Montreal cognitive assessment as a screening instrument for cognitive impairment in systemic lupus erythematosus patients without overt neuropsychiatric manifestations.

OBJECTIVES: The Montreal Cognitive Assessment (MoCA) is an increasingly used screening tool for cognitive impairment. The aim of this study was to examine how MoCA performed in identifying cognitive impairment (CI) domains in SLE patients compared with formal standardized neuropsychological testing (NPT). Factors related to SLE disease, immunologic and psychological state associated with CI were also explored. METHODS: This cross-sectional study recruited 50 SLE patients without overt neuropsychiatric manifestations from April 2017 to May 2018. The patients were evaluated with MoCA, formal NPT and the Depression, Anxiety, and Stress Scales (DASS) 42-item self-report questionnaire. Values of sensitivity and specificity were computed for different cut-offs of MoCA within each cognitive domain of NPT and descriptive analysis was used to identify the factors affecting cognitive function. RESULTS: The median score for MoCA was 27.5 (range 22-30). Using a MoCA cutoff of <26, 18 (36%) were identified to have CI using NPT compared to 8 (16%) using MoCA. The most frequently affected cognitive domain was executive functioning with 15 affected patients. Sensitivities and specificities of the MoCA range from 50% to 100% and 5.7% to 16.7%, respectively, across cognitive domains. A lower MoCA cutoff of <25 improve sensitivity of identifying impairment in executive functioning from 60% to 80%. In univariate analysis, DASS scores, disease activity, presence of antiphospholipid antibodies, presence of concurrent autoimmune disease, current, and cumulative corticosteroid therapy did not predict cognitive performance. CONCLUSION: MoCA may be a useful screening tool to identify the most frequently affected cognitive domain which is executive functioning using a lower cutoff of <25 in SLE patients without overt neuropsychiatric manifestations.

Defining CD4 T cell memory by the epigenetic landscape of CpG DNA methylation.

Memory T cells are primed for rapid responses to Ag; however, the molecular mechanisms responsible for priming remain incompletely defined. CpG methylation in promoters is an epigenetic modification, which regulates gene transcription. Using targeted bisulfite sequencing, we examined methylation of 2100 genes (56,000 CpGs) mapped by deep sequencing of T cell activation in human naive and memory CD4 T cells. Four hundred sixty-six CpGs (132 genes) displayed differential methylation between naive and memory cells. Twenty-one genes exhibited both differential methylation and gene expression before activation, linking promoter DNA methylation states to gene regulation; 6 of 21 genes encode proteins closely studied in T cells, whereas 15 genes represent novel targets for further study. Eighty-four genes demonstrated differential methylation between memory and naive cells that correlated to differential gene expression following activation, of which 39 exhibited reduced methylation in memory cells coupled with increased gene expression upon activation compared with naive cells. These reveal a class of primed genes more rapidly expressed in memory compared with naive cells and putatively regulated by DNA methylation. These findings define a DNA methylation signature unique to memory CD4 T cells that correlates with activation-induced gene expression.

New DSM-V neurocognitive disorders criteria and their impact on diagnostic classifications of mild cognitive impairment and dementia in a memory clinic setting.

OBJECTIVE: To examine diagnostic agreement between Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Neurocognitive Disorders (NCDs) criteria and DSM, Fourth Edition (DSM-IV) criteria for dementia and International Working Group (IWG) criteria for mild cognitive impairment (MCI) and DSM-V's impact on diagnostic classifications of NCDs. The authors further examined clinical factors for discrepancy in diagnostic classifications between the different operational definitions. METHODS: Using a cross-sectional study in tertiary memory clinic, the authors studied consecutive new patients aged 55 years or older who presented with cognitive symptoms. Dementia severity was scored based on the Clinical Dementia Rating scale (CDR). All patients completed neuropsychological evaluation. Agreement in diagnostic classifications between DSM-IV/IWG and DSM-V was examined using the kappa test and AC1 statistic, with multinomial logistic regression for factors contributing to MCI reclassification as major NCDs as opposed to diagnostically concordant MCI and dementia groups. RESULTS: Of 234 patients studied, 166 patients achieved concordant diagnostic classifications, with overall kappa of 0.41. Eighty-six patients (36.7%) were diagnosed with MCI and 131 (56.0%) with DSM-IV-defined dementia. With DSM-V, 40 patients (17.1%) were classified as mild NCDs and 183 (78.2%) as major NCDs, representing a 39.7% increase in frequency of dementia diagnoses. CDR sum-of-boxes score contributed independently to differentiation of MCI patients reclassified as mild versus major NCDs (OR: 0.01; 95% CI: 0-0.09). CDR sum-of-boxes score (OR: 5.18; 95% CI: 2.04-13.15), performance in amnestic (OR: 0.14; 95% CI: 0.06-0.34) and language (Boston naming: OR: 0.52; 95% CI: 0.29-0.94) tests, were independent determinants of diagnostically concordant dementia diagnosis. CONCLUSION: The authors observed moderate agreement between the different operational definitions and a 40% increase in dementia diagnoses with operationalization of the DSM-V criteria.

Improved therapeutic index of an acidic pH-selective antibody.

Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that prevents maximal efficacious clinical outcomes and can lead to discontinuation of treatment. We hypothesized that an acidic pH-selective ipilimumab (pH Ipi), which preferentially and reversibly targets the acidic tumor microenvironment over the neutral periphery, may have a more favorable therapeutic index. While ipilimumab has pH-independent CTLA-4 affinity, pH Ipi variants have been engineered to have up to 50-fold enhanced affinity to CTLA-4 at pH 6.0 compared to pH 7.4. In hCTLA-4 knock-in mice, these variants have maintained anti-tumor activity and reduced peripheral activation, a surrogate marker for toxicity. pH-sensitive therapeutic antibodies may be a differentiating paradigm and a novel modality for enhanced tumor targeting and improved safety profiles.