Effects of mild cognitive impairment on emotional scene memory.

Young and older adults experience benefits in attention and memory for emotional compared to neutral information, but this memory benefit is greatly diminished in Alzheimer's disease (AD). Little is known about whether this impairment arises early or late in the time course between healthy aging and AD. This study compared memory for positive, negative, and neutral items with neutral backgrounds between patients with mild cognitive impairment (MCI) and healthy older adults. We also used a divided attention condition in older adults as a possible model for the deficits observed in MCI patients. Results showed a similar pattern of selective memory for emotional items while forgetting their backgrounds in older adults and MCI patients, but MCI patients had poorer memory overall. Dividing attention during encoding disproportionately reduced memory for backgrounds (versus items) relative to a full attention condition. Participants performing in the lower half on the divided attention task qualitatively and quantitatively mirrored the results in MCI patients. Exploratory analyses comparing lower- and higher-performing MCI patients showed that only higher-performing MCI patients had the characteristic scene memory pattern observed in healthy older adults. Together, these results suggest that the effects of emotion on memory are relatively well preserved for patients with MCI, although emotional memory patterns may start to be altered once memory deficits become more pronounced.

Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers.

BACKGROUND: Experimental evidence supports the hypothesis that the development of blood vessels is fundamental to the growth and metastasis of solid tumors. Elevated levels of the angiogenic peptide basic fibroblast growth factor (bFGF) have been significantly correlated with the status and extent of disease in bladder cancer. PURPOSE: We measured the bFGF levels in patients with cancer in organs other than the bladder to determine whether elevated levels accompany these cancers. METHODS: Urine samples were collected from 950 patients having a wide variety of solid tumors, leukemia, or lymphoma and from a control group of 87 healthy volunteers and 198 patients with non-cancer-related diseases. Levels of bFGF in samples prepared from the urine were measured using an enzyme bioassay. RESULTS: Male control subjects had a median bFGF level of 151 pg/g and female control subjects a median of 237 pg/g, with a combined 90th percentile of 619 pg/g. An elevated level of bFGF was found in the urine of some of the patients with every type of tumor studied except cervical carcinoma. For example, patients with active local cancers had a median level of 312 pg/g. Those with active, metastatic cancers had a median level of 479 pg/g and a 90th percentile level of 14143 pg/g. After "elevated" was defined to mean higher than the 90th percentile level for controls, 31% of patients with local active and 47% of patients with metastatic active cancers showed elevated bFGF levels. Survival among cancer patients at the median follow-up time was 85%-88% for those with "normal" and 71%-72% for those with "elevated" urine bFGF levels. IMPLICATIONS: Our results suggest that bFGF in urine deserves further evaluation of its potential use as a monitor of therapy or as a predictor of outcome once a cancer has been diagnosed.

Pathophysiology underlying diminished attention to novel events in patients with early AD.

BACKGROUND: Patients with mild to moderate AD often are apathetic and fail to attend to novel aspects of their environment. OBJECTIVE: To investigate the mechanisms underlying these changes by studying the novelty P3 response that measures shifts of attention toward novel events. METHODS: While event-related potentials were recorded, mildly impaired AD patients and matched normal controls (NC) viewed line drawings that included a repetitive background stimulus, an infrequent target stimulus, and infrequent novel stimuli. Subjects controlled how long they viewed each stimulus by pressing a button. This served as a measure of their allocation of attention. They also responded to targets by depressing a foot pedal. Patients did not differ from NC in age, education, estimated IQ, or mood but were judged by informants to be more apathetic. RESULTS: P3 amplitude to novel stimuli was significantly smaller for AD patients than NC. However, P3 amplitude to target stimuli did not differ between groups. For NC, P3 response to novel stimuli was much larger than to background stimuli. In contrast, for patients with AD, there was no difference in P3 response to novel vs background stimuli. Although NC spent more time looking at novel than background stimuli, patients with AD distributed their viewing time evenly. Remarkably, for patients with AD, the amplitude of the novelty P3 response powerfully predicted how long they would spend looking at novel stimuli (R2 = 0.52) and inversely correlated with apathy severity. CONCLUSIONS: The decreased attention to novel events exhibited by patients with AD cannot be explained by a nonspecific reduction in their attentional abilities. The novelty P3 response is markedly diminished in mild AD, at a time when the target P3 response is preserved. The disruption of the novelty P3 response predicts diminished attention to novel stimuli and is associated with the apathy exhibited by patients with AD.

GDP beta S antagonizes whole-cell current responses to excitatory amino acids.

Guanine nucleotides have been predicted to be NMDA antagonists in tissue binding studies. Using the patch-clamp technique, we now show that the guanine nucleotide GDP beta S produces a rapidly reversible antagonism of NMDA, kainate, and, less potently, quisqualate whole-cell current responses. Furthermore, it does not appear that this antagonism is effected intracellularly. Our results suggest a novel extracellular role for guanine nucleotides apart from their traditional intracellular actions on G-proteins.

When false recognition is unopposed by true recognition: gist-based memory distortion in Alzheimer's disease.

The authors examined false recognition of semantic associates in patients with probable Alzheimer's disease (AD), older adults, and young adults using a paradigm that provided rates of false recognition after single and multiple exposures to word lists. Using corrected false recognition scores to control for unrelated false alarms, the authors found that (a) the level of false recognition after a single list exposure was lower in AD patients than in controls; (b) across 5 trials, false recognition increased in AD patients, decreased in young adults, and showed a fluctuating pattern in older adults; and (c) all groups showed an increase in true recognition over the 5 trials. Analyses suggested that AD patients built up semantic gist across trials, whereas both control groups were able to use increased item-specific recollection and more conservative response criteria to suppress gist-based false alarms.

Perceptual false recognition in Alzheimer's disease.

Previous research has found that patients with probable Alzheimer's disease (AD) show lower levels of false recognition of semantic associates than do healthy older adults. To investigate whether this finding is attributable to semantic impairments in patients with AD, the authors examined false recognition of perceptually related novel objects with little semantic content in patients with AD and healthy older adults. By using corrected recognition scores to control for unrelated false alarms, it was found that patients with AD showed lower levels of both true and false recognition of novel objects than did older adults. These results suggest that the previous difference in false recognition of semantic associates observed between patients with AD and older adults is not entirely attributable to semantic memory deficits in patients with AD but may also involve poorly developed gist information in these patients.

Event-related potential markers of brain changes in preclinical familial Alzheimer disease.

OBJECTIVES: Event-related potentials (ERPs) can reflect differences in brain electrophysiology underlying cognitive functions in brain disorders such as dementia and mild cognitive impairment. To identify individuals at risk for Alzheimer disease (AD) we used high-density ERPs to examine brain physiology in young presymptomatic individuals (average age 34.2 years) who carry the E280A mutation in the presenilin-1 (PSEN1) gene and will go on to develop AD around the age of 45. METHODS: Twenty-one subjects from a Colombian population with familial AD participated: 10 presymptomatic subjects positive for the PSEN1 mutation (carriers) and 11 siblings without the mutation (controls). Subjects performed a visual recognition memory test while 128-channel ERPs were recorded. RESULTS: Despite identical behavioral performance, PSEN1 mutation carriers showed less positivity in frontal regions and more positivity in occipital regions, compared to controls. These differences were more pronounced during the 200-300 msec period. Discriminant analysis at this time interval showed promising sensitivity (72.7%) and specificity (81.8%) of the ERP measures to predict the presence of AD pathology. CONCLUSIONS: Presymptomatic PSEN1 mutation carriers show changes in brain physiology that can be detected by high-density ERPs. The relative differences observed showing greater frontal positivity in controls and greater occipital positivity in carriers indicates that control subjects may use frontally mediated processes to distinguish between studied and unstudied visual items, whereas carriers appear to rely more upon perceptual details of the items to distinguish between them. These findings also demonstrate the potential usefulness of ERP brain correlates as preclinical markers of AD.

Health of organisms and health of persons: an embedded instrumentalist approach.

In a time when we as a society are in the process of deciding what our basic rights to health care are, it is critically important for us to have a full and complete understanding of what constitutes health. We argue for an analysis of health according to which certain states are healthy not in themselves but because they allow an individual to reach actual goals. Recognizing that the goals of an individual considered from the point of view of biology and the goals of the same individual considered as an agent in the world might be different, we introduce a distinction between the health of an individual qua organism and the health of an individual qua person. We then argue that this distinction characterizes the evaluations made by patients and healthcare providers better than the widely discussed distinction between disease and illness.

The angiogenesis inhibitor AGM-1470 selectively increases E-selectin.

The levels of E-selectin mRNA and protein were analyzed in bovine capillary cells treated with or without the angiogenesis inhibitor AGM-1470 (also known as TNP-470). Cells treated with AGM-1470 had a two- to sevenfold (median fivefold) increase in E-selectin mRNA compared with little or no increase in P-selectin, PECAM-1 and VCAM-1 mRNA. E-selectin protein was also significantly increased after exposure to AGM-1470. In contrast, there was no detectable effect on PECAM-1 protein. The increase in E-selectin mRNA and protein was always greater with subconfluent growing cells than with confluent cells. This apparent resistance of confluent endothelial cells to AGM-1470 may be relevant to its specificity in vivo. The fact that the effect of AGM-1470 on E-selectin is relatively selective for subconfluent growing cells may provide a clue as to how AGM-1470 is able to both reversibly inhibit endothelial cell proliferation in vitro and inhibit tumor growth in vivo without apparent effects to quiescent endothelium.

Suppression of false recognition in Alzheimer's disease and in patients with frontal lobe lesions.

Previous research has shown that patients with Alzheimer's disease show increasing levels of false recognition across five repeated study-test trials of semantic associates. The present study tested the hypotheses that (i) the increasing false recognition was partly due to the frontal lobe dysfunction of patients with Alzheimer's disease, and (ii) a failure of source monitoring was the central mechanism by which frontal lobe dysfunction led to increasing false recognition across trials. In Experiment 1, patients with frontal lobe lesions and controls were examined in the same repeated trials paradigm as that used previously in patients with Alzheimer's disease. Although controls were able to reduce their false recognition across trials, the patients with frontal lobe lesions were not, and instead showed a constant level of elevated false recognition across the study-test trials. In Experiment 2, two groups of patients with Alzheimer's disease and healthy older adult controls were studied: the first group was given a single study session followed by a recognition test, the second group was given five study sessions followed by a single recognition test. Older adults who were exposed to five study lists demonstrated lower levels of false relative to true recognition, whereas patients with Alzheimer's disease in this condition exhibited levels of false recognition elevated to that of their true recognition, even with the source memory confusion of intervening tests eliminated. The authors suggest that impairment in aspects of frontal lobe function, such as verification-inhibition mechanisms, probably contributes to the inability of patients with Alzheimer's disease to suppress their false recognition across repeated trials. Lastly, it is speculated that one way in which the frontal lobes enable normal episodic memory function is by facilitating the suppression of false recognition and other distortions of memory.

Frontal and parietal components of a cerebral network mediating voluntary attention to novel events.

Despite the important role that attending to novel events plays in human behavior, there is limited information about the neuroanatomical underpinnings of this vital activity. This study investigated the relative contributions of the frontal and posterior parietal lobes to the differential processing of novel and target stimuli under an experimental condition in which subjects actively directed attention to novel events. Event-related potentials were recorded from well-matched frontal patients, parietal patients, and non-brain-injured subjects who controlled their viewing duration (by button press) of line drawings that included a frequent, repetitive background stimulus, an infrequent target stimulus, and infrequent, novel visual stimuli. Subjects also responded to target stimuli by pressing a foot pedal. Damage to the frontal cortex resulted in a much greater disruption of response to novel stimuli than to designated targets. Frontal patients exhibited a widely distributed, profound reduction of the novelty P3 response and a marked diminution of the viewing duration of novel events. In contrast, damage to posterior parietal lobes was associated with a substantial reduction of both target P3 and novelty P3 amplitude; however, there was less disruption of the processing of novel than of target stimuli. We conclude that two nodes of the neuroanatomical network for responding to and processing novelty are the prefrontal and posterior parietal regions, which participate in the voluntary allocation of attention to novel events. Injury to this network is indexed by reduced novelty P3 amplitude, which is tightly associated with diminished attention to novel stimuli. The prefrontal cortex may serve as the central node in determining the allocation of attentional resources to novel events, whereas the posterior parietal lobe may provide the neural substrate for the dynamic process of updating one's internal model of the environment to take into account a novel event.