Exploring memory impairment and post-traumatic amnesia following traumatic brain injury

Memory disturbances are among the most common and significant consequences of traumatic brain injury (TBI). The severity of these deficits can vary widely across the trajectory of recovery from TBI and can be highly heterogenous across individuals. In the acute stages memory disturbance can occur in the form of post-traumatic amnesia (PTA), but deficits are also present into the chronic stages of recovery. I present four studies that aim to understand the characteristics and underlying mechanisms of memory impairment following TBI. I investigated the cognitive profile of acute TBI patients with and without PTA. I found PTA patients show a transient deficit in working memory binding. I then assessed electrophysiological abnormalities to test the hypothesis that the binding deficit is underpinned by pathological low frequency slow-wave activity. PTA patients showed a significantly higher delta to alpha power ratio that correlated with binding impairment. To understand how this disruption to cortical communication impacts upon large-scale networks I performed a dynamic functional connectivity analysis on the resting state fMRI of acute TBI patients. I found four independent brain states that showed striking anti-correlation between core cognitive control networks. Patients in a more profound period of PTA spent more time in fewer states than those with less cognitive impairment. These findings suggest that PTA is likely underpinned by disruption to communication required for integration of features in working memory. Finally, I examined enduring memory failures in chronic TBI patients and found that patients with episodic memory impairment showed differential activation of key networks required for memory and attention. Memory impairment related to the white matter integrity directly underpinning the task-derived encoding networks. These findings suggest that in chronic TBI memory impairment may be associated with failed control of attentional resources.Open Acces

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA datawas analysedwith tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737

Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder

Background. Schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls. Methods. 230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA. Results. As predicted, statistically significant reductions in FA across a widely distributed brain network (p < 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d = 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d = 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found. Discussion. We provide the first evidence in a predominantly Caucasian clinical sample, of an association between ZNF804A rs1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure

Active elite rugby participation is associated with altered precentral cortical thickness

There is growing concern that elite rugby participation may negatively influence brain health, but the underlying mechanisms are unclear. Cortical thickness is a widely applied biomarker of grey matter structure, but there is limited research into how it may be altered in active professional rugby players. Cross-sectional MRI data from 44 active elite rugby players, including 21 assessed within 1 week of head injury, and 47 healthy controls were analysed. We investigated how active elite rugby participation with and without sub-acute traumatic brain injury influenced grey matter structure using whole cortex and region of interest cortical thickness analyses. Relationships between cortical thickness and biomarkers of traumatic brain injury, including fractional anisotropy, plasma neurofilament light and glial fibrillary acidic protein, were also examined. In whole-cortex analyses, precentral cortical thickness in the right hemisphere was lower in rugby players compared with controls, which was due to reductions in non-injured players. Post hoc region of interest analyses showed non-injured rugby players had reduced cortical thickness in the inferior precentral sulcal thickness bilaterally ( P = 0.005) and the left central sulcus ( P = 0.037) relative to controls. In contrast, players in the sub-acute phase of mild traumatic brain injury had higher inferior precentral sulcal cortical thickness in the right hemisphere ( P = 0.015). Plasma glial fibrillary acidic protein, a marker of astrocyte activation, was positively associated with right inferior precentral sulcal cortical thickness in injured rugby players ( P = 0.0012). Elite rugby participation is associated with localized alterations in cortical thickness, specifically in sulcal motor regions. Sub-acute changes after mild traumatic brain injury are associated with evidence of astrocytic activation. The combination of cortical thickness and glial fibrillary acidic protein may be useful in understanding the pathophysiological relationship between sporting head injury and brain health. </p

Population incidence and associated mortality of urinary tract infection in people living with dementia

Objectives: Urinary tract infections (UTIs) frequently cause hospitalisation and death in people living with dementia (PLWD). We examine UTI incidence and associated mortality among PLWD relative to matched controls and people with diabetes and investigate whether delayed or withheld treatment further impacts mortality. Methods: Data were extracted for n = 2,449,814 people aged ≥ 50 in Wales from 2000–2021, with groups matched by age, sex, and multimorbidity. Poisson regression was used to estimate incidences of UTI and mortality. Cox regression was used to study the effects of treatment timing. Results: UTIs in dementia (HR=2.18, 95 %CI [1.88–2.53], p &lt; .0) and diabetes (1.21[1.01–1.45], p = .035) were associated with high mortality, with the highest risk in individuals with diabetes and dementia (both) (2.83[2.40–3.34], p &lt; .0) compared to matched individuals with neither dementia nor diabetes. 5.4 % of untreated PLWD died within 60 days of GP diagnosis—increasing to 5.9 % in PLWD with diabetes. Conclusions: Incidences of UTI and associated mortality are high in PLWD, especially in those with diabetes and dementia. Delayed treatment for UTI is further associated with high mortality.</p

Computerised cognitive assessment in patients with traumatic brain injury: an observational study of feasibility and sensitivity relative to established clinical scalesResearch in context

Summary: Background: Online technology could potentially revolutionise how patients are cognitively assessed and monitored. However, it remains unclear whether assessments conducted remotely can match established pen-and-paper neuropsychological tests in terms of sensitivity and specificity. Methods: This observational study aimed to optimise an online cognitive assessment for use in traumatic brain injury (TBI) clinics. The tertiary referral clinic in which this tool has been clinically implemented typically sees patients a minimum of 6 months post-injury in the chronic phase. Between March and August 2019, we conducted a cross-group, cross-device and factor analyses at the St. Mary’s Hospital TBI clinic and major trauma wards at Imperial College NHS trust and St. George’s Hospital in London (UK), to identify a battery of tasks that assess aspects of cognition affected by TBI. Between September 2019 and February 2020, we evaluated the online battery against standard face-to-face neuropsychological tests at the Imperial College London research centre. Canonical Correlation Analysis (CCA) determined the shared variance between the online battery and standard neuropsychological tests. Finally, between October 2020 and December 2021, the tests were integrated into a framework that automatically generates a results report where patients’ performance is compared to a large normative dataset. We piloted this as a practical tool to be used under supervised and unsupervised conditions at the St. Mary’s Hospital TBI clinic in London (UK). Findings: The online assessment discriminated processing-speed, visual-attention, working-memory, and executive-function deficits in TBI. CCA identified two significant modes indicating shared variance with standard neuropsychological tests (r = 0.86, p < 0.001 and r = 0.81, p = 0.02). Sensitivity to cognitive deficits after TBI was evident in the TBI clinic setting under supervised and unsupervised conditions (F (15,555) = 3.99; p < 0.001). Interpretation: Online cognitive assessment of TBI patients is feasible, sensitive, and efficient. When combined with normative sociodemographic models and autogenerated reports, it has the potential to transform cognitive assessment in the healthcare setting. Funding: This work was funded by a National Institute for Health Research (NIHR) Invention for Innovation (i4i) grant awarded to DJS and AH (II-LB-0715-20006)

Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.</p

Using home monitoring technology to study the effects of traumatic brain injury on older multimorbid adults: protocol for a feasibility study

Introduction The prevalence of traumatic brain injury (TBI) among older adults is increasing exponentially. The sequelae can be severe in older adults and interact with age-related conditions such as multimorbidity. Despite this, TBI research in older adults is sparse. Minder, an in-home monitoring system developed by the UK Dementia Research Institute Centre for Care Research and Technology, uses infrared sensors and a bed mat to passively collect sleep and activity data. Similar systems have been used to monitor the health of older adults living with dementia. We will assess the feasibility of using this system to study changes in the health status of older adults in the early period post-TBI.Methods and analysis The study will recruit 15 inpatients (&gt;60 years) with a moderate-severe TBI, who will have their daily activity and sleep patterns monitored using passive and wearable sensors over 6 months. Participants will report on their health during weekly calls, which will be used to validate sensor data. Physical, functional and cognitive assessments will be conducted across the duration of the study. Activity levels and sleep patterns derived from sensor data will be calculated and visualised using activity maps. Within-participant analysis will be performed to determine if participants are deviating from their own routines. We will apply machine learning approaches to activity and sleep data to assess whether the changes in these data can predict clinical events. Qualitative analysis of interviews conducted with participants, carers and clinical staff will assess acceptability and utility of the system.Ethics and dissemination Ethical approval for this study has been granted by the London-Camberwell St Giles Research Ethics Committee (REC) (REC number: 17/LO/2066). Results will be submitted for publication in peer-reviewed journals, presented at conferences and inform the design of a larger trial assessing recovery after TBI