[<sup>18</sup>F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion

Bevan-Jones, Richard; Cope, Thomas E.; Jones, Simon Peyton; Passamonti, Luca; Hong, Young T.; Fryer, Tim D.; Arnold, Robert; Coles, Jonathan P.; Aigbirhio, Franklin A.; Patterson, Karalyn; O’Brien, John T.; Rowe, James B.

doi:10.1002/acn3.631

Cited by 22 publications

(18 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apart from these regions no regions or voxels with increased 18 F-Flortaucipir retention were detected, including the cerebral cortex and hippocampus, where TDP-43 pathology is prominent in C9orf72 carriers 35,36,38 . A previous case report has shown an increased temporal retention of Flortaucipir in a subject with a C9orf72 mutation and a three year history of personality change 21 . The disease duration of the published subject is similar to the disease duration of the participants in this study.…”

Section: Discussionmentioning

confidence: 86%

“…This tracer primarily detects the mixed 3R/4R tau pathology related to AD 10–18 . In vivo , 18 F-Flortaucipir retention has unexpectedly shown an increased retention in svPPA 19,20 , and recently a report indicated temporal retention of Flortaucipir in a C9orf72 -mutation carrier 21 . By contrast, in vitro , using autoradiography, 18 F-Flortaucipir did not bind to TAR DNA-binding protein 43 (TDP-43) pathology 13 or only showed minimal binding 12,15 in some cases.…”

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

18F-Flortaucipir in TDP-43 associated frontotemporal dementia

Smith

Santillo

Waldö

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Retention of 18 F-Flortaucipir is reportedly increased in the semantic variant of primary progressive aphasia (svPPA), which is dominated by TDP-43 pathology. However, it is unclear if 18 F-Flortaucipir is also increased in other TDP-43 diseases, such as bvFTD caused by a C9orf72 gene mutation. We therefore recruited six C9orf72 expansion carriers, six svPPA patients, and 54 healthy controls. All underwent 18 F-Flortaucipir PET and MRI scanning. Data from 39 Alzheimer’s Disease patients were used for comparison. PET tracer retention was assessed both at the region-of-interest (ROI) and at the voxel-level. Further, autoradiography using 3 H-Flortaucipir was performed. SvPPA patients exhibited higher 18 F-Flortaucipir retention in the lateral temporal cortex bilaterally according to ROI- and voxel-based analyses. In C9orf72 patients, 18 F-Flortaucipir binding was slightly increased in the inferior frontal lobes in the ROI based analysis, but these results were not replicated in the voxel-based analysis. Autoradiography did not show specific binding in svPPA cases or in C9orf72 -mutation carriers. In conclusion, temporal lobe 18 F-Flortaucipir retention was observed in some cases of svPPA, but the uptake was of a lower magnitude compared to AD dementia. C9orf72 -mutation carriers exhibited none or limited 18 F-Flortaucipir retention, indicating that 18 F-Flortaucipir binding in TDP-43 proteinopathies is not a general TDP-43 related phenomenon.

show abstract

Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 95%

18F-Flortaucipir in TDP-43 associated frontotemporal dementia

Smith

Santillo

Waldö

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Further to this, upregulation of TSPO in reactive astrocytes could occur alongside that of MAO-B accounting for the regional correlation found between ligand binding. However, the pre-symptomatic dissociation of [ 11 C]PK-11195 and [ 18 F]AV-1451 binding (W Richard Bevan-Jones et al, 2018) argues strongly against such simple crossaffinity.…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum

Bevan-Jones

Cope

Jones

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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 aggregation of Tau and TDP-43 in frontotemporal dementia, and to the heterogeneity of clinical disease. We used positron emission tomography in vivo with (a) [11C]PK-11195, a marker of activated microglia and a proxy index of neuroinflammation, and (b) [18F]AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and diseases associated with TDP-43 protein aggregation, and which is used as a surrogate marker of non-β-amyloid protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant frontotemporal dementia, 11 with the semantic variant of primary progressive aphasia and 10 with the non-fluent variant of primary progressive aphasia), 28 of whom underwent both [18F]AV-1451 and [11C]PK-11195 PET, and matched controls (14 for [18F]AV-1451 and 15 for [11C]PK-11195). We used univariate region-of-interest analyses, and multivariate analysis of the distribution of binding that explicitly control for individual differences in ligand affinity for TDP-43 and different Tau isoforms. We found differences between patients and controls in frontotemporal regions for both neuroinflammation and protein aggregation, and a strong positive correlation between these two processes in all disease groups. Despite this regional co-localisation, the multivariate distribution of [11C]PK-11195 binding related better to clinical heterogeneity than did the distribution of [18F]AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate group 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.

show abstract

“…However, two particular MAPT mutations (V337M and R406W) are associated with PHF-tau and have shown strong binding with the AV1451 tracer [59–61]. Unfortunately, there is also off-target binding of this tracer, with binding seen in non-tau diseases such as in C9orf72 expansions, where the major pathology is TDP-43 [62].…”

Section: Natural History Studies and Biomarkersmentioning

confidence: 99%

An update on genetic frontotemporal dementia

2019

View full text Add to dashboard Cite

Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, with around 30% of patients having a strong family history. The majority of that heritability is accounted for by autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) genes, with mutations more rarely seen in a number of other genes. This review will discuss the recent updates in the field of genetic FTD. Age at symptom onset in genetic FTD is variable with recently identified genetic modifiers including TMEM106B (in GRN carriers particularly) and a polymorphism at a locus containing two overlapping genes LOC101929163 and C6orf10 (in C9orf72 carriers). Behavioural variant FTD (bvFTD) is the most common diagnosis in each of the genetic groups, although in C9orf72 carriers amyotrophic lateral sclerosis either alone, or with bvFTD, is also common. An atypical neuropsychiatric presentation is also seen in C9orf72 carriers and family members of carriers are at greater risk of psychiatric disorders including schizophrenia and autistic spectrum disorders. Large natural history studies of presymptomatic genetic FTD are now underway both in Europe/Canada (GENFI-the Genetic FTD Initiative) and in the US (ARTFL/LEFFTDS study), collaborating together under the banner of the FTD Prevention Initiative (FPI). These studies are taking forward the validation of cognitive, imaging and fluid biomarkers that aim to robustly measure disease onset, staging and progression in genetic FTD. Grey matter changes on MRI and hypometabolism on FDG-PET are seen at least 10 years before symptom onset with white matter abnormalities seen earlier, but the pattern and exact timing of changes differ between different genetic groups. In contrast, tau PET has yet to show promise in genetic FTD. Three key fluid biomarkers have been identified so far that are likely to be helpful in clinical trials-CSF or blood neurofilament light chain levels (in all groups), CSF or blood progranulin levels (in GRN carriers) and CSF poly(GP) dipeptide repeat protein levels (in C9orf72 carriers). Increased knowledge about genetic FTD has led to more clinical presymptomatic genetic testing but this has not yet been mirrored in the development of either an accepted FTD-specific testing protocol or provision of appropriate psychological support mechanisms for those living through the at-risk phase. This will become even more relevant as disease-modifying therapy trials start in each of the genetic groups over the next few years.

show abstract

[¹⁸F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion

Cited by 22 publications

References 21 publications

18F-Flortaucipir in TDP-43 associated frontotemporal dementia

18F-Flortaucipir in TDP-43 associated frontotemporal dementia

Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum

An update on genetic frontotemporal dementia

Contact Info

Product

Resources

About

[18F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion

Cited by 22 publications

References 21 publications

18F-Flortaucipir in TDP-43 associated frontotemporal dementia

18F-Flortaucipir in TDP-43 associated frontotemporal dementia

Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum

An update on genetic frontotemporal dementia

Contact Info

Product

Resources

About

[¹⁸F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion