99mTc-HMPAO SPECT Perfusion Signatures Associated With Clinical Progression in Patients With Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Idiopathic/isolated REM sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies and Parkinson disease. Despite evidence of abnormal cerebral perfusion in iRBD, there is currently no pattern that can predict whether an individual will develop dementia with Lewy bodies or Parkinson disease. The objective was to identify a perfusion signature associated with conversion to dementia with Lewy bodies in iRBD. METHODS: Patients with iRBD underwent video-polysomnography, neurologic and neuropsychological assessments, and baseline 99mTc-HMPAO SPECT to assess relative cerebral blood flow. Partial least squares correlation was used to identify latent variables that maximized covariance between 27 clinical features and relative gray matter perfusion. Patient-specific scores on the latent variables were used to test the association with conversion to dementia with Lewy bodies compared with that with Parkinson disease. The signature's expression was also assessed in 24 patients with iRBD who underwent a second perfusion scan, 22 healthy controls, and 19 individuals with Parkinson disease. RESULTS: Of the 137 participants, 93 underwent SPECT processing, namely 52 patients with iRBD (67.9 years, 73% men), 19 patients with Parkinson disease (67.3 years, 37% men), and 22 controls (67.0 years, 73% men). Of the 47 patients with iRBD followed up longitudinally (4.5 years), 12 (26%) developed a manifest synucleinopathy (4 dementia with Lewy bodies and 8 Parkinson disease). Analysis revealed 2 latent variables between relative blood flow and clinical features: the first was associated with a broad set of features that included motor, cognitive, and perceptual variables, age, and sex; the second was mostly associated with cognitive features and RBD duration. When brought back into the patient's space, the expression of the first variable was associated with conversion to a manifest synucleinopathy, whereas the second was associated with conversion to dementia with Lewy bodies. The expression of the patterns changed over time and was associated with worse motor features. DISCUSSION: This study identified a brain perfusion signature associated with cognitive impairment in iRBD and transition to dementia with Lewy bodies. This signature, which can be derived from individual scans, has the potential to be developed into a biomarker that predicts dementia with Lewy bodies in at-risk individuals.

Sleep disorders and mortality: A prospective study in the Canadian longitudinal study on aging.

BACKGROUND AND OBJECTIVES: Sleep disorders are commonly linked to various health conditions, although it remains unclear to what degree they are linked with overall mortality. We compared mortality in different self-reported sleep disorders in a large population-based prospective study. METHODS: In this case-control study within the CLSA cohort, participants completed a questionnaire at baseline (2011-2015) measuring overall sleep satisfaction, daily sleep duration, sleep-onset and sleep-maintenance insomnia, daytime somnolence, REM sleep behavior disorder (RBD), restless leg syndrome (RLS), and obstructive sleep apnea (OSA). The vital status of participants was assessed in July 2019. Baseline sleep problems of participants who died (cases) were compared to those who survived (controls). For each case, five age/sex-matched controls were selected. Binary logistic regression was used to estimate the association between sleep symptoms and mortality, adjusting for age, sex, marital status, province, education, alcohol consumption, smoking, caffeine, and body mass index. In a complementary model, anxiety and depression were also added. RESULTS: Among 30,097 participants at baseline, 974 deaths were reported in 2019 (60.7 % male, age = 72.3 ± 9.4 years). In the initial analysis, mortality cases reported more baseline sleep-maintenance insomnia (12.1 % vs. 8.0 %, Adjusted OR[95%CI] = 1.62[1.15,2.29]), daytime somnolence (2.4 % vs. 1.1 %, AOR = 2.70[1.34,5.44]), and higher possible RLS (16.4 % vs. 12.4 %, AOR = 1.50[1.09,2.05]). They were also more likely to screen positive for possible OSA (33.8 % vs. 24.2 %, AOR = 1.32[1.07,1.64]); however, this effect was not related to core apnea symptoms. Sleep durations exceeding 10 h/day were also associated with increased mortality (3.4 % vs. 1.9 %, AOR = 1.83[1.04,3.24]). Other sleep symptoms/disorders, such as sleep-onset insomnia (7.3 % vs. 4.3 %, AOR = 1.54 [1.00,2.37]), possible RBD (5.3 % vs. 5.1 %, AOR = 1.02[0.62,1.69]), and overall sleep dissatisfaction (26.5 % vs. 22.6 %, AOR = 1.14[0.93,1.41]) were not different among these groups. After adding anxiety and depression to the adjustment model, all differences attenuated to become statistically non-significant, except for daytime somnolence disorder. When stratified by sex, the association between sleep disorders and mortality was only observed in women, with men showing no association. DISCUSSION: We confirm a relationship between numerous sleep disorders and mortality. This effect is most evident in women, and appears to be strongly related to co-existing anxiety and depression.

Validation of the RBD Symptom Severity Scale in the North American Prodromal Synucleinopathy Consortium.

BACKGROUND AND OBJECTIVES: REM sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment. The International RBD Study Group developed the RBD Symptom Severity Scale (RBDSSS) to assess symptom severity for clinical or research use. We assessed the psychometric and clinimetric properties of the RBDSSS in participants enrolled in the North American Prodromal Synucleinopathy (NAPS) Consortium for RBD. METHODS: NAPS participants, who have polysomnogram-confirmed RBD, and their bedpartners completed the RBDSSS (participant and bedpartner versions). The RBDSSS contains 8 questions to assess the frequency and severity/impact of (1) dream content, (2) vocalizations, (3) movements, and (4) injuries associated with RBD. Total scores for participant (maximum score = 54) and bedpartner (maximum score = 38) questionnaires were derived by multiplying frequency and severity scores for each question. The Clinical Global Impression Scale of Severity (CGI-S) and RBD symptom frequency were assessed by a physician during a semistructured clinical interview with participants and, if available, bedpartners. Descriptive analyses, correlations between overall scores, and subitems were assessed, and item response analysis was performed to determine the scale's validity. RESULTS: Among 261 study participants, the median (interquartile range) score for the RBDSSS-PT (participant) was 10 (4-18) and that for the RBDSSS-BP (bedpartner) was 8 (4-15). The median CGI-S was 3 (3-4), indicating moderate severity. RBDSSS-BP scores were significantly lower in women with RBD (6 vs 9, p = 0.02), while there were no sex differences in RBDSSS-PT scores (8 vs 10.5, p = 0.615). Positive correlations were found between RBDSSS-PT vs RBDSSS-BP (Spearman rs = 0.561), RBDSSS-PT vs CGI-S (rs = 0.556), and RBDSSS-BP vs CGI-S (rs = 0.491, all p < 0.0001). Item response analysis showed a high discriminatory value (range 1.40-2.12) for the RBDSSS-PT and RBDSSS-BP (1.29-3.47). DISCUSSION: We describe the RBDSSS with adequate psychometric and clinimetric properties to quantify RBD symptom severity and good concordance between participant and bedpartner questionnaires and between RBDSSS scores and clinician-assessed global severity.

Montreal Cognitive Assessment and the Clock Drawing Test to Identify MCI and Predict Dementia in Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Patients with isolated/idiopathic REM sleep behavior disorder (iRBD) are at high risk for developing mild cognitive impairment (MCI) and dementia with Lewy bodies (DLB). However, there is a lack of scientific knowledge regarding the accuracy of cognitive screening tools to identify these conditions in iRBD. This study aimed to determine in iRBD the psychometrics of 2 screening tests to discriminate patients with MCI and those at risk of DLB. METHODS: We retrospectively selected and followed 64 patients with polysomnography-confirmed iRBD seen in sleep clinic between 2006 and 2021, 32 with MCI (mean age 68.44 years, 72% men), 32 without MCI (67.78 years, 66% men), and 32 controls (69.84 years, 47% men). Participants underwent a neurologic evaluation and neuropsychological assessment for MCI diagnosis. They also completed the Montreal Cognitive Assessment (MoCA) and Clock Drawing Test (CDT). Fifty-three patients were followed (mean of 5.10 ± 2.64 years); 6 developed DLB, and 16 developed Parkinson disease. An independent cohort of 10 patients with iRBD who later developed DLB was also recruited and followed. Receiver operating characteristic curves with area under the curve (AUC) were performed assessing the discriminant value of the MoCA and CDT. RESULTS: The cut-off values that best differentiated patients who developed DLB from controls were on the MoCA total score (≤25/30 with 100% [95% CI 61%-100%] sensitivity and 78% [61%-89%] specificity, AUC = 0.888) and delayed recall (≤3/5 with 83% [44%-97%] sensitivity and 78% [61%-89%] specificity, AUC = 0.875). Both values yielded a sensitivity of 90% (60%-98%) to detect patients at risk of DLB in the independent cohort. Cutoffs that best discriminated patients with MCI from controls were: ≤25/30 (MoCA total score) with 72% [55%-84%] sensitivity, 78% [61%-89%] specificity, AUC = 0.803 and ≤2/5 (MoCA delayed recall) with 63% [45%-77%] sensitivity, 94% [80%-98%] specificity, AUC = 0.843. No acceptable optimal values were found for the CDT. DISCUSSION: In iRBD, the MoCA demonstrates adequate psychometric properties to identify patients most at risk of developing DLB and to screen for MCI, whereas the CDT does not. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the MoCA, but not the CDT, is useful in screening patients with iRBD for the risk of developing DLB.

Comorbid neurotrauma increases neurodegenerative-relevant cognitive, motor, and autonomic dysfunction in patients with rapid eye movement sleep behavior disorder: a substudy of the North American Prodromal Synucleinopathy Consortium.

STUDY OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g. Parkinson's disease (PD), Lewy body dementia, and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)-henceforth "neurotrauma" (NT)-increase the odds of RBD by ~2.5-fold and are associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD. METHODS: Participants ≥18 years with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory, and autonomic function, were completed. This cross-sectional analysis compared cases (n = 24; RBD + NT) to controls (n = 96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years). RESULTS: RBD + NT reported earlier RBD symptom onset (37.5 ±â€…11.9 vs. 52.2 ±â€…15.1 years of age) and a more severe RBD phenotype. Similarly, RBD + NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed. CONCLUSIONS: This cross-sectional, matched case:control study shows individuals with RBD + NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD + NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study.

OBJECTIVE: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years. RESULTS: Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17). INTERPRETATION: Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530-543.

Is REM Sleep Behavior Disorder Changing? Secular Changes Versus Referral Patterns.

Background: Since 2014, there has been increasing public outreach effort regarding isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) in Montreal. Objective: To assess if, over time, milder iRBD cases are presenting earlier. Methods: Disease-free survival was compared in two iRBD recruitment epochs: 2004 to 2013 ("earlier") versus 2014to 2022 ("later") and by referral type ("self-referral" vs. "conventional-referral") in three large centers. Results: In Montreal, among 209 subjects followed prospectively, shorter time to phenoconversion was observed in the earlier epoch (5-year phenoconversion = 42% earlier vs. 23% later); diagnosis before 2014 had a 1.8-fold phenoconversion hazard. However, no difference was observed in 248 subjects from Barcelona and 166 from Innsbruck. Analysis of Montreal data found that increased survival in the later epoch was driven by an increasing number of self-referrals, who phenoconverted at 1/3 the rate of physician-referred subjects. Conclusions: Increased patient awareness of iRBD results in earlier presentation to clinical attention, with a longer time to phenoconversion.

DNA Methylation Age Acceleration as a Potential Biomarker for Early Onset of Rapid Eye Movement Sleep Behavior Disorder.

Rapid eye movement sleep behavior disorder (RBD) is the strongest prodromal marker for α-synucleinopathies. The Horvath DNA methylation age (DNAm-age) is an epigenetic clock reflecting biological aging. We found an association of DNAm-age acceleration with RBD age at onset at baseline (N = 162, B = -0.68, standard error [SE] = 0.12, p = 2.59e-08) and follow-up (n = 45, B = -1.07, SE = 0.21, p = 9.73e-06). The result remained similar after accounting for genetic risk factors (eg, RBD polygenic risk score). On average, RBD patients with faster versus slow/normal epigenetic aging had a 5.2-year earlier phenoconversion, and the Cox regression analysis revealed a trend toward significance (n = 53, hazard ratio = 1.05, 95% confidence interval = 0.99-1.11, p = 0.06). Our findings suggest that DNAm-age acceleration is a potential biomarker for earlier RBD onset. ANN NEUROL 2023.

Effects of Season and Daylight Saving Time Shifts on Sleep Symptoms: Canadian Longitudinal Study on Aging.

BACKGROUND AND OBJECTIVES: There has been conflicting evidence regarding the association between seasonal changes and daylight saving time (DST) and sleep disorders. This topic is of particular interest currently because the United States and Canada are considering the elimination of seasonal clock changes. The aim of this study was to compare sleep symptoms among participants who were interviewed in different seasons and before/after the transition into DST and standard time (ST). METHODS: A total of 30,097 people aged 45-85 years taking part in the Canadian Longitudinal Study on Aging were studied. Participants completed a questionnaire on sleep duration, satisfaction, sleep-onset insomnia, sleep-maintenance insomnia, and hypersomnolence symptoms. Sleep disorders were compared between participants who were interviewed during different seasons and at different times of the year (DST/ST). Data were analyzed using χ2, analysis of variance, binary logistic, and linear regression tests. RESULTS: Among participants interviewed in different seasons, we found no difference in dissatisfaction with sleep, sleep onset, sleep maintenance, and hypersomnolence. Those interviewed in summer had slightly shorter sleep duration compared with those in winter (6.76 ± 1.2 vs 6.84 ± 1.3 hours). Participants interviewed 1 week before vs 1 week after DST transition showed no difference in sleep symptoms, except for a 9-minute decrease in sleep duration a week after transition. However, those who were interviewed a week after transition to ST compared with a week before reported more dissatisfaction with sleep (28% vs 22.6%, adjusted odds ratio [aOR] 1.34, 95% CI 1.02-1.76), higher sleep-onset insomnia (7.1% vs 3.3%, aOR 2.26, 95% CI 1.19-4.27), higher sleep-maintenance insomnia (12.9% vs 8.2%, aOR 1.64, 95% CI 1.02-2.66), and more hypersomnolence with adequate sleep (7.3% vs 3.6%, aOR 2.08, 95% CI 1.14-3.79). DISCUSSION: We found small seasonal variations in sleep duration but no difference in other sleep symptoms. The transition from DST to ST was associated with a transient increase in sleep disorders.

Baseline characteristics of the North American prodromal Synucleinopathy cohort.

OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic-based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment. METHODS: Participants ≥18 years of age with overnight polysomnogram-confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were enrolled from nine sites across North America (8/2018 to 4/2021). Data collection included family/personal history of RBD and standardized assessments of cognitive, motor, sensory, and autonomic function. RESULTS: Outcomes are primarily reported based on sex (361 total: n = 295 male, n = 66 female), and secondarily based on history of antidepressant use (n = 200 with, n = 154 without; with correction for sex differences) and based on extent of synucleinopathy burden (n = 56 defined as isolated RBD, n = 305 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Overall, these participants commonly demonstrated abnormalities in global cognition (MoCA; 38%), motor function (alternate tap test; 48%), sensory (BSIT; 57%), autonomic function (orthostatic hypotension, 38.8%), and anxiety/depression (BAI and PHQ-9; 39.3% and 31%, respectively). INTERPRETATION: These RBD participants, assessed with extensive history, demographic, cognitive, motor, sensory, and autonomic function demonstrated a lack of sex differences and high frequency of concomitant neurological abnormalities. These participants will be valuable for future longitudinal study and neuroprotective clinical trials.

Evolution of Prodromal Multiple System Atrophy from REM Sleep Behavior Disorder: A Descriptive Study.

BACKGROUND: Prodromal multiple system atrophy (MSA) has been characterized mainly by retrospective chart reviews. Direct observation and tracking of prodromal markers in MSA have been very limitedObjective:To report the baseline characteristics and evolution of prodromal markers of MSA as they were prospectively measured in patients with idiopathic/isolated REM sleep behavior disorder (iRBD)Methods:Patients with iRBD were evaluated as part of a comprehensive protocol repeated annually. The protocol included assessment of motor, sleep, psychiatric, and autonomic symptoms supplemented by motor examination, quantitative motor testing, neuropsychological examination, orthostatic blood pressure measurement, and tests of olfaction and color vision. Patients who eventually developed MSA were described and compared with those who phenoconverted to Lewy body disease (Parkinson's disease and dementia with Lewy bodies). RESULTS: Of 67 phenocoverters, 4 developed MSA-P and 63 developed Lewy body disease. An additional 2 MSA-C patients were seen at baseline, already with cerebellar signs. Compared to those with Lewy body disease, those with MSA-P were younger, had less severe loss of tonic REM sleep atonia, more insomnia symptoms, and better olfaction. Clinically-evident autonomic dysfunction was not invariable in prodromal stages, often developing proximate to or after motor phenoconversion. Of the autonomic symptoms, genitourinary dysfunction was the first to develop in all cases. Olfaction and cognition remained normal throughout the prodromal and clinical disease course, in clear contrast to patients with Lewy body disease. CONCLUSION: Prodromal MSA progresses rapidly, often without substantial autonomic dysfunction, and with preserved olfaction and cognition throughout its prodromal course.

Cardiovascular Risk Factors and Phenoconversion to Neurodegenerative Synucleinopathies in Idiopathic REM Sleep Behavior Disorder.

Several studies have suggested that atherosclerotic diseases and diabetes may be risk factors for α-synucleinopathies. This prospective cohort study evaluated whether cardiovascular diseases and metabolic risk factors alter the rate or type of phenoconversion from idiopathic/isolated REM sleep behavior disorder (iRBD) to parkinsonism or dementia. Polysomnography-confirmed iRBD patients recruited between 2004 and 2020 were followed annually. Baseline history of cardiovascular disorders, hypertension, hypercholesterolemia, and diabetes were compared among patients who developed outcomes versus those who remained outcome-free. No atherosclerotic risk factors were associated with development of α-synucleinopathies. Patients with hypercholesterolemia were somewhat more likely to develop dementia with Lewy bodies rather than Parkinson's disease.

Risk Factors for Phenoconversion in Rapid Eye Movement Sleep Behavior Disorder.

OBJECTIVE: This study was undertaken to follow up predictive factors for α-synuclein-related neurodegenerative diseases in a multicenter cohort of idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 12 centers underwent a detailed assessment for potential environmental and lifestyle risk factors via a standardized questionnaire at baseline. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The cumulative incidence of parkinsonism or dementia was estimated with competing risk analysis. Cox regression analyses were used to evaluate the predictive value of environmental/lifestyle factors over a follow-up period of 11 years, adjusting for age, sex, and center. RESULTS: Of 319 patients who were free of parkinsonism or dementia, 281 provided follow-up information. After a mean follow-up of 5.8 years, 130 (46.3%) patients developed neurodegenerative disease. The overall phenoconversion rate was 24.2% after 3 years, 44.8% after 6 years, and 67.5% after 10 years. Patients with older age (adjusted hazard ratio [aHR] = 1.05) and nitrate derivative use (aHR = 2.18) were more likely to phenoconvert, whereas prior pesticide exposure (aHR = 0.21-0.64), rural living (aHR = 0.53), lipid-lowering medication use (aHR = 0.59), and respiratory medication use (aHR = 0.36) were associated with lower phenoconversion risk. Risk factors for those converting to primary dementia and parkinsonism were generally similar, with dementia-first converters having lower coffee intake and beta-blocker intake, and higher occurrence of family history of dementia. INTERPRETATION: Our findings elucidate the predictive values of environmental factors and comorbid conditions in identifying RBD patients at higher risk of phenoconversion. ANN NEUROL 2022;91:404-416.

Comprehensive Analysis of Brain Volume in REM Sleep Behavior Disorder with Mild Cognitive Impairment.

BACKGROUND: Rapid-eye-movement sleep behavior disorder (RBD) is a major risk factor for Parkinson's disease and dementia with Lewy bodies. More than a third of RBD patients have mild cognitive impairment (MCI), but their specific structural brain alterations remain poorly understood. OBJECTIVE: This study aimed to investigate the local deformation and volume of gray and white matter tissue underlying MCI in RBD. METHODS: Fifty-two idiopathic RBD patients, including 17 with MCI (33%), underwent polysomnography, neuropsychological, neurological, and magnetic resonance imaging assessments. MCI diagnosis was based on a subjective complaint, cognitive impairment on the neuropsychological battery, and preserved daily functioning. Forty-one controls were also included. Deformation-based morphometry (DBM), voxel-based morphometry (VBM), and regional volume analyses of the corpus callosum and cholinergic basal forebrain were performed. Multiple regression models were also computed using anatomical, cognitive (composite z scores), and motor parameters. RESULTS: Globally, patients with MCI displayed a widespread pattern of local deformation and volume atrophy in the cortical (bilateral insula, cingulate cortex, precuneus, frontal, temporal and occipital regions, right angular gyrus, and mid-posterior segment of the corpus callosum) and subcortical (brainstem, corona radiata, basal ganglia, thalamus, amygdala, and right hippocampus) regions compared to patients without MCI (DBM) or controls (DBM and VBM). Moreover, brain deformation (DBM) in patients were associated with lower performance in attention and executive functions, visuospatial abilities, and higher motor symptoms severity. CONCLUSION: The present study identified novel brain structural alterations in RBD patients with MCI which correlated with poorer cognitive performance. These results are consistent with those reported in patients with synucleinopathies-related cognitive impairment.

Insomnia symptom subtypes and manifestations of prodromal neurodegeneration: a population-based study in the Canadian Longitudinal Study on Aging.

STUDY OBJECTIVES: To identify the association between insomnia symptoms and signs of prodromal neurodegeneration, including an analysis of potential differences between sleep-onset and sleep-maintenance insomnia. METHODS: We included those aged 45-85 years, living in 1 of 10 Canadian provinces between 2012 and 2015 (at the baseline), recruited via 3 population-based sampling methods. Insomnia symptoms were assessed using questions adapted/modified from the Pittsburgh Sleep Quality Index. A panel of potential prodromal neurodegenerative markers including self-reported symptoms and objective gait motor, cognitive, and autonomic variables were assessed cross sectionally. We compared those who endorsed insomnia symptoms ≥ 3 times per week to controls, adjusting for age, sex, and education via logistic regression. RESULTS: Overall, 2,051/30,097 people screened positive for sleep-onset insomnia alone and 4,333 for sleep-maintenance insomnia alone, while 2,371 endorsed both subtypes. On objective gait tests, participants with sleep-onset insomnia, but not sleep-maintenance insomnia, had worse balance (odds ratio [OR] = 1.33, 95% confidence interval = [1.16, 1.52]) and slower gait speed (OR = 1.52 [1.34, 1.73]). Although participants with any insomnia subtype endorsed more motor symptoms, these were more severe in those with sleep-onset insomnia (OR onset vs maintenance = 1.13 [1.07, 1.18]). On objective cognitive tests, those with sleep-maintenance insomnia scored normally. However, participants with sleep-onset insomnia performed worse on tests of verbal fluency (OR = 1.24 [1.06, 1.43]), immediate memory (OR = 1.23 [1.08, 1.41]), and prospective memory task (OR = 1.29 [1.11, 1.50]). The sleep-onset insomnia group also had lower heart rate variability (OR = 1.23 [1.07, 1.43]). Secondary analyses found generally similar results in young vs older age of insomnia development. CONCLUSIONS: Compared to maintenance insomnia, those with sleep-onset insomnia have more motor, cognitive, and autonomic signs/symptoms. When evaluating neurodegenerative risk, differentiating insomnia subtypes may increase precision. CITATION: Yao CW, Pelletier A, Fereshtehnejad S-M, Cross N, Dang-Vu T, Postuma RB. Insomnia symptom subtypes and manifestations of prodromal neurodegeneration: a population-based study in the Canadian Longitudinal Study on Aging. J Clin Sleep Med. 2022;18(2):345-359.

Sleep Disorders and Future Diagnosis of Parkinsonism: A Prospective Study Using the Canadian Longitudinal Study on Aging.

BACKGROUND: Earlier detection of parkinsonism, specifically during its prodromal stage, may be key to preventing its progression. Previous studies have produced contradictory results on the association between sleep symptoms and prodromal parkinsonism. OBJECTIVE: We conducted a prospective study within the Canadian Longitudinal Study on Aging (CLSA) to determine whether self-reported symptoms of insomnia, somnolence, apnea, and restless legs syndrome predate the diagnosis of parkinsonism after three years of follow-up. METHODS: At baseline, amongst other information, participants completed a questionnaire for difficulty initiating or maintaining sleep, daytime somnolence, snoring or stopping breathing during sleep, and symptoms of restless legs syndrome. After 3 years of follow-up, baseline responses from participants who self-reported a new diagnosis of parkinsonism (cases) were compared to those who did not (controls). For each case, 10 controls were individually matched by age, sex, education, BMI, caffeine, smoking, and alcohol. Binary unconditional logistic regression models were used to estimate the association between sleep symptoms and new-onset parkinsonism, adjusting for age, sex, education, BMI, smoking, alcohol, and caffeine. RESULTS: We identified 58 incident-parkinsonism cases and 580 matched controls (65.5%male, mean age = 69.60, SD = 8.0). Baseline symptoms of sleep-onset insomnia (12.1%vs. 13.0%, Adjusted OR[95%CI] = 0.87[0.32,2.33]), sleep-maintenance insomnia (24.1%vs. 20.2%, AOR = 1.01[0.46,2.20]), daytime somnolence (8.6%vs. 7.4%, AOR = 1.11[0.37,3.39]), obstructive sleep apnea (27.3%vs. 26.2%, AOR = 0.84[0.40,1.79]), and restless leg syndrome (20.6%vs. 9.9%, AOR = 1.34[0.42,4.25]) were similar among those who developed parkinsonism and those who did not. CONCLUSION: Symptoms of insomnia, somnolence, apnea, and restless legs did not predate a new diagnosis of parkinsonism over 3 years.

Characterization of Depressive and Anxiety Symptoms in Idiopathic REM Sleep Behavior Disorder.

BACKGROUND: Depression and anxiety are common in synucleinopathies and often present during prodromal stages, including idiopathic/isolated REM sleep behavior disorder (iRBD). However, the specific profiles of depression/anxiety and their predictive values for phenoconversion remain unclear. OBJECTIVE: To assess the predominant manifestations, predictive value, and changes over time in depressive and anxiety symptoms in iRBD. METHODS: Patients with polysomnography-confirmed iRBD (n = 114) and healthy controls (n = 44) were recruited. The Beck Depression Inventory and Beck Anxiety Inventory were administered at baseline, which was repeated prospectively over follow-up. Factor solutions were generated to delineate symptom clusters within the scales, and to help disentangle primary mood symptoms from other neurodegenerative confounds. Total scores, individual scale items, and factors were evaluated to 1) compare patients and controls, 2) assess progression of symptoms over time, and 3) assess predictive value for phenoconversion. RESULTS: At baseline, iRBD patients had more severe depressive (9.0 = 6.7 vs 5.8 = 4.8) and anxiety (7.0 = 7.9 vs 4.5 = 6.0) symptoms than controls. Increased scores were seen in numerous individual scale items and most scales' factors. For depressive symptoms, there was no progression of total scores or factors over time. However, anxiety scores worsened slightly over prospective follow-up (annual slope = 0.58 points, p < 0.05). Over an average 2.4 = 3.1-year follow-up, 37 patients phenoconverted and 72 remained disease-free. Neither baseline depressive nor anxiety symptoms predicted phenoconversion to clinical neurodegenerative disease. CONCLUSIONS: Depressive and anxiety symptoms are common in iRBD. However, they do not predict phenoconversion and show only modest progression over time, solely for anxiety.