Psychic phenomena in partial seizures.
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Cognition Disorders↗
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Neural correlates of training-related memory improvement in adulthood and aging.
Cognitive studies show that both younger and older adults can increase their memory performance after training in using a visuospatial mnemonic, although age-related memory deficits tend to be magnified rather than reduced after training. Little is known about the changes in functional brain activity that accompany training-induced memory enhancement, and whether age-related activity changes are associated with the size of training-related gains. Here, we demonstrate that younger adults show increased activity during memory encoding in occipito-parietal and frontal brain regions after learning the mnemonic. Older adults did not show increased frontal activity, and only those elderly persons who benefited from the mnemonic showed increased occipito-parietal activity. These findings suggest that age-related differences in cognitive reserve capacity may reflect both a frontal processing deficiency and a posterior production deficiency.
Adult↗
Age-dependent decrease in the affinity of muscarinic M1 receptors in neocortex of rhesus monkeys.
In vitro autoradiography on tissue sections and receptor assay in cortical membrane homogenates revealed that pirenzepine high-affinity muscarinic sites (M1) decrease in affinity in the prefrontal cortex and in other cortical areas of aged rhesus monkey (Macaca mulatta). Carbachol competition experiments detected only a single, low-affinity class of sites in old monkeys, while two classes of sites (low and high affinity) were observed in young adults. The change in affinity in the aged monkeys is not accompanied by a decrease in the density of these sites and, further, the age-related decline in the affinity of the M1 site is reversible. In the presence of Mg2+, the M1 muscarinic receptors in the aged monkeys were capable of forming carbachol high-affinity sites. These results provide evidence for age-dependent functional changes in receptor activity in cerebral cortex and indicate that these receptors maintain a degree of plasticity that could be a strategic target for research aimed at treatment of memory disorders in aged humans.
Aging↗
Modulation of learning, pain thresholds, and thermoregulation in the rat by preparations of free purified alpha-linolenic and linoleic acids: determination of the optimal omega 3-to-omega 6 ratio.
Ingested polyunsaturated fatty acids are postulated to lead to changes in central nervous system activity, presumably by altering the lipid composition of neuronal membranes. In support of this hypothesis, we and other investigators have previously demonstrated cognitive effects in rats fed oils that contain both alpha-linolenic acid (18:3 omega 3) and linoleic acid (18:2 omega 6), with the relative content of alpha-linolenic acid being seen as the critical variable. The present study in rats examined the effects of preparations containing different ratios of highly purified free alpha-linolenic acid to linoleic acid (about 25 mg/kg of body weight daily) on learning performance (Morris water tank), pain thresholds (heated plate), and thermoregulatory control of d-amphetamine-induced hypothermia during 4 weeks of treatment. Preparations with omega 3-to-omega 6 ratios ranging from 1:3.5 to 1:5 (specifically a ratio of 1:4) produced significant favorable effects on all of these variables. Although the specific mode of action remains to be elucidated, these results suggest that such preparations of free fatty acids should be evaluated in the treatment of memory disorders and pain conditions.
Animals↗
Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus.
Pregnenolone sulfate (PREG S) is synthesized in the nervous system and is a major neurosteroid in the rat brain. Its concentrations were measured in the hippocampus and other brain areas of single adult and aged (22-24 month-old) male Sprague-Dawley rats. Significantly lower levels were found in aged rats, although the values were widely scattered and reached, in about half the animals, the same range as those of young ones. The spatial memory performances of aged rats were investigated in two different spatial memory tasks, the Morris water maze and Y-maze. Performances in both tests were significantly correlated and, accompanied by appropriate controls, likely evaluated genuine memory function. Importantly, individual hippocampal PREG S and distance to reach the platform in the water maze were linked by a significant correlation, i.e., those rats with lower memory deficit had the highest PREG S levels, whereas no relationship was found with the PREG S content in other brain areas (amygdala, prefrontal cortex, parietal cortex, striatum). Moreover, the memory deficit of cognitively impaired aged rats was transiently corrected after either intraperitoneal or bilateral intrahippocampal injection of PREG S. PREG S is both a gamma-aminobutyric acid antagonist and a positive allosteric modulator at the N-methyl-D-aspartate receptor, and may reinforce neurotransmitter system(s) that decline with age. Indeed, intracerebroventricular injection of PREG S was shown to stimulate acetylcholine release in the adult rat hippocampus. In conclusion, it is proposed that the hippocampal content of PREG S plays a physiological role in preserving and/or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems. Thus, neurosteroids should be further studied in the context of prevention and/or treatment of age-related memory disorders.
Aging↗
The noncatalytic beta-propeller domain of prolyl oligopeptidase enhances the catalytic capability of the peptidase domain.
Prolyl oligopeptidase, which is involved in memory disorders, is a member of a new family of serine peptidases. In addition to the peptidase domain, the enzyme contains a beta-propeller, which excludes large peptides from the active site. The enzyme is inhibited with thiol reagents, possibly by reacting with Cys-255 located close to the substrate binding site. This assumption was tested with the Cys-255 --> Thr, Cys-255 --> Ala, and Cys-255 --> Ser variants of prolyl oligopeptidase. In contrast to the wild type enzyme, the Cys-255 --> Thr variant was not inhibited with N-ethylmaleimide, indicating that Cys-255, of the 16 free cysteine residues, exclusively accounts for the enzyme inhibition. Unlike the wild type enzyme that showed a doubly bell-shaped pH rate profile, the modified enzyme displayed a single bell-shaped pH dependence with benzyloxycarbonyl-Gly-Pro-naphthylamide. It was the high pH form of the enzyme that virtually disappeared with all three enzyme variants. A substantial reduction was also observed in k(cat)/K(m) for the aminobenzoyl-Ser-Pro-Phe(NO(2))-Ala-OH substrate. The high pK(a) (9.77) of Cys-255 determined by titration with N-ethylmaleimide excluded the possibility that ionization of the thiol group was responsible for generation of the two active enzyme forms. The impaired activity of the enzyme variants could be rationalized in terms of weaker binding, which manifests itself in high K(m) for substrates and high K(i) for inhibitors, like benzyloxycarbonyl-Gly-Pro-OH and aminobenzoyl-Ser-d-Pro-Phe(NO(2))-Ala-OH. It was concluded that, besides selecting substrates by size, the beta-propeller domain containing Cys-255 remarkably contributed to catalysis of the peptidase domain.
Amino Acid Substitution↗
Substrate-dependent competency of the catalytic triad of prolyl oligopeptidase.
Prolyl oligopeptidase, a serine peptidase unrelated to trypsin and subtilisin, is implicated in memory disorders and is an important target of drug design. The catalytic competence of the Asp(641) residue of the catalytic triad (Ser(554), Asp(641), His(680)) was studied using the D641N and D641A variants of the enzyme. Both variants displayed 3 orders of magnitude reduction in k(cat)/K(m) for benzyloxycarbonyl-Gly-Pro-2-naphthylamide. Using an octapeptide substrate, the decrease was 6 orders of magnitude, whereas with Z-Gly-Pro-4-nitrophenyl ester there was virtually no change in k(cat)/K(m). This indicates that the contribution of Asp(641) is very much dependent on the substrate-leaving group, which was not the case for the classic serine peptidase, trypsin. The rate constant for benzyloxycarbonyl-Gly-Pro-thiobenzylester conformed to this series as demonstrated by a method designed for monitoring the hydrolysis of thiolesters in the presence of thiol groups. Alkylation of His(680) with Z-Gly-Pro-CH(2)Cl was concluded with similar rate constants for wild-type and D641A variant. However, kinetic measurements with Z-Gly-Pro-OH, a product-like inhibitor, indicated that the His(680) is not accessible in the enzyme variants. Crystal structure determination of these mutants revealed subtle perturbations related to the catalytic activity. Many of these observations show differences in the catalysis between trypsin and prolyl oligopeptidase.
Animals↗
Electrostatic effects and binding determinants in the catalysis of prolyl oligopeptidase. Site specific mutagenesis at the oxyanion binding site.
Prolyl oligopeptidase, a member of a new family of serine peptidases, plays an important role in memory disorders. Earlier x-ray crystallographic investigations indicated that stabilization of the tetrahedral transition state of the reaction involved hydrogen bond formation between the oxyanion of the tetrahedral intermediate and the OH group of Tyr(473). The contribution of the OH group was tested with the Y473F variant using various substrates. The charged succinyl-Gly-Pro-4-nitroanilide was hydrolyzed with a much lower k(cat)/K(m) compared with the neutral benzyloxycarbonyl-G1y-Pro-2-naphthylamide, although the binding modes of the two substrates were similar, as shown by x-ray crystallography. This suggested that electrostatic interactions between Arg(643) and the succinyl group competed with the productive binding mechanism. Unlike most enzyme reactions, catalysis by the wild-type enzyme exhibited positive activation entropy. In contrast, the activation entropy for the Y473F variant was negative, suggesting that the tyrosine OH group is involved in stabilizing both the transition state and the water shell at the active site. Importantly, Tyr(473) is also implicated in the formation of the enzyme-substrate complex. The nonlinear Arrhenius plot suggested a greater significance of the oxyanion binding site at physiological temperature. The results indicated that Tyr(473) was more needed at high pH, at high temperature, and with charged substrates exhibiting "internally competitive inhibition."
Amino Acid Substitution↗
Independent functioning of verbal memory stores: a neuropsychological study.
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Hearing↗
Alcoholic Korsakoff's syndrome: some unresolved issues concerning etiology, neuropathology, and cognitive deficits.
Recent neuropsychological and neuropathological investigations with long-term alcoholics suggest that the etiology and neuropathology of the Wernicke-Korsakoff syndrome are more complex than previously believed. While problem solving and visuoperceptual deficits seem to develop slowly during decades of alcoholism, the amnesic symptoms associated with Korsakoff's syndrome may appear acutely when severe malnutrition and alcoholism are combined. Furthermore, the report that alcoholic Korsakoff patients, like patients with Alzheimer's Disease, have endured a substantial neuronal loss in the nucleus basalis of Meynert has questioned the role of the medial diencephalon in the alcoholic patients' amnesic syndrome. Some initial demonstrations of similarities in the memory disorders of alcoholic Korsakoff and Alzheimer patients indicate that Korsakoff's syndrome may be more accurately characterized as a "basal forebrain" than as a "diencephalic" amnesia.
Alcohol Amnestic Disorder↗
Memory failure in Huntington's disease.
Patients with Huntington's disease (HD) were compared to normal controls of equivalent age and verbal intelligence on a set of verbal learning tasks. Although the HD patients showed the expected deficit in secondary (long-term) memory, their performance was otherwise comparable to that of the control groups. Primary (short-term) memory was normal, there was normal sensitivity to proactive interference, and the patients showed an advantage, albeit reduced, in recall of related compared to unrelated word lists. The findings suggest that mnemonic input is encoded semantically in HD though less efficiently than in unafflicted individuals, and that difficulty accessing information in semantic (knowledge-based) memory may be partially responsible for the memory disorder of HD.
Adolescent↗
Exploring visuospatial short-term memory defect in Alzheimer's disease.
The present study aimed at controlling two variables that may affect the visuospatial short-term memory of Alzheimer patients: visuospatial coding efficiency and response modality. Thirty patients affected by Alzheimer-type dementia with relatively spared visuo-perceptual functions were tested under three conditions, all of which employed the same kind of stimuli (visuospatial patterns). At all memory tasks, patients achieved scores significantly lower than those of 30 age- and education-matched normal subjects. Patients did not benefit from longer presentation time, nor did their performance improve with pointing response modality, although they performed perceptual pattern recognition as well as did controls. These data confirm that visuospatial immediate memory capacity is reduced in dementia.
Aged↗
Amsterdam Short-Term Memory test: a new procedure for the detection of feigned memory deficits.
The validity of two malingering tests, the newly developed Amsterdam Short-Term Memory (ASTM) test and the Distraction test (Baker, Hanley, Jackson, Kimmance, & Slade, 1993) was examined in a group of patients with closed-head injury (CHI), a normal control group, and a control group with instruction to feign memory deficits. Both control groups consisted of first-degree relatives of the patients. The ASTM test is a forced-choice verbal memory test, based on the technique of symptom validity testing. Stimulus material was chosen from category norms and chance level is not transparent. The CHI and normal control groups scored near ceiling on the ASTM test, whereas the feigned deficit group scored significantly worse. The ASTM test classified all subjects correctly. Contrary to expectation, the Distraction test appeared to be invalid. The score profiles of the CHI and feigning groups on conventional memory and concentration tests were indistinguishable from each other. Thus, the ASTM test may be very useful for the detection of malingering and other kinds of less than optimal performance. The test may readily be constructed in any language for which category norms are available.
Adult↗
Working memory deficits after traumatic brain injury: catecholaminergic mechanisms and prospects for treatment -- a review.
PRIMARY OBJECTIVE: To review the neural circuitry and neurochemistry of working memory and outline the evidence for working memory deficits after traumatic brain injury, and the evidence for the use of catecholaminergic agents in the amelioration of these deficits. Current knowledge gaps and research needs are identified. MAIN OUTCOMES AND RESULTS: Impairments in working memory are a core component of the cognitive deficits associated with traumatic brain injury. Recent progress in understanding the neural circuitry and neurochemistry of working memory suggests that catecholamines play a central role in the activation and regulation of working memory and thus lays a framework in which to consider the use of catecholaminergic agents (dopaminergic and alpha-2 adrenergic agonists) in the treatment of specific cognitive deficits after traumatic brain injury. CONCLUSIONS: The combined methods of cognitive neuroscience, functional brain imaging and neuropharmacology are proposed as an excellent method for studying working memory deficits. A strong rationale exists for the targeted use of catecholaminergic agonists in the treatment of working memory deficits after traumatic brain injury.
Adrenergic alpha-Agonists↗
Impairment of short-term memory in left hemispheric traumatic brain injuries.
We report on two patients with traumatic lesions in the temporal and parietal lobes who demonstrated disturbances of short-term memory (STM) following improvement on the aphasia. Patient 1 was a 66-year-old right-handed man who presented to our hospital with a cerebral contusion. One admission we observed a Wernicke's aphasia with paraphasic jargon in this patient that resolved within 8 weeks. Patient 2 was a 35-year-old right-handed woman, with an acute subdural haematoma and a cerebral contusion, who underwent craniotomy and evacuation of the haematoma. In this patient we noted a transient Wernicke's aphasia following the operation that improved within 3 months. Linguistically, the aphasia observed in each of these two patients was not a typical conduction aphasia because of the absence of paraphasia, and impairment of comprehension was unclear despite a decrease in performance on repetition tasks. Both verbal and non-verbal tasks suggested an impairment in STM. These findings suggest that involvement of the left hemisphere may cause disturbances in both verbal and non-verbal STM.
Adult↗
Age-related declines in context maintenance and semantic short-term memory.
This study reports age-related declines in context maintenance (Braver et al., 2001) and semantic short-term memory (STM) and evidencc for a relation between the two. A group of younger and older adults completed a context maintenance task (AX-CPT), a semantically oriented STM task (conceptual span), a phonologically oriented STM task (digit span), and a meaning integration task (semantic anomaly judgement). In the AX-CPT task, a target response is required to the probe letter "X" but only when it is preceded by the letter "A" (the context). Either three (short interference) or six distractor letters (long interference) were presented between the cue and the probe. Results indicated an age-related deficit in context maintenance. Age-related declines were also observed for conceptual span and semantic anomaly judgement but not for digit span. Context maintenance was correlated with conceptual span and semantic anomaly judgement but not with digit span. These correlations were largely mediated by age differences, which also explained variance that was unique to (and not shared among) context maintenance, conceptual span, and semantic anomaly judgement.
Adult↗
Ageing and switching of the focus of attention in working memory: results from a modified N-back task.
We conducted two experiments using a modified version of the N-Back task. For younger adults, there was an abrupt increase in reaction time of about 250 ms in passing from N = 1 to N > 1, indicating a cost associated with switching of the focus of attention within working memory. Response time costs remained constant over the range N = 2 to N = 5. Accuracy declined steadily over the full range of N (Experiment 1). Focus switch costs did not interact with either working memory updating (Experiment 1), or global task switching (Experiment 2). There were no age differences in RT costs once general slowing was taken into account, but there was a larger focus-switch-related accuracy cost in older adults than in younger adults. No age sensitivity was found for either updating or global task switching. The results suggest (a) that focus switching is a cognitive primitive, distinct from task switching and updating, and (b) that focus switching shows a specific age-related deficit in the accuracy domain.
Adolescent↗
How physicians appraise everyday memory failures of patients across the adult life span.
A person-perception paradigm was used to investigate how primary care physicians appraise young, middle-aged, young-old, or old-old hypothetical patients (targets) who experience incidences of everyday memory failure. The physicians distinguished among targets who experienced short-, long-, and very long-term types of failure. However, their ratings of the point at which they would recommend intervention and of the referrals they would make in response to the three types of failure were not affected by the age of the target. The physicians' responses are compared with prior research results obtained for lay subjects' appraisals of young versus older targets' memory failures. The implications for primary care physicians' views of the significance of everyday memory failures in older adults are discussed.
Adult↗