Health-Promoting Strategies for the Aging Brain.

As the world's population ages and people live longer, the changes in the aging brain present substantial challenges to our health and society. With greater longevity come age-related diseases, many of which have direct and indirect influences on the health of the brain. Although there is some degree of predictable decline in brain functioning with aging, meaningful cognitive decline is not inevitable and is perhaps preventable. In this review, we present the case that the course of aging-related brain disease and dysfunction can be modified. We present the evidence for conditions and risk factors that may contribute to cognitive decline and dementia and for interventions that may mitigate their impact on cognitive functioning later in life, or even prevent them and their cognitive sequelae from developing. Although much work remains to be done to meet the challenges of the aging brain, strategies to promote its health have been demonstrated and offer much promise, which can only be realized if we mount a vigorous public health effort to implement these strategies.

Polypharmacy in Treatment of Behavioral Issues in Dementia-Use of Atypical Antipsychotics.

Behavioral and psychological symptoms of dementia (BPSD) may occur in most patients with dementia. Symptoms such as agitation, aggression, and psychosis often lead to higher rates of hospitalization, morbidity, and mortality. Despite the prevalence of BPSD, safe and effective treatment options are limited. This often leads to off-label prescribing and trends toward polypharmacy. Notwithstanding modest efficacy in BPSD, antipsychotics seem to be one of the most commonly prescribed medications in its treatment. Polypharmacy with antipsychotics is particularly troublesome due to the increased risk of potentially lethal adverse effects. As such, their use should be judiciously monitored with the goal of gradual dose reduction.

Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade.

PURPOSE: CTL-associated antigen 4 (CTLA4)-blocking monoclonal antibodies induce long-term regression of metastatic melanoma in some patients, but the exact mechanism is unknown. In this study, biopsies of selected accessible tumor lesions from patients treated with tremelimumab were examined to further elucidate the mechanism of its antitumor activity. EXPERIMENTAL DESIGN: Fifteen tumor biopsies from 7 patients who had been treated with tremelimumab (CP-675,206) were collected. Samples were analyzed for melanoma markers, immune cell subset markers, the presence of the T regulatory-specific transcription factor FoxP3 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO). RESULTS: Clinically responding lesions had diffuse intratumoral infiltrates of CD8(+) T cells that were markedly increased in cases where comparison with a baseline biopsy was available. Nonregressing lesions had sparse, patchy CD8(+) intratumoral infiltrates. Patients with regressing lesions had an increased frequency of CD8(+) cells with or without a concomitant increase in CD4(+) cells. Two of 3 responding patients with paired samples showed a slight increase in the number of FoxP3(+) cells in the postdosing biopsies. In patients with regressing lesions who had paired samples, the intensity of IDO staining in macrophages and/or melanoma cells showed no clear pattern of change postdosing. CONCLUSIONS: Administration of tremelimumab was associated with massive intratumoral infiltrates of CD8(+) CTLs in patients with regressing tumors but had varying effects on intratumoral infiltrates of CD4(+) and FoxP3(+) cells or intratumoral expression of IDO.

Brain health consequences of digital technology use
.

Emerging scientific evidence indicates that frequent digital technology use has a significant impact-both negative and positive-on brain function and behavior. Potential harmful effects of extensive screen time and technology use include heightened attention-deficit symptoms, impaired emotional and social intelligence, technology addiction, social isolation, impaired brain development, and disrupted sleep. However, various apps, videogames, and other online tools may benefit brain health. Functional imaging scans show that internet-naive older adults who learn to search online show significant increases in brain neural activity during simulated internet searches. Certain computer programs and videogames may improve memory, multitasking skills, fluid intelligence, and other cognitive abilities. Some apps and digital tools offer mental health interventions providing self-management, monitoring, skills training, and other interventions that may improve mood and behavior. Additional research on the positive and negative brain health effects of technology is needed to elucidate mechanisms and underlying causal relationships.
.

La evidencia científica que está surgiendo muestra que el empleo frecuente de la tecnología digital tiene un impacto significativo, tanto negativo como positivo, en la función cerebral y en el comportamiento. Los posibles efectos nocivos del tiempo prolongado frente a la pantalla y del empleo de la tecnología incluyen síntomas como marcado déficit de atención, deterioro de la inteligencia emocional y social, adicción a la tecnología, aislamiento social, deterioro del desarrollo cerebral y alteraciones del sueño. Sin embargo, hay varias aplicaciones, videojuegos y otras herramientas en línea que pueden beneficiar la salud del cerebro. En las imágenes cerebrales funcionales se ha observado que los adultos mayores vírgenes a internet que aprenden a buscar en línea, muestran aumentos significativos en la actividad neuronal cerebral durante las búsquedas simuladas en internet. Ciertos programas computacionales y videojuegos pueden mejorar la memoria, las destrezas en tareas múltiples, la fluidez de la inteligencia y otras habilidades cognitivas. Hay varias aplicaciones y herramientas digitales que ofrecen intervenciones en salud mental y que proporcionan automanejo, monitoreo, capacitación junto a otras intervenciones que pueden mejorar el estado de ánimo y el comportamiento. Se require de investigación adicional acerca de los efectos positivos y negativos de la tecnología sobre la salud del cerebro para dilucidar los mecanismos y las relaciones causales subyacentes.

D'après de nouvelles données scientifiques, l'usage fréquent des technologies numériques influe significativement sur le comportement et le fonctionnement cérébral, de façon aussi bien négative que positive. Une pratique excessive des écrans et des technologies numériques peut avoir des effets néfastes comme des symptômes de déficit d'attention, une intelligence émotionnelle et sociale altérée, une dépendance à la technologie, un isolement social, un développement cérébral dégradé et des troubles du sommeil. Cependant, certaines applications, jeux vidéo et autres outils en ligne peuvent avoir des effets bénéfiques sur le cerveau. L'imagerie fonctionnelle montre une activité neuronale significativement augmentée chez des personnes âgées jamais exposées à Internet et qui apprennent à faire des recherches en ligne. Certains programmes informatiques et jeux vidéo peuvent améliorer la mémoire, les compétences multitâches, l'agilité de l'intelligence et d'autres capacités cognitives. Dans le domaine de la santé mentale, différents outils et applications numériques permettant l'autogestion, le suivi, l'acquisition de compétences et d'autres techniques sont susceptibles d'améliorer l'humeur et le comportement du patient. Les effets positifs et négatifs de la technologie sur la santé cérébrale nécessitent d'être encore étudiés afin d'en mieux comprendre les mécanismes et les relations de cause à effet.

CTLA4 blockade increases Th17 cells in patients with metastatic melanoma.

BACKGROUND: Th17 cells are CD4+ cells that produce interleukin 17 (IL-17) and are potent inducers of tissue inflammation and autoimmunity. We studied the levels of this T cell subset in peripheral blood of patients treated with the anti-CTLA4 antibody tremelimumab since its major dose limiting toxicities are inflammatory and autoimmune in nature. METHODS: Peripheral blood mononuclear cells (PBMC) were collected before and after receiving tremelimumab within two clinical trials, one with tremelimumab alone (21 patients) and another together with autologous dendritic cells (DC) pulsed with the melanoma epitope MART-126-35 (6 patients). Cytokines were quantified directly in plasma from patients and after in vitro stimulation of PBMC. We also quantified IL-17 cytokine-producing cells by intracellular cytokine staining (ICS). RESULTS: There were no significant changes in 13 assayed cytokines, including IL-17, when analyzing plasma samples obtained from patients before and after administration of tremelimumab. However, when PBMC were activated in vitro, IL-17 cytokine in cell culture supernatant and Th17 cells, detected as IL-17-producing CD4 cells by ICS, significantly increased in post-dosing samples. There were no differences in the levels of Th17 cells between patients with or without an objective tumor response, but samples from patients with inflammatory and autoimmune toxicities during the first cycle of therapy had a significant increase in Th17 cells. CONCLUSION: The anti-CTLA4 blocking antibody tremelimumab increases Th17 cells in peripheral blood of patients with metastatic melanoma. The relation between increases in Th17 cells and severe autoimmune toxicity after CTLA4 blockade may provide insights into the pathogenesis of anti-CTLA4-induced toxicities.

Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma.

BACKGROUND: CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated. METHODS: Peripheral blood from HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab (formerly CP-675,206) at 10 mg/kg monthly was repeatedly sampled during the first 4 cycles. Samples were analyzed by 1) tetramer and ELISPOT assays for reactivity to CMV, EBV, MART1, gp100, and tyrosinase; 2) activation HLA-DR and memory CD45RO markers on CD4+/CD8+ cells; and 3) real-time quantitative PCR of mRNA for FoxP3 transcription factor, preferentially expressed by T regulatory cells. The primary endpoint was difference in MART1-specific T cells by tetramer assay. Immunological data were explored for significant trends using clustering analysis. RESULTS: Three of 12 patients eligible for immune monitoring had tumor regression lasting > 2 years without relapse. There was no significant change in percent of MART1-specific T cells by tetramer assay. Additionally, there was no generalized trend toward postdosing changes in other antigen-specific CD8+ cell populations, FoxP3 transcripts, or overall changes in surface expression of T-cell activation or memory markers. Unsupervised hierarchical clustering based on immune monitoring data segregated patients randomly. However, clustering according to T-cell activation or memory markers separated patients with clinical response and most patients with inflammatory toxicity into a common subgroup. CONCLUSION: Administration of CTLA4-blocking antibody tremelimumab to patients with advanced melanoma results in a subset of patients with long-lived tumor responses. T-cell activation and memory markers served as the only readout of the pharmacodynamic effects of this antibody in peripheral blood. CLINICAL TRIAL REGISTRATION NUMBER: NCT00086489.

Natural killer T cells in advanced melanoma patients treated with tremelimumab.

A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro-apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT) can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-126-35 peptide-pulsed dendritic cells (MART-1/DC). Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8(+) cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity.

CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans.

BACKGROUND: CTLA4 blocking monoclonal antibodies provide durable clinical benefit in a subset of patients with advanced melanoma mediated by intratumoral lymphocytic infiltrates. A key question is defining whether the intratumoral infiltration (ITI) is a differentiating factor between patients with and without tumor responses. METHODS: Paired baseline and postdosing tumor biopsy specimens were prospectively collected from 19 patients with metastatic melanoma, including 3 patients with an objective tumor response, receiving the anti-CTLA4 antibody tremelimumab within a clinical trial with primary endpoint of quantitating CD8(+) cytotoxic T-lymphocyte (CTL) infiltration in tumors. Samples were analyzed for cell density by automated imaging capture and further characterized for functional lymphocyte properties by assessing the cell activation markers HLA-DR and CD45RO, the cell proliferation marker Ki67, and the regulatory T-cell marker FOXP3. RESULTS: There was a highly significant increase in ITI by CD8(+) cells in biopsy samples taken after tremelimumab treatment. This included increases between 1-fold and 100-fold changes in 14 of 18 evaluable cases regardless of clinical tumor response or progression. There was no difference between the absolute number, location, or cell density of infiltrating cells between clinical responders and patients with nonresponding lesions that showed acquired intratumoral infiltrates. There were similar levels of expression of T-cell activation markers (CD45RO, HLA-DR) in both groups and no difference in markers for cell replication (Ki67) or the suppressor cell marker FOXP3. CONCLUSION: CTLA4 blockade induces frequent increases in ITI by T cells despite which only a minority of patients have objective tumor responses.

The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations.

PURPOSE: PLX4032 (RG7204), an oncogenic BRAF kinase inhibitor undergoing clinical evaluation, has high response rates in early clinical trials in patients with advanced BRAF(V600E) mutant melanoma. Combining PLX4032 with immunotherapy may allow expanding the durability of responses. The effects of PLX4032 on immune cells were studied to explore the feasibility of future combinatorial approaches with immunotherapy for melanoma. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells (PBMC) and BRAF(V600E) mutant melanoma cells were exposed to increasing concentrations of PLX4032 and the cell viability, proliferation, cell cycle, apoptosis, and phosphorylation of signaling proteins were analyzed. Effects of PLX4032 on antigen-specific T-cell function were analyzed by specific cytokine release and cytotoxicity activity. RESULTS: The 50% inhibition concentration (IC(50)) of PLX4032 for resting human PBMC was between 50 and 150 µmol/L compared with an IC(50) below 1 µmol/L for sensitive BRAF(V600E) mutant melanoma cell lines. Activated lymphocytes were even more resistant with no growth inhibition up to concentrations of 250 µmol/L. PLX4032 had a marginal effect on cell-cycle arrest, apoptotic cell changes or alteration of phosphorylated signaling molecules in lymphocytes. Functional analysis of specific antigen recognition showed preserved T-cell function up to 10-µmol/L concentration of PLX4032, whereas the cytotoxic activity of PLX4032 was maintained up to high concentrations of 50 µmol/L. CONCLUSIONS: The preserved viability and function of lymphocytes exposed to high concentrations of PLX4032 suggest that this agent could be a potential candidate for combining with immunotherapy strategies for the treatment of patients with BRAF(V600)(E) mutant melanoma.

Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma.

BACKGROUND: The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4) using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC) samples from patients with metastatic melanoma. METHODOLOGY/PRINCIPAL: Findings Intracellular flow cytometry was used to detect phosphorylated (p) signaling molecules downstream of the T cell receptor (TCR) and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response. CONCLUSIONS/SIGNIFICANCE: The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; Registration numbers NCT00090896 and NCT00471887.

Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma.

PURPOSE: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. EXPERIMENTAL DESIGN: Autologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. RESULTS: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. CONCLUSION: The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.