Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be ...used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies. We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. Unified Parkinson's Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies.
Summary Background Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are brain disorders characterised by intracellular α-synuclein deposits. We aimed to assess whether ...reduction of α-synuclein concentrations in CSF was a marker for α-synuclein deposition in the brain, and therefore diagnostic of synucleinopathies. Methods We assessed potential extracellular-fluid markers of α-synuclein deposition in the brain (total α-synuclein and total tau in CSF, and total α-synuclein in serum) in three cohorts: a cross-sectional training cohort of people with Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders; a group of patients with autopsy-confirmed dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders (CSF specimens were drawn ante mortem during clinical investigations); and a validation cohort of patients who between January, 2003, and December, 2006, were referred to a specialised movement disorder hospital for routine inpatient admission under the working diagnosis of parkinsonism. CSF and serum samples were assessed by ELISA, and clinical diagnoses were made according to internationally established criteria. Mean differences in biomarkers between diagnostic groups were assessed with conventional parametric and non-parametric statistics. Findings In our training set (n=273), people with Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies had lower CSF α-synuclein concentrations than patients with Alzheimer's disease and other neurological disorders. CSF α-synuclein and tau values separated participants with synucleinopathies well from those with other disorders (p<0·0001; area under the receiver operating characteristic curve AUC=0·908). In the autopsy-confirmed cases (n=41), CSF α-synuclein discriminated between dementia with Lewy bodies and Alzheimer's disease (p=0·0190; AUC=0·687); in the validation cohort (n=407), CSF α-synuclein discriminated Parkinson's disease and dementia with Lewy bodies versus progressive supranuclear palsy, normal-pressure hydrocephalus, and other neurological disorders (p<0·0001; AUC=0·711). Other predictor variables tested in this cohort included CSF tau (p=0·0798), serum α-synuclein (p=0·0502), and age (p=0·0335). CSF α-synuclein concentrations of 1·6 pg/μL or lower showed 70·72% sensitivity (95% CI 65·3–76·1%) and 52·83% specificity (39·4–66·3%) for the diagnosis of Parkinson's disease. At this cutoff, the positive predictive value for any synucleinopathy was 90·7% (95% CI 87·3–94·2%) and the negative predictive value was 20·4% (13·7–27·2%). Interpretation Mean CSF α-synuclein concentrations as measured by ELISA are significantly lower in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy than in other neurological diseases. Although specificity was low, the high positive predictive value of CSF α-synuclein concentrations in patients presenting with synucleinopathy-type parkinsonism might be useful in stratification of patients in future clinical trials. Funding American Parkinson Disease Association, Stifterverband für die Deutsche Wissenschaft, Michael J Fox Foundation for Parkinson's Research, National Institutes of Health, Parkinson Research Consortium Ottawa, and the Government of Canada.
Background
Rapid eye movement (REM) sleep behavior disorder (RBD) is one of the most specific prodromal indicators for Parkinson's disease (PD).
Objectives
To test the validity of the RBD‐Screening ...Questionnaire (RBDSQ) in assessing RBD in early PD.
Methods
The RBDSQ was completed before video‐supported polysomnography (vPSG) by 134 de novo PD patients, 109 matched controls without neurological disorder (CTR) and 30 subjects with idiopathic RBD (iRBD) without clinical signs of PD; results were compared with vPSG‐confirmed RBD diagnosis.
Results and Conclusions
Sensitivity/specificity of the RBDSQ for the PD cohort were 0.44/0.84 at the previously published cut‐off score of 6 for PD patients, and the area under the curve (AUC) 0.68 (95% CI, 0.56–0.79). By contrast, in the iRBD/CTR cohort the RBDSQ (cut‐off = 5) had a sensitivity/specificity of 0.97/0.84 and an AUC of 0.95 (95% CI, 0.90–1.00). Subanalysis of question 6 only (4 subitems asking for dream enactment) at a cut‐off score of 1 revealed a sensitivity of 0.74 and a specificity of 0.70 for the de novo PD cohort, AUC was 0.74 (95% CI, 0.63–0.84). RBDSQ is an insufficient screening tool for RBD in de novo PD. New screening tools for RBD assessment need to be developed.
Intraoperative microelectrode recording (MER) and test-stimulation are regarded as the gold standard for proper placement of subthalamic (STN) deep brain stimulation (DBS) electrodes in Parkinson's ...disease (PD), requiring the patient to be awake during the procedure. In accordance with good clinical practice, most attending neurologists will request the clinically most efficacious trajectory for definite lead placement. However, the necessity of microelectrode-test-stimulation is disputed, as it may limit the access to DBS therapy, excluding those not willing or incapable of undergoing awake surgery.
We retrospectively analyzed the MERs and microelectrode-test-stimulation results with regard to the decision on definite lead placement and clinical outcome in a cohort of 67 PD-patients with STN-DBS. All patients received bilateral quadripolar ring electrodes. To ascertain overall procedural efficacy, we calculated the surgical index (SI) by comparing preoperative motor improvement induced by levodopa to that induced by stimulation 7 to 18 months after surgery, measured as the relative difference between ON and OFF-states on the Unified Parkinson's Disease Rating Scale motor part (UPDRS-3). Additionally, a side-specific surgical index (SSSI) was calculated using the unilateral assessable items of the UPDRS-3. The SSSI where microelectrode-test-stimulation overruled MER were compared to those where the result of microelectrode-test-stimulation was congruent to MER results.
A total of 134 electrodes were analyzed. For final lead placement, the central trajectory was chosen in 54% of patient hemispheres. The mean SI was 0.99 (± 0.24). SSSI averaged 1.04 (± 0.45). In 37 lead placements, microelectrode-test-stimulation overruled MER in the final trajectory selection, in 27 of these lead placements adverse effects during microelectrode-test-stimulation were decisive. Neither the number of test electrodes used nor the STN-signal length had an impact on the SSSI. The SSSI did not differ between lead placements with MER/microelectrode-test-stimulation congruency and those where the results of microelectrode-test-stimulation initiated lead placement in a trajectory with shorter STN signal.
Intraoperative testing is mandatory to ensure an optimal motor outcome of STN DBS in PD-patients when using quadripolar ring electrodes. However, we also demonstrated that neither the length of the STN-signal on MER nor the number of test electrodes influenced the motor outcome.
To investigate the frequency, phenomenology, and associated risk factors of REM sleep behavior disorder (RBD) in Parkinson disease (PD).
An unselected cohort of sleep-disturbed patients with PD ...(n=457) was investigated with video-supported polysomnography. We determined the frequency of RBD and analyzed the influence of age, clinical disease features, disease duration, cognitive and physical impairment, medication, comorbidity, and sleep architecture.
The overall frequency of RBD was 46%. According to our cohort and modified definition, there was no preferred PD subtype for RBD (p=0.142). There was no gender preference (p=0.770). RBD was associated with older age (p=0.000). Adjusted for age and gender, patients with PD and RBD had longer disease duration (p=0.024), higher Hoehn & Yahr stages (p=0.002), more falls (p=0.018), more fluctuations (p=0.005), more psychiatric comorbidity (p=0.026), and a higher dose of levodopa (p=0.002). The presence of RBD was related to slightly increased sleep efficiency (p=0.007), a higher amount of REM sleep (p=0.000), and more periodic leg movements during sleep (p=0.019).
RBD is a frequent and clinically relevant nocturnal disturbance for all stages of PD. It increases with age and disease duration and may contribute to the nocturnal problems of patients with PD and their bed partners.
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