A composite immune signature parallels disease progression across T1D subjects

At diagnosis, most people with type 1 diabetes (T1D) produce measurable levels of endogenous insulin, but the rate at which insulin secretion declines is heterogeneous. To explain this heterogeneity, we sought to identify a composite signature predictive of insulin secretion, using a collaborative assay evaluation and analysis pipeline that incorporated multiple cellular and serum measures reflecting beta cell health and immune system activity. The ability to predict decline in insulin secretion would be useful for patient stratification for clinical trial enrollment or therapeutic selection. Analytes from 12 qualified assays were measured in shared samples from subjects newly diagnosed with T1D. We developed a computational tool to identify a composite panel associated with decline in insulin secretion over 2 years after diagnosis. The tool employs multiple filtering steps to reduce data dimensionality, incorporates error-estimation techniques including cross-validation and sensitivity analysis, and is flexible to assay type, clinical outcome and disease setting. Using this novel analytical tool, we identified a panel of immune markers that, in combination, are highly associated with loss of insulin secretion. The methods used here represent a novel process for identifying combined immune signatures that predict outcomes relevant for complex and heterogeneous diseases like T1D

Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation

Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin-independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters--including time until insulin independence, insulin independence at one year, and C-peptide levels over one year--remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Clinicaltrials.gov NCT00623610

Reaction times and performance variability in normal aging, mild cognitive impairment, and Alzheimer's disease

This study evaluated whether reaction times (RT) and performance variability are potential markers for the early detection of Alzheimer’s disease (AD). Cognitively healthy elderly (n 218), persons with amnestic MCI (a-MCI) (n 29) and patients with AD (n 50) were examined with RT tasks with increasing complexity, subdividing RT into a decision and a movement compo-nent. Persons with cognitive deterioration demonstrated more intra-individual variability and more slowing than cognitively healthy elderly. The slowing in AD affects both the cognitive and the motor component, while performance variability mainly affects the cognitive component of the RT. Although in a-MCI not all dif-ferences reached statistical significance, primarily the cognitive component of the RT is affected in a-MCI. Intra-individual variability and RT of the complex tasks are the best predictors for a-MCI and AD status, respec-tively. We conclude that performance variability can be regarded as a useful preclinical marker for AD

Attentional processes discriminate between patients with mild Alzheimer's disease and cognitively healthy elderly.

Background: It is generally accepted that Alzheimer's disease (AD) is mainly characterized by memory disorders. Although recent studies also point to an important role of attention deficits early in the disease, this notion has not yet emerged in clinical practice. Our aim was to assess whether attention, quantified by reaction times, can discriminate between patients with mild AD and controls and therefore contribute to clinical diagnosis. Methods: In a cross-sectional study, 33 patients with mild AD were matched with cognitively healthy elderly controls for age, gender, educational level and depressive mood. Selective attention (SA), alternating attention (AA) and error-rates were measured by a modified reaction time test. Results: Significant differences between both groups were found for all measures. Logistic regression showed that SA (corrected for individual processing speed) and error-rates could correctly classify subjects with an overall hit ratio of 81%. When attention measures were not corrected for individual processing speed, the overall hit ratio improved to 97%. Conclusion: SA and AA deteriorate in patients with mild AD and these measures can be used to discriminate between patients and matched controls, independently of depressive mood. © 2006 International Psychogeriatric Association.SCOPUS: ar.jinfo:eu-repo/semantics/publishe