Jessika Suescun

Altered nigrostriatal and nigrocortical functional connectivity in rapid eye movement sleep behavior disorder

STUDY OBJECTIVES Rapid eye movement sleep behavior disorder (RBD) is a condition closely associated with Parkinson disease (PD). RBD is a sleep disturbance that frequently manifests early in the development of PD, likely reflecting disruption in normal functioning of anatomical areas affected by neurodegenerative processes. Although specific neuropathological aspects shared by RBD and PD have yet to be fully documented, further characterization is critical to discovering reliable biomarkers that predict PD onset. In the current study, we tested the hypothesis of altered functional connections of the substantia nigra (SN) in patients in whom RBD was diagnosed. DESIGN Between-groups, single time point imaging. SETTING UTHSC-H 3 telsa MRI center. PARTICIPANTS Ten patients with RBD, 11 patients with PD, and 10 age-matched controls. INTERVENTIONS NA. MEASUREMENTS AND RESULTS We measured correlations of SN time series using resting state blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) in patients with idiopathic RBD who were at risk for developing PD, patients in whom PD was diagnosed, and age-matched controls. Using voxelwise analysis of variance, different correlations (P < 0.01, whole-brain corrected) between left SN and left putamen were found in patients with RBD compared with controls and patients with PD. SN correlations with right cuneus/precuneus and superior occipital gyrus were significantly different for patients with RBD compared with both controls and patients with PD. CONCLUSIONS The results suggest that altered nigrostriatal and nigrocortical connectivity characterizes rapid eye movement sleep behavior disorder before onset of obvious motor impairment. The functional changes are discussed in the context of degeneration in dopaminergic and cognition-related networks.

Slowed prosaccades and increased antisaccade errors as a potential behavioral biomarker of multiple system atrophy

Current clinical diagnostic tools are limited in their ability to accurately differentiate idiopathic Parkinson’s disease (PD) from multiple system atrophy (MSA) and other parkinsonian disorders early in the disease course, but eye movements may stand as objective and sensitive markers of disease differentiation and progression. To assess the use of eye movement performance for uniquely characterizing PD and MSA, subjects diagnosed with PD (N = 21), MSA (N = 11), and age-matched controls (C, N = 20) were tested on the prosaccade and antisaccade tasks using an infrared eye tracker. Twenty of these subjects were retested ~7 months later. Saccade latencies, error rates, and longitudinal changes in saccade latencies were measured. Both PD and MSA patients had greater antisaccade error rates than C subjects, but MSA patients exhibited longer prosaccade latencies than both PD and C patients. With repeated testing, antisaccade latencies improved over time, with benefits in C and PD but not MSA patients. In the prosaccade task, the normal latencies of the PD group show that basic sensorimotor oculomotor function remain intact in mid-stage PD, whereas the impaired latencies of the MSA group suggest additional degeneration earlier in the disease course. Changes in antisaccade latency appeared most sensitive to differences between MSA and PD across short time intervals. Therefore, in these mid-stage patients, increased antisaccade errors combined with slowed prosaccade latencies might serve as a useful marker for early differentiation between PD and MSA, and, antisaccade performance, a measure of MSA progression. Together, our findings suggest that eye movements are promising biomarkers for early differentiation and progression of parkinsonian disorders.

Clinical Determinants of Progression of Parkinson Disease: Predicting Prognosis by Subtype

Parkinson disease (PD) is one of the most common agerelatedneurodegenerative diseases, affecting 1%of thepopulationolder than60years of age and0.3%of the general population. It is a chronic, progressive disorderwhose spectrumof clinical features canaffect an individual formore than40years of his or her natural life span. Idiopathic PD is clinically and pathologically aheterogeneousdisorder that is variable inprogression and phenotypic expression. Withnoknownbiomarker fordiseasediagnosisorprogression, clinicians and scientists have long recognized the importance of classifying patterns of PD into distinct subtypes in order to identify features that influence rate of progression and response to interventionsand that correlatewithneural and biochemical substratesofdisease pathogenesis. To that end,HoehnandYahr in their landmark studyof 1967mayhave been among the earliest clinical scientists to recognize the heterogeneity of PD by describing that “the clinical picture of one may be dominated by tremor, of another by rigidity or akinesia,”1(p433) andsubsequentlydevelopedascale to ratehow symptomsof PDprogress.Disability stagingby theHoehnand Yahrscalecontinues tobeuseduniversally in ratingdiseaseand progressionas it relates towalkingandpostural stability.1More recently, the global Unified Parkinson’s Disease Rating Scale (with its subscales that assessmentation,mood andbehavior, activities of daily living,motor and nonmotor symptoms, and complicationsoftherapy)has introducedtheimportanceofnonmotorsymptoms in impactingqualityof life.TheMontrealCognitive Assessment, which allows for a bedside evaluation of 8 domainsof cognition,hasbeenadded to the repertoireof clinicalmeasures that informcliniciansof the functional stateof the patientwith PD. Although powerfully informative, thesemeasures, which are routinely performed by neurologists, and the standardof care formovementdisorders fall short indetermining prognosis or predicting rate of change for patientswith PD. In this issue of JAMA Neurology, Fereshtehnejad et al2 introduceanovel subtypingschemederivedfromclusteranalysis of a prospectively observed large cohort of patients with earlyPDidentifiedat theCenter forAdvancedResearch inSleep Medicine, Hopital du Sacre–Coeur deMontreal, andMontreal General Hospital, Montreal, Quebec, Canada. To our knowledge, it is the second data-driven clinical research studywith longitudinal observation, and the first to propose a scheme in whichnonmotor symptomsare theclinicaldeterminants indefining subtypes of PD. Importantly, orthostatic hypotension (OH), mild cognitive impairment (MCI), and rapid eye movementsleepbehaviordisorder (RBD)presentat initialvisitswere thedefining features for a“diffuse/malignant” subgroupofpatients with PD who had the most rapid rate of progression. Overthelastseveraldecades,differentphenotypicsubtypes havebeenproposed, largelybasedon2classificationmethods: an empirically assigned (predefined) classification scheme or adata-drivenclassificationscheme.Specificclinical featuresthat favoredhypothesis-drivenempiricalclassificationschemeswere developed fromclinical observationsof study cohorts that examinedsuchfactorsasageatsymptomonset, levodoparesponsiveness, familial history,motor symptompredominance, dementia,depression,andrateofprogression.Themostdominant clinical subtyping of PD emerged from motor subtyping into tremor-dominantvsnontremor-dominantPD(patientswithpredominant bradykinesia, akinesia, and postural instability and gait dysfunction [PIGD]) and indeterminate or mixed phenotypes.Thedistinctionbetweenthesephenotypicmotorsubtypes wasoften referred toasbenignvsmalignant in reference to the more rapid rate of deterioration and greater cognitive impairmentexhibitedbypatientswiththeakinetic-dominantsubtype. Current practice parameter guidelines for disease prognosis predict that older age at onset and the presence of rigidity/ hypokinesiaorPIGDas initial symptomsdescribe amore rapid rateofmotorprogressionandearly cognitivedecline,whereas thepresenceof tremor as an initial symptompredicts a slower progression and a longer response to levodopa therapy.3 Contrary to this conventional knowledge, a 2012 studybyVuet al4 proposed that tremorandPIGD-dominant subtypeswere not distinctsubtypesreflectingtheheterogeneityofPDbutweredifferent stagesof thediseaseprocess, and that tremorprogresses moreslowlythanothercardinalmotorsymptoms,whereasPIGD is less responsive to levodopa therapy. In fact, the cardinalmotor featuresofPD (including tremor, rigidity, bradykinesia, and PIGD)progress atdifferent rates andshowvariable responsiveness to levodopatherapy,challengingthe ideathatbaselinemotor subtypeclassification is a significantpredictorofdeath,depression, or cognitive decline.4,5 Some clinician-scientists advocate that clinical subtypes derived fromempirical classification schemescreatemoredistinct groups,which are simpler to identify using readily available rating scales, while others advocate that this approach is limitedbecause thecomplexityof the features frommotor and nonmotor symptoms isnot assessed.6As a consequence, cluster analysis has become the preferred method for subtyping, mostly because it is a hypothesis-free analysis that removes the conditional bias of choosing specific criteria based on experience, thusallowingunexpectedpatterns toappearandproRelated article page 863 Opinion

Earlier Intervention with Deep Brain Stimulation for Parkinson's Disease

Neuromodulation of subcortical areas of the brain as therapy to reduce Parkinsonian motor symptoms was developed in the mid-twentieth century and went through many technical and scientific advances that established specific targets and stimulation parameters. Deep Brain Stimulation (DBS) was approved by the FDA in 2002 as neuromodulation therapy for advanced Parkinsons disease, prompting several randomized controlled trials that confirmed its safety and effectiveness. The implantation of tens of thousands of patients in North America and Europe ignited research into its potential role in early disease stages and the therapeutic benefit of DBS compared to best medical therapy. In 2013 the EARLY-STIM trial provided Class I evidence for the use of DBS earlier in Parkinsons disease. This finding led to the most recent FDA approval in patients with at least 4 years of disease duration and 4 months of motor complications as an adjunct therapy for patients not adequately controlled with medications. This following review highlights the historical development and advances made overtime in DBS implantation, the current application, and the challenges that come with it.

Serum Lymphocyte-Associated Cytokine Concentrations Change More Rapidly over Time in Multiple System Atrophy Compared to Parkinson Disease

Objective: Chronic inflammatory processes contribute to the eventual death of motor neurons and the development of symptoms in both idiopathic Parkinson disease (PD) and multiple system atrophy (MSA). Given the faster rate of progression and more severe symptoms associated with MSA, we hypothesized that markers of inflammation would be more evident in the peripheral blood of MSA than PD patients, and that evidence of this inflammation might assist early diagnosis of MSA versus PD. Methods: We performed multiplex analysis to determine the concentrations of 37 immune-associated cytokines and chemokines isolated from the plasma of patients with PD (n = 25) and MSA (n = 14) and compared our results to those of age-matched controls (n = 15). We then applied a mixed-effect multiple regression model to determine if the concentration of cytokines in the plasma of patients with PD and MSA changed significantly over time. Results: Patients with MSA had a trend towards overall lower levels of immune-associated cytokines, while serum cytokine levels were increased in patients with PD. Statistically adjusted comparisons of overall changes in cytokine concentrations between the PD and MSA groups revealed higher concentrations of T-cell-associated cytokines TNFβ and IL-7 in PD. Comparison of samples taken over time revealed significantly faster rates of change in 4 different cytokine concentrations (IL-4, IL-15, IL-2, and IL-9) in patients with MSA versus patients with PD. Conclusions: Our results suggest that single measurements of plasma concentrations of inflammation-associated cytokines cannot be used to distinguish disease states. However, measurements made over time may correlate with pathogenesis. The significant changes in T-cell-associated cytokines may shed light on immune mechanisms that contribute to PD and MSA disease progression.

Longitudinal connectome-based predictive modeling for REM sleep behavior disorder from structural brain connectivity

Methods to identify neuroplasticity patterns in human brains are of the utmost importance in understanding and potentially treating neurodegenerative diseases. Parkinson disease (PD) research will greatly benefit and advance from the discovery of biomarkers to quantify brain changes in the early stages of the disease, a prodromal period when subjects show no obvious clinical symptoms. Diffusion tensor imaging (DTI) allows for an in-vivo estimation of the structural connectome inside the brain and may serve to quantify the degenerative process before the appearance of clinical symptoms. In this work, we introduce a novel strategy to compute longitudinal structural connectomes in the context of a whole-brain data-driven pipeline. In these initial tests, we show that our predictive models are able to distinguish controls from asymptomatic subjects at high risk of developing PD (REM sleep behavior disorder, RBD) with an area under the receiving operating characteristic curve of 0.90 (p<0.001) and a longitudinal dataset of 46 subjects part of the Parkinson’s Progression Markers Initiative. By analyzing the brain connections most relevant for the predictive ability of the best performing model, we find connections that are biologically relevant to the disease.