Is it time to change the way we detect Alzheimer’s disease and monitor its progression? Towards affordable and theory-driven approaches from cognitive neurosciences

A large proportion of people suffering from Alzheimer’s disease (AD) worldwide are not receiving a timely diagnosis. The tools currently used to detect AD and monitor its progression are not sensitive to the preclinical stages and lack specificity for correctdiagnosis. Available biomarkers show acceptable levels of sensitivity but remain littlespecific and not accessible to everyone. We embrace the view that enhancing cognitive assessment of AD should be a research priority. This Perspective paper focuses on issues which, to our view, have been preventing cognitive tests from meeting outstanding needs in the early of detection, monitoring, and treatment development of AD dementia.We first outline the limitations of current diagnostic procedures both theoretically and practically. We then provide a rationale for theory-driven cognitive approaches which would allow mapping assessment tools to specific neuropathological stages of the neurodegenerative course of AD. Finally, we propose research strategies that would help test a hypothesis which, though launched five years ago, remains untested.That is: “Which memory system is impaired first in Alzheimer’s disease?

Feature binding of common everyday items is not affected by age

There is a surge of studies confirming that old age spares the ability to bind in visual working memory (VWM) multiple features within singular object representations. Furthermore, it has been suggested that such ability may also be independent of the cultural background of the assessed individual. However, this evidence has been gathered with tasks that use arbitrary bindings of unfamiliar features. Whether age spares memory binding functions when the memoranda are features of everyday life objects remains less well explored. The present study investigated the influence of age, memory delay, and education, on conjunctive binding functions responsible for representing everyday items in VWM. We asked 32 healthy young and 41 healthy older adults to perform a memory binding task. During the task, participants saw visual arrays of objects, colours, or coloured objects presented for 6 s. Immediately after they were asked either to select the objects or the colours that were presented during the study display from larger sets of objects or colours, or to recombine them by selecting from such sets the objects and their corresponding colours. This procedure was repeated immediately after but this time providing a 30 s unfiled delay. We manipulated familiarity by presenting congruent and incongruent object-colour pairings. The results showed that the ability to bind intrinsic features in VWM does not decline with age even when these features belong to everyday items and form novel or well-known associations. Such preserved memory binding abilities held across memory delays. The impact of feature congruency on item-recognition appears to be greater in older than in younger adults. This suggests that long-term memory (LTM) supports binding functions carried out in VWM for familiar everyday items and older adults still benefit from this LTM support. We have expanded the evidence supporting the lack of age effects on VWM binding functions to new feature and object domains (i.e., everyday items). We have confirmed that education does not negatively impact on such ability at old age. Such results have important implications for the selection of culturally unbiased tests to screen for abnormal ageing trajectories

Accelerated Long-Term Forgetting Can Become Apparent Within 3-8 Hours of Wakefulness in Patients With Transient Epileptic Amnesia

OBJECTIVE: Accelerated long-term forgetting (ALF) is typically defined as a memory disorder in which information that is learned and retained normally over standard intervals (∼30 min) is forgotten at an abnormally rapid rate thereafter. ALF has been reported, in particular, among patients with transient epileptic amnesia (TEA). Previous work in TEA has revealed ALF 24 hr - 1 week after initial memory acquisition. It is unclear, however, if ALF observed 24 hr after acquisition reflects (a) an impairment of sleep consolidation processes taking place during the first night's sleep, or (b) an impairment of daytime consolidation processes taking place during the day of acquisition. Here we focus on the daytime-forgetting hypothesis of ALF in TEA by tracking in detail the time course of ALF over the day of acquisition, as well as over 24 hr and 1 week. METHOD: Eleven TEA patients who showed ALF at 1 week and 16 matched controls learned 4 categorical word lists on the morning of the day of acquisition. We subsequently probed word-list retention 30 min, 3 hr, and 8 hr postacquisition (i.e., over the day of acquisition), as well as 24-hr and 1-week post acquisition. RESULTS: ALF became apparent in the TEA group over the course of the day of acquisition 3-8 hr after learning. No further forgetting was observed over the first night in either group. CONCLUSIONS: The results of this study show that ALF in TEA can result from a deficit in memory consolidation occurring within hours of learning without a requirement for intervening sleep. (PsycINFO Database Record (c) 2015 APA, all rights reserved)

Accelerated long-term forgetting in transient epileptic amnesia:an acquisition or consolidation deficit?

Accelerated Long-term Forgetting (ALF) is the rapid loss of newly acquired memories over days to weeks despite normal retention at standard (~30 min) intervals. It has recently been described in association with epilepsy, particularly the syndrome of Transient Epileptic Amnesia (TEA). The cognitive mechanisms underlying ALF remain uncertain, but disruption either of memory acquisition or consolidation processes has been postulated. To arbitrate between these accounts, we reanalysed data from an existing word-list recall data set to investigate whether ALF can be observed for words learned under precisely matched conditions in TEA patients and controls. We reanalysed the data of 24 patients with TEA and 24 matched healthy controls who learnt a 15-item word list to a learning criterion of 90% with a minimum of five learning trials. Free recall of the words was probed at delays of 30 min and 1 week and 3 weeks after learning. In addition, a 'yes-no' recognition test was conducted after the 3-week free recall. Forgetting rates across the first 30 min delay and the subsequent 1 week and 3 week delay were compared between patients and controls. To ensure that learning conditions were closely matched between patients and control participants, we excluded exceptionally fast (N(TEA)=1, N(controls)=4) and slow (N(TEA)=6, N(controls)=2) learners. Furthermore, we analysed only words that were presented five or six times during learning and retrieved successfully on four or five occasions during learning. Recall performance on the last learning trial and 30 min after acquisition were indistinguishable between TEA patients and controls. Over the delay interval of 30 min to 1 week, however, accelerated forgetting of this newly learned verbal material was observed in TEA patients. This severe forgetting is also reflected in the three-week recognition test, where TEA patients performed significantly worse than controls. Moreover, whereas recall on the last learning trial correlated significantly with the 30 min delayed recall in both groups, recall on the last learning trial correlated significantly with 1 week and 3 week delayed recall only in the controls. In both groups, the three-week free recall performance correlated with the three-week recognition test. Patients with TEA demonstrate ALF even for verbal material that is learned under precisely matched conditions. These results are consistent with the hypothesis that ALF represents a disruption of memory consolidation rather than an acquisition deficit

Impaired picture recognition in transient epileptic amnesia

Transient epileptic amnesia (TEA) is an epileptic syndrome characterized by recurrent, brief episodes of amnesia. Transient epileptic amnesia is often associated with the rapid decline in recall of new information over hours to days (accelerated long-term forgetting - 'ALF'). It remains unknown how recognition memory is affected in TEA over time. Here, we report a systematic study of picture recognition in patients with TEA over the course of one week. Sixteen patients with TEA and 16 matched controls were presented with 300 photos of everyday life scenes. Yes/no picture recognition was tested 5min, 2.5h, 7.5h, 24h, and 1week after picture presentation using a subset of target pictures as well as similar and different foils. Picture recognition was impaired in the patient group at all test times, including the 5-minute test, but it declined normally over the course of 1week. This impairment was associated predominantly with an increased false alarm rate, especially for similar foils. High performance on a control test indicates that this impairment was not associated with perceptual or discrimination deficits. Our findings suggest that, at least in some TEA patients with ALF in verbal recall, picture recognition does not decline more rapidly than in controls over 1week. However, our findings of an early picture recognition deficit suggest that new visual memories are impoverished after minutes in TEA. This could be the result of deficient encoding or impaired early consolidation. The early picture recognition deficit observed could reflect either the early stages of the process that leads to ALF or a separable deficit of anterograde memory in TEA. Lastly, our study suggests that at least some patients with TEA are prone to falsely recognizing new everyday visual information that they have not in fact seen previously. This deficit, alongside their ALF in free recall, likely affects everyday memory performance

Capturing real-life forgetting in transient epileptic amnesia via an incidental memory test.

Transient epileptic amnesia (TEA) is an epileptic syndrome characterized by recurrent, brief episodes of amnesia. Patients with TEA often complain of interictal (between attacks) retention deficits, characterised by an 'evaporation' of memories for recent events over days to weeks. Clinical tests of anterograde memory often fail to corroborate these complaints as TEA patients commonly perform within the normal range after the standard 10-30-min delay period. Modified laboratory tests that include a 1-3 week delay period frequently reveal clear evidence of 'accelerated long-term forgetting' (ALF). However, they are not used routinely and lack ecological validity. In the present study we examined whether 'real-life' ALF can be captured via a controlled incidental memory test in TEA patients. To this end, the experimenter told 27 TEA patients and 32 controls a well-rehearsed amusing story, apparently as a way of making light conversation before starting a set of research experiments. Without prior warning, the experimenter subsequently probed the participants' memory of this story via tests of free recall and forced choice recognition after 30 min or 1 week. After 30 min retention was comparable in TEA patients and controls. After 1 week TEA patients retained significantly less story material than controls, and significant ALF was revealed in the TEA patients in the recognition test. Our data show that ALF in a 'real-life' situation can occur even when standard memory tests indicate normal memory function. Moreover, our data suggest that incidental memory tests can capture real-life ALF, and that forced-choice recognition tests might be more sensitive than free recall tests for the detection of real-life ALF

Feature Binding of Common Everyday Items Is Not Affected by Age

There is a surge of studies confirming that old age spares the ability to bind in visual working memory (VWM) multiple features within singular object representations. Furthermore, it has been suggested that such ability may also be independent of the cultural background of the assessed individual. However, this evidence has been gathered with tasks that use arbitrary bindings of unfamiliar features. Whether age spares memory binding functions when the memoranda are features of everyday life objects remains less well explored. The present study investigated the influence of age, memory delay, and education, on conjunctive binding functions responsible for representing everyday items in VWM. We asked 32 healthy young and 41 healthy older adults to perform a memory binding task. During the task, participants saw visual arrays of objects, colours, or coloured objects presented for 6 s. Immediately after they were asked either to select the objects or the colours that were presented during the study display from larger sets of objects or colours, or to recombine them by selecting from such sets the objects and their corresponding colours. This procedure was repeated immediately after but this time providing a 30 s unfiled delay. We manipulated familiarity by presenting congruent and incongruent object-colour pairings. The results showed that the ability to bind intrinsic features in VWM does not decline with age even when these features belong to everyday items and form novel or well-known associations. Such preserved memory binding abilities held across memory delays. The impact of feature congruency on item-recognition appears to be greater in older than in younger adults. This suggests that long-term memory (LTM) supports binding functions carried out in VWM for familiar everyday items and older adults still benefit from this LTM support. We have expanded the evidence supporting the lack of age effects on VWM binding functions to new feature and object domains (i.e., everyday items). We have confirmed that education does not negatively impact on such ability at old age. Such results have important implications for the selection of culturally unbiased tests to screen for abnormal ageing trajectories

The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain - A detailed case report.

We describe a patient in whom long-term, therapeutic infusion of the selective gamma-amino-butyric acid type B (GABAB) receptor agonist, baclofen, into the cerebrospinal fluid (CSF) gave rise to three distinct varieties of memory impairment: i) repeated, short periods of severe global amnesia, ii) accelerated long-term forgetting (ALF), evident over intervals of days and iii) a loss of established autobiographical memories. This pattern of impairment has been reported in patients with temporal lobe epilepsy (TLE), in particular the subtype of Transient Epileptic Amnesia (TEA). The amnesic episodes and accelerated forgetting remitted on withdrawal of baclofen, while the autobiographical amnesia (AbA) persisted. This exceptional case highlights the occurrence of 'non-standard' forms of human amnesia, reflecting the biological complexity of memory processes. It suggests a role for GABAB signalling in the modulation of human memory over multiple time-scales and hints at its involvement in 'epileptic amnesia'