Search

Animal and human literature supports spatial-motor "Aiming" bias, a frontal-subcortical syndrome, as a core deficit in spatial neglect. However, spatial neglect treatment studies rarely assess Aiming errors. Two knowledge gaps result: spatial neglect rehabilitation studies fail to capture the impact on motor-exploratory aspects of functional disability. Also, across spatial neglect treatment studies, discrepant treatment effects may also result from sampling different proportions of patients with Aiming bias. We review behavioural evidence for Aiming spatial neglect, and demonstrate the importance of measuring and targeting Aiming bias for treatment, by reviewing literature on Aiming spatial neglect and prism adaptation treatment, and presenting new preliminary data on bromocriptine treatment. Finally, we review neuroanatomical and network disruption that may give rise to Aiming spatial neglect. Because Aiming spatial neglect predicts prism adaptation treatment response, assessment may broaden the ability of rehabilitation research to capture functionally-relevant disability. Frontal brain lesions predict both the presence of Aiming spatial neglect, and a robust response to some spatial neglect interventions. Research is needed that co-stratifies spatial neglect patients by lesion location and Aiming spatial neglect, to personalize spatial neglect rehabilitation and perhaps even open a path to spatial retraining as a means of promoting better mobility after stroke.

Spatial neglect commonly follows right hemisphere stroke. It is defined as impaired contralesional stimulus detection, response, or action, causing functional disability. While prism adaptation treatment is highly promising to promote functional recovery of spatial neglect, not all individuals respond. Consistent with a primary effect of prism adaptation on spatial movements, we previously demonstrated that functional improvement after prism adaptation treatment is linked to frontal lobe lesions (Chen, Goedert, Shah, Foundas, & Barrett, 2014). However, that study was a treatment-only study with no randomized control group. The current study randomized individuals with spatial neglect to receive ten days of prism adaptation treatment, or to receive only standard care (control group). Replicating our earlier results, we found that the presence of frontal lesions moderated response to prism adaptation treatment: Among prism-treated patients, only those with frontal lesions demonstrated functional improvements in their neglect symptoms. Conversely, among individuals in the standard-care control, the presence of frontal lesions did not modify recovery. These results suggest that further research is needed on how frontal lesions may predict response to prism adaptation treatment. Additionally, the results help elucidate the neural network involved in spatial movement and could be used to aid decisions about treatment.

Patterns of cerebral asymmetry related to visuospatial functions may change with age. The typical leftward bias on a line bisection task may reflect cerebral asymmetry. With age, such leftward bias decreases. This study demonstrated that the age-related decrease of leftward bias may actually be sex-specific. In addition, previous research suggests that young adults’ deviation in line bisection may reflect asymmetric hemispheric activation of perceptual–attentional “where” spatial systems, rather than motor-intentional “aiming” spatial systems; thus, we specifically fractionated “where” and “aiming” bias of men and women ranging in age from 22 to 93 years old. We observed that older men produced greater rightward line bisection errors, of primarily “where” spatial character. However, women's errors remained leftward biased, and did not significantly change with age. “Where” spatial systems may be linked to cortico-cortical processing networks involving the posterior part of the dorsal visuospatial processing stream. Thus, the current results are consistent with the conclusion that reduced right dorsal spatial activity in aging may occur in the male, but not female, adult spatial system development. (JINS, 2011, 17, 455–462)

Proposals that adaptation with left-shifting prisms induces neglect-like symptoms in normal individuals rely on a dissociation between the postadaptation performance of individuals trained with left- versus right-shifting prisms (e.g., Colent, Pisella, & Rossetti, 2000). A potential problem with this evidence is that normal young adults have an a priori leftward bias (e.g., Jewell & McCourt, 2000). In Experiment 1, we compared the line bisection performance of young adults to that of aged adults, who as a group may lack a leftward bias in line bisection. Participants trained with both left- and right-shifting prisms. Consistent with our hypothesis, while young adults demonstrated aftereffects for left, but not right prisms, aged adults demonstrated reliable aftereffects for both prisms. In Experiment 2, we recruited a larger sample of young adults, some of whom were right-biased at baseline. We observed an interaction between baseline bias and prism-shift, consistent with the results of Experiment 1: Left-biased individuals showed a reduced aftereffect when training with right-shifting prisms and right-biased individuals showed a reduced aftereffect when training with left-shifting prisms. These results suggest that previous failures to find generalizable aftereffects with right-shifting prisms may be driven by participants’ baseline biases rather than specific effects of the prism itself. (JINS, 2010, 16, 795–804.)

People use information about the covariation between a putative cause and an outcome to determine whether a causal relationship obtains. When there are two candidate causes and one is more strongly related to the effect than is the other, the influence of the second is underestimated. This phenomenon is called causal discounting. In two experiments, we adapted paradigms for studying causal learning in order to apply signal detection analysis to this phenomenon. We investigated whether the presence of a stronger alternative makes the task more difficult (indexed by differences in d') or whether people change the standard by which they assess causality (measured by beta). Our results indicate that the effect is due to bias.

Our goal was to determine whether the extent of off-line performance improvements on a visuomotor task depends on the amount of practice individuals experience prior to a 24-h between-session break. Subjects completed ten trials of a mirror-tracing task over two days. On Day 1, subjects experienced either one, three or seven trials. Twenty-four hours later subjects completed the remainder of the ten trials. Despite experiencing an equivalent number of total training trials, subjects experiencing the 24-h delay after one or three trials demonstrated off-line performance improvements, but those experiencing the delay after seven trials did not. Furthermore, the one- and three-trial groups reached a superior level of performance by the end of training relative to the seven-trial group.

Several experiments on human causal reasoning have demonstrated "discounting"--that the presence of a strong alternative cause may decrease the perceived efficacy of a moderate target cause. Some, but not all, of these effects have been shown to be attributable to subjects' use of conditional rather than unconditional contingencies (i.e., subjects control for alternative causes). We review experimental results that do not conform to the conditionalizing contingency account of causal judgment. In four experiments, we demonstrate that there is "nonnormative discounting" above what is accounted for by conditionalization, that discounting may depend on the nature of the question put to the subjects, and that discounting can be affected by motivation. We conclude that because nonnormative discounting occurs for summary presentations as well as trial-by-trial presentations of information and because nonnormative discounting depends on motivation, it is not a necessary result of cue competition during the contingency learning process.

Representation of sequential structure can occur with respect to the order of perceptual events or the order in which actions are linked. Neural correlates of sequence retrieval associated with the order of motor responses were identified in a variant of the serial reaction time task in which training occurred with a spatially incompatible mapping between stimuli and finger responses. After transfer to a spatially compatible version of the task, performance enhancements indicative of learning were only present in subjects required to make finger movements in the same order used during training. In contrast, a second group of subjects performed the compatible task using an identical sequence of stimuli (and different order of finger movements) as in training. They demonstrated no performance benefit, indicating that learning was response based. Analysis was restricted to subjects demonstrating low recall of the sequence structure to rule out effects of explicit awareness. The interaction of group (motor vs. perceptual transfer) with sequence retrieval (sequencing vs. rest) revealed significantly greater activation in the bilateral supplementary motor area, cingulate motor area, ventral premotor cortex, left caudate, and inferior parietal lobule for subjects in the motor group (illustrating successful sequence retrieval at the response level). Retrieval of sequential responses occurs within mesial motor areas and related motor planning areas.

UNLABELLED [Correction Notice: An Erratum for this article was reported in Vol 29(2) of Neuropsychology (see record 2014-42242-001). The funding source information was missing from the author note, and A. M. Barrett's institutional affiliation was incorrect. The funding source information and Barrett's correct institutional affiliation are provided in the erratum.] OBJECTIVE The sparse existing research on ipsilesional neglect supports an association of this disorder with damage to the right frontal and subcortical brain networks. It is believed that dysfunction in these networks may result in primarily "aiming" motor-intentional spatial errors. The purpose of this study was to confirm whether frontal-subcortical circuits are indeed commonly affected in ipsilesional neglect and to determine the relative presence of "aiming" motor-intentional versus "where" perceptual-attentional spatial errors in these individuals. METHODS We identified 12 participants with ipsilesional neglect based on a computerized line bisection task and used the line bisection data to quantify participants' perceptual-attentional and motor-intentional errors. We were able to discriminate between these 2 biases using the algebraic solutions for 2 separate equations, one for "aiming" and one for "where" biases. Lesion mapping was conducted for all participants using MRIcron software; lesion checklist and overlap analysis were created from these images. RESULTS A greater percentage of participants with ipsilesional neglect had frontal/subcortical damage (83%) compared with the expected percentage (27%) observed in published patient samples with contralesional neglect. We observed the greatest area of lesion overlap in frontal lobe white matter pathways. Nevertheless, participants with ipsilesional neglect made primarily "where" rather than "aiming" spatial errors. CONCLUSION Our data confirm previous research suggesting that ipsilesional neglect may result from lesions to the right frontal-subcortical networks. Furthermore, in our group, ipsilesional neglect was also strongly associated with primarily "where" perceptual-attentional bias, and less so with "aiming" motor-intentional spatial bias.

Prism adaptation treatment (PAT) is a promising rehabilitative method for functional recovery in persons with spatial neglect. Previous research suggests that PAT improves motor-intentional “aiming” deficits that frequently occur with frontal lesions. To test whether presence of frontal lesions predicted better improvement of spatial neglect after PAT, the current study evaluated neglect-specific improvement in functional activities (assessment with the Catherine Bergego Scale) over time in 21 right-brain-damaged stroke survivors with left-sided spatial neglect. The results demonstrated that neglect patients’ functional activities improved after two weeks of PAT and continued improving for four weeks. Such functional improvement did not occur equally in all of the participants: Neglect patients with lesions involving the frontal cortex (n = 13) experienced significantly better functional improvement than did those without frontal lesions (n = 8). More importantly, voxel-based lesion-behavior mapping (VLBM) revealed that in comparison to the group of patients without frontal lesions, the frontal-lesioned neglect patients had intact regions in the medial temporal areas, the superior temporal areas, and the inferior longitudinal fasciculus. The medial cortical and subcortical areas in the temporal lobe were especially distinguished in the “frontal lesion” group. The findings suggest that the integrity of medial temporal structures may play an important role in supporting functional improvement after PAT.

Filaments made of hyperphosphorylated tau protein are encountered in a number of neurodegenerative diseases referred to as 'tauopathies'. In the most prevalent tauopathy, Alzheimer's disease, tau pathology progresses in a stereotypical manner with the first lesions appearing in the locus coeruleus and the entorhinal cortex from where they appear to spread to the hippocampus and neocortex. Propagation of tau pathology is also characteristic of argyrophilic grain disease, where the tau lesions appear to spread throughout distinct regions of the limbic system. These findings strongly implicate neurone-to-neurone propagation of tau aggregates. Isoform composition and morphology of tau filaments can differ between tauopathies suggesting the existence of conformationally diverse tau strains. Altogether, this points to prion-like mechanisms in the pathogenesis of tauopathies.

Individuals have difficulty changing their causal beliefs in light of contradictory evidence. We hypothesized that this difficulty arises because people facing implausible causes give greater consideration to causal alternatives, which, because of their use of a positive test strategy, leads to differential weighting of contingency evidence. Across 4 experiments, participants learned about plausible or implausible causes of outcomes. Additionally, we assessed the effects of participants' ability to think of alternative causes of the outcomes. Participants either saw complete frequency information (Experiments 1 and 2) or chose what information to see (Experiments 3 and 4). Consistent with the positive test account, participants given implausible causes were more likely to inquire about the occurrence of the outcome in the absence of the cause (Experiments 3 and 4) than those given plausible causes. Furthermore, they gave less weight to Cells A and B in a 2 × 2 contingency table and gave either equal or less weight to Cells C and D (Experiments 1 and 2). These effects were inconsistently modified by participants' ability to consider alternative causes of the outcome. The total of the observed effects are not predicted by either dominant models of normative causal inference or by the particular positive test account proposed here, but they may be commensurate with a more broadly construed positive test account.

Background. Spatial neglect is a debilitating disorder for which there is no agreed on course of rehabilitation. The lack of consensus on treatment may result from systematic differences in the syndrome's characteristics, with spatial cognitive deficits potentially affecting perceptual-attentional “Where” or motor-intentional “Aiming” spatial processing. Heterogeneity of response to treatment might be explained by different treatment impacts on these dissociated deficits: prism adaptation, for example, might reduce Aiming deficits without affecting Where spatial deficits. Objective. Here, we tested the hypothesis that classifying patients by their profile of Where-versus-Aiming spatial deficit would predict response to prism adaptation and specifically that patients with Aiming bias would have better recovery than those with isolated Where bias. Methods. We classified the spatial errors of 24 subacute right stroke survivors with left spatial neglect as (1) isolated Where bias, (2) isolated Aiming bias, or (3) both. Participants then completed 2 weeks of prism adaptation treatment. They also completed the Behavioral Inattention Test and Catherine Bergego Scale (CBS) tests of neglect recovery weekly for 6 weeks. Results. As hypothesized, participants with only Aiming deficits improved on the CBS, whereas those with only Where deficits did not improve. Participants with both deficits demonstrated intermediate improvement. Conclusion. These results support behavioral classification of spatial neglect patients as a potential valuable tool for assigning targeted, effective early rehabilitation.

Cultural mindset is related to performance on a variety of cognitive tasks. In particular, studies of both chronic and situationally-primed mindsets show that individuals with a relatively interdependent mindset (i.e., an emphasis on relationships and connections among individuals) are more sensitive to background contextual information than individuals with a more independent mindset. Two experiments tested whether priming cultural mindset would affect sensitivity to background causes in a contingency learning and causal inference task. Participants were primed (either independent or interdependent), and then saw complete contingency information on each of 12 trials for two cover stories in Experiment 1 (hiking causing skin rashes, severed brakes causing wrecked cars) and two additional cover stories in Experiment 2 (school deadlines causing stress, fertilizers causing plant growth). We expected that relative to independent-primed participants, those interdependent-primed would give more weight to the explicitly-presented data indicative of hidden alternative background causes, but they did not do so. In Experiment 1, interdependents gave less weight to the data indicative of hidden background causes for the car accident cover story and showed a decreased sensitivity to the contingencies for that story. In Experiment 2, interdependents placed less weight on the observable data for cover stories that supported more extra-experimental causes, while independents' sensitivity did not vary with these extra-experimental causes. Thus, interdependents were more sensitive to background causes not explicitly presented in the experiment, but this sensitivity hurt rather than improved their acquisition of the explicitly-presented contingency information.

Spatial neglect is a debilitating post-stroke neurocognitive disorder, associated with longer hospitalization and worse rehabilitation outcomes. Prior literature suggests a high prevalence of this disorder, but in reality clinicians have difficulty reliably identifying affected survivors. This discrepancy may result from suboptimal use of validated neglect assessment procedures. In this article, we suggest a validated assessment tool, sensitive to identify neglect and its functional consequences, the Catherine Bergego Scale (CBS). We provide detailed item-by-item CBS instructions for observation and scoring: the Kessler Foundation Neglect Assessment Process (KF-NAP). We describe a unique attribute of the CBS and the KF-NAP: rehabilitation researchers may be able to use them to measure both ecological outcomes, and specific, separable perceptual-attentional and motor-exploratory spatial behaviors.

Spatial neglect increases hospital morbidity and costs in around 50% of the 795,000 people per year in the USA who survive stroke, and an urgent need exists to reduce the care burden of this condition. However, effective acute treatment for neglect has been elusive. In this article, we review 48 studies of a treatment of intense neuroscience interest: prism adaptation training. Due to its effects on spatial motor 'aiming', prism adaptation training may act to reduce neglect-related disability. However, research failed, first, to suggest methods to identify the 50-75% of patients who respond to treatment; second, to measure short-term and long-term outcomes in both mechanism-specific and functionally valid ways; third, to confirm treatment utility during the critical first 8 weeks poststroke; and last, to base treatment protocols on systematic dose-response data. Thus, considerable investment in prism adaptation research has not yet touched the fundamentals needed for clinical implementation. We suggest improved standards and better spatial motor models for further research, so as to clarify when, how and for whom prism adaptation should be applied.

Goedert KM, Chen P, Botticello A, Masmela JR, Adler U, Barrett AM. Psychometric evaluation of neglect assessment reveals motor-exploratory predictor of functional disability in acute-stage spatial neglect. Objective To determine the psychometric properties of 2 neglect measures, the Behavioral Inattention Test (BIT)-conventional and the Catherine Bergego Scale (CBS), in acute spatial neglect. Spatial neglect is a failure or slowness to respond, orient, or initiate action toward contralesional stimuli, associated with functional disability that impedes stroke recovery. Early identification of specific neglect deficits may identify patients likely to experience chronic disability. However, psychometric evaluation of assessments has focused on subacute/chronic populations. Design Correlational/psychometric study. Setting Inpatient rehabilitation hospital. Participants Screening identified 51 consecutive patients with a right-hemisphere stroke with left neglect (BIT score 11) tested an average of 22.3 days poststroke. Interventions Not applicable. Main Outcome Measures We obtained BIT, CBS, and Barthel Index assessments for each participant and clinical and laboratory measures of perceptual-attentional and motor-intentional deficits. Results The BIT showed good reliability and loaded onto a single factor. Consistent with our theoretical prediction, principal components analysis of the CBS identified 2 underlying factors: Where perceptual-attentional items (CBS-PA) and embodied, motor-exploratory items (CBS-ME). The CBS-ME uniquely predicted deficits in activities of daily living (ADLs) assessed by using the Barthel Index, but did not predict clinical and laboratory assessments of motor-intentional bias. More severe neglect on the CBS-PA correlated with greater Where perceptual-attentional bias on clinical and laboratory tests, but did not uniquely predict deficits in ADLs. Conclusions Our results indicate that assessments of spatial neglect may be used to detect specific motor-exploratory deficits in spatial neglect. Obtaining CBS-ME scores routinely might improve the detection of acute-stage patients with spatial action deficits requiring increased assistance that may persist to the chronic stage.

Prism adaptation may alleviate some symptoms of spatial neglect. However, the mechanism through which this technique works is still unclear. The current study investigated whether prism adaptation differentially affects dysfunction in perceptual-attentional “where” versus motor-intentional “aiming” bias. Five neglect patients performed a line bisection task in which lines were viewed under both normal and right-left reversed viewing conditions, allowing for the fractionation of “where” and “aiming” spatial bias components. Following two consecutive days of prism adaptation, participants demonstrated a significant improvement in “aiming” spatial bias, with no effect on “where” spatial bias. These findings suggest that prism adaptation may primarily affect motor-intentional “aiming” bias in post-stroke spatial neglect patients.

Prism adaptation (PA) has been shown to affect performance on a variety of spatial tasks in healthy individuals and neglect patients. However, little is still known about the mechanisms through which PA affects spatial cognition. In the present study we tested the effect of PA on the perceptual-attentional “where” and motor-intentional “aiming” spatial systems in healthy individuals. Eighty-four participants performed a line bisection task presented on a computer screen under normal or right-left reversed viewing conditions, which allows for the fractionation of “where” and “aiming” bias components (Schwartz et al., 1997). The task was performed before and after a short period of visuomotor adaptation either to left- or right-shifting prisms, or control goggles fitted with plain glass lenses. Participants demonstrated initial leftward “where” and “aiming” biases, consistent with previous research. Adaptation to left-shifting prisms reduced the leftward motor-intentional “aiming” bias. By contrast, the “aiming” bias was unaffected by adaptation to the right-shifting prisms or control goggles. The leftward “where” bias was also reduced, but this reduction was independent of the direction of the prismatic shift. These results mirror recent findings in neglect patients, who showed a selective amelioration of right motor-intentional “aiming” bias after right prism exposure (Fortis, Kornitzer, Goedert & Barrett, 2009; Striemer and Danckert, 2010a). Thus, these findings indicate that prism adaptation primarily affects the motor-intentional “aiming” system in both healthy individuals and neglect patients, and further suggest that improvement in neglect patients after PA may be related to changes in the aiming spatial system.

Cytomegalovirus (CMV) interstitial pneumonia is a frequent and often fatal complication of allogeneic bone marrow transplantation. Because therapy for CMV pneumonia was, until recently, largely ineffective, prophylactic methods were explored. This study shows that the strategy of using CMV seronegative blood products for seronegative patients with seronegative donors or weekly administration of intravenous immunoglobulin for all other patients reduced the attack rate of CMV pneumonia. The results of this study are put into the perspective of previously published data.

Objectives To explore the factor structure of the Kessler Foundation Neglect Assessment Process (KF-NAP), and evaluate the prevalence and clinical significance of spatial neglect among stroke survivors. Design Inception cohort. Setting Inpatient rehabilitation facility (IRF). Participants Participants (N=121) with unilateral brain damage from their first stroke were assessed within 72 hours of admission to an IRF, and 108 were assessed again within 72 hours before IRF discharge. Interventions Usual and standard IRF care. Main Outcome Measures During each assessment session, occupational therapists measured patients' functions with the KF-NAP, FIM, and Barthel Index (BI). Results The KF-NAP showed excellent internal consistency with a single-factor structure. The exploratory factor analysis revealed the KF-NAP to be unique from both the FIM and BI even though all 3 scales were correlated. Symptoms of spatial neglect (KF-NAP>0) were present in 67.8% of the participants at admission and 47.2% at discharge. Participants showing the disorder at IRF admission were hospitalized longer than those showing no symptoms. Among those presenting with symptoms, the regression analysis showed that the KF-NAP scores at admission negatively predicted FIM scores at discharge, after controlling for age, FIM at admission, and length of stay. Conclusions The KF-NAP uniquely quantifies symptoms of spatial neglect by measuring functional difficulties that are not captured by the FIM or BI. Using the KF-NAP to measure spatial neglect, we found the disorder persistent after inpatient rehabilitation, and replicated previous findings showing that spatial neglect adversely affects rehabilitation outcome even after prolonged IRF care.

When people are asked to judge the strengths of two potential causes of an effect, they often demonstrate discounting--devaluing the strength of a target cause when it is judged in the presence of a strong (relative to a weak) alternative cause. Devaluing the target cause sometimes results from conditionalization--holding alternative causes constant while evaluating the target cause. Yet discounting not attributable to conditionalization also occurs. We sought to dissociate conditionalization and discounting (beyond that accounted for by conditionalization) by having subjects perform either a spatial or a verbal working memory task while learning a causal relation. Conditionalization was disrupted by the verbal task but not the spatial task; however, discounting was disrupted by the spatial task but not the verbal task. Conditionalization and discounting are therefore cognitively dissociable processes in human causal inference.

The idea that memory is not unitary but is instead composed of multiple systems has a long history and has been debated with particular vigor in the last 20 years. Nevertheless, whether or not there are multiple memory systems remains unsettled. In this article, we suggest that psychologists wishing to classify memory can learn from biological systematics, the discipline that creates taxonomies of species. In so doing, we suggest that psychologists have made two assumptions in classifying memory: that features of memory are perfectly correlated, and that there is a straightforward mapping between taxonomy and theory. We argue that these assumptions are likely to be incorrect, but we also argue that there is a place for taxonomy in the study of memory. Taxonomies of memory are organizational schemes for data--they are descriptive, not explanatory--and so can inspire theory, although they cannot serve as theories themselves.

The studies reported here used an interference paradigm to determine whether a long-term consolidation process (i.e., one lasting from several hours to days) occurs in the learning of two implicit motor skills, learning of a movement sequence and learning of a visuo-motor mapping. Subjects learned one skill and were tested on that skill 48 h later. Between the learning session and test session, some subjects trained on a second skill. The amount of time between the learning of the two skills varied for different subjects. In both the learning of a movement sequence and the learning of a visuo-motor mapping, we found that remote memories were susceptible to interference, but the passage of time did not afford protection from interference. These results are inconsistent with the long-term consolidation of these motor skills. A possible difference between these tasks and those that do show long-term consolidation is that the present tasks are not dynamic motor skills.

Familial dementia with swollen achromatic neurons and corticobasal inclusion bodies is a neurodegenerative disease that resembles corticobasal degeneration. It is characterized by the presence of abundant neuronal and glial tau protein deposits. Here we describe a novel silent mutation in exon 10 of tau (N296N) in this familial dementia. By exon trapping, the mutation produced an increase in the splicing in of exon 10, indicating that it probably causes disease through an overproduction of four-repeat tau.

Exonic and intronic mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe a new mutation, consisting of a C-to-T transition at position +12 of the intron following exon 10 of the tau gene in the Kumamoto pedigree, showing frontotemporal dementia. The mutation caused a marked reduction in melting temperature of the tau exon 10-splicing regulatory element RNA and a large increase in exon 10-containing transcripts. Brain tissue from affected individuals showed an abnormal preponderance of exon 10-containing transcripts that was reflected at the protein level by an overproduction of tau isoforms with four microtubule-binding repeats. Immunostaining revealed the presence of tau aggregates in degenerating neurons and glial cells. Isolated tau filaments had a twisted ribbon-like morphology and were made of hyperphosphorylated four-repeat tau isoforms. The additional mutation located dose to the splice-donor site of the intron following exon 10 of the tau gene supports the view that intronic mutations exercize their pathogenic effect by destabilizing RNA secondary structure.

To facilitate studies of the normal biology of alpha-synuclein, a member of a family of neuronal proteins of unknown function, and to elucidate the role of alpha-synuclein pathologies in neurodegenerative diseases, we generated and characterized a panel of anti-synuclein antibodies. Here we demonstrate that these antibodies recognize defined epitopes spanning the entire length of human alpha-synuclein, and that some of these antibodies also cross-react with zebra finch and rodent synucleins. Since alpha-synuclein has been reported to be a major component of Lewy bodies (LBs) in Parkinson's disease (PD), dementia with LBs and common variants of Alzheimer's disease, we performed immunohistochemical studies showing that these antibodies label numerous LBs in the PD substantia nigra, thereby localizing protein domains throughout human alpha-synuclein in LBs. Taken together, our data indicate that this panel of antibodies can be exploited to probe the normal biology of alpha-synuclein as well as the role of pathological forms of this protein in PD and related neurodegenerative synucleinopathies.

Hyperphosphorylated microtubule-associated protein tau is the major proteinaceous component of the paired helical and straight filaments which constitute a defining neuropathological characteristic of Alzheimer's disease and a number of other neurodegenerative disorders. We have recently shown that full-length recombinant tau assembles into Alzheimer-like filaments upon incubation with heparin. Heparin also promotes phosphorylation of tau by a number of protein kinases, prevents tau from binding to taxol-stabilized microtubules, and produces rapid disassembly of microtubules assembled from tau and tubulin. Here, we have used the above parameters to study the interactions between tau protein and a number of naturally occurring and synthetic glycosaminoglycans. We show that the magnitude of the glycosaminoglycan effects is proportional to their degree of sulfation. Thus, the strongly sulfated glycosaminoglycans dextran sulfate, pentosan polysulfate, and heparin were the most potent, whereas the non-sulfated dextran and hyaluronic acid were without effect. The moderately sulfated glycosaminoglycans heparan sulfate, chondroitin sulfate, and dermatan sulfate had intermediate effects, whereas keratan sulfate had little or no effect. These in vitro interactions between tau protein and sulfated glycosaminoglycans reproduced the known characteristics of paired helical filament-tau from Alzheimer's disease brain. Sulfated glycosaminoglycans are present in nerve cells in Alzheimer's disease brain in the early stages of neurofibrillary degeneration, suggesting that their interactions with tau may constitute a central event in the development of the neuronal pathology of Alzheimer's disease.

In this experiment we explored age differences in frequency judgment. Young and older adults studied words occurring from one to six times under divided or focused attention and then completed either a frequency discrimination or a frequency estimation test for these items. Divided attention led to poorer performance on both frequency judgment tests, suggesting that distraction during the encoding of target events results in less optimal encoding of the information that is necessary for any type of frequency judgment. Contrary to the notion that older adults encode this information more superficially than young adults, older adults were as sensitive as young adults to relative differences in the frequency of target words, and distraction did not magnify age differences for either type of frequency judgment task. On the other hand, older adults were less accurate in assigning an absolute numerical value to the frequency of the target words. Altogether, the results are consistent with the idea that'the encoding and/or retrieval processes required for accurate numerical estimation of frequency suffer a larger age-related decline than do those required for accurate discrimination of relative frequency.

1. We have taken advantage of our recent development of highly potent and specific phosphinic inhibitors of endopeptidase 3.4.24.15 to examine the putative contribution of the enzyme in the secretion of A beta by HK293 transfected cells overexpressing the wild type and the Swedish (Sw) double mutated form of beta APP751. 2. First, we showed that HK293 cells contain a peptidase activity, the inhibition profile of which fully matches that of purified endopeptidase 3.4.24.15. Second, we established that the treatment of HK293 cells with specific phosphinic inhibitors leads to about 80% inhibition of intracellular endopeptidase 3.4.24.15 activity, indicating that these inhibitors penetrate the cells. 3. Metabolic labelling of wild type and Sw beta APP751-expressing cells, followed by immunoprecipitation of A beta-containing peptides, revealed the secretion of A beta and the intracellular formation of an A beta-containing 12 kDa product. 4. A beta secretion by Sw beta APP751 transfected cells was drastically enhanced when compared to cells expressing wild type beta APP751. This production was not affected by endopeptidase 3.4.24.15 inhibitors in either cell type. This correlates well with the observation that endopeptidase 3.4.24.15 does not cleave recombinant baculoviral Sw beta APP751, in vitro. 5. Our previous data indicated that endopeptidase 3.4.24.15 activity was reduced in the parietal cortex of Alzheimer's disease affected brains and that the enzyme probably participated, in this brain area, to the catabolism of somatostatin 1-14. However, the present work indicates that endopeptidase 3.4.24.15 does not seem to behave as a beta-secretase in HK293 transfected cells. Therefore, it is suggested that endopeptidase 3.4.24.15 could participate in the symptomatology, but probably not in the aetiology of Alzheimer's disease.

Abundant neurofibrillary tangles, neuropil threads and senile plaque neurites constitute the neurofibrillary pathology of Alzheimer's disease. They form in the nerve cells that undergo degeneration in the disease, in which their regional distribution correlates with the degree of dementia. Each lesion contains the paired helical filament (PHF) as its major fibrous component. Recent work has shown that PHFs are composed of the microtubule-associated protein tau in a hyperphosphorylated state. PHF-tau is hyperphosphorylated on six adult brain tau isoforms. As a consequence, tau is unable to bind to microtubules and is believed to self-assemble into the PHF. Current evidence suggests that protein kinases or protein phosphatases with a specificity for serine/threonine-proline residues are instrumental in the hyperphosphorylation of tau. Candidate protein kinases include mitogen-activated protein kinase, glycogen synthase kinase 3 and cyclin-dependent kinase 5, whereas the trimeric form of protein phosphatase 2A is a candidate phosphatase.

The paired helical filaments (PHFs) of Alzheimer's disease consist mainly of the microtubule-associated protein tau. PHF tau differs from normal human brain tau in that it has a higher Mr and a special state of phosphorylation. However, the protein kinase(s) involved, the phosphorylation sites on tau and the resulting conformational changes are only poorly understood. Here we show that a new monoclonal antibody, AT8, records the PHF-like state of tau in vitro, and we describe a kinase activity that turns normal tau into a PHF-like state. The epitope of AT8 is around residue 200, outside the region of internal repeats and requires the phosphorylation of serines 199 and/or 202. Both of these are followed by a proline, suggesting that the kinase activity belongs to the family of proline-directed kinases. The epitope of AT8 is nearly coincident with that of another phosphorylation-dependent antibody, TAU1 [Binder, L.I., Frankfurter, A. and Rebhun, L. (1985) J. Cell Biol., 101, 1371-1378], but the two are complementary since TAU1 requires a dephosphorylated epitope.

Full length cDNA clones encoding microtubule-associated proteins (MAP) 2b and 2c from rat brain have been isolated and sequenced. The cDNA fragments spanning the coding regions for both MAP2b and MAP2c were assembled and expressed in Escherichia coli. The mobility of these bacterial expressed proteins in sodium dodecyl sulfate gels is identical to that of MAP2b and MAP2c from rat brain. The protein sequence of rat MAP2b has been compared to the full length sequence from mouse and the partial sequence from human high molecular weight MAP2. This comparison has revealed that MAP2b is composed of several highly conserved domains flanked by domains with extensive sequence divergence. Two of the conserved domains, found either at the NH2 or COOH terminus, overlap with the binding domain for the regulatory subunit of the cAMP-dependent protein kinase II and the microtubule-binding domain, respectively. A third homologous domain of unknown function lies in a central region of MAP2b. Secondary structure prediction suggests that the portion of MAP2b which extends from the microtubule surface is composed of an extensive number of alpha-helices separated by small turns which may account for the extended yet flexible structure of MAP2. Interestingly, the 4000-base pair deletion from the middle of MAP2b which generates MAP2c not only removes these helices, but also this third highly conserved MAP2b domain.

The human mas oncogene, which renders transfected NIH/3T3 cells tumorigenic, was identified as a subtype of angiotensin receptor by transient expression in Xenopus oocytes and stable expression in the mammalian neuronal cell line, NG115-401L. The mas receptor preferentially recognizes angiotensin III, and is expressed at high levels in brain. The mas/angiotensin receptor functions through the breakdown of inositol lipids and can drive DNA synthesis, unlike another inositol-linked peptide receptor, that for bradykinin. Comparative analysis of several early biochemical events elicited by either angiotensin or bradykinin stimulation of mas-transfected cells has not indicated a specific difference correlated with mitogenic activity. In particular, the inositol lipid kinase, phosphatidylinositol-3-kinase, thought to be involved in the mitogenic mechanism of platelet-derived growth factor receptors, is unaffected by activation of mas. These results have shown that a proto-oncogene encodes a neural peptide receptor, indicating that peptide receptors may be involved in differentiation and proliferation processes, as are other identified proto-oncogenes.

Substantial amounts of both dopamine and norepinephrine in addition to serotonin were found in a mesenteric metastasis of an ileal carcinoid tumor. Correspondingly, the norepinephrine-synthesizing enzymes were present in the tumor tissue and tyrosine hydroxylase was found in amounts substantially higher than the levels normally present in adrenal medullary cells. These findings confirm that the carcinoid tumors belong to the APUDomas and indicate that catecholamines might play an important role in the pathogenesis of the carcinoid syndrome.