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Herholz, Karl. „Tau PET and tauopathies“. European Journal of Nuclear Medicine and Molecular Imaging 43, Nr. 9 (10.05.2016): 1684–85. http://dx.doi.org/10.1007/s00259-016-3406-5.
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Zimmer, Eduardo Rigon, Antoine Leuzy, Serge Gauthier und Pedro Rosa-Neto. „Developments in Tau PET Imaging“. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 41, Nr. 5 (September 2014): 547–53. http://dx.doi.org/10.1017/cjn.2014.15.
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ABSTRACTThe presence of neurofibrillary tangles in the brain is a hallmark feature of several neurodegenerative diseases termed “tauopathies,” including Alzheimer’s disease (AD) and the tau molecular subgroup of frontotemporal lobar degeneration (FTLD-tau). Recently, several positron emission tomography (PET) radiopharmaceuticals targeting abnormal conformations of the tau protein have been developed. To date, six novel tau imaging agents—[18F]THK523, [18F]THK5105, [18F]THK5117, [18F]T807, [18F]T808, and [11C]PBB3—have been described and are considered promising as potential tau radioligands. Tau imaging agents offer the opportunity of in vivo topographical mapping and quantification of tau aggregates in parallel with clinical and cognitive assessments. As such, tau imaging is considered of key importance for progress toward earlier and more accurate diagnosis of tauopathies as well as for the monitoring of therapeutic interventions and drug development. Here, we shed light on the most important developments in tau radiopharmaceuticals, highlighting challenges, possibilities and future directions.
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Mattsson-Carlgren, Niklas, Emelie Andersson, Shorena Janelidze, Rik Ossenkoppele, Philip Insel, Olof Strandberg, Henrik Zetterberg et al. „Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease“. Science Advances 6, Nr. 16 (April 2020): eaaz2387. http://dx.doi.org/10.1126/sciadv.aaz2387.
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The links between β-amyloid (Aβ) and tau in Alzheimer’s disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aβ pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aβ aggregation started. These results show that Aβ pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.
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Okamura, Nobuyuki, und Kazuhiko Yanai. „Applications of tau PET imaging“. Nature Reviews Neurology 13, Nr. 4 (17.03.2017): 197–98. http://dx.doi.org/10.1038/nrneurol.2017.38.
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Higuchi, Makoto. „PET imaging of tau lesions“. Folia Pharmacologica Japonica 145, Nr. 5 (2015): 268. http://dx.doi.org/10.1254/fpj.145.268.
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Lowe, Val J., Tyler J. Bruinsma, Heather J. Wiste, Hoon-Ki Min, Stephen D. Weigand, Ping Fang, Matthew L. Senjem et al. „Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults“. Neurology 93, Nr. 1 (30.05.2019): e29-e39. http://dx.doi.org/10.1212/wnl.0000000000007728.
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ObjectiveTo assess cross-sectional associations of neurofibrillary tangles, measured by tau-PET, with cognitive performance in cognitively unimpaired (CU) adults.MethodsTau- and amyloid-PET were performed in 579 CU participants aged 50–98 from the population-based Mayo Clinic Study of Aging. Associations between tau-PET signal in 43 brain regions and cognitive test scores were assessed using penalized linear regression. In additional models, participants were classified by normal/abnormal global amyloid-PET (A+/A−) and normal/abnormal regional tau-PET (T+/T−). Regional tau-PET cutpoints were defined as standardized uptake value ratio (SUVR) greater than the 95th percentile of tau-PET SUVR in that region among 117 CU participants aged 30–49.ResultsHigher tau-PET signal was associated with poorer memory performance in all medial temporal lobe (MTL) regions and also in the middle temporal pole and frontal olfactory regions. The largest association with tau-PET and memory z scores was seen in the entorhinal cortex; this association was independent of tau-PET signal in other brain regions. Tau-PET in the entorhinal cortex was also associated with poorer global and language performance. In the entorhinal cortex, T+ was associated with lower memory performance among both A− and A+.ConclusionsTau deposition in MTL regions, as reflected by tau-PET signal, was associated with poorer performance on memory tests in CU participants. The association with entorhinal cortex tau-PET was independent of tau-PET signal in other brain regions. Longitudinal studies are needed to understand the fate of CU participants with elevated medial temporal tau-PET signal.
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Tan, Meng-Shan, Yu-Xiang Yang, Hui-Fu Wang, Wei Xu, Chen-Chen Tan, Chuan-Tao Zuo, Qiang Dong, Lan Tan und Jin-Tai Yu. „PET Amyloid and Tau Status Are Differently Affected by Patient Features“. Journal of Alzheimer's Disease 78, Nr. 3 (24.11.2020): 1129–36. http://dx.doi.org/10.3233/jad-200124.
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Background: Amyloid-β (Aβ) plaques and tau neurofibrillary tangles are two neuropathological hallmarks of Alzheimer’s disease (AD), which both can be visualized in vivo using PET radiotracers, opening new opportunities to study disease mechanisms. Objective: Our study investigated 11 non-PET factors in 5 categories (including demographic, clinical, genetic, MRI, and cerebrospinal fluid (CSF) features) possibly affecting PET amyloid and tau status to explore the relationships between amyloid and tau pathology, and whether these features had a different association with amyloid and tau status. Methods: We included 372 nondemented elderly from the Alzheimer’s Disease Neuroimaging Initiative cohort. All underwent PET amyloid and tau analysis simultaneously, and were grouped into amyloid/tau quadrants based on previously established abnormality cut points. We examined the associations of above selected features with PET amyloid and tau status using a multivariable logistic regression model, then explored whether there was an obvious correlation between the significant features and PET amyloid or tau levels. Results: Our results demonstrated that PET amyloid and tau status were differently affected by patient features, and CSF biomarker features provided most significant values associating PET findings. CSF Aβ42/40 was the most important factor affecting amyloid PET status, and negatively correlated with amyloid PET levels. CSF pTau could significantly influence both amyloid and tau PET status. Besides CSF pTau and Aβ42, APOE ɛ4 allele status and Mini-Mental State Examination scores also could influence tau PET status, and significantly correlated with tau PET levels. Conclusion: Our results support that tau pathology possibly affected by Aβ-independent factors, implicating the importance of tau pathology in AD pathogenesis.
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Ishikawa, A., M. Tokunaga, I. Matsumoto, T. Minamihisamatsu, S. Uchida, J. Maeda, B. Ji et al. „Utilities of tau-pet and TSPO-pet for diagnosing severity of tau-induced disease progression“. Journal of the Neurological Sciences 381 (Oktober 2017): 664. http://dx.doi.org/10.1016/j.jns.2017.08.1869.
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Zhang, Rui-Qi, Shi-Dong Chen, Xue-Ning Shen, Yu-Xiang Yang, Jia-Ying Lu, Mei Cui, Chuan-Tao Zuo, Qiang Dong, Lan Tan und Jin-Tai Yu. „Elevated Tau PET Signal Depends on Abnormal Amyloid Levels and Correlates with Cognitive Impairment in Elderly Persons without Dementia“. Journal of Alzheimer's Disease 78, Nr. 1 (27.10.2020): 395–404. http://dx.doi.org/10.3233/jad-200526.
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Background: The recent developed PET ligands for amyloid-β (Aβ) and tau allow these two neuropathological hallmarks of Alzheimer’s disease (AD) to be mapped and quantified in vivo and to be examined in relation to cognition. Objective: To assess the associations among Aβ, tau, and cognition in non-demented subjects. Methods: Three hundred eighty-nine elderly participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent tau and amyloid PET scans. Cross-sectional comparisons and longitudinal analyses were used to evaluate the relationship between Aβ and tau accumulation. The correlations between biomarkers of both pathologies and performance in memory and executive function were measured. Results: Increased amyloid-PET retention was associated with greater tau-PET retention in widespread cortices. We observed a significant tau increase in the temporal composite regions of interest over 24 months in Aβ+ but not Aβ– subjects. Finally, tau-PET retention but not amyloid-PET retention significantly explained the variance in memory and executive function. Higher level of tau was associated with greater longitudinal memory decline. Conclusion: These findings suggested PET-detectable Aβ plaque pathology may be a necessary antecedent for tau-PET signal elevation. Greater tau-PET retention may demonstrate poorer cognition and predict prospective memory decline in non-demented subjects.
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Jack, Clifford R., Heather J. Wiste, Stephen D. Weigand, Terry M. Therneau, Val J. Lowe, David S. Knopman, Hugo Botha et al. „Predicting future rates of tau accumulation on PET“. Brain 143, Nr. 10 (24.06.2020): 3136–50. http://dx.doi.org/10.1093/brain/awaa248.
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Abstract Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer’s clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer’s disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.
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Reimand, Juhan, Lyduine Collij, Philip Scheltens, Femke Bouwman und Rik Ossenkoppele. „Association of amyloid-β CSF/PET discordance and tau load 5 years later“. Neurology 95, Nr. 19 (10.09.2020): e2648-e2657. http://dx.doi.org/10.1212/wnl.0000000000010739.
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ObjectiveTo investigate the association between discordant β-amyloid (Aβ) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later.MethodsWe included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]florbetapir PET and CSF Aβ42 available. Aβ CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (Aβ) PET (baseline to 4.3 ± 1.9 years), CSF (p)tau (baseline to 2.0 ± 0.1 years), cognition (baseline to 4.3 ± 2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2 ± 1.2 years after baseline to 1.6 ± 0.7 years later). We used linear mixed modeling to study the association between Aβ CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET− participants who during follow-up (1) progressed to Aβ CSF+/PET+ or (2) became tau-positive based on [18F]flortaucipir PET.ResultsAβ CSF+/PET+ (n = 318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET− (n = 80) participants were overall similar to the CSF−/PET− (N = 306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET− group (1.20 ± 0.13) did not differ from CSF−/PET− (1.18 ± 0.08, p = 0.69), but was substantially lower than CSF+/PET+ (1.48 ± 0.44, p < 0.001). Of the CSF+/PET− participants, 21/64 (33%) progressed to Aβ CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET.ConclusionsAβ load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal Aβ levels on both PET and CSF, the CSF+/PET− group has a distinctly better prognosis.
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Singleton, Ellen, Oskar Hansson, Yolande A. L. Pijnenburg, Renaud La Joie, William G. Mantyh, Pontus Tideman, Erik Stomrud et al. „Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer’s disease“. Journal of Neurology, Neurosurgery & Psychiatry 92, Nr. 8 (13.04.2021): 872–80. http://dx.doi.org/10.1136/jnnp-2020-325497.
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ObjectiveThe clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.MethodsFor the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a ‘typical’ memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).ResultsIndividual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05).ConclusionsBoth in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.
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Johnson, Keith. „Tau PET in aging and AD“. Neurobiology of Aging 39 (März 2016): S19. http://dx.doi.org/10.1016/j.neurobiolaging.2016.01.088.
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Shinotoh, Hitoshi, Hitoshi Shimada, Yasumasa Kokubo, Kenji Tagai, Fumitoshi Niwa, Soichiro Kitamura, Hironobu Endo et al. „Tau imaging detects distinctive distribution of tau pathology in ALS/PDC on the Kii Peninsula“. Neurology 92, Nr. 2 (07.12.2018): e136-e147. http://dx.doi.org/10.1212/wnl.0000000000006736.
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ObjectiveTo characterize the distribution of tau pathology in patients with amyotrophic lateral sclerosis/parkinsonism dementia complex on the Kii Peninsula (Kii ALS/PDC) by tau PET using [11C]PBB3 as ligand.MethodsThis is a cross-sectional study of 5 patients with ALS/PDC and one asymptomatic participant with a dense family history of ALS/PDC from the Kii Peninsula who took part in this study. All were men, and their age was 76 ± 8 (mean ± SD) years. Thirteen healthy men (69 ± 6 years) participated as healthy controls (HCs). Dynamic PET scans were performed following injection of [11C]PBB3, and parametric PET images were generated by voxel-by-voxel calculation of binding potential (BP*ND) using a multilinear reference tissue model. [11C] Pittsburgh compound B (PiB) PET, MRI, and cognitive tests were also performed.ResultsA voxel-based comparison of [11C]PBB3 BP*ND illustrated PET-detectable tau deposition in the cerebral cortex and white matter, and pontine basis including the corticospinal tract in Kii ALS/PDC patients compared with HCs (uncorrected p < 0.05). Group-wise volume of interest analysis of [11C]PBB3 BP*ND images showed increased BP*ND in the hippocampus and in frontal and parietal white matters of Kii ALS/PDC patients relative to HCs (p < 0.05, Holm-Sidak multiple comparisons test). BP*ND in frontal, temporal, and parietal gray matters correlated with Mini-Mental State Examination scores in Kii ALS/PDC patients (p < 0.05). All Kii ALS/PDC patients were negative for [11C]PiB (β-amyloid) except one with marginal positivity.Conclusion[11C]PBB3 PET visualized the characteristic topography of tau pathology in Kii ALS/PDC, corresponding to clinical phenotypes of this disease.
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La Joie, Renaud, Alexandre Bejanin, Anne M. Fagan, Nagehan Ayakta, Suzanne L. Baker, Viktoriya Bourakova, Adam L. Boxer et al. „Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample“. Neurology 90, Nr. 4 (27.12.2017): e282-e290. http://dx.doi.org/10.1212/wnl.0000000000004860.
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ObjectiveTo assess the relationships between fluid and imaging biomarkers of tau pathology and compare their diagnostic utility in a clinically heterogeneous sample.MethodsFifty-three patients (28 with clinical Alzheimer disease [AD] and 25 with non-AD clinical neurodegenerative diagnoses) underwent β-amyloid (Aβ) and tau ([18F]AV1451) PET and lumbar puncture. CSF biomarkers (Aβ42, total tau [t-tau], and phosphorylated tau [p-tau]) were measured by multianalyte immunoassay (AlzBio3). Receiver operator characteristic analyses were performed to compare discrimination of Aβ-positive AD from non-AD conditions across biomarkers. Correlations between CSF biomarkers and PET standardized uptake value ratios (SUVR) were assessed using skipped Pearson correlation coefficients. Voxelwise analyses were run to assess regional CSF–PET associations.Results[18F]AV1451-PET cortical SUVR and p-tau showed excellent discrimination between Aβ-positive AD and non-AD conditions (area under the curve 0.92–0.94; ≤0.83 for other CSF measures), and reached 83% classification agreement. In the full sample, cortical [18F]AV1451 was associated with all CSF biomarkers, most strongly with p-tau (r = 0.75 vs 0.57 for t-tau and −0.49 for Aβ42). When restricted to Aβ-positive patients with AD, [18F]AV1451 SUVR correlated modestly with p-tau and t-tau (both r = 0.46) but not Aβ42 (r = 0.02). On voxelwise analysis, [18F]AV1451 correlated with CSF p-tau in temporoparietal cortices and with t-tau in medial prefrontal regions. Within AD, Mini-Mental State Examination scores were associated with [18F]AV1451-PET, but not CSF biomarkers.Conclusion[18F]AV1451-PET and CSF p-tau had comparable value for differential diagnosis. Correlations were robust in a heterogeneous clinical group but attenuated (although significant) in AD, suggesting that fluid and imaging biomarkers capture different aspects of tau pathology.Classification of evidenceThis study provides Class III evidence that, in a clinical sample of patients with a variety of suspected neurodegenerative diseases, both CSF p-tau and [18F]AV1451 distinguish AD from non-AD conditions.
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Neitzel, Julia, Nicolai Franzmeier, Anna Rubinski und Michael Ewers. „Left frontal connectivity attenuates the adverse effect of entorhinal tau pathology on memory“. Neurology 93, Nr. 4 (24.06.2019): e347-e357. http://dx.doi.org/10.1212/wnl.0000000000007822.
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ObjectiveTo investigate whether higher global left frontal cortex (gLFC) connectivity, a putative neural substrate of cognitive reserve, attenuates the effect of entorhinal tau PET levels on episodic memory in older adults.MethodsCross-sectional 18F-AV-1451 PET (to assess tau pathology), 18F-AV-45 or 18F-BAY94-9172 PET (to assess β-amyloid [Aβ]), and resting-state fMRI were obtained in 125 elderly participants from the Alzheimer's Neuroimaging Initiative, including 82 cognitively normal participants (amyloid PET-positive [Aβ+], n = 27) and 43 patients with amnestic mild cognitive impairment (Aβ+ = 15). Resting-state fMRI gLFC connectivity was computed for each participant as the average functional connectivity between the left frontal cortex (LFC) (seed) and each remaining voxel in the gray matter. As a measure of tau pathology, we assessed the mean tau PET uptake in the entorhinal cortex. In linear mixed-effects regression analysis, we tested the interaction term gLFC connectivity × entorhinal tau PET on delayed free recall performance. In addition, we assessed whether higher connectivity of the whole frontoparietal control network (FPCN), of which the LFC is a major hub, is associated with reserve.ResultsHigher entorhinal tau PET was strongly associated with poorer delayed free recall performance (β/SE = −0.49/0.07, p < 0.001). A significant gLFC connectivity × entorhinal tau PET interaction was found (β/SE = 0.19/0.06, p = 0.003), such that at higher levels of gLFC connectivity, the decrease in memory score per unit of entorhinal tau PET was attenuated. The FPCN connectivity × tau interaction was also significant (β/SE = 0.10/0.04, p = 0.012).ConclusionBoth gLFC and FPCN connectivity are associated with higher resilience against the adverse effect of early-stage entorhinal tau pathology on memory performance.
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La Joie, Renaud, Adrienne V. Visani, Suzanne L. Baker, Jesse A. Brown, Viktoriya Bourakova, Jungho Cha, Kiran Chaudhary et al. „Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET“. Science Translational Medicine 12, Nr. 524 (01.01.2020): eaau5732. http://dx.doi.org/10.1126/scitranslmed.aau5732.
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β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer’s disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients’ diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid–PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient’s progression and design future clinical trials.
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Beyer, Leonie, Alexander Nitschmann, Henryk Barthel, Thilo van Eimeren, Marcus Unterrainer, Julia Sauerbeck, Ken Marek et al. „Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury“. European Journal of Nuclear Medicine and Molecular Imaging 47, Nr. 12 (21.04.2020): 2911–22. http://dx.doi.org/10.1007/s00259-020-04788-w.
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Abstract Purpose Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG). Methods Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson’s disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0–60 min p.i.) and static [18F]FDG-PET (30–50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers. Results Highest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5–2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers. Conclusion Early-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.
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Doecke, James D., Qiao-Xin Li, Christopher Fowler, Steven Collins, Vincent Dore, Christopher C. Rowe, Colin L. Masters, Olivier Salvado und Victor LL Villemagne. „CSF P-TAU IS CORRELATED WITH TAU PET, WHILE Aβ PET CORRELATES WITH Aβ1-42 AND THE T-TAU/Aβ1-42 RATIO“. Alzheimer's & Dementia 13, Nr. 7 (Juli 2017): P202—P203. http://dx.doi.org/10.1016/j.jalz.2017.07.067.
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Mishra, Sushil K., Yoshiki Yamaguchi, Makoto Higuchi und Naruhiko Sahara. „Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling“. International Journal of Molecular Sciences 22, Nr. 1 (31.12.2020): 349. http://dx.doi.org/10.3390/ijms22010349.
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In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer’s disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick’s disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick’s disease (TauPiD). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore TauPiD binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with TauPiD. The probes bind to TauPiD at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of TauPiD specific PET tracers.
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Franzmeier, Nicolai, Anna Rubinski, Julia Neitzel, Yeshin Kim, Alexander Damm, Duk L. Na, Hee Jin Kim et al. „Functional connectivity associated with tau levels in ageing, Alzheimer’s, and small vessel disease“. Brain 142, Nr. 4 (15.02.2019): 1093–107. http://dx.doi.org/10.1093/brain/awz026.
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Abstract In Alzheimer’s disease, tau pathology spreads hierarchically from the inferior temporal lobe throughout the cortex, ensuing cognitive decline and dementia. Similarly, circumscribed patterns of pathological tau have been observed in normal ageing and small vessel disease, suggesting a spatially ordered distribution of tau pathology across normal ageing and different diseases. In vitro findings suggest that pathological tau may spread ‘prion-like’ across neuronal connections in an activity-dependent manner. Supporting this notion, functional brain networks show a spatial correspondence to tau deposition patterns. However, it remains unclear whether higher network-connectivity facilitates tau propagation. To address this, we included 55 normal aged elderly (i.e. cognitively normal, amyloid-negative), 50 Alzheimer’s disease patients (i.e. amyloid-positive) covering the preclinical to dementia spectrum, as well as 36 patients with pure (i.e. amyloid-negative) vascular cognitive impairment due to small vessel disease. All subjects were assessed with AV1451 tau-PET and resting-state functional MRI. Within each group, we computed atlas-based resting-state functional MRI functional connectivity across 400 regions of interest covering the entire neocortex. Using the same atlas, we also assessed within each group the covariance of tau-PET levels among the 400 regions of interest. We found that higher resting-state functional MRI assessed functional connectivity between any given region of interest pair was associated with higher covariance in tau-PET binding in corresponding regions of interest. This result was consistently found in normal ageing, Alzheimer’s disease and vascular cognitive impairment. In particular, inferior temporal tau-hotspots, as defined by highest tau-PET uptake, showed high predictive value of tau-PET levels in functionally closely connected regions of interest. These associations between functional connectivity and tau-PET uptake were detected regardless of presence of dementia symptoms (mild cognitive impairment or dementia), amyloid deposition (as assessed by amyloid-PET) or small vessel disease. Our findings suggest that higher functional connectivity between brain regions is associated with shared tau-levels, supporting the view of prion-like tau spreading facilitated by neural activity.
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Wolters, Emma E., Rik Ossenkoppele, Sander C. J. Verfaillie, Emma M. Coomans, Tessa Timmers, Denise Visser, Hayel Tuncel et al. „Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer’s disease“. European Journal of Nuclear Medicine and Molecular Imaging 47, Nr. 12 (14.04.2020): 2866–78. http://dx.doi.org/10.1007/s00259-020-04758-2.
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Abstract Purpose In vivo Alzheimer’s disease (AD) biomarkers for tau pathology are cerebrospinal fluid (CSF) phosphorylated tau (p-tau) and [18F]flortaucipir positron emission tomography (PET). Our aim was to assess associations between CSF p-tau with [18F]flortaucipir PET and the associations of both tau biomarkers with cognition and atrophy. Methods We included 78 amyloid positive cognitively impaired patients (clinical diagnoses mild cognitive impairment (MCI, n = 8) and AD dementia (n = 45) and 25 cognitively normal subjects with subjective cognitive decline (SCD) (40% amyloid-positive)). Dynamic 130 min [18F]flortaucipir PET scans were acquired to generate binding potential (BPND) images using receptor parametric mapping and standardized uptake values ratios of 80–100 min (SUVr80-100min) post injection. We obtained regional BPND and SUVr from entorhinal, limbic, and neocortical regions-of-interest (ROIs), closely aligning to the neuropathological tau staging schemes. Cognition was assessed using MMSE and composite scores of four cognitive domains, and atrophy was measured using gray matter volume covering the major brain lobes. First, we used linear regressions to investigate associations between CSF p-tau (independent variable) and tau PET (dependent variable). Second, we used linear regressions to investigate associations between CSF p-tau, tau PET (separate independent variables, model 1), and cognition (dependent variable). We then assessed the independent effects of CSF p-tau and tau PET on cognition by simultaneously adding the other tau biomarker as a predictor (model 2). Finally, we performed the same procedure for model 1 and 2, but replaced cognition with atrophy. Models were adjusted for age, sex, time lag between assessments, education (cognition only), and total intracranial volume (atrophy only). Results Higher [18F]flortaucipir BPND was associated with higher CSF p-tau (range of standardized betas (sβ) across ROIs, 0.43–0.46; all p < 0.01). [18F]flortaucipir BPND was more strongly associated with cognition and atrophy than CSF p-tau. When [18F]flortaucipir BPND and CSF p-tau were entered simultaneously, [18F]flortaucipir BPND (range sβ = − 0.20 to – 0.57, all p < 0.05) was strongly associated with multiple cognitive domains and atrophy regions. SUVr showed comparable results to BPND. Conclusion Regional [18F]flortaucipir BPND correlated stronger with cognition and neurodegeneration than CSF p-tau, suggesting that tau PET more accurately reflects disease severity in AD.
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Schoemaker, Dorothee, Andreas Charidimou, Maria Clara Zanon Zotin, Nicolas Raposo, Keith A. Johnson, Justin S. Sanchez, Steven M. Greenberg und Anand Viswanathan. „Association of Memory Impairment With Concomitant Tau Pathology in Patients With Cerebral Amyloid Angiopathy“. Neurology 96, Nr. 15 (24.02.2021): e1975-e1986. http://dx.doi.org/10.1212/wnl.0000000000011745.
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ObjectiveRelying on tau-PET imaging, this cross-sectional study explored whether memory impairment is linked to the presence of concomitant tau pathology in individuals with cerebral amyloid angiopathy (CAA).MethodsForty-six patients with probable CAA underwent a neuropsychological examination and an MRI for quantification of structural markers of cerebral small vessel disease. A subset of these participants also completed a [11C]-Pittsburgh compound B (n = 39) and [18F]-flortaucipir (n = 40) PET for in vivo estimation of amyloid and tau burden, respectively. Participants were classified as amnestic or nonamnestic on the basis of neuropsychological performance. Statistical analyses were performed to examine differences in cognition, structural markers of cerebral small vessel disease, and amyloid- and tau-PET retention between participants with amnestic and those with nonamnestic CAA.ResultsPatients with probable CAA with an amnestic presentation displayed a globally more severe profile of cognitive impairment, smaller hippocampal volume (p < 0.001), and increased tau-PET binding in regions susceptible to Alzheimer disease neurodegeneration (p = 0.003) compared to their nonamnestic counterparts. Amnestic and nonamnestic patients with CAA did not differ on any other MRI markers or on amyloid-PET binding. In a generalized linear model including all evaluated neuroimaging markers, tau-PET retention (β = −0.85, p = 0.001) and hippocampal volume (β = 0.64 p = 0.01) were the only significant predictors of memory performance. The cognitive profile of patients with CAA with an elevated tau-PET retention was distinctly characterized by a significantly lower performance on the memory domain (p = 0.004).ConclusionsThese results suggest that the presence of objective memory impairment in patients with probable CAA could serve as a marker for underlying tau pathology.Classification of EvidenceThis study provides Class II evidence that tau-PET retention is related to the presence of objective memory impairment in patients with CAA.
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Jack, Clifford R., Heather J. Wiste, Hugo Botha, Stephen D. Weigand, Terry M. Therneau, David S. Knopman, Jonathan Graff-Radford et al. „The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes“. Brain 142, Nr. 10 (09.09.2019): 3230–42. http://dx.doi.org/10.1093/brain/awz268.
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See Gordon and Tijms (doi:10.1093/brain/awz278) for a scientific commentary on this article. Jack et al. examine relationships between the bivariate distribution of β-amyloid and tau on PET and established neurocognitive clinical syndromes. Amyloidosis appears to be required for high levels of 3R/4R tau deposition. Whereas abnormal amyloid PET is compatible with normal cognition, highly abnormal tau PET is not.
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Jones, David T., David S. Knopman, Jonathan Graff-Radford, Jeremy A. Syrjanen, Matthew L. Senjem, Christopher G. Schwarz, Christina Dheel et al. „In vivo 18F-AV-1451 tau PET signal in MAPT mutation carriers varies by expected tau isoforms“. Neurology 90, Nr. 11 (09.02.2018): e947-e954. http://dx.doi.org/10.1212/wnl.0000000000005117.
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ObjectiveTo evaluate 18F-AV-1451 tau PET binding among microtubule-associated protein tau (MAPT) mutation carriers.MethodsUsing a case-control study, we quantitatively and qualitatively compared tau PET scans in 10 symptomatic and 3 asymptomatic MAPT mutation carriers (n = 13, age range 42–67 years) with clinically normal (CN) participants (n = 241, age range 42–67 years) and an Alzheimer disease (AD) dementia cohort (n = 30, age range 52–67 years). Eight participants had MAPT mutations that involved exon 10 (N279K n = 5, S305N n = 2, P301L n = 1) and tend to form 4R tau pathology, and 5 had mutations outside exon 10 (V337M n = 2, R406W n = 3) and tend to form mixed 3R/4R tau pathology.ResultsTau PET signal was qualitatively and quantitatively different between participants with AD, CN participants, and MAPT mutation carriers, with the greatest signal intensity in those with AD and minimal regional signal in MAPT mutation carries with mutations in exon 10. However, MAPT mutation carriers with mutations outside exon 10 had uptake levels within the AD range, which was significantly higher than both MAPT mutation carriers with mutations in exon 10 and controls.ConclusionsTau PET shows higher magnitude of binding in MAPT mutation carriers who harbor mutations that are more likely to produce AD-like tau pathology (e.g., in our series, the non–exon 10 families tend to accumulate mixed 3R/4R aggregates). Exon 10 splicing determines the balance of 3R and 4R tau isoforms, with some mutations involving exon 10 predisposing to a greater proportion of 4R aggregates and consequently a lower level of AV-1451 binding, as seen in this case series, thus supporting the notion that this tau PET ligand has specific binding properties for AD-like tau pathology.
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Barrio, Jorge R. „The Irony of PET Tau Probe Specificity“. Journal of Nuclear Medicine 59, Nr. 1 (09.11.2017): 115–16. http://dx.doi.org/10.2967/jnumed.117.198960.
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Villemagne, Victor L., S. Furumoto, M. T. Fodero-Tavoletti, R. S. Mulligan, G. Jones, O. Piguet, J. Hodges et al. „81 In vivo tau imaging with PET“. Neurobiology of Aging 33 (Mai 2012): S35. http://dx.doi.org/10.1016/j.neurobiolaging.2012.01.099.
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Day, Gregory S., Brian A. Gordon, Austin McCullough, Robert C. Bucelli, Richard J. Perrin, Tammie L. S. Benzinger und Beau M. Ances. „Flortaucipir (tau) PET in LGI1 antibody encephalitis“. Annals of Clinical and Translational Neurology 8, Nr. 2 (07.01.2021): 491–97. http://dx.doi.org/10.1002/acn3.51297.
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Jones, David T., Ryan A. Townley, Jonathan Graff-Radford, Hugo Botha, David S. Knopman, Ronald C. Petersen, Clifford R. Jack, Val J. Lowe und Bradley F. Boeve. „Amyloid- and tau-PET imaging in a familial prion kindred“. Neurology Genetics 4, Nr. 6 (Dezember 2018): e290. http://dx.doi.org/10.1212/nxg.0000000000000290.
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ObjectiveTo study the in vivo binding properties of 18F-AV-1451 (tau-PET) and Pittsburgh compound B (PiB-PET) in a unique kindred with a familial prion disorder known to produce amyloid plaques composed of prion protein alongside Alzheimer disease (AD)–like tau tangles.MethodsA case series of 4 symptomatic family members with the 12-octapeptide repeat insertion in the PRNP gene were imaged with 3T MRI, PiB-PET, and tau-PET in their fourth decade of life.ResultsThere was significant neocortical uptake of the tau-PET tracer in all 4 familial prion cases. However, PiB-PET images did not demonstrate abnormally elevated signal in neocortical or cerebellar regions for any of the patients.ConclusionsIn vivo detection of molecular hallmarks of neurodegenerative diseases will be a prerequisite to well-conducted therapeutic trials. Understanding the in vivo behavior of these PET biomarkers in the setting of various neurodegenerative processes is imperative to their proper use in such trials and for research studies focused on the basic neurobiology of neurodegeneration. This study supports the high specificity of neocortical 18F-AV-1451 binding to AD-like tau and the lack of PiB binding to PrP plaques. It is uncertain how early in the disease course tau pathology appears in the brains of individuals who carry this PRNP gene mutation or how it evolves throughout the disease course, but future longitudinal 18F-AV-1451 imaging of symptomatic and asymptomatic individuals in this kindred will help address these uncertainties.
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Aschenbrenner, Andrew J., Brian A. Gordon, Tammie L. S. Benzinger, John C. Morris und Jason J. Hassenstab. „Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease“. Neurology 91, Nr. 9 (01.08.2018): e859-e866. http://dx.doi.org/10.1212/wnl.0000000000006075.
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ObjectiveTo examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline.MethodsA total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir (18F-AV-1451) tau PET scan, a florbetapir (18F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed.ResultsResults from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the largest negative influence on tests of episodic memory and executive functioning.ConclusionsTogether, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression.
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Therriault, Joseph, Tharick A. Pascoal, Melissa Savard, Andrea L. Benedet, Mira Chamoun, Cecile Tissot, Firoza Lussier et al. „Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease“. Neurology 96, Nr. 1 (22.10.2020): e81-e92. http://dx.doi.org/10.1212/wnl.0000000000011081.
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ObjectiveTo determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.MethodsWe assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity– and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [18F]AZD4694, tau-PET with [18F]MK6240, MRI, and neuropsychological testing.ResultsVoxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.ConclusionsOur results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.
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Arenaza-Urquijo, Eider M., Scott A. Przybelski, Mary M. Machulda, David S. Knopman, Val J. Lowe, Michelle M. Mielke, Ashritha L. Reddy et al. „Better stress coping associated with lower tau in amyloid-positive cognitively unimpaired older adults“. Neurology 94, Nr. 15 (21.01.2020): e1571-e1579. http://dx.doi.org/10.1212/wnl.0000000000008979.
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ObjectiveResearch in animals has shown that chronic stress exacerbates tau pathology. In humans, psychological stress has been associated with higher risk of Alzheimer disease clinical syndrome. The objective of this cross-sectional study was to assess the hypothesis that stress coping ability (assessed via the Brief Resilience Scale [BRS]) is associated with tau burden and to evaluate whether these associations differed by sex and amyloid status (A+/A−) in cognitively unimpaired (CU) older adults.MethodsWe included 225 CU participants (mean age 70.4 ± 10.2 years, 48% female) enrolled in the population-based Mayo Clinic Study of Aging who completed the BRS and underwent amyloid-PET (Pittsburgh compound B–PET) and tau-PET (AV1451-PET). We fitted multiple regression and analysis of covariance models to assess the associations between BRS and tau-PET and the interaction with amyloid status and sex. We focused on entorhinal cortex (ERC) tau burden and also performed voxel-wise analyses. Age, sex, education, depression, and anxiety were considered as covariates.ResultsHigher stress coping ability was associated with lower tau burden in the medial temporal lobe (including ERC) and occipito-temporal and cuneal/precuneal cortices. The association was present in both A+ and A− but weaker in A− CU older adults. There was an interaction between amyloid status and stress coping ability that was restricted to the medial temporal lobe tau such that A+ CU older adults with lower stress coping abilities showed higher tau. There were no significant interactions between stress coping and sex.ConclusionsA faster termination of the stress response (higher coping ability) may limit the negative effects of stress on tau deposition. Conversely, lower stress coping ability may be an early sign of accumulating tau pathology. Longitudinal studies are warranted to clarify whether stress mechanisms act to exacerbate tau pathology or tau influences stress-related brain mechanisms and lowers the ability to cope with stress.
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Mattsson-Carlgren, Niklas, Antoine Leuzy, Shorena Janelidze, Sebastian Palmqvist, Erik Stomrud, Olof Strandberg, Ruben Smith und Oskar Hansson. „The implications of different approaches to define AT(N) in Alzheimer disease“. Neurology 94, Nr. 21 (12.05.2020): e2233-e2244. http://dx.doi.org/10.1212/wnl.0000000000009485.
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ObjectiveTo compare different β-amyloid (Aβ), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies.MethodsA total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aβ42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation.ResultsAmong CU participants, A−T−(N)− or A+T−(N)− variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures.ConclusionsOur findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.
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Spotorno, Nicola, Julio Acosta-Cabronero, Erik Stomrud, Björn Lampinen, Olof T. Strandberg, Danielle van Westen und Oskar Hansson. „Relationship between cortical iron and tau aggregation in Alzheimer’s disease“. Brain 143, Nr. 5 (24.04.2020): 1341–49. http://dx.doi.org/10.1093/brain/awaa089.
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Abstract A growing body of evidence suggests that the dysregulation of neuronal iron may play a critical role in Alzheimer’s disease. Recent MRI studies have established a relationship between iron accumulation and amyloid-β aggregation. The present study provides further insight demonstrating a relationship between iron and tau accumulation using magnetic resonance-based quantitative susceptibility mapping and tau-PET in n = 236 subjects with amyloid-β pathology (from the Swedish BioFINDER-2 study). Both voxel-wise and regional analyses showed a consistent association between differences in bulk magnetic susceptibility, which can be primarily ascribed to an increase in iron content, and tau-PET signal in regions known to be affected in Alzheimer’s disease. Subsequent analyses revealed that quantitative susceptibility specifically mediates the relationship between tau-PET and cortical atrophy measures, thus suggesting a modulatory effect of iron burden on the disease process. We also found evidence suggesting the relationship between quantitative susceptibility and tau-PET is stronger in younger participants (age ≤ 65). Together, these results provide in vivo evidence of an association between iron deposition and both tau aggregation and neurodegeneration, which help advance our understanding of the role of iron dysregulation in the Alzheimer’s disease aetiology.
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Mattsson, Niklas, Ruben Smith, Olof Strandberg, Sebastian Palmqvist, Michael Schöll, Philip S. Insel, Douglas Hägerström et al. „Comparing 18F-AV-1451 with CSF t-tau and p-tau for diagnosis of Alzheimer disease“. Neurology 90, Nr. 5 (10.01.2018): e388-e395. http://dx.doi.org/10.1212/wnl.0000000000004887.
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ObjectiveTo compare PET imaging of tau pathology with CSF measurements (total tau [t-tau] and phosphorylated tau [p-tau]) in terms of diagnostic performance for Alzheimer disease (AD).MethodsWe compared t-tau and p-tau and 18F-AV-1451 in 30 controls, 14 patients with prodromal AD, and 39 patients with Alzheimer dementia, recruited from the Swedish BioFINDER study. All patients with AD (prodromal and dementia) were screened for amyloid positivity using CSF β-amyloid 42. Retention of 18F-AV-1451 was measured in a priori specified regions, selected for known associations with tau pathology in AD.ResultsRetention of 18F-AV-1451 was markedly elevated in Alzheimer dementia and moderately elevated in prodromal AD. CSF t-tau and p-tau was increased to similar levels in both AD dementia and prodromal AD. 18F-AV-1451 had very good diagnostic performance for Alzheimer dementia (area under the receiver operating characteristic curve [AUROC] ∼1.000), and was significantly better than t-tau (0.876), p-tau (0.890), hippocampal volume (0.824), and temporal cortical thickness (0.860). For prodromal AD, there were no significant AUROC differences between CSF tau and 18F-AV-1451 measures (0.836–0.939), but MRI measures had lower AUROCs (0.652–0.769).ConclusionsCSF tau and 18F-AV-1451 have equal performance in early clinical stages of AD, but 18F-AV-1451 is superior in the dementia stage, and exhibits close to perfect diagnostic performance for mild to moderate AD.Classification of evidenceThis study provides Class III evidence that CSF tau and 18F-AV-1451 PET have similar performance in identifying early AD, and that 18F-AV-1451 PET is superior to CSF tau in identifying mild to moderate AD.
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Smith, Ruben, Andreas Puschmann, Michael Schöll, Tomas Ohlsson, John van Swieten, Michael Honer, Elisabet Englund und Oskar Hansson. „18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology inMAPTmutation carriers“. Brain 139, Nr. 9 (29.06.2016): 2372–79. http://dx.doi.org/10.1093/brain/aww163.
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Jie, Caitlin, Valerie Treyer, Roger Schibli und Linjing Mu. „Tauvid™: The First FDA-Approved PET Tracer for Imaging Tau Pathology in Alzheimer’s Disease“. Pharmaceuticals 14, Nr. 2 (30.01.2021): 110. http://dx.doi.org/10.3390/ph14020110.
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Tauvid has been approved by the U.S. Food and Drug Administration (FDA) in 2020 for positron emission tomography (PET) imaging of adult patients with cognitive impairments undergoing evaluation for Alzheimer’s disease (AD) based on tau pathology. Abnormal aggregation of tau proteins is one of the main pathologies present in AD and is receiving increasing attention as a diagnostic and therapeutic target. In this review, we summarised the production and quality control of Tauvid, its clinical application, pharmacology and pharmacokinetics, as well as its limitation due to off-target binding. Moreover, a brief overview on the second-generation of Tau PET tracers is provided. The approval of Tauvid marks a step forward in the field of AD research and opens up opportunities for second-generation tau tracers to advance tau PET imaging in the clinic.
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Boerwinkle, Anna H., Julie K. Wisch, Charles D. Chen, Brian A. Gordon, Omar H. Butt, Suzanne E. Schindler, Courtney Sutphen et al. „Temporal Correlation of CSF and Neuroimaging in the Amyloid-Tau-Neurodegeneration Model of Alzheimer Disease“. Neurology 97, Nr. 1 (30.04.2021): e76-e87. http://dx.doi.org/10.1212/wnl.0000000000012123.
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ObjectiveTo evaluate temporal correlations between CSF and neuroimaging (PET and MRI) measures of amyloid, tau, and neurodegeneration in relation to Alzheimer disease (AD) progression.MethodsA total of 371 cognitively unimpaired and impaired participants enrolled in longitudinal studies of AD had both CSF (β-amyloid [Aβ]42, phosphorylated tau181, total tau, and neurofilament light chain) and neuroimaging (Pittsburgh compound B [PiB] PET, flortaucipir PET, and structural MRI) measures. The pairwise time interval between CSF and neuroimaging measures was binned into 2-year periods. Spearman correlations identified the time bin when CSF and neuroimaging measures most strongly correlated. CSF and neuroimaging measures were then binarized as biomarker-positive or biomarker-negative using Gaussian mixture modeling. Cohen kappa coefficient identified the time bin when CSF measures best agreed with corresponding neuroimaging measures when determining amyloid, tau, and neurodegeneration biomarker positivity.ResultsCSF Aβ42 and PiB PET showed maximal correlation when collected within 6 years of each other (R ≈ −0.5). CSF phosphorylated tau181 and flortaucipir PET showed maximal correlation when CSF was collected 4 to 8 years prior to PET (R ≈ 0.4). CSF neurofilament light chain and cortical thickness showed low correlation, regardless of time interval (Ravg ≈ −0.3). Similarly, CSF total tau and cortical thickness had low correlation, regardless of time interval (Ravg < −0.2).ConclusionsCSF Aβ42 and PiB PET best agree when acquired in close temporal proximity, whereas CSF phosphorylated tau precedes flortaucipir PET by 4 to 8 years. CSF and neuroimaging measures of neurodegeneration have low correspondence and are not interchangeable at any time interval.
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Franzmeier, Nicolai, Anna Dewenter, Lukas Frontzkowski, Martin Dichgans, Anna Rubinski, Julia Neitzel, Ruben Smith et al. „Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer’s disease“. Science Advances 6, Nr. 48 (November 2020): eabd1327. http://dx.doi.org/10.1126/sciadv.abd1327.
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In Alzheimer’s disease (AD), the Braak staging scheme suggests a stereotypical tau spreading pattern that does, however, not capture interindividual variability in tau deposition. This complicates the prediction of tau spreading, which may become critical for defining individualized tau-PET readouts in clinical trials. Since tau is assumed to spread throughout connected regions, we used functional connectivity to improve tau spreading predictions over Braak staging methods. We included two samples with longitudinal tau-PET from controls and AD patients. Cross-sectionally, we found connectivity of tau epicenters (i.e., regions with earliest tau) to predict estimated tau spreading sequences. Longitudinally, we found tau accumulation rates to correlate with connectivity strength to patient-specific tau epicenters. A connectivity-based, patient-centered tau spreading model improved the assessment of tau accumulation rates compared to Braak stage–specific readouts and reduced sample sizes by ~40% in simulated tau-targeting interventions. Thus, connectivity-based tau spreading models may show utility in clinical trials.
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Soleimani-Meigooni, David N., Leonardo Iaccarino, Renaud La Joie, Suzanne Baker, Viktoriya Bourakova, Adam L. Boxer, Lauren Edwards et al. „18F-flortaucipir PET to autopsy comparisons in Alzheimer’s disease and other neurodegenerative diseases“. Brain 143, Nr. 11 (November 2020): 3477–94. http://dx.doi.org/10.1093/brain/awaa276.
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Abstract Few studies have evaluated the relationship between in vivo18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34–76); eight female; median PET-to-autopsy interval of 30 months (range 4–59 months)]. Eight patients had primary Alzheimer’s disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration. Using an inferior cerebellar grey matter reference, 80–100-min 18F-flortaucipir PET standardized uptake value ratio (SUVR) images were created. Mean SUVRs were calculated for progressive supranuclear palsy, corticobasal degeneration, and neurofibrillary tangle Braak stage regions of interest, and these values were compared to SUVRs derived from young, non-autopsy, cognitively normal controls used as a standard for tau negativity. W-score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. There was excellent correspondence between areas of 18F-flortaucipir retention, on both SUVR images and W-score maps, and neurofibrillary tangle distribution in patients with primary Alzheimer’s disease neuropathology. Patients with non-Alzheimer tauopathies and non-tau frontotemporal lobar degeneration showed a range of tracer retention that was less than Alzheimer’s disease, though higher than age-matched, cognitively normal controls. Overall, binding across both tau-positive and tau-negative non-Alzheimer disorders did not reliably correspond with post-mortem tau pathology. 18F-flortaucipir SUVRs in subcortical regions were higher in autopsy-confirmed progressive supranuclear palsy and corticobasal degeneration than in controls, but were similar to values measured in Alzheimer’s disease and tau-negative neurodegenerative pathologies. Quantification of 18F-flortaucipir SUVR images at Braak stage regions of interest reliably detected advanced Alzheimer’s (Braak VI) pathology. However, patients with earlier Braak stages (Braak I–IV) did not show elevated tracer uptake in these regions compared to young, tau-negative controls. In summary, PET-to-autopsy comparisons confirm that 18F-flortaucipir PET is a reliable biomarker of advanced Braak tau pathology in Alzheimer’s disease. The tracer cannot reliably differentiate non-Alzheimer tauopathies and may not detect early Braak stages of neurofibrillary tangle pathology.
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Sugiyama, Atsuhiko, und Hitoshi Shimada. „Tau PET Imaging for Dementia in Clinical Practice“. RADIOISOTOPES 65, Nr. 12 (2016): 517–22. http://dx.doi.org/10.3769/radioisotopes.65.517.
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Jack, Clifford R., Heather J. Wiste, Christopher G. Schwarz, Val J. Lowe, Matthew L. Senjem, Prashanthi Vemuri, Stephen D. Weigand et al. „Longitudinal tau PET in ageing and Alzheimer’s disease“. Brain 141, Nr. 5 (12.03.2018): 1517–28. http://dx.doi.org/10.1093/brain/awy059.
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Johnson, Keith A., Aaron P. Schultz, Rema Raman, Michael C. Donohue, Chung-Kai Sun, Heidi IL Jacobs, Kenneth Marek et al. „P4-321: TAU PET IN A4: PRELIMINARY REPORT“. Alzheimer's & Dementia 14, Nr. 7S_Part_30 (01.07.2006): P1583—P1584. http://dx.doi.org/10.1016/j.jalz.2018.07.144.
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Zhou, Yongxia, und Bing Bai. „AV-1451 PET-TAU IMAGING QUANTIFICATION AND CORRELATIONS“. Alzheimer's & Dementia 13, Nr. 7 (Juli 2017): P151. http://dx.doi.org/10.1016/j.jalz.2017.06.2584.
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Hanyu, H., S. Shimizu, H. Sakurai und K. Ishii. „AMYLOID AND TAU PET IN DIABETES-RELATED DEMENTIA“. Innovation in Aging 1, suppl_1 (30.06.2017): 596. http://dx.doi.org/10.1093/geroni/igx004.2087.
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Golla, Sandeep S. V., Tessa Timmers, Rik Ossenkoppele, Colin Groot, Sander Verfaillie, Philip Scheltens, Wiesje M. van der Flier et al. „Quantification of Tau Load Using [18F]AV1451 PET“. Molecular Imaging and Biology 19, Nr. 6 (03.04.2017): 963–71. http://dx.doi.org/10.1007/s11307-017-1080-z.
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Watanabe, Hiroyuki, Masahiro Ono und Hideo Saji. „Novel PET/SPECT Probes for Imaging of Tau in Alzheimer’s Disease“. Scientific World Journal 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/124192.
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As the world’s population ages, the number of patients with Alzheimer’s disease (AD) is predicted to increase rapidly. The presence of neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau protein, is one of the neuropathological hallmarks of AD brain. Since the presence of NFTs is well correlated with neurodegeneration and cognitive decline in AD, imaging of tau using positron emission tomography (PET) and single-photon emission computed tomography (SPECT) is useful for presymptomatic diagnosis and monitoring of the progression of AD. Therefore, novel PET/SPECT probes for the imaging of tau have been developed. More recently, several probes were tested clinically and evaluated for their utility. This paper reviews the current state of research on the development and evaluation of PET/SPECT probes for the imaging of tau in AD brain.
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Graff-Radford, Jonathan, Eider M. Arenaza-Urquijo, David S. Knopman, Christopher G. Schwarz, Robert D. Brown, Alejandro A. Rabinstein, Jeffrey L. Gunter et al. „White matter hyperintensities: relationship to amyloid and tau burden“. Brain 142, Nr. 8 (14.06.2019): 2483–91. http://dx.doi.org/10.1093/brain/awz162.
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Abstract Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer’s disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer’s disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer’s biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.
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Blennow, Kaj, Chun Chen, Claudia Cicognola, Kristin R. Wildsmith, Paul T. Manser, Sandra M. Sanabria Bohorquez, Zhentao Zhang et al. „Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology“. Brain 143, Nr. 2 (13.12.2019): 650–60. http://dx.doi.org/10.1093/brain/awz346.
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Abstract To date, there is no validated fluid biomarker for tau pathology in Alzheimer’s disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer’s disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoa® assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer’s disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer’s disease = 37, control = 45), and finally in a third cohort where the correlation with 18F-GTP1 tau PET was evaluated (Alzheimer’s disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer’s disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and 18F-GTP1 retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer’s disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer’s disease and other tauopathies.
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McSweeney, Melissa, Alexa Pichet Binette, Pierre-François Meyer, Julie Gonneaud, Christophe Bedetti, Hazal Ozlen, Anne Labonté et al. „Intermediate flortaucipir uptake is associated with Aβ-PET and CSF tau in asymptomatic adults“. Neurology 94, Nr. 11 (03.02.2020): e1190-e1200. http://dx.doi.org/10.1212/wnl.0000000000008905.
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ObjectiveTo investigate relationships between flortaucipir (FTP) uptake, age, and established Alzheimer disease (AD) markers in asymptomatic adults at increased risk of AD.MethodsOne-hundred nineteen individuals with a family history of AD (Presymptomatic Evaluation of Experimental or Novel Treatments of Alzheimer’s Disease [PREVENT-AD] cohort, mean age 67 ± 5 years) underwent tau-PET ([18F]FTP), β-amyloid (Aβ)-PET ([18F]NAV4694 [NAV]), and cognitive assessment. Seventy-four participants also had CSF phosphorylated tau and total tau data available. We investigated the association between age and FTP in this relatively young cohort of older adults. We also investigated regional FTP standardized uptake value ratio (SUVR) differences between Aβ-positive and Aβ-negative individuals and regional correlations between FTP and NAV retention. In cortical regions showing consistent associations across analyses, we assessed whether FTP was in addition related to CSF tau and cognitive performance. Lastly, we identified the lowest FTP value at which associations with Aβ-PET, CSF, and cognition were detectable.ResultsIncreased age was associated only with amygdala and transverse temporal lobe FTP retention. Aβ-positive individuals had higher FTP SUVR values in several brain regions, further showing correlation with NAV load through the cortex. Increased FTP SUVRs in medial temporal regions were associated with increased CSF tau values and worse cognition. The SUVRs at which associations between entorhinal FTP SUVR and other AD markers were first detected differed by modality, with a detection point of 1.12 for CSF values, 1.2 for Aβ-PET, and 1.4 for cognition.ConclusionsRelatively low FTP-PET SUVRs are associated with pathologic markers of AD in the preclinical phase of the disease. Adjustment in the tau threshold should be considered, depending on the purpose of the tau classification.