Search

Background: Positron emission tomography (PET) imaging with [18F]flortaucipir allows for in‐vivo visualization of aggregated tau in Alzheimer's disease (AD). The FDA‐approved label for [18F]flortaucipir PET provides a standardized, clinically applicable definition of tau‐PET positivity by visual interpretation. Here, we studied the concordance between this visual interpretation and quantitative approaches employed in research. Method: We included 2692 participants (cognitively unimpaired [CU] and impaired [CI, MCI or AD dementia]) from four cohorts (Mayo Clinic Study of Aging and ADRC, ADNI, A4, and A05) with available [18F]flortaucipir PET (mean age: 70.2 y, 50.0% females). Three trained readers assessed each [18F]flortaucipir PET scan according to the FDA‐approved method. Visual reads were compared to an established approach for defining tau‐PET positivity based on SUVR values in a temporal meta‐ROI (Jack, et al. Alzheimers Dement. 2017). Previously defined "lenient" (SUVR = 1.22) and "conservative" (SUVR = 1.30) cut‐points were explored. In addition, visual reads were compared to tau‐PET positivity as defined by a scheme based on the expected spatial progression of tau pathology from the medial temporal lobe (MTL) to the temporal neocortex (NEO) (Ossenkoppele, et al. Nat Med. 2022; cut‐points: SUVRMTL = 1.30, SUVRNEO = 1.37). Result: Concordance between visual and quantitative approaches was limited (Figure 1): the "lenient" and MTL‐NEO methods yielded high rates of quantitative‐positive, visual‐negative scans (73‐52% and 26‐18% for CU and CI, respectively), while the "conservative" cut‐point failed to detect 45% and 13% of the CU and CI visual‐positive scans, respectively. The prevalence of tau‐PET positivity in Aβ‐negative individuals was highest with the "lenient" cut‐point (∼24%) and lowest with visual interpretation (∼3%) (Figure 2). Visual‐positive, quantitative‐negative individuals were more frequently Aβ‐positive than visual‐negative, quantitative‐positive individuals ("lenient": 86% vs 50%, p<0.001; "conservative": 87% vs 58%, p<0.001; MTL‐NEO: 85% vs 70%, p = 0.005). Among visually‐positive participants, 164 (28%) showed a tau deposition pattern that deviated from the expected MTL to NEO progression (Figure 3). Conclusion: Visual and quantitative methods for [18F]flortaucipir PET are non‐exchangeable. Tau‐PET positivity based on visual interpretation aligns better with Aβ‐pathology. A significant number of visually‐positive participants showed a pattern of tau accumulation that deviated from the expected stereotypical spatial progression and was not detected by standard quantitative methods. [ABSTRACT FROM AUTHOR]

Background: Positron emission tomography (PET) imaging with [18F]flortaucipir allows for in‐vivo visualization of aggregated tau in Alzheimer's disease (AD). The FDA‐approved label for [18F]flortaucipir PET provides a standardized, clinically applicable definition of tau‐PET positivity by visual interpretation. Here, we studied the concordance between this visual interpretation and quantitative approaches employed in research. Method: We included 2692 participants (cognitively unimpaired [CU] and impaired [CI, MCI or AD dementia]) from four cohorts (Mayo Clinic Study of Aging and ADRC, ADNI, A4, and A05) with available [18F]flortaucipir PET (mean age: 70.2 y, 50.0% females). Three trained readers assessed each [18F]flortaucipir PET scan according to the FDA‐approved method. Visual reads were compared to an established approach for defining tau‐PET positivity based on SUVR values in a temporal meta‐ROI (Jack, et al. Alzheimers Dement. 2017). Previously defined "lenient" (SUVR = 1.22) and "conservative" (SUVR = 1.30) cut‐points were explored. In addition, visual reads were compared to tau‐PET positivity as defined by a scheme based on the expected spatial progression of tau pathology from the medial temporal lobe (MTL) to the temporal neocortex (NEO) (Ossenkoppele, et al. Nat Med. 2022; cut‐points: SUVRMTL = 1.30, SUVRNEO = 1.37). Result: Concordance between visual and quantitative approaches was limited (Figure 1): the "lenient" and MTL‐NEO methods yielded high rates of quantitative‐positive, visual‐negative scans (73‐52% and 26‐18% for CU and CI, respectively), while the "conservative" cut‐point failed to detect 45% and 13% of the CU and CI visual‐positive scans, respectively. The prevalence of tau‐PET positivity in Aß‐negative individuals was highest with the "lenient" cut‐point (∼24%) and lowest with visual interpretation (∼3%) (Figure 2). Visual‐positive, quantitative‐negative individuals were more frequently Aß‐positive than visual‐negative, quantitative‐positive individuals ("lenient": 86% vs 50%, p<0.001; "conservative": 87% vs 58%, p<0.001; MTL‐NEO: 85% vs 70%, p = 0.005). Among visually‐positive participants, 164 (28%) showed a tau deposition pattern that deviated from the expected MTL to NEO progression (Figure 3). Conclusion: Visual and quantitative methods for [18F]flortaucipir PET are non‐exchangeable. Tau‐PET positivity based on visual interpretation aligns better with Aß‐pathology. A significant number of visually‐positive participants showed a pattern of tau accumulation that deviated from the expected stereotypical spatial progression and was not detected by standard quantitative methods. [ABSTRACT FROM AUTHOR]

Purpose: This study explores the relationship between age and resting-state regional cerebral blood flow (rCBF) in regions associated with higher order language skills using a population of normal children, adolescents, and young adults. Method: rCBF was measured in 33 normal participants between the ages of 7 and 19 years using single photon emission computed tomography. Participants' ages were regressed on rCBF values (normalized to whole-brain CBF) in 2 ways: (a) within anatomically defined, language-related regions of interest (ROIs) including Wernicke's area, Broca's area, angular gyrus, planum temporale, and Heschl's gyrus and (b) within clusters of voxels found to be significantly related to age in voxel-wise analyses. Results: rCBF in all anatomically defined ROIs except Heschl's gyrus declined as a function of age. Additionally, voxel-wise analyses revealed clusters where rCBF declined with age in left inferior parietal, left superior temporal, and right middle temporal regions--areas often implicated in higher order language functions. Conclusions: These data suggest that ongoing maturation (e.g., dendritic pruning) in higher order cognitive areas (e.g., angular gyrus) continues into adolescence, as reflected by declining rCBF, while the primary auditory area (Heschl's gyrus) has become a stable neuronal population by age 7 years.

Background: Tau neurofibrillary tangle burden increases with Alzheimer's disease (AD) stage and correlates with degree of cognitive impairment. Tau PET imaging could facilitate understanding the relationship between tau pathology and cognitive impairment.Objective: Evaluate the relationship between 18F flortaucipir uptake patterns and cognition across multiple cognitive domains.Methods: We acquired flortaucipir PET scans in 84 amyloid-positive control, mild cognitive impairment (MCI), and AD subjects. Flortaucipir standardized uptake value ratio (SUVr) values were obtained from a neocortical volume of interest (VOI), a precuneus VOI, and VOIs defined by the correlation between flortaucipir SUVr images and domain-specific cognitive tests. Cognitive assessments included Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and a neuropsychological test battery (i.e., Wechsler Memory Scale-Revised Logical Memory (WMS-R), Trail Making Test, Boston Naming Test, Digit Symbol Substitution Test, Animal List Generation, WMS-R Digit Span, American National Adult Reading Test, Clock Drawing Test, Judgment of Line Orientation, and WMS-R Logical Memory II (Delayed Recall)) and the Functional Activities Questionnaire (FAQ). Correlation analyses compared regional and voxel-wise VOIs to cognitive scores.Results: Subjects included 5 controls, 47 MCI, and 32 AD subjects. Significant correlations were seen between both flortaucipir and florbetapir SUVrs and MMSE, ADAS-Cog, and FAQ. Cognitive impairment was associated with increased flortaucipir uptake in regionally specific patterns consistent with the neuroanatomy underlying specific cognitive tests.Conclusion: Flortaucipir SUVr values demonstrated significant inverse correlations with cognitive scores in domain-specific patterns. Findings support the hypothesis that PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD)‐like tau pathology in the medial temporal lobe (MTL) is also commonly observed in older individuals without amyloid‐β (Aβ) pathology, a condition termed primary age‐related tauopathy (PART). Little is known about the longitudinal course of this condition and its association with the AD continuum remains controversial. We used serial PET, MRI, and CSF data to study the longitudinal pathologic course of older individuals who show PET‐measured MTL tau pathology in the absence of Aβ pathology. Method: We included older individuals with varying degrees of cognitive performance from the Alzheimer's Disease Neuroimaging Initiative, the Harvard Aging Brain Study, and AVID's A05 Study who had undergone baseline (n=1097) and follow‐up [18F]flortaucipir (FTP) (n=489, follow‐up: 1.83±0.84 years) and Aβ‐PET scanning (n=398, follow‐up: 2.36±0.76 years). Participants were separated into three groups according to Aβ and tau positivity (A‐T‐, A‐T+, A+T+), using a cut‐off of 12 centiloids for A+ and the 95th percentile of entorhinal (ERC) FTP SUVR values in healthy young controls (n=16, ≤39y) for T+. In complementary analyses we also assessed longitudinal changes in CSF biomarkers (n=99, follow‐up: 2.34±1.05 years) and cortical atrophy on MRI (n=650, follow‐up: 2.00±0.86 years). Result: 43% of A‐ individuals and 81% of A+ individuals were ERC‐tau positive. Cross‐sectionally, A‐T+ showed elevated FTP SUVR restricted to the medial/inferior temporal lobe, while A+T+ displayed a more AD‐characteristic pattern of widespread cortical FTP uptake (Fig. 1A). A‐T+ showed moderate FTP SUVR increases over time largely limited to the temporal lobe, whereas FTP SUVR increases were widespread in A+T+ (Fig. 1B). Notably, A‐T+ individuals did not increase Aβ accumulation over time (Fig. 1C). CSF analysis confirmed longitudinal tau increases in A‐T+ in the absence of increased Aβ accumulation (Fig. 1D). Compared to A‐T‐, A‐T+ individuals demonstrated accelerated MTL atrophy, whereas A+T+ showed more widespread AD‐typical cortical atrophy (Fig. 2). Conclusion: Elevated MTL tau‐PET signal is frequently observed in older individuals without notable Aβ pathology, reminiscent of pathology‐defined PART. These A‐T+ individuals exhibit a comparably slow course of progressive tau accumulation and neurodegeneration confined to the temporal lobe and do not appear to be on a pathologic trajectory towards AD. [ABSTRACT FROM AUTHOR]

The development of tau-PET allows paired helical filament tau pathology to be visualized in vivo. Increased knowledge about conditions affecting the rate of tau accumulation could guide the development of therapies halting the progression of Alzheimer's disease. However, the factors modifying the rate of tau accumulation over time in Alzheimer's disease are still largely unknown. Large-scale longitudinal cohort studies, adjusting for baseline tau load, are needed to establish such risk factors. In the present longitudinal study, 419 participants from four cohorts in the USA (Avid 05e, n = 157; Expedition-3, n = 82; ADNI, n = 123) and Sweden (BioFINDER, n = 57) were scanned repeatedly with tau-PET. The study participants were cognitively unimpaired (n = 153), or patients with mild cognitive impairment (n = 139) or Alzheimer's disease dementia (n = 127). Participants underwent two to four tau-PET (18F-flortaucipir) scans with a mean (± standard deviation) of 537 (±163) days between the first and last scan. The change in tau-PET signal was estimated in temporal meta- and neocortical regions of interest. Subject specific tau-PET slopes were predicted simultaneously by age, sex, amyloid status (determined by amyloid-β PET), APOE ε4 genotype, study cohort, diagnosis and baseline tau load. We found that accelerated increase in tau-PET signal was observed in amyloid-β-positive mild cognitive impairment (3.0 ± 5.3%) and Alzheimer's disease dementia (2.9 ± 5.7%), respectively, when compared to either amyloid-β-negative cognitively unimpaired (0.4 ± 2.7%), amyloid-β-negative mild cognitive impairment (-0.4 ± 2.3%) or amyloid-β-positive cognitively unimpaired (1.2 ± 2.8%). Tau-PET uptake was accelerated in females (temporal region of interest: t = 2.86, P = 0.005; neocortical region of interest: t = 2.90, P = 0.004), younger individuals (temporal region of interest: t = -2.49, P = 0.013), and individuals with higher baseline tau-PET signal (temporal region of interest: t = 3.83, P < 0.001; neocortical region of interest: t = 5.01, P < 0.001). Tau-PET slopes decreased with age in amyloid-β-positive subjects, but were stable by age in amyloid-β-negative subjects (age × amyloid-β status interaction: t = -2.39, P = 0.018). There were no effects of study cohort or APOE ε4 positivity. In a similar analysis on longitudinal amyloid-β-PET (in ADNI subjects only, n = 639), we found significant associations between the rate of amyloid-β accumulation and APOE ε4 positivity, older age and baseline amyloid-β positivity, but no effect of sex. In conclusion, in this longitudinal PET study comprising four cohorts, we found that the tau accumulation rate is greater in females and younger amyloid-β-positive individuals, while amyloid-β accumulation is greater in APOE ε4 carriers and older individuals. These findings are important considerations for the design of clinical trials, and might improve our understanding of factors associated with faster tau aggregation and spread. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to make a quantitative comparison of flortaucipir PET retention with pathological tau and β-amyloid across a range of brain regions at autopsy. Methods: Patients with dementia (two with clinical diagnosis of AD, one undetermined), nearing the end of life, underwent 20-min PET, beginning 80 min after an injection of ~370 mBq flortaucipir [18F]. Neocortical, basal ganglia, and limbic tissue samples were obtained bilaterally from 19 regions at autopsy and subject-specific PET regions of interest corresponding to the 19 sampled target tissue regions in each hemisphere were hand drawn on the PET images. SUVr values were calculated for each region using a cerebellar reference region. Abnormally phosphorylated tau (Ptau) and amyloid-β (Aβ) tissue concentrations were measured for each tissue region with an antibody capture assay (Histelide) using AT8 and H31L21 antibodies respectively. Results: The imaging-to-autopsy interval ranged from 4–29 days. All three subjects had intermediate to high levels of AD neuropathologic change at autopsy. Mean cortical SUVr averaged across all three subjects correlated significantly with the Ptau immunoassay (Pearson r = 0.81; p < 0.0001). When Ptau and Aβ1-42 were both included in the model, the Ptau correlation with flortaucipir SUVr was preserved but there was no correlation of Aβ1-42 with flortaucipir. There was also a modest correlation between limbic (hippocampal/entorhinal and amygdala) flortaucipir SUVr and Ptau (Pearson r = 0.52; p < 0.080). There was no significant correlation between SUVr and Ptau in basal ganglia. Conclusions: The results of this pilot study support a quantitative relationship between cortical flortaucipir SUVr values and quantitative measures of Ptau at autopsy. Additional research including more cases is needed to confirm the generalizability of these results. Trial registration, NIH Clinicaltrials.gov NCT # 02516046. Registered August 27, 2015. https://clinicaltrials.gov/ct2/show/NCT02516046?term=02516046&draw=2&rank=1 [ABSTRACT FROM AUTHOR]

Background: Tau PET tracers have proven useful for diagnostic purposes, but their prognostic utility for predicting future cognitive changes over time is unclear. We aimed to examine the prognostic accuracy of [18F]flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer’s disease (AD) spectrum. Method: We included 673 cognitively unimpaired individuals (CU, 277/673 amyloid‐β+), 443 participants with mild cognitive impairment (MCI, 279/443 amyloid‐β+) and 315 amyloid‐β+ participants with AD dementia. Amyloid‐β status was determined by PET and/or CSF. The participants underwent [18F]flortaucipir (n=1135, discovery cohort) or [18F]RO948 (n=296, replication cohort) PET, T1‐weighted MRI and repeated Mini‐Mental State Examination (MMSE). Baseline [18F]flortaucipir/[18F]RO948 PET standardized uptake value ratios (SUVR) within in a temporal region‐of‐interest (ROI)and an MRI‐based AD‐signature cortical thickness ROI were used to predict longitudinal changes of MMSE using linear mixed effect models. Additionally, we performed mediation analyses to test whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures, and examined whether age, sex and APOE genotype modified the association between baseline tau PET and cognitive change. Result: Tau PET in a temporal ROI predicted changes in MMSE, and associations were stronger than for AD‐signature cortical thickness across all participants (R2: 0.34 vs 0.24, bootstrapped p‐value for difference: <0.001), in amyloid‐β+ MCI (R2: 0.27 vs 0.13, p<0.001) and in amyloid‐β+ CU (R2: 0.14 vs 0.04, p<0.001, Figure‐1). AD signature cortical thickness only modestly mediated the association between tau PET and MMSE scores over time in amyloid‐β+ AD dementia (34.2%[95%CI: 16.8%‐59.0%] of the total effect, p<0.001) and in amyloid‐β+ MCI (11.6%[0‐25.0%], p=0.044), but not in amyloid‐β+ CU (p=0.848, Figure‐2). Age (T=‐2.24, p=0.025), but not sex (T=0.95, p=0.341) or APOE genotype (T=1.32, p=0.188), modified the association between baseline tau PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels (Figure‐3). Most results were replicated in the [18F]RO948 PET cohort. Conclusion: Tau PET is a promising tool for predicting future cognitive change and could support the prognostic process in preclinical(i.e. amyloid‐β+ CU) and prodromal (i.e. amyloid‐β+ MCI) stages of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

At autopsy, individuals with Alzheimer's disease (AD) exhibit heterogeneity in the distribution of neurofibrillary tangles in neocortical and hippocampal regions. Subtypes of AD, defined using an algorithm based on the relative number of tangle counts in these regions, have been proposed-hippocampal sparing (relative sparing of the hippocampus but high cortical load), limbic predominant (high hippocampal load but lower load in association cortices), and typical (balanced neurofibrillary tangles counts in the hippocampus and association cortices) AD-and shown to be associated with distinct antemortem clinical phenotypes. The ability to distinguish these AD subtypes from the more typical tau signature in vivo could have important implications for clinical research. Flortaucipir positron emission tomography (PET) images acquired from 45 amyloid-positive participants, defined clinically as mild cognitive impairment or AD, aged 50-92 years, 56% female, and estimated to be Braak V-VI based on their PET pattern of tau pathology, were studied. By translating the neuropathologic algorithm to flortaucipir PET scans, patterns of tau pathology consistent with autopsy findings, and with a similar prevalence, were identified in vivo. 6/45 (13%) participants were identified as hippocampal sparing and 6/45 (13%) as limbic predominant AD subtypes. Hippocampal sparing participants were significantly younger than those assigned to the other two subtypes. Worse performance on delayed recall was associated with increased hippocampal tau signal, and worse performance on the trail making test B-A was associated with lower values of the hippocampus to cortex ratio. Prospective studies can further validate the flortaucipir SUVR cut-points and the phenotype of the corresponding AD subtypes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Tau pathology is a key hallmark of Alzheimer's disease (AD), but factors modifying the rate of tau accumulation are still largely unknown. Tau‐PET allows tau pathology to be visualized in vivo in AD. Our aim was to study factors associated with the accumulation rate of tau pathology, using [18F]flortaucipir PET. Method: 419 participants from four longitudinal cohorts in the United States (AVID05, n=157; Expedition 3, n=82; and ADNI, n=123) and Sweden (n=57) were scanned between June 2014 and May 2019. Study participants were cognitively unimpaired (CU, n=153), or patients with mild cognitive impairment (MCI, n=139) or AD with dementia (AD, n=127).Participants underwent two to four [18F]‐flortaucipir PET scans with a mean of 538 (±163[SD]) days between the first and last scan. Amyloid‐β(Aβ) status was determined using PET. [18F]‐flortaucipir was quantified in a temporal meta‐region of interest (ROI) and a neocortical ROI. Subject‐specific slopes (reflecting annual change) of [18F]‐flortaucipir SUVR were derived from linear regression models for each ROI. Generalized linear models were used to predict the subject‐specific slopes using the following variables: diagnostic group, age, sex, baseline tau‐PET SUVR, baseline Aβ‐status, APOE‐ε4 status and study cohort. Result: Accelerated increase in [18F]‐flortaucipir retention was observed in Aβ+ MCI and AD dementia, respectively, when compared to either Aβ‐ CU and Aβ‐ MCI (Figure 1). We found associations between change in [18F]‐flortaucipir over time and female sex (temporal meta‐ROI: t=2.93, p=0.004; neocortical ROI: t=2.96, p=0.003), younger age (temporal‐meta ROI: t=‐2.42, p=0.02), and baseline [18F]‐flortaucipir retention (temporal‐meta ROI: t=3.60, p<0.001; neocortical ROI: t=4.88, p<0.001) (Figure 2). There was a significant interaction between age and Aβ‐status on change in [18F]‐flortaucipir SUVR (temporal‐meta ROI: t=‐2.50, p=0.013). There was no effect of study cohort or APOE‐ε4 genotype. In a similar analysis on longitudinal Aβ‐PET (in ADNI subjects only, n=639) we found significant associations between the rate of Aβ‐accumulation and APOE‐ε4 positivity, older age and baseline Aβ‐positivity, but no effect of sex. Conclusion: These findings indicate that the tau accumulation rate is increased in females and Aβ‐positive younger individuals, in contrast to Aβ‐accumulation which is increased in APOE‐ε4 carriers and older individuals. [ABSTRACT FROM AUTHOR]

Background: The advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in‐vivo visualization of aggregated tau in Alzheimer's disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD‐associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD. Method: We included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID's A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow‐up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual's FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories. Result: A total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β‐amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups. Conclusion: Our large‐scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials. [ABSTRACT FROM AUTHOR]

Background: The introduction of tau positron emission tomography (PET) ligands has allowed for the in vivo assessment of tau pathology in Alzheimer's disease (AD). The recent development and FDA approval of [18F]flortaucipir (FTP) reader guidelines has enabled standardized visual assessment of FTP PET scans as showing negative, moderate or advanced AD tau patterns, thereby facilitating implementation of FTP scans in clinical practice. Although various studies have reported associations between regional FTP signal and neurodegeneration, the relationship between the standardized visual FTP AD patterns and markers of neurodegeneration has not yet been studied. This study aims to understand how FTP AD visual patterns relate to markers of neurodegeneration from structural MRI and FDG‐PET scans. Specifically, it focusses on characterizing regional neurodegeneration associated with the moderate AD pattern, both in cognitively normal (CN) and cognitively impaired participants (CI). Method: Participants from five cohorts were included: the Alzheimer's Disease Neuroimaging Initiative, Harvard Aging Brain Study, A4 study, the Geneva Memory Clinic cohort and AVID's A05 study. These cohorts include CN participants, mild cognitively impaired and AD dementia patients who have available FTP, MRI and/or FDG scans, a subset also received follow‐up MRI scans. Furthermore, Centiloid values are available for all participants to quantitatively determine amyloid‐β (Aβ) positivity. All FTP scans are currently independently evaluated by three trained readers, blinded to clinical and imaging information. Majority read is used to assign scans to the negative, moderate or advanced AD tau pattern groups. Result: A total of 1948 participants underwent baseline FTP PET and MRI scans, a subset of 462 participants also underwent FDG‐PET scans. Between‐group differences in MRI‐ and FDG‐derived patterns of neurodegeneration are evaluated cross‐sectionally. In addition, the value of FTP AD patterns for predicting longitudinal neurodegeneration using MRI‐derived atrophy measures is assessed using Linear Mixed Models. All analyses are conducted separately for CN and CI participants, as well as stratified by Aβ (positive vs. negative) status. NB. Results of these analyses will be presented during the conference. Conclusion: This study will contribute to our understanding of the clinical relevance and prognostic value of the moderate and advanced FTP AD patterns in CN and CI individuals. [ABSTRACT FROM AUTHOR]