Objective
To assess whether risk factors for Parkinson disease and dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior ...disorder (RBD).
Methods
Twelve centers administered a detailed questionnaire assessing risk factors for neurodegenerative synucleinopathy to patients with idiopathic RBD. Variables included demographics, lifestyle factors, pesticide exposures, occupation, comorbid conditions, medication use, family history, and autonomic/motor symptoms. After 4 years of follow‐up, patients were assessed for dementia or parkinsonism. Disease risk was assessed with Kaplan–Meier analysis, and epidemiologic variables were compared between convertors and those still idiopathic using logistic regression.
Results
Of 305 patients, follow‐up information was available for 279, of whom 93 (33.3%) developed defined neurodegenerative disease. Disease risk was 25% at 3 years and 41% after 5 years. Patients who converted were older (difference = 4.5 years, p < 0.001), with similar sex distribution. Neither caffeine, smoking, nor alcohol exposure predicted conversion. Although occupation was similar between groups, those who converted had a lower likelihood of pesticide exposure (occupational insecticide = 2.3% vs 9.0%). Convertors were more likely to report family history of dementia (odds ratio OR = 2.09), without significant differences in Parkinson disease or sleep disorders. Medication exposures and medical history were similar between groups. Autonomic and motor symptoms were more common among those who converted. Risk factors for primary dementia and parkinsonism were generally similar, except for a notably higher clonazepam use in dementia convertors (OR = 2.6).
Interpretation
Patients with idiopathic RBD are at very high risk of neurodegenerative synucleinopathy. Risk factor profiles between convertors and nonconvertors have both important commonalities and differences. Ann Neurol 2015;77:830–839
Parkinson's disease has a long prodromal stage with various subclinical motor and non-motor manifestations; however, their evolution in the years before Parkinson's disease is diagnosed is unclear. ...We traced the evolution of early motor and non-motor manifestations of synucleinopathy from the stage of idiopathic rapid eye movement (REM) sleep behaviour disorder until defined neurodegenerative disease. During 2004-16, we recruited and then annually followed 154 polysomnography-proven patients with idiopathic REM sleep behaviour disorder, of whom 55 phenoconverted to defined parkinsonism or dementia. Longitudinal data on multiple prodromal features, including the Unified Parkinson's Disease Rating Scale parts I-III, quantitative motor tests, olfaction, colour vision, cognition, and autonomic functions were gathered annually (average = five follow-up visits, range: 2-12 years). The same measures were also assessed in 102 age- and sex-matched healthy control subjects. By looking backward from the time of dementia or parkinsonism diagnosis, we examined trajectories of each prodromal feature using mixed effect models. Based on analysis, olfactory loss was first to develop, with predicted onset >20 years before phenoconversion. This was followed by impaired colour vision, constipation, and erectile dysfunction, starting 10-16 years prior to phenoconversion. At 7-9 years before phenoconversion, slight urinary dysfunction and subtle cognitive decline could be detected. Among motor symptoms altered handwriting, turning in bed, walking, salivation, speech, and facial expression began to be disrupted starting 7-11 years prior to parkinsonism diagnosis, but remained mild until soon before phenoconversion. Motor examination abnormalities began 5-7 years before phenoconversion, with the alternate tap test having the longest interval (8 years before phenoconversion). Among cardinal motor phenotypes, bradykinesia appeared first, ∼5-6 years prior to phenoconversion, followed by rigidity (Year -3) and tremor (Year -2). With direct prospective evaluation of an idiopathic REM sleep behaviour disorder cohort during phenoconversion, we documented an evolution of prodromal manifestations similar to that predicted by pathological staging models, with predicted prodromal intervals as long as 20 years.
See Morris and Weil (doi:10.1093/brain/awz014) for a scientific commentary on this article.
In a prospective multicentre study involving 1280 patients with idiopathic RBD, Postuma et al. show that ...approximately 6% of patients each year (>73.5% over 12 years) convert to full neurodegenerative disease. They test the predictive power of 21 prodromal markers of neurodegeneration, providing a template for planning neuroprotective trials.
Abstract
Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing hazard ratio (HR) = 3.16, objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.
OBJECTIVE:To precisely delineate clinical risk factors for conversion from idiopathic REM sleep behavior disorder (RBD) to Parkinson disease, dementia with Lewy bodies, and multiple system atrophy, ...in order to enable practical planning and stratification of neuroprotective trials against neurodegenerative synucleinopathy.
METHODS:In a 10-year prospective cohort, we tested prodromal Parkinson disease markers in 89 patients with idiopathic RBD. With Kaplan-Meier analysis, we calculated risk of neurodegenerative synucleinopathy, and using Cox proportional hazards, tested the ability of prodromal markers to identify patients at higher disease risk. By combining predictive markers, we then designed stratification strategies to optimally select patients for definitive neuroprotective trials.
RESULTS:The risk of defined neurodegenerative synucleinopathy was high30% developed disease at 3 years, rising to 66% at 7.5 years. Advanced age (hazard ratio HR = 1.07), olfactory loss (HR = 2.8), abnormal color vision (HR = 3.1), subtle motor dysfunction (HR = 3.9), and nonuse of antidepressants (HR = 3.5) identified higher risk of disease conversion. However, mild cognitive impairment (HR = 1.8), depression (HR = 0.63), Parkinson personality, treatment with clonazepam (HR = 1.3) or melatonin (HR = 0.55), autonomic markers, and sex (HR = 1.37) did not clearly predict clinical neurodegeneration. Stratification with prodromal markers increased risk of neurodegenerative disease conversion by 200%, and combining markers allowed sample size reduction in neuroprotective trials by >40%. With a moderately effective agent (HR = 0.5), trials with fewer than 80 subjects per group can demonstrate definitive reductions in neurodegenerative disease.
CONCLUSIONS:Using stratification with simply assessed markers, it is now not only possible, but practical to include patients with RBD in neuroprotective trials against Parkinson disease, multiple system atrophy, and dementia with Lewy bodies.
Objective:
For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying “preclinical” neurodegeneration are ...limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein‐mediated neurodegenerative disease—this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease.
Methods:
Patients with RBD without neurodegenerative disease were enrolled in a prospective cohort starting in 2004. Olfaction and color vision were tested at baseline, then annually for 5 years. Test results were compared between patients who developed neurodegenerative disease and those who remained disease‐free.
Results:
Out of 64 patients, 62 (97%) participated in annual follow‐up. During follow‐up, 21 developed disease, and 41 remained disease‐free. Out of 21, 16 developed a combination of parkinsonism and dementia, 4 developed isolated parkinsonism (all with tremor), and 1 developed isolated dementia. Compared to those remaining disease‐free, patients destined to develop disease had worse baseline olfaction (University of Pennsylvania Smell Identification Test UPSIT = 58.3 ± 27.0% age/sex‐adjusted normal vs 80.2 ± 26.3%; p = 0.003) and color vision (Farnsworth‐Munsell 100‐Hue color test FM‐100 errors 153.0 ± 82.2% normal vs 120.2 ± 26.5%; p = 0.022). Kaplan‐Meier 5‐year‐disease‐free survival in those with normal olfaction was 86.0%, vs 35.4% with impaired olfaction (p = 0.029). Disease‐free survival with normal color vision was 70.3%, vs 26.0% with impaired vision (p = 0.009). Both olfaction and color vision were reduced as much as 5 years before disease diagnosis, with only slight decline in preclinical stages.
Interpretation:
Olfaction and color vision identify early‐stage synuclein‐mediated neurodegenerative diseases. In most cases, abnormalities are measurable at least 5 years before disease onset, and progress slowly in the preclinical stages. Ann Neurol 2011;
Abstract REM sleep behavior disorder is a unique parasomnia characterized by dream enactment behavior during REM sleep. Unless triggered by pharmacologic agents such as antidepressants, it is ...generally related to damage of pontomedullary brainstem structures. Idiopathic REM sleep behavior disorder (RBD) is a well-established risk factor for neurodegenerative disease. Prospective studies have estimated that at least 40–65% of patients with idiopathic RBD will eventually develop a defined neurodegenerative phenotype, almost always a ‘synucleinopathy’ (Parkinson's disease, Lewy Body dementia or multiple system atrophy). In most cases, patients appear to develop a syndrome with overlapping features of both Parkinson's disease and Lewy body dementia. The interval between RBD onset and disease onset averages 10–15 years, suggesting a promisingly large window for intervention into preclinical disease stages. The ability of RBD to predict disease has major implications for design and development of neuroprotective therapy, and testing of other predictive markers of synuclein-mediated neurodegeneration. Recent studies in idiopathic RBD patients have demonstrated that olfaction, color vision, severity of REM atonia loss, transcranial ultrasound of the substantia nigra, and dopaminergic neuroimaging can predict development of neurodegenerative disease.
The aim of the study was to investigate the associations between longitudinal sleep duration patterns and behavioral/cognitive functioning at school entry.
Hyperactivity-impulsivity (HI), ...inattention, and daytime sleepiness scores were measured by questionnaire at 6 years of age in a sample of births from 1997 to 1998 in a Canadian province (N=1492). The Peabody Picture Vocabulary Test--Revised (PPVT-R) was administered at 5 years of age and the Block Design subtest (WISC-III) was administered at 6 years of age. Sleep duration was reported yearly by the children's mothers from age 2.5 to 6 years. A group-based semi-parametric mixture model was used to estimate developmental patterns of sleep duration. The relationships between sleep duration patterns and both behavioral items and neurodevelopmental tasks were tested using weighted multivariate logistic regression models to control for potentially confounding psychosocial factors.
Four sleep duration patterns were identified: short persistent (6.0%), short increasing (4.8%),10-hour persistent (50.3%), and 11-hour persistent (38.9%). The association of short sleep duration patterns with high HI scores (P=0.001), low PPVT-R performance (P=0.002), and low Block Design subtest performance (P=0.004) remained significant after adjusting for potentially confounding variables.
Shortened sleep duration, especially before the age of 41 months, is associated with externalizing problems such as HI and lower cognitive performance on neurodevelopmental tests. Results highlight the importance of giving a child the opportunity to sleep at least 10 hours per night throughout early childhood.
Objective
The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome‐wide association studies of Parkinson disease (PD). We aimed to identify the specific disease‐associated variants in ...this locus, and their potential implications.
Methods
Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta‐analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function.
Results
Two coding variants, TMEM175 p.M393T (odds ratio OR = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side‐chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants.
Interpretation
Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139–153
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