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PubMed1998

Assessment of memory in multiple sclerosis patients using the Memory Assessment Scale.

Previous assessment of memory function in multiple sclerosis patients has yielded mixed findings regarding the type and severity of memory deficits, which may be due to (1) differential selection of scales for memory assessment; (2) limited, inconsistent or weak reliability and validity data for the memory scales employed; (3) poor standardization techniques; (4) lack of theoretical foundation for the measure; and (5) limited control of confounding variables, e.g., education, age and the use of nonverbal memory tests. The purpose of the present study was to assess memory function in multiple sclerosis subjects using the verbal subtests of the Memory Assessment Scale, a relatively new measure designed to overcome many of the aforementioned problems. Participants included 57 patients diagnosed as relapsing-remitting, 47 diagnosed as chronic progressive (two generally recognized types of multiple sclerosis), and 132 control participants. A multivariate analysis controlling for age and verbal IQ was significant (Wilks = 5.64, p < .001). One way follow-up tests showed both groups with multiple sclerosis had significantly diminished performance across all memory variables when compared with controls, with the exception of List Clustering Acquisition. This indicated that the patients used clustering (mentally grouping similar words together) as often as controls did. These findings provide support for the presence of significant and consistent verbal memory impairment in multiple sclerosis patients and the particular importance of using psychometrically sound measures in the assessment of this population.

Adolescent↗
PubMed2000

Expression of cutaneous lymphocyte-associated antigen regulated by a set of glycosyltransferases in human T cells: involvement of alpha1, 3-fucosyltransferase VII and beta1,4-galactosyltransferase I.

Cutaneous lymphocyte-associated antigen (CLA), which plays a key part in skin homing of human CD4+ memory T cells via CLA/E-selectin binding, is upregulated by IL-12 and downregulated by IL-4. Although alpha1,3-fucosyltransferase VII is essential for synthesis of the CLA carbohydrate epitope, little is known about how the CLA expression is regulated by a number of glycosyltransferases. A 6 wk long-term culture for the in vitro differentiation of naïve Th cells to memory Th1 cells was employed. By repeated activation in the presence of IL-12, naïve T cells differentiated into memory Th1 cells, resulting in the upregulation of CLA expression. The switching of cytokine from IL-12 to IL-4 at three cycles resulted in a marked downregulation of CLA. The transcript levels of 16 glycosyltransferases and P-selectin glycoprotein ligand-1, all considered to be potentially involved in CLA synthesis, were determined after each cycle. The level of CLA expression was well correlated with the amounts of alpha1,3-fucosyltransferase VII and beta1,4-galactosyltransferase I. Both were upregulated by IL-12 and downregulated by IL-4. In particular, alpha1,3-fucosyltransferase VII levels decreased markedly in the presence of IL-4. P-selectin glycoprotein ligand-1 and Core 2 beta1, 6-N-acetylglucosaminyltransferase were progressively up-regulated by repeated IL-12 stimulation, but they were not downregulated by IL-4. The transcript levels of some genes examined were constitutive without any correlation to CLA expression. These results suggest that the level of CLA expression is determined by alpha1, 3-fucosyltransferase VII and beta1,4-galactosyltransferase I, the other enzymes merely participating in the synthesis of CLA. In peripheral blood mononuclear cells, IL-12 and IL-4 profoundly upregulated and downregulated the alpha1,3-fucosyltransferase VII transcripts, respectively, but not the beta1,4-galactosyltransferase I ones, within only 2 h of in vitro culture. This suggested that alpha1,3-fucosyltransferase VII is transcriptionally regulated directly by IL-12 and IL-4.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2006

Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T cells.

DNA methylation is an epigenetic mechanism of gene regulation. We have determined that specific modifications in DNA methylation at the IFN-gamma locus occur during memory CD8 T cell differentiation in vivo. Expression of the antiviral cytokine IFN-gamma in CD8 T cells is highly developmental stage specific. Most naive cells must divide before they express IFN-gamma, while memory cells vigorously express IFN-gamma before cell division. Ag-specific CD8 T cells were obtained during viral infection of mice and examined directly ex vivo. Naive cells had an IFN-gamma locus with extensive methylation at three specific CpG sites. An inhibitor of methylation increased the amount of IFN-gamma in naive cells, indicating that methylation contributes to the slow and meager production of IFN-gamma. Effectors were unmethylated and produced large amounts of IFN-gamma. Interestingly, while memory cells were also able to produce large amounts of IFN-gamma, the gene was partially methylated at the three CpG sites. Within 5 h of antigenic stimulation, however, the gene was rapidly demethylated in memory cells. This was independent of DNA synthesis and cell division, suggesting a yet unidentified demethylase. Rapid demethylation of the IFN-gamma promoter by an enzymatic factor only in memory cells would be a novel mechanism of differential gene regulation. This differentiation stage-specific mechanism reflects a basic immunologic principle: naive cells need to expand before becoming an effective defense factor, whereas memory cells with already increased precursor frequency can rapidly mount effector functions to eliminate reinfecting pathogens in a strictly Ag-dependent fashion.

Animals↗
PubMed1989

Enhanced responsiveness of human memory T cells to CD2 and CD3 receptor-mediated activation.

Previous investigations have defined phenotypic differences between unprimed (naive) and antigen-primed (memory) T cells from human peripheral blood. We now report that memory T cells proliferate much more than naive cells when stimulated with anti-CD3 monoclonal antibody or pairs of anti-CD2 monoclonal antibodies. Enhanced responsiveness to receptor-mediated triggering is a novel mechanism for T cells which could facilitate memory cell response to specific antigen. Furthermore, when triggered via either CD2 or CD3, memory T cells produce substantial amounts of interferon gamma while naive cells produce virtually none; this suggests that differentiation from naive to memory state is accompanied by a stable change in regulation of the gene for interferon-gamma. We conclude that naive and memory T cells are dramatically different in function as well as phenotype.

Antibodies, Monoclonal↗
PubMed1994

Distinct pathways of B cell differentiation. I. Residual T cells in athymic mice support the development of splenic germinal centers and B cell memory without an induction of antibody.

B cell memory to T cell-dependent Ags develops in the germinal centers (GC). Here we report that thymus-deficient, nu/nu mice immunized with phosphorylcholine coupled to keyhole limpet hemocyanin (EPC-KLH) develop GC in the spleen in the absence of Ab-forming cell (AFC) response. However, the formation of GC on EPC-KLH immunization requires T cells, because 1) CB.1.7-scid mice reconstituted with B lymphocytes failed to develop GC without a supplement of CD4+ cells and 2) in vivo administration of an anti-CD4 mAb abolished the GC response in euthymic mice. Thus, it appears that the formation of GC in nu/nu mice was due to a low number of T cells that were detectable in situ within the splenic lymphoid follicles. The numbers of GC in individual Ag-stimulated nu/nu mice appeared to correlate with the density of T cells in the splenic sections. The B cells in these GC expressed T15, the dominant Id of anti-PC Ab, and became primed for an anamnestic response. Secondary challenge with EPC-KLH resulted in an increased number of GC without detectable AFC. However, when the Ag-primed nu/nu mice received CD4+ lymphocytes 1 day before the challenge, they demonstrated a vigorous AFC response that was predominantly IgM and significantly higher than the secondary response of nu/nu mice that had been reconstituted with CD4+ cells during both primary and secondary immunizations. Therefore, it appears that immunization of nu/nu mice may lead to an early step of B cell activation and memory development even though the T lymphocytes in these mice are incompetent to provide help for Ab formation. The memory and Ab pathways of B cell differentiation may involve different mechanisms of T cell help.

Animals↗
PubMed2006

Differential activation of ventrolateral prefrontal cortex during working memory retrieval.

Brain imaging studies have suggested a predominant involvement of prefrontal areas during retrieval of information from working memory (WM). This study used event-related functional magnetic resonance imaging to assess the gradual recruitment of brain areas during verbal WM-retrieval with a parametrically varied modified version of the Sternberg Item Recognition Paradigm. In particular, we were interested in activation differences during retrieval of negative and positive probes. Fifteen subjects performed a WM-task which required the retrieval of a probe letter from a set of a maximum of three letters. The analysis of the retrieval period regardless of probe type revealed bilateral VLPFC activation during retrieval from a single remembered item. These initially activated regions showed a gradual activation increase of left VLPFC (BA 47) and anterior PFC (BA 10) as well as and bilateral DLPFC (BA 9) with increasing retrieval demand, i.e. during retrieval of two and three previously remembered letters. The comparison of negative and positive probes (non-targets versus targets) revealed greater activity in VLPFC (BA 47) in response to negative than to positive probes. These findings demonstrate that ventral areas of prefrontal cortex seem to be differentially engaged during the discrimination of a non-target from a previously manipulated set.

Adult↗
PubMed2001

[Verbal memory disorders provoked by a variety of stokes].

In recent years a consensus has been reached about the neuroanatomical substrate of verbal memory, but this state of knowledge has not yet been implemented in clinical practice. One reason for this may be that most of the neuroscientific studies on verbal memory used different neuropsychological instruments and that only a small set of patient groups with the same etiology but different lesion sites were analysed. Returning to three earlier studies, we analyse the possibility to make differential judgements on the verbal memory impairments of four different patient groups by using the California Verbal Learning Test (CVLT). We compare patients with left-sided (n = 16) and right-sided (n = 10) posterior cerebral artery infarcts and patients with infarcts of the left (n = 10) or right (n = 21) frontal lobe, and we integrated data about their retention errors that had not been analysed so far. Our findings reveal significant differences between these patient groups, concerning the quantitative aspects of impairments, and also the profiles of memory errors (recall, interference and perseverations). Our study documents a relation between the site of the lesion and the type of verbal memory impairment, agreeing with some of the most recent neuroscientific findings. Starting from this observation we try to define a neuropsychological pattern of memory impairment which enables differential clinical diagnoses using the CVLT as a memory test.

Female↗
PubMed1996

Shuttle-box memory facilitation by posttraining intracranial self-stimulation: differential effects in rats with high and low basic conditioning levels.

The effects of intracranial self-stimulation (ICSS) on retention (after 24 hr, 7, 15, or 60 days) of a massed 2-way active avoidance task were studied in independent groups of rats. All groups showed a higher performance on the retention session than on the acquisition one. In the control subjects, the higher retention performances were observed in the 7- and 15-day groups. However, the ICSS treatment facilitated the 24-hr retention compared with its control group, allowing the treated subjects to achieve the same level of performance on the 24-hr retention session than that achieved by the control rats at the 7-day retention test. In the 24-hr groups, the facilitatory ICSS effect was stronger in the subjects with a low level of conditioning and weaker in those with a high level. Results suggest that posttraining ICSS accelerates memory consolidation and equalizes the performance of poor and good learners.

Animals↗
PubMed2005

Novel role of the Ras cascade in memory B cell response.

Engagement of the B cell antigen receptor (BCR) triggers the Ras cascade, but the biological role of the latter in B cell response is unknown. Here, we report that in T cell-dependent response, the role of the Ras cascade is confined to memory B cells and possibly marginal zone B cells. When Ras-dependent BCR signaling was impaired, the generation of IgG germinal center B cells was unaffected but the recruitment of high-affinity cells into the memory compartment and terminal differentiation were inhibited. Furthermore, inhibition of MEK activity consistently impaired antibody production by IgG memory B cells (but not naïve B cells) in vitro. Notably, this impairment was countered by overexpression of Bcl-2. Thus, our data suggest that upon antigen stimulation, memory B cells are susceptible to apoptosis but can be rescued via an antiapoptotic effect mediated through the Ras cascade.

3T3 Cells↗
PubMed2003

Infants' learning, memory, and generalization of learning for bimodal events.

Study 1 investigated whether infants 3 and 7 months of age show differential learning of and memory for sight-sound pairs depending on whether or not temporal synchrony was present; memory was assessed after a 10-min and 1-week interval. Study 2 examined whether 7-month-olds show generalization of learning when they encounter novel bimodal events that are similar (changes in size, orientation, or color, and spectral sound properties) to the sight-sound pairs learned 1 week earlier based on temporal synchrony. For Study 1, infants received a familiarization phase followed by a paired-comparison preference procedure to assess for learning of the sight-sound pairs. One week later a memory test was given. Results confirmed that 7-month-olds had no difficulty learning auditory-visual pairings regardless of whether or not events were temporally synchronous, and they remembered these 10 min and 1 week later. In contrast, 3-month-olds showed poorer learning of sight-sound associations in the no-synchrony than synchrony conditions, and memory for sight-sound pairs 1 week later was shown only for the synchrony conditions. Results for Study 2 revealed generalization of learning of bimodal pairings under all stimulus conditions after a 1-week interval at 7 months of age. Implications of these findings for development of intersensory knowledge are discussed.

Discrimination Learning↗
PubMed1991

Automatic and effortful memory processes in elderly persons with organic brain pathology.

This study investigated the automatic and effortful memory encoding model of Hasher and Zacks (1979) and the potential it may hold for aiding in the differentiation between aging-related memory decline and dementia. College students, normal elders, and dementia patients were compared on a 96-item picturebook task utilizing measures of free recall, recognition accuracy, memory for location, and memory for frequency. There were no differences between students and elders on any of the dependent measures. However, differences were found between elders and patients on each measure, and a discriminant function correctly classified the two groups with 93.3% accuracy. Subsequent discriminant analysis found patients could be correctly classified into diagnostic subgroups, i.e., dementia of the Alzheimer's type (DAT), multi-infarct dementia (MID), and Korsakoff's disease (KD) with 80.8% accuracy. The model holds promise as a guide for clinicians who are asked to make differential diagnoses of memory-impaired individuals.

Adolescent↗
PubMed2002

Frequent detection of thyroid peroxidase-specific IgG+ memory B cells in blood of patients with autoimmune thyroid disease.

Centrocytes in germinal centers on selection differentiate into plasma cells and/or memory B cells. Cells that have acquired autoreactivity by somatic mutation generally fail to undergo positive selection and die by apoptosis. Presence of isotype-switched high-affinity autoantibodies in serum of autoimmune patients suggests that autoreactive plasma cells eventually emerge from a germinal center reaction. Currently, it is still unclear to which extent the same is true for autoreactive memory B cells. To address this question, we have analyzed whether IgG-bearing memory B cells with specificity for thyroid peroxidase (TPO) can be found in blood of patients with autoimmune thyroid disease and in normal blood donors. Autoreactive TPO-specific IgG+ memory B cells were identified using a previously described assay combining two-step immunomagnetic enrichment with flow cytometric detection. Autoreactive IgG+ memory B cells were found in 65% of the patients with autoimmune thyroid disease and in 17% of normal blood donors; 40% of the latter had no detectable TPO-specific IgG in the serum. The specificity of enriched TPO-specific IgG+ memory B cells was confirmed by in vitro proliferation and differentiation into antibody-secreting cells at limiting dilution and analysis of the supernatants for the presence of TPO-specific IgG. Detection of TPO-specific IgG+ memory B cells in most patients with clinically manifested autoimmune thyroid disease and few normal blood donors may argue for a role of circulating memory B cells in onset of disease.

Adolescent↗
PubMed2004

Differential contribution of left and right prefrontal cortex to associative cued-recall memory: a parametric PET study.

Several brain imaging studies have implicated prefrontal regions bilaterally during cued-recall memory tasks and yet the functional significance of these regions remains poorly understood. Using PET, we examined the neural activity in prefrontal regions of 15 subjects while they performed three cued-recall tasks differing in pre-experimental semantic associations between cues and targets. This manipulation produced varying levels of retrieval performance when one member (a semantic category name) of the triad was used as a cue for the retrieval of the other two members. The percentage of items correctly recalled was 10, 46, and 70 in the low, medium, and high cued-recall conditions, respectively. Linear contrast analyses of the PET data identified brain regions where neural activity varied with the number of items retrieved from memory. A left lateral prefrontal region showed maximal activity during the high cued-recall condition, which likely reflects processes involved in retrieval success and possibly in the generation of memory responses. Three right prefrontal regions (anterior and dorsolateral) showed maximal activity during the low cued-recall condition, which likely reflects processes involved in memory search/monitoring. These findings add further support for a bilateral prefrontal contribution to memory cued-recall tasks and point to differential roles of the two hemispheres.

Adult↗
PubMed2003

T cell fitness determined by signal strength.

Two potential outcomes confront proliferating antigen-stimulated naive T cells: differentiation to effector and memory cells, or deletion. How stimulation affects cell fate is unclear. Autonomous CD8+ T cell differentiation has been proposed, but this does not explain the abortive proliferation of T cells induced by immature dendritic cells. Here we show that human and mouse CD4+ and CD8+ T cells receiving short or weak stimulation of the T cell receptor proliferate in response to interleukin 2 (IL-2) but are not 'fit' because they die by neglect, fail to proliferate in response to IL-7 and IL-15 and disappear in vivo. Conversely, prolonged or strong stimulation promotes 'fitness' by enhancing survival and cytokine responsiveness. Our results are consistent with the concept that signal strength drives progressive T cell differentiation and the acquisition of fitness.

CD4-Positive T-Lymphocytes↗
PubMed2003

Anti-human immunodeficiency virus-gag CD8+ memory T cells generated in vitro from Listeria-immunized mice.

The goal of vaccination is the generation of immune memory, an immune state that permits rapid and intense recall responses to a pathogen. Considerable effort is being made to understand the nature of memory T cells. We report here that by extending the length of in vitro culture following a single restimulation with specific peptide, preparations of highly enriched, highly active antigen-specific CD8+ memory T cells could be obtained. These cultures were begun with splenocytes from mice primed by infection either with an attenuated strain of Listeria monocytogenes or vaccinia virus, both expressing the human immunodeficiency virus-1-gag gene. In the cultures, antigen-specific cytotoxic T lymphocyte (CTL) activity reached a maximum at about 9 days and thereafter fell to negligible values. Concomitant with the fall of CTL activity, however, we observed enrichment for a subset of CD11ahigh antigen-specific gag-tetramerpos CD8+ T cells. The cells showed little or no 4-hr CTL activity, but had high delayed (18-hr) CTL activity, and very high cytolytic activity after restimulation. They rapidly expressed interferon-gamma production. Their growth and survival after sorting was completely dependent on interleukin-2 or -15. As few as 5000 of the fluorescence-activated cell sorting-purified cells protected recipients against challenge 3 months after transfer. In response to the challenge, the cells repopulated lymphoid and non-lymphoid organs and showed a sizeable increase in number. The cells therefore demonstrate high protective activity for long periods of time. These cultured cells are thus a potential source of enriched natural memory T cells for reperfusion studies and in which the mechanisms that underlie the generation, differentiation and persistence of memory can be examined.

AIDS Vaccines↗
PubMed2006

Attenuation of cytokine responsiveness during T cell development and differentiation.

Cytokines play critical roles during T cell development; however, it is unclear to what extent development is altered by the high levels of cytokines produced during immune responses. A potential mechanism to shield developing cells from cytokine influence is attenuation of cytokine signaling. Using intracellular staining and flow cytometry to detect cytokine-induced Stat phosphorylation, we analyzed the cytokine responsiveness of developmentally defined mouse T cells. We assessed CD4(-)CD8(-) (DN), CD4(+)CD8(+) (DP), CD4(+)CD8(-) (SP4), and CD4(-)CD8(+) (SP8) in the thymus, and CD4(+)CD44(lo) (naive), CD4(+)CD44(hi) (memory), CD8(+)CD44(lo) (naive), and CD8(+)CD44(hi) (memory) in the periphery for responsiveness to interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL- 10, IL-15, interferon-alpha (IFN-alpha), and IFN-gamma. SP thymocytes responded to a wider range of cytokines than did the less mature DN and DP subpopulations. DP thymocytes were nonresponsive to all cytokines tested except for modest responses to IL-4 and IFN-alpha. Peripheral naive and memory T cells also displayed differential cytokine sensitivity. Memory T cells were less responsive to the proinflammatory cytokines IL-6 and IFN-gamma when compared with naive T cells, and the memory CD4(+) subset was less responsive to IL-4. In summary, developing thymocytes and memory T cells appear to be resistant to the influences of numerous cytokines produced during immune responses.

Animals↗
PubMed2006

Interaction of negative olfactory stimulation and working memory in schizophrenia patients: development and evaluation of a behavioral neuroimaging task.

Negative affect plays a crucial role in the psychopathology of schizophrenia. Although it is known that negative emotion has a strong effect on cognitive performance, this interaction has mainly been studied in healthy volunteers. Hence, working memory was assessed in 24 schizophrenia patients and 24 matched comparison subjects with a 0-back/2-back continuous performance test. Simultaneously, negative emotion was induced by olfactory stimulation. Although subjective ratings confirmed that stimulation with a negative odor was associated with a significant increase in negative affect in patients and healthy volunteers, working memory performance was affected differentially in healthy volunteers and schizophrenia patients. Whilst a similar trend of a reduced behavioral performance during negative odor stimulation was observed in patients, only controls demonstrated a significantly higher response time and a reduced number of correct reactions during higher working memory demands (2-back). Patients, on the other hand, revealed an increase in false alarms during both conditions. The present data indicate a differential effect of negative mood induction on working memory performance in schizophrenia patients and healthy subjects.

Adult↗