Mild cognitive decline. A position statement of the Cognitive Decline Group of the European Innovation Partnership for Active and Healthy Ageing (EIPAHA)

Introduction Mild cognitive impairment (MCI) is a term used to describe a level of decline in cognition which is seen as an intermediate stage between normal ageing and dementia, and which many consider to be a prodromal stage of neurodegeneration that may become dementia. That is, it is perceived as a high risk level of cognitive change. The increasing burden of dementia in our society, but also our increasing understanding of its risk factors and potential interventions, require diligent management of MCI in order to find strategies that produce effective prevention of dementia. Aim To update knowledge regarding mild cognitive impairment, and to bring together and appraise evidence about the main features of clinical interest: definitions, prevalence and stability, risk factors, screening, and management and intervention. Methods Literature review and consensus of expert opinion. Results and conclusion MCI describes a level of impairment in which deteriorating cognitive functions still allow for reasonable independent living, including some compensatory strategies. While there is evidence for some early risk factors, there is still a need to more precisely delineate and distinguish early manifestations of frank dementia from cognitive impairment that is less likely to progress to dementia, and furthermore to develop improved prospective evidence for positive response to intervention. An important limitation derives from the scarcity of studies that take MCI as an endpoint. Strategies for effective management suffer from the same limitation, since most studies have focused on dementia. Behavioural changes may represent the most cost-effective approach.

The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure

Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.

Mobility changes in older age: neuropsychological, neurophysiological and cognitive predictors of successful adaptation in a real world scenario

The aims of this thesis were to investigate the neuropsychological, neurophysiological, and cognitive contributors to mobility changes with increasing age. In a series of studies with adults aged 45-88 years, unsafe pedestrian behaviour and falls were investigated in relation to i) cognitive functions (including response time variability, executive function, and visual attention tests), ii) mobility assessments (including gait and balance and using motion capture cameras), iii) motor initiation and pedestrian road crossing behavior (using a simulated pedestrian road scene), iv) neuronal and functional brain changes (using a computer based crossing task with magnetoencephalography), and v) quality of life questionnaires (including fear of falling and restricted range of travel). Older adults are more likely to be fatally injured at the far-side of the road compared to the near-side of the road, however, the underlying mobility and cognitive processes related to lane-specific (i.e. near-side or far-side) pedestrian crossing errors in older adults is currently unknown. The first study explored cognitive, motor initiation, and mobility predictors of unsafe pedestrian crossing behaviours. The purpose of the first study (Chapter 2) was to determine whether collisions at the near-side and far-side would be differentially predicted by mobility indices (such as walking speed and postural sway), motor initiation, and cognitive function (including spatial planning, visual attention, and within participant variability) with increasing age. The results suggest that near-side unsafe pedestrian crossing errors are related to processing speed, whereas far-side errors are related to spatial planning difficulties. Both near-side and far-side crossing errors were related to walking speed and motor initiation measures (specifically motor initiation variability). The salient mobility predictors of unsafe pedestrian crossings determined in the above study were examined in Chapter 3 in conjunction with the presence of a history of falls. The purpose of this study was to determine the extent to which walking speed (indicated as a salient predictor of unsafe crossings and start-up delay in Chapter 2), and previous falls can be predicted and explained by age-related changes in mobility and cognitive function changes (specifically within participant variability and spatial ability). 53.2% of walking speed variance was found to be predicted by self-rated mobility score, sit-to-stand time, motor initiation, and within participant variability. Although a significant model was not found to predict fall history variance, postural sway and attentional set shifting ability was found to be strongly related to the occurrence of falls within the last year. Next in Chapter 4, unsafe pedestrian crossing behaviour and pedestrian predictors (both mobility and cognitive measures) from Chapter 2 were explored in terms of increasing hemispheric laterality of attentional functions and inter-hemispheric oscillatory beta power changes associated with increasing age. Elevated beta (15-35 Hz) power in the motor cortex prior to movement, and reduced beta power post-movement has been linked to age-related changes in mobility. In addition, increasing recruitment of both hemispheres has been shown to occur and be beneficial to perform similarly to younger adults in cognitive tasks (Cabeza, Anderson, Locantore, & McIntosh, 2002). It has been hypothesised that changes in hemispheric neural beta power may explain the presence of more pedestrian errors at the farside of the road in older adults. The purpose of the study was to determine whether changes in age-related cortical oscillatory beta power and hemispheric laterality are linked to unsafe pedestrian behaviour in older adults. Results indicated that pedestrian errors at the near-side are linked to hemispheric bilateralisation, and neural overcompensation post-movement, 4 whereas far-side unsafe errors are linked to not employing neural compensation methods (hemispheric bilateralisation). Finally, in Chapter 5, fear of falling, life space mobility, and quality of life in old age were examined to determine their relationships with cognition, mobility (including fall history and pedestrian behaviour), and motor initiation. In addition to death and injury, mobility decline (such as pedestrian errors in Chapter 2, and falls in Chapter 3) and cognition can negatively affect quality of life and result in activity avoidance. Further, number of falls in Chapter 3 was not significantly linked to mobility and cognition alone, and may be further explained by a fear of falling. The objective of the above study (Study 2, Chapter 3) was to determine the role of mobility and cognition on fear of falling and life space mobility, and the impact on quality of life measures. Results indicated that missing safe pedestrian crossing gaps (potentially indicating crossing anxiety) and mobility decline were consistent predictors of fear of falling, reduced life space mobility, and quality of life variance. Social community (total number of close family and friends) was also linked to life space mobility and quality of life. Lower cognitive functions (particularly processing speed and reaction time) were found to predict variance in fear of falling and quality of life in old age. Overall, the findings indicated that mobility decline (particularly walking speed or walking difficulty), processing speed, and intra-individual variability in attention (including motor initiation variability) are salient predictors of participant safety (mainly pedestrian crossing errors) and wellbeing with increasing age. More research is required to produce a significant model to explain the number of falls.

Event related potential (ERP) evidence for selective impairment of verbal recollection in abstinent recreational methylenedioxymethamphetamine (“Ecstasy”)/polydrug users

Objectives Ecstasy is a recreational drug whose active ingredient, 3,4-methylenedioxymethamphetamine (MDMA), acts predominantly on the serotonergic system. Although MDMA is known to be neurotoxic in animals, the long-term effects of recreational Ecstasy use in humans remain controversial but one commonly reported consequence is mild cognitive impairment particularly affecting verbal episodic memory. Although event-related potentials (ERPs) have made significant contributions to our understanding of human memory processes, until now they have not been applied to study the long-term effects of Ecstasy. The aim of this study was to examine the effects of past Ecstasy use on recognition memory for both verbal and non-verbal stimuli using ERPs. Methods We compared the ERPs of 15 Ecstasy/polydrug users with those of 14 cannabis users and 13 non-illicit drug users as controls. Results Despite equivalent memory performance, Ecstasy/polydrug users showed an attenuated late positivity over left parietal scalp sites, a component associated with the specific memory process of recollection. Conlusions This effect was only found in the word recognition task which is consistent with evidence that left hemisphere cognitive functions are disproportionately affected by Ecstasy, probably because the serotonergic system is laterally asymmetrical. Experimentally, decreasing central serotonergic activity through acute tryptophan depletion also selectively impairs recollection, and this too suggests the importance of the serotonergic system. Overall, our results suggest that Ecstasy users, who also use a wide range of other drugs, show a durable abnormality in a specific ERP component thought to be associated with recollection.

Metaphors in spoken academic discourse in german and english

Metaphors have been increasingly associated with cognitive functions, which means that metaphors structure how we think and express ourselves. Metaphors are embodied in our basic physical experience, which is one reason why certain abstract concepts are expressed in more concrete terms, such as visible entities, journeys, and other types of movement, spaces etc. This communicative relevance also applies to specialised, institutionalised settings and genres, such as those produced in or related to higher education institutions, among which is spoken academic discourse. A significant research gap has been identified regarding spoken academic discourse and metaphors therein, but also given the fact that with increasing numbers of students in higher education and international research and cooperation e.g. in the form of invited lectures, spoken academic discourse can be seen as nearly omnipresent. In this context, research talks are a key research genre. A mixed methods study has been conducted, which investigates metaphors in a corpus of eight fully transcribed German and English L1 speaker conference talks and invited lectures, totalling to 440 minutes. A wide range of categories and functions were identified in the corpus. Abstract research concepts, such as results or theories are expressed in terms of concrete visual entities that can be seen or shown, but also in terms of journeys or other forms of movement. The functions of these metaphors are simplification, rhetorical emphasis, theory-construction, or pedagogic illustration. For both the speaker and the audience or discussants, anthropomorphism causes abstract and complex ideas to become concretely imaginable and at the same time more interesting because the contents of the talk appear to be livelier and hence closer to their own experience, which ensures the audience’s attention. These metaphor categories are present in both the English and the German sub corpus of this study with similar functions.

Limits to tDCS effects in language:failures to modulate word production in healthy participants with frontal or temporal tDCS

Transcranial direct current stimulation (tDCS) is a method of non-invasive brain stimulation widely used to modulate cognitive functions. Recent studies, however, suggests that effects are unreliable, small and often non-significant at least when stimulation is applied in a single session to healthy individuals. We examined the effects of frontal and temporal lobe anodal tDCS on naming and reading tasks and considered possible interactions with linguistic activation and selection mechanisms as well possible interactions with item difficulty and participant individual variability. Across four separate experiments (N, Exp 1A = 18; 1B = 20; 1C = 18; 2 = 17), we failed to find any difference between real and sham stimulation. Moreover, we found no evidence of significant effects limited to particular conditions (i.e., those requiring suppression of semantic interference), to a subset of participants or to longer RTs. Our findings sound a cautionary note on using tDCS as a means to modulate cognitive performance. Consistent effects of tDCS may be difficult to demonstrate in healthy participants in reading and naming tasks, and be limited to cases of pathological neurophysiology and/or to the use of learning paradigms.

Neurophysiology of CSWS-associated cognitive dysfunction

The phenomenon of continuous spikes and waves during slow-wave sleep (CSWS) is associated with a number of epileptic syndromes, which share a behavioral phenotype characterized by deterioration of cognitive, behavioral, or sensorimotor functions. Available evidence seems to suggest that spike-wave activity is a result of a complex interaction between cortical and subcortical inhibitory networks and can "per se" produce a transient loss of underlying cortical functions. Syndromes like Landau-Kleffner syndrome, CSWS, and phenomena such as negative myoclonus could share in common--at least at the neurophysiological level--some similarities. Differences in behavioral phenotypes could be explained in term of maturational and genetic differences, as well as by the functional specificity of the involved areas.

Sensory thresholds obtained from MEG data:cortical psychometric functions

Sensory sensitivity is typically measured using behavioural techniques (psychophysics), which rely on observers responding to very large numbers of stimulus presentations. Psychophysics can be problematic when working with special populations, such as children or clinical patients, because they may lack the compliance or cognitive skills to perform the behavioural tasks. We used an auditory gap-detection paradigm to develop an accurate measure of sensory threshold derived from passively-recorded MEG data. Auditory evoked responses were elicited by silent gaps of varying durations in an on-going noise stimulus. Source modelling was used to spatially filter the MEG data and sigmoidal ‘cortical psychometric functions’ relating response amplitude to gap duration were obtained for each individual participant. Fitting the functions with a curve and estimating the gap duration at which the evoked response exceeded one standard deviation of the prestimulus brain activity provided an excellent prediction of psychophysical threshold. Thus we have demonstrated that accurate sensory thresholds can be reliably extracted from MEG data recorded while participants listen passively to a stimulus. Because we required no behavioural task, the method is suitable for studies of populations where variations in cognitive skills or vigilance make traditional psychophysics unsuitable.

Examining links between cognitive markers, movement initiation and change, and pedestrian safety in older adults

Objective: The purpose of this study was to determine the extent to which mobility indices (such as walking speed and postural sway), motor initiation, and cognitive function, specifically executive functions, including spatial planning, visual attention, and within participant variability, differentially predicted collisions in the near and far sides of the road with increasing age. Methods: Adults aged over 45 years participated in cognitive tests measuring executive function and visual attention (using Useful Field of View; UFoV®), mobility assessments (walking speed, sit-to-stand, self-reported mobility, and postural sway assessed using motion capture cameras), and gave road crossing choices in a two-way filmed real traffic pedestrian simulation. Results: A stepwise regression model of walking speed, start-up delay variability, and processing speed) explained 49.4% of the variance in near-side crossing errors. Walking speed, start-up delay measures (average & variability), and spatial planning explained 54.8% of the variance in far-side unsafe crossing errors. Start-up delay was predicted by walking speed only (explained 30.5%). Conclusion: Walking speed and start-up delay measures were consistent predictors of unsafe crossing behaviours. Cognitive measures, however, differentially predicted near-side errors (processing speed), and far-side errors (spatial planning). These findings offer potential contributions for identifying and rehabilitating at-risk older pedestrians.

Representation, control, or reasoning? Distinct functions for theory of mind within the medial prefrontal cortex

The medial pFC (mPFC) is frequently reported to play a central role in Theory of Mind (ToM). However, the contribution of this large cortical region in ToM is not well understood. Combining a novel behavioral task with fMRI, we sought to demonstrate functional divisions between dorsal and rostral mPFC. All conditions of the task required the representation of mental states (beliefs and desires). The level of demands on cognitive control (high vs. low) and the nature of the demands on reasoning (deductive vs. abductive) were varied orthogonally between conditions. Activation in dorsal mPFC was modulated by the need for control, whereas rostral mPFC was modulated by reasoning demands. These findings fit with previously suggested domain-general functions for different parts of mPFC and suggest that these functions are recruited selectively in the service of ToM.

Cognitive processing in non-communicative patients:what can event-related potentials tell us?

Event-related potentials (ERP) have been proposed to improve the differential diagnosis of non-responsive patients. We investigated the potential of the P300 as a reliable marker of conscious processing in patients with locked-in syndrome (LIS). Eleven chronic LIS patients and 10 healthy subjects (HS) listened to a complex-tone auditory oddball paradigm, first in a passive condition (listen to the sounds) and then in an active condition (counting the deviant tones). Seven out of nine HS displayed a P300 waveform in the passive condition and all in the active condition. HS showed statistically significant changes in peak and area amplitude between conditions. Three out of seven LIS patients showed the P3 waveform in the passive condition and five of seven in the active condition. No changes in peak amplitude and only a significant difference at one electrode in area amplitude were observed in this group between conditions. We conclude that, in spite of keeping full consciousness and intact or nearly intact cortical functions, compared to HS, LIS patients present less reliable results when testing with ERP, specifically in the passive condition. We thus strongly recommend applying ERP paradigms in an active condition when evaluating consciousness in non-responsive patients.