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70 Objectives Clinical measures of Parkinson’s disease progression suggest a slow process with significant variability both between patients and also within the individual over the course of disease. A number of “objective” imaging and non-imaging measures have been proposed as putative progression biomarkers although there is limited validation data available. The Parkinson9s (PD) progression marker initiative (PPMI) is an international, multicenter, longitudinal study assessing biochemical, clinical, and imaging biomarkers of disease progression. Scintigraphic biomarkers are being evaluated as indicators of progression include dopamine transporter (DAT) imaging with 123-I ioflupane SPECT. This study evaluates subregion-dependent striatal changes in dopamine transporter (DAT) binding using 123-I Ioflupane SPECT in PD participants in the PPMI study. Methods Baseline (n= 241), 1 year, and 2 year 123-I Ioflupane SPECT scans were acquired from 22 centers. Data were reconstructed, attenuation corrected, and analyzed by the core lab using a volume of interest template for extraction of counts and calculation of specific binding ratios (SBRs) and percent SBRs changes over time in six striatal subregions. Results Ongoing serial evaluation shows SBR reduction at 1 yr in 80% of 241 PD subjects. Specific binding ratios demonstrate 11.6% and 7.4% reductions over one year in the ipsilateral and contralateral striatum, respectively. Differences in the rates of DAT signal change are evident in subregions of the striatum. The fastest rates of change annualized over two years were noted, in order, for ipsilateral striatum; posterior putamen (-9.2% +/-11.4), anterior putamen(-8.7% +/- 8.8), and caudate( -6.9% +/-8.9). In contrast, contralaterally, posterior putamen (-6.4% +/-15.4), demonstrated the slowest rate of change with the anterior putamen (-8.0% +/-10.3), and the caudate ( -7.5%+/-9.4). Conclusions These data have implications for the potential use of dopamine transporter imaging as a serial marker of change in longitudinal Parkinson9s studies. Specifically, areas with greatest signal change and lowest variability might be more sensitive for detecting slowing rates of change with a disease modifying therapy. In summary, this study shows consistently increasing signal loss over one and two years with regional differences demonstrated for DAT imaging and confirmation of previously noted between subject variability.

Background Newborns have frequent infections and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant but might confer a T H 2 bias. Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes demonstrate impaired T H 1-polarizing responses to many TLR agonists caused by plasma adenosine acting through cyclic AMP. TLR8 agonists, including imidazoquinolines (IMQs), such as the small synthetic 3M-002, induce adult-level TNF from neonatal monocytes, but the scope and mechanisms of IMQ-induced activation of neonatal monocytes and monocyte-derived dendritic cells (MoDCs) have not been reported. Objective We sought to characterize IMQ-induced activation of neonatal monocytes and MoDCs. Methods Neonatal cord and adult peripheral blood monocytes and MoDCs were cultured in autologous plasma; levels of alum- and TLR agonist–induced cytokines and costimulatory molecules were measured. TLR8 and inflammasome function were assayed by using small interfering RNA and Western blotting/caspase-1 inhibitory peptide, respectively. The ontogeny of TLR8 agonist–induced cytokine responses was defined in rhesus macaque whole blood ex vivo . Results IMQs were more potent and effective than alum at inducing TNF and IL-1β from monocytes. 3M-002 induced robust TLR pathway transcriptome activation and T H 1-polarizing cytokine production in neonatal and adult monocytes and MoDCs, signaling through TLR8 in an adenosine/cyclic AMP–refractory manner. Newborn MoDCs displayed impaired LPS/ATP-induced caspase-1–mediated IL-1β production but robust 3M-002–induced caspase-1–mediated inflammasome activation independent of exogenous ATP. TLR8 IMQs induced robust TNF and IL-1β in whole blood of rhesus macaques at birth and infancy. Conclusions IMQ TLR8 agonists engage adenosine-refractory TLR8 and inflammasome pathways to induce robust monocyte and MoDC activation and represent promising neonatal adjuvants.