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      An autoradiographic evaluation of AV-1451 Tau PET in dementia

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          It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates.


          Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy ( n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and α-synuclein and compared to AV-1451 autoradiography on adjacent sections.


          AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to α-synuclein was detected. “Off-target” binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin.


          Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA-binding protein-43 or TAR DNA-binding protein-43 positive regions can be weakly positive. Clinical use of AV-1451 will require a familiarity with distinct types of “off-target” binding.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s40478-016-0315-6) contains supplementary material, which is available to authorized users.

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          Most cited references 25

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          Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain.

          We have isolated cDNA clones encoding a 383-amino acid isoform of the human microtubule-associated protein tau. It differs from previously determined tau sequences by the presence of an additional repeat of 31 amino acids, giving four, rather than three, tandem repeats in its carboxy-terminal half. The extra repeat is encoded by a separate exon. Probes derived from cDNA clones encoding the three (type I) and four repeat (type II) tau protein isoforms detected mRNAs for both forms in all adult human brain areas examined. However, in foetal brain only type I mRNA was found. Type I and type II mRNAs were present in pyramidal cells in cerebral cortex. In the hippocampal formation, type I mRNA was found in pyramidal and granule cells; type II mRNA was detected in most, though not all, pyramidal cells but not in granule cells. These observations indicate that tau protein mRNAs are expressed in a stage- and cell-specific manner. Tau protein is found in the protease-resistant core of the paired helical filament, the major constituent of the neurofibrillary tangle in Alzheimer's disease. Taken in conjunction with previous findings, the present results indicate that both the three and four repeat-containing tau protein isoforms are present in the core of the paired helical filament.
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            Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy).

            We present the preliminary neuropathologic criteria for progressive supranuclear palsy (PSP) as proposed at a workshop held at the National Institutes of Health, Bethesda, MD, April 24 and 25, 1993. The criteria distinguish typical, atypical, and combined PSP. A semiquantitative distribution of neurofibrillary tangles is the basis for the diagnosis of PSP. A high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brain-stem is crucial for the diagnosis of typical PSP. Tau-positive astrocytes or their processes in areas of involvement help to confirm the diagnosis. Atypical cases of PSP are variants in which the severity or distribution of abnormalities deviates from the typical pattern. Criteria excluding the diagnosis of typical and atypical PSP are large or numerous infarcts, marked diffuse or focal atrophy, Lewy bodies, changes diagnostic of Alzheimer's disease, oligodendroglial argyrophilic inclusions, Pick bodies, diffuse spongiosis, and prion protein-positive amyloid plaques. The diagnosis of combined PSP is proposed when other neurologic disorders exist concomitantly with PSP.
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              Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function.

              To test the hypothesis that the association of amyloid load with clinical Alzheimer disease (AD) and cognitive impairment is mediated through neurofibrillary tangles. Longitudinal clinicopathologic cohort study. Forty-four individuals with clinically diagnosed AD and 53 without dementia who participated in the Religious Orders Study underwent a uniform structured clinical evaluation for AD and cognitive testing about 8 months prior to death, and brain autopsy at death. The percent area occupied by amyloid-beta and the density of neurofibrillary tangles were quantified from 6 brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multivariate regression analyses were used to simultaneously examine the effects of amyloid load and neurofibrillary tangles on clinically diagnosed AD and level of cognition. Clinically diagnosed AD and level of global cognitive function proximate to death. In separate logistic regression analyses, each 1% increase in amyloid load was associated with about a 50% increase in the odds of clinical AD (P =.002), and each neurofibrillary tangle was associated with a greater than 20% increase in the odds of clinical AD (P<.001). When a term for tangles was added to the regression model with amyloid, the association of amyloid load with clinical disease was reduced by more than 60% and was no longer significant, whereas the association of tangles with clinical disease was essentially unchanged. Similar results were found in analyses of global cognitive function. These findings are consistent with a sequence of pathologic events whereby the effect of amyloid deposition on clinical disease is mediated by neurofibrillary tangles.

                Author and article information

                507 284-4104 , vlowe@mayo.edu
                Acta Neuropathol Commun
                Acta Neuropathol Commun
                Acta Neuropathologica Communications
                BioMed Central (London )
                13 June 2016
                13 June 2016
                : 4
                [ ]Department of Radiology, Mayo Clinic, Rochester, MN USA
                [ ]Department of Neurology, Mayo Clinic, Rochester, MN USA
                [ ]Department of Anatomic Pathology, Mayo Clinic, Rochester, MN USA
                [ ]Department of Neuroscience, Mayo Clinic, Jacksonville, Florida USA
                [ ]Department of Neurology, Mayo Clinic, Jacksonville, Florida USA
                © Lowe et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funded by: National Institutes of Health (US)
                Award ID: P50-AG016574
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;
                Award ID: R01 NS89757
                Award ID: R01 DC10367
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: P50-NS072187
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