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[Alzheimer disease: what is the status today?].
In populations with high life expectancy, about 7% of persons aged 65 and over suffer from Alzheimer's Disease. Diagnosis is based on the demonstration of dementia, characteristic clinical, neuropsychological, and neuro-imaging findings allowing the exclusion of other etiologies. Alzheimer's Disease may be caused by a number of genetic etiologies. Mutation of the preseniline genes or the APP gene are rare and lead to early onset of the disease. Late onset of Alzheimer's Disease is mostly polygenetic or of multifactorial origin. Genetic and exogenous factors interact in the manifestation of the disease. Of importance is apolipoprotein E; carriers of the allele apo E4 run a markedly increased risk of developing Alzheimer's Disease. The biochemical hallmark of Alzheimer's Disease is the marked reduction of the cholinergic innervation of the CNS; thus, cholinergic substitution allows today for the first time a therapy of the disease based on pathophysiological findings. The specificity of therapy and the necessity of an early intervention require a two-step diagnostic procedure; i) By appropriate screening procedures, the primary care physician detects already mild dementias. ii) Persons with dementia are referred to specialists (neurology, psychogeriatrics, geriatrics or memory clinic) for differential diagnostic work-up. The diagnosis of "probable Alzheimer's Disease" is the indication for specific pharmacotherapy. The holistic therapeutic approach to patients with Alzheimer's Disease includes not only a drug treatment, but also psychotherapy (milieu therapy) and counselling of the caregivers. The interdisciplinary collaboration between primary care physicians, specialists and institutions for care of patients with dementia is a prerequisite for optimal therapeutic success. The aim is the preservation of quality of life, and to maintain patients as long as possible in their personal environment.
Expression of Fas(APO-1/CD95) in tumor-infiltrating and peripheral blood lymphocytes in patients with renal cell carcinoma.
The functional expression of Fas-ligand on tumor cells reported in a variety of neoplasms has been proposed by several groups as a mechanism of tumor escape from immunological detection. To better support this hypothesis, we have evaluated and quantified for the first time the presence of the Fas(CD95)-R molecule on tumor-infiltrating lymphocytes and on matched peripheral blood lymphocytes (PBLs) of renal cell cancer patients. By two-color flow cytometry we have detected a significant increase in the Fas(CD95)-R expression on tumor-infiltrating lymphocytes compared with matched patient and normal volunteer PBLs. We also observed a decreased expression of the Fas(CD95)-R expression on PBLs from renal cell cancer patients compared with normal healthy controls. The Fas(CD95)-R expression was observed predominantly on the CD4+ subset in all three groups. These different distributions of the Fas(CD95)-R molecule support the hypothesis that the Fas(CD95)-R/Fas(CD95)-L pathway and tumor microenvironment play a major role in the modulation of T-cell function and differentiation to either memory and activation or apoptosis.
Antigen density presented by dendritic cells in vivo differentially affects the number and avidity of primary, memory, and recall CD8+ T cells.
We studied the size and avidity of primary and recall CD8(+) T cell responses in vivo in mice immunized with dendritic cells presenting different densities of a MHC class I-restricted peptide. Increasing the epitope density on a fixed number of dendritic cells increased the size of the primary response, yet had no influence on the avidity of the effector cells. However, epitope density-based selection of cells with different avidities was evident in the subsequent memory population, and in recall responses. Additionally, mice primed with different peptide densities had similarly sized quiescent memory and recall responses. Our findings provide evidence for an important role for epitope density in the selection of T cells in vivo.
Dynamic differentiation of activated human peripheral blood CD8+ and CD4+ effector memory T cells.
Two functionally different memory T cell subsets were originally defined based on their different CCR7 expression profile, but the lineage relationship between these subsets referred to as central memory T cells (T(CM)) and effector memory T cells (T(EM)), is not resolved. A prevalent model proposes a linear progressive differentiation from T(CM) to T(EM). Our results demonstrate that on activation, human CCR7-CD62L- peripheral blood CD8+ and CD4+ T(EM) cells exhibit a dynamic differentiation, involving transient as well as stable changes to T(CM) phenotype and properties. Whereas the larger fraction of T(EM) cells increases expression of effector molecules, such as perforin or IFN-gamma, a smaller fraction first acquires CCR7 expression. We demonstrate that this acquisition of lymph node homing potential is associated with strong proliferation similar to that of activated T(CM) cells. After proliferation, most of these cells lose CCR7 expression again and acquire effector functions (e.g., perforin production). A small proportion (approximately 6%), however, maintain phenotypic and functional T(CM) properties over a long time interval. These results suggest that T(EM) cells provide immediate effector function by a fraction of cells as well as self-renewal by others through up-regulation of CCR7 followed by either secondary peripheral effector function or long term maintenance of T(CM)-like properties.
Differential expression of human granzymes A, B, and K in natural killer cells and during CD8+ T cell differentiation in peripheral blood.
NK cells and cytotoxic T lymphocytes can induce apoptosis in virus-infected and transformed target cells via the granule exocytosis pathway. The key components of the cytolytic granules are perforin and several serine esterases, termed granzymes. While the cellular distribution of human granzymes A (GrA) and B (GrB) has been well characterized much less is known about the expression pattern of human granzyme K (GrK). In this study GrA, GrB, and GrK expression was analyzed in human peripheral blood lymphocytes using flow cytometry. There was a distinct population of GrK expressing CD8+ T cells with a CD27+/CD28+/CCR5high/CCR7-/perforin-/low/IFN-gamma+ memory-like phenotype, while all CD56bright NK cells were also positive for GrK. In addition, GrK was also expressed in subpopulations of CD56+ T cells, CD4+ T cells, and TCRgammadelta+ T cells. In contrast, GrB was primarily expressed in CD56dim NK cells and differentiated memory CD8+ T cells with the CD27-/low/CD28-/low/CCR5-/low/CCR7-/CD11b+/perforinhigh phenotype. Only few CD8+ T cells expressed both GrB and GrK. GrA was found to be co-expressed in all GrB- and GrK-expressing T cells. Our findings suggest that granzyme expression during the differentiation process of memory CD8+ T cells might be as follows: GrA+/GrB-/GrK+ --> GrA+/GrB+/GrK+ --> GrA+/GrB+/GrK-.
Memory for sequences of stimuli and responses.
Two experiments sought to determine if pigeons could discriminate and remember recent sequences of stimuli and responses. A variant of Konorski's short-term memory procedure involving successive presentation of sample and test stimuli was used. The samples were stimulus-response pairs of the form, (S-R)(1)-(S-R)(2). Differential test responding disclosed memory of the two-item samples, with birds showing earlier and greater control by the second item than the first (Experiment 1). When the retention interval separating the second item of the sample sequence from the test stimulus was lenghtened from .5 to 2.0 or 4.0 sec, a systematic loss of stimulus control resulted; however, when varied over the same temporal range, the interval between the two items of the sample sequence had a much smaller effect, or none at all (Experiment 2). These results support an account of response-sequence differentiation that stresses short-term memory of organized behavior patterns.
Molecular characterization of single memory B cells.
Primary antigenic exposure results in an initial antibody response and the T cell-dependent induction of B-cell memory. Memory B-cell differentiation is characterized by somatic hypermutation in antibody variable region genes (V) and selection of B cells expressing high-affinity variants of this antigen receptor. Despite our current understanding of B-cell memory, the origin of memory B cells and the regulation of their differentiation remain elusive. This is largely due to the difficulties in observing and purifying this minor component of the immunized spleen. Further, molecular characterization of memory B cells requires hybridoma formation which restricts analyses to only those clones capable of fusion and does not allow isolation of cells in a normal physiological state. We have therefore developed a unique system which allows isolation and unambiguous enumeration of IgG1+ memory B cells, based on six-parameter flow cytometry, secretion of antibody in clonal cultures and analysis of clonally expressed V genes using the polymerase chain reaction. Here we report that single IgG1+ antigen-binding B cells from an early secondary immune response proliferate in lipopolysaccharide-driven microcultures and produce antigen-specific IgG1 antibodies. Individual B-cell clones in these cultures express somatically mutated heavy chain V genes, confirming their designation as memory B cells. Although isolated memory B cells undergo extensive proliferation in vitro, V gene sequence analysis of their individual progeny shows that further hypermutation does not occur.
Differential effects of emotional arousal in short- and long-term memory in healthy adults.
Recent studies demonstrated important differences between short- and long-term memory mechanisms. Besides, the emotional component has a crucial role in memory formation. This study was carried out to answer whether there is a differential influence of emotional arousal in short- and long-term memory in healthy adults. Thirty-one healthy volunteers were divided into two major groups. In the first group long-term memory (LTM) was evaluated, with the testing session one week after training. The second group was tested 1h after training, where short-term memory (STM) was evaluated. Each group was divided in to two subgroups. One half of the volunteers was exposed to an emotionally neutral story, and the other half of each group was exposed to a closely matched but more emotionally arousing story. The testing session consisted of a questionary containing 80 questions of multiple choices. The results were evaluated through percentage of correct answers. Results showed that correct answers were increased, in LTM measures, in the subjects that were given the emotional version of the test. In STM measures, no differences were found between the emotional and neutral version. However, the presentation of emotional story caused an emotional reaction in both groups. The lack of effect of emotional arousal in STM suggests that amygdala is not related to STM mechanisms. Further studies using different approaches are needed to elucidate if STM processes are influenced by emotional arousal.
The ERP old-new effect: A useful indicator in studying the effects of sleep on memory retrieval processes.
STUDY OBJECTIVES: To verify that the classic "Old/New" memory effect can be detected after a long delay, and to investigate the differential influence of declarative memory processes after normal sleep and daytime wake. DESIGN: The protocol is a variation of a more traditional study-recognition test used in event-related potential (ERP) studies in which sleep or wake is inserted between the learning and recognition session in order to verify the existence of the Old/New effect (ie, positive shift that occurs when stimuli are repeated). ERPs were recorded during the recognition-test session. The protocol was based on early work that compared the effect of sleep on memory without recording sleep. SETTING: Data collection occurred in the outpatient sleep laboratory. PATIENTS OR PARTICIPANTS: Results from 13 subjects (6 men) aged between 21 and 39 years. MEASUREMENTS AND RESULTS: The subjects performed the recognition memory test after sleep and daytime wake periods. More-accurate performance for the old (studied) stimuli occurred after the sleep session. Analysis of variance on correctly answered reaction times revealed a significant effect of condition (old/new) with no difference across session. A repeated-measure analysis revealed differences in "Old/New" effect, whereby the amplitude difference between the old and new items was larger after sleep than after wake. CONCLUSIONS: This effect of sleep was found in early frontal and later posterior ERP components, processes that represent strategic, contextual processing and facilitation of episodic memory. Memory representation was not different across sessions. These findings suggest that sleep and wake facilitate 2 components of memory unequally, ie, episodic recognition and memory representation functioning.
[Selective use of the Eight-Word subtest in psychogeriatrics].
Performance on the Amsterdam Dementia Screening Test (ADS) and the Expanded Mental Control Test (EMCT) was examined in a consecutive sample of 204 attendants of a psychogeriatric day care department. The ADS has six subtests: picture recognition, orientation, drawing alternating sequences, category fluency, copying geometric figures, and free recall with immediate yes-no recognition of eight words. As was determined by logistic regression analysis, attentional control (EMCT), category fluency and picture recognition scores were significant predictors of verbal free recall. Recognition memory for pictures and a short orientation questionnaire (month, year, place) predicted word recognition performance. In 97% of the subjects with poor scores on EMCT and category fluency, an equally poor free recall performance was found. In those cases the incremental diagnostic value of the free recall test is doubtful. Since word recall and word recognition were conceptually related to working memory and episodic memory respectively, the two components of the verbal learning test allow detection of differential impairments of these memory systems.
IL-7R alpha versus CCR7 and CD45 as markers of virus-specific CD8+ T cell differentiation: contrasting pictures in blood and tonsillar lymphoid tissue.
In humans, circulating CD8(+) memory T cells to a nonpersistent virus (influenza) lie within CCR7(+)CD45RA(-) central memory, whereas memory to Epstein-Barr virus (EBV) latent, EBV lytic, and cytomegalovirus (CMV) antigens are progressively larger in size and are more biased toward CCR7(-)CD45RA(-) effector memory and CCR7(-)CD45RA(+) terminally differentiated compartments. We found that these populations are also distinguished by progressively lower expression of the interleukin-7 receptor (IL-7R alpha) and by lower IL-7 responsiveness; indeed, percentage IL-7R alpha -positive values showed a tight inverse correlation with population size. However, these relationships among size, differentiation phenotype, and IL-7R alpha status in blood did not hold in tonsillar tissue. In tonsil tissue, although EBV reactivities outnumbered their CMV and influenza counterparts, the distinct CCR7/CD45 isoform signatures of the different virus-specific populations were retained. Moreover, all detectable reactivities showed high levels of IL-7R alpha expression. As a discriminator between different virus-specific populations, IL-7R alpha therefore appears to be more susceptible to tissue location than the classical CCR7/CD45 markers.
Human CD4+ T cell differentiation and effector function: implications for autoimmunity.
Human CD4+ memory T cells progress through stages of postthymic differentiation that have been characterized by distinct phenotypes. We have investigated the factors regulating cytokine production, and the correlation between phenotype and effector function in normal and autoimmune individuals. These studies suggest that antigen-induced proliferation in the periphery drives CD4+ T cells through successive stages of differentiation that culminate in optimal effector function and resistance to external modulatory influences. Moreover, these studies support the concept that in autoimmune individuals, the chronic accumulation of differentiated proinflammatory T cells perpetuate the inflammatory response resulting in aggressive disease.
Flt3 ligand-generated murine plasmacytoid and conventional dendritic cells differ in their capacity to prime naive CD8 T cells and to generate memory cells in vivo.
Mature dendritic cells (DCs) have the capacity to induce efficient primary T cell response and effector cell differentiation. Thus, these cells are a major tool in the design of various immunotherapeutic protocols. We have tested the capacity of different subsets of matured DCs pulsed with a peptide to induce the differentiation of naive CD8 T cells into memory cells in vivo. Flt3 ligand (FL) induces the differentiation of conventional DCs (cDCs) and plasmacytoid DCs (PDCs) from murine bone marrow precursors in vitro. After maturation, both subsets become strong stimulators of Ag-specific T cell responses in vitro. However, the in vivo T cell stimulatory capacity of these DC subsets has not been studied in detail. In the present study, we demonstrate that mature FL-generated DCs induce efficient peptide-specific CD8 T cell response and memory cell differentiation in vivo. This is mainly due to the cDC subset because the PDC subset induced only a negligible primary CD8 response without detectable levels of memory CD8 T cell differentiation. Thus, in vitro FL-generated mature cDCs, but not PDCs, are potent stimulators of peptide-specific CD8 T cell responses and memory generation in vivo.
The role of motives in the content and structure of autobiographical memory.
Findings from 4 studies suggest that differentiation and integration are used by individuals high in agency and communion to structure motive-related information in episodic memory. Studies 1 and 2 demonstrated that agentic and communal individuals recalled more emotional experiences related to their motives, and that agentic individuals used more differentiation whereas communal individuals used more integration to structure these memories. Study 3 showed that agentic and communal individuals used more differentiation and integration to structure memories about social separation and connection, respectively. Study 4 demonstrated a similar pattern of recall in an experimentally controlled retrieval task. For a motive-congruent topic, agentic individuals recognized more differentiated information and had fewer differentiation recognition errors, and communal individuals freely recalled more integration.
Regulation of T-cell apoptosis by reactive oxygen species.
To ensure that a constant number of T cells are preserved in the peripheral lymphoid organs, the production and proliferation of T cells must be balanced out by their death. Newly generated T cells exit the thymus and are maintained as resting T cells. Transient disruption of homeostasis occurs when naïve T cells undergo antigen-induced expansion, a process involving intracellular signaling events that lead to T cell proliferation, acquisition of effector functions, and, ultimately, either apoptosis or differentiation into long-lived memory cells. The last decision point (death vs. differentiation) is a crucial one: it resets lymphoid homeostasis, promotes protective immunity, and limits autoimmunity. Despite its importance, relatively little is known about the molecular mechanisms involved in this cell fate decision. Although multiple mechanisms are likely involved, recent data suggest an underlying regulatory role for reactive oxygen species in controlling the susceptibility of T cells to apoptosis. This review focuses on recent advances in our understanding of how reactive oxygen species modulate T-cell apoptosis.
Toward an understanding of age-related memory and visual search effects.
Young and old Ss were tested in 3 experiments conducted to explore factors leading to age-related performance differences in consistent mapping (CM) and varied mapping (VM) search tasks. The separate and combined influences of memory scanning and visual search on age-related search effects were examined. In both CM letter and CM semantic category search, age interacted with comparison load in visual and hybrid memory-visual search conditions, whereas differential age effects were not present in pure memory search. For VM search, age effects were present only in pure memory search. These data support the view that the separation of type of search training (CM and VM) as well as memory and visual search components is critical for predicting age-related performance differences. The dissociation of the pattern of age effects in memory and visual search suggests that memory and visual search involve different processing mechanisms.
Relative significance of different pathways of immune reconstitution in HIV type 1 infection as estimated by mathematical modeling.
A major goal of antiretroviral HIV-1 therapy is the reversal of HIV-1-associated immunological dysfunction. However, the pathogenetic mechanisms involved and their significance are largely unknown. On the basis of the life cycle of naive, activated, and memory CD4(+) T cell subsets, a mathematical model of immune reconstitution was developed and applied to data for T cell subsets in individuals with acute or chronic HIV-1 infection receiving antiretroviral therapy. The final model that most accurately fitted the data, and resulted in realistic estimates for CD4(+) T cell turnover, considered three pathways of immune reconstitution for naive cells, including thymic production, peripheral expansion, and redistribution of naive cells from lymphoid tissue. The reconstitution of the memory compartment was fitted through differentiation and expansion of naive cells and peripheral expansion of memory cells as well as redistribution of memory cells trapped in the lymphoid tissue. Estimated median half-lives for naive and memory CD4(+) T cells were 114 and 21 days, while total production rates were 9.1 x 10(7) and 2.4 x 10(9) cells/day, respectively. Peripheral expansion and thymic production contributed equally to the regeneration of naive cells, but peripheral expansion of memory cells was larger than production of these cells by differentiation of naive cells. A comparison of immune reconstitution in acute and chronic HIV-1 infection revealed that, after adjustment for age, the main difference was the more rapid release of a larger number of naive cells in treated acute HIV-1 infection. Thymic function and peripheral expansion rates, however, were similar in both cohorts.