Feasibility of Dual-Task Gait to Estimate Alzheimer\u27s Related Cognitive Decline in Down Syndrome

Introduction: The striatum and frontal lobes have been shown to have early Alzheimer\u27s disease (AD) neuropathology and are critical for motor and cognitive function. We hypothesized gait would be associated with early-stage dementia in Down syndrome (DS), a cohort at risk for AD. Methods: Twenty-eight participants with DS were enrolled in the study. Participants walked at their self-selected pace and while completing a dual task (counting, obstacle, or counting+obstacle). Results: All participants were able to complete the self-paced condition and 78.57-96.42% completed the dual-task conditions. There was a trend for greater dual-task effects on gait velocity based on dementia diagnosis. Gait velocity had stronger associations with clinical dementia assessments than age or diagnosis. Discussion: A dual-task gait paradigm is feasible to conduct with adults with DS and is associated with age and cognitive impairment. Dual-task gait may serve as an indicator of early stage dementia in DS

Chronic Neuropsychological Sequelae in a Patient with Nontumorous Anti-NMDA-Receptor Encephalitis

Anti-N-methyl-D-aspartate receptor encephalitis is a neurological, autoimmune disorder tightly conceptualized only as recently as the mid-2000s. It presents itself in a combination of psychiatric, neurological, and autonomic features. We observe a unique case with probable earlier episode (prior to the mid-2000s conceptualization of the disease) and a later relapse, accompanying a comprehensive neuropsychological profile tracked after the relapse and subsequent improvement. Neurocognitive findings revealed residual frontal deficits with mood changes even in the state after plasmapheresis. This case is the first to describe posttreatment cognition in anti-NMDAR encephalitis after probable serial autoimmune episodes

Cognitive and Behavioral Domains That Reliably Differentiate Normal Aging and Dementia in Down Syndrome

Primary care integration of Down syndrome (DS)-specific dementia screening is strongly advised. The current study employed principal components analysis (PCA) and classification and regression tree (CART) analyses to identify an abbreviated battery for dementia classification. Scale- and subscale-level scores from 141 participants (no dementia n = 68; probable Alzheimer’s disease n = 73), for the Severe Impairment Battery (SIB), Dementia Scale for People with Learning Disabilities (DLD), and Vineland Adaptive Behavior Scales—Second Edition (Vineland-II) were analyzed. Two principle components (PC1, PC2) were identified with the odds of a probable dementia diagnosis increasing 2.54 times per PC1 unit increase and by 3.73 times per PC2 unit increase. CART analysis identified that the DLD sum of cognitive scores (SCS \u3c 35 raw) and Vineland-II community subdomain (\u3c 36 raw) scores best classified dementia. No significant difference in the PCA versus CART area under the curve (AUC) was noted (D(65.196) = −0.57683; p = 0.57; PCA AUC = 0.87; CART AUC = 0.91). The PCA sensitivity was 80% and specificity was 70%; CART was 100% and specificity was 81%. These results support an abbreviated dementia screening battery to identify at-risk individuals with DS in primary care settings to guide specialized diagnostic referral

Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study

Background Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome. Methods We did a multicentre cohort study, including adults with Down syndrome (>= 18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively;NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses. Findings Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia;ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3.6 years (SD 1.6, range 0.6-9.2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0.83 (95% CI 0.76-0.91) in the prodromal group and 0.94 (0.90-0.97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1.04-fold risk of clinical progression (95% CI 1.01-1.07;p=0.0034). Plasma NfL concentrations showed an annual increase of 3.0% (95% CI 0.4-5.8) per year in the asymptomatic non-progressors group, 11.5% (4.9-18.5) per year in the asymptomatic progressors group, and 16.0% (8.4-24.0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24.3% (15.3-34.1). Interpretation Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials. Copyright (C) 2021 Elsevier Ltd. All rights reserved

Membrane-Bound IL-21 Promotes Sustained Ex Vivo Proliferation of Human Natural Killer Cells

NK cells have therapeutic potential for a wide variety of human malignancies. However, because NK cells expand poorly in vitro, have limited life spans in vivo, and represent a small fraction of peripheral white blood cells, obtaining sufficient cell numbers is the major obstacle for NK-cell immunotherapy. Genetically-engineered artificial antigen-presenting cells (aAPCs) expressing membrane-bound IL-15 (mbIL15) have been used to propagate clinical-grade NK cells for human trials of adoptive immunotherapy, but ex vivo proliferation has been limited by telomere shortening. We developed K562-based aAPCs with membrane-bound IL-21 (mbIL21) and assessed their ability to support human NK-cell proliferation. In contrast to mbIL15, mbIL21-expressing aAPCs promoted log-phase NK cell expansion without evidence of senescence for up to 6 weeks of culture. By day 21, parallel expansion of NK cells from 22 donors demonstrated a mean 47,967-fold expansion (median 31,747) when co-cultured with aAPCs expressing mbIL21 compared to 825-fold expansion (median 325) with mbIL15. Despite the significant increase in proliferation, mbIL21-expanded NK cells also showed a significant increase in telomere length compared to freshly obtained NK cells, suggesting a possible mechanism for their sustained proliferation. NK cells expanded with mbIL21 were similar in phenotype and cytotoxicity to those expanded with mbIL15, with retained donor KIR repertoires and high expression of NCRs, CD16, and NKG2D, but had superior cytokine secretion. The mbIL21-expanded NK cells showed increased transcription of the activating receptor CD160, but otherwise had remarkably similar mRNA expression profiles of the 96 genes assessed. mbIL21-expanded NK cells had significant cytotoxicity against all tumor cell lines tested, retained responsiveness to inhibitory KIR ligands, and demonstrated enhanced killing via antibody-dependent cell cytotoxicity. Thus, aAPCs expressing mbIL21 promote improved proliferation of human NK cells with longer telomeres and less senescence, supporting their clinical use in propagating NK cells for adoptive immunotherapy

Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy

Tumor-derived lactic acid inhibits T and natural killer (NK) cell function and, thereby, tumor immunosurveillance. Here, we report that melanoma patients with high expression of glycolysis-related genes show a worse progression free survival upon anti-PD1 treatment. The non-steroidal anti-inflammatory drug (NSAID) diclofenac lowers lactate secretion of tumor cells and improves anti-PD1-induced T cell killing in vitro. Surprisingly, diclofenac, but not other NSAIDs, turns out to be a potent inhibitor of the lactate transporters monocarboxylate transporter 1 and 4 and diminishes lactate efflux. Notably, T cell activation, viability, and effector functions are preserved under diclofenac treatment and in a low glucose environment in vitro. Diclofenac, but not aspirin, delays tumor growth and improves the efficacy of checkpoint therapy in vivo. Moreover, genetic suppression of glycolysis in tumor cells strongly improves checkpoint therapy. These findings support the rationale for targeting glycolysis in patients with high glycolytic tumors together with checkpoint inhibitors in clinical trials

Neurocognitive effects of Moyamoya disease and concomitant epilepsy

Objective: Moyamoya disease (MMD) is a rare degenerative cerebrovascular disorder that leads to recurrent strokes and cerebral hypoperfusion. Seizures are not uncommon in MMD especially following surgical treatment for the disease. Cognitive changes that are largely executive in nature have been documented following MMD and surgical treatment, although research is limited in adults. Methods: The present case report details the comprehensive neurocognitive evaluation of a patient with MMD and concomitant epilepsy. Results: Neurocognitive findings revealed a prominent dysexecutive pattern and atypically poor performance in areas such as visual and verbal memory. The patient reported significant affective symptoms and functional decline. Conclusions: This case offers insight into unique neurocognitive results that may present in adult MMD cases and underscores the importance of interpreting results in the context of neurological comorbidities in this rare disease

Cognitive and Behavioral Domains That Reliably Differentiate Normal Aging and Dementia in Down Syndrome

Primary care integration of Down syndrome (DS)-specific dementia screening is strongly advised. The current study employed principal components analysis (PCA) and classification and regression tree (CART) analyses to identify an abbreviated battery for dementia classification. Scale- and subscale-level scores from 141 participants (no dementia n = 68; probable Alzheimer’s disease n = 73), for the Severe Impairment Battery (SIB), Dementia Scale for People with Learning Disabilities (DLD), and Vineland Adaptive Behavior Scales—Second Edition (Vineland-II) were analyzed. Two principle components (PC1, PC2) were identified with the odds of a probable dementia diagnosis increasing 2.54 times per PC1 unit increase and by 3.73 times per PC2 unit increase. CART analysis identified that the DLD sum of cognitive scores (SCS < 35 raw) and Vineland-II community subdomain (<36 raw) scores best classified dementia. No significant difference in the PCA versus CART area under the curve (AUC) was noted (D(65.196) = −0.57683; p = 0.57; PCA AUC = 0.87; CART AUC = 0.91). The PCA sensitivity was 80% and specificity was 70%; CART was 100% and specificity was 81%. These results support an abbreviated dementia screening battery to identify at-risk individuals with DS in primary care settings to guide specialized diagnostic referral