Mario A. Parra

Visual short-term memory binding deficits in familial Alzheimer’s disease

Short-term memory binding is a memory function that underpins the temporary retention of complex objects (e.g. shapes with colours). In the verbal domain, this function has been found to be impaired in sporadic Alzheimers disease. Whether short-term memory binding is also impaired in familial Alzheimers disease, whether this impairment extends to the visual domain and whether it could be detected earlier than other cognitive deficits are issues yet to be investigated. Twenty two patients with familial Alzheimers disease caused by the E280A single presenilin-1 mutation, thirty carriers of the mutation who did not meet Alzheimers disease criteria (asymptomatic carriers) and 30 healthy relatives (non-carrier healthy controls) were assessed with a visual short-term memory task and a neuropsychological battery. The short-term memory task assessed the recognition of shapes, colours or shape-colour bindings presented in two consecutive arrays (i.e. study and test). Changes, which always occurred in the test array, consisted of new features replacing studied features (single feature conditions) or of features swapping across items (the binding condition). The neuropsychological battery comprised tests of associative and non-associative memory, attention, language, visuospatial and executive functions. Patients with Alzheimers disease and asymptomatic carriers performed significantly worse than healthy controls in the feature binding condition only. Group comparisons between asymptomatic carriers and healthy controls on standard neuropsychological tasks revealed no significant differences. Classification and area under the curve analyses confirmed that the binding task combines more sensitivity and specificity for patients with Alzheimers disease and most notably for asymptomatic carriers of the mutation than other traditional neuropsychological measures. This suggests that visual short-term memory binding deficits may be a preclinical marker for familial Alzheimers disease.

Do binding deficits account for age-related decline in visual working memory?

Remembering visual material, such as objects, faces, and spatial locations, over a short period of time (seconds) becomes more difficult as we age. We investigated whether these deficits could be explained by a simple reduction in visual working memory capacity or by an impairment in one’s ability to form or maintain appropriate associations among pieces of related information. In three experiments, we used recognition and recall tests to address the efficacy with which older adults can create bound object representations by varying the number of features of each object that had to be remembered for a subsequent memory test. Results demonstrated that whereas older adults exhibited reduced memory capacity as compared with that of younger adults, both groups stored integrated object representations in visual working memory. These results are contrasted with other work that suggests that age-related memory decline is due, at least in part, to associative deficits.

Short-term memory binding is impaired in AD but not in non-AD dementias.

Binding is a cognitive function responsible for integrating features within complex stimuli (e.g., shape-colour conjunctions) or events within complex memories (e.g., face-name associations). This function operates both in short-term memory (STM) and in long-term memory (LTM) and is severely affected by Alzheimers disease (AD). However, forming conjunctions in STM is the only binding function which is not affected by healthy ageing or chronic depression. Whether this specificity holds true across other non-AD dementias is as yet unknown. The present study investigated STM conjunctive binding in a sample of AD patients and patients with other non-AD dementias using a task which has proved sensitive to the effects of AD. The STM task assesses the free recall of objects, colours, and the bindings of objects and colours. Patients with AD, frontotemporal dementia, vascular dementia, lewy body dementia and dementia associated with Parkinsons disease showed memory, visuo-spatial, executive and attentional deficits on standard neuropsychological assessment. However, only AD patients showed STM binding deficits. This deficit was observed even when memory for single features was at a similar level across patient groups. Regression and discriminant analyses confirmed that the STM binding task accounted for the largest proportion of variance between AD and non-AD groups and held the greatest classification power to identify patients with AD. STM conjunctive binding places little demands on executive functions and appears to be subserved by components of the memory network which are targeted by AD, but not by non-AD dementias.

Visual short-term memory binding in Alzheimer’s disease and depression

The differential diagnosis between Alzheimer’s disease (AD) and major depression (MD) in the elderly can be problematic because the cognitive profile of the two conditions overlaps. Associative learning tasks seem to separate AD from MD. However, they are sensitive to the effects of normal ageing. Short-term memory-binding tasks have proved insensitive to the effects of normal ageing and highly sensitive to AD. However, they have not been used to differentiate AD from MD. The present study was aimed at investigating visual short-term memory binding in AD and MD. Fourteen AD patients, 14 patients with MD, and 14 healthy older adults were asked to perform a visual short-term memory binding task that investigated the retention of shapes, colors, or combinations of shapes and colors. Participants were to recognize changes occurring between two consecutive displays either in a single dimension (i.e., shape or color only) or in two dimensions (i.e., shape-color binding). Short-term memory performance for shape or color only was equivalent across groups. The only significant effect found was in short-term memory for shape-color binding and this was due to AD patients performing poorly in this condition only. The results extend previous findings in AD to visual short-term memory and suggest that the specific impairment in binding information in memory differentiates between the performance of AD and patients with MD.

Specific deficit of colour-colour short-term memory binding in sporadic and familial Alzheimer's disease.

Short-term memory binding of visual features which are processed across different dimensions (shape-colour) is impaired in sporadic Alzheimers disease, familial Alzheimers disease, and in asymptomatic carriers of familial Alzheimers disease. This study investigated whether Alzheimers disease also impacts on within-dimension binding processes. The study specifically explored whether visual short-term memory binding of features of the same type (colour-colour) is sensitive to Alzheimers disease. We used a neuropsychological battery and a short-term memory binding task to assess patients with sporadic Alzheimers disease (Experiment 1), familial Alzheimers disease (Experiment 2) due to the mutation E280A of the Presenilin-1 gene and asymptomatic carriers of the mutation. The binding task assessed change detection within arrays of unicoloured objects (Colour Only) or bicoloured objects the colours of which had to be remembered separately (Unbound Colours) or together (Bound Colours). Performance on the Bound Colours condition (1) explained the largest proportion of variance between patients (sporadic and familial Alzheimers disease), (2) combined more sensitivity and specificity for the disease than other more traditional neuropsychological tasks, (3) identified asymptomatic carriers of the mutation even when traditional neuropsychological measures and other measures of short-term memory did not and, (4) contrary to shape-colour binding, correlated with measures of hippocampal functions. Colour-colour binding and shape-colour binding both appear to be sensitive to AD even though they seem to rely on different brain mechanisms.

Neural correlates of shape-color binding in visual working memory

The present study addressed an outstanding issue regarding feature binding in working memory (WM): whether this function engages specific resources relative to those required to process individual features. We investigated the brain regions supporting the encoding and maintenance of features and bindings in a change detection task, in which 22 healthy young volunteers remembered visual arrays of abstract shapes, colors or shape-color bindings while undergoing fMRI. After an unfilled delay they saw a second array and judged whether the features or combination of features presented across the two arrays were the same or different. Temporary retention of feature bindings was found to involve additional cortical regions compared with retaining single features, regardless of whether the number of objects or the number of features differed between feature-only and binding conditions. This binding-specific activation is consistent with the involvement of different neural generators that collectively support visual temporary memory for features and for feature bindings. Regions within the parietal, temporal and occipital cortex, but not within the prefrontal cortex or the medial temporal lobe, appear to support the integrated object binding function investigated in this study. Our findings suggest that both individual features and their binding within integrated objects are used to represent complex objects in WM.

P300 and Neuropsychological Assessment in Mild Cognitive Impairment and Alzheimer Dementia

Only a small proportion of individuals with Mild Cognitive Impairment (MCI) will convert to dementia. Methods currently available to identify risk for conversion do not combine enough sensitivity and specificity, which is even more problematic in low-educated populations. Current guidelines suggest the use of combined markers for dementia to enhance the prediction accuracy of assessment methods. The present study adhered to this proposal and investigated the sensitivity and specificity of the electrophysiological component P300 and standard neuropsychological tests to assess patients with Alzheimer’s disease (AD) and MCI recruited from a low-income country. The neuropsychological battery comprised tests of memory, attention, language, praxis, and executive functions. The P300 was recorded using a classical visual odd-ball paradigm. Three variables were found to achieve sensitivity and specificity values above 80% (Immediate and Delayed recall of word list – CERAD – and the latency of P300) for both MCI and AD. When they entered the model together (i.e., combined approach) the sensitivity for MCI increased to 96% and the specificity remained high (80%). Our preliminary findings suggest that the combined use of sensitive neuropsychological tasks and the analysis of the P300 may offer a very useful method for the preclinical assessment of AD, particularly in populations with low socioeconomic and educational levels. Our results provide a platform and justification to employ more resources to convert P300 and related parameters into a biological marker for AD.

Relational and conjunctive binding functions dissociate in short-term memory

Remembering complex events requires binding features within unified objects (conjunctions) and holding associations between objects (relations). Recent studies suggest that the two functions dissociate in long-term memory (LTM). Less is known about their functional organization in short-term memory (STM). The present study investigated this issue in patient AE affected by a stroke which caused damage to brain regions known to be relevant for relational functions both in LTM and in STM (i.e., the hippocampus). The assessment involved a battery of standard neuropsychological tasks and STM binding tasks. One STM binding task (Experiment 1) presented common objects and common colors forming either pairs (relations) or integrated objects (conjunctions). Free recall of relations or conjunctions was assessed. A second STM binding task used random polygons and non-primary colors instead (Experiment 2). Memory was assessed by selecting the features that made up the relations or the conjunctions from a set of single polygons and a set of single colors. The neuropsychological assessment revealed impaired delayed memory in AE. AE’s pronounced relational STM binding deficits contrasted with his completely preserved conjunctive binding functions in both Experiments 1 and 2. Only 2.35% and 1.14% of the population were expected to have a discrepancy more extreme than that presented by AE in Experiments 1 and 2, respectively. Processing relations and conjunctions of very elementary nonspatial features in STM led to dissociating performances in AE. These findings may inform current theories of memory decline such as those linked to cognitive aging.

Does the Addenbrooke's Cognitive Examination-revised add to the Mini-Mental State Examination in established Alzheimer disease? Results from a national dementia research register

To evaluate how much the Addenbrookes Cognitive Examination‐revised (ACE‐R) improves the estimate of cognitive ability from the Mini‐Mental State Examination (MMSE) in people with Alzheimer disease (AD).

Memory binding and white matter integrity in familial Alzheimer’s disease

Binding information in short-term and long-term memory are functions sensitive to Alzheimers disease. They have been found to be affected in patients who meet criteria for familial Alzheimers disease due to the mutation E280A of the PSEN1 gene. However, only short-term memory binding has been found to be affected in asymptomatic carriers of this mutation. The neural correlates of this dissociation are poorly understood. The present study used diffusion tensor magnetic resonance imaging to investigate whether the integrity of white matter structures could offer an account. A sample of 19 patients with familial Alzheimers disease, 18 asymptomatic carriers and 21 non-carrier controls underwent diffusion tensor magnetic resonance imaging, neuropsychological and memory binding assessment. The short-term memory binding task required participants to detect changes across two consecutive screens displaying arrays of shapes, colours, or shape-colour bindings. The long-term memory binding task was a Paired Associates Learning Test. Performance on these tasks were entered into regression models. Relative to controls, patients with familial Alzheimers disease performed poorly on both memory binding tasks. Asymptomatic carriers differed from controls only in the short-term memory binding task. White matter integrity explained poor memory binding performance only in patients with familial Alzheimers disease. White matter water diffusion metrics from the frontal lobe accounted for poor performance on both memory binding tasks. Dissociations were found in the genu of corpus callosum which accounted for short-term memory binding impairments and in the hippocampal part of cingulum bundle which accounted for long-term memory binding deficits. The results indicate that white matter structures in the frontal and temporal lobes are vulnerable to the early stages of familial Alzheimers disease and their damage is associated with impairments in two memory binding functions known to be markers for Alzheimers disease.