Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition.

The advent of tau-targeted positron emission tomography tracers such as flortaucipir (18F-AV-1451, also known as 18F-T807) have made it possible to investigate the sequence of development of tau and amyloid-β in relationship to age, and to the development of cognitive impairment due to Alzheimer's disease. In this study, flortaucipir tau and florbetapir amyloid positron emission tomography were obtained for 217 subjects including 16 young and 58 older cognitively normal subjects, 95 subjects with mild cognitive impairment (Mini-Mental State Examination 24-30) and 48 subjects with clinically-defined possible or probable Alzheimer's disease (Mini-Mental State Examination >10). Images were evaluated visually and quantitatively by regional and voxel-based cortical to cerebellar standard uptake value ratios. For amyloid positron emission tomography positive (Aβ+) subjects, flortaucipir neocortical standard uptake value ratio was significantly higher with more advanced clinical stage (Alzheimer's disease > mild cognitive impairment > older cognitively normal) and was significantly elevated for Aβ+ mild cognitive impairment and Alzheimer's disease subjects relative to the respective Aβ- subjects. In contrast, florbetapir Aβ- older cognitively normal subjects showed an increase in flortaucipir standard uptake value ratios in mesial temporal lobe regions (amygdala, hippocampus/choroid plexus region of interest) compared to younger cognitively normal subjects, but no increased standard uptake value ratios in neocortical regions. Analysis of covariance with planned contrasts showed no differences in regional or composite posterior neocortical flortaucipir standard uptake value ratio as a function of diagnostic group among Aβ- older cognitively normal or clinically diagnosed Alzheimer's disease or mild cognitive impairment subjects. The pattern of flortaucipir distribution among Aβ+ subjects was reminiscent of the cross-sectional distribution of tau reported in post-mortem pathology studies, in that the most commonly affected regions were the inferior and lateral temporal lobes, the same regions where the first signs of increased retention appeared in Aβ+ cognitively normal subjects. However, there was large variability in extent/density of flortaucipir tau binding among Aβ+ subjects. Although high neocortical flortaucipir retention was consistently associated with an Aβ+ florbetapir positron emission tomography scan, not all Aβ+ subjects had elevated flortaucipir standard uptake value ratios. Finally, within the Aβ+ group, increasing levels of flortaucipir tau binding were associated with increased cognitive impairment, as assessed by Mini-Mental State Examination and Alzheimer's Disease Assessment Scale. These results suggest development of tau beyond the mesial temporal lobe is associated with, and may be dependent on, amyloid accumulation. Further, the results are consistent with the hypothesis that cortical tau is associated with cognitive impairment.

Pontecorvo MJ ，Devous MD Sr ，Navitsky M ，Lu M ，Salloway S ，Schaerf FW ，Jennings D ，Arora AK ，McGeehan A ，Lim NC ，Xiong H ，Joshi AD ，Siderowf A ，Mintun MA ，18F-AV-1451-A05 investigators ... -  《-》

A multicentre longitudinal study of flortaucipir (18F) in normal ageing, mild cognitive impairment and Alzheimer's disease dementia.

The advent of tau-targeted PET tracers such as flortaucipir (18F) (flortaucipir, also known as 18F-AV-1451 or 18F-T807) have made it possible to investigate the sequence of development of tau in relationship to age, amyloid-β, and to the development of cognitive impairment due to Alzheimer's disease. Here we report a multicentre longitudinal evaluation of the relationships between baseline tau, tau change and cognitive change, using flortaucipir PET imaging. A total of 202 participants 50 years old or older, including 57 cognitively normal subjects, 97 clinically defined mild cognitive impairment and 48 possible or probable Alzheimer's disease dementia patients, received flortaucipir PET scans of 20 min in duration beginning 80 min after intravenous administration of 370 MBq flortaucipir (18F). On separate days, subjects also received florbetapir amyloid PET imaging, and underwent a neuropsychological test battery. Follow-up flortaucipir scans and neuropsychological battery assessments were also performed at 9 and 18 months. Fifty-five amyloid-β+ and 90 amyloid-β- subjects completed the baseline and 18-month study visits and had valid quantifiable flortaucipir scans at both time points. There was a statistically significant increase in the global estimate of cortical tau burden as measured by standardized uptake value ratio (SUVr) from baseline to 18 months in amyloid-β+ but not amyloid-β- subjects (least squared mean change in flortaucipir SUVr : 0.0524 ± 0.0085, P < 0.0001 and 0.0007 ± 0.0024 P = 0.7850, respectively), and a significant association between magnitude of SUVr increase and baseline tau burden. Voxel-wise evaluations further suggested that the regional pattern of change in flortaucipir PET SUVr over the 18-month study period (i.e. which regions exhibited the greatest change) also varied as a function of baseline global estimate of tau burden. In subjects with lower global SUVr, temporal lobe regions showed the greatest flortaucipir retention, whereas in subjects with higher baseline SUVr, parietal and frontal regions were increasingly affected. Finally, baseline flortaucipir and change in flortaucipir SUVr were both significantly (P < 0.0001) associated with changes in cognitive performance. Taken together, these results provide a preliminary characterization of the longitudinal spread of tau in Alzheimer's disease and suggest that the amount and location of tau may have implications both for the spread of tau and the cognitive deterioration that may occur over an 18-month period.

Pontecorvo MJ ，Devous MD ，Kennedy I ，Navitsky M ，Lu M ，Galante N ，Salloway S ，Doraiswamy PM ，Southekal S ，Arora AK ，McGeehan A ，Lim NC ，Xiong H ，Truocchio SP ，Joshi AD ，Shcherbinin S ，Teske B ，Fleisher AS ，Mintun MA ... -  《-》

Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease.

Quiroz YT ，Sperling RA ，Norton DJ ，Baena A ，Arboleda-Velasquez JF ，Cosio D ，Schultz A ，Lapoint M ，Guzman-Velez E ，Miller JB ，Kim LA ，Chen K ，Tariot PN ，Lopera F ，Reiman EM ，Johnson KA ... -  《-》

Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global β-Amyloid Burden.

Buckley RF ，Hanseeuw B ，Schultz AP ，Vannini P ，Aghjayan SL ，Properzi MJ ，Jackson JD ，Mormino EC ，Rentz DM ，Sperling RA ，Johnson KA ，Amariglio RE ... -  《-》

Association between tau deposition and antecedent amyloid-β accumulation rates in normal and early symptomatic individuals.

See Vandenberghe and Schaeverbeke (doi:10.1093/awx065) for a scientific commentary on this article. A long-term goal of our field is to determine the sequence of pathological events, which ultimately lead to cognitive decline and dementia. In this study, we first assessed the patterns of brain tau tangle accumulation (measured with the positron emission tomography tracer 18F-AV-1451) associated with well-established Alzheimer's disease factors in a cohort including cognitively healthy elderly individuals and individuals at early symptomatic stages of Alzheimer's disease. We then explored highly associated patterns of greater 18F-AV-1451 binding and increased annualized change in cortical amyloid-β plaques measured as florbetapir positron emission tomography binding antecedent to 18F-AV-1451 positron emission tomography scans, and to what extent these multimodal pattern associations explained the variance in cognitive performance and clinical outcome measures, independently and jointly. We found that: (i) 18F-AV-1451 positron emission tomography retention was differentially associated with age, and cross-sectional florbetapir positron emission tomography retention, but not with years of education, gender, or APOE genotype; (ii) increased annualized change in florbetapir retention, antecedent to 18F-AV-1451 positron emission tomography scans, in the parieto-temporal and precuneus brain regions was associated with greater 18F-AV-1451 PET retention most prominently in the inferior temporal and inferior parietal regions in the full cohort, with florbetapir positive/negative-associated variability; and (iii) this 18F-AV-1451 positron emission tomography retention pattern significantly explained the variance in cognitive performance and clinical outcome measures, independent of the associated antecedent increased annualized change in florbetapir positron emission tomography retention. These findings are in agreement with the pathology literature, which suggests that tau tangles but not amyloid-β plaques correlate with cognition and clinical symptoms. Furthermore, non-local associations linking increased amyloid-β accumulation rates with increased tau deposition are of great interest and support the idea that the amyloid-β pathology might have remote effects in disease pathology spread potentially via the brain's intrinsic connectivity networks.

Tosun D ，Landau S ，Aisen PS ，Petersen RC ，Mintun M ，Jagust W ，Weiner MW ，Alzheimer’s Disease Neuroimaging Initiative ... -  《-》