Poor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE study, 2024, Graham et al.

[SNT Gatchaman]

Poor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE study
Neil SN Graham; Grace Blissitt; Karl Zimmerman; Lydia Orton; Daniel Friedland; Emma Coady; Rhiannon Laban; Elena Veleva; Amanda J Heslegrave; Henrik Zetterberg; Susie Schofield; Nicola T Fear; Christopher J Boos; Anthony M J Bull; Alexander Bennett; David J Sharp

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-β 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 (β=1.65, 95% CI (1.33 to 2.03)), anxiety (β=1.65 (1.34 to 2.03)) and post-traumatic stress disorder (β=1.30 (1.19 to 1.41)) symptoms were more common after TBI, alongside poorer 6 minute walk distance (β=0.79 (0.74 to 0.84)) and quality of life (β=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.


Link | PDF (Journal of Neurology, Neurosurgery & Psychiatry) [Open Access]

 

[Hutan]

This study seems a bit circular. We've seen elsewhere how hard it is to diagnose traumatic brain injury, with cases often only being diagnosed after death. People are often given mental illness diagnoses. Even brain scans don't seem to reliably identify the pathology.

In this case, I don't think they did brain scans.

There's a paywall, so I'm only going by the abstract. But, they seem to have looked at the history of possible brain injury, asked about functioning and mental health and measured six biomarkers that they say indicate brain injury. And then identified people with traumatic brain injury (including dividing these people into mild and moderate/severe categories) and reported that they have lower functioning, poorer mental health and elevated biomarkers.

I assume they have related symptoms and signs to some measure of the severity of the initial impact, and they have seemed to narrow the biomarkers down from six to just GFAP. Presumably the others, including NfL was not a useful marker, which is interesting as NfL levels have, from memory been normal in people with ME/CFS and this has been reported as evidence of no brain damage.

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.

But, see what I mean about the circularity? It could be that GFAP is a marker of brain injury acquired during service, and it probably is. But, it could also be the result of the consequences of poverty such as smoking, or a genetic brain issue.

 

[Hutan]

We've seen some hints that GFAP may be raised in Long Covid, but it is difficult to disentangle the impact of the acute disease and hospitalisation. The Peluso paper with a good sized cohort seemed to find that GFAP was only elevated early on in PASC:

Results Of 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04–1.63, p = 0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89–1.26, p = 0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison with those who did not report CNS PASC symptoms (p = 0.041). Those who went on to report CNS PASC also exhibited elevations in interleukin 6 (48% higher during early recovery and 38% higher during late recovery), monocyte chemoattractant protein 1 (19% higher during early recovery), and tumor necrosis factor α (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune activation markers during early recovery; these correlations were attenuated during late recovery.

But, did the PASC people actually have long term PASC?

I haven't looked closely at the evidence for raised GFAP in post-infection illness, so the above is just my sense of where we are at.

 

[SNT Gatchaman]

There's a paywall

It's open access so you should be able to access.

 

[Hutan]

Ah yes, I got confused with the 'Request Permission' heading.

Here's information about how they worked out if TBI was present or not:

TBI ascertainment and definition
In the ADVANCE study, combat trauma-exposed participants were defined as those with exposure to major battlefield trauma requiring aeromedical evacuation back to the UK with hospital admission, but not necessarily TBI. To establish the presence or absence of TBI, medical history data, collected using study case report forms and trauma registry data (joint theatre trauma registry), were reviewed by two of the study investigators, including a neurologist. Clinical features, including relevant imaging findings, neuropathologies, lowest conscious level, duration of post-traumatic amnesia, and other available details, were documented.

Most mild TBI diagnoses were based on self-reported past medical history, whereas moderate-to-severe cases were more frequently classified using registry data, such as CT findings.

They reviewed medical history data in order to define who had a TBI, so it does seem likely that there was some circularity. A momentary loss of consciousness was enough to define a mild case, but I wonder if that could just be fainting associated with a non-head injury. Also, I wonder how many of the personnel not classed as having a TBI had in fact suffered brain damage as a result of repeated relatively small exposures such as in training with explosives.

Nevertheless, it does seem as though the military personnel classified as having a TBI probably had had one, especially if they were classed as moderate/severe.

 

[Hutan]

Plasma GFAP was significantly elevated after TBI, being 11% higher (95% CI 2% to 21%, geometric mean ratio, adjusted for age/rank, p=0.013) than unexposed participants. The elevation in plasma GFAP was TBI-specific, with no elevation in the extracranial injury group. GFAP after TBI was 13% higher (95% CI 3 to 23, p=0.007) than in participants with extracranial injury alone. There was no significant TBI-associated elevation in concentration of NfL, Aβ40, Aβ 42, Aβ42:40 ratio, p-tau181 or total tau (after adjusting for confounders age and rank) (online supplemental table 4).

The elevation of GFAP seems fairly subtle when the mild and moderate/severe participants are combined and compared with unexposed participants and with people with other sorts of injuries.

The effect of TBI severity was assessed by comparing participants with moderate-to-severe TBI with those with mild-probable TBI. Plasma GFAP was 47% higher (95% CI 20% to 82%, p<0.001).

There was no severity-associated change in concentrations of the other biomarkers (all analyses adjusted for confounders age and rank, see online supplemental table 5). A sensitivity analysis comparing only participants with moderate-to-severe TBI with unexposed participants was performed, given the possible influ- ence of self-reported injuries in the mild TBI group. In this anal- ysis, GFAP levels were significantly elevated, being 42% higher (95% CI 26 to 61, p<0.001).

The elevation is much more pronounced in the moderate/severe group. Oddly, the levels in the moderate/severe group were more elevated compared to the mild group than compared to the unexposed group. So, again, I'm wondering what is going on with the mild group, and how accurate the diagnosis was.

Ah, here's the chart of the individual GFAP results (although not separated out by TBI severity):

Some of the people with TBI had some pretty bad injuries. Given that, and even considering some of the people in the uninjured category may have suffered from repeated small brain injuries, GFAP is not really looking like a marker of ongoing effects of mild brain injury 8 years later. I'm not really sure how the moderate/severe group had a mean GFAP 42% higher than the Uninjured cohort. There can't have been many in the moderate/severe group.

Figure 3 is interesting simply to demonstrate that the supposed biomarkers didn't mark much at all and there is a lot of individual variation.

Sorry for the waffle, I'm struggling today.

In summary, look at the scatter chart. They really should have plotted individual GFAP results separately for mild and moderate/severe TBI so we could see what was going on. Perhaps GFAP is a marker of ongoing delayed effects resulting from a major brain injury, but it doesn't seem to be very useful as a marker of long term effects from more mild brain injuries. And none of the other markers of brain injury in this study were helpful either.