Parkinson’s disease (PD) is one of the world’s fastest growing neurological disorders. Much is unknown about PD-associated economic burdens in the United States (U.S.) and other high-income nations. This study provides a comprehensive analysis of the economic burdens of PD in the U.S. (2017) and projections for the next two decades. Multiple data sources were used to estimate the costs of PD, including public and private administrative claims data, Medicare Current Beneficiary Survey, Medical Expenditure Panel Survey, and a primary survey ( n = 4,548) designed for this study. We estimated a U.S. prevalence of approximately one million individuals with diagnosed Parkinson’s disease in 2017 and a total economic burden of $51.9 billion. The total burden of PD includes direct medical costs of $25.4 billion and $26.5 billion in indirect and non-medical costs, including an indirect cost of $14.2 billion (PWP and caregiver burden combined), non-medical costs of $7.5 billion, and $4.8 billion due to disability income received by PWPs. The Medicare program bears the largest share of excess medical costs, as most PD patients are over age 65. Projected PD prevalence will be more than 1.6 million with projected total economic burden surpassing $79 billion by 2037. The economic burden of PD was previously underestimated. Our findings underscore the substantial burden of PD to society, payers, patients, and caregivers. Interventions to reduce PD incidence, delay disease progression, and alleviate symptom burden may reduce the future economic burden of PD.

Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules. Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m 2 daily for 5 days with cycles repeated every 21days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily  3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies. Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m 2 on the daily  5 schedule; 112 mg/m 2 on the daily  3 schedule; and 220 mg/m 2 on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily  5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1were observed in biomarker studies. Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stress-survival response, protein refolding, and the conformational maturation of a subset of signaling proteins (1 -3). Several natural products that bind selectively to Hsp90 and inhibit its function have been used to determine its biological role (4 -7). These natural products, which include geldanamycin and radicicol, induce the selective degradation of proteins whose activity and/or expression are regulated by . Sensitive Hsp90 clients include protein kinases [human epidermal growth factor receptor 2 (HER2), Raf-1, and Akt], steroid hormone receptors (androgen receptor and estrogen receptor), and mutant oncoproteins (mutant p53,.Geldanamycin, the lead compound of the class, proved too toxic for clinical use (16). However, 17-allylamino-17-demethoxygeldanamycin (17-AAG) has activity in human xenograft and genetic murine tumor models as a single agent (12, 17 -20). Hsp90 inhibition also has additive and synergistic effects in combination with cytotoxics, biologics, radiation, and antiangiogenics (17, 20 -24). The objectives of the current trial were to determine the safety, pharmacokinetics, and pharmacodynamics of 17-AAG and to define a dose and schedule of administration that could be used in ...

Primates exhibit complex social and cognitive behavior in the wild. In the laboratory, however, the expression of their behavior is usually limited. A large body of literature shows that living in an enriched environment alters dendrites and synapses in the brains of adult rodents. To date, no studies have investigated the influence of living in a complex environment on brain structure in adult primates. We assessed dendritic architecture, dendritic spines, and synaptic proteins in adult marmosets housed in either a standard laboratory cage or in one of two differentially complex habitats. A month-long stay in either complex environment enhanced the length and complexity of the dendritic tree and increased dendritic spine density and synaptic protein levels in the hippocampus and prefrontal cortex. No differences were detected between the brains of marmosets living in the two differentially complex environments. Our results show that the structure of the adult primate brain remains highly sensitive even to modest levels of experiential complexity. For adult primates, living in standard laboratory housing may induce reversible dendritic spine and synapse decreases in brain regions important for cognition.dendritic spine ͉ enriched environments ͉ hippocampus ͉ marmoset ͉ prefrontal cortex E xperience can change the structure of the adult mammalian brain. A large body of evidence documents that exposing laboratory rodents to complex or ''enriched'' settings enhances multiple aspects of brain structure, including the size and weight of brain regions, the number and size of neurons and glia, the complexity of dendritic trees, and the number of synapses (e.g., refs. 1-7). Studies suggest that dendritic spines, a primary site of excitatory synapses, are particularly sensitive to experience. Indeed, dendritic spines and synapses in the rodent brain are enhanced by living in an enriched environment (e.g., refs. 8-15). More specific experiences, such as learning, physical exercise, and experimentally induced neural activity, have also been linked to changes in the number, shape, and size of dendritic spines and synapses in rodents (16)(17)(18)(19)(20)(21)(22). In this regard, experiences that alter dendritic spines and synapses also affect the NMDA and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes of the glutamate receptor (23-27).Primates are known for their complex social and cognitive functions, but most laboratory monkeys are housed under conditions that do not allow for the expression of the full repertoire of their behaviors. Although previous work has demonstrated structural changes in the developing primate brain in animals raised under conditions of social and sensory deprivation (28)(29)(30), no studies have investigated the effects of living in ''enriched'' environments on any aspect of brain structure or biochemistry in the adult primate.To investigate this issue, we examined the brains of common marmosets (Callithrix jacchus), New World monkeys, raised under standard laboratory conditio...

Objective Post-cardiac arrest therapeutic hypothermia (TH) improves outcomes in comatose cardiac arrest survivors. This study tests the hypothesis that the efficacy of post-cardiac arrest TH is dependent on the onset and duration of therapy. Design Prospective randomized laboratory investigation Setting University research laboratory Subjects 268 male Long Evans rats Interventions Post-cardiac arrest therapeutic hypothermia Measurements and Main Results Adult male Long Evans rats that achieved return of spontaneous circulation (ROSC) after a 10-min asphyxial cardiac arrest were block randomized to normothermia (37±1°C) or TH (33±1°C) initiated 0, 1, 4, or 8 hrs after ROSC and maintained for 24 or 48 hrs. TH initiated 0, 1, 4, and 8 hours after ROSC resulted in 7-day survival rates of 45%*, 36%*, 36%*, and 14% respectively compared to 17% for normothermic controls, and survival with good neurologic function rates of 24%*, 24%*, 19%*, and 0% respectively compared to 2% for normothermic controls (*p<0.05 vs. normothermia). These outcomes were not different when TH was maintained for 24 vs. 48 hours. In contrast, hippocampal CA1 pyramidal neuron counts were 53±27%*, 53±19%*, 51±24%*, and 65±16%* of normal respectively when TH initiated 0, 1, 4, or 8 hrs after ROSC compared to 9% in normothermic controls (*p<0.01 vs. normothermia). Furthermore, surviving neuron counts were greater when TH was maintained for 48 hrs compared to 24 hrs (68%±15%* vs. 42%±22%, *p<0.0001) Conclusions In this study, post-cardiac arrest TH resulted in comparable improvement of survival and survival with good neurologic function when initiated within 4-hours after ROSC. However, histological assessment of neuronal survival revealed a potentially broader therapeutic window and greater neuroprotection when TH was maintained for 48 vs. 24 hours.

Background-The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.

ObjectiveThe Systemic Synuclein Sampling Study (S4) measured α-synuclein in multiple tissues and biofluids within the same PD subjects vs healthy controls (HC).MethodsS4 was a 6-site cross-sectional observational study of participants with early, moderate, or advanced PD and HCs. Motor and non-motor measures and dopamine transporter SPECT were obtained. Biopsies of skin, colon, submandibular gland (SMG), CSF, saliva, and blood were collected. Tissue biopsy sections were stained with 5C12 monoclonal antibody against pathologic α-synuclein; digital images were interpreted by neuropathologists blinded to diagnosis. Biofluid total α-synuclein was quantified using ELISA.ResultsThe final cohort included 59 PD and 21 HC. CSF α-synuclein was lower in PD vs HC; sensitivity/specificity of CSF α-synuclein for PD diagnosis was 87.0%/63.2% respectively. Sensitivity of α-synuclein immunoreactivity for PD diagnosis was 56.1% for SMG and 24.1% for skin; specificity was 92.9% and 100% respectively. There were no significant relationships between different measures of α-synuclein within subjects.ConclusionsS4 confirms lower total α-synuclein levels in CSF in PD compared to HC, but specificity is low. In contrast, α-synuclein immunoreactivity in skin and SMG is specific for PD but sensitivity is low. Relationships within subjects across different tissues and biofluids could not be demonstrated. Measures of pathologic forms of α-synuclein with higher accuracy are critically needed.Classification of evidenceThis study provides Class III evidence that total CSF α-synuclein does not accurately distinguish PD from HC, and that monoclonal antibody staining for SMG and skin total α-synuclein is specific but not sensitive for PD diagnosis.

The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact.

Background Identifying PD-specific biomarkers in biofluids will greatly aid in diagnosis, monitoring progression, and therapeutic interventions. PD biomarkers have been limited by poor discriminatory power, partly driven by heterogeneity of the disease, and variability of collection protocols, and focus on de novo, un-medicated patients. Thus, a platform for biomarker discovery and validation in well-characterized, clinically typical, moderate to advanced PD cohorts is critically needed. Methods BioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson’s Disease) is a cross-sectional, multi-center biomarker study that established a repository of clinical data, blood, DNA, RNA, CSF, saliva and urine samples from 118 moderate to advanced PD and 88 healthy control subjects. Inclusion criteria were designed to maximize diagnostic specificity by selecting participants with clinically typical PD symptoms, and clinical data and biospecimen collection utilized standardized procedures to minimize variability across sites. Results We present the study methodology and data on the cohort’s clinical characteristics. Motor scores and biospecimen samples including plasma are available for practically defined “off” states and “on” states and thus enable testing the effects of PD medications on biomarkers. Other biospecimens are available from “off” state PD assessments and from controls. Conclusion Our cohort provides a valuable resource for biomarker discovery and validation in PD. Clinical data and biospecimens, available through The Michael J. Fox Foundation for Parkinson’s Research and the National Institute of Neurological Disorders and Stroke, can serve as a platform for discovering biomarkers in clinically typical PD and comparisons across PD’s broad and heterogeneous spectrum.