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A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice.

Humanin (HN) is a 24-amino acid peptide that protects neuronal cells from death caused by Alzheimer's disease (AD)-related genes and amyloid-beta (Abeta). Multiple studies have revealed its biochemical and neuroprotective characteristics in vitro; however, little has been known regarding whether HN is effective in vivo in AD model systems. We examined the effect of S14G-HN, a 1,000-fold more potent derivative of HN in vitro, on amnesia induced by Abeta25-35 in mice. The Y-maze test revealed that at least 50 pmol of S14G-HN by intracerebroventricular injection prevented Abeta-induced impairment of short-term/spatial working memory; however, 5 nmol of S14A-HN, a neuroprotection-defective mutant in vitro, did not prevent Abeta-induced amnesia. These results are in agreement with the structure-function correlation shown previously in vitro. In the water-finding task, S14G-HN prevented prolongation of finding latency (the time to find water) observed in Abeta-amnesic mice, indicating that S14G-HN also blocked Abeta-induced impairment of latent learning. In accordance with these observations, immunohistochemical analysis showed that S14G-HN sustained the number of cholinergic neurons in the basal forebrain and the striata nearly to the normal level. Furthermore, genistein, a specific inhibitor of tyrosine kinases, blocked recovery from scopolamine-induced amnesia by S14G-HN, suggesting that certain tyrosine kinase(s) are involved in the inhibitory function of S14G-HN in vivo. Taking these findings together, we conclude that S14G-HN has rescue activity against memory impairment caused by AD-related insults in vivo by activating the same intracellular neuroprotective machinery as elucidated previously in vitro.

Amnesia↗

Age and APOE-epsilon4 genotype influence the effect of physostigmine infusion on the in-vivo distribution volume of the muscarinic-2-receptor dependent tracer [18F]FP-TZTP.

The apolipoprotein E-epsilon4 allele (APOE-epsilon4) confers greater susceptibility to age-related memory disorders. Abnormalities in the cholinergic system are likely contributors to these disorders with both age and APOE-epsilon4 genotype modifying behavioral and physiological responses to drugs that alter cholinergic pathway function. Recently, we reported a greater in vivo distribution volume of the F-18 labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[18F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([18F]FP-TZTP), in aging healthy subjects with an APOE-epsilon4 allele. To examine the effects of aging and the APOE-epsilon4 allele on the response of the muscarinic component of cholinergic pathway to pharmacologic augmentation, two [18F]FP-TZTP PET scans were conducted in 19 subjects varying in age from 22 to 74 years, the first served as baseline for the second scan that was performed while the subjects were either infused with saline (n = 6) or with the acetylcholinesterase inhibitor physostigmine (6 with an APOE-epsilon4 allele and 7 without an APOE-epsilon4 allele). Using a multiple regression analysis, both AGE (beta = 0.621 +/- 0.135, B = 0.353 +/- 0.077, t(10) = 4.61, P < 0.001) and APOE-epsilon4 genotype (beta = 0.742, B = 14.8 +/- 2.69, t(10) = 5.51, P < 0.0003) were found to be significant contributors to subject response to physostigmine. The adjusted R2 for the model as a whole was 0.786 (F(2,10) = 23.00, P < 0.0002) with both increasing age and the presence of the APOE-epsilon4 allele modifying the response to physostigmine in the direction of larger decreases in [18F]FP-TZTP distribution volumes in all brain regions examined. The findings, particularly the absence of an interaction between AGE and APOE-epsilon4 genotype, contribute to the growing body of evidence that suggests that the APOE-epsilon4 genotype is likely to contribute to brain structure and function prior to aging.

Adult↗

Thalamic amnesia following venous infarction: evidence from a single case study.

The present paper describes the case of a right-handed Italian-English bilingual male patient suffering from amnesia following a bilateral thalamic lesion due to venous infarction. Within a few months from the onset, the lesion gradually shrank and was finally confined to the left thalamus only, in particular to the antero-medial portion and the pulvinar. The mammillary bodies and the cortical areas of both hemispheres were spared. After the regression of a series of generalized cognitive deficits implying slow psychic activity confusion, and spatial and temporal disorientation, the patient presented a persistent amnesic syndrome with mild language disorders, both in Italian and in English. Major disorders of memory included a dissociation between verbal memory, which was severely impaired, and spatial memory, which was largely preserved.

Brain Ischemia↗

Is the attentional blink effect located in short-term memory?

The attentional blink (AB) effect is characterized by a failure to detect a second target following the identification of a previous target in a RSVP stream. This effect has been attributed to capacity limitations at a central level of visual information processes. Postperceptual models suppose that the AB locus is located in short-term memory. To test this hypothesis, we investigated the influence of a short-term memory deficit on the AB effect in a patient with such a deficit. The three main results of this study are (1) the persistence of an AB effect, (2) a large number of T1 missed identifications and (3) a T2 detection deficit for a specific delay (367 ms). These results indicate that a short-term memory deficit disrupts the processing of each target (T1 and T2) but does not product an abolition of the AB effect.

Adult↗

Children's arithmetical difficulties: contributions from processing speed, item identification, and short-term memory.

Children's arithmetical difficulties are often explained in terms of a short-term memory deficit. However, the underlying cause of this memory deficit is unclear, with some researchers suggesting a slow articulation rate and hence increased decay of information during recall, while others offer an explanation in terms of slow speed of item identification, indicating difficulty in retrieving information stored in long-term memory. General processing speed is also related to measures of short-term memory but has rarely been assessed in studies of children's arithmetic. Measures of short-term memory, processing speed, sequencing ability, and retrieval of information from long-term memory were therefore given to 7-year-old children. When reading ability was controlled for, arithmetic ability was best predicted by processing speed, with short-term memory accounting for no further unique variance. It was concluded that children with arithmetic difficulties have problems specifically in automating basic arithmetic facts which may stem from a general speed of processing deficit.

Analysis of Variance↗

Short-term memory, working memory, and inhibitory control in children with difficulties in arithmetic problem solving.

The relations between short-term memory, working memory, inhibitory control, and arithmetic word problem solution were studied in children who were poor in arithmetic problem solving (n = 23). The children were compared with a group of good problem solvers (n = 26), matched for vocabulary, age, and gender. The results corroborate the hypothesis of poor problem solvers' general deficit in inhibitory processes. They had lower scores and made more intrusion errors in a series of working memory tasks requiring inhibition of irrelevant information. The results showed that problem solving performance is related to the ability of reducing the accessibility of nontarget and irrelevant information in memory. Span tasks that imply passive storage of information showed that poor problem solvers were impaired when they have to retain numerical information, but they did not differ from children who did not have difficulty with mathematics when the material included words.

Child↗

Memory and learning in epileptic patients treated by amygdalotomy and anterior hippocampotomy.

The memory and learning capacity in patients treated for temporal epilepsy was studied. The study was performed in 55 patients, observed before and after stereotaxic amygdalotomy and hippocampotomy. Very often disturbances in memory and learning capability were present before surgery. After surgery their learning efficiency increased. Disturbances in memory tracing, as provoked by distraction, remained at the same level after neurosurgery. No decrease in general intelligence was noted.

Adolescent↗

Physiology of short-term verbal memory.

These studies document a series of brain events accompanying short-term memory functions. For auditory verbal material the sequence involves at least two different sites within auditory cortex subserving sensory and cognitive processes of memorization. During the scanning of the short-term store structures within the medial temporal lobes, presumably the hippocampus, are active. There is an inconsistency between these results and the clinical observations of the need for an intact dominant parietal lobe for auditory short-term memory to function normally. Magnetic recordings showed no focal dipolar source of activity in the parietal lobe during any aspect of auditory short-term memory. The discrepancy could be accounted for by considering the parietal lobe lesion as "disconnecting" the lateral temporal cortex from the deep medial hippocampal structures thereby impeding auditory short-term functions (Geschwind, 1965). These studies show that the physiological analysis of brain events in the msec range can provide information about relatively complex cognitive processes underlying short-term memory. The magnetic and electrical recording methods provide a noninvasive way to study human brain functions involved in cognition that can then be correlated with behavioral measures of specific cognitive activities.

Brain↗

Enhancement by secoverine and physostigmine of retention of passive avoidance response in mice.

A one-trial passive avoidance test in the mouse, in which drugs were injected intraperitoneally immediately after the shocked acquisition trial, was used. The effects of enhancing central cholinergic transmission on retention of passive avoidance was investigated using secoverine, which blocks muscarinic autoreceptor-mediated inhibition of acetylcholine release, and using physostigmine, an acetylcholinesterase inhibitor. Secoverine (1.0-5.0 mg/kg) and physostigmine (0.1-0.4 mg/kg) were found to improve retention of the avoidance response measured 24 h after acquisition. These effects were augmented when the two drugs were given in combination. In contrast, atropine (5.0 mg/kg) tended to impair retention of passive avoidance and blocked the facilitatory effects of physostigmine. The results support the hypothesis of a novel approach to treatment of memory disorders based on blockade of muscarinic autoreceptors, to augment central cholinergic activity.

Animals↗

Cognitive and psychiatric impairment in herpes simplex virus encephalitis suggest involvement of the amygdalo-frontal pathways.

The long-term neuropsychological and psychiatric sequelae of herpes simplex virus encephalitis (HSVE) and their relationship to the volume of temporal lesions and to amygdala and hippocampus damage remain undefined. We have conducted a prospective study of long-term sequelae in 11 patients with clinically presumed HSVE and detection of HSV DNA in the cerebrospinal fluid by polymerase chain reaction. Six months after encephalitis, patients underwent neuropsychological and language assessment. At the same stage, single photon emission computed tomography (SPECT) evaluated the occurrence of hypoperfusion with an index of asymmetry. MRI was used for the measurement of amygdala, hippocampus and cerebral lesions by two blind neurologists. The volume of the amygdala and hippocampus was compared with those of five controls, matched for age and level of education. Long-term memory disorders were seen in 6 patients, associated with the larger lesions and damage of at least two structures. Long-term behavioural changes with emotionalism, irritability, anxiety or depression were prominent in 7. Left prefrontal hypoperfusion appeared in 8 patients, associated with psychiatric disorders in 7 and left amygdala damage in 6. The reduction of amygdala and hippocampus volume was correlated with the overall volume of lesions. Different patterns of mesial temporal lobe damage occurred, involving either amygdala alone, or amygdala and hippocampus, but never hippocampus alone. MRI volumetric measurements in HSVE could be a good indicator of long-term prognosis. Persistant behavioural changes could be related to an amygdala and frontal dysfunction.

Acyclovir↗

Studies on new, centrally active and reversible acetylcholinesterase inhibitors.

We have synthesized the tertiary amines of pyridostigmine and neostigmine, 3-pyridinol dimethylcarbamate (norpyridostigmine) and 3-dimethylaminophenol dimethylcarbamate (norneostigmine) respectively, and we have tested their abilities to cross the blood-brain barrier and inhibit mouse brain AChE activity. The in vivo inhibition of AChE activity by norpyridostigmine reaches 72% at 10 minutes which is comparable to that seen with physostigmine (73% at 10 minutes). Inhibition by norneostigmine is less effective (50% at 10 minutes) and approaches that obtained with tetrahydroaminoacridine (57% at 10 minutes). These data show that both norpyridostigmine and norneostigmine cross the blood-brain barrier and that they are effective inhibitors of mouse brain AChE activity. These drugs could be useful in the treatment of memory impairment associated with Alzheimer's disease, and other memory disorders.

Acetylcholinesterase↗

3,4-Dihydroxyphenylacetic acid (DOPAC) as an index of noradrenaline turnover: effects of Hydergine and vincamine.

Among the drugs commonly used in the treatment of memory disorders of the elderly, vincamine and hydergine have been shown to moderately increase the firing rate of noradrenergic locus coeruleus (LC) neurons. Since changes in electrical activity of noradrenergic neurons are generally reflected in corresponding alterations of the turnover of this transmitter, the effects of these drugs on the accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) in the presence and absence of the dopamine-beta-hydroxylase inhibitor, FLA 63, were studied in the LC as well as in two of its projection areas, the hippocampus and the cerebellum. Characterization of this procedure with the alpha 2-adrenoceptor antagonist, idazoxan, the corresponding agonist, clonidine, the alpha 1-adrenoceptor antagonist prazosine, and haloperidol, suggested that--DOPAC changes are more suitable than those of DA or DOPAC/DA ratios in reflecting changes in noradrenaline (NA) turnover, inhibiting DBH is advantageous if NA turnover is to be measured in projection areas, but not in LC, and haloperidol and prazosine, in principle, did not affect NA turnover. Vincamine and hydergine at 10 mg/kg doses, at which they were reported to increase LC firing by 50%, did not induce a change in NA turnover in any of the areas. This, together with the data obtained with haloperidol, suggests that a minimal increase in the firing rate of LC cells (+140%) is required before it could influence the turnover of NA, as measured by DOPAC changes. Thus, the stimulating effect of nootropics on the central noradrenergic system may be more sensitively detected by electrophysiological techniques than by biochemical ones.

3,4-Dihydroxyphenylacetic Acid↗

One hundred years of neuropsychology in Japan: retrospect and prospect.

The development of neuropsychology in Japan since the end of the 19th century will be outlined, including a number of pioneering works that gave a scientific basis to contemporary Japanese neuropsychology. The activities of societies/associations of related disciplines as well as the educational systems of clinical and experimental neuropsychology, which represents in Japan an interdisciplinary field, will be described. After national and international activities are mentioned, a review of significant Japanese contributions to main topics in neuropsychology will be given in some detail: dementia, memory disorders, frontal lobe syndromes, aphasia-alexia-agraphia, callosal syndromes, and specific right hemisphere syndromes. The issues of these interdisciplinary scientific investigations have found application in language and cognitive disabilities of brain-damaged patients, as well as evaluation of medical treatments and comedical rehabilitational effects, care, and counseling. Finally, some comments will be presented on possible and desirable developments of Japanese neuropsychology in the future.

History, 19th Century↗

Memory improvement without toxicity during chronic, low dose intravenous arecoline in Alzheimer's disease.

Arecoline, a cholinergic agonist, administered at low doses by continuous intravenous infusion for up to 2 weeks, significantly and replicably improved memory in five of nine subjects with mild-moderate Alzheimer's disease. During dose finding, performance on a verbal memory task improved with an inverted U-shaped relation to dose. Six of nine subjects were classified as responders. During blinded, placebo-controlled, individualized optimal dosing for 5 days, verbal memory again improved in five of six responders but not in any non-responder. No adverse drug effects occurred. Arecoline, and possibly other cholinergic agonists, can safely improve memory in Alzheimer's disease at doses much lower than previously studied.

Aged↗

Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats.

Amnesia can be induced in rats in the passive avoidance paradigm by administration of scopolamine, a central muscarinic receptor antagonist. Tacrine or galanthamine, inhibitors of acetylcholinesterase, given in conjunction with scopolamine partially reversed the scopolamine-induced deficit in passive avoidance performance. Four so-called cognitive enhancers, all widely used for the treatment of the symptoms associated with mental aging, cerebral insufficiency and senile memory disorder, were investigated in this paradigm. Piracetam, an extract of Ginkgo biloba, dihydroergocristine and a combination of raubasine with dihydroergocristine, all attenuated the amnesia induced by scopolamine. In contrast, nicergoline had no significant effect. Raubasine alone also failed to significantly attenuate scopolamine-induced amnesia, although some doses of raubasine had a non-significant tendency (P less than 0.10) to reduce the amnesia.

Amnesia↗

Environmentally induced long-term structural changes: cues for functional orientation and vulnerabilities.

Environmental challenges profoundly modify phenotypes and disrupt inherent developmental programs both at functional and structural levels. As an example, we have studied the impact of these environmental influences on adult neurogenesis in the dentate gyrus. Neurogenesis results from an inherent program, participates to hippocampal network organization and, as a consequence, to the various functional abilities depending on this region, including memories. In preclinical studies of aging we have shown that phenotypes vulnerable to the development of spatial memory disorders are characterized by lower hippocampal neurogenesis. We have hypothesized that these interindividual variations in functional expression of neurogenesis in senescent subjects could be predicted early in life. Indeed, a behavioral response (novelty-induced locomotor reactivity) and a biological trait (hypothalamo-pituitary-adrenal axis activity), which are predictive of cognitive impairments later in life, are related to neurogenesis in young adult rats. This suggests that subjects starting off with an impaired neurogenesis, here rats that are high reactive to stress, are predisposed for the development of age-related cognitive disorders. We have further shown that these inter-individual differences result from early deleterious life events. Indeed, prenatal stress orients neurogenesis in pathological ways for the entire life, and precipitates age-related cognitive impairments. Altogether these data suggest first that hippocampal neurogenesis plays a pivotal role in environmentally-induced vulnerability to the development of pathological aging, and second that environmental challenges and life events orient structural developments, leading to different phenotypes.

Animals↗

[Alfred Döblin (1878-1957). Notes on the cover picture].

Alfred Döblin studied medicine after completing his Abitur (A-levels). In 1905 he earned his doctorate under Alfred Hoche, director of the psychiatric clinic, by presenting a study on "Memory disorders in Korsakoff's psychosis." He subsequently worked as an assistant doctor in various psychiatric clinics until he switched to internal medicine in 1908. He opened a practice as panel doctor in 1911, which he operated until 1930. Although Döblin had already published a few stories, he first became generally known in 1929 with the appearance of his novel entitled "Berlin Alexanderplatz: the story of Franz Biberkopf." After the burning of the Reichstag in February 1933, as a Jewish socialist Döblin was forced to emigrate. He was unable to work as a physician during his exile, but remained active in his literary pursuits. Döblin died on 26 June 1957 in the state hospital in Emmendingen.

Germany↗