[<sup>18</sup>F]AV‐1451 tau‐PET and primary progressive aphasia

Josephs, Keith A.; Martin, Peter R.; Botha, Hugo; Schwarz, Christopher G.; Duffy, Joseph R.; Clark, Heather M.; Machulda, Mary M.; Graff‐Radford, Jonathan; Weigand, Stephen D.; Senjem, Matthew L.; Utianski, Rene L.; Drubach, Daniel A.; Boeve, Bradley F.; Jones, David T.; Knopman, David S.; Petersen, Ronald C.; Jack, Clifford R.; Lowe, Val J.; Whitwell, Jennifer L.

doi:10.1002/ana.25183

Cited by 78 publications

(82 citation statements)

References 49 publications

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“…Based on a quantitative analysis of MRI scans relatively close to death and stereologic estimations of AD neuropathology lacking in previous studies of PPA‐AD or DAT‐AD, we found that NFTs, not APs, showed a distribution reflective of the asymmetric aphasic profile that was also significantly associated with cortical atrophy. We show for the first time that NFTs were commensurate with cortical atrophy inside and outside the language network of PPA‐AD (Figure A), which is consistent with the NFT and atrophy relationship measured by tau‐PET (positron emission tomography) in individuals with PPA . Moreover, the asymmetry of only NFTs agrees with previous clinicopathologic relationships reported by our group and others which have shown that NFTs have an anatomical distribution that is mostly concordant with the atrophy and clinical symptoms characteristic of the PPA phenotype .…”

Section: Discussionsupporting

confidence: 90%

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

et al. 2019

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The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language‐based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid‐ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA‐AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA‐AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense‐core APs visualized with the Thioflavin‐S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non‐language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non‐language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA‐AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.

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Section: Discussionsupporting

confidence: 90%

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

et al. 2019

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“…Left-hemisphere lateralization of cortical disease has been demonstrated in vivo 10,11 and confirmed qualitatively postmortem, 3 yet righthemisphere disease appears to contribute to language deficits in antemortem imaging of autopsy-confirmed PPA. Furthermore, despite the limited reliability of clinicopathological correlations using PPA syndromic variants, individual clinical features of PPA have only rarely been related to specific anatomic distributions of disease in patients with presumed proteinopathies during life, 17,18 or with a categorical neuropathological diagnosis. Furthermore, despite the limited reliability of clinicopathological correlations using PPA syndromic variants, individual clinical features of PPA have only rarely been related to specific anatomic distributions of disease in patients with presumed proteinopathies during life, 17,18 or with a categorical neuropathological diagnosis.…”

mentioning

confidence: 99%

Divergent patterns of TDP‐43 and tau pathologies in primary progressive aphasia

Giannini

Xie

McMillan

et al. 2019

Annals of Neurology

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Objective: To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) or tau (FTLD-Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies. Methods: In an autopsy cohort of PPA (FTLD-TDP = 13, FTLD-Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features. Results: Postmortem cortical pathology was left-lateralized in both FTLD-TDP (beta = −0.15, standard error [SE] = 0.05, p = 0.007) and FTLD-Tau (beta = −0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = −8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD-TDP, which was greater than in FTLD-Tau (F = 47.07, df = 1,17, p < 0.001), and in left midfrontal cortex (MFC) in FTLD-Tau, which was greater than in FTLD-TDP (F = 19.34, df = 1,16, p < 0.001). Postmortem pathology was inversely associated with antemortem magnetic resonance imaging cortical thickness (beta = −0.04, SE = 0.01, p = 0.007) in regions matching autopsy sampling. Irrespective of PPA syndromic variant, single-word comprehension impairment was associated with greater left OFC pathology (t = −3.72, df = 10.72, p = 0.004) and nonfluent speech with greater left MFC pathology (t = −3.62, df = 12.00, p = 0.004) among the 5 core pathology regions. Interpretation: In PPA, FTLD-TDP and FTLD-Tau have divergent anatomic distributions of left-lateralized postmortem pathology that relate to antemortem structural imaging and distinct language deficits. Although other brain regions may be implicated in neural networks supporting these complex language measures, our observations may eventually help to improve antemortem diagnosis of neuropathology in PPA.

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“…Furthermore, unlike other tau PET tracers, 18 F-AV-1451 is not appreciably blocked by monoamine oxidase B inhibitors (44), ruling out the possibility that the increased 18 F-AV-1451 signal may simply correspond to an increase in monoamine oxidase B induced by the pathologic process (45). In FTD, small but detectable and accurate 18 F-AV-1451 binding has been found in most studies (39,43), and its regional distribution corresponds well to the clinical syndromes (46). The lower 18 F-AV-1451 signal in FTD than in AD could be related to lower 18 F-AV-1451 binding to FTD tau but also reflects the lower tau load in FTD, which is about 10% of that in AD (47).…”

Section: Discussionmentioning

confidence: 87%

Multimodal ¹⁸F-AV-1451 and MRI Findings in Nonfluent Variant of Primary Progressive Aphasia: Possible Insights on Nodal Propagation of Tau Protein Across the Syntactic Network

Pascual¹,

Funk²,

Zanotti‐Fregonara³

et al. 2019

J Nucl Med

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Although abnormally folded tau protein has been found to selfpropagate from neuron to connected neuron, similar propagation through human brain networks has not been fully documented. We studied tau propagation in the left hemispheric syntactic network, which comprises an anterior frontal node and a posterior temporal node connected by the white matter of the left arcuate fasciculus. This network is affected in the nonfluent variant of primary progressive aphasia, a neurodegenerative disorder with tau accumulation. Methods: Eight patients with the nonfluent variant of primary progressive aphasia (age, 67.0 ± 7.4 y; 4 women) and 8 healthy controls (age, 69.6 ± 7.0 y; 4 women) were scanned with 18 F-AV-1451 tau PET to determine tau deposition in the brain and with MRI to determine the fractional anisotropy of the arcuate fasciculus. Normal syntactic network characteristics were confirmed with structural MRI diffusion imaging in our healthy controls and with blood oxygenation level-dependent functional imaging in 35 healthy participants from the Alzheimer Disease Neuroimaging Initiative database. Results: Language scores in patients indicated dysfunction of the anterior node. 18 F-AV-1451 deposition was greatest in the 2 nodes of the syntactic network. The left arcuate fasciculus had decreased fractional anisotropy, particularly near the anterior node. Normal MRI structural connectivity from an area similar to the one containing tau in the anterior frontal node projected to an area similar to the one containing tau in the patients in the posterior temporal node. Conclusion: Tau accumulation likely started in the more affected anterior node and, at the disease stage at which we studied these patients, appeared as well in the brain region (in the temporal lobe) spatially separate from but most connected with it. The arcuate fasciculus, connecting both of them, was most severely affected anteriorly, as would correspond to a loss of axons from the anterior node. These findings are suggestive of tau propagation from node to connected node in a natural human brain network and support the idea that neurons that wire together die together. This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

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[¹⁸F]AV‐1451 tau‐PET and primary progressive aphasia

Cited by 78 publications

References 49 publications

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

Divergent patterns of TDP‐43 and tau pathologies in primary progressive aphasia

Multimodal ¹⁸F-AV-1451 and MRI Findings in Nonfluent Variant of Primary Progressive Aphasia: Possible Insights on Nodal Propagation of Tau Protein Across the Syntactic Network

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[18F]AV‐1451 tau‐PET and primary progressive aphasia

Cited by 78 publications

References 49 publications

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

Divergent patterns of TDP‐43 and tau pathologies in primary progressive aphasia

Multimodal 18F-AV-1451 and MRI Findings in Nonfluent Variant of Primary Progressive Aphasia: Possible Insights on Nodal Propagation of Tau Protein Across the Syntactic Network

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[¹⁸F]AV‐1451 tau‐PET and primary progressive aphasia

Multimodal ¹⁸F-AV-1451 and MRI Findings in Nonfluent Variant of Primary Progressive Aphasia: Possible Insights on Nodal Propagation of Tau Protein Across the Syntactic Network