sub-groups with (n=86, RBDSA) and without SA (n=19, RBDNSA). Patient demographics, PSG characteristics, and co-morbid conditions were reviewed. Random forest (RF) models of PSG indices and Deep Learning (DL) methods identified predictive characteristics of RBD/RWA, sensitivity and specificity for RBD/RWA detection were estimated, and feature importance analysis was performed. Results Subjects with RBDSA compared to RBDNSA demonstrated greater BMI, AHI, Arousals (ArI), and Periodic Limb Movements (PLMs). In a Parkinson’s disease subgroup (n=12, RBDPD) compared to non-Parkinson’s sub-group, sleep was more fragmented, showing higher WASO, ArI, and PLMs. RF modeling demonstrated sensitivity/specificity of 67%/96% for RBDNSA subjects, and 79%/52% for RBDSA. Feature importance analysis resulted in several top-features for RBDNSA: N3 time, TST, AHI, REM duration, and sleep latency, while different top-features were observed for RBDSA: ratio of leg events in REM vs. non-REM, TST, ratio of arousals in REM vs. non-REM, REM duration, and REM time. Conclusion AI approaches including RF models produced high specificity and moderate sensitivity for RBDNSA subjects. Observed specificity was lower for RBDSA patients. We hypothesize the performance difference attributable to similarity and additional complexity in sleep disturbance characteristics between RBD and SA. Broad implementation of AI methods show potential to expand early detection and diagnosis of RBD and associated neurodegenerative conditions through expanded analysis, and follow-up, including RWA spectrum patients that don’t meet clinical thresholds for diagnosable RBD. Support (if any) None

Oligomeric Alpha-Synuclein and STX-1A from Neural-Derived Extracellular Vesicles (NDEVs) as Possible Biomarkers of REM Sleep Behavior Disorder in Parkinson's Disease: A Preliminary Cohort Study.

REM sleep behavior disorder (RBD) has a tighter link with synucleinopathies than other neurodegenerative disorders. Parkinson's Disease (PD) patients with RBD have a more severe motor and cognitive impairment; biomarkers for RBD are currently unavailable. Synaptic accumulation of α-Syn oligomers and their interaction with SNARE proteins is responsible for synaptic dysfunction in PD. We verified whether oligomeric α-Syn and SNARE components in neural-derived extracellular vesicles (NDEVs) in serum could be biomarkers for RBD. Forty-seven PD patients were enrolled, and the RBD Screening Questionnaire (RBDSQ) was compiled. A cut-off score > 6 to define probable RBD (p-RBD) and probable non-RBD (p non-RBD) was used. NDEVs were isolated from serum by immunocapture, and oligomeric α-Syn and SNARE complex components VAMP-2 and STX-1 were measured by ELISA. NDEVs' STX-1A resulted in being decreased in p-RBD compared to p non-RBD PD patients. A positive correlation between NDEVs' oligomeric α-Syn and RBDSQ total score was found (p = 0.032). Regression analysis confirmed a significant association between NDEVs' oligomeric α-Syn concentration and RBD symptoms (p = 0.033) independent from age, disease duration, and motor impairment severity. Our findings suggest that synuclein-mediated neurodegeneration in PD-RBD is more diffuse. NDEVs' oligomeric α-Syn and SNARE complex components' serum concentrations could be regarded as reliable biomarkers for the RBD-specific PD endophenotype.

Composite Measures of Prodromal Parkinson’s Disease and the Probability of Phenoconversion at 3 Years (S37.003)

<h3>Objective:</h3> To assess the ability of composite measures of prodromal Parkinson’s disease (PD) to predict phenoconversion at 3 years. <h3>Background:</h3> Features suggestive of prodromal PD are individually insufficient for early disease detection. Using composite measures may improve predictive validity and capture a more representative patient population. <h3>Design/Methods:</h3> The study population comprised 19,757 individuals without PD at baseline (2014–2015). Two composite measures were created: i) the co-occurrence of probable REM sleep behavior disorder (pRBD), constipation and hyposmia, 3 major features of prodromal PD, and ii) a probability score which incorporated information on 8 risk (e.g., sex, physical inactivity) and 7 prodromal markers following the MDS research criteria. For each composite measure we calculated the positive predictive value (PPV) of being diagnosed with PD within 3 years. We additionally calculated the PPV for pRBD, constipation and hyposmia independently, and that of all 3 features along with parkinsonism. We repeated analyses restricting to participants &lt;70 years old. <h3>Results:</h3> Between 2014–15 and 2017–18, we identified a total of 86 incident PD cases. The PPV of being diagnosed with PD within 3 years was 2.48% for those with the 3 prodromal features, 2.62% for those with possible prodromal PD (score≥0.5) and 4.55% for those with probable prodromal PD (score≥0.8). The PPV of individual features was lower than those of the composite measures. Parkinsonism plus the co-occurrence of 3 features resulted in the highest PPV (11.8%). Measures based on the presence of 3 features performed somewhat better among men than women. The PPVs of measures based on the MDS score or parkinsonism were higher among those aged &lt;70 years. <h3>Conclusions:</h3> The ability to predict phenoconversion at 3 years was comparable between the two composite measures evaluated. The performance of composite measures was superior to that of individual features. Longer follow-up may be needed to better understand the validity of these measures. <b>Disclosure:</b> Mr. Torres has nothing to disclose. Dr. Hughes has received personal compensation for serving as an employee of Optum. The institution of Dr. Bjornevik has received research support from Michael J. Fox Foundation. The institution of Dr. Bjornevik has received research support from National Multiple Sclerosis Society. The institution of Dr. Bjornevik has received research support from Department of Defense. Dr. Cortese has received personal compensation in the range of $500-$4,999 for serving as a speaker at educational event with Roche. The institution of Dr. Hung has received research support from Parkinson’s Foundation. The institution of Dr. Hung has received research support from Rho, Inc.. The institution of Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bial Biotech (indirectly, as a service of the Parkinson Study Group service). The institution of Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen (indirectly, as a service of the Parkinson Study Group service). The institution of Dr. Schwarzschild has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB (indirectly, as a service of the Parkinson Study Group service). Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. The institution of Dr. Schwarzschild has received research support from NIH. The institution of Dr. Schwarzschild has received research support from Parkinson’s Foundation. The institution of Dr. Schwarzschild has received research support from Michael J Fox Foundation. The institution of Dr. Schwarzschild has received research support from Farmer Family Foundation. Dr. Schwarzschild has a non-compensated relationship as a Chair, Executive Committee with the Parkinson Study Group that is relevant to AAN interests or activities. The institution of Dr. Ascherio has received research support from NIH and US Department of Defense .

Influence of RBD onset on the clinical characteristics of Parkinson's disease patients: a retrospective study.

In Parkinson's disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) might either precede the appearance of motor symptoms, or develop during the disease course. PD patients with RBD are characterized by a higher burden of cognitive impairment and hallucinations. However, few studies have analyzed the clinical characteristics of PD patients according to the timeline of RBD onset. PD patients have been retrospectively enrolled. Presence and onset of probable RBD (pRBD) has been evaluated using RBD Screening Questionnaire (score ≥ 6). Presence of Mild Cognitive Impairment (MCI) at baseline has been evaluated using the MDS criteria level II. Presence of motor complications and hallucinations has been evaluated at a 5-year follow-up. A total of 115 PD patients (65 men, 56.5%; mean age 62.5 ± 9.7years; mean disease duration 3.7 ± 3.9years) have been enrolled. Out of these, 63 fulfilled the diagnosis of pRBD (54.8%) with 21 (33.3%) reporting the RBD onset before the onset of the motor symptoms (PD-RBDpre), and 42 (66.7%) after the motor symptoms (PD-RBDpost). At enrolment presence of MCI was associated with PD-RBDpre patients (OR 5.04; 95% CI 1.33-19.05; p value 0.02). At follow-up, a higher risk of developing hallucinations was also associated with PD-RBDpre (OR 4.68; 95% CI 1.24-17.63; p = 0.022). PD patients with RBD occurring before the onset of motor symptoms represent a subgroup of patients with a more severe cognitive phenotype and with a higher risk of developing hallucinations along the disease course, with significant implications in terms of prognostic stratification and therapeutic approach.

The relationship between serum neurofilament light chain and glial fibrillary acidic protein with the REM sleep behavior disorder subtype of Parkinson's disease.

Studies have shown that rapid eye movement (REM) sleep behavior disorder (RBD) is a subtype of Parkinson's disease (PD) characterized by severe cognitive impairment and rapid disease progression. However, reliable biological markers are lacking presently. Neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) have been widely studied as biomarkers of cognition impairment. This study aimed to find biomarkers for the RBD subtype of PD by investigating the possible relationship between serum NFL, GFAP levels, and the RBD subtype. A total of 109 PD patients and 37 healthy controls (HCs) were included, and their clinical characteristics were evaluated. PD patients were divided into two groups based on whether they had probable RBD or not. Serum NFL and GFAP levels were measured using the ultrasensitive single molecule array (Simoa) platform. The obtained data were statistically analyzed using SPSS 25.0 (IBM, Chicago, IL, USA). NFL and GFAP in the PD-RBD group were elevated compared with the PD-nRBD and control groups. Moreover, serum NFL and GFAP levels positively correlated with RBD. The combination of NFL and GFAP showed good performance in identifying PD-RBD patients from PD-nRBD. After considering potential confounding factors such as age, and disease duration, serum NFL and GFAP emerged as independent risk factors for RBD. Serum NFL and GFAP were related to RBD in PD patients. Concludingly, serum NFL and GFAP might serve as promising biomarkers for the RBD subtype of PD.

Body-First Subtype of Parkinson's Disease with Probable REM-Sleep Behavior Disorder Is Associated with Non-Motor Dominant Phenotype.

The hypothesis of body-first vs. brain-first subtype of PD has been proposed with REM-Sleep behavior disorder (RBD) defining the former. The body-first PD presumes an involvement of the brainstem in the pathogenic process with higher burden of autonomic dysfunction. To identify distinctive clinical subtypes of idiopathic Parkinson's disease (iPD) in line with the formerly proposed concept of body-first vs. brain-first subtypes in PD, we analyzed the presence of probable RBD (pRBD), sex, and the APOEɛ4 carrier status as potential sub-group stratifiers. A total of 400 iPD patients were included in the cross-sectional analysis from the baseline dataset with a completed RBD Screening Questionnaire (RBDSQ) for classifying as pRBD by using the cut-off RBDSQ≥6. Multiple regression models were applied to explore (i) the effect of pRBD on clinical outcomes adjusted for disease duration and age, (ii) the effect of sex on pRBD, and (iii) the association of APOEɛ4 and pRBD. iPD-pRBD was significantly associated with autonomic dysfunction (SCOPA-AUT), level of depressive symptoms (BDI-I), MDS-UPDRS I, hallucinations, and constipation, whereas significantly negatively associated with quality of life (PDQ-39) and sleep (PDSS). No significant association between sex and pRBD or APOE ɛ4 and pRBD in iPD was found nor did we determine a significant effect of APOE ɛ4 on the PD phenotype. We identified an RBD-specific PD endophenotype, characterized by predominant autonomic dysfunction, hallucinations, and depression, corroborating the concept of a distinctive body-first subtype of PD. We did not observe a significant association between APOE ɛ4 and pRBD suggesting both factors having an independent effect on cognitive decline in iPD.

Resting-state network connectivity changes in drug-naive Parkinson's disease patients with probable REM sleep behavior disorder.

Epidemiological studies have shown that Parkinson's disease (PD) patients with probable REM sleep behavior disorder (pRBD) present an increased risk of worse cognitive progression over the disease course. The aim of this study was to investigate, using resting-state functional MRI (RS-fMRI), the functional connectivity (FC) changes associated with the presence of pRBD in a cohort of newly diagnosed, drug-naive and cognitively unimpaired PD patients compared to healthy controls (HC). Fifty-six drug-naïve patients (25 PD-pRBD+ and 31 PD-pRBD-) and 23 HC underwent both RS-fMRI and clinical assessment. Single-subject and group-level independent component analysis was used to analyze intra- and inter-network FC differences within the major large-scale neurocognitive networks, namely the default mode (DMN), frontoparietal (FPN), salience (SN) and executive-control (ECN) networks. Widespread FC changes were found within the most relevant neurocognitive networks in PD patients compared to HC. Moreover, PD-pRBD+ patients showed abnormal intrinsic FC within the DMN, ECN and SN compared to PD-pRBD-. Finally, PD-pRBD+ patients showed functional decoupling between left and right FPN. In the present study, we revealed that FC changes within the most relevant neurocognitive networks are already detectable in early drug-naïve PD patients, even in the absence of clinical overt cognitive impairment. These changes are even more evident in PD patients with RBD, potentially leading to profound impairment in cognitive processing and cognitive/behavioral integration, as well as to fronto-striatal maladaptive compensatory mechanisms.

Gait Correlates of Cognitive Function and Future Decline

AbstractBackgroundSlow walking speed is associated with numerous negative health outcomes including global cognitive decline.1 More detailed gait analysis can differentiate among different dementia subtypes,10 but the predictive power of baseline gait metrics for domain‐specific cognitive decline needs further characterization.MethodWe conducted a follow up study on 534 participants of the Mayo Clinic Study of Aging who underwent evaluations every 15 months (median follow‐up = 5.4 years). We analyzed quantitative gait metrics, acquired with a pressure‐sensing walkway (GAITRite® instrument), and cognitive scores using a linear mixed effects model to identify correlations between z‐scored baseline gait metrics (cadence, swing time, stance time, velocity, double support time (DST), stride length, stride length standard deviation (SD), stride time SD, swing time SD, stance time SD, DST SD) and cognitive domain z‐scores (memory, attention, language, visuospatial, global) at baseline and over time. Models controlled for age, sex, and probable REM sleep behavior disorder at baseline.ResultThe table includes both baseline associations and difference in slopes (Δ), relative to the average person, in cognitive domains. These slopes ranged from about ‐0.05 for visuospatial to ‐0.12 for attention.ConclusionIncreased gait velocity and stride length are associated with less severe domain‐specific and global cognitive decline while increased swing time SD and DST are associated with more severe rates of decline in some domains. These findings suggest that baseline gait characteristics could be a helpful predictor of future cognitive changes.

Clinical features in prodromal disease: Comparing dementia with Lewy bodies with Alzheimer’s disease

AbstractBackgroundDementia with Lewy bodies (DLB) is a common neurodegenerative disorder; however, DLB can be difficult to differentiate from Alzheimer’s disease dementia (AD), particularly in the early stages. Research criteria for prodromal DLB were published in 2020 and further studies are needed to validate and refine future clinical criteria.MethodWe analyzed data from the Uniform Data Set from the National Alzheimer’s Coordinating Center (NACC database is funded by NIA/NIH U01‐AG016976). Annual visits occurred across 39 Alzheimer’s Disease Research Centers between September 2005 and September 2021. We identified non‐demented participants [i.e., normal cognition, impaired‐not mild cognitive impairment (MCI) or MCI] at baseline who subsequently received a clinical diagnosis of DLB or AD. Core clinical features (CCF) for DLB (i.e., motor features, visual hallucinations, probable REM sleep behavior disorder (pRBD), cognitive fluctuations), and supportive neuropsychiatric features (NPF; anxiety, apathy, and depression) were assessed through clinical exam and informant responses up to five years prior to dementia diagnosis.ResultThe sample consisted of 160 participants with DLB and 480 age/sex‐matched (1:3) participants with AD at first visit with dementia diagnosis. There was no significant difference in the number of visits prior to dementia diagnosis. The AD group was more racially and ethnically diverse than the DLB group. At the time of diagnosis, DLB participants demonstrated greater functional impairment. Descriptive results indicate CCF and NPF are common in DLB up to five years prior to conversion to dementia; however, motor slowing and NPF were reported in over 20% of the AD participants within the prodromal phase. The presence of 2 or more CCF yielded the greatest AUC (0.786; 95% CI: 0.743, 0.830) in distinguishing DLB from AD one year prior to dementia diagnosis. Combinations of 1 or more CCF with 1, 2, or 3 NPF resulted in significantly lower AUCs (0.725, 0.651, 0.547, respectively) due to decreased specificity.ConclusionCCF and supportive NPF are common in the prodromal phase of DLB; however, parkinsonism and NPF also occurred in the prodromal AD group. Parkinsonism may provide lower discrimination than cognitive fluctuations, visual hallucinations, or pRBD in differentiating DLB from AD in the prodromal phase.

18F]FEOBV positron emission tomography may not be a suitable method to measure parasympathetic denervation in patients with Parkinson's disease

IntroductionThe peripheral autonomic nervous system may be involved years before onset of motor symptoms in some patients with Parkinson's disease (PD). Specific imaging techniques to quantify the cholinergic nervous system in peripheral organs are an unmet need. We tested the hypothesis that patients with PD display decreased [18F]FEOBV uptake in peripheral organs – a sign of parasympathetic denervation. MethodsWe included 15 PD patients and 15 age- and sex matched healthy controls for a 70 min whole-body dynamic positron emission tomography (PET) acquisition. Compartmental modelling was used for tracer kinetic analyses of adrenal gland, pancreas, myocardium, spleen, renal cortex, muscle and colon. Standard uptake values (SUV) at 60–70 min post injection were also extracted for these organs. Additionally, SUVs were also determined in the total colon, prostate, parotid and submandibular glands. ResultsWe found no statistically significant difference of [18F]FEOBV binding parameters in any organs between patients with PD and healthy controls, although trends were observed. The pancreas SUV showed a 14% reduction in patients (P = 0.021, not statistically significant after multiple comparison correction). We observed a trend towards lower SUVs in the pancreas, colon, adrenal gland, and myocardium of PD patients with versus without probable REM sleep behavior disorder. Conclusion[18F]FEOBV PET may not be a sensitive marker for parasympathetic degeneration in patients with PD.