RESUMO
We investigated the biomarker profile of neurodegeneration, Alzheimer's and Lewy body pathology in the CSF of 148 polysomnography-confirmed patients with isolated REM sleep behavior disorder (IRBD), a condition that precedes Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We assessed misfolded α-synuclein (AS) by RT-QuIC assay, amyloid-beta peptides (Aß42 and Aß40), phosphorylated tau (p-tau), and total tau (t-tau) by CLEIA and neurofilament light chain (NfL) by ELISA. We detected AS in 75.3% of patients, pathologically decreased Aß42/Aß40 ratio in 22.5%, increased p-tau in 15.5%, increased t-tau in 14.9%, and elevated NfL in 14.7%. After a mean follow-up of 2.48 ± 2.75 years, 47 (38.1%) patients developed PD (n = 24) or DLB (n = 23). At CSF collection, AS positivity [HR 4.05 (1.26-12.99), p = 0.019], mild cognitive impairment [3.86 (1.96-7.61), p < 0.001], and abnormal DAT-SPECT [2.31 (1.09-4.91), p < 0.030] were independent predictors of conversion to PD and DLB. Among the other CSF markers, only elevated p-tau/Aß42 was predictive of conversion, although only to DLB and not as an independent variable. In IRBD, CSF AS assessment by RT-QuIC provides an added value in defining the risk of short-term conversion to PD and DLB independent of clinical and instrumental investigations. Positive Alzheimer's disease (AD) pathology markers and elevated NfL occur in a subgroup of patients, but p-tau/Aß42 is the only marker that predicts short-term conversion to DLB. Longer follow-up is needed to assess if AD biomarkers predict the later development of PD and DLB in IRBD.
RESUMO
OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.
Assuntos
Dopamina , Doença por Corpos de Lewy , Aprendizado de Máquina , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Sinucleinopatias , Humanos , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Masculino , Feminino , Idoso , Sinucleinopatias/diagnóstico por imagem , Pessoa de Meia-Idade , Doença por Corpos de Lewy/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/complicações , Dopamina/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Terminações Pré-Sinápticas/metabolismo , Imageamento DopaminérgicoRESUMO
BACKGROUND: Using 11 C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. OBJECTIVES: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. METHODS: Fifteen iRBD patients previously scanned with 11 C-(R)-PK11195 and 18 F-DOPA-PET underwent repeat 18 F-DOPA-PET after 3 years. 18 F-DOPA Ki changes from baseline were evaluated with volumes-of-interest and voxel-based analyses. RESULTS: Significant 18 F-DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11 C-(R)-PK11195 binding at baseline was a predictor of 18 F-DOPA Ki reduction in left caudate (coef = -0.0426, P = 0.016). CONCLUSIONS: Subjects with increased baseline 11 C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMO
BACKGROUND: Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) represents the prodromal stage of Lewy body disorders (Parkinson's disease (PD) and dementia with Lewy bodies (DLB)) which are linked to variations in circulating cell-free mitochondrial DNA (cf-mtDNA). Here, we assessed whether altered cf-mtDNA release and integrity are already present in IRBD. METHODS: We used multiplex digital PCR (dPCR) to quantify cf-mtDNA copies and deletion ratio in cerebrospinal fluid (CSF) and serum in a cohort of 71 participants, including 1) 17 patients with IRBD who remained disease-free (non-converters), 2) 34 patients initially diagnosed with IRBD who later developed either PD or DLB (converters), and 3) 20 age-matched controls without IRBD or Parkinsonism. In addition, we investigated whether CD9-positive extracellular vesicles (CD9-EVs) from CSF and serum samples contained cf-mtDNA. FINDINGS: Patients with IRBD, both converters and non-converters, exhibited more cf-mtDNA with deletions in the CSF than controls. This finding was confirmed in CD9-EVs. The high levels of deleted cf-mtDNA in CSF corresponded to a significant decrease in cf-mtDNA copies in CD9-EVs in both IRBD non-converters and converters. Conversely, a significant increase in cf-mtDNA copies was found in serum and CD9-EVs from the serum of patients with IRBD who later converted to a Lewy body disorder. INTERPRETATION: Alterations in cf-mtDNA copy number and deletion ratio known to occur in Lewy body disorders are already present in IRBD and are not a consequence of Lewy body disease conversion. This suggests that mtDNA dysfunction is a primary molecular mechanism of the pathophysiological cascade that precedes the full clinical motor and cognitive manifestation of Lewy body disorders. FUNDING: Funded by Michael J. Fox Foundation research grant MJFF-001111. Funded by MICIU/AEI/10.13039/501100011033 "ERDF A way of making Europe", grants PID2020-115091RB-I00 (RT) and PID2022-143279OB-I00 (ACo). Funded by Instituto de Salud Carlos III and European Union NextGenerationEU/PRTR, grant PMP22/00100 (RT and ACo). Funded by AGAUR/Generalitat de Catalunya, grant SGR00490 (RT and ACo). MP has an FPI fellowship, PRE2018-083297, funded by MICIU/AEI/10.13039/501100011033 "ESF Investing in your future".
Assuntos
Doença de Parkinson , Transtornos Parkinsonianos , Transtorno do Comportamento do Sono REM , Humanos , Transtorno do Comportamento do Sono REM/diagnóstico , Transtorno do Comportamento do Sono REM/genética , Doença de Parkinson/genética , Previsões , DNA Mitocondrial/genéticaRESUMO
BACKGROUND: Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. METHODS: Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). RESULTS: From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR. CONCLUSIONS: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores.
Assuntos
Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Transtorno do Comportamento do Sono REM/psicologia , Acetilcolinesterase , Donepezila , Encéfalo/diagnóstico por imagemRESUMO
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.
RESUMO
INTRODUCTION: Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of the synucleinopathies Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Aggregation of abnormal α-synuclein and its increased expression in the brain is crucial in the development of the synucleinopathies. Whereas α-synuclein gene (SNCA) transcripts are overexpressed in brain, a concomitant reduction occurs in blood of DLB patients. We assessed whether this decrease is also detectable in IRBD. METHODS: 108 IRBD patients and 149 controls were included of which 29 IRBD and 32 control cases were available for expression studies. Expression of SNCAtv1, SNCAtv2, SNCAtv3 and SNCA126 isoforms, and GBA were determined by real-time PCR. Genotype distribution of SNCA SNPs, rs356219 and rs2736990, and correlation with SNCA expression was analyzed. RESULTS: Expression of all SNCA transcripts was reduced in IRBD blood whereas GBA expression did not change. SNCAtv3 expression correlated inversely with IRBD duration, being lower in patients with longer follow-up. Rs356219-AA genotype frequency was increased in IRBD patients who later developed PD and DLB. Rs2736990-CC frequency was increased among IRBD cases who remained disease-free. No correlation was observed between rs356219 and rs2736990 genotypes and SNCA transcript levels. CONCLUSION: SNCA transcript expression is decreased in blood in IRBD, and levels decrease with IRBD duration. Our findings indicate that changes in SNCA expression occur in the earliest stages of the synucleinopathies before motor and cognitive symptoms become apparent.
RESUMO
OBJECTIVE: Traumatic brain injury is associated with the late development of neurodegenerative diseases such as the synucleinopathies. Isolated REM sleep behavior disorder (IRBD) constitutes an early manifestation of the synucleinopathies. We assessed whether lifetime history of concussive episodes is common in IRBD and examined its characteristics and clinical significance. METHODS: Prior exposure to concussions was evaluated by interviewing polysomnographically-confirmed IRBD patients and controls without IRBD, and by the BRAIN-Q questionnaire. RESULTS: We recruited 199 IRBD patients aged 73.2 ± 7.7 years and 168 age and sex matched controls. Previous history of concussion was more common in patients than in controls (21.1% versus 10.1%, p = 0.004). In patients, concussions occurred at the age of 24.7 ± 20.6 years. The interval between concussion and IRBD diagnosis was 43.0 ± 19.0 years. There were no differences between patients and controls in the causes of concussions (e.g., traffic accidents, sport practice), and number of events resulting in skull fractures, urgent medical assistance, and hospitalization. After a follow-up of 5.7 ± 4.7 years from IRBD diagnosis, 21.1% patients developed an overt synucleinopathy with an interval of 49.3 ± 24.2 years between concussion and synucleinopathy diagnosis. The risk to develop a synucleinopathy was similar between patients with and without concussions (p = 0.57). CONCLUSIONS: Previous history of concussion is common in IRBD. Our observations may suggest that in individuals with increased susceptibility, early-life concussions may trigger a slow neurodegenerative process leading four decades later to IRBD. This study highlights the need for head injury prevention, particularly in early life.
Assuntos
Concussão Encefálica , Lesões Encefálicas Traumáticas , Transtorno do Comportamento do Sono REM , Sinucleinopatias , Humanos , Transtorno do Comportamento do Sono REM/epidemiologia , Transtorno do Comportamento do Sono REM/etiologia , Concussão Encefálica/complicações , Concussão Encefálica/epidemiologia , EncéfaloRESUMO
BACKGROUND: Correct diagnosis of rapid eye movement sleep behavior disorder (RBD) is critical due to its link to α-synucleinopathies and risk of injuries and requires video-polysomnography (V-PSG). Usefulness of screening questionnaires outside the context of validation studies is limited. OBJECTIVE: The aim was to assess the performance of three validated RBD screening questionnaires compared with gold-standard V-PSG. METHODS: In this bicentric prospective study, 400 consecutive subjects referred to a sleep center for the first time filled three RBD questionnaires (RBD Screening Questionnaire, RBD Single Question, and Innsbruck RBD Inventory) in random order before sleep experts' interview. Subjects positive for at least one questionnaire were invited to undergo V-PSG. Data from patients negative for all questionnaires undergoing V-PSG for other reasons were also evaluated. Questionnaire performances were compared to gold-standard V-PSG RBD diagnosis. RESULTS: Three hundred ninety-nine patients (median age: 51 [interquartile range: 37-64] years, 54.9% men) participated. Two hundred thirty-eight (59.6%) were positive for at least one questionnaire, and RBD was diagnosed using V-PSG in 30 patients (7.5%). Questionnaire specificity was 48.1% to 67.4%, sensitivity 80% to 92%, accuracy 51% to 68.3%, negative predictive value 94.2% to 98%, and positive predictive value 14.1% to 20.7%, with no relevant differences in performances among the evaluated questionnaires. CONCLUSIONS: RBD questionnaires have low specificity and low positive predictive value and should not be used as a standalone tool for the diagnosis of RBD. Further development of RBD screening methods is needed, particularly for upcoming neuroprotective trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Doença de Parkinson , Transtorno do Comportamento do Sono REM , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Transtorno do Comportamento do Sono REM/diagnóstico , Estudos Prospectivos , Doença de Parkinson/diagnóstico , Polissonografia/métodos , Inquéritos e QuestionáriosRESUMO
BACKGROUND AND OBJECTIVES: Real-time quaking-induced conversion (RT-QuIC) assay detects misfolded α-synuclein (AS) in the skin and CSF of patients with the synucleinopathies Parkinson disease and dementia with Lewy bodies. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of these synucleinopathies. We aimed to compare the ability of RT-QuIC to identify AS in the skin and CSF of patients with IRBD. METHODS: This was a cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. Three-millimeter skin punch biopsies were obtained bilaterally in the cervical region from dorsal C7 and C8 dermatomes and in distal legs. RT-QuIC assessed AS in these 6 skin sites and the CSF. RESULTS: We recruited 91 patients with IRBD and 41 controls. In the skin, sensitivity to detect AS was 76.9% (95% CI 66.9-85.1), specificity 97.6% (95% CI 87.1-99.9) positive predictive value 98.6% (95% CI 91.0-99.8), negative predictive value 65.6% (95% CI 56.6-73.6), and accuracy 83.3% (95% CI 75.9-89.3). In the CSF, the sensitivity was 75.0% (95% CI 64.6-83.6), the specificity was 97.5% (95% CI 86.8-99.9), the positive predictive value was 98.5% (95% CI 90.5-99.8), the negative predictive value was 63.9% (95% CI 55.2-71.9), and the accuracy was 82.0% (95% CI 74.3-88.3). Results in the skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC AS-positive patients had a higher likelihood ratio of prodromal Parkinson disease (p < 0.001) and showed more frequently hyposmia (p < 0.001), dopamine transporter imaging single-photon emission CT deficit (p = 0.002), and orthostatic hypotension (p = 0.014). No severe or moderate adverse effects were reported. There was no difference between the percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% vs 17.2%; p = 0.053). One hundred and ten (83%) and 104 (80%) participants, respectively, stated they would accept to undergo skin biopsy and lumbar puncture again for research purposes. DISCUSSION: Our study in IRBD shows that (1) RT-QuIC detects AS in the skin and CSF with similar high sensitivity, specificity, and agreement, (2) AS RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and (3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. RT-QuIC in the skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting AS in IRBD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that RT-QuIC-detected AS in the skin and CSF distinguishes patients with IRBD from controls.
Assuntos
Doença de Parkinson , Transtorno do Comportamento do Sono REM , Sinucleinopatias , Humanos , alfa-Sinucleína , Sinucleinopatias/diagnóstico , Transtorno do Comportamento do Sono REM/diagnóstico , Estudos TransversaisRESUMO
BACKGROUND: Contact sports such as football are associated with late development of neurodegenerative diseases, in part due to the deleterious effect of repetitive head impacts during participation. Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of neurodegenerative diseases including Parkinson disease (RBD) and dementia with Lewy bodies (DLB). We hypothesized that former professional football participation would be overrepresented in IRBD. OBJECTIVE: To assess former participation in professional football as an occupation in IRBD. METHODS: In a case-control retrospective study, having played football as a professional occupation in the Spanish Football Professional Leagues was examined interviewing polysomnographically confirmed IRBD patients and matched controls without IRBD. RESULTS: Among 228 Caucasian Spanish IRBD patients with 68.5 ± 7.2 years, six (2.63%) were retired professional footballers. Length professional football career ranged between 11 and 16 years. Interval between football retirement and IRBD diagnosis was 39.5 ± 6.4 years. At IRBD diagnosis, the six footballers had synucleinopathy biomarkers including pathologic synuclein in the CSF and tissues, nigrostriatal dopaminergic deficit and hyposmia. Follow-up showed that three footballers developed PD and two DLB. None of the controls was a professional footballer. The percentage of professional footballers was higher in IRBD patients than in controls (2.63% versus 0.00%; p = 0.030) and among the general Spanish population (2.63% versus 0.62%; p < 0.0001). CONCLUSION: We found an overrepresentation of former professional footballers in IRBD patients who later developed PD and DLB after four decades from professional retirement. In professional footballers the development of a neurodegenerative disease may be first manifested by IRBD. Screening for IRBD in former footballers might identify individuals with underlying synucleinopathies. Further studies with larger samples are needed to confirm our observations.
Assuntos
Futebol Americano , Doenças Neurodegenerativas , Transtorno do Comportamento do Sono REM , Sinucleinopatias , Humanos , Sinucleinopatias/patologia , Transtorno do Comportamento do Sono REM/epidemiologia , Transtorno do Comportamento do Sono REM/diagnóstico , Doenças Neurodegenerativas/epidemiologia , Estudos de Casos e Controles , Estudos Retrospectivos , OcupaçõesRESUMO
BACKGROUND: Isolated rapid eye movement sleep behavior disorder (IRBD) is a well-established clinical risk factor for Lewy body diseases (LBDs), such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). OBJECTIVE: To elucidate whether serum microRNA (miRNA) deregulation in IRBD can antedate the diagnosis of LBD by performing a longitudinal study in different progression stages of IRBD before and after LBD diagnosis and assessing the predictive performance of differentially expressed miRNAs by machine learning-based modeling. METHODS: Using genome-wide miRNA analysis and real-time quantitative polymerase chain reaction validation, we assessed serum miRNA profiles from patients with IRBD stratified by dopamine transporter (DaT) single-photon emission computed tomography into DaT-negative IRBD (n = 17) and DaT-positive IRBD (n = 21), IRBD phenoconverted into LBD (n = 13), and controls (n = 20). Longitudinally, we followed up the IRBD cohort by studying three time point serum samples over 26 months. RESULTS: We found sustained cross-sectional and longitudinal deregulation of 12 miRNAs across the RBD continuum, including DaT-negative IRBD, DaT-positive IRBD, and LBD phenoconverted IRBD (let-7c-5p, miR-19b-3p, miR-140, miR-22-3p, miR-221-3p, miR-24-3p, miR-25-3p, miR-29c-3p, miR-361-5p, miR-425-5p, miR-4505, and miR-451a) (false discovery rate P < 0.05). Age- and sex-adjusted predictive modeling based on the 12 differentially expressed miRNA biosignatures discriminated IRBD and PD or DLB from controls with an area under the curve of 98% (95% confidence interval: 89-99%). CONCLUSIONS: Besides clinical diagnosis of IRBD or imaging markers such as DaT single-photon emission computed tomography, specific miRNA biosignatures alone hold promise as progression biomarkers for patients with IRBD for predicting PD and DLB clinical outcomes. Further miRNA studies in other PD at-risk populations, such as LRRK2 mutation asymptomatic carriers or hyposmic subjects, are warranted. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Doença por Corpos de Lewy , MicroRNAs , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Biomarcadores , Estudos Transversais , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Humanos , Corpos de Lewy , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/genética , Estudos Longitudinais , MicroRNAs/sangue , MicroRNAs/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Transtorno do Comportamento do Sono REM/diagnóstico , Transtorno do Comportamento do Sono REM/genéticaRESUMO
Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of Lewy-type synucleinopathies (LTS), which can present either with an initial predominant parkinsonism (Parkinson's disease (PD)) or dementia (dementia with Lewy bodies (DLB)). To provide insights into the underlying pathogenic mechanisms, the lipoprotein and protein glycosylation profile of 82 iRBD patients, collected before and/or after their conversion to an overt LTS, and 29 matched control serum samples were assessed by nuclear magnetic resonance (NMR) spectroscopy. Data were statistically analyzed to identify altered metabolites and construct predictive models. Univariant analysis detected no differences between iRBD patients with an LTS compared to controls. However, significant differences were found when the analysis distinguished between iRBD patients that manifested initially predominant parkinsonism (pre-PD) or dementia (pre-DLB). Significant differences were also found in the analysis of paired iRBD samples pre- and post-LTS diagnosis. Predictive models were built and distinguished between controls and pre-DLB patients, and between pre-DLB and pre-PD patients. This allowed a prediction of the possible future clinical outcome of iRBD patients. We provide evidence of altered lipoprotein and glycosylation profiles in subgroups of iRBD patients. Our results indicate that metabolic alterations and inflammation are involved in iRBD pathophysiology, and suggest biological differences underlying the progression of LTS in iRBD patients. Our data also indicate that profiling of serum samples by NMR may be a useful tool for identifying short-term high-risk iRBD patients for conversion to parkinsonism or dementia.
RESUMO
Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P < 0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P < 0.001). We provide evidence that the α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.
Assuntos
Mucosa Olfatória/metabolismo , Doença de Parkinson/patologia , Transtorno do Comportamento do Sono REM/patologia , alfa-Sinucleína/análise , Idoso , Biomarcadores/análise , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Sintomas Prodrômicos , Transtorno do Comportamento do Sono REM/metabolismo , Sensibilidade e Especificidade , alfa-Sinucleína/metabolismoRESUMO
During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism.
Assuntos
Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/patologia , Transtorno do Comportamento do Sono REM/patologia , Idoso , Circulação Cerebrovascular , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Microcirculação , Pessoa de Meia-IdadeRESUMO
Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.
Assuntos
Neurônios , Tomografia por Emissão de Pósitrons , Transtorno do Comportamento do Sono REM , Substância Negra , Idoso , Biomarcadores/sangue , Antígeno CD11b/sangue , Antígeno CD11b/imunologia , Feminino , Antígenos HLA-DR/sangue , Antígenos HLA-DR/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/imunologia , Substância Negra/diagnóstico por imagem , Substância Negra/imunologia , Substância Negra/metabolismo , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/imunologiaRESUMO
BACKGROUND: Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy. METHODS: In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3-12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations. FINDINGS: 52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90·4% (95% CI 79·4-95·8) and a specificity of 90·0% (95% CI 76·9-96·0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7·1 years (SD 2·8) in patients with IRBD and 7·7 years (2·9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3·4 years (SD 2·6) after lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were α-synuclein positive (log-rank test p=0·028; hazard ratio 0·143, 95% CI 0·019-1·063). During follow-up, none of the controls developed an α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were α-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p<0·0001; hazard ratio 0·024, 95% CI 0·003-0·177). INTERPRETATION: In patients with IRBD, RT-QuIC detects misfolded α-synuclein in the CSF with both sensitivity and specificity of 90%, and α-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of α-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF α-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target α-synuclein. FUNDING: Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.
Assuntos
Transtorno do Comportamento do Sono REM/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Idoso , Sistemas Computacionais , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Doença por Corpos de Lewy/etiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/etiologia , Polissonografia , Sintomas Prodrômicos , Transtorno do Comportamento do Sono REM/complicações , Medição de Risco , Sensibilidade e Especificidade , Punção EspinalRESUMO
STUDY OBJECTIVES: To describe the characteristics of stridor during sleep (SDS) in a series of adults identified by video-polysomnography (V-PSG). METHODS: Retrospective clinical, V-PSG, laryngoscopic, and therapeutic data of patients diagnosed with SDS in a tertiary referral sleep disorders center between 1997 and 2017. RESULTS: A total of 81 patients were identified (56.8% males, age 61.8 ± 11.2 years). Related etiologies were multiple system atrophy (MSA), amyotrophic lateral sclerosis, spinocerebellar ataxia type 1, anti-IgLON5 disease, fatal familial insomnia, brainstem structural lesions, vagus nerve stimulation, recurrent laryngeal nerve injury, the effect of radiotherapy on the vocal cords, cervical osteophytes, and others. Stridor during wakefulness coexisted in 13 (16%) patients and in MSA was only seen in the parkinsonian form. Laryngoscopy during wakefulness in 72 (88.9%) subjects documented vocal cord abductor impairment in 65 (90.3%) and extrinsic lesions narrowing the glottis in 2 (2.4%). The mean apnea-hypopnea index (AHI) was 21.4 ± 18.6 and CT90 was 11.5 ± 19.1. Obstructive AHI > 10 occurred in 52 (64.2%) patients and central apnea index >10 in 2 (2.4%). CPAP abolished SDS, obstructive apneic events and oxyhemoglobin desaturations in 58 of 60 (96.7%) titrated patients with optimal pressure of 9.0 ± 2.3 cm H20. Tracheostomy in 19 (23.4%) and cordotomy in 3 (3.7%) subjects also eliminated SDS. CONCLUSIONS: SDS in adults is linked to conditions that damage the brainstem, recurrent laryngeal nerve, and vocal cords. V-PSG frequently detects obstructive sleep apnea and laryngoscopy usually shows vocal cord abductor dysfunction. CPAP, tracheostomy, and laryngeal surgery abolish SDS.
Assuntos
Sons Respiratórios , Transtornos do Sono-Vigília , Adulto , Idoso , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Sons Respiratórios/etiologia , Estudos Retrospectivos , SonoRESUMO
STUDY OBJECTIVES: Patients with isolated rapid eye movement (REM) sleep behavior disorder (IRBD) develop Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). Magnetic resonance imaging (MRI) is abnormal in MSA showing abnormalities in the putamen, cerebellum, and brainstem. Our objective was to evaluate the usefulness of MRI to detect MRI abnormalities in IRBD and predict development of MSA and not PD and DLB. METHODS: In IRBD patients that eventually developed PD, DLB, and MSA, we looked for the specific structural MRI abnormalities described in manifest MSA (e.g. hot cross-bun sign, putaminal rim, and cerebellar atrophy). We compared the frequency of these MRI changes among groups of converters (PD, DLB, and MSA) and analyzed their ability to predict development of MSA. The clinical and radiological features of the IRBD patients that eventually converted to MSA are described in detail. RESULTS: A total of 61 IRBD patients who underwent MRI phenoconverted to PD (n = 30), DLB (n = 26), and MSA (n = 5) after a median follow-up of 2.4 years from neuroimaging. MRI changes typical of MSA were found in four of the five (80%) patients who converted to MSA and in three of the 56 (5.4%) patients who developed PD or DLB. MRI changes of MSA had sensitivity of 80.0%, specificity of 94.6%, positive likelihood ratio of 14.9 (95% CI 4.6-48.8), and negative likelihood ratio of 0.2 (95% CI 0.04-1.2) to predict MSA. CONCLUSIONS: In IRBD, conventional brain MRI is helpful to predict conversion to MSA. The specific MRI abnormalities of manifest MSA may be detected in its premotor stage.
Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Encéfalo , Humanos , Imageamento por Ressonância Magnética , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/diagnóstico por imagemRESUMO
OBJECTIVE: To determine if hyposmia in isolated REM sleep behavior disorder (IRBD) predicts short-term conversion to any α-synucleinopathy and declines with time. METHODS: Olfaction was tested using the University of Pennsylvania Smell Identification Test (UPSIT-40) in 140 consecutive patients with polysomnography-confirmed IRBD and in 77 matched controls. Patients were followed-up during 5.6 ± 3.9 (range 0.2-13) years. Twenty-one patients underwent serial UPSIT-40 evaluations at 1-3 and 4-6 years after baseline. RESULTS: UPSIT-40 score was lower in patients than in controls (20.2 ± 6.5 vs. 28.6 ± 5.0; p < 0.001). Hyposmia (UPSIT-40 score < 19 points) occurred in 42.9% patients. Forty-three (30.7%) patients developed Parkinson disease (PD = 27), dementia with Lewy bodies (DLB = 13) and multiple system atrophy (MSA = 3). Kaplan-Meier analysis showed that hyposmics had higher risk than normosmics to develop a synucleinopathy at the short term (p = 0.030). UPSIT-40 score was similar between patients who developed PD and DLB (p = 0.136). Normal smell occurred in all three (100%) IRBD patients who developed MSA, 12 of 27 (44%) who developed PD, and 4 of 13 (31%) that developed DLB. Serial UPSIT-40 evaluations showed no changes with time (p = 0.518). CONCLUSION: In IRBD, hyposmia is a short-term risk for synucleinopathies but cannot distinguish underlying PD from DLB. Normosmia not only occurs in latent MSA but also in latent PD and DLB. In future IRBD neuroprotective trails, individuals at entry could be enriched for hyposmia, whereas serial evaluation of smell would not be useful to monitor the efficacy of a therapeutic intervention.