Applicability of the CANTAB-PAL Computerized Memory Test in Identifying Amnestic Mild Cognitive Impairment and Alzheimer's Disease

Aim: To compare the diagnostic accuracy of a computerized test, the CANTAB paired associate learning (PAL) to that of an established and validated noncomputerized test, the CERAD Wordlist Learning task in differentiating between normal aging, aMCI and AD in a cross-sectional design. Methods: 58 participants were assessed (19 with mild probable AD, 17 aMCI, 22 healthy controls). Results: The variables found to best discriminate between the three groups were the CANTAB PAL total errors adjusted (p < 0.0001, 81.0% of the cases correctly classified), and CERAD Wordlist Learning Delayed Recall (p < 0.0001, 77.6% of the cases correctly classified). Using both PAL total errors adjusted and Wordlist Learning Delayed Recall, 84.5% of the cases were correctly classified. Discussion: The results suggest that the CANTAB could be used for screening of AD-typical memory impairment.     

How does the hippocampal formation mediate memory for stimuli processed by the magnocellular and parvocellular visual pathways? Evidence from the comparison of schizophrenia and amnestic mild cognitive impairment (aMCI)

Paired associates learning is impaired in both schizophrenia and amnestic mild cognitive impairment (aMCI), which may reflect hippocampal pathology. In addition, schizophrenia is characterized by the dysfunction of the retino-geniculo-striatal magnocellular (M) visual pathway. The purpose of this study was to investigate the interaction between visual perceptual and memory dysfunctions. We administered a modified version of the CANTAB paired associates learning task to patients with schizophrenia (n=20), aMCI (n=20), and two groups of matched healthy controls (n=20 for each patient group). The stimuli in the paired associates learning task biased information processing toward the M pathways (low contrast, low spatial frequency) and parvocellular (P) pathways (high contrast, high spatial frequency). Results revealed that patients with schizophrenia exhibited a more pronounced learning deficit for M-biased relative to P-biased stimuli. In aMCI, there were similar memory deficits for both types of stimuli. Orientation discrimination for M- and P-biased stimuli was intact in both groups of patients. The number of errors in the M-biased memory condition significantly and inversely correlated with the volume of the right hippocampus in schizophrenia. These results suggest an interaction between M-biased perceptual processing and short-term relational memory in schizophrenia, which may be associated with the structural alteration of the right hippocampus.     

Attentional aspects of classroom behavior and discrimination learning.

Teachers' ratings of their mentally handicapped pupils' classroom behavior were examined as correlates of the child's performance on a discrimination learning task. Teachers completed the 23-item version of the Attention/Distraction Inhibition/Excitation Classroom Assessment Scale (ADIECAS) for a total of 77 pupils. Factors identified as attention/distractibility and responsivity to consequences correlated significantly with number of errors and number of trials to criterion during acquisition of a simultaneous visual discrimination. Attention/distractibility scores also correlated significantly with number of dimensions "attended to" during discrimination learning.     

Procedural memory in Parkinson's disease: impaired motor but not visuoperceptual learning

A current model proposes that memory consists of two functionally separate systems that have different neurological substrates. Declarative memory appears to be dependent on the diencephalic medial temporal lobe system whereas some speculate that the basal ganglia may be a neurological substrate for procedural memory. This study tested the role of the basal ganglia in regulating different types of procedural skills by comparing performance on a motor and a visuoperceptual skill learning task. Twenty Parkinson's (PD) patients and 20 normal control subjects performed two procedural learning tasks (rotary pursuit and mirror reading) and one declarative learning task (paired associates) over 3 days. The results showed that PD patients were not impaired on mirror reading or paired associate learning. On rotary pursuit, performance levels on day 1 were similar between groups, but the PD group showed less improvement across days than controls. However, only patients with more advanced symptoms of PD showed impaired rotary pursuit learning, and this could not be attributed directly to deficits in primary motor or general cognitive function. These findings suggest that the underlying processes/procedures for procedural learning are specific to the task, and are supported by different neuroanatomical systems.     

Is the WMS-IV Verbal Paired Associates as Effective as Other Memory Tasks in Discriminating Amnestic Mild Cognitive Impairment from Normal Aging?

Paired associate learning tasks are reportedly particularly sensitive to preclinical Alzheimer’s disease. We aimed to determine the effectiveness of the recently updated Wechsler Memory Scale verbal paired associates (VPA) in distinguishing the earliest stages of memory impairment (amnestic mild cognitive impairment, aMCI), and the clinical application at the case level, compared with other episodic memory tasks. Participants were 77 people with aMCI and 77 matched healthy older adults (HOA). VPA performance distinguished aMCI from HOA at the group level with large effect sizes, of similar size to the other tasks at immediate recall, but smaller than the CVLT-II list-learning task at delayed recall. Similarly, receiver operating characteristic (ROC) analysis demonstrated good discrimination, similar to other tasks, but again with CVLT-II more accurate at delayed recall. Although group differences remained for normative data, on a case basis using existing normative data the VPA failed to identify 70% of aMCI as impaired. The findings suggest further examination of the normative data is required before the VPA is useful in clinical practice, and highlight the importance of comprehensive neuropsychological assessment in detecting mild memory changes in older adults.     

Stimulus-preference and memory factors in Korsakoff's syndrome

Patients with Korsakoff's syndrome were compared to aphasic patients and to neurologically-intact control subjects on a task designed to assess the effects of stimulus preferences on visual discrimination learning and retention. Although both the Korsakoff and the aphasic groups made more errors on this task than the normal controls, the two brain-damaged groups showed different patterns of response: (1) Korsakoff patients made more errors on non-preferred than on preferred stimulus dimensions, while the aphasics did not, and (2) only the Korsakoffs made significantly more errors on later test trials than on earlier ones. These results support previous suggestions that Korsakoff's disease may affect cognitive functioning independently of retention.     

Functional neuroanatomy of successful paired associate learning in Alzheimer's disease

OBJECTIVE: The purpose of the study was to develop a strategy for functional imaging of neurodegenerative disorders that overcomes confounds associated with differential performance between patient and comparison groups. METHOD: Functional magnetic resonance imaging was used to examine responses to increasing difficulty of visuospatial paired associate learning in 12 patients with mild probable Alzheimer's disease and 12 age-matched healthy comparison subjects. Performance was matched across groups by only examining successful encoding and retrieval attempts. Adjustment for task difficulty was made on an individual basis so that the patients with Alzheimer's disease and the comparison subjects performed at the same relative levels of difficulty. RESULTS: A network of lateral and medial frontoparietal and occipital regions was engaged in all subjects during successful associative learning. As task difficulty increased, blood-oxygen-level-dependent responses increased linearly in occipitoparietal regions during encoding and retrieval. Differential activations in patients with Alzheimer's disease and comparison subjects were small and were found only when an uncorrected statistical threshold was used. CONCLUSIONS: By controlling for confounds of varying task difficulty and subsequent performance, remarkably similar brain activations were identified during successful paired associate learning in patients with Alzheimer's disease and in healthy comparison subjects. The study methods provide a useful model for further applications of functional imaging involving cognitive activation paradigms in the study of neuropsychiatric disorders.     

Procedural memory in Parkinson's disease: Impaired motor but not visuoperceptual learning

Abstract

A current model proposes that memory consists of two functionally separate systems that have different neurological substrates. Declarative memory appears to be dependent on the diencephalic medial temporal lobe system whereas some speculate that the basal ganglia may be a neurological substrate for procedural memory. This study tested the role of the basal ganglia in regulating different types of procedural skills by comparing performance on a motor and a visuoperceptual skill learning task. Twenty Parkinson's (PD) patients and 20 normal control subjects performed two procedural learning tasks (rotary pursuit and mirror reading) and one declarative learning task (paired associates) over 3 days. The results showed that PD patients were not impaired on mirror reading or paired associate learning. On rotary pursuit, performance levels on day 1 were similar between groups, but the PD group showed less improvement across days than controls. However, only patients with more advanced symptoms of PD showed impaired rotary pursuit learning, and this could not be attributed directly to deficits in primary motor or general cognitive function. These findings suggest that the underlying processes/procedures for procedural learning are specific to the task, and are supported by different neuroanatomical systems.     

Egocentric and allocentric memory as assessed by virtual reality in individuals with amnestic mild cognitive impairment

Present evidence suggests that medial temporal cortices subserve allocentric representation and memory, whereas egocentric representation and memory also depends on parietal association cortices and the striatum. Virtual reality environments have a major advantage for the assessment of spatial navigation and memory formation, as computer-simulated first-person environments can simulate navigation in a large-scale space. Twenty-nine patients with amnestic MCI (aMCI) were compared with 29 healthy matched controls on two virtual reality tasks affording to learn a virtual park (allocentric memory) and a virtual maze (egocentric memory). Participants further received a neuropsychological investigation and MRI volumetry at the time of the assessment. Results indicate that aMCI patients had significantly reduced size of the hippocampus bilaterally and the right-sided precuneus and inferior parietal cortex. aMCI patients were severely impaired learning the virtual park and the virtual maze. Smaller volumes of the right-sided precuneus were related to worse performance on the virtual maze. Participants with striatal lacunar lesions committed more errors than participants without such lesions on the virtual maze but not on the virtual park. aMCI patients later converting to dementia (n = 15) had significantly smaller hippocampal size when compared with non-converters (n = 14). However, both groups did not differ on virtual reality task performance. Our study clearly demonstrates the feasibility of virtual reality technology to study spatial memory deficits of persons with aMCI. Future studies should try to design spatial virtual reality tasks being specific enough to predict conversion from MCI to dementia and conversion from normal to MCI.     

Impaired context reversal learning, but not cue reversal learning, in patients with amnestic mild cognitive impairment

It has been proposed that reversal learning is impaired following damage to the orbitofrontal and ventromedial frontal cortex (OFC/VMFC) and to the medial temporal lobe (MTL), including the hippocampal formation. However, the exact characteristics of the MTL-associated reversal learning deficit are not known. To investigate this issue, we assessed 30 newly diagnosed patients with amnestic mild cognitive impairment (aMCI) and 30 matched healthy controls. All patients fulfilled the aMCI criteria of the Mayo Clinic Alzheimer's Disease Research Center and underwent head magnetic resonance imaging that confirmed MTL atrophy. Reversal learning was assessed using a novel reinforcement learning task. Participants first acquired and then reversed stimulus-outcome associations based on negative and positive feedback (losing and gaining points). Stimuli consisted of a cue (geometric shapes) and a spatial context (background color or pattern). Neuropsychological assessment included tasks related to the MTL (paired associates learning), dorsolateral prefrontal cortex (DLPFC) (extradimensional shift, One-touch Stockings of Cambridge), and OFC/VMFC (Holiday Apartment Task). Results revealed that, relative to controls, patients with aMCI exhibited a marked reversal learning deficit, which was highly selective for the reversal of context. The acquisition of stimulus-outcome associations and cue reversal learning were spared. Performance on the context reversal learning task significantly correlated with the right hippocampal volume. In addition, patients with aMCI had deficits on tests related to DLPFC but not to OFC/VMFC. However, DLPFC dysfunctions were not associated with context reversal learning. These results suggest that MTL deficits in aMCI selectively affect context reversal learning when OFC/VMFC functions are spared. This deficit is not influenced by the valence of the outcome (positive or negative feedback) and by executive dysfunctions.     

Conditional associative learning and the hippocampal system

Rats with lesions of the fornix, the dorsal hippocampus, or a control operation were trained on a spatial-visual conditional associative learning task in which they had to learn to associate particular locations with specific visual stimuli. Animals with damage of the fornix were able to learn the task at a rate comparable to that of the control animals, but the performance of the hippocampal rats was significantly impaired in comparison with that of both the control and the fornix groups. In a second experiment, lesions to the fornix or the dorsal hippocampus significantly impaired performance on a spatial working memory task, the eight-arm radial maze. These findings suggest that the interaction between the hippocampus and subcortical structures via the fornix may be critical only for certain types of spatial learning and memory. Hippocampus 1998;8:131–137. © 1998 Wiley-Liss, Inc.     

Age and education adjusted normative data and discriminative validity for Rey’s Auditory Verbal Learning Test in the elderly Greek population

Rey’s Auditory Verbal Learning Test (RAVLT) is a widely used neuropsychological test to assess episodic memory. In the present study we sought to establish normative and discriminative validity data for the RAVLT in the elderly population using previously adapted learning lists for the Greek adult population. We administered the test to 258 cognitively healthy elderly participants, aged 60–89 years, and two patient groups (192 with amnestic mild cognitive impairment, aMCI, and 65 with Alzheimer’s disease, AD). From the statistical analyses, we found that age and education contributed significantly to most trials of the RAVLT, whereas the influence of gender was not significant. Younger elderly participants with higher education outperformed the older elderly with lower education levels. Moreover, both clinical groups performed significantly worse on most RAVLT trials and composite measures than matched cognitively healthy controls. Furthermore, the AD group performed more poorly than the aMCI group on most RAVLT variables. Receiver operating characteristic (ROC) analysis was used to examine the utility of the RAVLT trials to discriminate cognitively healthy controls from aMCI and AD patients. Area under the curve (AUC), an index of effect size, showed that most of the RAVLT measures (individual and composite) included in this study adequately differentiated between the performance of healthy elders and aMCI/AD patients. We also provide cutoff scores in discriminating cognitively healthy controls from aMCI and AD patients, based on the sensitivity and specificity of the prescribed scores. Moreover, we present age- and education-specific normative data for individual and composite scores for the Greek adapted RAVLT in elderly subjects aged between 60 and 89 years for use in clinical and research settings.     

Dynamic working memory performance in individuals with single-domain amnestic mild cognitive impairment

Previous studies have observed poorer working memory performance in individuals with amnestic mild cognitive impairment than in healthy older adults. It is unclear, however, whether these difficulties are true only of the multiple-domain clinical subtype in whom poorer executive functioning is common. The current study examined working memory, as measured by the self-ordered pointing task (SOPT) and an n-back task, in healthy older adults and adults with single-domain amnestic mild cognitive impairment (aMCI). Individuals with single-domain aMCI committed more errors and required longer to develop an organizational strategy on the SOPT. The single-domain aMCI group did not differ from healthy older adults on the 1-back or 2-back, but had poorer discrimination on the 3-back task. This is, to our knowledge, the first characterization of dynamic working memory performance in a single-domain aMCI group. These results lend support for the idea that clinical amnestic MCI subtypes may reflect different stages on a continuum of progression to dementia and question whether standardized measures of working memory (span tasks) are sensitive enough to capture subtle changes in performance.     

Ralentissement cognitif dans le vieillissement : fonctions exécutives et apprentissage procédural lors d'une tâche informatisée de labyrinthe

General slowing of performance speed is a common finding associated with normal aging. However, which aspects of information processing are playing a major role in this decline are not well understood. Impairment in maze learning has been shown in patients with neurological disorders. Hippocampal bilateral lesions are associated mith larger deficits and interfere with both storage and retrieval of spatial information. Frontal lesions also produce similar effects and are characterized by perseverative errors. Reduced working memory has also been implicated in cognitive aging and is reflected in difficulties encountered in the execution of a task in real time when alterning between encoding and retrieval of information. A computerized maze learning task (Groton Maze Learning Task, GMLT) was developed specifically to determine the extent to which perseverative behaviors, working memory difficulties or other factors are implicated in the cognitive slowing generally observed in aging. Two groups of right-handed subjects (20 young adults: M =22.6; SD =1.54; 19 older adults: M =64; SD3 =0.93) were compared looking at speed of learning and perseverative errors. Subjects were also assessed on tasks of procedural learning (Tower of Toronto), working memory (Paced Auditory Serial Addition Test; PASAT), and four subtests of the Wechsler Memory Scale-III (logical memory, faces, paired associates, family pictures) with immediate and delayed recall. With respect to the GMLT, subjects were required to find the correct path through a hidden maze by pressing on the computer’s touchscreen to move to the location of their choice. After practice trials, all subjects underwent ten consecutive trials followed, ten minutes later, by one last trial. Results of interest showed significant differences between the two groups in the time needed to complete all trials and in the number of perseverative errors. More specifically, the older subjects made more perseverative errors and were slower in learning the maze. In addition, a canonical correlation analysis was performed to determine the relationship between maze learning and the cognitive systems involved (executive function, working memory, procedural learning). The analysis revealed a canonical variate explaining 49% of the total variance, showing that the number of perseverative errors and number of moves on the Tower of Toronto test are the main components principally implicated in the performance of subjects on the GMLT. We conclude that the tendency for healthy elderly adults to make perseverative errors while completing the learning trials, often related to frontal-lobe dysexecutive syndromes, may also be associated with normal aging. It is suggested that the poorer monitoring of errors and/or the inhibition of a choice in response to new information observed in the elderly accounts, at least in part, for the overall finding of slowed information processing speed.     

Subtle memory decline over 12 months in mild cognitive impairment

OBJECTIVE: Screening of normal older persons for progressive memory decline is a worthwhile strategy in the pursuit of the earliest possible stages of pre-clinical Alzheimer's disease (AD) or mild cognitive impairment (MCI). Reliable tests are needed to both detect MCI and measure the natural history of decline over months rather than years. We aimed to detect memory decline over 1 year in a group of older individuals with well-characterised amnestic MCI. METHODS: The continuous learning task (CLT) from the CogState test battery was administered 8 times in 12 months to 15 individuals with MCI and 35 controls matched for age, education, IQ and gender. All subjects were recruited from an ongoing aging study. The rate of change in CLT performance over the year was compared between groups and also compared to that detected with a word list learning task and a computerised paired associate learning task. RESULTS: At baseline, memory performance in the amnestic MCI group was significantly worse than controls on all memory tests. However, at 12 months the magnitude of the difference between the groups had increased significantly on the CLT due to decline in memory accuracy in the MCI group. No decline over 12 months was detectable on the routine memory tests. CONCLUSIONS: Subtle memory decline is detectable in amnestic MCI using reliable and sensitive tests of memory. Such measures may assist in the early identification of AD and also in trials of putative disease-modifying therapies to be conducted over as little as 12 months.     

Memory performance profile in occupational chronic solvent encephalopathy suggests working memory dysfunction

This pilot study characterizes memory functioning of 11 men with occupational chronic solvent encephalopathy (CSE). Pattern (PRM) and spatial recognition (SRM), spatial span (SSP), spatial working memory (SWM), and paired associate learning (PAL) from Cambridge Neuropsychological Test Automated Battery were performed twice. The most sensitive variables to show impairment were PAL trials, SRM total correct, and SWM number of between-search errors. The majority of the CSE patients demonstrated mild deficits. The most persistent dysfunction was in tasks demanding working memory processing, which predicted well the CSE status. Qualitatively, the memory deficits resemble those seen in moderate or severe Parkinson's disease.     

Effects of chronic manganese exposure on attention and working memory in non-human primates

Manganese (Mn) is essential for a variety of physiological processes, but at elevated levels, can be neurotoxic. While cognitive dysfunction has been recently appreciated to occur as a result of chronic Mn exposures, it is still unclear as to which cognitive domains are most susceptible to disruption by Mn exposure. We previously described early appearing Mn-induced changes in performance on a paired associate learning task in monkeys chronically exposed to Mn and suggested that performance of this task might be a sensitive tool for detecting cognitive dysfunction resulting from Mn exposure. As chronic Mn exposure has been suggested to be associated with attention, working memory and executive function deficits, the present study was conducted to assess the extent to which detrimental effects of chronic Mn exposure could be detected using tasks specifically designed to preferentially assess attention, working memory, and executive function. Six cynomolgus monkeys received Mn exposure over an approximate 12 month period and three served as control animals. All animals were trained to perform a self-ordered spatial search (SOSS) task and a five choice serial reaction time (5-CSRT) task. Deficits in performance of the SOSS task began to appear by the fourth month of Mn exposure but only became consistently significantly impaired beginning at the ninth month of Mn exposure. Performance on the 5-CSRT became significantly affected by the third month of Mn exposure. These data suggest that in addition to the paired associate learning task, cognitive processing speed (as measured by the 5-CSRT) may be a sensitive measure of Mn toxicity and that brain circuits involved in performance of the SOSS task may be somewhat less sensitive to disruption by chronic Mn exposure.     

Where did I put that? Patients with amnestic mild cognitive impairment demonstrate widespread reductions in activity during the encoding of ecologically relevant object-location associations

Remembering the location of objects in the environment is both important in everyday life and difficult for patients with amnestic mild cognitive impairment (aMCI), a clinical precursor to Alzheimer's disease. To test the hypothesis that memory impairment for object location in aMCI reflects hippocampal dysfunction, we used an event-related functional magnetic resonance imaging paradigm to compare patients with aMCI and healthy elderly controls (HEC) as they encoded 90 ecologically relevant object-location associations (OLAs). Two additional OLAs, repeated a total of 45 times, served as control stimuli. Memory for these OLAs was assessed following a 1-h delay. The groups were well matched on demographics and brain volumetrics. Behaviorally, HEC remembered significantly more OLAs than did aMCI patients. Activity differences were assessed by contrasting activation for successfully encoded Novel stimuli vs. Repeated stimuli. The HEC demonstrated activity within object-related (ventral visual stream), spatial location-related (dorsal visual stream), and feature binding-related cortical regions (hippocampus and other memory-related regions) as well as in frontal cortex and associated subcortical structures. Activity in most of these regions correlated with memory test performance. Although the aMCI patients demonstrated a similar activation pattern, the HEC showed significantly greater activity within each of these regions. Memory test performance in aMCI patients, in contrast to the HEC, was correlated with activity in regions involved in sensorimotor processing. We conclude that aMCI patients demonstrate widespread cerebral dysfunction, not limited to the hippocampus, and rely on encoding-related mechanisms that differ substantially from healthy individuals.     

Deficit in conditional visuomotor learning by local infusion of bicuculline into the ventral prefrontal cortex in monkeys

To explore the role of the ventral prefrontal cortex (PFv) in conditional visuomotor learning, we infused locally bicuculline, a GABAergic antagonist, into the PFv of two monkeys, well trained on a two-problem visuomotor task. The task required the monkeys to execute one of two motor actions (moving a handle to the left or to the right) in response to one of two familiar visual patterns (circle or triangle). The two patterns mapped 1:1 onto the two motor actions: for each pattern one and only one motor action was scored, correct and reinforced. In contrast to these sessions with familiar patterns, in the learning sessions the monkeys were presented with one or two novel patterns and required to learn the arbitrarily determined associations between these patterns and the two motor actions. We found that bilateral infusion of bicuculline into PFv dramatically impaired the monkeys' ability to learn novel pattern-response associations: the trials and errors to criterion (90% correct) increased significantly. The errors were mainly an inability to apply 'Win-Stay', 'Lose-Shift' and 'Change-Shift' strategies. There was no effect on the monkeys' performance in responding to familiar patterns. Similar infusion of bicuculline into the dorsal prefrontal cortex was without effect on either novel-pattern learning or familiar-pattern performance. We conclude that the ventral prefrontal cortex is necessary for learning new visuomotor associations, but has less importance, if any, for performing pre-established ones.     

Hippocampal-parietal cortex interactions: evidence from a disconnection study in the rat

The goal of the present experiments was to use a disconnection paradigm to test the interactions between the hippocampus and parietal cortex (PC) during an object-place paired associate learning task, dry-land water maze task, and a reaction-to-change task. Previous research indicates that these tasks are sensitive to hippocampal or PC disruption. Unilateral lesions were made to the dorsal hippocampus or posterior PC in contralateral hemispheres or ipsilateral hemispheres. It was hypothesized that if the hippocampus and PC interact, then contralateral lesioned animals should be markedly impaired compared to ipsilateral lesions. The results indicate that contralateral lesioned animals were significantly more impaired than animals with ipsilateral lesions during object-place paired-associate learning; however, both groups readily learned single discriminations (i.e., objects or places). Furthermore, contralateral lesioned animals traveled further to find the reward during acquisition of the dry-land water maze task and spent less time in the rewarded quadrant during the probe trial. Conversely, contralateral lesioned animals' performance matched ipsilateral lesioned animals during the reaction-to-change paradigm. Thus, the hippocampus and PC interact during some tasks, presumably when tasks require multiple trials across days, but not during the detection of novelty within a single day.