Dietary Tyrosine Intake (FFQ) Is Associated with Locus Coeruleus, Attention and Grey Matter Maintenance: An MRI Structural Study on 398 Healthy Individuals of the Berlin Aging Study-II.

BACKGROUND AND OBJECTIVE: It is documented that low protein and amino-acid dietary intake is related to poorer cognitive health and increased risk of dementia. Degradation of the neuromodulatory pathways, (comprising the cholinergic, dopaminergic, serotoninergic and noradrenergic systems) is observed in neurodegenerative diseases and impairs the proper biosynthesis of key neuromodulators from micro-nutrients and amino acids. How these micro-nutrients are linked to neuromodulatory pathways in healthy adults is less studied. The Locus Coeruleus-Noradrenergic System (LC-NA) is the earliest subcortical structure affected in Alzheimer's disease, showing marked neurodegeneration, but is also sensitive for age-related changes. The LC-NA system is critical for supporting attention and cognitive control, functions that are enhanced both by tyrosine administration and chronic tyrosine intake. The purpose of this study was to 1) investigate whether the dietary intake of tyrosine, the key precursor for noradrenaline (NA), is related to LC signal intensity 2) whether LC mediates the reported association between tyrosine intake and higher cognitive performance (measured with Trail Making Test - TMT), and 3) whether LC signal intensity relates to an objective measure of brain maintenance (BrainPAD). METHODS: The analyses included 398 3T MRIs of healthy participants from the Berlin Aging Study II to investigate the relationship between LC signal intensity and habitual dietary tyrosine intake-daily average (HD-Tyr-IDA - measured with Food Frequency Questionnaire - FFQ). As a control procedure, the same analyses were repeated on other main seeds of the neuromodulators' subcortical system (Dorsal and Medial Raphe, Ventral Tegmental Area and Nucleus Basalis of Meynert). In the same way, the relationships between the five nuclei and BrainPAD were tested. RESULTS: Results show that HD-Tyr-IDA is positively associated with LC signal intensity. Similarly, LC disproportionally relates to better brain maintenance (BrainPAD). Mediation analyses reveal that only LC, relative to the other nuclei tested, mediates the relationship between HD-Tyr-IDA I and performance in the TMT and between HD-Tyr-IDA and BrainPAD. CONCLUSIONS: These findings provide the first evidence linking tyrosine intake with LC-NA system signal intensity and its correlation with neuropsychological performance. This study strengthens the role of diet for maintaining brain and cognitive health and supports the noradrenergic theory of cognitive reserve. Within this framework, adequate tyrosine intake might increase the resilience of LC-NA system functioning, by preventing degeneration and supporting noradrenergic metabolism required for LC function and neuropsychological performance.

Lost in Time: Temporal Monitoring Elicits Clinical Decrements in Sustained Attention Post-Stroke.

OBJECTIVES: Mental fatigue, 'brain fog', and difficulties maintaining engagement are commonly reported issues in a range of neurological and psychiatric conditions. Traditional sustained attention tasks commonly measure this capacity as the ability to detect target stimuli based on sensory features in the auditory or visual domains. However, with this approach, discrete target stimuli may exogenously capture attention to aid detection, thereby masking deficits in the ability to endogenously sustain attention over time. METHODS: To address this, we developed the Continuous Temporal Expectancy Task (CTET) where individuals continuously monitor a stream of patterned stimuli alternating at a fixed temporal interval (690 ms) and detect an infrequently occurring target stimulus defined by a prolonged temporal duration (1020 ms or longer). As such, sensory properties of target and non-target stimuli are perceptually identical and differ only in temporal duration. Using the CTET, we assessed stroke survivors with unilateral right hemisphere damage (N = 14), a cohort in which sustained attention deficits have been extensively reported. RESULTS: Stroke survivors had overall lower target detection accuracy compared with neurologically healthy age-matched older controls (N = 18). Critically, stroke survivors performance was characterised by significantly steeper within-block performance decrements, which occurred within short temporal windows (˜3 ½ min), and were restored by the break periods between blocks. CONCLUSIONS: These findings suggest that continuous temporal monitoring taxes sustained attention processes to capture clinical deficits in this capacity over time, and outline a precise measure of the endogenous processes hypothesised to underpin sustained attention deficits following right hemisphere stroke.

Verbal intelligence is a more robust cross-sectional measure of cognitive reserve than level of education in healthy older adults.

BACKGROUND: Cognitive reserve is most commonly measured using socio-behavioural proxy variables. These variables are easy to collect, have a straightforward interpretation, and are widely associated with reduced risk of dementia and cognitive decline in epidemiological studies. However, the specific proxies vary across studies and have rarely been assessed in complete models of cognitive reserve (i.e. alongside both a measure of cognitive outcome and a measure of brain structure). Complete models can test independent associations between proxies and cognitive function in addition to the moderation effect of proxies on the brain-cognition relationship. Consequently, there is insufficient empirical evidence guiding the choice of proxy measures of cognitive reserve and poor comparability across studies. METHOD: In a cross-sectional study, we assessed the validity of 5 common proxies (education, occupational complexity, verbal intelligence, leisure activities, and exercise) and all possible combinations of these proxies in 2 separate community-dwelling older adult cohorts: The Irish Longitudinal Study on Ageing (TILDA; N = 313, mean age = 68.9 years, range = 54-88) and the Cognitive Reserve/Reference Ability Neural Network Study (CR/RANN; N = 234, mean age = 64.49 years, range = 50-80). Fifteen models were created with 3 brain structure variables (grey matter volume, hippocampal volume, and mean cortical thickness) and 5 cognitive variables (verbal fluency, processing speed, executive function, episodic memory, and global cognition). RESULTS: No moderation effects were observed. There were robust positive associations with cognitive function, independent of brain structure, for 2 individual proxies (verbal intelligence and education) and 16 composites (i.e. combinations of proxies). Verbal intelligence was statistically significant in all models. Education was significant only in models with executive function as the cognitive outcome variable. Three robust composites were observed in more than two-thirds of brain-cognition models: the composites of (1) occupational complexity and verbal intelligence, (2) education and verbal intelligence, and (3) education, occupational complexity, and verbal intelligence. However, no composite had larger average effects nor was more robust than verbal intelligence alone. CONCLUSION: These results support the use of verbal intelligence as a proxy measure of CR in cross-sectional studies of cognitively healthy older adults.

Cognitive rehabilitation for early stage Alzheimer's disease: a pilot study with an Irish population.

OBJECTIVES: Research shows that cognitive rehabilitation (CR) has the potential to improve goal performance and enhance well-being for people with early stage Alzheimer's disease (AD). This single subject, multiple baseline design (MBD) research investigated the clinical efficacy of an 8-week individualised CR intervention for individuals with early stage AD. METHODS: Three participants with early stage AD were recruited to take part in the study. The intervention consisted of eight sessions of 60-90 minutes of CR. Outcomes included goal performance and satisfaction, quality of life, cognitive and everyday functioning, mood, and memory self-efficacy for participants with AD; and carer burden, general mental health, quality of life, and mood of carers. RESULTS: Visual analysis of MBD data demonstrated a functional relationship between CR and improvements in participants' goal performance. Subjective ratings of goal performance and satisfaction increased from baseline to post-test for three participants and were maintained at follow-up for two. Baseline to post-test quality of life scores improved for three participants, whereas cognitive function and memory self-efficacy scores improved for two. CONCLUSIONS: Our findings demonstrate that CR can improve goal performance, and is a socially acceptable intervention that can be implemented by practitioners with assistance from carers between sessions. This study represents one of the promising first step towards filling a practice gap in this area. Further research and randomised-controlled trials are required.

Change in perceived stress and 2-year change in cognitive function among older adults: The Irish Longitudinal Study on Ageing.

Prolonged or severe stress can adversely affect older adults' cognitive function, but population-based studies investigating this relationship over time are rare. Previous studies have largely focused on stress either evaluated at a single time point or linked to specific life events. This study aimed to investigate whether a change in perceived stress over 2 years predicts a change in cognitive performance over the same time period in a population-based sample of older adults. Data from the first 2 waves of The Irish Longitudinal Study on Ageing were analyzed. Five thousand and seventy adults aged 50 and older completed the 4-item Perceived Stress Scale and measures of verbal fluency, immediate and delayed word recall 2 years apart. A first differences regression model revealed that the change in stress over 2 years was inversely associated with a change in immediate word recall performance, even after adjustment for change in possible confounders (B = -0.030, 95% CI [-.056, -.004], p < .05). No association was observed for delayed recall or verbal fluency performance. Change in perceived stress is inversely correlated with change in immediate recall, even over a short period. Stress modifying interventions could potentially reduce the risk of cognitive decline associated with ageing.

Effectiveness of a low support, remotely accessible, cognitive remediation training programme for chronic psychosis: cognitive, functional and cortical outcomes from a single blind randomised controlled trial.

BACKGROUND: Cognitive remediation (CR) training has emerged as a promising approach to improving cognitive deficits in schizophrenia and related psychosis. The limited availability of psychological services for psychosis is a major barrier to accessing this intervention however. This study investigated the effectiveness of a low support, remotely accessible, computerised working memory (WM) training programme in patients with psychosis. METHODS: Ninety patients were enrolled into a single blind randomised controlled trial of CR. Effectiveness of the intervention was assessed in terms of neuropsychological performance, social and occupational function, and functional MRI 2 weeks post-intervention, with neuropsychological and social function again assessed 3-6 months post-treatment. RESULTS: Patients who completed the intervention showed significant gains in both neuropsychological function (measured using both untrained WM and episodic task performance, and a measure of performance IQ), and social function at both 2-week follow-up and 3-6-month follow-up timepoints. Furthermore, patients who completed MRI scanning showed improved resting state functional connectivity relative to patients in the placebo condition. CONCLUSIONS: CR training has already been shown to improve cognitive and social function in patient with psychosis. This study demonstrates that, at least for some chronic but stable outpatients, a low support treatment was associated with gains that were comparable with those reported for CR delivered entirely on a 1:1 basis. We conclude that CR has potential to be delivered even in services in which psychological supports for patients with psychosis are limited.

Cognitive reserve and self-efficacy as moderators of the relationship between stress exposure and executive functioning among spousal dementia caregivers.

BACKGROUND: A substantial literature has reported that stress negatively impacts on cognitive processes. As dementia caregiving can be stressful, it has been hypothesized that the challenges of dementia care may increase caregivers' own vulnerability to cognitive decline. Prefrontal processes are thought to be most vulnerable to stress; however, few studies have examined whether greater caregiver stress predicts poorer executive dysfunction, and no previous research has considered potential moderators of this relationship. We examined (1) whether greater psychological stress mediated a relationship between caregiver stress exposure and executive functioning and (2) whether greater self-efficacy and cognitive reserve (CR) moderated this relationship. METHOD: Spousal dementia caregivers (n = 253) completed the Neuropsychiatric Inventory Questionnaire (stress exposure), the Perceived Stress Scale, the National Adult Reading Test (CR), the Fortinsky dementia-specific caregiver self-efficacy scale, and the Color Trails Test (executive functioning). Moderated mediation was tested using the PROCESS macro. Age, gender, and dementia risk factors were included as covariates. RESULTS: Greater stress exposure indirectly predicted executive functioning through psychological stress. Stronger relationships between greater psychological stress and poorer executive functioning were observed among caregivers with lower CR; there was no evidence that self-efficacy moderated the relationship between stress exposure and psychological stress. CONCLUSIONS: Our findings are in line with the idea that greater psychological stress in response to challenges associated with dementia care predicts poorer caregiver executive functioning, particularly among caregivers with low CR. However, these findings are cross sectional; it is also possible that poorer executive functioning contributes to greater caregiver stress.

Computerised working-memory focused cognitive remediation therapy for psychosis--A preliminary study.

BACKGROUND: Cognitive deficits are a core feature of schizophrenia and related psychotic disorders and are associated with decreased levels of functioning. Behavioural interventions have shown success in remediating these deficits; determining how best to maximise this benefit while minimising the cost is an important next step in optimising this intervention for clinical use. AIMS: To examine the effects of a novel working-memory focused cognitive remediation (CR) training on cognitive difficulties based on internet delivery of training and weekly telephone support. METHOD: Participants with a diagnosis of psychosis (n=56) underwent either 8 weeks of CR (approximately 20 h) or 8 weeks of treatment as usual (TAU). General cognitive ability, working memory and episodic memory were measured both pre and post intervention for all participants. RESULTS: In addition to improvements on trained working memory tasks, CR training was associated with significant improvements in two tests of verbal episodic memory. No association between CR and changes in general cognitive ability was observed. Effect sizes for statistically significant changes in memory were comparable to those reported in the literature based primarily on 1:1 training. CONCLUSIONS: The cognitive benefits observed in this non-randomised preliminary study indicate that internet-based working memory training can be an effective cognitive remediation therapy. The successes and challenges of an internet-based treatment are discussed.

Right-sided spatial difficulties in ADHD demonstrated in continuous movement control.

Children with Attention Deficit Hyperactivity Disorder (ADHD) often show spatial attentional deficits, exhibiting a subtle rightwards bias, possibly due to dysfunction within the right hemisphere fronto-parietal network. Approximately 50% of children with ADHD also show signs of movement dysfunction. The nature of this movement dysfunction and possible interactions with spatial attention difficulties has not been clearly described. This study compared 31 children with and 31 children without ADHD on a movement kinematic task that tested hand-drawing movement precision. Participants used an electronic pen on a digitizing tablet. The pen tip position was sampled as X and Y coordinates at 200Hz. The task was to join targets of either 10 or 20mm diameter that were separated by a distance of 62.5 or 125 mm. Constant error in the X and Y planes, peak absolute velocity and acceleration, movement time, the number of pauses and pause time were analysed. Apart from a significantly increased rate of acceleration across all conditions, the children with ADHD demonstrated no temporal difficulties with the task; rather they showed subtle spatial difficulties, possibly suggestive of cerebellar involvement. The children with ADHD showed difficulties in accuracy of movement towards the right. They were less accurate in the X plane when moving towards the right-sided targets over the long distance. Greater variability in target accuracy was shown when moving towards the small target on the right side. The children with ADHD made significantly more pauses on the left target, when preparing the right movement, than the control group. These results suggest that the subtle spatial bias towards the right that has been demonstrated in ADHD in spatial attention also extends into the continuous movement domain.

Dopaminergic genotype biases spatial attention in healthy children.

In everyday life, our sensory system is bombarded with visual input and we rely upon attention to select only those inputs that are relevant to behavioural goals. Typically, humans can shift their attention from one visual field to the other with little cost to perception. In cases of 'unilateral neglect', however, there is a persistent bias of spatial attention towards the same side as the damaged cerebral hemisphere. We used a visual orienting task to examine the influence of functional polymorphisms of the dopamine transporter gene (DAT1) on individual differences in spatial attention in normally developing children. DAT1 genotype significantly influenced spatial bias. Healthy children who were homozygous for alleles that influence the expression of dopamine transporters in the brain displayed inattention for left-sided stimuli, whereas heterozygotes did not. Our data provide the first evidence in healthy individuals of a genetically mediated bias in spatial attention that is related to dopamine signalling.

Loss of insight in frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy.

Loss of insight is one of the core features of frontal/behavioural variant frontotemporal dementia (FTD). FTD shares many clinical and pathological features with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). The aim of this study was to investigate awareness of cognitive deficits in FTD, CBD and PSP using a multidimensional approach to assessment, which examines metacognitive knowledge of the disorders, online monitoring of errors (emergent awareness) and ability to accurately predict performance on future tasks (anticipatory awareness). Thirty-five patients (14 FTD, 11 CBD and 10 PSP) and 20 controls were recruited. Results indicated that loss of insight was a feature of each of the three patient groups. FTD patients were most impaired on online monitoring of errors compared to the other two patient groups. Linear regression analysis demonstrated that different patterns of neuropsychological performance and behavioural rating scores predicted insight deficits across the three putative awareness categories. Furthermore, higher levels of depression were associated with poor anticipatory awareness, reduced empathy was related to impaired metacognitive awareness and impaired recognition of emotional expression in faces was associated with both metacognitive and anticipatory awareness deficits. The results are discussed in terms of neurocognitive models of awareness and different patterns of neurobiological decline in the separate patient groups.

Characterising error-awareness of attentional lapses and inhibitory control failures in patients with traumatic brain injury.

Awareness deficits are a significant problem following traumatic brain injury (TBI). This study examined error processing as candidate marker of awareness and compared the performance of 18 TBI participants and 18 controls using an online error-monitoring task while participants performed simple go/no-go tasks. Error-monitoring performance was compared where the no-go target was part of (a) a predictive sequence, (b) predictive sequence plus a dual-task element and (c) a random sequence. Results showed that the TBI participants, in contrast to control participants, were significantly impaired at monitoring their errors during both predictive sequence tasks but were not impaired on the random sequence task. These findings suggest that following TBI, when an error is more impulsive it may be more easily monitored, whereas when an error is characterised by attentional drift, subsequent error-processing mechanisms may fail to engage. Higher levels of online error-awareness were also associated with lower levels of anxiety, fewer symptoms of frontal dysfunction and greater competence in everyday functioning.

Asymmetric deterioration of spatial awareness with diminishing levels of alertness in normal children and children with ADHD.

BACKGROUND: There is growing literature suggesting that some children diagnosed with attention deficit hyperactivity disorder (ADHD) can show a significant bias in attention away from left space. Here we examine mechanisms that may underpin these effects in both clinical and non-clinical child populations. Unilateral spatial inattention (unilateral neglect) is a commonly reported consequence of stroke in adults. Although for most patients the problem is relatively transient, persistent forms of neglect are almost exclusively associated with right hemisphere lesions. It has been suggested that this chronicity may result from co-existing disruption to right hemisphere dominant systems that mediate alertness. Here we present two studies examining the relationship between sustained attention and left spatial awareness in childhood. METHOD: In the first, normal children without the ADHD diagnosis were administered a non-spatial test of sustained attention/alertness. Children who performed poorly at this task, relative to their more attentive peers, showed a modest but reliable delay in awareness of left-sided visual information. Furthermore, attention towards the left declined for both groups as a function of time-on-task, suggesting a significant within-subject modulatory effect of alertness on spatial awareness. The second study examines this relationship in children referred to clinical services for attention problems. Irrespective of their final diagnosis, children were divided into two groups according to their performance in sustained attention/alertness tasks. RESULTS: The results suggest that, regardless of the children's clinical diagnosis, diminished sustained attention/alertness levels formed the strongest predictor of relatively delayed awareness of information presented within left visual space. Two children within this group exhibited signs of hitherto undetected spatial neglect as severe as that observed in some brain-injured adults. CONCLUSIONS: Clinical and theoretical implications are discussed.

A topography of executive functions and their interactions revealed by functional magnetic resonance imaging.

We used fMRI to study the brain processes involved in the executive control of behavior. The Sustained Attention to Response Task (SART), which allows unpredictable and predictable NOGO events to be contrasted, was imaged using a mixed (block and event-related) fMRI design to examine tonic and phasic processes involved in response inhibition, error detection, conflict monitoring and sustained attention. A network of regions, including right ventral prefrontal cortex (PFC), left dorsolateral PFC (DLPFC) and right inferior parietal cortex, was activated for successful unpredictable inhibitions, while rostral anterior cingulate was implicated in error processing and the pre-SMA in conflict monitoring. Furthermore, the pattern of correlations between left dorsolateral PFC, implicated in task-set maintenance, and the pre-SMA were indicative of a tight coupling between prefrontally mediated control and conflict levels monitored more posteriorly. The results reveal that the executive control of behavior can be separated into distinct functions performed by discrete cortical regions.

Can specific deficits in executive functioning explain the negative symptoms of schizophrenia? A review.

The relationship between clinical symptoms and neurocognitive impairment has been a growing interest in the field of schizophrenia research. We review the empirical evidence for whether some schizophrenia symptoms can be viewed as expressions of disordered executive functioning. A specific focus of our review is Frith's (1992) neurocognitive theory of negative symptoms, and whether this theory is supported by studies of executive functioning in schizophrenia. The current trend towards viewing executive functioning in terms of fractionable cognitive processes is discussed. Difficulties with traditional clinical measures (e.g. the Wisconsin Card Sorting Test; WCST) in separating these processes are highlighted. Neurocognitive studies of schizophrenia are then reviewed in terms of this fractionated view of executive processes. We conclude that a more specific approach to executive functioning deficits in schizophrenia using more selective measures is needed before stronger conclusions can be drawn about their relationship to clinical symptoms.