Reactive oxygen species (ROS) have been implicated as second messengers that activate protein kinase cascades, although the means by which ROS regulate signal transduction remains unclear. In the present study, we show that interleukin 1beta (IL1beta), H2O2, and sorbitol-induced hyperosmolarity mediate a 5- to 10-fold increase in phosphorylation (activation) of the p38 protein kinase in rat primary glial cells as measured by analyses of Western blots using an antibody directed against the dually phosphorylated (active) p38. Additionally, IL1beta was found to elicit H2O2 synthesis in these cells. Concurrent with p38 phosphorylation, all three stimulation paradigms caused an inhibition of protein phosphatase activity. Phenyl-tert-butyl nitrone (PBN), a nitrone-based free radical trap and N-acetyl-cysteine (NAC), a thiol reducing agent, were examined for their effects on the phosphorylation of p38 as well as phosphatase activity. Pretreatment of cells with either PBN or NAC at 1.0 mM suppressed IL1beta H2O2, and sorbitol-mediated activation of p38 and significantly increased phosphatase activity. These data suggest that ROS, particularly H2O2, are used as second messenger substances that activate p38 in part via the transient inactivation of regulatory protein phosphatases.

BACKGROUND: Alzheimer’s disease and related dementias are irreversible, progressive brain disorders that slowly destroy memory, language, problem solving, and cognition. In the United States, dementia is the fifth leading cause of death for people age 65 years and older. Early diagnosis could have important benefits stigma related to dementia remains a significant impediment to diagnosis, treatment, and accessing services. While a growing body of research documents the existence and negative outcomes of stigma, less is known about how dementia-related stigma produces ill effects. AIMS: The purpose of this study was to use qualitative methods to explore how stigma manifests within families from the perspective of family caregivers of people with dementia. METHOD: Using a grounded theory approach, we interviewed 13 family caregivers of people with dementia. RESULTS: Shame emerged as the central theme experienced by family caregivers of people with dementia. Attempting to manage shame, produced three categories of responses: (1) silencing and not calling attention to the symptoms, (2) concealing the diagnosis, and (3) shunning and avoiding contact. CONCLUSIONS: Shame may be an underlying mechanism by which stigma is enacted and perpetuated, resulting in caregivers’ isolation and delay in access to diagnostic and supportive services. Efforts to dispel the misconception that dementia is a shameful disease may be one way to diminish stigma.

Prevalence rates for mild cognitive impairment in Parkinson’s disease (PD-MCI) remain variable, obscuring the diagnosis’ predictive utility of greater dementia risk. A primary factor of this variability is inconsistent operationalization of normative cutoffs for cognitive impairment. We aimed to determine which cutoff was optimal for classifying individuals as PD-MCI by comparing classifications against data-driven PD cognitive phenotypes. Participants with idiopathic PD (n = 494; mean age 64.7 ± 9) completed comprehensive neuropsychological testing. Cluster analyses (K-means, Hierarchical) identified cognitive phenotypes using domain-specific composites. PD-MCI criteria were assessed using separate cutoffs (−1, −1.5, −2 SD) on ≥2 tests in a domain. Cutoffs were compared using PD-MCI prevalence rates, MCI subtype frequencies (single/multi-domain, executive function (EF)/non-EF impairment), and validity against the cluster-derived cognitive phenotypes (using chi-square tests/binary logistic regressions). Cluster analyses resulted in similar three-cluster solutions: Cognitively Average (n = 154), Low EF (n = 227), and Prominent EF/Memory Impairment (n = 113). The −1.5 SD cutoff produced the best model of cluster membership (PD-MCI classification accuracy = 87.9%) and resulted in the best alignment between PD-MCI classification and the empirical cognitive profile containing impairments associated with greater dementia risk. Similar to previous Alzheimer’s work, these findings highlight the utility of comparing empirical and actuarial approaches to establish concurrent validity of cognitive impairment in PD.