Toddlers' action learning and memory from active and observed instructions.

From early in life, children learn to perform actions on the objects in their environments. Although children learn from observing others' actions, actively engaging with the material to be learned can be important for learning. This study tested whether instruction that included opportunities for children to be active supported toddlers' action learning. In a within-participants design, 46 22- to 26-month-old toddlers (average age = 23.3 months; 21 male) were introduced to target actions for which instruction was either active or observed (instruction order counterbalanced across children). During active instruction, toddlers were coached to perform a set of target actions. During observed instruction, toddlers saw a teacher perform the actions. Toddlers were then tested on their action learning and generalization. Surprisingly, action learning and generalization did not differ between instruction conditions. However, toddlers' cognitive maturity supported their learning from both types of instruction. One year later, children from the original sample were tested on their long-term memory for information learned from active and observed instructions. Of this sample, 26 children provided usable data for the follow-up memory task (average age = 36.7 months, range = 33-41; 12 male). Children demonstrated better memory for information learned from active instruction than for information learned from observed instruction (odds ratio = 5.23) 1 year after instruction. Active experience during instruction appears to be pivotal for supporting children's long-term memory.

Retinal Angiogenesis Regulates Astrocytic Differentiation in Neonatal Mouse Retinas by Oxygen Dependent Mechanisms.

In mice, retinal vascular and astrocyte networks begin to develop at birth, expanding radially from the optic nerve head (ONH) towards the retinal periphery. The retinal vasculature grows towards the periphery ahead of differentiated astrocytes, but behind astrocytic progenitor cells (APCs) and immature astrocytes. Endothelial cell specific Vegfr-2 disruption in newborn mice not only blocked retinal vascular development but also suppressed astrocytic differentiation, reducing the abundance of differentiated astrocytes while causing the accumulation of precursors. By contrast, retinal astrocytic differentiation was accelerated by the exposure of wild-type newborn mice to hyperoxia for 24 hours, or by APC specific deficiency in hypoxia inducible factor (HIF)-2α, an oxygen labile transcription factor. These findings reveal a novel function of the retinal vasculature, and imply that in normal neonatal mice, oxygen from the retinal circulation may promote astrocytic differentiation, in part by triggering oxygen dependent HIF-2α degradation in astrocytic precursors.

Early retinal inflammatory biomarkers in the middle cerebral artery occlusion model of ischemic stroke.

PURPOSE: The transient middle cerebral artery occlusion (MCAO) model of stroke is one of the most commonly used models to study focal cerebral ischemia. This procedure also results in the simultaneous occlusion of the ophthalmic artery that supplies the retina. Retinal cell death is seen days after reperfusion and leads to functional deficits; however, the mechanism responsible for this injury has not been investigated. Given that the eye may have a unique ocular immune response to an ischemic challenge, this study examined the inflammatory response to retinal ischemia in the MCAO model. METHODS: Young male C57B/6 mice were subjected to 90-min transient MCAO and were euthanized at several time points up to 7 days. Transcription of inflammatory cytokines was measured with quantitative real-time PCR, and immune cell activation (e.g., phagocytosis) and migration were assessed with ophthalmoscopy and flow cytometry. RESULTS: Observation of the affected eye revealed symptoms consistent with Horner's syndrome. Light ophthalmoscopy confirmed the reduced blood flow of the retinal arteries during occlusion. CX3CR1-GFP reporter mice were then employed to evaluate the extent of the ocular microglia and monocyte activation. A significant increase in green fluorescent protein (GFP)-positive macrophages was seen throughout the ischemic area compared to the sham and contralateral control eyes. RT-PCR revealed enhanced expression of the monocyte chemotactic molecule CCL2 early after reperfusion followed by a delayed increase in the proinflammatory cytokine TNF-α. Further analysis of peripheral leukocyte recruitment by flow cytometry determined that monocytes and neutrophils were the predominant immune cells to infiltrate at 72 h. A transient reduction in retinal microglia numbers was also observed, demonstrating the ischemic sensitivity of these cells. Blood-eye barrier permeability to small and large tracer molecules was increased by 72 h. Retinal microglia exhibited enhanced phagocytic activity following MCAO; however, infiltrating myeloid cells were significantly more efficient at phagocytizing material at all time points. Immune homeostasis in the affected eye was largely restored by 7 days. CONCLUSIONS: This work demonstrates that there is a robust inflammatory response in the eye following MCAO, which may contribute to a worsening of retinal injury and visual impairment. These results mirror what has been observed in the brain after MCAO, suggesting a conserved inflammatory signaling response to ischemia in the central nervous system. Imaging of the eye may therefore serve as a useful non-invasive prognostic indicator of brain injury after MCAO. Future studies are needed to determine whether this inflammatory response is a potential target for therapeutic manipulation in retinal ischemia.

CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study.

The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aß1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aß1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aß1-42, or highest t-tau/Aß1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aß1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.

Aging augments the impact of influenza respiratory tract infection on mobility impairments, muscle-localized inflammation, and muscle atrophy.

Although the influenza virus only infects the respiratory system, myalgias are commonly experienced during infection. In addition to a greater risk of hospitalization and death, older adults are more likely to develop disability following influenza infection; however, this relationship is understudied. We hypothesized that upon challenge with influenza, aging would be associated with functional impairments, as well as upregulation of skeletal muscle inflammatory and atrophy genes. Infected young and aged mice demonstrated decreased mobility and altered gait kinetics. These declines were more prominent in hind limbs and in aged mice. Skeletal muscle expression of genes involved in inflammation, as well as muscle atrophy and proteolysis, increased during influenza infection with an elevated and prolonged peak in aged mice. Infection also decreased expression of positive regulators of muscle mass and myogenesis components to a greater degree in aged mice. Gene expression correlated to influenza-induced body mass loss, although evidence did not support direct muscle infection. Overall, influenza leads to mobility impairments with induction of inflammatory and muscle degradation genes and downregulation of positive regulators of muscle. These effects are augmented and prolonged with aging, providing a molecular link between influenza infection, decreased resilience and increased risk of disability in the elderly.

Age- and location-related changes in microglial function.

Inflammation in the central nervous system (CNS) is primarily regulated by microglia. No longer considered a homogenous population, microglia display a high degree of heterogeneity, immunological diversity and regional variability in function. Given their low rate of self-renewal, the microenvironment in which microglia reside may play an important role in microglial senescence. This study examines age-related changes in microglia in the brain and spinal cord. Using ex-vivo flow cytometry analyses, functional assays were performed to assess changes in microglial morphology, oxidative stress, cytokine production, and phagocytic activity with age in both the brain and spinal cord. The regional CNS environment had a significant effect on microglial activity with age. Blood-CNS barrier permeability was greater in the aging spinal cord compared with aging brain; this was associated with increased tissue cytokine levels. Aged microglia had deficits in phagocytosis at baseline and after stimulus-induced activation. The identification of age-specific, high scatter microglia together with the use of ex-vivo functional analyses provides the first functional characterization of senescent microglia. Age and regional-specificity of CNS disease should be taken into consideration when developing immune-modulatory treatments.

Knowledge and attitudes about Parkinson's disease among a diverse group of older adults.

Underserved minorities are vulnerable to diagnostic delays and under-treatment of Parkinson's disease (PD). The purpose of this mixed-methods study was to understand knowledge and attitudes about PD among a racially/ethnically diverse group of community members. In the qualitative arm, ten homogeneous focus groups of 6 to 8 White, African-American and Chinese American older adults at senior centers in Philadelphia were conducted. Next, for the quantitative arm, a questionnaire of knowledge and attitudes about PD was administered among a larger group of senior center members. Themes were identified from the focus group discussions. ANOVA and chi-square tests were used to assess differences in PD knowledge and attitudes among the different racial/ethnic groups. Logistic regression analyzed for independent factors associated with barriers to treatment. Seventy-five adults participated in the focus groups (23 Whites, 36 African-Americans and 16 Chinese-Americans) and 154 completed the questionnaire (62 Whites, 47 African-Americans and 45 Chinese-Americans). One common theme about developing PD was fear of losing independence. Racial/ethnic groups identified unique barriers to care: mistrust in the healthcare system by African-Americans and language difficulties by Chinese-Americans. Eighty percent of all participants had no to some knowledge of PD. African-Americans and Chinese-Americans were more likely to perceive PD as a part of normal aging than whites. Chinese-Americans were more likely to perceive barriers to treatment than whites. A diverse sample of older adults demonstrated low levels of PD knowledge through both qualitative and quantitative methods. Many barriers to PD care were identified. Targeted community outreach and education efforts should incorporate information about PD and how to receive care.

Association of cerebrospinal fluid ß-amyloid 1-42, T-tau, P-tau181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease.

IMPORTANCE: We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and α-synuclein, but not ß-amyloid 1-42 (Aß1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. OBJECTIVE: To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (Aß1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau181], and α-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson's Progression Markers Initiative (PPMI) study. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. MAIN OUTCOMES AND MEASURES: The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Aß1-42, T-tau, and P-tau181; Innogenetics Inc) or by enzyme-linked immunosorbent assay (α-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. RESULTS: Slightly, but significantly, lower levels of Aß1-42, T-tau, P-tau181, α-synuclein, and T-tau/Aß1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower Aß1-42 and P-tau181 levels were associated with PD diagnosis and that decreased CSF T-tau and α-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF Aß1-42 and P-tau181 concentrations were associated with the postural instability-gait disturbance-dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of α-synuclein with the levels of T-tau and P-tau181. CONCLUSIONS AND RELEVANCE: In this first report of CSF biomarkers in PPMI study subjects,we found that measures of CSF Aß1-42, T-tau, P-tau181, and α-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression

Public health and law collaboration: the Philadelphia Lead Court study.

OBJECTIVES: We determined whether Philadelphia Lead Court is effective in enforcing lead hazard remediation in the homes of children with elevated blood lead levels. METHODS: We created a deidentified data set for properties with an initial failed home inspection (IFHI) for lead hazards from January 1, 1998, through December 31, 2008, and compared compliance rates within the first year and time to compliance for lead hazard remediation between 1998 and 2002 (precourt period) and between 2003 and 2008 (court period). We evaluated predictors of time to compliance. RESULTS: Within 1 year of the IFHI, 6.6% of the precourt and 76.8% of the court cases achieved compliance (P < .001) for the 3764 homes with data. Four years after the IFHI, 18% had attained compliance in the precourt period compared with 83.1% for the court period (P < .001). A proportional hazard analysis found that compliance was 8 times more likely in the court than the precourt period (P < .001). CONCLUSIONS: Lead court was more effective than precourt enforcement strategies. Most properties were remediated within 1 year of the IFHI, and time to compliance was significantly reduced. This model court could be replicated in other cities with similar enforcement problems.

Philadelphia's Lead Court is making a difference.

The Philadelphia Lead Court (PLC) was created as an innovative law enforcement strategy to compel property owners to comply with city health codes to remediate their properties of lead hazards, which had led to elevated blood lead levels and lead poisoning in resident children. This study presents a detailed account of and analyzes the opinions of fifteen key informants drawn from the Philadelphia health and law departments and judicial system that staff and run the PLC in response to a fifteen-question structured survey. Main themes reviewed include the effectiveness of the PLC as compared with precourt law enforcement strategies and within the context of a specialized court, the use of fines, the impact of grant funding for remediation work, the major advantages and disadvantages of the PLC, and suggested changes to improve court function, followed by key recommendations. The article concludes that our informants found that the PLC has been very effective and successful. This model could be replicated by other cities with similar health code enforcement challenges.