OBJECTIVE:To examine functional connectivity within the basal ganglia network (BGN) in a group of cognitively normal patients with early Parkinson disease (PD) on and off medication compared to age- ...and sex-matched healthy controls (HC), and to validate the findings in a separate cohort of participants with PD.
METHODS:Participants were scanned with resting-state fMRI (RS-fMRI) at 3T field strength. Resting-state networks were isolated using independent component analysis. A BGN template was derived from 80 elderly HC participants. BGN maps were compared between 19 patients with PD on and off medication in the discovery group and 19 age- and sex-matched controls to identify a threshold for optimal group separation. The threshold was applied to 13 patients with PD (including 5 drug-naive) in the validation group to establish reproducibility of findings.
RESULTS:Participants with PD showed reduced functional connectivity with the BGN in a wide range of areas. Administration of medication significantly improved connectivity. Average BGN connectivity differentiated participants with PD from controls with 100% sensitivity and 89.5% specificity. The connectivity threshold was tested on the validation cohort and achieved 85% accuracy.
CONCLUSIONS:We demonstrate that resting functional connectivity, measured with MRI using an observer-independent method, is reproducibly reduced in the BGN in cognitively intact patients with PD, and increases upon administration of dopaminergic medication. Our results hold promise for RS-fMRI connectivity as a biomarker in early PD.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that average connectivity in the BGN as measured by RS-fMRI distinguishes patients with PD from age- and sex-matched controls.
REM Sleep Behavior Disorder (RBD) is a chronic sleep condition characterized by dream enactment and loss of REM atonia. Individuals often present to clinic with complaints of injury to themselves or ...their bed-partner due to violent movements during sleep. RBD patients have a high risk of developing one of the neurodegenerative α-synucleinopathy diseases: over 70% will develop parkinsonism or dementia within 12 years of their diagnosis. RBD patients also exhibit accelerated disease progression and a more severe phenotype than α-synucleinopathy sufferers without RBD. The disease's low prevalence and the relatively limited awareness of the condition amongst medical professionals makes the diagnosis and treatment of RBD challenging. Uncertainty in patient management is further exacerbated by a lack of clinical guidelines for RBD patient care. There are no binary prognostic markers for RBD disease course and there are no clinical guidelines for neurodegeneration scaling or tracking in these patients. Both clinicians and patients are therefore forced to deal with uncertain outcomes. In this review, we summarize RBD pathology and differential diagnoses, diagnostic, and treatment guidelines as well as prognostic recommendations with a look to current research in the scientific field. We aim to raise awareness and develop a framework for best practice for RBD patient management.
•REM Sleep Behaviour Disorder (RBD) concomitant with olfactory dysfunction is indicative of underlying synucleinopathy such as Parkinson’s Disease (PD) and Dementia with Lewy Bodies.•Clinicians often ...rely on olfactory function self-report from RBD patients.•Accuracy of olfactory function self-report was compared to Sniffin’ Sticks 16-item olfactory function test scores in Control, PD and RBD groups.•RBD group were less accurate in their self-report of olfactory dysfunction compared to Control and PD groups.•Olfactory function self-report may not be suitable in an RBD population context and may reduce prognosis accuracy.
The earliest stages of alpha-synucleinopathies are accompanied by non-specific prodromal symptoms such as diminished sense of smell, constipation and depression, as well as more specific prodromal conditions including REM Sleep Behaviour Disorder (RBD). While the majority of RBD patients will develop an alpha-synucleinopathy, one of the greatest clinical challenges is determining whether and when individual patients will phenoconvert. Clinical evaluation of a patient presenting with RBD should therefore include robust and objective assessments of known alpha-synucleinopathy prodromes.
This study compared olfactory function self-report measures with psychophysical ‘Sniffin’ Stick 16-item Identification’ test scores in Control (n = 19), RBD (n = 16) and PD (n = 17) participants.
We confirm that olfactory test scores are significantly diminished in RBD and PD groups compared to Controls (p < 0.001, One-Way ANOVA with Tukey-Kramer Post-Hoc, effect size = 0.401). However, RBD participants were only 56 % accurate when self-reporting olfactory dysfunction, hence markedly less likely to perceive or acknowledge their own hyposmia compared to Controls (p = 0.045, Fisher’s Exact Test, effect-size = 0.35).
When isolated RBD presents with hyposmia, there is an increased likelihood of phenoconversion to Parkinson’s Disease (PD) or Dementia with Lewy Bodies (DLB); unawareness of olfactory dysfunction in an individual with isolated RBD may therefore confound differential diagnosis and prognosis. Our results evidence the fallibility of olfactory function self-report in the context of RBD prognosis, indicating that clinical assessments of RBD patients should include more reliable measures of olfactory status.
IntroductionThe impact of disease-modifying agents on disease progression in Parkinson’s disease is largely assessed in clinical trials using clinical rating scales. These scales have drawbacks in ...terms of their ability to capture the fluctuating nature of symptoms while living in a naturalistic environment. The SPHERE (Sensor Platform for HEalthcare in a Residential Environment) project has designed a multi-sensor platform with multimodal devices designed to allow continuous, relatively inexpensive, unobtrusive sensing of motor, non-motor and activities of daily living metrics in a home or a home-like environment. The aim of this study is to evaluate how the SPHERE technology can measure aspects of Parkinson’s disease.Methods and analysisThis is a small-scale feasibility and acceptability study during which 12 pairs of participants (comprising a person with Parkinson’s and a healthy control participant) will stay and live freely for 5 days in a home-like environment embedded with SPHERE technology including environmental, appliance monitoring, wrist-worn accelerometry and camera sensors. These data will be collected alongside clinical rating scales, participant diary entries and expert clinician annotations of colour video images. Machine learning will be used to look for a signal to discriminate between Parkinson’s disease and control, and between Parkinson’s disease symptoms ‘on’ and ‘off’ medications. Additional outcome measures including bradykinesia, activity level, sleep parameters and some activities of daily living will be explored. Acceptability of the technology will be evaluated qualitatively using semi-structured interviews.Ethics and disseminationEthical approval has been given to commence this study; the results will be disseminated as widely as appropriate.
PurposeThe Oxford Parkinson’s Disease Centre (OPDC) Discovery Cohort MRI substudy (OPDC-MRI) collects high-quality multimodal brain MRI together with deep longitudinal clinical phenotyping in ...patients with Parkinson’s, at-risk individuals and healthy elderly participants. The primary aim is to detect pathological changes in brain structure and function, and develop, together with the clinical data, biomarkers to stratify, predict and chart progression in early-stage Parkinson’s and at-risk individuals.ParticipantsParticipants are recruited from the OPDC Discovery Cohort, a prospective, longitudinal study. Baseline MRI data are currently available for 290 participants: 119 patients with early idiopathic Parkinson’s, 15 Parkinson’s patients with pathogenic mutations of the leucine-rich repeat kinase 2 or glucocerebrosidase (GBA) genes, 68 healthy controls and 87 individuals at risk of Parkinson’s (asymptomatic carriers of GBA mutation and patients with idiopathic rapid eye movement sleep behaviour disorder-RBD).Findings to dateDifferences in brain structure in early Parkinson’s were found to be subtle, with small changes in the shape of the globus pallidus and evidence of alterations in microstructural integrity in the prefrontal cortex that correlated with performance on executive function tests. Brain function, as assayed with resting fMRI yielded more substantial differences, with basal ganglia connectivity reduced in early Parkinson’sand RBD. Imaging of the substantia nigra with the more recent adoption of sequences sensitive to iron and neuromelanin content shows promising results in identifying early signs of Parkinsonian disease.Future plansOngoing studies include the integration of multimodal MRI measures to improve discrimination power. Follow-up clinical data are now accumulating and will allow us to correlate baseline imaging measures to clinical disease progression. Follow-up MRI scanning started in 2015 and is currently ongoing, providing the opportunity for future longitudinal imaging analyses with parallel clinical phenotyping.
Resting state functional MRI (rs-fMRI) has been previously shown to be a promising tool for the assessment of early Parkinson's disease (PD). In order to assess whether changes within the basal ...ganglia network (BGN) are disease specific or relate to neurodegeneration generally, BGN connectivity was assessed in 32 patients with early PD, 19 healthy controls and 31 patients with Alzheimer's disease (AD). Voxel-wise comparisons demonstrated decreased connectivity within the basal ganglia of patients with PD, when compared to patients with AD and healthy controls. No significant changes within the BGN were seen in AD, when compared to healthy controls. Moreover, measures of functional connectivity extracted from regions within the basal ganglia were significantly lower in the PD group. Consistent with previous radiotracer studies, the greatest change when compared to the healthy control group was seen in the posterior putamen of PD subjects. When combined into a single component score, this method differentiated PD from AD and healthy control subjects, with a diagnostic accuracy of 81%. Rs-fMRI can be used to demonstrate the aberrant functional connectivity within the basal ganglia of patients with early PD. These changes are likely to be representative of patho-physiological basal ganglia dysfunction and are not associated with generalised neurodegeneration seen in AD. Further studies are necessary to ascertain whether this method is sensitive enough to detect basal ganglia dysfunction in prodromal PD, and its utility as a potential diagnostic biomarker for premotor and early motoric disease.
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.
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