Tau pathology in cognitively normal older adults

Ziontz, Jacob; Bilgel, Murat; Shafer, Andrea T.; Moghekar, Abhay; Elkins, Wendy; Helphrey, Jessica H; Gómez, Gabriela; June, Danielle; McDonald, Michael; Dannals, Robert F.; Azad, Babak Behnam; Ferrucci, Luigi; Wong, Dean F.; Resnick, Susan M.

doi:10.1016/j.dadm.2019.07.007

Cited by 45 publications

(28 citation statements)

References 43 publications

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“…for all controls (both Aβ+ and Aβ-). This difference is probably due to the age related tau deposition in Aβ+ controls ( Johnson et al, 2016b , Pontecorvo et al, 2017 , Scholl et al, 2016 , Tosun et al, 2017 ) and the presence of Aβ may even induce tau to spread outside of the MTL ( Jacobs et al, 2018 , Ziontz et al, 2019 ). Therefore there may be an increase in the diagnostic performance of [ 18 F]flortaucipir BP ND in DLB vs. Aβ- controls compared to both Aβ- and Aβ+ controls and this may explain the larger differences found between DLB patients and controls in other studies who used Aβ- controls ( Gomperts et al, 2016 , Lee et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study

Wolters

Beek

Ossenkoppele

et al. 2020

NeuroImage: Clinical

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Section: Discussionmentioning

confidence: 99%

Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study

Wolters

Beek

Ossenkoppele

et al. 2020

NeuroImage: Clinical

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“…Neurite clusters in PrC were the only MTL TauC3-positive pathology that was different between stage III and stages II or IV. Since in preclinical AD and normal aging, the PrC is one of the earliest regions to show tau pathology, our TauC3 findings may highlight a neuropathological corollary for memory problems observed in CTE [15, 62, 109].…”

Section: Discussionmentioning

confidence: 99%

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study

Kelley

Perez

Mufson

2019

acta neuropathol commun

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Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropathological diagnosis defined as stage II, III, or IV. Sections were immunolabeled using an early (AT8) or a late (TauC3) marker for pathological tau and for amyloid beta (Aβ) species (6E10, Aβ1–42 and thioflavin S). Stereological analysis revealed that stage III had significantly less AT8-positive neurons and dystrophic neurites than stage IV in all MTL regions except hippocampal subfield CA3, whereas significantly more AT8-positive neurons, dystrophic neurites, and neurite clusters were found in the perirhinal cortex, entorhinal cortex, hippocampal CA1, and subiculum of CTE stage III compared with stage II. TauC3-positive pathology was significantly higher in the perirhinal and subicular cortex of stage IV compared to stage III and the perirhinal cortex of stage III compared to stage II. AT8-positive neurite clusters were observed in stages III and IV, but virtually absent in stage II. When observed, Aβ pathology appeared as amyloid precursor protein (APP)/Aβ (6E10)-positive diffuse plaques independent of region. Thioflavine S labeling, did not reveal evidence for fibril or neuritic pathology associated with plaques, confirming a diffuse, non-cored plaque phenotype in CTE. Total number of AT8-positive profiles correlated with age at death, age at symptom onset, and time from retirement to death. There was no association between AT8-positive tau pathology and age sport began, years played, or retirement age, and no difference between CTE stage and the highest level of sport played. In summary, our findings demonstrate different tau profiles in the MTL across CTE stages, proffering CA3 tau pathology and MTL dystrophic neurite clusters as possible markers for the transition between early (II) and late (III/IV) stages, while highlighting CTE as a progressive noncommunicative tauopathy.

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“…In cognitively normal elderly, [ 18 F]flortaucipir uptake is typically mostly confined to the medial temporal lobe (MTL) [ 56 , 97 , 102 , 116 ]. The presence of amyloid-β may induce tau to spread outside of the MTL [ 53 , 128 ], although neocortical tau was present in amyloid-negative controls [ 67 , 120 ]. Both cross-sectional [ 56 , 66 , 70 , 85 , 95 , 100 , 105 , 110 , 119 , 128 ] and antecedent amyloid accumulation [ 62 , 116 ] were correlated with more (extra-)MTL [ 18 F]flortaucipir in the cognitively unimpaired.…”

Section: Resultsmentioning

confidence: 99%

Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer’s disease in the context of a structured 5-phase biomarker development framework

Wolters

Dodich

Boccardi

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose In 2017, the Geneva Alzheimer’s disease (AD) Biomarker Roadmap initiative adapted the framework of the systematic validation of oncological diagnostic biomarkers to AD biomarkers, with the aim to accelerate their development and implementation in clinical practice. With this work, we assess the maturity of [18F]flortaucipir PET and define its research priorities. Methods The level of maturity of [18F]flortaucipir was assessed based on the AD Biomarker Roadmap. The framework assesses analytical validity (phases 1–2), clinical validity (phases 3–4), and clinical utility (phase 5). Results The main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. [18F]Flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties and excellent discriminative accuracy for AD. The majority of secondary aims of phase 2 were fully achieved. Multiple studies showed high correlations between ante-mortem [18F]flortaucipir PET and post-mortem tau (as assessed by histopathology), and also the effects of covariates on tracer binding are well studied. The aims of phase 3 (early detection ability) were only partially or preliminarily achieved, and the aims of phases 4 and 5 were not achieved. Conclusion Current literature provides partial evidence for clinical utility of [18F]flortaucipir PET. The aims for phases 1 and 2 were mostly achieved. Phase 3 studies are currently ongoing. Future studies including representative MCI populations and a focus on healthcare outcomes are required to establish full maturity of phases 4 and 5.

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Tau pathology in cognitively normal older adults

Cited by 45 publications

References 43 publications

Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study

Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study

Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer’s disease in the context of a structured 5-phase biomarker development framework

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