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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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
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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. |
- Smith, Ruben, et al.
(författare)
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Clinical Utility of Tau Positron Emission Tomography in the Diagnostic Workup of Patients With Cognitive Symptoms
- 2023
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Ingår i: JAMA Neurology. - 2168-6149. ; 80:7, s. 749-756
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Tidskriftsartikel (refereegranskat)abstract
- Importance: It is important to determine the added clinical value for tau positron emission tomography (PET) in the diagnostic workup of patients with cognitive symptoms before widespread implementation in clinical practice. Objective: To prospectively study the added clinical value of PET detecting tau pathology in Alzheimer disease (AD). Design, Setting, and Participants: This prospective cohort study (Swedish BioFINDER-2 study) took place from May 2017 through September 2021. A total of 878 patients with cognitive complaints were referred to secondary memory clinics in southern Sweden and then recruited to the study. In total, 1269 consecutive participants were approached, but 391 did not meet inclusion criteria or did not complete the study. Exposures: Participants underwent a baseline diagnostic workup, including clinical examination, medical history, cognitive testing, blood and cerebrospinal fluid sampling, magnetic resonance imaging of the brain, and a tau PET ([18F]RO948) scan. Main Outcomes and Measures: The primary end points were change in diagnosis and change in AD drug therapy or other drug treatment between the pre- and post-PET visits. A secondary end point was the change in diagnostic certainty between the pre- and post-PET visits. Results: A total of 878 participants with a mean age of 71.0 (SD, 8.5) years (491 male [56%]) were included. The tau PET result led to a change in diagnoses in 66 participants (7.5%) and a change in medication in 48 participants (5.5%). The study team found an association with overall increased diagnostic certainty after tau PET in the whole data set (from 6.9 [SD, 2.3] to 7.4 [SD, 2.4]; P <.001). The certainty was higher in participants with a pre-PET diagnosis of AD (from 7.6 [SD, 1.7] to 8.2 [SD, 2.0]; P <.001) and increased even further in participants with a tau PET positive result supporting an AD diagnosis (from 8.0 [SD, 1.4] to 9.0 [SD, 0.9]; P <.001). The association with tau PET results had the largest effect sizes in participants with pathological amyloid-β (Aβ) status, whereas no significant change in diagnoses was seen in participants with normal Aβ status. Conclusions and Relevance: The study team reported a significant change in diagnoses and patient medication when tau PET was added to an already extensive diagnostic workup that included cerebrospinal fluid AD biomarkers. Including tau PET was associated with a significant increase in certainty of underlying etiology. The effect sizes for certainty of etiology and diagnosis were largest in the Aβ-positive group and the study team suggests that clinical use of tau PET be limited to populations with biomarkers indicating Aβ positivity.
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| 9. |
- Smith, Ruben, et al.
(författare)
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In vivo retention of (18)F-AV-1451 in corticobasal syndrome.
- 2017
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Ingår i: Neurology. - 1526-632X. ; 89:8, s. 845-853
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Tidskriftsartikel (refereegranskat)abstract
- To study the usefulness of (18)F-AV-1451 PET in patients with corticobasal syndrome (CBS).We recruited 8 patients with CBS, 17 controls, 31 patients with Alzheimer disease (AD), and 11 patients with progressive supranuclear palsy (PSP) from the Swedish BioFINDER study. All patients underwent clinical assessment, (18)F-AV-1451 PET, MRI, and quantification of β-amyloid pathology. A subset of participants also underwent (18)F-FDG-PET.In the 8 patients with CBS, 6 had imaging findings compatible with the corticobasal degeneration pathology and 2 with typical AD pathology. In the 6 patients with CBS without typical AD pathology, there were substantial retentions of (18)F-AV-1451 in the motor cortex, corticospinal tract, and basal ganglia contralateral to the most affected body side. These patients could be clearly distinguished from patients with AD dementia or PSP using (18)F-AV-1451. However, cortical atrophy was more widespread than the cortical retention of (18)F-AV1451 in these CBS cases, and cortical AV-1451 uptake did not correlate with cortical thickness or glucose hypometabolism. These results are in sharp contrast to AD dementia, where (18)F-AV-1451 retention was more widespread than cortical atrophy, and correlated well with cortical thickness and hypometabolism.Patients with CBS without typical AD pathology exhibited AV-1451 retention in the motor cortex, corticospinal tract, and basal ganglia contralateral to the affected body side, clearly different from controls and patients with AD dementia or PSP. However, cortical atrophy measured with MRI and decreased (18)F-fluorodeoxyglucose uptake were more widespread than (18)F-AV-1451 uptake and probably represent earlier, yet less specific, markers of CBS.This study provides Class III evidence that (18)F-AV-1451 PET distinguishes between CBS and AD or PSP.
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| 10. |
- Smith, Ruben, et al.
(författare)
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Increased basal ganglia binding of 18F-AV-1451 in patients with progressive supranuclear palsy
- 2017
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 32:1, s. 108-114
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work-up of PSP. Methods: Regional tau accumulation was studied using 18F-AV-1451 PET in 11 patients with PSP and 11 age-matched healthy controls in the Swedish BioFinder study. Results: 18F-AV-1451 standard uptake volume ratios were significantly higher in the basal ganglia in PSP patients when compared with controls (globus pallidus 1.75 vs 1.50; putamen 1.51 vs 1.35). Retention in the basal ganglia was correlated with age in both groups (r=.43-.78, P<.05). In PSP, we observed a significant correlation between clinical deterioration measured with the PSP rating scale and standard uptake volume ratios in the globus pallidus (r=.74, P<.05). However, no 18F-AV-1451 retention was observed in the cerebral cortex or white matter of either PSP patients or controls, and autoradiography did not reveal any specific binding of AV-1451 to PSP tau aggregates. Conclusion: We found higher 18F-AV-1451 retention in the basal ganglia of PSP patients when compared with healthy elderly controls, but also increases with age in both controls and patients. As a result of the overlap in retention between diagnostic groups and the age-dependent increase present also in controls, 18F-AV-1451 PET might not reliably distinguish individual patients with PSP from controls. However, further studies are needed to evaluate whether 18F-AV-1451 PET might be useful as a progression marker in clinical PSP trials.
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