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.
It is not known exactly where amyloid-β (Aβ) fibrils begin to accumulate in individuals with Alzheimer's disease (AD). Recently, we showed that abnormal levels of Aβ42 in cerebrospinal fluid (CSF) ...can be detected before abnormal amyloid can be detected using PET in individuals with preclinical AD. Using these approaches, here we identify the earliest preclinical AD stage in subjects from the ADNI and BioFINDER cohorts. We show that Aβ accumulation preferentially starts in the precuneus, medial orbitofrontal, and posterior cingulate cortices, i.e., several of the core regions of the default mode network (DMN). This early pattern of Aβ accumulation is already evident in individuals with normal Aβ42 in the CSF and normal amyloid PET who subsequently convert to having abnormal CSF Aβ42. The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.
Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer's disease. We studied 150 cognitively unimpaired participants and 100 patients with mild ...cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-β-positive cognitively unimpaired, n = 62) and prodromal (amyloid-β-positive mild cognitive impairment, n = 49) Alzheimer's disease had accelerated p-tau217 compared to amyloid-β-negative cognitively unimpaired (β = 0.56, P < 0.001, using linear mixed effects models) and amyloid-β-negative mild cognitive impairment patients (β = 0.67, P < 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer's disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (β = 0.79, P < 0.001). P-tau217 did not change in amyloid-β-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer's disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-β-positive cognitively unimpaired (71 participants per arm in amyloid-β-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer's disease and can be used to monitor disease progression.
Purpose
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Fflortaucipir binds to paired helical filament tau and accurately identifies tau in Alzheimer’s disease (AD). However, “off-target” binding interferes with the quantification of
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...Fflortaucipir in several brain regions. Recently, other tau PET tracers have been developed. Here, we compare
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Fflortaucipir with the novel tau tracer
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FRO948 head-to-head in vivo.
Methods
We included 18 participants with AD, three with amyloid-β-positive amnestic mild cognitive impairment, and four healthy controls. All underwent
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Fflortaucipir (80–100 min) and
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FRO948 (70–90) PET scans within approximately 1 month. Four study participants underwent 0–100-min dynamic scanning. Standardized uptake value ratios (SUVRs) were created using an inferior cerebellar reference region.
Results
Neocortical tracer retention was highly comparable using both SUVR and distribution volume ratio-1 values obtained from dynamic scans. However,
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FRO948 retention was significantly higher in the entorhinal cortex and lower in the basal ganglia, thalamus, and choroid plexus compared with
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Fflortaucipir. Increased off-target binding was observed with age for both tracers. Several cases exhibited strong
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FRO948 retention in the skull/meninges. This extra-cerebral signal, however, did not affect diagnostic accuracy and remained relatively unchanged when re-examining a subsample after 1 year. Kinetic modeling showed an increase in
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Fflortaucipir SUVR over the scanning interval, compared with a plateau for
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FRO948.
Conclusion
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FRO948 and
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Fflortaucipir bound comparably in neocortical regions, but
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FRO948 showed higher retention in the medial temporal lobe and lower intracerebral “off-target” binding. Time-dependent bias of SUVR estimates may prove less of a factor with
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FRO948, compared with previous tau ligands.
IMPORTANCE: There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). OBJECTIVE: To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic ...biomarker for AD. DESIGN, SETTING, AND PARTICIPANTS: Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). EXPOSURES: Plasma P-tau217. MAIN OUTCOMES AND MEASURES: Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography PET). RESULTS: Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve AUC, 0.89 95% CI, 0.81-0.97) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 95% CI, 0.93-0.98) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 95% CI, 0.91-0.96) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22). CONCLUSIONS AND RELEVANCE: Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.
OBJECTIVETo compare different β-amyloid (Aβ), tau, and neurodegeneration (ATN) 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 (Fflutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET (Fflortaucipir); 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.
IMPORTANCE: The diagnostic performance of second-generation tau positron emission tomographic (PET) tracers is not yet known. OBJECTIVE: To examine the novel tau PET tracer RO948 F 18 (18FRO948) ...performance in discriminating Alzheimer disease (AD) from non-AD neurodegenerative disorders. DESIGN, SETTING, AND PARTICIPANTS: In this diagnostic study, 613 participants in the Swedish BioFINDER-2 study were consecutively enrolled in a prospective cross-sectional study from September 4, 2017, to August 28, 2019. Participants included 257 cognitively unimpaired controls, 154 patients with mild cognitive impairment, 100 patients with AD dementia, and 102 with non-AD neurodegenerative disorders. Evaluation included a comparison of tau PET tracer 18FRO948 with magnetic resonance imaging (MRI) and cerebrospinal fluid and a head-to-head comparison between 18FRO948 and flortaucipir F 18 (18Fflortaucipir) in patients with semantic variant primary progressive aphasia (svPPA). EXPOSURES: 18FRO948 (all patients) and 18Fflortaucipir (3 patients with svPPA) tau PET; MRI (hippocampal volume, composite temporal lobe cortical thickness, whole-brain cortical thickness) and cerebrospinal fluid measures (p-tau181 and amyloid Aβ42 and Aβ40 ratioAβ42/Aβ40, and Aβ42/p-tau181 ratio). MAIN OUTCOMES AND MEASURES: Standard uptake value ratios (SUVRs) in 4 predefined regions of interest (ROIs) reflecting Braak staging scheme for tau pathology and encompass I-II (entorhinal cortex), III-IV (inferior/middle temporal, fusiform gyrus, parahippocampal cortex, and amygdala), I-IV, and V-VI (widespread neocortical areas), area under the receiver operating characteristic curve (AUC) values, and subtraction images between 18FRO948 and 18Fflortaucipir. RESULTS: Diagnostic groups among the 613 participants included cognitively unimpaired (mean SD age, 65.8 12.1 years; 117 men 46%), mild cognitive impairment (age, 70.8 8.3 years; 82 men 53%), AD dementia (age, 73.5 6.7 years; 57 men 57%), and non-AD disorders (age, 70.5 8.6 years; 41 men 40%). Retention of 18FRO948 was higher in AD dementia compared with all other diagnostic groups. 18FRO948 could distinguish patients with AD dementia from individuals without cognitive impairment and those with non-AD disorders, and the highest AUC was obtained using the I-IV ROI (AUC = 0.98; 95% CI, 0.96-0.99 for AD vs no cognitive impairment and AUC = 0.97; 95% CI, 0.95-0.99 for AD vs non-AD disorders), which outperformed MRI (highest AUC = 0.91 for AD vs no cognitive impairment using whole-brain thickness, and AUC = 0.80 for AD vs non-AD disorders using temporal lobe thickness) and cerebrospinal fluid measures (highest AUC = 0.94 for AD vs no cognitive impairment using Aβ42/p-tau181, and AUC = 0.93 for AD vs non-AD disorders using Aβ42/Aβ40). Generally, tau PET positivity using 18FRO948 was observed only in Aβ-positive cases or in MAPT R406W mutation carriers. Retention of 18FRO948 was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temporal lobe uptake than with 18Fflortaucipir. CONCLUSIONS AND RELEVANCE: In this study, elevated 18FRO948 SUVRs were most often seen among Aβ-positive cases, which suggests that 18FRO948 has high specificity for AD-type tau and highlights its potential as a diagnostic marker in the differential diagnosis of AD.
Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe ...neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease.
Purpose: The hippocampus is affected by tau pathology early in Alzheimer's disease (AD) development. Accurate quantification of hippocampal tau signal using the tau-PET tracer 18F-flortaucipir is ...complicated, however, by off-target binding in the adjacent choroid plexus. We here present a new method for compensating for this off-target choroid plexus signal.
Methods: As off-target binding in the choroid plexus is known to be higher using 18F-flortaucipir compared to 18F-RO948, we created a binary hippocampal mask in template space where 18F-flortaucipir signal was higher than 18F-RO948, using data from 30 patients that underwent both 18F-flortaucipir and 18F-RO948 PET. This mask, presumably representing hippocampal voxels affected by off-target binding from the choroid plexus, was then converted to native space and applied as an exclusion mask to 145 patients across the AD-spectrum scanned with 18F-flortaucipir. As an alternative approach exclusion masks were generated by expanding the choroid plexus ROI in native space. Results were analysed both without and with partial volume error correction (non-PVEc/PVEc).
Results: Unmasked hippocampal standardized uptake value ratios (SUVR) were significantly correlated to choroid plexus SUVRs using both non-PVEc (p < 0.001, r = 0.28) and PVEc data (p < 0.05, r = 0.18). After applying the mask, however, these correlations disappeared. The diagnostic accuracy in separating cognitively impaired (CI) from cognitively unimpaired (CU) subjects improved after masking, from an AUC of 0.792 (95% C.I.,0.715–0.869) to 0.837 (95% C.I.,0.768–0.906) for non-PVEc data (p < 0.001), and from 0.798 (95% C.I.,0.722–0.873) to 0.834 (95% C.I.,0.766–0.903) for PVEc data (p < 0.001). The correlations to memory improved significantly for MMSE for unmasked vs. masked data both without (r = −0.440 vs. r = −0.499, p < 0.001) and with (r = −0.454 vs. r = −0.503, p < 0.001) PVEc. Similar results were found using the ADAS-Cog Delayed Word Recall test.
Conclusion: Choroid plexus off-target binding interferes with the estimation of true hippocampal retention using 18F-flortaucipir PET. Using a mask to correct for this off-target signal, we improved the diagnostic accuracy of 18F-flortaucipir in the hippocampus and the correlation between 18F-flortaucipir hippocampal SUVR and cognitive measures.
Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification ...of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer's Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.
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