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Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons and dysregulation of the basal ganglia. Cardinal motor symptoms include bradykinesia, rigidity, and tremor. Deep brain stimulation (DBS) of select subcortical nuclei is standard-of-care for medication-refractory PD. Conventional open-loop DBS delivers continuous stimulation with fixed parameters that do not account for a patient's dynamic activity state or medication cycle. In comparison, closed-loop, or adaptive DBS (aDBS) adjusts stimulation based on biomarker feedback that correlates with clinical state. Recent work has identified several neurophysiological biomarkers in local field potential recordings from PD patients, the most promising of which are: 1) elevated beta (~13-30 Hz) power in the subthalamic nucleus (STN), 2) increased beta synchrony throughout basal ganglia-thalamocortical circuits, notably, observed as coupling between the STN beta phase and cortical broadband gamma (~50-200 Hz) amplitude, and 3) prolonged beta bursts in the STN and cortex. In this review, we highlight relevant frequency and time domain features of STN beta measured in PD patients and summarize how spectral beta power, oscillatory beta synchrony, phase-amplitude coupling, and temporal beta bursting informs PD pathology, neurosurgical targeting, and DBS therapy. We then review how STN beta dynamics inform predictive, biomarker-driven aDBS approaches for optimizing PD treatment. We therefore provide clinically useful and actionable insight that can be applied towards aDBS implementation for PD.

DYT-TUBB4A, formerly known as DYT4, has not been comprehensively described as only one large family and three individual cases have been published. We have recently described an in depth genetic and protein structural analysis of eleven additional cases from four families with four new pathogenic variants. We aim to report on the phenomenology of these cases suffering from DYT-TUBB4A and to perform a comprehensive review of the clinical presentation and treatment responses of all DYT-TUBB4A cases reported in the literature.The clinical picture was typically characterized by laryngeal dystonia (more than three quarters of all cases), associated with cervical dystonia, upper limb dystonia and frequent generalization. Extension of the dystonia to the lower limbs, creating the famous "hobby horse" gait, was present in more than 20% of cases (in only one of ours). Globus pallidus pars interna (GPi) deep brain stimulation (DBS), performed in 4 cases, led to a good improvement with greatest benefit in motoric and less benefit in laryngeal symptoms. Medical treatment was generally rather poorly effective, except some benefit from propranolol, tetrabenazine and alcohol intake.Laryngeal involvement is a hallmark of DYT-TUBB4A. Symptomatic treatment with GPi-DBS led to the greatest benefit in motoric symptoms. Nevertheless

Background: Deep brain stimulation (DBS) is an effective surgical treatment for movement disorders. Early versions of implantable systems delivered stimulation with constant voltage (CV); however, advances in available and newer platforms have permitted programming in constant current (CC). From a treatment management perspective, there are theoretical advantages of CC stimulation. In this case series, we present clinical evidence supporting the maintenance of current regardless of changes to impedance. Materials and Methods: This case series included 3 patients with Parkinson’s disease status post-bilateral subthalamic nucleus DBS. Patients in this series self-reported intermittent diplopia with pressure applied to the scalp. Patients were subsequently examined and converted from CV to CC and re-examined. Impedances were checked prior to and after conversion from CV to CC as well as while applying pressure to the scalp that induced the adverse effects. Results: Across patients, we observed that compression of the scalp overlying the connector, while patients were maintained in CV, consistently and objectively induced unilateral adduction of an eye. In addition, during scalp compression, while in CV, impedance was reduced, which would increase current delivery. Converting the patients to CC stimulation without changing other stimulation parameters eliminated diplopia and objective findings of eye deviation with compression of the scalp overlying the hardware despite changes in impedance. Conclusions: In this case series, we provide clinical support for the principal differences between CV and CC stimulation.

ObjectivesDeep brain stimulation (DBS), targeting the subthalamic nucleus (STN) and globus pallidus interna, is a surgical therapy with class 1 evidence for Parkinson’s disease (PD). Bilateral DBS electrodes may be implanted within a single operation or in separate staged surgeries with an interval of time that varies patient by patient. In this study, we used the variation in the timing of implantation from the first to the second implantation allowing for examination of potential volumetric changes of the basal ganglia in patients with PD who underwent staged STN DBS.MethodsThirty-two patients with a mean time interval between implantations of 141.8 (±209.1; range: 7–700) days and mean duration of unilateral stimulation of 244.7 (±227.7; range: 20–672) days were included in this study. Using volumetric analysis of whole hemisphere and subcortical structures, we observed whether implantation or stimulation affected structural volume.ResultsWe observed that DBS implantation, but not the duration of stimulation, induced a significant reduction of volume in the caudate, pallidum, putamen and thalamus ipsilateral to the implanted hemisphere. These findings were not dependent on the trajectory of the implanted electrode nor on first surgery pneumocephalus (0.07%: %Δ for intracranial volume between first and second surgery). In addition, unique regional atrophy differences were evident in each of the structures.ConclusionOur results demonstrate that DBS implantation surgery may affect hemisphere volume at the level of subcortical structures connected to the surgical target.

Advanced therapies in neurosurgery, such as deep brain stimulation (DBS), would benefit from improved patient education materials. Three-dimensional (3D) printed anatomical models represent a recent development for improving patient education for neurosurgical procedures.In this study, 40 patients undergoing DBS surgery consultation were randomly assigned to 1 of 2 groups: an experimental group, which received a demonstration of DBS therapeutic neuroanatomical targets in a 3D printed brain model plus standard patient education (PE), or a control group, which received standard PE alone.Patients in the DBS model plus PE group showed a significant increase in patient confidence and understanding of the brain structures targeted during a DBS procedure compared with patients in the PE-only group (P0.01). There was no difference in perceived risk, comfort, or anxiety related to the procedure.In the first randomized controlled study to our knowledge of 3D printed models for DBS consultation, our results demonstrate that patients had improved understanding of their therapy with the models. However, the models alone did not affect risk evaluation or comfort with surgery. A 3D printed brain model may help improve patient understanding of DBS surgery.

The MDS Video Challenge continues to be the one of most widely attended sessions at the International Congress. Although the primary focus of this event is the presentation of complex and challenging cases through videos, a number of cases over the years have also presented an unusual or important neuroimaging finding related to the case. We reviewed the previous Video Challenge cases and present here a selection of those cases which incorporated such imaging findings. We have compiled these “imaging pearls” into two anthologies. The first focuses on pearls where the underlying diagnosis was a genetic condition. This second anthology focuses on imaging pearls in cases where the underlying condition was acquired. For each case we present brief clinical details along with neuroimaging findings, the characteristic imaging findings of that disorder and, finally, the differential diagnosis for the imaging findings seen.

The neurosurgical treatment of movement disorders, primarily via deep brain stimulation (DBS), is a rapidly expanding and evolving field. Although conventional targets including the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) for Parkinson's disease and ventral intermediate nucleus of the thalams (VIM) for tremor provide substantial benefit in terms of both motor symptoms and quality of life, other targets for DBS have been explored in an effort to maximize clinical benefit and also avoid undesired adverse effects associated with stimulation. These novel targets primarily include the rostral zona incerta (rZI), caudal zona incerta (cZI)/posterior subthalamic area (PSA), prelemniscal radiation (Raprl), pedunculopontine nucleus (PPN), substantia nigra pars reticulata (SNr), centromedian/parafascicular (CM/PF) nucleus of the thalamus, nucleus basalis of Meynert (NBM), dentato-rubro-thalamic tract (DRTT), dentate nucleus of the cerebellum, external segment of the globus pallidus (GPe), and ventral oralis (VO) complex of the thalamus. However, reports of outcomes utilizing these targets are scattered and disparate. In order to provide a comprehensive resource for researchers and clinicians alike, we have summarized the existing literature surrounding these novel targets, including rationale for their use, neurosurgical techniques where relevant, outcomes and adverse effects of stimulation, and future directions for research.

Background: Globus pallidus internus (GPi) deep brain stimulation (DBS) and thalamotomy are interventions for writer’s cramp (WC). Ventralis intermedius nucleus (VIM) DBS is targeted for tremor, however, many aspects of VIM DBS remained underexplored in WC. Case Report: A 62-year-old man with WC underwent DBS. Dystonic tremor improved intraoperatively with ventralis oralis anterior (VoA)/ventral oralis posterior (VoP) and with subthalamic nucleus stimulation; although greatest benefit was obtained with VIM stimulation. Sustained benefit with VIM DBS at ten months post-operative was obtained. Discussion: This case demonstrates an intraoperative approach in target selection and supports benefits of VIM DBS for WC. Highlights: This case highlights the intraoperative approach and clinical effects of VIM DBS in the treatment of medically refractory writer’s cramp (WC). We contextualize our results from this case with previous reports of VoA/VoP stimulation for WC.

Introduction: Deep brain stimulation of the zona incerta is effective at treating tremor and other forms of parkinsonism. However, the structure is not well visualized with standard MRI protocols making direct surgical targeting unfeasible and contributing to inconsistent clinical outcomes. In this study, we applied coronal gradient echo MRI to directly visualize the rostral zona incerta in Parkinson’s disease patients to improve targeting for deep brain stimulation. Methods: We conducted a prospective study to optimize and evaluate an MRI sequence to visualize the rostral zona incerta in patients with Parkinson’s disease (n = 31) and other movement disorders (n = 13). We performed a contrast-to-noise ratio analysis of specific regions of interest to quantitatively assess visual discrimination of relevant deep brain structures in the optimized MRI sequence. Regions of interest were independently assessed by 2 neuroradiologists, and interrater reliability was assessed. Results: Rostral zona incerta and subthalamic nucleus were well delineated in our 5.5-min MRI sequence, indicated by excellent interrater agreement between neuroradiologists for region-of-interest measurements (>0.90 intraclass coefficient). Mean contrast-to-noise ratio was high for both rostral zona incerta (6.39 ± 3.37) and subthalamic nucleus (17.27 ± 5.61) relative to adjacent white matter. There was no significant difference between mean signal intensities or contrast-to-noise ratio for Parkinson’s and non-Parkinson’s patients for either structure. Discussion/Conclusion: Our optimized coronal gradient echo MRI sequence delineates subcortical structures relevant to traditional and novel deep brain stimulation targets, including the zona incerta, with high contrast-to-noise. Future studies will prospectively apply this sequence to surgical planning and postimplantation outcomes.

Objectives: The objective of this study was to determine phenotypic features that differentiate nonparkinsonian first-degree relatives of PD leucine-rich repeat kinase 2 (LRRK2) G2019S multiplex families, regardless of carrier status, from healthy controls because nonparkinsonian individuals in multiplex families seem to share a propensity to present neurological features. Methods: We included nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases and unrelated healthy controls participating in established multiplex family LRRK2 cohorts. Study participants underwent neurologic assessment including cognitive screening, olfaction testing, and questionnaires for daytime sleepiness, depression, and anxiety. We used a multiple logistic regression model with backward variable selection, validated with bootstrap resampling, to establish the best combination of motor and nonmotor features that differentiates nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases from unrelated healthy controls. Results: We included 142 nonparkinsonian family members and 172 unrelated healthy controls. The combination of past or current symptoms of anxiety (adjusted odds ratio, 4.16; 95% confidence interval, 2.01-8.63), less daytime sleepiness (adjusted odds ratio [1 unit], 0.90; 95% confidence interval, 0.83-0.97], and worse motor UPDRS score (adjusted odds ratio [1 unit], 1.4; 95% confidence interval, 1.20-1.67) distinguished nonparkinsonian family members, regardless of LRRK2 G2019S mutation status, from unrelated healthy controls. The model accuracy was good (area under the curve = 79.3%). Conclusions: A set of motor and nonmotor features distinguishes first-degree relatives of LRRK2 G2019S probands, regardless of mutation status, from unrelated healthy controls. Environmental or non-LRRK2 genetic factors in LRRK2-associated PD may influence penetrance of the LRRK2 G2019S mutation. The relationship of these features to actual PD risk requires longitudinal observation of LRRK2 familial PD cohorts. © 2018 International Parkinson and Movement Disorder Society.

Background Heart rate variability is reduced in idiopathic PD, indicating cardiac autonomic dysfunction likely resulting from peripheral autonomic synucleinopathy. Little is known about heart rate variability in leucine-rich repeat kinase 2-associated PD. Objectives This study investigated heart rate variability in LRRK2-associated PD. Methods Resting electrocardiograms were obtained from 20 individuals with LRRK2-associated PD, 37 nonmanifesting carriers, 48 related noncarriers, 26 idiopathic PD patients, and 32 controls. Linear regression modelling compared time and frequency domain values, adjusting for age, sex, heart rate, and disease duration. Results Low-frequency power and the ratio of low–high frequency power were reduced in idiopathic PD versus controls (P

Objective: to report four novel TUBB4A mutations leading to laryngeal and cervical dystonia with frequent generalization. Background: DYT-TUBB4A, formerly known as DYT4, has only been described in one large family and two individual cases. The clinical picture highlighted in the original family comprises laryngeal and cervical dystonia extending to generalized dystonia, plus a “hobby horse” gait disorder. The variant identified as causative in the original family was a heterozygous missense mutation R2G in exon 1 of the TUBB4A gene. Methods: we screened four families including a total of eleven definitely affected members with a clinical picture resembling the original description. Results: four novel variants in the TUBB4A gene have been identified: D295N, R46M, Q424H, R121W . In silico modeling showed that all variants have similar characteristics to R2G. The variants segregate with the disease in three of the families with evidence of incomplete penetrance in two of them. All four variants would be classified as likely pathogenic. The clinical picture particularly included laryngeal dystonia (often the site of onset), associated with cervical and upper limb dystonia and frequent generalization. Laryngeal dystonia was extremely prevalent (>90%) both in the original cases and in this case series. The “hobby horse” gait was evident in only one patient in this case series. Interpretation: laryngeal involvement is a hallmark feature of DYT-TUBB4A. Nevertheless, TUBB4A mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia.

Observations using invasive neural recordings from patient populations undergoing neurosurgical interventions have led to critical breakthroughs in our understanding of human neural circuit function and malfunction. The opportunity to interact with patients during neurophysiological mapping allowed for early insights in functional localization to improve surgical outcomes, but has since expanded into exploring fundamental aspects of human cognition including reward processing, language, the storage and retrieval of memory, decision-making, as well as sensory and motor processing. The increasing use of chronic neuromodulation, via deep brain stimulation, for a spectrum of neurological and psychiatric conditions has in tandem led to increased opportunity for linking theories of cognitive processing and neural circuit function. Our purpose here is to motivate the neuroscience and neurosurgical community to capitalize on the opportunities that this next decade will bring. To this end, we will highlight recent studies that have successfully leveraged invasive recordings during deep brain stimulation surgery to advance our understanding of human cognition with an emphasis on reward processing, improving clinical outcomes, and informing advances in neuromodulatory interventions.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by complex recapitulations of waking acts during REM sleep due to unsuppressed voluntary muscle tone. Long-term studies indicate that RBD strongly predicts the subsequent development of Parkinson's disease (PD), Lewy body disease, and multiple system atrophy, with a conversion rate approaching 80%. Localizing the aberrant circuits involved in RBD has focused on the networks associated with REM generation, including the sublateral dorsal nucleus, the mesopontine tegmentum, and the pedunculopontine tegmental nucleus—nuclei affected by circuit dysregulation in PD. Interestingly, parkinsonism transiently abates during RBD complex movements, suggesting that movement during RBD may bypass the circuitry affected in PD, including the basal ganglia. Only recently have electrophysiological recordings in PD during sleep informed our understanding of how abnormal activity in the basal ganglia contributes to sleep dysregulation, specifically to RBD. Here, we highlight the pathophysiology shared between RBD and PD, focusing on the presumed aberrant neural networks, based on neuroimaging and neurophysiology data collected from human RBD and PD populations.

Background Classification of parkinsonian symptoms, including tremor and bradykinesia, require the application of validated clinical rating scales which are inherently subjective. In this study, we assessed an objective measure of parkinsonian symptomology using automated analysis of hand gestures. New method We constructed and evaluated a hand and finger motion capture apparatus and analysis pipeline that recorded hand/finger motion of control subjects and patients with Parkinson's disease. The detailed three-dimensional (3D) motion features of each finger joint was extracted by using Discrete Wavelet Transform (DWT). The severity of tremor for each finger joint was quantitated by analyzing the motion changes in the frequency domain on four types of motion from five patients and twenty-two control subjects. Results The proposed approach could distinguish the behavior of patients with Parkinson's disease and control subjects by analyzing the detailed motion features of their hands/fingers. Comparison with existing methods Previously established methods to quantitate finger movement dynamics focus on speed and amplitude. In contrast, our approach measures unsupervised motion features, in real-time, using wavelet analysis, of each individual finger joint during active free movement. Conclusions The proposed study provides an objective assessment of tremor and bradykinesia in Parkinson's disease. Accordingly, this may help movement disorder clinicians to detect, diagnose and monitor treatment efficacy in Parkinson's disease.

We investigate the potential association between leucine-rich repeat kinase 2 (LRRK2) mutations and voice. Sustained phonations ('aaah' sounds) were recorded from 7 individuals with LRRK2-associated Parkinson's disease (PD), 17 participants with idiopathic PD (iPD), 20 non-manifesting LRRK2-mutation carriers, 25 related non-carriers, and 26 controls. In distinguishing LRRK2-associated PD and iPD, the mean sensitivity was 95.4% (SD 17.8%) and mean specificity was 89.6% (SD 26.5%). Voice features for non-manifesting carriers, related non-carriers, and controls were much less discriminatory. Vocal deficits in LRRK2-associated PD may be different than those in iPD. These preliminary results warrant longitudinal analyses and replication in larger cohorts.

Background/Aims: Interleaving stimulation (ILS) in deep brain stimulation (DBS) provides individualized stimulation of 2 contacts delivered in alternating order. Currently, limited information on the utility of ILS exists. The aims of this study were to determine the practical applications and outcomes of ILS DBS in Parkinson’s disease (PD), tremor, and dystonia. Methods: We performed a single-center, unblinded, retrospective chart review of all patients with DBS attempted on ILS at our referral center assessing for rationale and outcomes. Results: Fifty patients (PD, n = 27; tremor, n = 7; dystonia, n = 16 patients) tried ILS for 2 rationales: management of adverse effects (n = 29) and to improve clinical efficacy (n = 21). A total of 19 patients demonstrated improvement with ILS for adverse effect management predominately for the treatment of dyskinesias (n = 12). In the vast majority of dyskinetic patients, a contact added into the rostral zona incerta with ILS was performed. Nine out of 21 patients demonstrated improved clinical efficacy with ILS with all 6 PD patients who tried ILS for this rationale demonstrating benefit. Conclusions: In PD, ILS provided benefits for dyskinesias and parkinsonism, with minimal improvement of other adverse effects. In tremor and dystonia, marginal effects in terms of mitigation of adverse effects and improvement of clinical outcomes were evident.

BACKGROUND With recent advances in the search for disease-modifying therapies for Parkinson's disease (PD) the importance of identifying prodromal markers becomes greater. Non-manifesting LRRK2 mutation carriers (NMC) are at risk for developing PD, and provide a population in which to identify possible markers. OBJECTIVE The aim of this study was to test the hypothesis that NMC have differences in daily activity, fragmentation of sleep, arm swing asymmetry, and movement variability during walking, detectable by actigraphy, as compared to matched control subjects. METHODS Eleven NMC, fourteen PD patients (4 LRRK2-PD, 10 idiopathic PD (iPD)), and twenty-nine controls wore wristbands containing an accelerometer for seven days, and performed a daily walking task. Outcome measures included daily activity, fragmentation of activity, fragmentation of sleep, arm swing asymmetry during walking, and intra-individual variability. RESULTS Compared to healthy controls, both NMC and LRRK2/iPD showed higher intra-individual variability in activity during walking compared to healthy controls. Individuals with LRRK2-PD/iPD, but not NMC, tend to have lower activity levels, more arm swing asymmetry and less increase of arm swing with transition from slow to faster walking speed compared to healthy controls. CONCLUSION Higher intra-individual variability of gait-associated movements might be a useful biomarker of prodromal PD. These results encourage replication in a larger sample and longitudinal analysis is warranted.

Dravet syndrome is a severe, childhood-onset epileptic encephalopathy characterized by febrile seizures progressing to pharmacoresistant epilepsy. Many cases are linked to a heterozygous loss-of-function mutation in the SCN1A gene, which codes for an alpha subunit of the voltage-gated sodium channel.1 Life expectancy is dramatically shortened, with status epilepticus and sudden unexplained death in epilepsy the most frequent causes of death.2 Consequently, studies describing the natural history of Dravet syndrome into adulthood are rare. Additional neurologic symptoms have been recognized as these patients age, including ataxia, gait impairment, anterocollis, and parkinsonism, the last of which may be levodopa-responsive.3,4 It remains unclear, however, what underlies the dopaminergic pathway dysfunction in individuals with Dravet syndrome.

Objective To examine sex differences and trends in comorbid disease and health care utilization in individuals with newly diagnosed Parkinson disease (PD). Design Retrospective cohort study. Participants Over 133,000 Medicare beneficiaries with a new PD diagnosis in 2002 followed through 2008. Methods We compared the prevalence and cumulative incidence of common medical conditions, trends in survival and health care utilization between men and women with PD. Results Female PD patients had higher adjusted incidence rate ratio (IRR) of depression (IRR: 1.28, 1.25–1.31), hip fracture (IRR: 1.51, 1.45–1.56), osteoporosis (3.01, 2.92–3.1), and rheumatoid/osteoarthritis (IRR: 1.47, 1.43–1.51) than men. In spite of greater survival, women with PD used home health and skilled nursing facility care more often, and had less outpatient physician contact than men throughout the study period. Conclusions Women experience a unique health trajectory after PD diagnosis as suggested by differing comorbid disease burden and health care utilization compared to men. Future studies of sex differences in care needs, care quality, comorbidity related disability, PD progression, and non-clinical factors associated with disability are needed to inform research agendas and clinical guidelines that may improve quality survival for women with PD.

Objective:To examine rehabilitation therapy utilization for Parkinson disease (PD).Methods:We identified 174,643 Medicare beneficiaries with a diagnosis of PD in 2007 and followed them through 2009. The main outcome measures were annual receipt of physical therapy (PT), occupational therapy (OT), or speech therapy (ST).Results:Outpatient rehabilitation fee-for-service use was low. In 2007, only 14.2% of individuals with PD had claims for PT or OT, and 14.6% for ST. Asian Americans were the highest users of PT/OT (18.4%) and ST (18.4%), followed by Caucasians (PT/OT 14.4%, ST 14.8%). African Americans had the lowest utilization (PT/OT 7.8%, ST 8.2%). Using logistic regression models that accounted for repeated measures, we found that African American patients (adjusted odds ratio [AOR] 0.63 for PT/OT, AOR 0.63 for ST) and Hispanic patients (AOR 0.97 for PT/OT, AOR 0.91 for ST) were less likely to have received therapies compared to Caucasian patients. Patients with PD with at least one neurologist visit per year were 43% more likely to have a claim for PT evaluation as compared to patients without neurologist care (AOR 1.43, 1.30–1.48), and this relationship was similar for OT evaluation, PT/OT treatment, and ST. Geographically, Western states had the greatest use of rehabilitation therapies, but provider supply did not correlate with utilization.Conclusions:This claims-based analysis suggests that rehabilitation therapy utilization among older patients with PD in the United States is lower than reported for countries with comparable health care infrastructure. Neurologist care is associated with rehabilitation therapy use; provider supply is not.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterised by complex motor enactment of dreams and is a potential prodromal marker of Parkinson9s disease (PD). Of note, patients with PD observed during RBD episodes exhibit improved motor function, relative to baseline states during wake periods. Here, we review recent epidemiological and mechanistic findings supporting the prodromal value of RBD for PD, incorporating clinical and electrophysiological studies. Explanations for the improved motor function during RBD episodes are evaluated in light of recent publications. In addition, we present preliminary findings describing changes in the activity of the basal ganglia across the sleep–wake cycle that contribute to our understanding of RBD.

Heart rate variability is reduced in idiopathic PD, indicating cardiac autonomic dysfunction likely resulting from peripheral autonomic synucleinopathy. Little is known about heart rate variability in leucine-rich repeat kinase 2-associated PD.This study investigated heart rate variability in LRRK2-associated PD.Resting electrocardiograms were obtained from 20 individuals with LRRK2-associated PD, 37 nonmanifesting carriers, 48 related noncarriers, 26 idiopathic PD patients, and 32 controls. Linear regression modelling compared time and frequency domain values, adjusting for age, sex, heart rate, and disease duration.Low-frequency power and the ratio of low-high frequency power were reduced in idiopathic PD versus controls (P .008, P .029 respectively). In contrast, individuals with LRRK2-associated PD were not statistically different from controls in any parameter measured. Furthermore, all parameters trended toward being higher in LRRK2-associated PD when compared with idiopathic PD.Heart rate variability may remain intact in LRRK2-associated PD, adding to a growing literature supporting clinical-pathologic differences between LRRK2-associated and idiopathic PD. © 2017 International Parkinson and Movement Disorder Society.

Tau accumulation, in the form of neurofibrillary tangles (NFT), is an early neuropathological characteristic of Alzheimer's disease (AD) and early onset AD frequently seen in Down syndrome (DS). We investigated the presence of tau accumulation in the brains of aging DS mice using the Ts65Dn mouse model. All aged mice appeared to have substantial clusters of extracellular granules that were positive for tau and reelin, but not for amyloid-β or APP. These clusters were found primarily in CA1 of the hippocampus. In addition, the aged trisomic DS mice had a significantly greater accumulation of extracellular tau/reelin granular deposits compared to disomic littermates. These granules were similar to those described by others who also found extracelluar proteinous granules in the brains of non-DS mice engineered to model aging and/or AD. When neural stem cells (NSC) were implanted unilaterally into the hippocampus of the Ts65Dn mice, the tau/reelin-positive granules were significantly reduced in both trisomic and disomic mice. Our findings indicate that changes in tau/reelin-positive granules could be used as an index for neuropathological assessment in aging DS and AD. Furthermore, changes in granule density could be used to test the efficacy of novel treatments, such as NSC implantation. Lastly, it is speculated that the unique abilities of NSC to migrate and express growth factors might be a contributing factor to reducing tau/reelin accumulation in aging DS and AD.

Tailored delivery of neurotrophic factors (NFs) is a critical challenge that continues to inhibit strategies for guidance of axonal growth in vivo. Of particular importance is the ability to recreate innervation of distant brain regions by transplant tissue, for instance rebuilding the nigrostriatal track, one focus in Parkinson's disease research. Many strategies have utilized polymer drug delivery to target NF release in space and time, but combinatorial approaches are needed to deliver multiple NFs at relevant therapeutic times and locations without toxic side effects. Here we engineered a paradigm of PLGA microparticles entrapped within a degradable PEG-based hydrogel device to locally release two different types of NFs with two different release profiles. Hydrogel/microparticle devices were developed and analyzed for their ability to release GDNF in the caudal area of the brain, near the substantia nigra, or BDNF in the rostral area, near the striatum. The devices delivered their respective NFs in a region localized to within 100 μm of the bridge, but not exclusively to the targeted rostral or caudal ends. BDNF was slowly released over a 56-day period, whereas a bolus of GDNF was released around 28 days. The timed delivery of NFs from implanted devices significantly reduced the microglial response relative to sham surgeries. Given the coordinated drug delivery ability and reduced localized inflammatory response, this multifaceted PEG hydrogel/PLGA microparticle strategy may be a useful tool for further development in combining tissue engineering and drug delivery, and recreating the nigrostriatal track.

Degradable polymers have been used successfully in a wide variety of peripheral applications from tissue regeneration to drug delivery. These polymers induce little inflammatory response and appear to be well accepted by the host environment. Their use in the brain, for neural tissue reconstruction or drug delivery, also could be advantageous in treating neurodegenerative disorders. Because the brain has a unique immune response, a polymer that is compatible in the body may not be so in the brain. In the present study, polyethylene glycol (PEG)-based hydrogels were implanted into the striatum and cerebral cortex of nonhuman primates. Four months after implantation, brains were processed to evaluate the extent of astrogliosis and scaring, the presence of microglia/macrophages, and the extent of T-cell infiltration. Hydrogels with 20% w/v PEG implanted into the brain stimulated a slight increase in astrocytic and microglial/macrophage presence, as indicated by a small increase in glial fibrillary acidic protein (GFAP) and CD68 staining intensity. This increase was not substantially different from that found in the sham-implanted hemispheres of the brain. Staining for CD3+ T cells indicated no presence of peripheral T-cell infiltration. No gliotic scarring was seen in any implanted hemisphere. The combination of low density of GFAP-positive cells and CD68-positive cells, the absence of T cells, and the lack of gliotic scarring suggest that this level of immune response is not indicative of immunorejection and that the PEG-based hydrogel has potential to be used in the primate brain for local drug delivery or neural tissue regeneration.

The finger tapping test evaluates bradykinesia, focusing on decrement in rate, amplitude, or both with repetitive action. Vertical positioning of the hands during this task may also be clinically relevant. We developed a "TAP score," measuring the vertical level above the lap where the patient performs the finger tapping ranging from 1 (task performed with the hand close to the lap) to 4 (above the head). In this pilot study, we retrospectively applied the TAP score in addition to usual motor scales during acute levodopa challenge in 123 PD patients (of whom 88 presented l-dopa-induced dyskinesia [LID]). TAP ON was higher than TAP OFF. Patients with LID presented higher TAP ON. TAP ON was related to LID severity, whereas TAP OFF was inversely related to the OFF motor symptoms. The TAP score may be a measure of proximal movement amplitude representing an easy method to evaluate defective or excessive motor output in patients with advanced disease.

To determine the utility of detecting a-synuclein (aSyn) in colonic mucosal biopsy tissue as a potential diagnostic biomarker for Parkinson disease (PD).We used the paraffin-embedded tissue (PET) blot, which degrades physiologic nonaggregated aSyn using proteinase K and enhances antigen retrieval allowing sensitive and selective detection of remaining protein aggregates, to detect aSyn in colonic mucosal biopsies from 15 patients with early PD (,3 years), 7 patients with later PD (.5 years), and 11 individuals without PD. aSyn and serine 129–phosphorylated aSyn (Ser129p-aSyn) were assessed by PET blot and conventional immunohistochemistry.PET blot–resistant aggregated aSyn and Ser129p-aSyn was present in 12 of 15 individuals with early PD, 7 of 7 individuals with later PD, and 11 of 11 control subjects. The number of biopsies positive by PET blot relative to conventional immunohistochemistry was significantly lower in both PD groups compared with the control group for both aSyn and Ser129p-aSyn,whereas routine immunohistochemistry was positive more often in PD, but was positive in as many as 9 of 11 control individuals.Strong evidence of the presence of aggregated hyperphosphorylated aSyn in individuals with and without PD, using such a sensitive and specific method as the PET blot, suggests that colonic deposition of aSyn is not a useful diagnostic test for PD. The utility of detecting aSynin the colon as a biomarker in combination with other assessments remains to be determined.

Despite limited data on humans, previous studies suggest that there is an association between the duration of daily muscle activity and the proportion of type I muscle fibers. We quantified the activity of limb muscles in healthy men and women during normal use and compared these measurements with published reports on fiber-type proportions. Seven men (age range = 21–28 yr) and seven women (age range = 18–26 yr) participated in two 10-h recording sessions. Electromyogram (EMG) activity of four muscles in nondominant upper (first dorsal interosseus and biceps brachii) and lower limbs (vastus medialis and vastus lateralis) was recorded with surface electrodes. Hand and arm muscles were active for 18% of the recording time, whereas leg muscles were active for only 10% of the recording time. On average, upper-limb muscles were activated 67% more often than lower-limb muscles. When lower-limb muscles were activated, however, the mean amplitude of each burst was greater in leg muscles [18 and 17% maximum voluntary contraction (MVC)] compared with hand (8% MVC) and arm (6% MVC) muscles. Temporal association in activity between pairs of muscles was high for the two lower-limb muscles ( r 2 = 0.7) and relatively weak for the two upper-limb muscles ( r 2 = 0.09). Long-term muscle activity was only different between men and women for the biceps brachii muscle. We found no relation between duration of muscle activity in 10-h recordings and the reported values of type I fibers in men and women.

Poly(ethylene glycol) or PEG-based hydrogels provide a useful methodology for tissue engineering and the controlled-release of drugs within the central nervous system (CNS). To be successful, the local neuroinflammatory response to an implant must be well understood. Toward this end, the focus was to examine the localized recruitment and activation of microglia and astrocytes following implantation of PEG-based hydrogels in the brain. Because they are of clinical relevance and may impact brain tissue differently, hydrogels with different mass loss profiles were examined. At all time points, a needle penetration in sham animals evoked a greater astrocytic response than hydrogel conditions. The astrocyte response that ensued varied with degradation rate. An attenuated response was present in more slowly degrading and nondegrading conditions. Relative to sham, hydrogel conditions attenuated the acute microglial response during the week after implant. By 56 days, microglial levels in shams decreased below the observed response in slowly degrading and nondegradable gels, which remained constant overtime. Although the inflammatory response to PEG-based hydrogels was complex depending on degradation rates, the magnitude of the acute microglia response and the long-term astrocyte response were attenuated suggesting the use of these materials for drug and cell delivery to the CNS.

Background: Deep brain stimulation (DBS) for the treatment of neurologic diseases has markedly increased in popularity over the past 15 years. This review primarily focuses on movement disorder applications and efficacy of DBS, but also briefly reviews other promising new and old uses of DBS. Review Summary: A multidisciplinary team consisting of a movement disorders neurologist, a functional neurosurgeon, and a neuropsychologist optimally selects patients for DBS. Patients must be significantly disabled despite optimal medical therapy and be cognitively healthy without significant psychiatric disorders. Although this surgery is elective, it should not be withheld until the patient suffers marked loss of quality of life. Patients must have support from caregivers and postoperatively multiple DBS programming visits may be required. DBS of the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) significantly improves motor performance, activities of daily living, and quality of life in advanced Parkinson disease. In addition, STN DBS allows for marked reductions of antiparkinson medication. Stimulation of the ventralis intermedius nucleus of the thalamus is an effective treatment for essential tremor with sustained long-term effects. The GPi may be the preferred site of stimulation for dystonia with movement scores typically improved by 75% in patients with primary dystonia. Conclusions: DBS is an effective surgical treatment for movement disorders with sustained long-term benefits. Further research is ongoing to better understand the mechanism of DBS, refine the hardware to improve efficacy and reduce adverse effects, and identify additional applications and new anatomic targets.

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) are widely expressed in the mature nervous system and are thought to mediate plasticity and repair. We report the generation of transgenic mice that can be induced to express a dominant-negative FGFR (dnFGFR) in select neuronal populations. We show that a modified Thy1 promoter [Vidal, M., Morris, R., Grosveld, F., and Spanopoulou, E. 1990. Tissue-specific control elements of the Thy-1 gene. EMBO J 9 833–840] can be used to drive widespread neuronal expression of the reverse tetracycline transactivator M2 (rtTA-M2 [Urlinger, S., Baron, U., Thellmann, M., Hasan, M.T., Bujard, H., and Hillen, W., 2000. Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc. Natl. Acad. Sci. U. S. A. 97, 7963–7968]), which after stimulation with doxycycline induces co-expression of dnFGFR in mosaic subpopulations of rtTA-M2-positive forebrain neurons, but not in hindbrain and spinal cord rtTA-M2-positive neurons. Expression of dnFGFR did not cause overt neurodegeneration, but led to increased neuronal vulnerability: four days after a stab injury, cell death was marked in the hippocampus of dnFGFR-expressing animals when compared to controls. The nuclear morphology of dying CA1 pyramidal cells suggested an apoptotic mechanism of cell death. These observations demonstrate the importance of endogenous FGFs in the maintenance of the nervous system.