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IntroductionTo establish clinical trial readiness for dystonia, a crucial step is to develop a Patient-Centered Outcome (PCO) measure to capture therapeutic response in focal dystonia such as in cervical dystonia (CD). Botulinum neurotoxin (BoNT) is the gold standard treatment for focal dystonia and yields improvement; yet the therapy may not meet all patient expectations as there is a high rate of discontinuation. A PCO that can measure therapeutic response, including the waxing and waning benefit of BoNT, across multiple domains and is easy to use on a frequent basis in the home environment is critical.MethodsA modified iterative Delphi process based on FDA (Food and Drug Administration) guidelines was used to develop and select items to document patient symptoms and response to treatment. Potential items then were improved using patient focus groups, validated for content with specialist panels, and confirmed items based on a patient survey. Using data from 200 CD patients in the Dystonia Coalition Natural History Database, initial PCO items were identified. Utilizing Random Forests, prospective items were analyzed for their contribution to the overall severity scores on the clinical and patient-centered outcome scales. Items that were repetitive were merged. Iterative meetings with a specialist panel consisting of neurologists, physical therapists, and Patient Advocacy Group (PAG) representatives as well as virtual focus groups of CD patients were held. An online survey was conducted with over 600 CD patients participating. Finally, specialist panel members provided input for a content validity ratio (CVR) with iterations until there was good agreement as to the relevance and clarity of the items.ResultsPCO measures tailored for CD were successfully developed. The PCO consists of 16 items covering three domains (motor, disability, and psychosocial) and reflects the input of international specialist panels, more than 800 CD patients, and PAGs (patient advocacy groups) following FDA guidance. The PCO is simple enough to be used in an app-based format compatible with smartphones and tablets.ConclusionThis comprehensive CD PCO measure was developed through the combination of using robust existing patient centered data (from previous Dystonia Coalition Projects); active engagement with PAGs to provide the patient voice; and use of virtual focus groups and online surveys. This PCO will be used in a prospective study to characterize the therapeutic response to BoNT over time. This will provide peak effect size as well as capturing the “yo-yo” effect during BoNT treatment; and will prepare for a future trials.

Abstract The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn.

Background: Cervical dystonia (CD) is the most common form of focal dystonia encountered in the clinic. Approximately one-third of CD patients have co-existing tremor in the head and hands. Assessment of tremor as regular or irregular in context of its oscillation trajectory, frequency, and amplitude is a major clinical challenge and can confound the diagnosis of CD. The misdiagnosis may lead to therapeutic failures, poor quality of life, and poor utilization of medical and financial resources.Methods: We analyzed the largest cohort of CD patients (n = 3117) available to date, collected from 37 movement disorder centers in North America, Europe, and Asia. We used machine learning to determine what clinical features from clinician reports predicted the presence of tremor as well as its regular or irregular appearance.Results: Out of 3,117 CD patients, 1,367 had neck tremor. The neck tremor was interpreted as irregular in 1,022, regular in 345, and mixed (both irregular and regular) in 442. A feature importance analysis determined that greater severity of CD, longer disease duration, and older age, in descending order, predicted the presence of neck tremor. The probability of neck tremor was reduced if the dystonia affected other body parts in addition to the neck. We also found a significantly heightened risk for developing neck tremor in women. An additional feature importance analysis indicated that increased severity of dystonia affecting other body parts, severity of CD, and prolonged disease duration was associated with a lower likelihood of regular neck tremor while increased age predicted a higher likelihood.Conclusion: Machine learning recognized the most relevant clinical features that can predict concurrent neck tremor and its irregularity in a large multi-center dystonia cohort. These results may facilitate a more accurate description of neck tremor and improved care path in CD.

Abstract Common and rare variants in the LRRK2 locus are associated with Parkinson’s disease (PD) risk, but the downstream effects of these variants on protein levels remain unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7006 aptamers (6138 unique proteins) in 3107 individuals). The dataset comprised six different and independent cohorts (five using the SomaScan7K (ADNI, DIAN, MAP, Barcelona-1 (Pau), and Fundació ACE (Ruiz)) and the PPMI cohort using the SomaScan5K panel). We identified eleven independent SNPs in the LRRK2 locus associated with the levels of 25 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk, and seven were validated in the PPMI cohort. Mendelian randomization analyses identified GPNMB, LCT, and CD68 causal for PD and nominate one more (ITGB2). These 25 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also that LRRK2 is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways.

Summary: There is a need for affordable, scalable, and specific blood-based biomarkers for Alzheimer’s disease that can be applied to a population level. We have developed and validated disease-specific cell-free transcriptomic blood-based biomarkers composed by a scalable number of transcripts that capture AD pathobiology even in the presymptomatic stages of the disease. Accuracies are in the range of the current CSF and plasma biomarkers, and specificities are high against other neurodegenerative diseases.

Dystonia is an uncommon complication of relapsing-remitting multiple sclerosis (MS) and related disorders. The types of dystonia described associated with MS are heterogenous, and the relationship between dystonia and MS remains unclear. Moreover, the anatomical correspondence between MS lesions and the site of dystonia has not been determined. Onset, treatment response, and outcomes of dystonia associated with MS still remain largely uncharacterized. Here, we report a case series of 14 patients with dystonia affecting different body parts in people with MS and neuromyelitis optica (NMO). We characterize the brain regions associated with this form of secondary dystonia and the response to botulinum toxin injections.

Objective: With Huntington disease (HD), a fatal neurodegenerative disease where the prevalence of suicidal thoughts and behavior (STB) remains elevated as compared to other neurological disorders, it is unknown whether STB and health-related quality of life (HRQoL) affect plans for the end of life or more broadly, advance care planning (ACP). Conversely, it is unknown whether ACP would provoke future changes to STB and HRQoL. Therefore, we sought to evaluate whether STB and HRQoL patient-reported outcomes (PROs) contribute to ACP and whether ACP relates to changes in STB and HRQoL at 24 months. Methods: HD-validated clinician- and patient-assessments (i.e., HRQoL PROs) were obtained at baseline enrollment, 12 and 24 months through our multi-center study (HDQLIFE?) throughout the United States among people with premanifest, early-stage, and late-stage manifest HD. We used linear mixed-effects models to determine the relationships between STB and HRQoL at baseline and HDQLIFE End of Life Planning at follow-up. Separate linear mixed-effects models were used to assess the relationship between HDQLIFE End of Life Planning at baseline, and HRQoL and STB at 12 and 24 months. False discovery rate adjustments were used to account for multiple comparisons. Results: At baseline enrollment, STB and HRQoL were not related to HDQLIFE End of Life Planning at 12 or 24 months. Similarly, at baseline, HDQLIFE End of Life Planning demonstrated no association with STB or HRQoL at 12 or 24 months. Interpretation: STB and HRQoL PROs do not significantly affect patient engagement with ACP. Most importantly, engaging in ACP does not cause untoward effects on HRQoL or STB for this rare neurodegenerative disease where the lifetime prevalence of STB approaches 30%.

The Dystonia Medical Research Foundation organized an expert virtual workshop in March 2023 to review the evidence on non-motor symptoms across the spectrum of dystonia, discuss existing assessment methods, need for their harmonisation and roadmap to achieve this, and evaluate potential treatment approaches. Albeit the most investigated non-motor domains, experts highlighted the need to identify the most accurate screening procedure for depression and anxiety, clarify their mechanistic origin and quantify their response to already available therapies. Future exploration of sleep disruption in dystonia should include determining the accuracy and feasibility of wearable devices, understanding the contribution of psychotropic medication to its occurrence, and defining the interaction between maladaptive plasticity and abnormal sleep patterns. Despite recent advances in the assessment of pain in dystonia, more research is needed to elucidate the relative importance of different mechanisms called into play to explain this impactful sensory feature and the most appropriate treatments. Amongst the different non-motor features investigated in dystonia, cognitive dysfunction and fatigue require an in-depth observation to evaluate their functional impact, their clinical profile and assessment methods and, in the case of cognition, whether impairment represents a prodrome of dementia. Finally, experts identified the development and field validation of a self-rated screening tool encompassing the full spectrum of non-motor symptoms as the most urgent step towards incorporating the management of these features into routine clinical practice.

Abstract Objective Deviated head posture is a defining characteristic of cervical dystonia (CD). Head posture severity is typically quantified with clinical rating scales such as the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Because clinical rating scales are inherently subjective, they are susceptible to variability that reduces their sensitivity as outcome measures. The variability could be circumvented with methods to measure CD head posture objectively. However, previously used objective methods require specialized equipment and have been limited to studies with a small number of cases. The objective of this study was to evaluate a novel software system—the Computational Motor Objective Rater (CMOR)—to quantify multi‐axis directionality and severity of head posture in CD using only conventional video camera recordings. Methods CMOR is based on computer vision and machine learning technology that captures 3D head angle from video. We used CMOR to quantify the axial patterns and severity of predominant head posture in a retrospective, cross‐sectional study of 185 patients with isolated CD recruited from 10 sites in the Dystonia Coalition. Results The predominant head posture involved more than one axis in 80.5% of patients and all three axes in 44.4%. CMOR's metrics for head posture severity correlated with severity ratings from movement disorders neurologists using both the TWSTRS‐2 and an adapted version of the Global Dystonia Rating Scale (rho = 0.59–0.68, all p

Abstract Objective Parkinson disease (PD) is defined by the accumulation of misfolded α‐synuclein (α‐syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α‐syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions. Methods We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α‐syn, Aβ, and tau with recently developed sandwich ELISAs. Results We detected a wide range of insoluble α‐syn accumulation in LBD cases. The majority had substantial α‐syn accumulation in most regions, and dementia severity correlated with neocortical α‐syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aβ accumulation, although the mean Aβ level in LBD was lower than in AD. The presence of Aβ was associated with greater α‐syn accumulation. Tau accumulation accompanied Aβ in only one LBD case. Interpretation LBD is associated with insoluble α‐syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aβ and α‐syn accumulation suggests a pathophysiologic relationship between these two processes.

Abstract Objective To examine specific symptom progression patterns and possible disease staging in Parkinson disease clinical subtypes. Methods We recently identified Parkinson disease clinical subtypes based on comprehensive behavioral evaluations, “Motor Only,” “Psychiatric & Motor,” and “Cognitive & Motor,” which differed in dementia and mortality rates. Parkinson disease participants (“Motor Only”: n = 61, “Psychiatric & Motor”: n = 17, “Cognitive & Motor”: n = 70) and controls (n = 55) completed longitudinal, comprehensive motor, cognitive, and psychiatric evaluations (average follow‐up = 4.6 years). Hierarchical linear modeling examined group differences in symptom progression. A three‐way interaction among time, group, and symptom duration (or baseline age, separately) was incorporated to examine disease stages. Results All three subtypes increased in motor dysfunction compared to controls. The “Motor Only” subtype did not show significant cognitive or psychiatric changes compared to the other two subtypes. The “Cognitive & Motor” subtype’s cognitive dysfunction at baseline further declined compared to the other two subtypes, while also increasing in psychiatric symptoms. The “Psychiatric & Motor” subtype’s elevated psychiatric symptoms at baseline remained steady or improved over time, with mild, steady decline in cognition. The pattern of behavioral changes and analyses for disease staging yielded no evidence for sequential disease stages. Interpretation Parkinson disease clinical subtypes progress in clear, temporally distinct patterns from one another, particularly in cognitive and psychiatric features. This highlights the importance of comprehensive clinical examinations as the order of symptom presentation impacts clinical prognosis.

Abstract Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1–42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1–42 levels (effect = − 0.5, p = 9.2 × 10−19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson’s disease risk meta-analysis were associated with Parkinson’s disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1–42 (R2 = 2.29%; p = 2.5 × 10−11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1–42 levels (p = 7.3 × 10−04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1–42 plays a role in Parkinson’s disease (p = 1.4 × 10−05) and age at onset (p = 7.6 × 10−06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1–42 (p = 3.8 × 10−06), higher mean cortical binding potentials (p = 5.8 × 10−08), and higher Braak amyloid beta score (p = 4.4 × 10−04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson’s disease, CSF amyloid beta1–42, and APOE.

Abstract Objectives Based on multi‐domain classification of Parkinson disease (PD) subtypes, we sought to determine the key features that best differentiate subtypes and the utility of PD subtypes to predict clinical milestones. Methods Prospective cohort of 162 PD participants with ongoing, longitudinal follow‐up. Latent class analysis (LCA) delineated subtypes based on score patterns across baseline motor, cognitive, and psychiatric measures. Discriminant analyses identified key features that distinguish subtypes at baseline. Cox regression models tested PD subtype differences in longitudinal conversion to clinical milestones, including deep brain stimulation (DBS), dementia, and mortality. Results LCA identified distinct subtypes: “motor only” (N = 63) characterized by primary motor deficits; “psychiatric & motor” (N = 17) characterized by prominent psychiatric symptoms and moderate motor deficits; “cognitive & motor” (N = 82) characterized by impaired cognition and moderate motor deficits. Depression, executive function, and apathy best discriminated subtypes. Since enrollment, 22 had DBS, 48 developed dementia, and 46 have died. Although there were no subtype differences in rate of DBS, dementia occurred at a higher rate in the “cognitive & motor” subtype. Surprisingly, mortality risk was similarly elevated for both “cognitive & motor” and “psychiatric & motor” subtypes compared to the “motor only” subtype (relative risk = 3.15, 2.60). Interpretation Psychiatric and cognitive features, rather than motor deficits, distinguish clinical PD subtypes and predict greater risk of subsequent dementia and mortality. These results emphasize the value of multi‐domain assessments to better characterize clinical variability in PD. Further, differences in dementia and mortality rates demonstrate the prognostic utility of PD subtypes.

Background: Although abnormal head and neck postures are defining features of cervical dystonia (CD), head tremor (HT) is also common. However, little is known about the relationship between abnormal postures and HT in CD. Methods: We analyzed clinical data and video recordings from 185 patients enrolled by the Dystonia Coalition. We calculated the likelihood of their HT and HT type (“regular” vs. “jerky”) given directionality of abnormal head postures, disease duration, sex, and age. Results: Patients with retrocollis were more likely to have HT than patients with anterocollis (X2 (1, N = 121) = 7.98, p = 0.005). There was no difference in HT likelihood given left or right turning in laterocollis and rotation. Patients with HT had longer disease duration (t(183) = 2.27, p = 0.024). There was no difference in age between patients with and without HT. In a logistic regression model, anterocollis/retrocollis direction (X2 (1, N = 121) = 6.04, p = 0.014), disease duration (X2 (1, N = 121) = 7.28, p = 0.007), and the interaction term between age and disease duration (X2 (1, N = 121) = 7.77, p = 0.005) collectively contributed to HT likelihood. None of the postural directionality or demographic variables were associated with differential likelihood of having regular versus jerky HT. Discussion: We found that HT is more likely for CD patients with a specific directionality in their predominant posture. Our finding that CD patients with longer disease duration have a higher likelihood of HT also raises the question of whether HT becomes more likely over time in individual patients.

Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis.Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers.Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology.Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies.

Abstract Background: Non‐motor symptoms are well established phenotypic components of adult‐onset idiopathic, isolated, focal cervical dystonia (AOIFCD). However, improved understanding of their clinical heterogeneity is needed to better target therapeutic intervention. Here, we examine non‐motor phenotypic features to identify possible AOIFCD subgroups. Methods: Participants diagnosed with AOIFCD were recruited via specialist neurology clinics (dystonia wales: n = 114, dystonia coalition: n = 183). Non‐motor assessment included psychiatric symptoms, pain, sleep disturbance, and quality of life, assessed using self‐completed questionnaires or face‐to‐face assessment. Both cohorts were analyzed independently using Cluster, and Bayesian multiple mixed model phenotype analyses to investigate the relationship between non‐motor symptoms and determine evidence of phenotypic subgroups. Results: Independent cluster analysis of the two cohorts suggests two predominant phenotypic subgroups, one consisting of approximately a third of participants in both cohorts, experiencing increased levels of depression, anxiety, sleep impairment, and pain catastrophizing, as well as, decreased quality of life. The Bayesian approach reinforced this with the primary axis, which explained the majority of the variance, in each cohort being associated with psychiatric symptomology, and also sleep impairment and pain catastrophizing in the Dystonia Wales cohort. Conclusions: Non‐motor symptoms accompanying AOIFCD parse into two predominant phenotypic sub‐groups, with differences in psychiatric symptoms, pain catastrophizing, sleep quality, and quality of life. Improved understanding of these symptom groups will enable better targeted pathophysiological investigation and future therapeutic intervention.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition is a consortium of investigators that was established to address these challenges. Since 2009, the Dystonia Coalition has encouraged collaboration by engaging 56 sites across North America, Europe, Asia, and Australia. Its emphasis on collaboration has facilitated establishment of international consensus for the definition and classification of all dystonias, diagnostic criteria for specific subtypes of dystonia, standardized evaluation strategies, development of clinimetrically sound measurement tools, and large multicenter studies that document the phenotypic heterogeneity and evolution of specific types of dystonia.

Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in infectious diseases. Targeting S1PR1 provides protection against pathogens, such as influenza viruses. This study is aimed at investigating S1PR1 in response to bacterial infection by assessing S1PR1 expression in S. aureus-infected mice. A rodent local muscle bacterial infection model was developed by injecting S. aureus to the lower hind limb of Balb/c mice. The changes of S1PR1 expression in response to bacterial infection and blocking treatment were assessed using ex vivo biodistribution and in vivo positron emission tomography (PET) after intravenous injection of an S1PR1-specific radiotracer [18F]TZ4877. The specificity of [18F]TZ4877 was assessed using S1PR1-specific antagonist, NIBR-0213, and S1PR1-specific DsiRNA pretreated the animals. Immunohistochemical studies were performed to confirm the increase of S1PR1 expression in response to infection. Ex vivo biodistribution data showed that the uptake of [18F]TZ4877 was increased 30.6%, 54.3%, 74.3%, and 115.3% in the liver, kidney, pancreas, and thymus of the infected mice, respectively, compared to that in normal control mice, indicating that S1PR1 is involved in the early immune response to bacterial infection. NIBR-0213 or S1PR1-specific DsiRNA pretreatment reduced the tissue uptake of [18F]TZ4877, suggesting that uptake of [18F]TZ4877 is specific. Our PET/CT study data also confirmed that infected mice have increased [18F]TZ4877 uptake in several organs comparing to that in normal control mice. Particularly, compared to control mice, a 39% increase of [18F]TZ4877 uptake was observed in the infected muscle of S. aureus mice, indicating that S1PR1 expression was directly involved in the inflammatory response to infection. Overall, our study suggested that S1PR1 plays an important role in the early immune response to bacterial infection. The uptake of [18F]TZ4877 is tightly correlated with the S1R1 expression in response to S. aureus infection. PET with S1PR1-specific radiotracer [18F]TZ4877 could provide a noninvasive tool for detecting the early S1PR1 immune response to infectious diseases.

Denoising fMRI data requires assessment of frame-to-frame head motion and removal of the biases motion introduces. This is usually done through analysis of the parameters calculated during retrospective head motion correction (i.e., ‘motion’ parameters). However, it is increasingly recognized that respiration introduces factitious head motion via perturbations of the main (B0) field. This effect appears as higher-frequency fluctuations in the motion parameters (>0.1 ​Hz, here referred to as ‘HF-motion’), primarily in the phase-encoding direction. This periodicity can sometimes be obscured in standard single-band fMRI (TR 2.0–2.5 ​s) due to aliasing. Here we examined (1) how prevalent HF-motion effects are in seven single-band datasets with TR from 2.0 to 2.5 ​s and (2) how HF-motion affects functional connectivity. We demonstrate that HF-motion is more common in older adults, those with higher body mass index, and those with lower cardiorespiratory fitness. We propose a low-pass filtering approach to remove the contamination of high frequency effects from motion summary measures, such as framewise displacement (FD). We demonstrate that in most datasets this filtering approach saves a substantial amount of data from FD-based frame censoring, while at the same time reducing motion biases in functional connectivity measures. These findings suggest that filtering motion parameters is an effective way to improve the fidelity of head motion estimates, even in single band datasets. Particularly large data savings may accrue in datasets acquired in older and less fit participants.

Abstract Background Subthalamic nucleus deep brain stimulation (STN-DBS) reduces tremor, muscle stiffness, and bradykinesia in people with Parkinson’s Disease (PD). Walking speed, known to be reduced in PD, typically improves after surgery; however, other important aspects of gait may not improve. Furthermore, balance may worsen and falls may increase after STN-DBS. Thus, interventions to improve balance and gait could reduce morbidity and improve quality of life following STN-DBS. Physical therapy (PT) effectively improves balance and gait in people with PD, but studies on the effects of PT have not been extended to those treated with STN-DBS. As such, the efficacy, safety, and feasibility of PT in this population remain to be determined. The purpose of this pilot study is to address these unmet needs. We hypothesize that PT designed to target balance and gait impairment will be effective, safe, and feasible in this population. Methods/design Participants with PD treated with STN-DBS will be randomly assigned to either a PT or control group. Participants assigned to PT will complete an 8-week, twice-weekly PT program consisting of exercises designed to improve balance and gait. Control group participants will receive the current standard of care following STN-DBS, which does not include prescription of PT. The primary aim is to assess preliminary efficacy of PT on balance (Balance Evaluation Systems Test). A secondary aim is to assess efficacy of PT on gait (GAITRite instrumented walkway). Participants will be assessed OFF medication/OFF stimulation and ON medication/ON stimulation at baseline and at 8 and 12 weeks after baseline. Adverse events will be measured over the duration of the study, and adherence to PT will be measured to determine feasibility. Discussion To our knowledge, this will be the first study to explore the preliminary efficacy, safety, and feasibility of PT for individuals with PD with STN-DBS. If the study suggests potential efficacy, then this would justify larger trials to test effectiveness and safety of PT for those with PD with STN-DBS. Trial registration NCT03181282 (clinicaltrials.gov). Registered on 7 June 2017.

Abstract Background The genetic architecture of Parkinson’s Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Nevertheless, most of the expected genetic heritability remains unexplained. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (α-synuclein, Aβ1–42, t-tau and p-tau). Methods The weighted PRS was created using the genome-wide loci from Nalls et al., 2014 PD GWAs meta-analysis. The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry. Results The PRS was associated with PD status (p = 5.83×10−08) and age at onset (p = 5.70×10−07). The CSF t-tau levels showed a nominal association with the PRS (p = 0.02). However, CSF α-synuclein, amyloid beta and phosphorylated tau were not found to be associated with the PRS. Conclusion Our study suggests that there is an overlap in the genetic architecture of PD risk and onset, although the different loci present different weights for those phenotypes. In our dataset we found a marginal association of the PRS with CSF t-tau but not with α-synuclein CSF levels, suggesting that the genetic architecture for the CSF biomarker levels is different from that of PD risk.

Microglia and astrocytes play important roles in mediating the immune processes and nutritional support in the central nervous system (CNS). Neuroinflammation has been indicated in the progression of neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD). Chronic neuroinflammation with sustained activation of microglia and astrocytes may affect white matter tracts and disrupt communication between neurons. Recent studies indicate astrogliosis may inhibit remyelination in demyelinating disorders such as multiple sclerosis. In this study, we investigated the relationship between neuroinflammation and myelin status in postmortem human brain tissue (n = 15 including 6 AD, 5 PD, and 4 age-matched, neurologically normal controls (NC)). We conducted systematic and quantitative immunohistochemistry for glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), amyloid beta, and highly phosphorylated tau (tauopathy). White matter intactness was evaluated by myelin and axon staining in adjacent brain tissue sections. Eight of 15 cases (4 AD, 3 PD, and 1 NC) showed increased immunoreactivity for microglia and astrocytes in the white matter that connects striatum and cortex. Quantitative analysis of these 8 cases showed a significant negative correlation between GFAP (but not Iba-1) and myelin (but not axon) staining in white matter (r2 = 0.78, p

MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside triphosphatase, has potential as a biomarker for monitoring cancer progression and quantifying target engagement for relevant therapies. In this study, we validate one MTH1 inhibitor TH287 as a PET MTH1 radiotracer. TH287 was radiolabeled with tritium and the binding of [3H]TH287 to MTH1 was evaluated in live glioblastoma cells (U251MG) through saturation and competitive binding assays, together with in vitro enzymatic assays. Furthermore, TH287 was radiolabeled with carbon-11 for in vivo microPET studies. Saturation binding assays show that [3H]TH287 has a dissociation constant (Kd) of 1.97 ± 0.18 nM, Bmax of 2676 ± 122 fmol/mg protein for U251MG cells, and nH of 0.98 ± 0.02. Competitive binding assays show that TH287 (Ki: 3.04 ± 0.14 nM) has a higher affinity for MTH1 in U251MG cells compared to another well studied MTH1 inhibitor: (S)-crizotinib (Ki: 153.90 ± 20.48 nM). In vitro enzymatic assays show that TH287 has an IC50 of 2.2 nM in inhibiting MTH1 hydrolase activity and a Ki of 1.3 nM from kinetics assays, these results are consistent with our radioligand binding assays. Furthermore, MicroPET imaging shows that [11C]TH287 gets into the brain with rapid clearance from the brain, kidney, and heart. The results presented here indicate that radiolabeled TH287 has favorable properties to be a useful tool for measuring MTH1 in vitro and for further evaluation for in vivo PET imaging MTH1 of brain tumors and other central nervous system disorders.

Subthalamic nucleus deep brain stimulation (STN-DBS) and levodopa are common treatment strategies for Parkinson’s disease (PD). However, the specific effects of these treatment strategies on balance and its components remain unclear. This cross-sectional study of people with PD and STN-DBS compared balance in the treated state (ON-medication/ON-stimulation) and untreated state (OFF-medication/OFF-stimulation) using the Balance Evaluation Systems Test (BESTest). Total BESTest scores from the treated and untreated states were compared to assess overall balance. Scores for the six sections of the BESTest were further compared to assess differences in specific components of balance between treatment conditions. Twenty-nine participants were included (Male: 21, Female: 8, Mean Age ± SD: 65.0 ± 6.9). Total BESTest scores showed improved balance in the treated state compared to the untreated state (Treated: 67.56 ± 10.92; Untreated: 59.23 ± 16.51, p < 0.001). Four sections (Stability Limits/Verticality, Anticipatory Postural Reactions, Sensory Orientation, Stability in Gait) of the BESTest significantly improved in the treated state relative to the untreated state, after correcting for multiple comparisons (p < 0.05). These results demonstrate that STN-DBS and levodopa improve overall balance and provide a first step toward understanding the effects of these treatment strategies on specific components of balance.

We found interactions between dopamine and oxidative damage in the striatum involved in advanced neurodegeneration, which probably change the microglial phenotype. We observed possible microglia dystrophy in the striatum of neurodegenerative brains. To investigate the interactions between oxidative damage and microglial phenotype, we quantified myeloperoxidase (MPO), poly (ADP-Ribose) (PAR), and triggering receptors expressed on myeloid cell 2 (TREM2) using enzyme-linked immunosorbent assay (ELISA). To test the correlations of microglia dystrophy and tauopathy, we quantified translocator protein (TSPO) and tau fibrils using autoradiography. We chose the caudate and putamen of Lewy body diseases (LBDs) (Parkinson’s disease, Parkinson’s disease dementia, and Dementia with Lewy body), Alzheimer’s disease (AD), and control brains and genotyped for TSPO, TREM2, and bridging integrator 1 (BIN1) genes using single nucleotide polymorphisms (SNP) assays. TREM2 gene variants were absent across all samples. However, associations between TSPO and BIN1 gene polymorphisms and TSPO, MPO, TREM2, and PAR level variations were found. PAR levels reduced significantly in the caudate of LBDs. TSPO density and tau fibrils decreased remarkably in the striatum of LBDs but increased in AD. Oxidative damage, induced by misfolded tau proteins and dopamine metabolism, causes microglia dystrophy or senescence during the late stage of LBDs. Consequently, microglia dysfunction conversely reduces tau propagation. The G allele of the BIN1 gene is a potential risk factor for tauopathy.

Background: The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established.Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients.Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP), Presenilin 1 and 2 (PSEN1, PSEN2), and Granulin (GRN) genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES) data by single variant and gene base (SKAT-O and burden tests) analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status.Results: Known AD pathogenic mutations in the PSEN1 (p.A79V) and PSEN2 (p.V148I) genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10−4), independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site.Conclusions: Pathogenic mutations in the Alzheimer disease-causing genes (PSEN1 and PSEN2) are found in sporadic PD patients. PD patients with cognitive decline carry rare variants in dementia-causing genes. Variants in genes causing Mendelian neurodegenerative diseases exhibit pleiotropic effects.

The anatomical connections of the subthalamic nucleus (STN) have driven hypotheses about its functional anatomy, including the hypothesis that the precise anatomical location of STN deep brain stimulation (DBS) contributes to the variability of motor and non-motor responses across patients with Parkinson's disease (PD). We previously tested the hypothesis using a three-dimensional (3D) statistical method to interpret the acute effects of unilateral DBS at each patient's clinically optimized DBS settings and active contact. Here, we report a similar analysis from a new study in which DBS parameters were standardized and DBS locations were chosen blind to clinical response. In 74 individuals with PD and STN DBS, STN contacts were selected near the dorsal and ventral borders of the STN contralateral to the more affected side of the body. Participants were tested off PD medications in each of three unilateral DBS conditions (ventral STN DBS, dorsal STN DBS and DBS off) for acute effects on mood, apathy, working memory, response inhibition and motor function. Voltage, frequency and pulse width were standardized, and participants and raters were blind to condition. In a categorical analysis, both dorsal and ventral STN DBS improved mean motor function without affecting cognitive measures. Ventral STN DBS induced greater improvement in rigidity and anxiety than dorsal STN DBS. In the 3D analysis, contact location was significant for body hypokinesia, rigidity and resting tremor, with the greatest improvement occurring with DBS in dorsal STN and zona incerta. The 3D results provide new, direct functional evidence for the anatomically derived model of STN, in which motor function is best represented in dorsal STN. However, our data suggest that functional segregation between motor and non-motor areas of the STN is limited, because locations that induced improvements in motor function and mood overlapped substantially.

Dystonia, which causes intermittent or sustained abnormal postures and movements, can present in a focal or a generalized manner. In the limbs, focal dystonia can occur in either the upper or lower limbs and may be task-specific causing abnormal motor performance for only a specific task, such as in writer’s cramp, runner’s dystonia, or musician’s dystonia. Focal limb dystonia can be non-task-specific and may, in some circumstances, be associated with parkinsonian disorders. The true prevalence of focal limb dystonia is not known and is likely currently underestimated, leaving a knowledge gap and an opportunity for future research. The pathophysiology of focal limb dystonia shares some commonalities with other dystonias with a loss of inhibition in the central nervous system and a loss of the normal regulation of plasticity, called homeostatic plasticity. Functional imaging studies revealed abnormalities in several anatomical networks that involve the cortex, basal ganglia, and cerebellum. Further studies should focus on distinguishing cause from effect in both physiology and imaging studies to permit focus on most relevant biological correlates of dystonia. There is no specific therapy for the treatment of limb dystonia given the variability in presentation, but off-label botulinum toxin therapy is often applied to focal limb and task-specific dystonia. Various rehabilitation techniques have been applied and rehabilitation interventions may improve outcomes, but small sample size and lack of direct comparisons between methods to evaluate comparative efficacy limit conclusions. Finally, non-invasive and invasive therapeutic modalities have been explored in small studies with design limitations that do not yet clearly provide direction for larger clinical trials that could support new clinical therapies. Given these gaps in our clinical, pathophysiologic, and therapeutic knowledge, we have identified priorities for future research including: the development of diagnostic criteria for limb dystonia, more precise phenotypic characterization and innovative clinical trial design that considers clinical heterogeneity, and limited available number of participants.

To determine how different methods of normalizing for global cerebral blood flow (gCBF) affect image quality and sensitivity to cortical activation, pulsed arterial spin labeling (pASL) scans obtained during a visual task were normalized by either additive or multiplicative normalization of modal gCBF. Normalization by either method increased the statistical significance of cortical activation by a visual stimulus. However, image quality was superior with additive normalization, whether judged by intensity histograms or by reduced variability within gray and white matter.

Background: Dystonia constitutes a heterogeneous group of movement abnormalities, characterized by sustained or intermittent muscle contractions causing abnormal postures. Overwhelming data suggest involvement of basal ganglia and dopaminergic pathways in dystonia. In this review, we critically evaluate recent neuroimaging studies that investigate dopamine receptors, endogenous dopamine release, morphology of striatum, and structural or functional connectivity in cortico-basal ganglia-thalamo-cortical and related cerebellar circuits in dystonia.Methods: A PubMed search was conducted in August 2014.Results: Positron emission tomography(PET) imaging offers strong evidence for altered D2/D3 receptor binding and dopaminergic release in many forms of idiopathic dystonia. Functional magnetic resonance imaging(fMRI) and diffusion tensor imaging(DTI) data reveal likely involvement of related cerebello-thalamo-cortical and sensory-motor networks in addition to basal ganglia.Discussion: PET imaging of dopamine receptors or transmitter release remains an effective means to investigate dopaminergic pathways, yet may miss factors affecting dopamine homeostasis and related subcellular signaling cascades that could alter the function of these pathways. fMRI and DTI methods may reveal functional or anatomical changes associated with dysfunction of dopamine-mediated pathways. Each of these methods can be used to monitor target engagement for potential new treatments. PET imaging of striatal phosphodiesterase and development of new selective PET radiotracers for dopamine D3-specific receptors and Mechanistic target of rampamycin(mTOR) are crucial to further investigate dopaminergic pathways. A multimodal approach may have the greatest potential, using PET to identify the sites of molecular pathology and magnetic resonance methods to determine their downstream effects.

Two small case series of platelet mitochondrial complex I activity assays in Huntington’s Disease (HD) report discrepant results. We measured platelet complex I and complex I/III activity in 21 subjects with early gene-positive HD and 14 age-matched controls. The 21 participants with HD that we studied are greater than the total of 16 in the two previously published of platelet ETS activity in HD. Reductions ?>>10% were excluded with 80% confidence. A systemic defect in complex I activity is not present in early HD when striatal neuronal degeneration is already present.

OBJECTIVE:Interpretation of diffusion MRI in the living brain requires validation against gold standard histological measures. We compared diffusion values of the nigrostriatal tract to PET and histological results in non-human primates (NHPs) with varying degrees of unilateral nigrostriatal injury induced by MPTP, a toxin selective for dopaminergic neurons. METHODS:Sixteen NHPs had MRI and PET scans of three different presynaptic radioligands and blinded video-based motor ratings before and after unilateral carotid artery infusion of variable doses of MPTP. Diffusion measures of connections between midbrain and striatum were calculated. Then animals were euthanized to quantify striatal dopamine concentration, stereologic measures of striatal tyrosine hydroxylase (TH) immunostained fiber density and unbiased stereologic counts of TH stained nigral cells. RESULTS:Diffusion measures correlated with MPTP dose, nigral TH-positive cell bodies and striatal TH-positive fiber density but did not correlate with in vitro nigrostriatal terminal field measures or in vivo PET measures of striatal uptake of presynaptic markers. Once nigral TH cell count loss exceeded 50% the stereologic terminal field measures reached a near zero floor effect but the diffusion measures continued to correlate with nigral cell counts. CONCLUSION:Diffusion measures in the nigrostriatal tract correlate with nigral dopamine neurons and striatal fiber density, but have the same relationship to terminal field measures as a previous report of striatal PET measures of presynaptic neurons. These diffusion measures have the potential to act as non-invasive index of the severity of nigrostriatal injury. Diffusion imaging of the nigrostriatal tract could potentially have diagnostic value in humans with Parkinson disease or related disorders.

Objective: To compile a comprehensive summary of published human experience with levodopa given intravenously, with a focus on information required by regulatory agencies.Background: While safe intravenous (IV) use of levodopa has been documented for over 50 years, regulatory supervision for pharmaceuticals given by a route other than that approved by the U.S. Food and Drug Administration (FDA) has become increasingly cautious. If delivering a drug by an alternate route raises the risk of adverse events, an investigational new drug (IND) application is required, including a comprehensive review of toxicity data.Methods: Over 200 articles referring to IV levodopa were examined for details of administration, pharmacokinetics, benefit and side effects.Results: We identified 142 original reports describing IVLD use in humans, beginning with psychiatric research in 1959-1960 before the development of peripheral decarboxylase inhibitors. Over 2750 subjects have received IV levodopa, and reported outcomes include parkinsonian signs, sleep variables, hormone levels, hemodynamics, CSF amino acid composition, regional cerebral blood flow, cognition, perception and complex behavior. Mean pharmacokinetic variables were summarized for 49 healthy subjects and 190 with Parkinson’s disease. Side effects were those expected from clinical experience with oral levodopa and dopamine agonists. No articles reported deaths or induction of psychosis.Conclusion: Over 2750 patients have received IV levodopa with a safety profile comparable to that seen with oral administration.

Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index

Apathy commonly occurs in Parkinson disease (PD) patients; however, the role of dopamine in the pathophysiology of apathy remains elusive. We previously demonstrated that dopaminergic dysfunction within the ventral tegmental area (VTA)-nucleus accumbens (NAcc) pathway contributes to the manifestation of apathetic behaviors in monkeys treated with the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We now extend these studies to identify dopaminergic dysfunction in cortical regions that correlate with development of apathetic behaviors. Specifically, we measured the effects of MPTP on monkeys' willingness to attempt goal directed behaviors, which is distinct from their ability to perform tasks. A total of 16 monkeys had baseline magnetic resonance imaging (MRI) and positron emission tomography (PET), using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2β-[11C]carbomethoxy-3β-(4-fluorophenyl)tropane (CFT). The monkeys received unilateral infusion of different doses of MPTP (0 - 0.31mg/kg) to produce a wide range of severity of motor parkinsonism. Eight weeks after MPTP, PET scans were repeated and animals were euthanized. Apathetic behavior and motor impairments were assessed blindly both pre- and post-MPTP infusion. Apathy scores were compared to in vitro and in vivo dopaminergic measures. Apathy scores increased following MPTP and correlated with PET measures of dopaminergic terminals (DTBZ or CFT) in dorsal lateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex (VMPFC), and insular cortex (IC). Among all the cortical regions assessed, forward step-wise regression analyses indicated that only stereologic cell counts in VTA, and not counts in the substantia nigra (SN), predict dopamine transporter changes in IC. Our findings suggest that dopaminergic dysfunction within the VTA-IC pathway plays a role in the manifestation of apathetic behaviors in MPTP-lesioned primates.

The putamen has a somatotopic organization of neurons identified by correspondence of firing rates with selected body part movements, as well as by complex, but organized, differential cortical projections onto putamen. In isolated focal dystonia, whole putaminal binding of dopamine D2-like receptor radioligands is quantitatively decreased, but it has not been known whether selected parts of the putamen are differentially affected depending upon the body part affected by dystonia. The radioligand [(18)F]spiperone binds predominantly to D2-like receptors in striatum. We hypothesized that the spatial location of [(18)F]spiperone binding within the putamen would differ in patients with dystonia limited to the hand versus the face, and we tested that hypothesis using positron emission tomography and magnetic resonance imaging. To address statistical and methodological concerns, we chose a straightforward but robust image analysis method. An automated algorithm located the peak location of [(18)F]spiperone binding within the striatum, relative to a brain atlas, in each of 14 patients with cranial dystonia and 8 patients with hand dystonia. The mean (left and right) |x|, y, and z coordinates of peak striatal binding for each patient were compared between groups by t test. The location of peak [(18)F]spiperone binding within the putamen differed significantly between groups (cranial dystonia z

Accumulation of α-synuclein (α-syn) fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson disease (PD). Ligands that bind α-syn fibrils could be utilized as imaging agents to improve the diagnosis of PD and to monitor disease progression. However, ligands for α-syn fibrils in PD brain tissue have not been previously identified and the feasibility of quantifying α-syn fibrils in brain tissue is unknown. We report the identification of the (125)I-labeled α-syn radioligand SIL23. [(125)I]SIL23 binds α-syn fibrils in postmortem brain tissue from PD patients as well as an α-syn transgenic mouse model for PD. The density of SIL23 binding sites correlates with the level of fibrillar α-syn in PD brain tissue, and [(125)I]SIL23 binding site densities in brain tissue are sufficiently high to enable in vivo imaging with high affinity ligands. These results identify a SIL23 binding site on α-syn fibrils that is a feasible target for development of an α-syn imaging agent. The affinity of SIL23 for α-syn and its selectivity for α-syn versus Aβ and tau fibrils is not optimal for imaging fibrillar α-syn in vivo, but we show that SIL23 competitive binding assays can be used to screen additional ligands for suitable affinity and selectivity, which will accelerate the development of an α-syn imaging agent for PD.

Radioligands for DAT and VMAT2 are widely used presynaptic markers for assessing dopamine (DA) nerve terminals in Parkinson disease (PD). Previous in vivo imaging and postmortem studies suggest that these transporter sites may be regulated as the numbers of nigrostriatal neurons change in pathologic conditions. To investigate this issue, we used in vitro quantitative autoradioradiography to measure striatal DAT and VMAT2 specific binding in postmortem brain from 14 monkeys after unilateral internal carotid artery infusion of 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP) with doses varying from 0 to 0.31 mg/kg. Quantitative estimates of the number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in substantia nigra (SN) were determined with unbiased stereology, and quantitative autoradiography was used to measure DAT and VMAT2 striatal specific binding. Striatal VMAT2 and DAT binding correlated with striatal DA (r(s) = 0.83, r(s) = 0.80, respectively, both with n = 14, p

The dopamine D(1), D(2), D(3) receptors, vesicular monoamine transporter type-2 (VMAT2), and dopamine transporter (DAT) densities were measured in 11 aged human brains (aged 77-107.8, mean: 91 years) by quantitative autoradiography. The density of D(1) receptors, VMAT2, and DAT was measured using [(3)H]SCH23390, [(3)H]dihydrotetrabenazine, and [(3)H]WIN35428, respectively. The density of D(2) and D(3) receptors was calculated using the D(3)-preferring radioligand, [(3)H]WC-10 and the D(2)-preferring radioligand [(3)H]raclopride using a mathematical model developed previously by our group. Dopamine D(1), D(2), and D(3) receptors are extensively distributed throughout striatum; the highest density of D(3) receptors occurred in the nucleus accumbens (NAc). The density of the DAT is 10-20-fold lower than that of VMAT2 in striatal regions. Dopamine D(3) receptor density exceeded D(2) receptor densities in extrastriatal regions, and thalamus contained a high level of D(3) receptors with negligible D(2) receptors. The density of dopamine D(1) linearly correlated with D(3) receptor density in the thalamus. The density of the DAT was negligible in the extrastriatal regions whereas the VMAT2 was expressed in moderate density. D(3) receptor and VMAT2 densities were in similar level between the aged human and aged rhesus brain samples, whereas aged human brain samples had lower range of densities of D(1) and D(2) receptors and DAT compared with the aged rhesus monkey brain. The differential density of D(3) and D(2) receptors in human brain will be useful in the interpretation of PET imaging studies in human subjects with existing radiotracers, and assist in the validation of newer PET radiotracers having a higher selectivity for dopamine D(2) or D(3) receptors.