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Mapping neuroinflammation in frontotemporal dementia with molecular PET imaging.

ABSTRACT: Recent findings have led to a renewed interest and support for an active role of inflammation in neurodegenerative dementias and related neurologic disorders. Detection of neuroinflammation in vivo throughout the course of neurodegenerative diseases is of great clinical interest. Studies have shown that microglia activation (an indicator of neuroinflammation) may present at early stages of frontotemporal dementia (FTD), but the role of neuroinflammation in the pathogenesis of FTD is largely unknown. The first-generation translocator protein (TSPO) ligand ([(11)C]-PK11195) has been used to detect microglia activation in FTD, and the second-generation TSPO ligands have imaged neuroinflammation in vivo with improved pharmacokinetic properties. This paper reviews related literature and technical issues on mapping neuroinflammation in FTD with positron-emission tomography (PET) imaging. Early detection of neuroinflammation in FTD may identify new tools for diagnosis, novel treatment targets, and means to monitor therapeutic efficacy. More studies are needed to image and track neuroinflammation in FTD. It is anticipated that the advances of TSPO PET imaging will overcome technical difficulties, and molecular imaging of neuroinflammation will aid in the characterization of neuroinflammation in FTD. Such knowledge has the potential to shed light on the poorly understood pathogenesis of FTD and related dementias, and provide imaging markers to guide the development and assessment of new therapies.

SUBMITTER: Zhang J

PROVIDER: S-EPMC4451729 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Mapping neuroinflammation in frontotemporal dementia with molecular PET imaging.

Zhang Jing J

Journal of neuroinflammation 20150529

Recent findings have led to a renewed interest and support for an active role of inflammation in neurodegenerative dementias and related neurologic disorders. Detection of neuroinflammation in vivo throughout the course of neurodegenerative diseases is of great clinical interest. Studies have shown that microglia activation (an indicator of neuroinflammation) may present at early stages of frontotemporal dementia (FTD), but the role of neuroinflammation in the pathogenesis of FTD is largely unkn ...[more]

PMID: 26022249

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Project description: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.

Project description:Abstract Background: Epidemiological, genetic and clinical evidence all indicates that inflammation plays a role in schizophrenia. Microglia are the resident immune cells of the CNS and act as major mediators of neuroinflammation. When microglia are activated, they express high levels of the 18-kDa translocator protein (TSPO). TSPO can be measured in vivo with Positron Emission Tomography (PET) radiotracers, such as [11C]PK11195 and [11C]PBR28. In the present investigation we seek to determine whether microglial activity is elevated in patients with schizophrenia and in ultra high risk (UHR) for developing a psychotic disorder using the novel TSPO radioligand [11C]PBR28 while testing if there is a relationship between microglial activity, symptom severity and grey matter volume. Finally, we also aim to estimate the non-displaceable binding component (VND) of [11C]PBR28 in schizophrenia patients. Methods: A total of 56 subjects completed the study. 14 subjects meet UHR criteria and were matched with 14 healthy volunteers (HV), while 14 subjects with schizophrenia were matched with 14 HV. We used [11C]PBR28 PET to image microglial activity with the main outcome measure being total grey matter [11C]PBR28 binding ratio. All subjects were genotyped for the rs6971 polymorphism, and all patients were homozygote high-affinity binders (HABs) or mixed-affinity binders (HABs). A subgroup of 7 schizophrenia patients were invited for a follow-up PET scan. In this visit patients received a selective TSPO blocker (90mg of XBD173) followed 2 hours later by a repeat [11C]PBR28 scan. Results: UHR subjects and schizophrenia patients showed greater PET TSPO binding, indicating microglia activity, relative to controls, in total gray matter, fronta,l and temporal cortices, with large effect sizes (0.9–1.8). Moreover, we found that microglia activity was positively correlated with greater prodromal symptom severity. In schizophrenia patients, the gray matter microglia activity could be predicted by the volumes of several gray matter regions, indicating a positive correlation between volume deficits and neuroinflammation. Following blockade with XBD173 schizophrenia patients showed a significant reduction in TSPO specific binding across different brain regions. Regional VT data for individual subjects were fitted to an occupancy plot. By constraining the VND to be equal for all patients, the population VND was estimated to be 1.99. Conclusion: Our main finding is that [11C]PBR28 binding ratio is elevated in people at UHR as well as in schizophrenia patients, relative to HV. This data implicates microglial activation in the pathophysiology and severity of schizophrenia and potentially account for the brain structural changes seen in schizophrenia. Moreover, a substantial component of [11C]PBR28 VT represents specific binding,

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Mapping neuroinflammation in frontotemporal dementia with molecular PET imaging.

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Mapping neuroinflammation in frontotemporal dementia with molecular PET imaging.

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