Poor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE study.

BACKGROUND: Traumatic brain injury (TBI) is common in military campaigns and is a risk factor for dementia. ArmeD SerVices TrAuma and RehabilitatioN OutComE-TBI (ADVANCE-TBI) aims to ascertain neurological outcomes in UK military personnel with major battlefield trauma, leveraging advances in quantification of axonal breakdown markers like neurofilament light (NfL), and astroglial marker glial fibrillar acidic protein (GFAP) in blood. We aimed to describe the causes, prevalence and consequences of TBI, and its fluid biomarker associations. METHODS: TBI history was ascertained in 1145 servicemen and veterans, of whom 579 had been exposed to major trauma. Functional and mental health assessments were administered, and blood samples were collected approximately 8 years postinjury, with plasma biomarkers quantified (n=1125) for NfL, GFAP, total tau, phospho-tau181, amyloid-ß 42 and 40. Outcomes were related to neurotrauma exposure. RESULTS: TBI was present in 16.9% (n=98) of exposed participants, with 46.9% classified as mild-probable and 53.1% classified as moderate to severe. Depression (ß=1.65, 95% CI (1.33 to 2.03)), anxiety (ß=1.65 (1.34 to 2.03)) and post-traumatic stress disorder (ß=1.30 (1.19 to 1.41)) symptoms were more common after TBI, alongside poorer 6 minute walk distance (ß=0.79 (0.74 to 0.84)) and quality of life (ß=1.27 (1.19 to 1.36), all p<0.001). Plasma GFAP was 11% (95% CI 2 to 21) higher post-TBI (p=0.013), with greater concentrations in moderate-to-severe injuries (47% higher than mild-probable (95% CI 20% to 82%, p<0.001). Unemployment was more common among those with elevated GFAP levels post-TBI, showing a 1.14-fold increase (95% CI 1.03 to 1.27, p<0.001) for every doubling in GFAP concentration. CONCLUSIONS: TBI affected nearly a fifth of trauma-exposed personnel, related to worse mental health, motor and functional outcomes, as well as elevated plasma GFAP levels 8 years post-injury. This was absent after extracranial trauma, and showed a dose-response relationship with the severity of the injury.

Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease.

Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ('converters'; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.

Acceptability and feasibility of plasma phosphorylated-tau181 in two memory services.

BACKGROUND: Plasma phosphorylated-tau181 (p-tau181) represents a novel blood-based biomarker of Alzheimer's disease pathology. We explored clinicians' experience of the utility of plasma p-tau181 in Camden and Islington Memory Services. METHODS: Patients were identified by their clinician as appropriate for p-tau181. Their p-tau181 result was plotted on a reference range graph provided to clinicians. This was discussed with the patient at diagnostic feedback appointment. RESULTS: Twenty-nine participants' plasma p-tau181 samples were included (mean age 74 SD 8.5, 65% female). Nine clinicians participated in the study. Eighty-six percent of clinicians found the p-tau181 result to be helpful and in 93% of cases it was clearly understandable. The p-tau181 result was useful in making the diagnosis in 44% of cases. CONCLUSIONS: Plasma p-tau181 is a feasible test for use in memory services and acceptable to clinicians. Clinician feedback on utility in dementia diagnoses was mixed. Further work is required to provide education and training in understanding and interpreting ambiguity in biomarker results.

Neuroimaging and plasma evidence of early white matter loss in Parkinson's disease with poor outcomes.

Parkinson's disease is a common and debilitating neurodegenerative disorder, with over half of patients progressing to postural instability, dementia or death within 10 years of diagnosis. However, the onset and rate of progression to poor outcomes is highly variable, underpinned by heterogeneity in underlying pathological processes. Quantitative and sensitive measures predicting poor outcomes will be critical for targeted treatment, but most studies to date have been limited to a single modality or assessed patients with established cognitive impairment. Here, we used multimodal neuroimaging and plasma measures in 98 patients with Parkinson's disease and 28 age-matched controls followed up over 3 years. We examined: grey matter (cortical thickness and subcortical volume), white matter (fibre cross-section, a measure of macrostructure; and fibre density, a measure of microstructure) at whole-brain and tract level; structural and functional connectivity; and plasma levels of neurofilament light chain and phosphorylated tau 181. We evaluated relationships with subsequent poor outcomes, defined as development of mild cognitive impairment, dementia, frailty or death at any time during follow-up, in people with Parkinson's disease. We show that extensive white matter macrostructural changes are already evident at baseline assessment in people with Parkinson's disease who progress to poor outcomes (n = 31): with up to 19% reduction in fibre cross-section in multiple tracts, and a subnetwork of reduced structural connectivity strength, particularly involving connections between right frontoparietal and left frontal, right frontoparietal and left parietal and right temporo-occipital and left parietal modules. In contrast, grey matter volumes and functional connectivity were preserved in people with Parkinson's disease with poor outcomes. Neurofilament light chain, but not phosphorylated tau 181 levels were increased in people with Parkinson's disease with poor outcomes, and correlated with white matter loss. These findings suggest that imaging sensitive to white matter macrostructure and plasma neurofilament light chain may be useful early markers of poor outcomes in Parkinson's disease. As new targeted treatments for neurodegenerative disease are emerging, these measures show important potential to aid patient selection for treatment and improve stratification for clinical trials.

Serum neurofilament light chain in hereditary transthyretin amyloidosis: validation in real-life practice.

BACKGROUND: Neurofilament light chain (NfL) has emerged as a sensitive biomarker in hereditary transthyretin amyloid polyneuropathy (ATTRv-PN). We hypothesise that NfL can identify conversion of gene carriers to symptomatic disease, and guide treatment approaches. METHODS: Serum NfL concentration was measured longitudinally (2015-2022) in 59 presymptomatic and symptomatic ATTR variant carriers. Correlations between NfL and demographics, biochemistry and staging scores were performed as well as longitudinal changes pre- and post-treatment, and in asymptomatic and symptomatic cohorts. Receiver-operating analyses were performed to determine cut-off values. RESULTS: NfL levels correlated with examination scores (CMTNS, NIS and MRC; all p < .01) and increased with disease severity (PND and FAP; all p < .05). NfL was higher in symptomatic and sensorimotor converters, than asymptomatic or sensory converters irrespective of time (all p < .001). Symptomatic or sensorimotor converters were discriminated from asymptomatic patients by NfL concentrations >64.5 pg/ml (sensitivity= 91.9%, specificity = 88.5%), whereas asymptomatic patients could only be discriminated from sensory or sensorimotor converters or symptomatic individuals by a NfL concentration >88.9 pg/ml (sensitivity = 62.9%, specificity = 96.2%) However, an NfL increment of 17% over 6 months could discriminate asymptomatic from sensory or sensorimotor converters (sensitivity = 88.9%, specificity = 80.0%). NfL reduced with treatment by 36%/year and correlated with TTR suppression (r = 0.64, p = .008). CONCLUSIONS: This data validates the use of serum NfL to identify conversion to symptomatic disease in ATTRv-PN. NfL levels can guide assessment of disease progression and response to therapies.

CSF concentrations of soluble TREM2 as a marker of microglial activation in HIV-1 infection.

Objective: To explore changes in CSF sTREM2 concentrations in the evolving course of HIV-1 infection. Methods: In this retrospective cross-sectional study, we measured concentrations of the macrophage/microglial activation marker sTREM2 in CSF samples from 121 HIV-1-infected adults and 11 HIV-negative controls and examined their correlations with other CSF and blood biomarkers of infection, inflammation, and neuronal injury. Results: CSF sTREM2 increased with systemic and CNS HIV-1 disease severity, with the highest levels found in patients with HIV-associated dementia (HAD). In untreated HIV-1-infected patients without an HAD diagnosis, levels of CSF sTREM2 increased with decreasing CD4+ T-cell counts. CSF concentrations of both sTREM2 and the neuronal injury marker neurofilament light protein (NFL) were significantly associated with age. CSF sTREM2 levels were also independently correlated with CSF NFL. Notably, this association was also observed in HIV-negative controls with normal CSF NFL. HIV-infected patients on suppressive antiretroviral treatment had CSF sTREM2 levels comparable to healthy controls. Conclusions: Elevations in CSF sTREM2 levels, an indicator of macrophage/microglial activation, are a common feature of untreated HIV-1 infection that increases with CD4+ T-cell loss and reaches highest levels in HAD. The strong and independent association between CSF sTREM2 and CSF NFL suggests a linkage between microglial activation and neuronal injury in HIV-1 infection. CSF sTREM2 has the potential of being a useful biomarker of innate CNS immune activation in different stages of untreated and treated HIV-1 infection.