26 Summary: In all three types of frontotemporal dementia, researchers found the more the inflammation in each part of the brain, the more harmful the build-up of junk proteins. Source: University of Cambridge Inflammation in the brain may be more widely implicated in dementias than was previously thought, suggests new research from the University of Cambridge. The researchers say it offers hope for potential new treatments for several types of dementia. Inflammation is usually the body’s response to injury and stress – such as the redness and swelling that accompanies an injury or infection. However, inflammation in the brain – known as neuroinflammation – has been recognised and linked to many disorders including depression, psychosis and multiple sclerosis. It has also recently been linked to the risk of Alzheimer’s disease. In a study published today in the journal Brain, a team of researchers at the University of Cambridge set out to examine whether neuroinflammation also occurs in other forms of dementia, which would imply that it is common to many neurodegenerative diseases. The team recruited 31 patients with three different types of frontotemporal dementia (FTD). FTD is a family of different conditions resulting from the build-up of several abnormal ‘junk’ proteins in the brain. Patients underwent brain scans to detect inflammation and the junk proteins. Two Positron Emission Tomography (PET) scans each used an injection with a chemical ‘dye’, which lights up special molecules that reveal either the brain’s inflammatory cells or the junk proteins. In the first scan, the dye lit up the cells causing neuroinflammation. These indicate ongoing damage to the brain cells and their connections. In the second scan, the dye binds to the different types of ‘junk’ proteins found in FTD. The researchers showed that across the brain, and in all three types of FTD, the more inflammation in each part of the brain, the more harmful build-up of the junk proteins there is. To prove the dyes were picking up the inflammation and harmful proteins, they went on to analyse under the microscope 12 brains donated after death to the Cambridge Brain Bank. “We predicted the link between inflammation in the brain and the build-up of damaging proteins, but even we were surprised by how tightly these two problems mapped on to each other,” said Dr Thomas Cope from the Department of Clinical Neurosciences at Cambridge. Dr Richard Bevan Jones added, “There may be a vicious circle where cell damage triggers inflammation, which in turn leads to further cell damage.” The team stress that further research is needed to translate this knowledge of inflammation in dementia into testable treatments. But, this new study shows that neuroinflammation is a significant factor in more types of dementia than was previously thought. The researchers showed that across the brain, and in all three types of FTD, the more inflammation in each part of the brain, the more harmful build-up of the junk proteins there is. The image is in the public domain. “It is an important discovery that all three types of frontotemporal dementia have inflammation, linked to the build-up of harmful abnormal proteins in different parts of the brain. The illnesses are in other ways very different from each other, but we have found a role for inflammation in all of them,” says Professor James Rowe from the Cambridge Centre for Frontotemporal Dementia. “This, together with the fact that it is known to play a role in Alzheimer’s, suggests that inflammation is part of many other neurodegenerative diseases, including Parkinson’s disease and Huntington’s disease. This offers hope that immune-based treatments might help slow or prevent these conditions.” Funding: The research was supported by Wellcome, the Medical Research Council, National Institute for Health Research Cambridge Biomedical Research Centre, Association of British Neurologists, Patrick Berthoud Charitable Trust, and the Lundbeck Foundation.See alsoFeaturedNeuroscienceOpen Neuroscience ArticlesPsychology·February 29, 2020Wine glass size may influence how much you drink in restaurants [divider]About this neuroscience research article[/divider] Source: University of Cambridge Media Contacts: Craig Brierley – University of Cambridge Image Source: The image is in the public domain. Original Research: Open access “Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum”. Bevan-Jones, WR & Cope, TE et al. Brain doi:10.1093/brain/awaa033. Abstract Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-β protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both 18F-AV-1451 and 11C-PK-11195 PET, and matched control subjects (14 for 18F-AV-1451 and 15 for 11C-PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in ligand affinity for TDP-43 and different tau isoforms. We found significant group-wise differences in 11C-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. 18F-AV-1451 binding was increased in semantic variant primary progressive aphasia compared to controls in the temporal regions, and both semantic variant primary progressive aphasia and behavioural variant frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between 11C-PK-11195 and 18F-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in FTLD-TDP (A), FTLD-TDP (C), and FTLD-Pick’s. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of 11C-PK-11195 binding related better to clinical heterogeneity than did 18F-AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia. 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