Background Nurse care managers (NCM) operate through care management programs to provide care for persons living with dementia (PLWD) and interact regularly with their family caregivers; however, most do not receive formal instruction in dementia care or caregiver support. CRESCENT (CaReEcoSystem primary Care Embedded demeNtia Treatment) is a telephone-based dementia care intervention adapted from the Care EcoSystem model designed to equip NCMs with these tools. For this study, we aimed to measure intervention fidelity and understand how dementia care training impacted NCMs’ provision of dementia care management services during interactions with caregivers of PLWD. Methods We recruited 30 active NCMs; 15 were randomly assigned to receive training. For each nurse, we randomly selected 1–3 patients with a diagnosis of dementia in each nurse’s care during January-June 2021 for a total of 54 medical charts. To assess training uptake and fidelity, we identified documentation by NCMs of CRESCENT protocol implementation in the medical records. To understand how the training impacted the amount and types of dementia care management services provided in interactions with family caregivers, we compared attention to key dementia topic areas between trained NCMs (intervention) and untrained NCMs (control). Results Within the trained group only, community resources for PLWD, followed by safety, medication reconciliation, and advanced care planning topic areas were addressed most frequently (> 30%), while behavior management was addressed least frequently (12%). Trained NCMs were more likely to document addressing aspects of caregiver wellbeing ( p = 0.03), community resources ( p = 0.002), and identification of behavior ( p = 0.03) and safety issues ( p = 0.02) compared to those without training. There was no difference between groups in the amount of care coordination provided ( p = 0.64). Conclusion Results from this study demonstrate that focused dementia care training enriches care conversations in important topic areas for PLWD and family caregivers. Future research will clarify how best to sustain and optimize high quality dementia care in care management programs with special attention to the NCM-family caregiver relationship. Trial number NCT04556097.

In Alzheimer’s disease (AD), cognitive symptoms have varying associations with tau, amyloid and neurodegeneration. Patients with early‐onset AD (EOAD, age<65) have more non‐amnestic symptoms, greater AD pathological burden, and less co‐pathologies than late‐onset AD (LOAD, age≥65). It is unknown whether the association between cognitive symptoms and Alzheimer’s disease biomarkers differs with age, and this has implications for clinical trials. The goal of this study was (1) to evaluate the association between domain‐specific cognitive performance and PET‐based pathology in AD, and (2) to compare whether theses associations differ in EOAD versus LOAD.

Tanner et al. evaluate the correlation between cognition and PET biomarkers in early- versus late-onset Alzheimer's disease. Tau and neurodegeneration were similarly associated with cognition in both age groups, supporting tau PET as a biomarker that captures clinical severity and molecular pathology across ages. Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 +/- 4, MMSE 21 +/- 6, 58% female) and late-onset (n = 53, mean age 74 +/- 6, MMSE 23 +/- 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, C-11-Pittsburgh compound B PET (amyloid-PET) and F-18-flortaucipir PET (tau-PET). F-18-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET x Age group interaction. Mediation analyses estimated direct and indirect (F-18-fluorodeoxyglucose mediated) local associations between F-18-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher F-18-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe F-18-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater C-11-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.F-18-flortaucipir and F-18-fluorodeoxyglucose, but not C-11-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). F-18-fluorodeoxyglucose mediated the relationship between F-18-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of F-18-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer's disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer's disease across the broad spectrum of ages and clinical phenotypes in Alzheimer's disease.

To compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer’s Disease (AD) Research Framework derived from [18F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181). We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/mL). FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181. The choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.

We assessed sex differences in amyloid- and tau-PET retention in 119 amyloid positive patients with mild cognitive impairment or Alzheimer's disease (AD) dementia. Patients underwent 3T-MRI, 11C-PIB amyloid-PET and 18F-Flortaucipir tau-PET. Linear ordinary least squares regression models tested sex differences in Flortaucipir-PET SUVR in a summary temporal region of interest as well as global PIB-PET. No sex differences were observed in demographics, Clinical Dementia Rating Sum of Boxes (CDR-SoB), Mini-Mental State Exam (MMSE), raw episodic memory scores, or cortical thickness. Females had higher global PIB SUVR (ηp²=.043, p=.025) and temporal Flortaucipir SUVR (ηp²=.070, p=.004), adjusting for age and CDR-SoB. Sex differences in temporal Flortaucipir-PET remained significant when controlling additionally for PIB SUVR and APOE4 status (ηp²=.055, p=.013), or when using partial volume-corrected data. No sex differences were present in areas of known Flortaucipir off-target binding. Overall, females demonstrated greater AD regional tau-PET burden than males despite clinical comparability. Further characterization of sex differences will provide insight into AD pathogenesis and support development of personalized therapeutic strategies.

We used 18 F-FDG-PET to investigate the frequency of crossed cerebellar diaschisis (CCD) in 197 patients with various syndromes associated with neurodegenerative diseases. In a subset of 117 patients, we studied relationships between CCD and cortical asymmetry of Alzheimer’s pathology (β-amyloid ( 11 C-PIB) and tau ( 18 F-Flortaucipir)). PET images were processed using MRIs to derive parametric SUVR images and define regions of interest. Indices of asymmetry were calculated in the cerebral cortex, basal ganglia and cerebellar cortex. Across all patients, cerebellar 18 F-FDG asymmetry was associated with reverse asymmetry of 18 F-FDG in the cerebral cortex (especially frontal and parietal areas) and basal ganglia. Based on our operational definition (cerebellar asymmetry >3% with contralateral supratentorial hypometabolism), significant CCD was present in 47/197 (24%) patients and was most frequent in corticobasal syndrome and semantic and logopenic variants of primary progressive aphasia. In β-amyloid-positive patients, mediation analyses showed that 18 F-Flortaucipir cortical asymmetry was associated with cerebellar 18 F-FDG asymmetry, but that cortical 18 F-FDG asymmetry mediated this relationship. Analysis of 18 F-FDG-SUVR values suggested that CCD might also occur in the absence of frank cerebellar 18 F-FDG asymmetry due to symmetrical supratentorial degeneration resulting in a bilateral diaschisis process.

Objective To assess whether Alzheimer disease (AD) clinical presentation and APOE4 relate to the burden and topography of β-amyloid (Aβ) and tau pathologies using in vivo PET imaging. Methods We studied 119 Aβ-positive symptomatic patients aged 48–95 years, including 29 patients with logopenic variant primary progressive aphasia (lvPPA) and 21 with posterior cortical atrophy (PCA). Pittsburgh compound B (PiB)–Aβ and flortaucipir (tau)–PET standardized uptake value ratio (SUVR) images were created. General linear models assessed relationships between demographic/clinical variables (phenotype, age), APOE4, and PET (including global cortical and voxelwise SUVR values) while controlling for disease severity using the Clinical Dementia Rating Sum of Boxes. Results PiB-PET binding showed a widespread cortical distribution with subtle differences across phenotypes and was unrelated to demographic/clinical variables or APOE4. Flortaucipir-PET was commonly elevated in temporoparietal regions, but showed marked phenotype-associated differences, with higher binding observed in occipito-parietal areas for PCA, in left temporal and inferior frontal for lvPPA, and in medial temporal areas for other AD. Cortical flortaucipir-PET binding was higher in younger patients across phenotypes (r = −0.63, 95% confidence interval [CI] −0.72, −0.50), especially in parietal and dorsal prefrontal cortices. The presence of APOE4 was associated with a focal medial temporal flortaucipir-SUVR increase, controlling for all other variables (entorhinal: + 0.310 SUVR, 95% CI 0.091, 0.530). Conclusions Clinical phenotypes are associated with differential patterns of tau but not amyloid pathology. Older age and APOE4 are not only risk factors for AD but also seem to affect disease expression by promoting a more medial temporal lobe–predominant pattern of tau pathology.

Monday, April 27April 14, 2020Free Access [18F]Flortaucipir PET to Autopsy Pathology Correlation in Alzheimer’s Disease and Other Neurodegenerative Diseases (2630)David Soleimani-Meigooni, Leonardo Iaccarino, Renaud La Joie, Suzanne Baker, Viktoriya Bourakova, Adam Boxer, Lauren Edwards, … Show All … , Rana Eser, Maria Gorno-Tempini, William Jagust, Mustafa Janabi, Joel Kramer, Orit Lesman-Segev, Taylor Mellinger, Bruce Miller, Julie Pham, Howard Rosen, Salvatore Spina, Amelia Strom, William Seeley, Lea Grinberg, and Gil Rabinovici Show FewerAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.2630 Letters to the Editor

Few studies have evaluated the relationship between in vivo F-18-flortaucipir PET and post-mortem pathology. We sought to compare antemortem F-18-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 F-18-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 F-18-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. F-18-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 F-18-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 F-18-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.

We used F-18-FDG-PET to investigate the frequency of crossed cerebellar diaschisis (CCD) in 197 patients with various syndromes associated with neurodegenerative diseases. In a subset of 117 patients, we studied relationships between CCD and cortical asymmetry of Alzheimer's pathology (beta-amyloid (C-11-PIB) and tau (F-18-Flortaucipir)). PET images were processed using MRIs to derive parametric SUVR images and define regions of interest. Indices of asymmetry were calculated in the cerebral cortex, basal ganglia and cerebellar cortex. Across all patients, cerebellar F-18-FDG asymmetry was associated with reverse asymmetry of F-18-FDG in the cerebral cortex (especially frontal and parietal areas) and basal ganglia. Based on our operational definition (cerebellar asymmetry >3% with contralateral supratentorial hypometabolism), significant CCD was present in 47/197 (24%) patients and was most frequent in corticobasal syndrome and semantic and logopenic variants of primary progressive aphasia. In beta-amyloid-positive patients, mediation analyses showed that F-18-Flortaucipir cortical asymmetry was associated with cerebellar F-18-FDG asymmetry, but that cortical F-18-FDG asymmetry mediated this relationship. Analysis of F-18-FDG-SUVR values suggested that CCD might also occur in the absence of frank cerebellar F-18-FDG asymmetry due to symmetrical supratentorial degeneration resulting in a bilateral diaschisis process.

AbstractBackgroundTau‐PET is included in the AT(N) research framework to define T‐status. However, no consensus exists as to how to classify patients as T+ or T‐ with this modality. We aim to compare T‐status derived from 18F‐Flortaucipir (FTP) PET visual assessment, 18F‐FTP SUVR quantification, and CSF pTau.Methods278 subjects who underwent 18F‐FTP PET and CSF analysis within 1 year were included from UCSF and ADNI. The cohort consisted of a continuum from cognitively normal controls (CN) to Alzheimer’s disease dementia (AD), and non‐Alzheimer’s disorders (clinical diagnoses, Table 1). T‐status was derived from: (1) 18F‐FTP consensus between two readers performing blinded visual assessment based on a priori criteria (Figure 1, inter‐rater k=0.68, 95%CI 0.59‐0.76; Provost et al, HAI Conference, 2020); (2) 18F‐FTP SUVR quantification of from a temporal meta‐ROI using a previously validated threshold (SUVR >1.27, Ossenkoppele et al. 2018); (3) Elecsys® Phospho‐Tau (181P) CSF (Roche Diagnostics) applying a ROC‐based threshold derived from an external ADNI cohort comparing amyloid‐positive AD vs. healthy controls (pTau >24.5 pg/mL).ResultsT+ was assigned in a higher proportion of AD, MCI and amyloid‐positive CN with 18F‐FTP visual assessment compared to 18F‐FTP SUVR and CSF pTau (Table 2). However, visual ratings also yielded the highest proportion of T+ in amyloid‐negative CN and MCI. Contrasting amyloid‐positive AD/MCI with other groups, sensitivity was highest for 18F‐FTP visual assessment, while specificity was highest for 18F‐FTP SUVR (Table 3). In a subset of patients with autopsy (n=11), T‐status derived from 18F‐FTP visual assessment had an accuracy of 100%, compared to 82% for SUVR quantification and 64% for CSF pTau. Overall agreement between the 3 classification criteria ranged from 68% to 76% in the whole cohort (Figure 2) and was highest in patients with AD (94%). Patients with concordant T‐status across all three modalities were significantly younger, had higher CSF pTau, higher 18F‐FTP SUVR (Figure 3), and were more likely to be amyloid positive.ConclusionsConcordance of T‐status derived from 18F‐FTP visual assessment, SUVR quantification and CSF pTau varies across disease stage, being highest in AD. 18F‐FTP visual assessment offers highest sensitivity, while SUVR threshold maximizes specificity.

A deeper understanding of the spatial relationships of β-amyloid (Aβ), tau, and neurodegeneration in Alzheimer's disease (AD) could provide insight into pathogenesis and clinical trial design. We included 81 amyloid-positive patients (age 64.4 ± 9.5) diagnosed with AD dementia or mild cognitive impairment due to AD and available 11C-PiB (PIB), 18F-Flortaucipir (FTP),18F-FDG-PET, and 3T-MRI, and 31 amyloid-positive, cognitively normal participants (age 77.3 ± 6.5, no FDG-PET). W-score voxel-wise deviation maps were created and binarized for each imaging-modality (W > 1.64, P < 0.05) adjusting for age, sex, and total intracranial volume (sMRI-only) using amyloid-negative cognitively normal adults. For symptomatic patients, FDG-PET and atrophy W-maps were combined into neurodegeneration maps (ND). Aβ-pathology showed the greatest proportion of cortical gray matter suprathreshold voxels (spatial extent) for both symptomatic and asymptomatic participants (median 94-55%, respectively), followed by tau (79-11%) and neurodegeneration (41-3%). Amyloid > tau > neurodegeneration was the most frequent hierarchy for both groups (79-77%, respectively), followed by tau > amyloid > neurodegeneration (13-10%) and amyloid > neurodegeneration > tau (6-13%). For symptomatic participants, most abnormal voxels were PIB+/FTP+/ND- (median 35%), and the great majority of ND+ voxels (91%) colocalized with molecular pathology. Amyloid spatially exceeded tau and neurodegeneration, with individual heterogeneities. Molecular pathology and neurodegeneration showed a progressive overlap along AD course, indicating shared vulnerabilities or synergistic toxic mechanisms.

Importance Biomarkers for chronic traumatic encephalopathy (CTE) are currently lacking. The radiotracer fluorine F 18-labeled (F-18)-flortaucipir (FTP) detects tau pathology in Alzheimer disease, and positron emission tomography (PET) with FTP shows elevated binding in individuals at risk for CTE. No study, however, has assessed the correlation between in vivo FTP PET and postmortem tau in CTE. Objective To assess the regional association between in vivo FTP binding and postmortem tau pathology in a patient with pathologically confirmed CTE. Design, Setting, and Participants A white male former National Football League player with 17 years of US football exposure was clinically diagnosed with traumatic encephalopathy syndrome at a neurology tertiary referral center. F-18-Fludeoxyglucose, carbon 11-labeled Pittsburgh compound B, and FTP PET were performed 52 months prior to death, and magnetic resonance imaging, 50 months prior to death. Brain images were assessed qualitatively for abnormalities blinded to autopsy data. Autopsy was performed using a neurodegenerative research protocol. The FTP standardized uptake value ratios (inferior cerebellar gray reference region) and W-score (age-adjusted z-score) maps were compared with phosphorylated tau immunohistochemical analysis with monoclonal antibody CP13. Main Outcomes and Measures Qualitative and quantitative comparisons between antemortem FTP PET and tau pathology at autopsy. Results Flortaucipir uptake was distributed in a patchy, frontotemporal-predominant pattern that overlapped with regions showing neurodegeneration on magnetic resonance imaging and hypometabolism on F-18-fludeoxyglucose PET. Pathological assessment revealed stage 4 CTE; limbic argyrophilic grain disease; stage 2 limbic-predominant, age-related transactive response DNA-binding protein 43 encephalopathy; and Braak neurofibrillary tangle stage 3. F-18-Flortaucipir W-maps matched areas of high postmortem tau burden in left fusiform and inferior temporal gyri and juxtacortical frontal white matter. High FTP W-scores with low tau burden were found in the basal ganglia, thalamus, motor cortex, and calcarine cortex. No regions with low FTP W-scores corresponded to areas with high pathological tau burden. A modest correlation, which did not reach statistical significance (rho = 0.35, P = .17), was found between FTP standardized uptake value ratio and tau area fraction at the regional level. Conclusions and Relevance In this patient, FTP PET findings during life showed a modest correspondence with postmortem pathology in CTE. These findings suggest that FTP may have limited utility as a tau biomarker in CTE. Question Does in vivo binding of the tau positron emission tomography radioligand fluorine F 18-labeled (F-18)-flortaucipir correspond to tau pathology in chronic traumatic encephalopathy? Findings In a patient with pathologically confirmed chronic traumatic encephalopathy, F-18-flortaucipir positron emission tomography performed 52 months prior to death showed a patchy, frontotemporal pattern corresponding qualitatively to regions with tau pathology found at autopsy. There was a modest correlation between regional F-18-flortaucipir standardized uptake value ratios and tau immunohistochemistry area fraction that did not reach statistical significance. Meaning Findings in this case suggest that F-18-flortaucipir may have limited utility as a biomarker of tau pathology in chronic traumatic encephalopathy. This case report compares in vivo F-18-flortaucipir at positron emission tomography with regions of tau pathology found at postmortem analysis in a former US football player with pathologically confirmed chronic traumatic encephalopathy.

Individuals with early-onset Alzheimer's disease (EOAD, age-of-onset < 65 years old) are likely to experience unique challenges with financial, legal, and social decision-making following their diagnosis. Yet, there are limited data characterizing the types of decisions patients and families make after a diagnosis or potential barriers to decision-making. Semi-structured interviews with caregivers (n=13) of patients with EOAD enrolled in a longitudinal observational study. Interview guides assessed financial, legal, and social decision-making within 30 days following the patient's EOAD diagnosis. Data analysis implemented data immersion, theme identification, indexing, charting and interpretation. Of the 13 caregivers interviewed, 11 were spouses and 2 were siblings of EOAD patients (See Table 1. Demographics). Caregivers described experiences with patients in seeking a diagnosis, including multiple visits to different physicians and misdiagnosis. Caregivers who were shown the patient's amyloid and/or tau PET scans as part of the larger longitudinal study (7/13) reported that these images helped them better understand and accept the diagnosis. Participants reported that the EOAD symptoms or the diagnosis interfered with the patient's continued employment (10/13), affected financial decision-making (12/13), and led to a shift in the role of primary decision maker within the family (8/13). Referencing the financial consequences of his wife's early retirement due to EOAD, one participant reports: “Everything was going to be paid off. We were going to have a good income coming in. [. . .] And it just kind of blew up when she got Alzheimer's.” Seven participants described changes in housing, including decisions to sell homes or move closer to family. Additionally, caregivers (6/12) reported challenges in accessing resources that would help prepare for future long-term care needs due to EOAD, including difficulties in accessing disability pay. While caregivers endorsed an understanding that long-term care services may be necessary in the future, only five had initiated plans.

OBJECTIVE:To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy.METHODS:Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B [PiB]+ , age = 77.6 ± 4.6 years, 25 female [F]/17 male [M]) and 19 PiB+ patients with AD (age = 63.1 ± 10.3 years, 12 F/7 M) over 1 to 3 years of follow-up. FTP change, structural MRI measures of atrophy, and cross-modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated.RESULTS:Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow-up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status.INTERPRETATION:Our findings indicate that tau accumulates even in amyloid-negative healthy OA and this process can be measured with in vivo tau-PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy. Ann Neurol 2019; 1-12 ANN NEUROL 2019;85:229-240.

Alzheimer's disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-β plaques and tau neurofibrillary tangles. Post-mortem studies indicate that in ageing and Alzheimer's disease tau tangles deposit early in the transentorhinal cortex, a region located in the anterior-temporal lobe that is critical for object memory. In contrast, amyloid-β pathology seems to target a posterior-medial network that subserves spatial memory. In the current study, we tested whether anterior-temporal and posterior-medial brain regions are selectively vulnerable to tau and amyloid-β deposition in the progression from ageing to Alzheimer's disease and whether this is reflected in domain-specific behavioural deficits and neural dysfunction. 11C-PiB PET and 18F-flortaucipir uptake was quantified in a sample of 131 cognitively normal adults (age: 20-93 years; 47 amyloid-β-positive) and 20 amyloid-β-positive patients with mild cognitive impairment or Alzheimer's disease dementia (65-95 years). Tau burden was relatively higher in anterior-temporal regions in normal ageing and this difference was further pronounced in the presence of amyloid-β and cognitive impairment, indicating exacerbation of ageing-related processes in Alzheimer's disease. In contrast, amyloid-β deposition dominated in posterior-medial regions. A subsample of 50 cognitively normal older (26 amyloid-β-positive) and 25 young adults performed an object and scene memory task while functional MRI data were acquired. Group comparisons showed that tau-positive (n = 18) compared to tau-negative (n = 32) older adults showed lower mnemonic discrimination of object relative to scene images [t(48) = -3.2, P = 0.002]. In a multiple regression model including regional measures of both pathologies, higher anterior-temporal flortaucipir (tau) was related to relatively worse object performance (P = 0.010, r = -0.376), whereas higher posterior-medial PiB (amyloid-β) was related to worse scene performance (P = 0.037, r = 0.309). The functional MRI data revealed that tau burden (but not amyloid-β) was associated with increased task activation in both systems and a loss of functional specificity, or dedifferentiation, in posterior-medial regions. The loss of functional specificity was related to worse memory. Our study shows a regional dissociation of Alzheimer's disease pathologies to distinct memory networks. While our data are cross-sectional, they indicate that with ageing, tau deposits mainly in the anterior-temporal system, which results in deficits in mnemonic object discrimination. As Alzheimer's disease develops, amyloid-β deposits preferentially in posterior-medial regions additionally compromising scene discrimination and anterior-temporal tau deposition worsens further. Finally, our findings propose that the progression of tau pathology is linked to aberrant activation and dedifferentiation of specialized memory networks that is detrimental to memory function.