Peripheral sTREM2-Related Inflammatory Activity Alterations in Early-Stage Alzheimer's Disease.

Alzheimer's disease (AD) has been linked to multiple immune system-related genetic variants. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. In addition, soluble TREM2 (sTREM2) isoform is elevated in cerebrospinal fluid in the early stages of AD and is associated with slower cognitive decline in a disease stage-dependent manner. Multiple studies have reported an altered peripheral immune response in AD. However, less is known about the relationship between peripheral sTREM2 and an altered peripheral immune response in AD. The objective of this study was to explore the relationship between human plasma sTREM2 and inflammatory activity in AD. The hypothesis of this exploratory study was that sTREM2-related inflammatory activity differs by AD stage. We observed different patterns of inflammatory activity across AD stages that implicate early-stage alterations in peripheral sTREM2-related inflammatory activity in AD. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups that was lost in later AD-related stages with high levels in mild cognitive impairment. Although multiple other inflammatory factors either differed significantly between groups or were significantly correlated with sTREM2 within specific groups, three inflammatory factors (fibroblast growth factor-2, GM-CSF, and IL-1ß) are notable because they exhibited both lower levels in AD, compared with mild cognitive impairment, and a change in the relationship with sTREM2. This evidence provides important support to the hypothesis that sTREM2-related inflammatory activity alterations are AD stage specific and provides critical information for therapeutic strategies focused on the immune response.

An Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome: A Preliminary Report.

Individuals with Down syndrome (DS) develop Alzheimer's disease (AD)-related neuropathology, characterized by amyloid plaques with amyloid ß (Aß) and neurofibrillary tangles with tau accumulation. Peripheral inflammation and the innate immune response are elevated in DS. Triggering receptor expressed in myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. Soluble TREM2 (sTREM2), a soluble cleavage product of TREM2, is elevated in AD cerebrospinal fluid and positively correlates with cognitive decline. There is relatively little information about TREM2 in DS. Our objective was to examine the relationship between sTREM2 and inflammatory markers in young adults with DS, prior to the development of dementia symptoms. Because TREM2 plays a role in the innate immune response and has been associated with dementia, the hypothesis of this exploratory study was that young adults with DS predementia (n = 15, mean age = 29.5 y) would exhibit a different relationship between sTREM2 and inflammatory markers in plasma, compared with neurotypical, age-matched controls (n = 16, mean age = 29.6 y). Indeed, young adults with DS had significantly elevated plasma sTREM2 and inflammatory markers. Additionally, in young adults with DS, sTREM2 correlated positively with 24 of the measured cytokines, whereas there were no significant correlations in the control group. Hierarchical clustering of sTREM2 and cytokine concentrations also differed between the groups, supporting the hypothesis that its function is altered in people with DS predementia. This preliminary report of human plasma provides a basis for future studies investigating the relationship between TREM2 and the broader immune response predementia.

High-resolution functional connectivity of the default mode network in young adults with down syndrome.

Studies of resting-state functional connectivity MRI in Alzheimer's disease suggest that disease stage plays a role in functional changes of the default mode network. Individuals with the genetic disorder Down syndrome show an increased incidence of early-onset Alzheimer's-type dementia, along with early and nearly universal neuropathologic changes of Alzheimer's disease. The present study examined high-resolution functional connectivity of the default mode network in 11 young adults with Down syndrome that showed no measurable symptoms of dementia and 11 age- and sex-matched neurotypical controls. We focused on within-network connectivity of the default mode network, measured from both anterior and posterior aspects of the cingulate cortex. Sixty-eight percent of connections to the posterior cingulate and 26% to the anterior cingulate showed reduced strength in the group with Down syndrome (p < 0.01). The Down syndrome group showed increased connectivity strength from the anterior cingulate to the bilateral inferior frontal gyri and right putamen (p < 0.005). In an exploratory analysis, connectivity in the group with Down syndrome showed regional relationships to plasma measures of inflammatory markers and t-tau. In non-demented adults with Down syndrome, functional connectivity within the default mode network may be analogous to changes reported in preclinical Alzheimer's disease, and warrants further investigation as a measure of dementia risk.

Sero-catalytic and Antibody Acquisition Models to Estimate Differing Malaria Transmission Intensities in Western Kenya.

We sought to identify a subset of Plasmodium falciparum antibody targets that would inform monitoring efforts needed to eliminate malaria in high transmission settings. IgG antibodies to 28 recombinant Pf antigens were measured in residents of two communities in western Kenya examined in 2003 and 2013, when the respective prevalence of asymptomatic parasitemia among children was 81 and 15 percent by microscopy. Annual seroconversion rates based on a sero-catalytic model that dichotomised antibody values to negative versus positive showed that rates were higher in 2003 than 2013 for 1 pre-erythrocytic and 7 blood-stage antigens. Antibody acquisition models that considered antibody levels as continuous variables showed that age-related antibody levels to Circumsporozoite Protein and 10 merozoite proteins increased at different rates with age in 2003 versus 2013. Both models found that antibodies to 5 proteins of the Merozoite Surface Protein 1 complex were differentially acquired between the cohorts, and that changes in antibody levels to Apical Membrane Antigen 1 suggested a decrease in transmission that occurred ~10 years before 2013. Further studies evaluating antibodies to this subset of Pf antigens as biomarkers of malaria exposure and naturally acquired immunity are warranted in endemic settings where transmission has been reduced but persists.