| 1. |
- Hansson, Oskar, et al.
(författare)
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Tau pathology distribution in Alzheimer's disease corresponds differentially to cognition-relevant functional brain networks
- 2017
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 11:MAR
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Tidskriftsartikel (refereegranskat)abstract
- Neuropathological studies have shown that the typical neurofibrillary pathology of hyperphosphorylated tau protein in Alzheimer's disease (AD) preferentially affects specific brain regions whereas others remain relatively spared. It has been suggested that the distinct regional distribution profile of tau pathology in AD may be a consequence of the intrinsic network structure of the human brain. The spatially distributed brain regions that are most affected by the spread of tau pathology may hence reflect an interconnected neuronal system. Here, we characterized the brain-wide regional distribution profile of tau pathology in AD using 18F-AV 1451 tau-sensitive positron emission tomography (PET) imaging, and studied this pattern in relation to the functional network organization of the human brain. Specifically, we quantified the spatial correspondence of the regional distribution pattern of PET-evidenced tau pathology in AD with functional brain networks characterized by large-scale resting state functional magnetic resonance imaging (rs-fMRI) data in healthy subjects. Regional distribution patterns of increased PET-evidenced tau pathology in AD compared to controls were characterized in two independent samples of prodromal and manifest AD cases (the Swedish BioFINDER study, n = 44; the ADNI study, n = 35). In the BioFINDER study we found that the typical AD tau pattern involved predominantly inferior, medial, and lateral temporal cortical areas, as well as the precuneus/posterior cingulate, and lateral parts of the parietal and occipital cortex. This pattern overlapped primarily with the dorsal attention, and to some extent with higher visual, limbic and parts of the default-mode network. PET-evidenced tau pathology in the ADNI replication sample, which represented a more prodromal group of AD cases, was less pronounced but showed a highly similar spatial distribution profile, suggesting an earlier-stage snapshot of a consistently progressing regional pattern. In conclusion, the present study indicates that the regional deposition of tau aggregates in AD predominantly affects higher-order cognitive over primary sensory-motor networks, but does not appear to be specific for the default-mode or related limbic networks.
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| 2. |
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| 3. |
- Heurling, Kerstin, et al.
(författare)
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Regional times to equilibria and their impact on semi-quantification of [18F]AV-1451 uptake
- 2019
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - 0271-678X .- 1559-7016. ; 39:11, s. 2223-2232
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Tidskriftsartikel (refereegranskat)abstract
- The semi-quantitative estimate standardised uptake value ratios (SUVR) correlate well with specific binding of the tracer expressed as distribution volume ratios (DVR) for the tau positron emission tomography tracer [18F]AV-1451 uptake and are therefore widely used as proxy for tracer binding. With regard to tracer kinetic modelling, there exists a time point when SUVR deviates minimally from DVR, occurring when the specific binding reaches a transient equilibrium. Here, we have investigated whether the time to equilibrium affects the agreement between SUVR and DVR across different brain regions. We show that the time required to reach equilibrium differs across brain regions, resulting in region-specific biases. However, even though the 80–100 min post-injection time window did not show the smallest bias numerically, the disagreement between SUVR and DVR varied least between regions during this time. In conclusion, our findings suggest a regional component to the bias of SUVR related to the time to transient equilibrium of the specific binding. [18F]AV-1451 uptake should consequently be interpreted with some caution when compared across brain regions using this method of quantification. The commonly used time window 80–100 min post-injection shows the most consistent bias across regions and is recommended for semi-quantification of [18F]AV-1451.
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| 4. |
- Leuzy, Antoine, et al.
(författare)
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Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
- 2022
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 79:2, s. 149-158
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Tidskriftsartikel (refereegranskat)abstract
- Importance: There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD). Objective: To describe longitudinal [18F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment. Design, Setting, and Participants: This longitudinal cohort study consecutively enrolled amyloid-β (Aβ)-negative cognitively unimpaired (CU) participants, Aβ-positive CU individuals, Aβ-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies. Exposures: Baseline plasma and cerebrospinal fluid Aβ42/Aβ40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([18F]flutemetamol), and tau PET ([18F]RO948 in the BioFINDER-2 study; [18F]flortaucipir in the BioFINDER-1 study). Main Outcomes and Measures: Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial. Results: Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aβ-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aβ-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aβ-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2= 0.27, P <.005), tau PET (stage I baseline SUVR; R2= 0.13, P <.05) and amyloid PET (R2= 0.10, P <.05) were significantly associated with longitudinal tau PET in stage I in Aβ-positive CU individuals. In Aβ-positive individuals with MCI, plasma p-tau217 (R2= 0.24, P <.005) and tau PET (stage II baseline SUVR; R2= 0.44, P <.001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal [18F]flortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P <.005) in Aβ-positive CU individuals and of 68% (95% CI, 61%-73%; P <.001) in Aβ-positive individuals with MCI. Conclusions and Relevance: In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD..
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| 5. |
- Leuzy, Antoine, et al.
(författare)
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Diagnostic Performance of RO948 F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease from Other Neurodegenerative Disorders
- 2020
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 77:8, s. 955-965
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Tidskriftsartikel (refereegranskat)abstract
- 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 ([18F]RO948) 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 [18F]RO948 with magnetic resonance imaging (MRI) and cerebrospinal fluid and a head-to-head comparison between [18F]RO948 and flortaucipir F 18 ([18F]flortaucipir) in patients with semantic variant primary progressive aphasia (svPPA). Exposures: [18F]RO948 (all patients) and [18F]flortaucipir (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 ratio[Aβ42/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 [18F]RO948 and [18F]flortaucipir. 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 [18F]RO948 was higher in AD dementia compared with all other diagnostic groups. [18F]RO948 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 [18F]RO948 was observed only in Aβ-positive cases or in MAPT R406W mutation carriers. Retention of [18F]RO948 was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temporal lobe uptake than with [18F]flortaucipir. Conclusions and Relevance: In this study, elevated [18F]RO948 SUVRs were most often seen among Aβ-positive cases, which suggests that [18F]RO948 has high specificity for AD-type tau and highlights its potential as a diagnostic marker in the differential diagnosis of AD.
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| 6. |
- Mattsson, Niklas, et al.
(författare)
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18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease
- 2017
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 9, s. 1212-1223
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the relationship between cerebrospinal fluid (CSF) total-tau (T-tau) and phosphorylated tau (P-tau) with the tau PET ligand 18F-AV-1451 in Alzheimer's disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T-tau and P-tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F-AV-1451, and mainly in demented AD patients. 18F-AV-1451, but not CSF T-tau or P-tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18F-AV-1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18F-AV-1451 retention was always increased at this disease stage. We conclude that CSF T-tau and P-tau mainly behave as biomarkers of "disease state", since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18F-AV-1451 is a biomarker of "disease stage", since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.
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| 7. |
- Mattsson, Niklas, et al.
(författare)
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Comparing 18F-AV-1451 with CSF t-tau and p-tau for diagnosis of Alzheimer disease
- 2018
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Ingår i: Neurology. - 0028-3878. ; 90:5, s. e388-e395
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Tidskriftsartikel (refereegranskat)abstract
- To compare PET imaging of tau pathology with CSF measurements (total tau [t-tau] and phosphorylated tau [p-tau]) in terms of diagnostic performance for Alzheimer disease (AD).We compared t-tau and p-tau and 18F-AV-1451 in 30 controls, 14 patients with prodromal AD, and 39 patients with Alzheimer dementia, recruited from the Swedish BioFINDER study. All patients with AD (prodromal and dementia) were screened for amyloid positivity using CSF β-amyloid 42. Retention of 18F-AV-1451 was measured in a priori specified regions, selected for known associations with tau pathology in AD.Retention of 18F-AV-1451 was markedly elevated in Alzheimer dementia and moderately elevated in prodromal AD. CSF t-tau and p-tau was increased to similar levels in both AD dementia and prodromal AD. 18F-AV-1451 had very good diagnostic performance for Alzheimer dementia (area under the receiver operating characteristic curve [AUROC] ∼1.000), and was significantly better than t-tau (0.876), p-tau (0.890), hippocampal volume (0.824), and temporal cortical thickness (0.860). For prodromal AD, there were no significant AUROC differences between CSF tau and 18F-AV-1451 measures (0.836-0.939), but MRI measures had lower AUROCs (0.652-0.769).CSF tau and 18F-AV-1451 have equal performance in early clinical stages of AD, but 18F-AV-1451 is superior in the dementia stage, and exhibits close to perfect diagnostic performance for mild to moderate AD.This study provides Class III evidence that CSF tau and 18F-AV-1451 PET have similar performance in identifying early AD, and that 18F-AV-1451 PET is superior to CSF tau in identifying mild to moderate AD.
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| 8. |
- Mattsson, Niklas, et al.
(författare)
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Greater tau load and reduced cortical thickness in APOE ε4-negative Alzheimer’s disease : a cohort study
- 2018
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer’s disease is characterized by aggregated β-amyloid and tau proteins, but the clinical presentations and patterns of brain atrophy vary substantially. A part of this heterogeneity may be linked to the risk allele APOE ε4. The spread of tau pathology is related to atrophy and cognitive decline, but little data exist on the effects of APOE ε4 on tau. The objective of this preliminary study was therefore to test if tau load and brain structure differ by APOE ε4 in Alzheimer’s disease. Methods: Sixty-five β-amyloid-positive patients at the prodromal and dementia stages of Alzheimer’s disease were enrolled, including APOE ε4-positive (n = 46) and APOE ε4-negative (n = 19) patients. 18F-AV-1451 positron emission tomography was used to measure tau and brain magnetic resonance imaging (MRI) was used to measure cortical thickness. Results: Compared with their APOE ε4-positive counterparts, APOE ε4-negative patients had greater tau load and reduced cortical thickness, with the most pronounced effects for both in the parietal cortex. Relative to the overall cortical tau load, APOE ε4-positive patients had greater tau load in the entorhinal cortex. APOE ε4-positive patients also had slightly greater cortical β-amyloid load. There was an interaction between APOE ε4 and 18F-AV-1451 on cortical thickness, with greater effects of 18F-AV-1451 on cortical thickness in APOE ε4-negative patients. APOE ε4 and 18F-AV-1451 were independent predictors of cognition, but showed distinct associations with different cognitive tests. Conclusions: APOE genotype may be associated with differences in pathways in Alzheimer’s disease, potentially through differential development and spread of tau, as well as through effects on cognitive outcomes involving non-tau-related mechanisms.
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| 9. |
- Ossenkoppele, Rik, et al.
(författare)
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Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 28:11, s. 2381-2387
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Tidskriftsartikel (refereegranskat)abstract
- A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T- and A-T- groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1-26.4) and A+T- (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A-T- (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4-10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T- group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A+TMTL+ (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A+T- (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T- (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T- group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.
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| 10. |
- Ossenkoppele, Rik, et al.
(författare)
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Associations between tau, Aβ, and cortical thickness with cognition in Alzheimer disease
- 2019
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Ingår i: Neurology. - 1526-632X. ; 92:6, s. 601-612
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the cross-sectional associations between regional tau, β-amyloid (Aβ), and cortical thickness and neuropsychological function across the preclinical and clinical spectrum of Alzheimer disease (AD). METHODS: We included 106 participants from the Swedish Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study, of whom 33 had preclinical AD (Aβ-positive cognitively normal individuals), 25 had prodromal AD (Aβ-positive mild cognitive impairment), and 48 had probable AD dementia. All underwent [18F]flortaucipir (tau) and structural MRI (cortical thickness), and 88 of 106 underwent [18F]flutemetamol (Aβ) PET. Linear regression models adjusted for age, sex, and education were performed to examine associations between 7 regions of interest and 7 neuropsychological tests for all 3 imaging modalities. RESULTS: In preclinical AD, [18F]flortaucipir, but not [18F]flutemetamol or cortical thickness, was associated with decreased global cognition, memory, and processing speed (range standardized β = 0.35-0.52, p < 0.05 uncorrected for multiple comparisons). In the combined prodromal AD and AD dementia group, both increased [18F]flortaucipir uptake and reduced cortical thickness were associated with worse performance on a variety of neuropsychological tests (most regions of interest survived correction for multiple comparisons at p < 0.05), while increased [18F]flutemetamol uptake was specifically associated with lower scores on a delayed recall memory task (p < 0.05 uncorrected for multiple comparisons). The strongest effects for both [18F]flortaucipir and cortical thickness on cognition were found in the lateral and medial parietal cortex and lateral temporal cortex. The effect of [18F]flutemetamol on cognition was generally weaker and less region specific. CONCLUSION: Our findings suggest that tau PET is more sensitive than Aβ PET and measures of cortical thickness for detecting early cognitive changes in preclinical AD. Furthermore, both [18F]flortaucipir PET and cortical thickness show strong cognitive correlates at the clinical stages of AD.
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