Plasma phosphorylated tau (p-tau) has emerged as a promising biomarker for Alzheimer's disease (AD). Studies have reported strong associations between p-tau and tau-PET that are mainly driven by ...differences between amyloid-positive and amyloid-negative patients. However, the relationship between p-tau and tau-PET is less characterized within cognitively impaired patients with a biomarker-supported diagnosis of AD. We conducted a head-to-head comparison between plasma p-tau217 and tau-PET in patients at the clinical stage of AD and further assessed their relationships with demographic, clinical, and biomarker variables.
We retrospectively included 87 amyloid-positive patients diagnosed with MCI or dementia due to AD who underwent structural MRI, amyloid-PET (
C-PIB), tau-PET (
F-flortaucipir, FTP), and blood draw assessments within 1 year (age = 66 ± 10, 48% female). Amyloid-PET was quantified in Centiloids (CL) while cortical tau-PET binding was measured using standardized uptake value ratios (SUVRs) referenced against inferior cerebellar cortex. Plasma p-tau217 concentrations were measured using an electrochemiluminescence-based assay on the Meso Scale Discovery platform. MRI-derived cortical volume was quantified with FreeSurfer. Mini-Mental State Examination (MMSE) scores were available at baseline (n = 85) and follow-up visits (n = 28; 1.5 ± 0.7 years).
Plasma p-tau217 and cortical FTP-SUVR were correlated (r = 0.61, p < .001), especially in temporo-parietal and dorsolateral frontal cortices. Both higher p-tau217 and FTP-SUVR values were associated with younger age, female sex, and lower cortical volume, but not with APOE-ε4 carriership. PIB-PET Centiloids were weakly correlated with FTP-SUVR (r = 0.26, p = 0.02), but not with p-tau217 (r = 0.10, p = 0.36). Regional PET-plasma associations varied with amyloid burden, with p-tau217 being more strongly associated with tau-PET in temporal cortex among patients with moderate amyloid-PET burden, and with tau-PET in primary cortices among patients with high amyloid-PET burden. Higher p-tau217 and FTP-SUVR values were independently associated with lower MMSE scores cross-sectionally, while only baseline FTP-SUVR predicted longitudinal MMSE decline when both biomarkers were included in the same model.
Plasma p-tau217 and tau-PET are strongly correlated in amyloid-PET-positive patients with MCI or dementia due to AD, and they exhibited comparable patterns of associations with demographic variables and with markers of downstream neurodegeneration.
Traumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES ...overlap with Alzheimer's disease (AD), and features of AD pathology like beta-amyloid (Aβ) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer's neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls.
We studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aβ +), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aβ +), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aβ +). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aβ + or Aβ - and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen's d > 0.50) were interpreted as potentially meaningful.
Cognitively, within the TES group, Aβ + RHI/TES performed worse than Aβ- RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing voxel-wise brain volume, both Aβ + and Aβ - RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aβ + RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and did not significantly differ from AD. Conversely, Aβ - RHI/TES had higher NfL than HC (p = .004, d = 0.93) and higher IL-6 than all other groups (p's ≤ .004, d's > 1.0).
Presence of Alzheimer's pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aβ-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aβ - RHI/TES. Measuring well-validated Alzheimer's biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.
Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in ...patients with TES during life necessitates autopsy-based determination of the neuropathological profile. We report a clinicopathological series of nine patients with previous repetitive head impacts (RHI) classified retrospectively using the recent TES research framework (100% male and white/Caucasian, age at death 49-84) who completed antemortem neuropsychological evaluations, T1-weighted magnetic resonance imaging, diffusion tensor imaging (
= 6), (18)F-fluorodeoxyglucose-positron emission tomography (
= 5), and plasma measurement of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (
= 8). Autopsies were performed on all patients. Cognitively, low test scores and longitudinal decline were relatively consistent for memory and executive function. Medial temporal lobe atrophy was observed in all nine patients. Poor white matter integrity was consistently found in the fornix. Glucose hypometabolism was most common in the medial temporal lobe and thalamus. Most patients had elevated plasma GFAP, NfL, and total tau at their initial visit and a subset showed longitudinally increasing concentrations. Neuropathologically, five of the nine patients had CTE pathology (
= 4 "High CTE"/McKee Stage III-IV,
= 1 "Low CTE"/McKee Stage I). Primary neuropathological diagnoses (i.e., the disease considered most responsible for observed symptoms) were frontotemporal lobar degeneration (
= 2 FTLD-TDP,
= 1 FTLD-tau), Alzheimer disease (
= 3), CTE (
= 2), and primary age-related tauopathy (
= 1). In addition, hippocampal sclerosis was a common neuropathological comorbidity (
= 5) and associated with limbic-predominant TDP-43 proteinopathy (
= 4) or FTLD-TDP (
= 1). Memory and executive function decline, limbic system brain changes (atrophy, decreased white matter integrity, hypometabolism), and plasma biomarker alterations are common in RHI and TES but may reflect multiple neuropathologies. In particular, the neuropathological differential for patients with RHI or TES presenting with medial temporal atrophy and memory loss should include limbic TDP-43. Researchers and clinicians should be cautious in attributing cognitive, neuroimaging, or other biomarker changes solely to CTE tau pathology based on previous RHI or a TES diagnosis alone.
Background
The majority of individuals with unambiguously positive tau biomarkers (T++) have positive amyloid biomarkers. Here we describe cases with clinical features associated with an unusual ...biomarker profile: very high tau PET binding and negative amyloid PET (A‐T++).
Method
We searched the Longitudinal Early‐Onset Alzheimer’s Disease (AD) Study, University of California San Francisco AD Research Center and the AD Neuroimaging Initiative cohorts on 09/01/2021 for participants with completed amyloid PET (Florbetapir, Florbetaben, Pittsburgh Compound B) and Tau PET (Flortaucipir (FTP)) scans and identified 1420 participants (mean age 69, 49.7% male). Using a pathology‐based, neocortical centiloid threshold of 24.4 (amyloid positivity) and a pre‐defined region of interest (Temporal MetaROI) standardized uptake value ratio (SUVR) > 1.27 threshold (tau positivity), we identified 64 amyloid negative, tau positive cases. An additional MetaROI FTP‐SUVR threshold > 2.0 (based on visual plot of data) was then applied to identify 7 A‐T++ cases (Figure 1).
Result
Among A‐T++ individuals mean age was 66.2 (range 53.8 ‐ 77.1), 4/7 were female, mean years of education was 15 (range 12 ‐ 20), mean MMSE was 20 (range 14‐29), 3/7 were APOE e3/e4 and clinical phenotypes included amnestic and atypical AD phenotypes (Table 1).
Mean neocortical centiloid value was 11.4 (range: ‐1.39 ‐ 17.11) among A‐T++ cases and 4/7 had centiloid values between 12.2 ‐ 24.4 (may be indicative of early positivity). Mean FTP SUVR was 2.28 (range 2.03 ‐ 2.63) (Table 2). All A‐T++ cases demonstrated FTP tracer binding within the middle temporal cortex, medial temporal structures, and posterior cingulate regions (Figure 2). Neuropathological data from 1 case (UCSF3) revealed frequent CERAD Neuritic Plaques, Thal Amyloid Plaque Phase 5, and Braak Neurofibrillary Degeneration Stage 6 (autopsy performed 1 year after amyloid PET).
Conclusion
A‐T++ individuals were heterogeneous clinically but all displayed FTP tracer binding in AD‐signature regions. Four cases had amyloid centiloid values above 12.2 (threshold to detect moderate‐to‐frequent CERAD scores) but below 24.4 (threshold to detect intermediate‐to high Alzheimer’s disease neuropathologic change (ADNC) levels). Pathological data available for 1 case revealed a high level of ADNC. False negative amyloid PET in A‐T++ individuals is an important consideration; future studies are needed.
Background
Negative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset ...AD (EOAD, <65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amyloid‐, tau‐, and FDG‐PET.
Method
We identified 380 patients who i) met clinical criteria for MCI or dementia due to AD, and ii) completed baseline amyloid‐PET (Florbetaben) and tau‐PET (Flortaucipir). Of these patients, 93 (24.5%) were amyloid‐PET negative based on a combination of visual read and quantification (“EOnonAD”). A subset of EononAD participants completed FDG‐PET (n = 63), 5 had follow‐up amyloid‐PET and 2 had follow‐up tau‐PET. 63 age‐matched cognitively normal controls were also included. Image acquisition and processing followed ADNI protocols.
Result
Compared to amyloid‐positive patients (EOAD), EononAD patients were less frequently female or APOE4 carriers, and less severely impaired (Figure 1). EononAD patients had a mean Centiloid of 5.6 (Figure 2A). At the group level, temporal Flortaucipir‐SUVR was low (1.20.3, not significantly different from controls), although 3 cases had Flortaucipir‐SUVR>2 (Figure 2A). Visual inspection showed these cases had asymmetric AD‐like Flortaucipir‐PET patterns (Figure 2B). Within patients with EononAD, amyloid‐ and tau‐PET were correlated (Spearman’s ρ = 0.29, p = 0.005), even when excluding the 3 high Flortaucipir‐SUVR outliers (Figure‐2C). 5 patients had follow‐up amyloid‐PET: 2 showed major amyloid‐PET increase (+20 CL over 3 years), exceeding the 25 CL threshold at follow‐up, while the other 3 remained amyloid‐negative (Figure 2D). Two patients had follow‐up Flortaucipir‐PET: a low‐Flortaucipir case remained low, and one of the three high‐tau cases showed increased signal over time (Figure 2D). Group‐level FDG‐PET analysis showed frontal, temporal, and/or parietal hypometabolism in EOnonAD (Figure 3A). However, individual maps showed high heterogeneity: while ∼50% showing no clear hypometabolism (normal‐looking FDG), the remaining cases showed heterogeneous patterns suggestive of various underlying etiologies (e.g., FTLD‐like or AD‐like patterns, Figure 3B).
Conclusion
Amyloid‐PET negative patients included in LEADS are heterogeneous. While a minority of cases might have underlying AD with subthreshold amyloid‐ and/or tau‐PET values, FDG‐PET showed heterogeneous patterns suggesting underlying etiologies include various degenerative and non‐degenerative causes. ”
Background
Negative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset ...AD (EOAD, <65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amyloid‐, tau‐, and FDG‐PET.
Methods
We identified 380 patients who i) met clinical criteria for MCI or dementia due to AD, and ii) completed baseline amyloid‐PET (Florbetaben) and tau‐PET (Flortaucipir). Of these patients, 93 (24.5%) were amyloid‐PET negative based on a combination of visual read and quantification (“EOnonAD”). A subset of EononAD participants completed FDG‐PET (n = 63), 5 had follow‐up amyloid‐PET and 2 had follow‐up tau‐PET. 63 age‐matched cognitively normal controls were also included. Image acquisition and processing followed ADNI protocols.
Results
Compared to amyloid‐positive patients (EOAD), EononAD patients were less frequently female or APOE4 carriers, and less severely impaired (Figure 1). EononAD patients had a mean Centiloid of 5.6 (Figure 2A). At the group level, temporal Flortaucipir‐SUVR was low (1.20.3, not significantly different from controls), although 3 cases had Flortaucipir‐SUVR>2 (Figure 2A). Visual inspection showed these cases had asymmetric AD‐like Flortaucipir‐PET patterns (Figure 2B). Within patients with EononAD, amyloid‐ and tau‐PET were correlated (Spearman’s ρ = 0.29, p = 0.005), even when excluding the 3 high Flortaucipir‐SUVR outliers (Figure‐2C). 5 patients had follow‐up amyloid‐PET: 2 showed major amyloid‐PET increase (+20 CL over 3 years), exceeding the 25 CL threshold at follow‐up, while the other 3 remained amyloid‐negative (Figure 2D). Two patients had follow‐up Flortaucipir‐PET: a low‐Flortaucipir case remained low, and one of the three high‐tau cases showed increased signal over time (Figure 2D). Group‐level FDG‐PET analysis showed frontal, temporal, and/or parietal hypometabolism in EOnonAD (Figure 3A). However, individual maps showed high heterogeneity: while ∼50% showing no clear hypometabolism (normal‐looking FDG), the remaining cases showed heterogeneous patterns suggestive of various underlying etiologies (e.g., FTLD‐like or AD‐like patterns, Figure 3B).
Conclusions
Amyloid‐PET negative patients included in LEADS are heterogeneous. While a minority of cases might have underlying AD with subthreshold amyloid‐ and/or tau‐PET values, FDG‐PET showed heterogeneous patterns suggesting underlying etiologies include various degenerative and non‐degenerative causes.
Background
We aimed to describe amyloid‐ and tau‐PET in patients with sporadic Early Onset AD (sEOAD) from the Longitudinal Early‐onset Alzheimer’s Disease Study. We focused on amyloid‐tau ...relationships and on the association between i) age, sex, and ii) cross‐sectional and longitudinal PET measures.
Methods
In December 2022, we selected patients who fulfilled the following criteria: 1) clinical diagnosis of MCI or mild dementia, 2) available amyloid‐PET (18F‐florbetaben), tau‐PET (18F‐fortaucipir), and structural MRI, 3) positive amyloid‐PET based on a process including visual read and quantification. Image acquisition, quality control, and processing followed ADNI procedures. Florbetaben‐PET Centiloids and mean cortical Flortaucipir‐SUVR were extracted in native space using FreeSurfer. Cross‐sectional analyses were performed using general linear models; longitudinal analyses (up to 4 scans/patient) were performed using linear mixed effect models with random intercepts.
Results
Out of the 372 cognitively impaired patients included in LEADS, 280 (75.3%) were amyloid‐positive patients with sEOAD (Table 1 for demographics and clinical characteristics). Cross‐sectionally, Centiloids and cortical Flortaucipir‐SUVR were correlated (r = 0.29, p<.001; Fig 1a). Patient’s age was associated with cortical tau‐PET (older patients showing lower Flortaucipir‐SUVR, r = ‐0.47, p<0.001, Fig 1b) but not amyloid‐PET (r = ‐0.02, p = 0.68). Females showed greater amyloid (d = 0.43, p<0.001, Fig 1c) and tau‐PET burden (d = 0.35, p = 0.004), in the absence of sex differences in MMSE or CDR‐SB (d’s<0.16, p’s>0.37). Sex differences in tau‐PET remained significant (p = 0.04) when controlling for age and Centiloids. Both Centiloids and Flortaucipir‐SUVR increased longitudinally (p<0.001, Figure 3a‐b). The rate of Centiloid change was not modulated by age (time*age, p = 0.79) or sex (time*sex, p = 0.91). Changes in tau‐PET were independent of sex (time*sex, p = 0.15), but younger patients tended to show greater FTP‐SUVR progression (time*age, p = 0.07). In a subsample of 123 patients with at least 2 timepoints for both amyloid and tau‐PET (Fig 3c), rates of amyloid and tau changes were correlated (r = 0.22, p = 0.013).
Conclusion
In patients with sEOAD, amyloid‐ and tau‐PET are modestly correlated at baseline and continue to increase together over time. In EOAD, younger age is associated with higher tau‐PET burden, independent of amyloid. Females show greater amyloid and tau burden than males despite similar clinical severity measures.
Background
The longitudinal progression of tau pathology in sporadic early‐onset Alzheimer’s disease (EOAD, age‐at‐onset<65) has not been well established and may be key to its understanding and ...treatment. We utilized in vivo PET imaging to characterize regional patterns of pathological tau accumulation in the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS), an ongoing, large‐sample, multi‐site cohort.
Method
18FFlortaucipir tau‐PET was acquired 75‐105min post‐injection in 277 amyloid‐PET‐positive patients with sporadic EOAD and 90 healthy controls (Table 1). Patients had mild cognitive impairment (CDR‐SB = 0.5‐4, n = 206) or mild dementia (CDR‐SB = 4.5‐8, n = 71) at baseline. Longitudinal tau‐PET was collected in 126 patients (2‐4 scans/subject, 1.3 ± 0.4 years apart). Tau‐PET SUVRs were calculated in 72 FreeSurfer‐defined regions referenced against inferior cerebellar gray matter, and SUVRs were W‐scored within‐region to adjust for age and sex associations in controls (control W‐score mean = 0, SD = 1). Baseline tau‐PET W‐score differences between patients and controls were assessed using linear regression. Linear mixed‐effects models were used to calculate tau‐PET W‐score change rates among EOAD patients.
Result
Tau‐PET was significantly elevated in EOAD patients at baseline in every region examined (p<0.05, FDR‐corrected), with highest tau‐PET signal in lateral prefrontal, parietal, and posterior cingulate cortices bilaterally, and relative sparing of primary cortices (Figure 1a). In longitudinal analyses, tau‐PET increased significantly in 69/72 regions (p<0.05, FDR‐corrected; Figure 1b), and regions with higher tau‐PET at baseline had faster prospective accumulation rates on average (r = 0.47, p<0.0001; Figure 2). Exceptions were noted in posterior cingulate and parietal association regions, which had high tau‐PET at baseline but comparatively slow accumulation; and in anterior prefrontal and occipital regions with low‐to‐moderate tau‐PET at baseline yet rapid accumulation.
Conclusion
Tau pathology is present throughout cortex by the mild dementia stage in EOAD and is still accumulating globally, especially in anterior prefrontal and occipital cortices. Parietal association regions have high baseline tau but slower‐than‐expected prospective accumulation, suggesting these regions are early pathological foci that plateau early in the clinical disease stage.
Background
Patients with a history of repetitive head impacts (RHI) risk progressive memory loss and executive dysfunction consistent with traumatic encephalopathy syndrome (TES). TES is a clinical ...phenotype sensitive but non‐specific to underlying chronic traumatic encephalopathy (CTE). Cognitive symptoms overlap with Alzheimer’s disease (AD), and features of AD pathology like beta‐amyloid (Aβ) plaques often co‐occur with CTE. We investigated whether Alzheimer’s neuropathological changes influences cognition, brain volume, and plasma biomarkers in patients with RHI or TES.
Methods
We studied 154 patients who underwent Aβ‐PET, including 33 with RHI/TES (age 61.5±11.5, 100% male, 11/33 Aβ+), 62 with AD and no prior RHI (age 67.1±10.2, 48% male, 62/62 Aβ+), and 59 healthy controls without RHI (HC; age 73.0±6.2, 40% male, 0/59 Aβ+). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (regions of interest: frontal, temporal, parietal, occipital, hippocampus) and provided plasma samples analyzed for GFAP and NfL. Patients with RHI/TES were stratified as Aβ+ or Aβ‐ and compared to each other and with AD and HC groups (ANCOVA adjusting for age and sex).
Results
Cognitively, Aβ+ RHI/TES performed worse than Aβ‐ RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing brain volume, Aβ+ RHI/TES, but not Aβ‐ RHI/TES, had lower parietal volume than HC (p = .003, d = 1.3). Conversely, Aβ‐ RHI/TES had lower hippocampal volume than patients with AD (p = .03, d = 0.77). Comparing plasma biomarkers, Aβ+ RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and similar GFAP levels to patients with AD (p = .26, d = 0.38). Conversely, Aβ‐ RHI/TES had higher NfL than HC (p = .004, d = 0.93) and a trend towards higher plasma NfL than Aβ+ RHI/TES (p = .11; d = 0.61).
Conclusions
Patients with RHI/TES and positive Aβ‐PET have cognitive, brain volume, and plasma biomarker changes that more closely align to patients with AD than patients with Aβ‐ RHI/TES. Visuospatial impairment and associated parietal atrophy may suggest the presence of AD pathology in participants with RHI. The suggestion of greater neuronal injury in patients with Aβ‐ RHI/TES warrants further evaluation in supporting a diagnosis of TES due to suspected underlying CTE. Measuring these biomarkers in patients with RHI/TES could guide precise clinical management.
