[18F]AV-1451 binding is increased in frontotemporal dementia due to C9orf72 expansion.
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ABSTRACT:
SUBMITTER: Bevan-Jones RW
PROVIDER: S-EPMC6186940 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain.MethodsWe performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches.ResultsOn qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology.Conclusions18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.
| S-EPMC6357510 | biostudies-literature
Project description:BackgroundProgressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work-up of PSP.MethodsRegional tau accumulation was studied using 18 F-AV-1451 PET in 11 patients with PSP and 11 age-matched healthy controls in the Swedish BioFinder study.Results18 F-AV-1451 standard uptake volume ratios were significantly higher in the basal ganglia in PSP patients when compared with controls (globus pallidus 1.75 vs 1.50; putamen 1.51 vs 1.35). Retention in the basal ganglia was correlated with age in both groups (r?=?.43-.78, P?<?.05). In PSP, we observed a significant correlation between clinical deterioration measured with the PSP rating scale and standard uptake volume ratios in the globus pallidus (r?=?.74, P?<?.05). However, no 18 F-AV-1451 retention was observed in the cerebral cortex or white matter of either PSP patients or controls, and autoradiography did not reveal any specific binding of AV-1451 to PSP tau aggregates.ConclusionWe found higher 18 F-AV-1451 retention in the basal ganglia of PSP patients when compared with healthy elderly controls, but also increases with age in both controls and patients. As a result of the overlap in retention between diagnostic groups and the age-dependent increase present also in controls, 18 F-AV-1451 PET might not reliably distinguish individual patients with PSP from controls. However, further studies are needed to evaluate whether 18 F-AV-1451 PET might be useful as a progression marker in clinical PSP trials. © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC6204612 | biostudies-literature
Project description:Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.
| S-EPMC3944829 | biostudies-literature
Project description: Not available
| S-EPMC5384840 | biostudies-literature
Project description:18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurologic disorders including Alzheimer disease and traumatic brain injury (TBI). The current study characterizes 18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Methods: Nine subjects (4 controls, 3 with a history of TBI, 2 with mild cognitive impairment due to suspected Alzheimer disease) underwent dynamic PET imaging for up to 120 min after bolus injection of 18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (1- and 2-tissue configurations) and graphical analysis techniques (Logan and multilinear analysis 1 [MA1] regression methods). Reference region-based methods of quantification were explored including Logan distribution volume ratio (DVR) and static SUV ratio (SUVR) using the cerebellum as a reference tissue. Results: The percentage of unmetabolized 18F-T807 in plasma followed a single exponential with a half-life of 17.0 ± 4.2 min. Metabolite-corrected plasma radioactivity concentration fit a biexponential (half-lives, 18.1 ± 5.8 and 2.4 ± 0.5 min). 18F-T807 in gray matter peaked quickly (SUV > 2 at ∼5 min). Compartmental modeling resulted in good fits, and the 2-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding. VT was greater in mild cognitive impairment subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 min, yielding regional estimates of VT in excellent agreement with compartmental analysis and providing high-quality parametric maps when applied in voxelwise fashion. Reference region-based approaches including Logan DVR (t* = 55 min) and SUVR (80- to 100-min interval) were highly correlated with DVR estimated using 2Tv (R2 = 0.97, P < 0.0001). Conclusion:18F-T807 showed rapid clearance from plasma and properties suitable for tau quantification with PET. Furthermore, simplified approaches using DVR (t* = 55 min) and static SUVR (80-100 min) with cerebellar reference tissue were found to correlate highly with compartmental modeling outcomes.
| S-EPMC5334185 | biostudies-literature
Project description:Primary progressive apraxia of speech (PPAOS) is a term used to describe a neurodegenerative condition in which apraxia of speech (AOS; a planning and/or programming deficit) occurs in the absence of aphasia (a language deficit). PPAOS is strongly associated with 4-repeat tau pathology. Elevated flortaucipir ([18F]AV-1451; FTP) uptake has been observed cross-sectionally in patients with PPAOS and those with aphasia. Here, we evaluated longitudinal changes in previously-identified regions of uptake and their relationship with clinical presentation. Thirteen patients who were diagnosed with PPAOS (5 female) at presentation underwent FTP PET imaging at two visits (mean 1 year interval). Median age was 72, with a median of 4 years disease duration at initial testing. Beta-amyloid status was assessed with Pittsburgh Compound B (PiB), where a global PiB ratio>1.48 was deemed amyloid positive (n = 4). FTP uptake was assessed as cortical to cerebellar crus ratios (SUVr) in cortical regions of interest. A single hierarchical linear model (HLM) compared PPAOS patients to 52 cognitively unimpaired controls of similar age and sex. Annualized SUVr change was the outcome, predicted by region, clinical status, and age. Person-specific effects accounted for intra-patient correlations and contralateral regions were included as repeated measures. Changes in clinical measures were assessed using Wilcoxon signed-rank tests; statistically significant changes in the Montreal Cognitive Assessment, MDS-UPDRS, motor section, and PSP Rating Scale were noted between visits. Changes in FTP SUVr were greater for patients than controls. The strongest changes in PPAOS patients were in the precentral gyrus, pallidum, and mid and superior frontal gyri, per the HLM. Qualitatively, larger changes were seen in patients who had developed aphasia by the time of their baseline scan (n = 5). While the biological mechanisms of FTP signal in non-AD tauopathies are unknown, this study demonstrates the utility of FTP in tracking disease progression in 4R tauopathies.
| S-EPMC7060829 | biostudies-literature
Project description:An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity.
| S-EPMC3753468 | biostudies-literature
Project description:A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n?=?190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in 'non-expansion' patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5-17% of patients (21-41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine 'expansion-positive' patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an 'intermediate' allele with a mean size of only ?65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of 'non-expansion' FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as ?65 repeats may be sufficient to cause disease.
| S-EPMC3577667 | biostudies-literature
Project description:ObjectiveTo determine the frequency of a hexanucleotide repeat expansion in C9ORF72, a gene of unknown function implicated in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), in Australian FTD patient cohorts and to examine the clinical and neuropathologic phenotypes associated with this expansion.MethodsWe examined a clinically ascertained FTD cohort (n = 89) and a neuropathologically ascertained cohort of frontotemporal lobar degeneration cases with TDP-43 pathology (FTLD-TDP) (n = 22) for the C9ORF72 hexanucleotide repeat expansion using a repeat primed PCR assay. All expansion-positive patients were genotyped for rs3849942, a surrogate marker for the chromosome 9p21 risk haplotype previously associated with FTD and ALS.ResultsThe C9ORF72 repeat expansion was detected in 10% of patients in the clinically diagnosed cohort, rising to 29% in those with a positive family history of early-onset dementia or ALS. The prevalence of psychotic features was significantly higher in expansion-positive cases (56% vs 14%). In the pathology cohort, 41% of TDP-43-positive cases harbored the repeat expansion, and all exhibited type B pathology. One of the 17 expansion-positive probands was homozygous for the "nonrisk" G allele of rs3849942.ConclusionsThe C9ORF72 repeat expansion is a relatively common cause of FTD in Australian populations, and is especially common in those with FTD-ALS, psychotic features, and a strong family history. Detection of a repeat expansion on the 9p21 putative "nonrisk" haplotype suggests that not all mutation carriers are necessarily descended from a common founder and indicates that the expansion may have occurred on multiple haplotype backgrounds.
| S-EPMC3430710 | biostudies-literature
Project description:ObjectiveTo describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion.MethodsA total of 648 patients with frontotemporal dementia (FTD)-related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD-motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS).ResultsAll C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers.ConclusionsPatients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature.
| S-EPMC3430713 | biostudies-literature