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Predictors of motor complications in early Parkinson's disease: A prospective cohort study.
OBJECTIVE: The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis. METHODS: An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete-time survival analysis. A subset analysis was used to validate an online dyskinesia-risk calculator developed from the results of the Stalevo Reduction in Dyskinesia Evaluation PD trial. RESULTS: A total of 186 cases of dyskinesia and 254 cases of motor fluctuations were observed. Dyskinesia incidence increased with time (risk per 100 participants [95% confidence interval] 13 [11-16] <3.5 years, 16 [13-21] 3.5-5.0 years, 19 [14-26] 5-6.5 years, and 23 [16-33] >6.5 years from diagnosis). Motor complication predictors were grouped as medication predictors, disease predictors and patient predictors. Baseline nonmotor feature severity, low mood, anxiety, and age at symptom onset were associated with motor complications among a number of previously identified predictors. Replication of the Stalevo Reduction in Dyskinesia Evaluation PD calculator was reasonable with the area under the curve for dyskinesia risk score as a predictor of dyskinesia being 0.68 (95% confidence interval, 0.55-0.81). CONCLUSIONS: This study quantifies risk of motor complications, finds consistent predictors, and demonstrates the novel finding that nonmotor features of PD, particularly low mood and anxiety, are significant risk factors for motor complications. Further validation of dyskinesia risk scores are required as well as evidence to determine if the routine use of such scores can be clinically valuable in enhancing patient care and quality of life. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Impulse control disorders in Parkinson disease and RBD: A longitudinal study of severity.
OBJECTIVE: To describe the prevalence, natural history, and risk factors for impulse control behaviors (ICBs) among people with Parkinson disease (PD), those with REM sleep behavior disorder (RBD), and controls. METHODS: Participants with early PD (within 3.5 years of diagnosis), those with RBD, and controls were clinically phenotyped and screened for ICBs longitudinally (with the Questionnaire for Impulsivity in Parkinson's Disease). ICB-positive individuals were invited for a semistructured interview, repeated 1 year later. The severity of the ICB was assessed with the Parkinson's Impulse Control Scale. Multiple imputation and regression models were used to estimate ICB prevalence and associations. RESULTS: Data from 921 cases of PD at baseline, 768 cases at 18 months, and 531 cases at 36 months were included, with 21% to 25% screening positive for ICBs at each visit. Interviews of ICB screen-positive individuals revealed that 10% met formal criteria for impulse control disorders (ICD), while 33% had subsyndromal ICD (ICB symptoms without reaching the formal diagnostic criteria for ICD). When these data were combined through the use of multiple imputation, the prevalence of PD-ICB was estimated at 19.1% (95% confidence interval 10.1-28.2). On follow-up, 24% of cases of subsyndromal ICD had developed full symptoms of an ICD. PD-ICD was associated with dopamine agonist use, motor complications, and apathy but not PD-RBD. ICD prevalence in the RBD group (1%) was similar to that in controls (0.7%). CONCLUSIONS: ICBs occur in 19.1% of patients with early PD, many persisting or worsening over time. RBD is not associated with increased ICD risk. Psychosocial drivers, including mood and support networks, affect severity.
Developing and validating Parkinson's disease subtypes and their motor and cognitive progression.
OBJECTIVES: To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson's disease (PD) using two large independent cohorts of patients newly diagnosed with this condition. METHODS: 1601 and 944 patients with idiopathic PD, from Tracking Parkinson's and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models. RESULTS: We identified four clusters: (1) fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease, poor psychological well-being and poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson's at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1-1.1). In Tracking Parkinson's, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%. CONCLUSIONS: We have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials.
Smartphone motor testing to distinguish idiopathic REM sleep behavior disorder, controls, and PD.
OBJECTIVE: We sought to identify motor features that would allow the delineation of individuals with sleep study-confirmed idiopathic REM sleep behavior disorder (iRBD) from controls and Parkinson disease (PD) using a customized smartphone application. METHODS: A total of 334 PD, 104 iRBD, and 84 control participants performed 7 tasks to evaluate voice, balance, gait, finger tapping, reaction time, rest tremor, and postural tremor. Smartphone recordings were collected both in clinic and at home under noncontrolled conditions over several days. All participants underwent detailed parallel in-clinic assessments. Using only the smartphone sensor recordings, we sought to (1) discriminate whether the participant had iRBD or PD and (2) identify which of the above 7 motor tasks were most salient in distinguishing groups. RESULTS: Statistically significant differences based on these 7 tasks were observed between the 3 groups. For the 3 pairwise discriminatory comparisons, (1) controls vs iRBD, (2) controls vs PD, and (3) iRBD vs PD, the mean sensitivity and specificity values ranged from 84.6% to 91.9%. Postural tremor, rest tremor, and voice were the most discriminatory tasks overall, whereas the reaction time was least discriminatory. CONCLUSIONS: Prodromal forms of PD include the sleep disorder iRBD, where subtle motor impairment can be detected using clinician-based rating scales (e.g., Unified Parkinson's Disease Rating Scale), which may lack the sensitivity to detect and track granular change. Consumer grade smartphones can be used to accurately separate not only iRBD from controls but also iRBD from PD participants, providing a growing consensus for the utility of digital biomarkers in early and prodromal PD.
Multi-parametric quantitative MRI of normal appearing white matter in multiple sclerosis, and the effect of disease activity on T2
White matter (WM) lesions with a distinct lesion-tissue contrast are the main radiological hallmark of multiple sclerosis (MS) in standard magnetic resonance imaging (MRI). Pathological WM changes beyond lesion development lack suitable contrasts, rendering the investigation of normal appearing WM (NAWM) more challenging. In this study, repeat quantitative MRI (qMRI) was collected in 9 relapsing remitting MS patients with mild disease over nine months. The relaxation times T1 and T2, the proton density (PD), and the magnetization transfer ratio (MTR) were analysed in the NAWM. For each parameter, both the mean value and the standard deviation were determined across large NAWM regions. The resulting 8-dimensional multi-parameter space includes parameter non-uniformities as additional descriptors of NAWM inhomogeneity. The goals of the study were to investigate (1) which of the eight parameters differ significantly between NAWM and normal WM, (2) if parameter time courses differ between patients with and without radiological disease activity, and (3) if a suitable biomarker can be derived from the multi-parameter space, allowing for NAWM characterization and differentiation from controls. On a group level, all parameters investigated except mean T1 values were significantly affected in MS NAWM. Group classification accuracy using a multi-parametric support vector machine approach in NAWM was 66.7 %. In addition, mean T2 values increased significantly with time for patients with radiological disease activity, but not for patients without radiological activity. In conclusion, our data demonstrate the potential of qMRI for investigating MS pathology in NAWM. T2 measurements in NAWM may enable monitoring of disease activity outside of overt lesions.
Changes in brain functional connectivity patterns are driven by an individual lesion in MS: a resting-state fMRI study
Diffuse inflammation in multiple sclerosis (MS) extends beyond focal lesion sites, affecting interconnected regions; however, little is known about the impact of an individual lesion affecting major white matter (WM) pathways on brain functional connectivity (FC). Here, we longitudinally assessed the effects of acute and chronic lesions on FC in relapsing-remitting MS (RRMS) patients using resting-state fMRI. 45 MRI data sets from 9 RRMS patients were recorded using 3T MR scanner over 5 time points at 8 week intervals. Patients were divided into two groups based on the presence (n = 5; MS+) and absence (n = 4; MS-) of a lesion at a predilection site for MS. While FC levels were found not to fluctuate significantly in the overall patient group, the MS+ patient group showed increased FC in the contralateral cuneus and precuneus and in the ipsilateral precuneus (p < 0.01, corrected). This can be interpreted as the recruitment of intact cortical regions to compensate for tissue damage. During the study, one patient developed an acute WM lesion in the left posterior periventricular space. A marked increase in FC in the right pre-, post-central gyrus, right superior frontal gyrus, the left cuneus, the vermis and the posterior and anterior lobes of the cerebellum was noted following the clinical relapse, which gradually decreased in subsequent follow-ups, suggesting short-term functional reorganization during the acute phase. This strongly suggests that the lesion-related network changes observed in patients with chronic lesions occur as a result of reorganization processes following the initial appearance of an acute lesion.
Statins are underused in recent-onset Parkinson's disease with increased vascular risk: findings from the UK Tracking Parkinson's and Oxford Parkinson's Disease Centre (OPDC) discovery cohorts.
BACKGROUND: Cardiovascular disease (CVD) influences phenotypic variation in Parkinson's disease (PD), and is usually an indication for statin therapy. It is less clear whether cardiovascular risk factors influence PD phenotype, and if statins are prescribed appropriately. OBJECTIVES: To quantify vascular risk and statin use in recent-onset PD, and examine the relationship between vascular risk, PD severity and phenotype. METHODS: Cardiovascular risk was quantified using the QRISK2 calculator (high ≥20%, medium ≥10 and <20%, low risk <10%). Motor severity and phenotype were assessed using the Movement Disorder Society Unified PD Rating Scale (UPDRS) and cognition by the Montreal cognitive assessment. RESULTS: In 2909 individuals with recent-onset PD, the mean age was 67.5 years (SD 9.3), 63.5% were men and the mean disease duration was 1.3 years (SD 0.9). 33.8% of cases had high vascular risk, 28.7% medium risk, and 22.3% low risk, while 15.2% of cases had established CVD. Increasing vascular risk and CVD were associated with older age (p<0.001), worse motor score (p<0.001), more cognitive impairment (p<0.001) and worse motor phenotype (p=0.021). Statins were prescribed in 37.2% with high vascular risk, 15.1% with medium vascular risk and 6.5% with low vascular risk, which compared with statin usage in 75.3% of those with CVD. CONCLUSIONS: Over 60% of recent-onset PD patients have high or medium cardiovascular risk (meriting statin usage), which is associated with a worse motor and cognitive phenotype. Statins are underused in these patients, compared with those with vascular disease, which is a missed opportunity for preventive treatment. TRIAL REGISTRATION NUMBER: GN11NE062, NCT02881099.
Changes and variability of proton density and T1 relaxation times in early multiple sclerosis: MRI markers of neuronal damage in the cerebral cortex
Objectives: Proton density (PD) and T1 relaxation time are promising quantitative MRI (qMRI) markers of neuronal damage in multiple sclerosis (MS). However, it is unknown whether cortical differences of these parameters between patients and controls exist in the early stages of disease. This study investigates cortical T1 and PD in early MS stages, hypothesizing that these are altered and display a high spatial variability. Methods: Quantitative T1 and PD mapping was performed on 11 patients with clinically isolated syndrome (CIS)/early MS in remission and 11 healthy controls. The normal appearing cortical gray matter was extracted, lobar regions were identified, and mean values and standard deviations of both parameters were calculated within each region. Results: Increased PD was detected in MS/CIS patients in the cerebral cortex as a whole and all subregions, indicating an increase of water content. Increase of PD variability reached significance in the whole cortex and in the frontal and parietal regions. Longer T1 relaxation times and increased variability were found in the cerebral cortex in all regions studied, indicating a change of microstructural tissue composition that is spatially heterogeneous. Conclusions: The data show spatially heterogeneous cortical involvement in early MS is reflected in T1 and PD qMRI. Key Points: • Cortical involvement in early MS is reflected in T1/PD quantitative MRI. • The changes are spatially heterogeneous. • Cortical damage goes beyond increased water content.
Assessment of cortical damage in early multiple sclerosis with quantitative T2 relaxometry
T2 relaxation time is a quantitative MRI in vivo surrogate of cerebral tissue damage in multiple sclerosis (MS) patients. Cortical T2 prolongation is a known feature in later disease stages, but has not been demonstrated in the cortical normal appearing gray matter (NAGM) in early MS. This study centers on the quantitative evaluation of the tissue parameter T2 in cortical NAGM in a collective of early MS and clinically isolated syndrome (CIS) patients, hypothesizing that T2 prolongation is already present at early disease stages and variable over space, in line with global and focal inflammatory processes in MS. Additionally, magnetization transfer ratio (MTR) mapping was performed for further characterization of the expected cortical T2 alteration. Quantitative T2 and MTR maps were acquired from 12 patients with CIS and early MS, and 12 matched healthy controls. The lesion-free part of the cortical volume was identified, and the mean T2 and MTR values and their standard deviations within the cortical volume were determined. For evaluation of spatial specificity, cortical lobar subregions were tested separately for differences of mean T2 and T2 standard deviation. We detected significantly prolonged T2 in cortical NAGM in patients. T2 prolongation was found across the whole cerebral cortex and in all individual lobar subregions. Significantly higher standard deviations across the respective region of interest were found for the whole cerebral cortex and all subregions, suggesting the occurrence of spatially inhomogeneous cortical damage in all regions studied. A trend was observed for MTR reduction and increased MTR variability across the whole cortex in the MS group, suggesting demyelination. In conclusion, our results suggest that cortical damage in early MS is evidenced by spatially inhomogeneous T2 prolongation which goes beyond demyelination. Iron deposition, which is known to decrease T2, seems less prominent.
Quantitative T1 and proton density mapping with direct calculation of radiofrequency coil transmit and receive profiles from two-point variable flip angle data
Quantitative T1 mapping of brain tissue is frequently based on the variable flip angle (VFA) method, acquiring spoiled gradient echo (GE) datasets at different excitation angles. However, accurate T1 calculation requires a knowledge of the sensitivity profile B1 of the radiofrequency (RF) transmit coil. For an additional derivation of proton density (PD) maps, the receive coil sensitivity profile (RP) must also be known. Mapping of B1 and RP increases the experiment duration, which may be critical when investigating patients. In this work, a method is presented for the direct calculation of B1 and RP from VFA data. Thus, quantitative maps of T1, PD, B1 and RP can be obtained from only two spoiled GE datasets. The method is based on: (1) the exploitation of the linear relationship between 1/PD and 1/T1 in brain tissue and (2) the assumption of smoothly varying B1 and RP, so that a large number of data points can be fitted across small volume elements where B1 and RP are approximately constant. The method is tested and optimized on healthy subjects.
Meningeal disorders
Meningeal disorders of the spine form a heterogenous group of diseases, affecting the spinal cord and its nerve roots through their intimate contact. Meningeal disease can, at times, present with back pain only. However, neurological symptoms are the more common manifestation leading to diagnosis, be it through compression of the spinal cord or of the spinal nerves. MRI is the imaging modality of choice when meningeal disease of the spine is suspected. Wherever possible, imaging studies should precede diagnostic lumbar puncture, because contrast enhancement of the dural sac can occur subsequent to lumbar puncture. If imaging is performed after lumbar puncture, it may be impossible to distinguish between enhancement through meningeal disease and transient changes subsequent to opening of the dural space.
Gray matter diseases of the spinal cord
Gray matter diseases of the spinal cord cover a heterogenous group of inherited disorders, infectious and sporadic diseases. Typical examples include the spinal muscular atrophies, poliomyelitis, and motor neuron diseases. Clinical symptoms, age at onset, rate of progression, family history, and electrophysiological findings will help make the diagnosis.
Diseases of the spinal cord: Novel imaging, diagnosis and treatment
This book documents current knowledge on the mechanisms involved in sports injuries to the shoulder and elbow, reviews essential physical examinations, and explains the role of diagnostic imaging. Above all, it describes in detail the treatment modalities that are appropriate to the injuries encountered in throwing and overhead athletes, including chronic repetitive and acute traumatic injuries. Both conservative and surgical treatments are covered; the author's own preferred operative techniques are identified and explained, and helpful treatment algorithms offer guidance in selecting an approach fitting to the circumstances. In addition, the inclusion of instructive case reviews will assist readers in achieving a full understanding of the implementation of treatment protocols. Methods of rehabilitation are also described with the aid of demonstration videos, and advice is provided on appropriate timing. The book will be invaluable for all professionals who deal with sports injuries of the shoulder and elbow, including surgeons, physiotherapists, other medical practitioners, and trainers.?Spinal cord imaging has significantly benefited from a variety of new MR imaging methods. Recent decades have also witnessed fundamental progress in understanding of the pathophysiology of spinal cord diseases, treatment options, neurosurgical procedures, and endovascular treatments. This textbook provides an interdisciplinary overview of the new imaging modalities, identifies clues for MR imaging diagnosis and differential diagnosis and describes the anatomical background required to understand spinal cord diseases. Important neurological symptoms are highlighted, and modern treatment options for different diseases are fully explained and discussed. High-quality illustrations, including numerous images, are provided for all important spinal cord diseases, documenting relevant anatomical details, special MR imaging methods, differential diagnoses and possible treatment procedures.
White matter damage is related to ataxia severity in SCA3
Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms. © Springer-Verlag 2013.
The value of putaminal diffusion imaging versus 18-fluorodeoxyglucose positron emission tomography for the differential diagnosis of the Parkinson variant of multiple system atrophy
Differentiating the Parkinson variant of multiple system atrophy (MSA-P) from idiopathic Parkinson's disease (PD) and other forms of atypical parkinsonism can be difficult because symptoms overlap considerably. 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) is a powerful imaging technique that can assist in the diagnosis of MSA-P via detection of putaminal and cerebellar hypometabolism. Recent studies suggest that diffusion-weighted imaging (DWI) might be of similar diagnostic value, as it can detect microstructural damage in the putamen by means of an increased mean diffusivity (MD). The aim of this study was a direct comparison of DWI and FDG-PET by using both methods on the same subject cohort. To this end, combined DWI and FDG-PET were employed in patients with MSA-P (n=11), PD (n=13), progressive supranuclear palsy (n=8), and in 6 control subjects. MD values and FDG uptake ratios were derived from volumetric parcellations of the putamen and subjected to further analysis of covariance (ANCOVA) and receiver operating characteristics analyses. MSA-P was found to be associated with an increased posterior putaminal MD (P<0.001 in all subgroup comparisons) that correlated strongly with local reductions in FDG uptake (r=-0.85, P=0.002). DWI discriminated patients with MSA-P from other subgroups nearly as accurately as FDG-PET (area under the curve=0.89 vs 0.95, P=0.27 [pooled data]). Our data suggest a close association between the amount of putaminal microstructural damage and a reduced energy metabolism in patients with MSA-P. The clinical use of DWI for the differential diagnosis of MSA-P is encouraged. © 2013 International Parkinson and Movement Disorder Society.
Diffusion Imaging in Tremor
In recent years, diffusion-weighted magnetic resonance imaging (DWI) has complemented established imaging techniques for studying the human brain in health and disease. DWI is an MR technique that probes the motion of free water undergoing spontaneous diffusion in the living tissue. Unlike conventional, structural MRI, this method provides insights into the microscopic composition, integrity, and orientation of structures in the human brain (Le Bihan 2003).