MedicalResearch.com Interview with:
Prof David K Menon MD PhD FRCP FRCA FFICM FMedSci
Head, Division of Anaesthesia, University of Cambridge Consultant,
Neurosciences Critical Care Unit BOC Professor,
Royal College of Anaesthetists
Professorial Fellow, Queens’ College, Cambridge
Senior Investigator, National Institute for Health Research
Box 93, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK
MedicalResearch.com: What is the background for your study?
Dr. Menon: We have known for some time that a history of traumatic brain injury (TBI) results in a significant (between 2 and 10 fold) increase in the likelihood of getting dementia in later life. On possible mechanistic explanation for this comes from the finding that about a third of individuals who died of TBI, regardless of age, are found at autopsy to have deposits of β-amyloid in the brain, often Aβ42, which is the same variant of amyloid seen in the brain of patients who have Alzheimer’s Disease.
However, such detection after death has made it impossible to examine the linkage of such early amyloid deposition to late dementia. More recently, imaging with positron emission tomography (PET) and Pittsburgh compound B (PIB) has been used to image amyloid deposits in Alzheimer’s Disease. However, the technique had not been validated in traumatic brain injury.
MedicalResearch.com: What are the highlights of this report?
Dr. Menon: We used [11C]PIB PET to image amyloid deposition in the brain in 15 patients after TBI, and validated the specificity of this binding by showing that 3H-labelled PIB bound to amyloid plaque in the brain of patients who dies after TBI. Specifically, we demonstrated significantly greater cortical and striatal PIB binding PET studies in TBI patients compared to controls. Our research has validated, for the first time, PET imaging of amyloid deposits in the brain after TBI by showing that the PET tracer used also binds to the substance in post-mortem tissue obtained from patients who have died after TBI. This study replicates the findings seen at autopsy in fatal cases, by demonstrating amyloid deposition in survivors after a TBI. This means that patients can be imaged with PET to detect early amyloid deposition, and then followed up to see whether this early amyloid deposition resolves, whether it recurs, and how these processes relate to later cognitive decline.
Our study also provides intriguing clues which suggest mechanisms of amyloid accumulation in TBI. Axons normally transport amyloid precursor protein (or APP), which escapes in small amounts into the tissue spaces in the brain, where it is broken down by enzymes to form β amyloid. If the amount of Aβ in the brain is excessive, the molecules can clump together to produce plaques. Such plaque formation is far commoner with certain types of β amyloid molecule such as Aβ42. Increases in brain amyloid deposits can be either the consequence of increased production or reduced clearance of the molecule. In conventional Alzheimer’s Disease, impaired clearance is thought to play a much greater part. However, TBI is associated with tearing of axons in the brain (a process called traumatic axonal injury), and the accumulation of large amounts of APP at sites of axonal injury. The enzymatic machinery required for transformation to Aβ is also present locally, resulting in the production of large amounts of β amyloid that overwhelm clearance mechanisms for the molecule. The large amounts of β amyloid present then predispose to plaque formation. The patterns of amyloid deposition we show in TBI, with prominent striatal binding, replicate patterns seen in settings (such as PS-1 mutations) where overproduction of amyloid is the cause of dementia. We also observed variable binding of the PET ligand in the white matter after TBI, but increases in [11C]PIB binding did not reach significance across the patient group, and we were unable to show increased [3H]PIB binding to white matter in autopsy acquired tissue. We believe that further work is needed in this area.
Individuals with a certain genotype for the ApoE gene (the E4 variant) are at high risk (over ten-fold) of developing Alzheimer’s Disease, of showing amyloid deposition after TBI, and of increased risk of Alzheimer’s Disease after TBI. Future studies will assess temporal patterns of amyloid binding within individuals and examine the impact of genotype on such binding. We also plan to undertake imaging at late time points after head injury to see if such deposition recurs (as has been shown in other studies, and relate these to late life cognitive decline and Alzheimer’s Disease.