Neurocognitive predictors of post-stroke cognitive trajectory

The current thesis examined cognitive trajectories following stroke, and tested potential predictors of cognitive outcome, and trajectories. It used data from two existing databases: the Birmingham Cognitive Screen Study (BUCS) collected in the UK, and the C-BCoS collected in China, and newly collected data as part of the HiPPS-CI study (The role of Hippocampus Pathology in Post-Stroke-Cognitive Impairment). Chapter two aimed to answer the question; does the proportional recovery rule exist in cognition, as it does with motor recovery? We found that 80% of patients showed 40- 50% proportional recovery of cognition at nine months post-stroke. This was evident across and within cognitive domains. Recovery was not limited to the first three months following stroke. We further identified two other recovery trajectories, where around 10% of patients showed an accelerated recovery, while around 10% showed decelerated recovery and even decline. We then investigated the predictive value of years of education on post-stroke cognitive outcomes, and recovery rate (Chapter three). We found that education improved cognitive outcomes following stroke, and accelerated recovery in the first year following stroke beyond age. Finally, we explored the predictive value of hippocampal pathology, and the impact of hippocampal pathology on post-stroke cognition. We found that beyond stroke and age, hippocampal pathology predicted cognition within three months post-stroke. This was evident in grey matter volume, mean diffusivity, creatine, choline and N-acetylaspartate. Hippocampus pathology (specifically grey matter volume) interacted with education, age, vascular risk, cortical atrophy and small vessel disease. These factors also predicted cognition. It is concluded that post-stroke cognitive outcomes are affected by pre-stroke clinical, and socio-demographic factors, where education ameliorates the impact of stroke on cognition potentially by preserving the hippocampus, while neurovascular health potentially aggravates the cognitive impairments

Mechanisms underlying selecting objects for action

We assessed the factors which affect the selection of objects for action, focusing on the role of action knowledge and its modulation by distracters. 14 neuropsychological patients and 10 healthy aged-matched controls selected pairs of objects commonly used together among distracters in two contexts: with real objects and with pictures of the same objects presented sequentially on a computer screen. Across both tasks, semantically related distracters led to slower responses and more errors than unrelated distracters and the object actively used for action was selected prior to the object that would be passively held during the action. We identified a sub-group of patients (N=6) whose accuracy was 2SD below the controls performances in the real object task. Interestingly, these impaired patients were more affected by the presence of unrelated distracters during both tasks than intact patients and healthy controls. Note the impaired had lesions to left parietal, right anterior temporal and bilateral pre-motor regions. We conclude that: (1) motor procedures guide object selection for action, (2) semantic knowledge affects action-based selection, (3) impaired action decision is associated with the inability to ignore distracting information and (4) lesions to either the dorsal or ventral visual stream can lead to deficits in making action decisions. Overall, the data indicate that impairments in everyday tasks can be evaluated using a simulated computer task. The implications for rehabilitation are discussed

Measurement of retinal vessels as a biomarker of cerebrovascular ageing in older HIV positive men compared to controls

Background: To compare retinal vascular measurements, biomarkers of cerebral small vessel disease (SVD), in HIV positive men aged 50 years and above with similarly-aged HIV negative men and younger HIV positive men. Methods: We recruited white, non-diabetic men to a cross-sectional substudy of a larger cohort including three demographically-matched groups. Optic disc centred 45° colour fundus photographs were used to calculate central retinal arterial and venous calibre and the arterial- venous ratio (AVR). We used univariate and multivariable linear regression to compare retinal vessel measurements in the three groups and to identify factors associated with AVR. Results: All HIV positive men were virologically suppressed. In a multivariable model, study group was not associated with AVR (adjusted β 0.010 for HIV positive men 50 years [n=120], 95% CI -0.018 to 0.038, p=0.47; adjusted β 0.00002 for HIV negative men >50 years [n=52], 95% CI -0.022 to 0.022, p=0.99). Factors associated with lower AVR were systolic BP (adjusted β -0.009 per +10 mmHg, 95% CI - 0.015 to -0.003, p=0.002), history of stroke or transient ischemic attack (adjusted β -0.070, 95% CI -0.12 to -0.015, p=0.01), and recent recreational drug use (adjusted β -0.037, 95% CI -0.057 to -0.018, p=0.0002). Conclusion: There were no differences in retinal vascular indices between HIV positive men aged >50 years and HIV negative men aged >50 years or HIV positive men aged <50 years, suggesting that HIV is not associated with an increased burden of cerebral SVD

The efficacy of a task model approach to ADL rehabilitation in stroke apraxia and action disorganisation syndrome:A randomised controlled trial

BACKGROUND: Apraxia and action disorganization syndrome (AADS) after stroke can disrupt activities of daily living (ADL). Occupational therapy has been effective in improving ADL performance, however, inclusion of multiple tasks means it is unclear which therapy elements contribute to improvement. We evaluated the efficacy of a task model approach to ADL rehabilitation, comparing training in making a cup of tea with a stepping training control condition. METHODS: Of the 29 stroke survivors with AADS who participated in this cross-over randomized controlled feasibility trial, 25 were included in analysis [44% females; mean(SD) age = 71.1(7.8) years; years post-stroke = 4.6(3.3)]. Participants attended five 1-hour weekly tea making training sessions in which progress was monitored and feedback given using a computer-based system which implemented a Markov Decision Process (MDP) task model. In a control condition, participants received five 1-hour weekly stepping sessions. RESULTS: Compared to stepping training, tea making training reduced errors across 4 different tea types. The time taken to make a cup of tea was reduced so the improvement in accuracy was not due to a speed-accuracy trade-off. No improvement linked to tea making training was evident in a complex tea preparation task (making two different cups of tea simultaneously), indicating a lack of generalisation in the training. CONCLUSIONS: The clearly specified but flexible training protocol, together with information on the distribution of errors, provide pointers for further refinement of task model approaches to ADL rehabilitation. It is recommended that the approach be tested under errorless learning conditions with more impaired patients in future research. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov on 5(th) August 2019 [NCT04044911] https://clinicaltrials.gov/ct2/show/NCT04044911?term=Cogwatch&rank=

Level of agreement between frequently used cardiovascular risk calculators in people living with HIV

Objectives The aim of the study was to describe agreement between the QRISK2, Framingham and Data Collection on Adverse Events of Anti‐HIV Drugs (D:A:D) cardiovascular disease (CVD) risk calculators in a large UK study of people living with HIV (PLWH). Methods PLWH enrolled in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study without a prior CVD event were included in this study. QRISK2, Framingham CVD and the full and reduced D:A:D CVD scores were calculated; participants were stratified into ‘low’ ( 20%) categories for each. Agreement between scores was assessed using weighted kappas and Bland–Altman plots. Results The 730 included participants were predominantly male (636; 87.1%) and of white ethnicity (645; 88.5%), with a median age of 53 [interquartile range (IQR) 49–59] years. The median calculated 10‐year CVD risk was 11.9% (IQR 6.8–18.4%), 8.9% (IQR 4.6–15.0%), 8.5% (IQR 4.8–14.6%) and 6.9% (IQR 4.1–11.1%) when using the Framingham, QRISK2, and full and reduced D:A:D scores, respectively. Agreement between the different scores was generally moderate, with the highest level of agreement being between the Framingham and QRISK2 scores (weighted kappa = 0.65) but with most other kappa coefficients in the 0.50–0.60 range. Conclusions Estimates of predicted 10‐year CVD risk obtained with commonly used CVD risk prediction tools demonstrate, in general, only moderate agreement among PLWH in the UK. While further validation with clinical endpoints is required, our findings suggest that care should be taken when interpreting any score alone

Depression, lifestyle factors and cognitive function in people living with HIV and comparable HIV-negative controls

We investigated whether differences in cognitive performance between people living with HIV (PLWH) and comparable HIV-negative people were mediated or moderated by depressive symptoms and lifestyle factors. METHODS: A cross-sectional study of 637 'older' PLWH aged ≥ 50 years, 340 'younger' PLWH aged < 50 years and 276 demographically matched HIV-negative controls aged ≥ 50 years enrolled in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study was performed. Cognitive function was assessed using a computerized battery (CogState). Scores were standardized into Z-scores [mean = 0; standard deviation (SD) = 1] and averaged to obtain a global Z-score. Depressive symptoms were evaluated via the Patient Health Questionnaire (PHQ-9). Differences between the three groups and the effects of depression, sociodemographic factors and lifestyle factors on cognitive performance were evaluated using median regression. All analyses accounted for age, gender, ethnicity and level of education. RESULTS: After adjustment for sociodemographic factors, older and younger PLWH had poorer overall cognitive scores than older HIV-negative controls (P < 0.001 and P = 0.006, respectively). Moderate or severe depressive symptoms were more prevalent in both older (27%; P < 0.001) and younger (21%; P < 0.001) PLWH compared with controls (8%). Depressive symptoms (P < 0.001) and use of hashish (P = 0.01) were associated with lower cognitive function; alcohol consumption (P = 0.02) was associated with better cognitive scores. After further adjustment for these factors, the difference between older PLWH and HIV-negative controls was no longer significant (P = 0.08), while that between younger PLWH and older HIV-negative controls remained significant (P = 0.01). CONCLUSIONS: Poorer cognitive performances in PLWH compared with HIV-negative individuals were, in part, mediated by the greater prevalence of depressive symptoms and recreational drug use reported by PLWH

Validation of a novel multivariate method of defining HIV-associated cognitive impairment

Background. The optimum method of defining cognitive impairment in virally suppressed people living with HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient– reported outcome measures (PROMs), and neuroimaging markers of brain structure across 3 cohorts. Methods. Differences in the prevalence of cognitive impairment, PROMs, and neuroimaging data from the COBRA, CHARTER, and POPPY cohorts (total n = 908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS), and NMM criteria. Results. The prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (eg, 48% for HAND vs 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints generally were weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (P < .05). There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (P < .05), as well as smaller brain volumes (P < .01). The associations with measures of white matter microstructure and brain-predicted age generally were weaker. Conclusion. Different methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer selfreported health status. This may be due to the statistical advantage of using a multivariate approac

Selecting object pairs for action: is the active object always first?

Perception is linked to action via two routes: a direct route based on affordance information in the environment and an indirect route based on semantic knowledge about objects. The present study explored the factors modulating the recruitment of the two routes, in particular which factors affecting the selection of paired objects. In Experiment 1, we presented real objects among semantically related or unrelated distracters. Participants had to select two objects that can interact. The presence of distracters affected selection times, but not the semantic relations of the objects with the distracters. Furthermore, participants first selected the active object (e.g. teaspoon) with their right hand, followed by the passive object (e.g. mug), often with their left hand. In Experiment 2, we presented pictures of the same objects with no hand grip, congruent or incongruent hand grip. Participants had to decide whether the two objects can interact. Action decisions were faster when the presentation of the active object preceded the presentation of the passive object, and when the grip was congruent. Interestingly, participants were slower when the objects were semantically but not functionally related; this effect increased with congruently gripped objects. Our data showed that action decisions in the presence of strong affordance cues (real objects, pictures of congruently gripped objects) relied on sensory-motor representation, supporting the direct route from perception-to-action that bypasses semantic knowledge. However, in the case of weak affordance cues (pictures), semantic information interfered with action decisions, indicating that semantic knowledge impacts action decisions. The data support the dual-route account from perception-to-action