With any brain cells at all in the stroke world we would get the exact possibility of dementia from stroke rather than the allover the board crapola we have now.
Your risk of dementia, has your doctor told you of this?
1. A documented 33% dementia chance post-stroke from an Australian study? May 2012.
2. Then this study came out and seems to have a range from 17-66%. December 2013.`
3. A 20% chance in this research. July 2013.
4. Dementia Risk Doubled in Patients Following Stroke September 2018
Progress towards predicting neurodegeneration and dementia after traumatic brain injury
This scientific commentary refers to ‘Post-acute blood biomarkers and disease progression in traumatic brain injury’ by Newcombe et al. (https://doi.org/10.1093/brain/awac126).
Ultrasensitive tests to quantify neuronal and glial proteins in blood promise to improve diagnosis, monitoring and prognostication in a broad range of neurological diseases. The clinical use-case in traumatic brain injury (TBI) is particularly strong. Acutely, the extent of traumatic injury is often difficult to define, particularly the extent of any axonal injury. This matters, because axonal damage is a key determinant of cognitive problems early post-injury—the so-called ‘direct effects’ of injury—and because axonal damage is implicated in the development of chronic post-traumatic neurodegenerative disease.1 It is increasingly clear that fluid injury biomarkers provide a highly sensitive readout of the extent of acute parenchymal damage, which can inform early decision-making, for example obviating the need for brain imaging if blood biomarker concentrations are very low after mild TBI. Acute injury biomarkers appear also to predict long-term post-TBI outcomes, which could inform acute management in a more sophisticated way.2
However, predicting outcomes years after an injury has historically been challenging, reflecting the heterogeneity of the disease and its consequences, as well as our inability to precisely define the insult. In this issue of Brain, Newcombe and colleagues3 leverage recent advances in fluid and imaging biomarkers to investigate the relationships between injury biomarkers and functional outcomes up to half a decade after TBI, with important findings.
The lifetime probability of dementia following TBI is around 1.8× background risk. Risk is higher after more severe injuries, or after a greater number of injuries in the case of repeated TBI, pointing to a dose-response relationship.4,5 Though a range of neurodegenerative diseases have been related to TBI exposure, it is difficult to be precise about TBI and dementia subtypes. There are also epidemiological challenges, particularly around ascertainment of injury, the potential for non-progressive cognitive problems arising from direct effects of injury to be mislabelled as ‘dementia’, and a frequent lack of biomarker or post-mortem pathological data. Chronic traumatic encephalopathy (CTE), a head injury-associated tauopathy related to repeated mild TBI exposure, does not yet benefit from validated biomarkers to confirm the diagnosis in vivo. Alongside uncertainty about dementia subtypes, it remains unclear which injuries pose the greatest risk of progressive problems, whether there is a threshold for a dangerous cumulative dose of repeated injuries, what that threshold might be, and which individual susceptibility factors are most relevant.
The pathological mechanisms casually relating injury to chronic neurodegenerative disease are increasingly well defined, however. Traumatic axonal cytoskeletal disruption sustained acutely provides the means for early generation of amyloid-β and hyperphosphorylated tau (pTau), which may continue to propagate in a prion-like manner long after the injury.6 Inflammatory pathologies, such as microglial activation, abnormal pTau and amyloid deposition are features of chronic TBI, where progressive brain atrophy—the final end-product of neurodegeneration—may be seen on longitudinal volumetric T1-weighted MRI.1 Unfortunately, given the mechanistic importance of axonal injury in the genesis of chronic post-injury problems, conventional imaging tools and clinical characteristics are poor measures of this type of damage. Diffusion tensor imaging (DTI) MRI provides an alternative means of assessing white matter integrity.7 DTI measures of white matter damage predict progressive brain volume loss and chronic memory problems after TBI.8 Nonetheless, widespread clinical use of this tool has been limited by the need for scanner-specific controls and complex image processing pipelines.
Ultrasensitive blood assays for brain proteins released acutely after TBI and in chronic neurodegeneration may be able to assist clinically. In the acute phase, dramatic increases in concentration are seen across a range of biomarkers, including axonal proteins such as neurofilament light (NfL) and the microtubule-associated protein tau (Tau), the neuronal somal marker ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), and the astroglial markers glial fibrillary acidic protein (GFAP) and S100 calcium binding protein B (S100-B). DTI axonal injury measures and plasma NfL were found to be closely related, supporting the validity of the fluid biomarker assessment.2
Turning to the chronic phase, in observational studies GFAP and NfL were both elevated in a substantial proportion of patients with moderate-severe TBI up to 5 years after injury. This phenomenon is thought to indicate ongoing neurodegeneration with an inflammatory response,2,9 but its precise origin is unclear. One possibility is that it reflects slow Wallerian degeneration in response to the initial injury, which may decrease in intensity over time and may even be accompanied by improving clinical status. Alternatively, these signs may be a harbinger of progressive degeneration, reflecting presymptomatic disease, which may eventually manifest as progressive clinical deficits and even accelerate over time.
Newcombe et al.3 assessed TBI patients largely cross-sectionally, at early and late chronic time points (n = 165 around 8 months and n = 38 around 8 years post-TBI). Functional outcomes were measured using the widely-employed Glasgow Outcome Scale Extended (GOSE), MRI was performed incorporating volumetric and diffusion imaging, and NfL and GFAP were quantified in serum on a single molecule ELISA platform (Quanterix). A subgroup of patients (n = 12) was assessed at both time points to facilitate longitudinal analyses. A spectrum of TBI severities was included, with a median acute Glasgow Coma Scale (GCS) in the early-chronic group of 14, in contrast to the late chronic group which typically had more severe injuries with a median GCS of 7.
Assessing patients across two centres, the team validated previous work showing significant elevation of NfL in blood in the early chronic phase post-injury.2 Though a number of patients had elevated NfL concentrations at the 8-year time point, this proportion was not significantly different from controls at the group level. This is in contrast to a previous report, which did find significantly elevated serum NfL versus healthy controls for all injury severities at 5 years post-injury. The reasons for this difference are unclear, particularly as Newcombe and colleagues identified clear signs of neurodegeneration on imaging.10 In the small subgroup with longitudinal biomarker quantification (n = 12), NfL typically declined over time, in contrast to GFAP which was not significantly elevated early on, but increased over time. Linking fluid and MRI injury measures, serum NfL and GFAP were correlated with DTI white matter damage indices at the early chronic time point, while NfL alone correlated with mean diffusivity measured at the late time point.
Examining the chronic consequences of injury, Newcombe and colleagues3 provided MRI evidence of substantial injury-associated grey and white matter volume loss, in keeping with previous work. They used a machine learning classifier to assess the difference between an algorithmically determined ‘brain age’ based upon volumetric MRI appearances, and the patient’s chronological age. This showed that brains after TBI appeared 8–10 years ‘older’ than expected at the late chronic time point. Using a voxel-based morphometric approach to provide more spatial specificity, the group revealed abnormal atrophy rates in grey and white matter, with concomitant ventricular expansion. Notably, early chronic serum NfL predicted this progressive white matter loss over the 8-year period spanning early and late chronic time points.
Newcombe and colleagues3 also established an important link between biomarkers of neurodegeneration and their clinical correlates. In their 12 longitudinally assessed patients, they found that the GOSE measure of function remained stable in three, improved in five and worsened in four subjects. Two markers of neurodegeneration—predicted brain age from MRI, and serum NfL levels—were significantly higher at the late chronic time point in those with worsening function, suggesting that these may be correlates of symptomatic, progressive post-TBI neurodegeneration (Fig. 1). This is a novel finding pointing to the clinical relevance of these biomarkers. Importantly, the presence of late functional decline did not appear to relate simply to the initial injury severity, with early chronic NfL levels failing to predict which patients would deteriorate.
Relationship between NfL levels in the late chronic phase after TBI and progressive change in patient function. Serum NfL concentration in healthy volunteers (HV) and in patients around 8 years post-TBI whose Glasgow Outcome Scale Extended scores were improving, stable or worsening longitudinally. Figure adapted from Newcombe et al.3
No comments:
Post a Comment