| 1. |
- Ashton, Nicholas J., et al.
(författare)
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Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer's trial selection and disease monitoring.
- 2022
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 28:12, s. 2555-2562
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Tidskriftsartikel (refereegranskat)abstract
- 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 4-6years 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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| 2. |
- Binette, Alexa Pichet, et al.
(författare)
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Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Method: We included 327 participants from the Swedish BioFINDER-2 cohort with cerebrospinal fluid (CSF) p-tau217, Aβ-PET, longitudinal tau-PET, and longitudinal cognition. The main groups of interest were Aβ-positive non-demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p-tau217 and regional Aβ-PET were associated with tau-PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p-tau217 between Aβ-PET and tau-PET change. Second, we investigated how soluble p-tau217 and tau-PET change related to change in cognition, and mediation between these variables. Result: In early AD stages (non-demented participants), increased concentration of soluble p-tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau-PET rate of change), beyond the effect of regional Aβ-PET and baseline tau-PET (Figure 2A-C). Further, averaged across all regions, soluble p-tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p-tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p-tau levels have plateaued, soluble p-tau217 was not associated with accumulation of tau aggregates beyond baseline tau-PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p-tau217 (Figure 4B-C). Conclusion: Soluble p-tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.
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| 3. |
- Coomans, Emma M., et al.
(författare)
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Interactions between vascular burden and amyloid-β pathology on trajectories of tau accumulation
- 2024
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Ingår i: Brain. - 0006-8950. ; 147:3, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrovascular pathology often co-exists with Alzheimer’s disease pathology and can contribute to Alzheimer’s disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer’s disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-β pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-β pathology. All underwent baseline tau-PET (18F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0 years. Tau-PET uptake was computed for a temporal meta-region-of-interest. We focused on four main vascular imaging features and risk factors: microbleeds; white matter lesion volume; stroke-related events (infarcts, lacunes and haemorrhages); and the Framingham Heart Study Cardiovascular Disease risk score. To validate our in vivo results, we examined 1610 autopsy cases from an Arizona-based neuropathology cohort on three main vascular pathological features: cerebral amyloid angiopathy; white matter rarefaction; and infarcts. For the in vivo cohort, primary analyses included age-, sex- and APOE ε4-corrected linear mixed models between tau-PET (outcome) and interactions between time, amyloid-β and each vascular feature (predictors). For the neuropathology cohort, age-, sex- and APOE ε4-corrected linear models between tau tangle density (outcome) and an interaction between plaque density and each vascular feature (predictors) were performed. In cognitively unimpaired individuals, we observed a significant interaction between microbleeds and amyloid-β pathology on greater baseline tau load (β = 0.68, P < 0.001) and longitudinal tau accumulation (β = 0.11, P < 0.001). For white matter lesion volume, we did not observe a significant independent interaction effect with amyloid-β on tau after accounting for microbleeds. In cognitively unimpaired individuals, we further found that stroke-related events showed a significant negative interaction with amyloid-β on longitudinal tau (β = −0.08, P < 0.001). In cognitively impaired individuals, there were no significant interaction effects between cerebrovascular and amyloid-β pathology at all. In the neuropathology dataset, the in vivo observed interaction effects between cerebral amyloid angiopathy and plaque density (β = 0.38, P < 0.001) and between infarcts and plaque density (β = −0.11, P = 0.005) on tau tangle density were replicated. To conclude, we demonstrated that cerebrovascular pathology—in the presence of amyloid-β pathology—modifies tau accumulation in early stages of Alzheimer’s disease. More specifically, the co-occurrence of microbleeds and amyloid-β pathology was associated with greater accumulation of tau aggregates during early disease stages. This opens the possibility that interventions targeting microbleeds may attenuate the rate of tau accumulation in Alzheimer’s disease.
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| 4. |
- Franzmeier, Nicolai, et al.
(författare)
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Earlier Alzheimer's disease onset is associated with a shift of tau pathology towards brain hubs which facilitates tau spreading
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: In Alzheimer’s disease (AD), younger symptom onset is associated accelerated cognitive decline and tau spreading, yet the drivers of faster disease manifestation in patients with earlier symptom onset are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto-parietal regions which typically harbor globally connected hubs that are central for cognition. Since tau spreads across connected regions, globally connected hubs may accelerate tau spreading due to their large number of connections to other brain regions. Thus, we hypothesized that a pattern shift of tau pathology towards globally connected brain hubs may facilitate tau spreading and earlier symptom manifestation in AD. Method: We included two independent samples with longitudinal Flortaucipir tau-PET covering the AD spectrum (ADNI: n(controls/AD-preclinical/AD-symptomatic)=93/60/89, BioFINDER, n(controls/AD-preclinical/AD-symptomatic)=16/16/25). In addition, we included resting-state fMRI from human connectome project participants (n=1000), applying a 200-ROI brain atlas to obtain a global connectivity map for assessing brain hubs (Fig.1A-D). Applying the same atlas to tau-PET we transformed SUVRs to tau positivities using a pre-established gaussian-mixture modeling approach (Fig.1E-F). By mapping tau-PET positivities to the fMRI-derived global connectivity map (Fig.1G-L), we assessed the degree to which subject specific tau-PET patterns were shifted towards globally connected hubs or non-hubs, while adjusting for global tau levels. Using linear regression, we then tested whether a stronger shift of tau towards hubs was associated with earlier symptom manifestation and faster longitudinal tau accumulation. Result: In symptomatic AD patients, younger age was associated with a stronger shift of tau-PET towards globally connected brain hubs (p[ADNI/BiOFINDER]=0.024/0.018, Fig.2A&B), and with higher global connectivity of epicenters with highest tau pathology (p[ADNI/BiOFINDER]<0.001/0.001, Fig.2C&D). In symptomatic AD, younger age (p[ADNI/BiOFINDER]=0.009/0.001) and a stronger shift of tau-PET towards hubs predicted faster subsequent tau accumulation (p[ADNI/BiOFINDER]=0.004/0.002), supporting the view that that hubs facilitate tau spreading (Fig.3). Further, a stronger shift of tau-PET towards globally connected brain hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients (p[ADNI/BiOFINDER]=0.039/0.046). Conclusion: Younger AD symptom onset is associated with stronger tau pathology in globally connected brain hubs, which facilitates faster tau spreading.
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| 5. |
- Frontzkowski, Lukas, et al.
(författare)
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Earlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- In Alzheimer’s disease (AD), younger symptom onset is associated with accelerated disease progression and tau spreading, yet the mechanisms underlying faster disease manifestation are unknown. To address this, we combined resting-state fMRI and longitudinal tau-PET in two independent samples of controls and biomarker-confirmed AD patients (ADNI/BioFINDER, n = 240/57). Consistent across both samples, we found that younger symptomatic AD patients showed stronger tau-PET in globally connected fronto-parietal hubs, i.e., regions that are critical for maintaining cognition in AD. Stronger tau-PET in hubs predicted faster subsequent tau accumulation, suggesting that tau in globally connected regions facilitates connectivity-mediated tau spreading. Further, stronger tau-PET in hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients, which predicted faster cognitive decline. These independently validated findings suggest that younger AD symptom onset is associated with stronger tau pathology in brain hubs, and accelerated tau spreading throughout connected brain regions and cognitive decline.
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| 6. |
- Groot, Colin, et al.
(författare)
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A biomarker profile of elevated CSF p-tau with normal tau PET is associated with increased tau accumulation rates on PET in early Alzheimer’s disease
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Different tau biomarkers become abnormal at different stages of Alzheimer’s disease (AD), with CSF p-tau typically being elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we selected a group of amyloid-β-positive (A+) individuals with elevated CSF p-tau levels but negative tau-PET scans and assessed longitudinal changes in tau-PET, cortical thickness and cognitive decline. Method: Individuals without dementia (i.e., cognitively unimpaired (CU) or mild cognitive impairment, n=231) were selected from the BioFINDER-2 study. These subjects were categorized into biomarker groups based on Gaussian mixture modelling to determine cut-offs for abnormal CSF Aβ42/40 (A; <0.078), CSF p-tau217 (P; >110 pg/ml) and [18F]RO948 tau-PET SUVR within a temporal meta-ROI (T; SUVR >1.40). Resulting groups were: A+P-T- (concordant, n=30), A+P+T- (discordant, n=48) and A+P+T+ (concordant, n=18). We additionally used 135 A- CU individuals (A- CU) as a reference group (Tables 1 and 2). Differences in annual change in regional tau-PET SUVR, cortical thickness and cognition between the A+P+T- group and the other groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures) education. Result: Longitudinal change in tau-PET was faster in the A+P+T- group than in the A- CU and A+P-T- groups across medial temporal and neocortical regions, with the medial temporal increases being more pronounced. The A+P+T- group showed slower rate of increases in tau-PET compared to the A+P+T+ group, primarily in neocortical regions (Figures 1 and 2). We did not detect differences in yearly change in cortical thickness (Figure 3) or in cognitive decline (Figure 3) between the A+P+T- and A+P-T- groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Conclusion: These findings suggest that the A+P+T- biomarker profile is associated with early tau accumulation, and with relative sparing of cortical thinning and cognitive decline compared to A+P+T+ individuals. Therefore, the A+P+T- group represents an interesting target-group for early anti-tau interventions and for examining the emergence of tau aggregates in early AD.
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| 7. |
- Groot, Colin, et al.
(författare)
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Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals
- 2023
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 146:4, s. 1580-1591
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Tidskriftsartikel (refereegranskat)abstract
- Different tau biomarkers become abnormal at different stages of Alzheimer's disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in Tau-PET, cortical thickness and cognitive decline in amyloid-β-positive (A+) individuals with elevated CSF P-tau levels (P+) but subthreshold Tau-PET retention (T-). To this end, individuals without dementia (i.e., cognitively unimpaired or mild cognitive impairment, N = 231) were selected from the BioFINDER-2 study. Amyloid-β-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF P-tau217 and [18F]RO948 (Tau) PET, yielding groups of tau-concordant-negative (A + P-T-; n = 30), tau-discordant (i.e., A + P+T-; n = 48) and tau-concordant-positive (A + P+T+; n = 18) individuals. In addition, 135 amyloid-β-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional Tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was ∼2 years. Longitudinal increase in Tau-PET was faster in the A + P+T- group than in the control and A + P-T- groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A + P+T- group showed a slower rate of increases in tau-PET compared to the A + P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A + P+T- and A + P-T- groups. The A + P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A + P+T- biomarker profile in persons without dementia is associated with an isolated effect on increased Tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring effects of interventions with disease modifying agents on tau accumulation in early Alzheimer's disease, and for examining the emergence of tau aggregates in Alzheimer's disease. Further, we suggest to update the AT(N) criteria for Alzheimer's disease biomarker classification to APT(N).
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| 8. |
- Horie, Kanta, et al.
(författare)
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CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
- 2023
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Ingår i: Nature Medicine. - 1078-8956. ; 29:8, s. 1954-1963
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R 2 ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R 2 ≤ 0.48) approached that of tau-PET (0.44 ≤ R 2 ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates (‘T’).
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| 9. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 10. |
- 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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| 11. |
- Leuzy, Antoine, et al.
(författare)
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Comparison of Group-Level and Individualized Brain Regions for Measuring Change in Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
- 2023
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Ingår i: JAMA Neurology. - 2168-6149. ; 80:6, s. 614-623
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Longitudinal tau positron emission tomography (PET) is a relevant outcome in clinical trials evaluating disease-modifying therapies in Alzheimer disease (AD). A key unanswered question is whether the use of participant-specific (individualized) regions of interest (ROIs) is superior to conventional approaches where the same ROI (group-level) is used for each participant. Objective: To compare group- and participant-level ROIs in participants at different stages of the AD clinical continuum in terms of annual percentage change in tau-PET standardized uptake value ratio (SUVR) and sample size requirements. Design, Setting, and Participants: This was a longitudinal cohort study with consecutive participant enrollment between September 18, 2017, and November 15, 2021. Included in the analysis were participants with mild cognitive impairment and AD dementia from the prospective and longitudinal Swedish Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably 2 (BioFINDER-2) study; in addition, a validation sample (the AVID 05e, Expedition-3, Alzheimer's Disease Neuroimaging Initiative [ADNI], and BioFINDER-1 study cohorts) was also included. Exposures: Tau PET (BioFINDER-2, [18F]RO948; validation sample, [18F]flortaucipir), 7 group-level (5 data-driven stages, meta-temporal, whole brain), and 5 individualized ROIs. Main Outcomes and Measures: Annual percentage change in tau-PET SUVR across ROIs. Sample size requirements in simulated clinical trials using tau PET as an outcome were also calculated. Results: A total of 215 participants (mean [SD] age, 71.4 (7.5) years; 111 male [51.6%]) from the BioFINDER-2 study were included in this analysis: 97 amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals, 77 with Aβ-positive mild cognitive impairment (MCI), and 41 with AD dementia. In the validation sample were 137 Aβ-positive CU participants, 144 with Aβ-positive MCI, and 125 with AD dementia. Mean (SD) follow-up time was 1.8 (0.3) years. Using group-level ROIs, the largest annual percentage increase in tau-PET SUVR in Aβ-positive CU individuals was seen in a composite ROI combining the entorhinal cortex, hippocampus, and amygdala (4.29%; 95% CI, 3.42%-5.16%). In individuals with Aβ-positive MCI, the greatest change was seen in the temporal cortical regions (5.82%; 95% CI, 4.67%-6.97%), whereas in those with AD dementia, the greatest change was seen in the parietal regions (5.22%; 95% CI, 3.95%-6.49%). Significantly higher estimates of annual percentage change were found using several of the participant-specific ROIs. Importantly, the simplest participant-specific approach, where change in tau PET was calculated in an ROI that best matched the participant's data-driven disease stage, performed best in all 3 subgroups. For the power analysis, sample size reductions for the participant-specific ROIs ranged from 15.94% (95% CI, 8.14%-23.74%) to 72.10% (95% CI, 67.10%-77.20%) compared with the best-performing group-level ROIs. Findings were replicated using [18F]flortaucipir. Conclusions and Relevance: Finding suggest that certain individualized ROIs carry an advantage over group-level ROIs for assessing longitudinal tau changes and increase the power to detect treatment effects in AD clinical trials using longitudinal tau PET as an outcome.
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| 12. |
- Mattsson-Carlgren, Niklas, et al.
(författare)
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Plasma Biomarker Strategy for Selecting Patients With Alzheimer Disease for Antiamyloid Immunotherapies
- 2024
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Ingår i: JAMA neurology. - 2168-6157 .- 2168-6149. ; 81:1, s. 69-78
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Tidskriftsartikel (refereegranskat)abstract
- Antiamyloid immunotherapies against Alzheimer disease (AD) are emerging. Scalable, cost-effective tools will be needed to identify amyloid β (Aβ)-positive patients without an advanced stage of tau pathology who are most likely to benefit from these therapies. Blood-based biomarkers might reduce the need to use cerebrospinal fluid (CSF) or positron emission tomography (PET) for this.To evaluate plasma biomarkers for identifying Aβ positivity and stage of tau accumulation.The cohort study (BioFINDER-2) was a prospective memory-clinic and population-based study. Participants with cognitive concerns were recruited from 2017 to 2022 and divided into a training set (80% of the data) and test set (20%).Baseline values for plasma phosphorylated tau 181 (p-tau181), p-tau217, p-tau231, N-terminal tau, glial fibrillary acidic protein, and neurofilament light chain.Performance to classify participants by Aβ status (defined by Aβ-PET or CSF Aβ42/40) and tau status (tau PET). Number of hypothetically saved PET scans in a plasma biomarker-guided workflow.Of a total 912 participants, there were 499 males (54.7%) and 413 females (45.3%), and the mean (SD) age was 71.1 (8.49) years. Among the biomarkers, plasma p-tau217 was most strongly associated with Aβ positivity (test-set area under the receiver operating characteristic curve [AUC]=0.94; 95% CI, 0.90-0.97). A 2-cut-point procedure was evaluated, where only participants with ambiguous plasma p-tau217 values (17.1% of the participants in the test set) underwent CSF or PET to assign definitive Aβ status. This procedure had an overall sensitivity of 0.94 (95% CI, 0.90-0.98) and a specificity of 0.86 (95% CI, 0.77-0.95). Next, plasma biomarkers were used to differentiate low-intermediate vs high tau-PET load among Aβ-positive participants. Plasma p-tau217 again performed best, with the test AUC=0.92 (95% CI, 0.86-0.97), without significant improvement when adding any of the other plasma biomarkers. At a false-negative rate less than 10%, the use of plasma p-tau217 could avoid 56.9% of tau-PET scans needed to identify high tau PET among Aβ-positive participants. The results were validated in an independent cohort (n=118).This study found that algorithms using plasma p-tau217 can accurately identify most Aβ-positive individuals, including those likely to have a high tau load who would require confirmatory tau-PET imaging. Plasma p-tau217 measurements may substantially reduce the number of invasive and costly confirmatory tests required to identify individuals who would likely benefit from antiamyloid therapies.
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| 13. |
- Meyer, Pierre-François, et al.
(författare)
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Plasma p-tau231, p-tau181, PET Biomarkers, and Cognitive Change in Older Adults.
- 2022
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 91:4, s. 548-560
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to evaluate novel plasma p-tau231 and p-tau181, as well as Aβ40 and Aβ42 assays as indicators of tau and Aβ pathologies measured with positron emission tomography (PET), and their association with cognitive change, in cognitively unimpaired older adults.In a cohort of 244 older adults at risk of Alzheimer's disease (AD) owing to a family history of AD dementia, we measured single molecule array (Simoa)-based plasma tau biomarkers (p-tau231 and p-tau181), Aβ40 and Aβ42 with immunoprecipitation mass spectrometry, and Simoa neurofilament light (NfL). A subset of 129 participants underwent amyloid-β (18 F-NAV4694) and tau (18 F-flortaucipir) PET assessments. We investigated plasma biomarker associations with Aβ and tau PET at the global and voxel level and tested plasma biomarker combinations for improved detection of Aβ-PET positivity. We also investigated associations with 8-year cognitive change.Plasma p-tau biomarkers correlated with flortaucipir binding in medial temporal, parietal, and inferior temporal regions. P-tau231 showed further associations in lateral parietal and occipital cortices. Plasma Aβ42/40 explained more variance in global Aβ-PET binding than Aβ42 alone. P-tau231 also showed strong and widespread associations with cortical Aβ-PET binding. Combining Aβ42/40 with p-tau231 or p-tau181 allowed for good distinction between Aβ-negative and -positive participants (area under the receiver operating characteristic curve [AUC] range=0.81-0.86). Individuals with low plasma Aβ42/40 and high p-tau experienced faster cognitive decline.Plasma p-tau231 showed more robust associations with PET biomarkers than p-tau181 in presymptomatic individuals. The combination of p-tau and Aβ42/40 biomarkers detected early AD pathology and cognitive decline. Such markers could be used as prescreening tools to reduce the cost of prevention trials. ANN NEUROL 2022.
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| 14. |
- Nilsson, Johanna, 1993, et al.
(författare)
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Cerebrospinal fluid biomarker panel for synaptic dysfunction in a broad spectrum of neurodegenerative diseases.
- 2024
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Ingår i: Brain : a journal of neurology. - 1460-2156.
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic dysfunction and degeneration is likely the key pathophysiology for the progression of cognitive decline in various dementia disorders. Synaptic status can be monitored by measurement of synaptic proteins in cerebrospinal fluid (CSF). In the current study, the aim was to investigate and compare both known and new synaptic proteins as potential biomarkers of synaptic dysfunction, especially in the context of Alzheimer's disease (AD). Seventeen synaptic proteins were quantified in CSF using two different targeted mass spectrometry assays in the prospective Swedish BioFINDER-2 study. The study included 958 individuals, characterized as having mild cognitive impairment (MCI, n=205), AD dementia (n=149), and a spectrum of other neurodegenerative diseases (n=171), as well as cognitively unimpaired (CU, n=443). Synaptic protein levels were compared between diagnostic groups and their associations with cognitive decline and key neuroimaging measures (Aβ-PET, tau-PET, and cortical thickness) were assessed. Among the 17 synaptic proteins examined, 14 were specifically elevated in the AD continuum. SNAP-25, 14-3-3 zeta/delta, beta-synuclein, and neurogranin exhibited the highest discriminatory accuracy to differentiate AD dementia from controls (AUCs=0.81-0.93). SNAP-25 and 14-3-3 zeta/delta also had the strongest associations with tau-PET, Aβ-PET, and cortical thickness at baseline, and were associated with longitudinal changes in these imaging biomarkers (β(SE)=-0.056(0.0006) to 0.058(0.005), p<0.0001). SNAP-25 was the strongest predictor of progression to AD dementia in non-demented individuals (Hazard ratio=2.11). In contrast, neuronal pentraxins were decreased in all neurodegenerative diseases (except for Parkinson's disease), and NPTX2 showed the strongest associations with subsequent cognitive decline (longitudinal MMSE; β(SE)=0.57(0.1), p≤0.0001 and mPACC; β(SE)=0.095(0.024), p≤0.001) across the AD continuum. Interestingly, utilizing a ratio of the proteins that displayed higher levels in AD, such as SNAP-25 or 14-3-3 zeta/delta, over NPTX2 improved the biomarkers' association with cognitive decline and brain atrophy. We found that especially 14-3-3 zeta/delta and SNAP-25 are promising synaptic biomarkers of pathophysiological changes in AD. Neuronal pentraxins were identified as general indicators of neurodegeneration and associated with cognitive decline across various neurodegenerative dementias. The ratios of SNAP-25/NPTX2 and 14-3-3 zeta/delta/NPTX2 were found to best predict cognitive decline and brain atrophy.
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| 15. |
- 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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| 16. |
- Ourry, Valentin, et al.
(författare)
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How Do Modifiable Risk Factors Affect Alzheimer's Disease Pathology or Mitigate Its Effect on Clinical Symptom Expression?
- 2024
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Ingår i: Biological Psychiatry. - 0006-3223. ; 95:11, s. 1006-1019
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Forskningsöversikt (refereegranskat)abstract
- Epidemiological studies show that modifiable risk factors account for approximately 40% of the population variability in risk of developing dementia, including sporadic Alzheimer's disease (AD). Recent findings suggest that these factors may also modify disease trajectories of people with autosomal-dominant AD. With positron emission tomography imaging, it is now possible to study the disease many years before its clinical onset. Such studies can provide key knowledge regarding pathways for either the prevention of pathology or the postponement of its clinical expression. The former “resistance pathway” suggests that modifiable risk factors could affect amyloid and tau burden decades before the appearance of cognitive impairment. Alternatively, the resilience pathway suggests that modifiable risk factors may mitigate the symptomatic expression of AD pathology on cognition. These pathways are not mutually exclusive and may appear at different disease stages. Here, in a narrative review, we present neuroimaging evidence that supports both pathways in sporadic AD and autosomal-dominant AD. We then propose mechanisms for their protective effect. Among possible mechanisms, we examine neural and vascular mechanisms for the resistance pathway. We also describe brain maintenance and functional compensation as bases for the resilience pathway. Improved mechanistic understanding of both pathways may suggest new interventions.
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| 17. |
- Pichet Binette, Alexa, et al.
(författare)
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Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer's disease
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 6635-6635
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Tidskriftsartikel (refereegranskat)abstract
- For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.
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| 18. |
- Pichet Binette, Alexa, et al.
(författare)
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Combining plasma phospho-tau and accessible measures to evaluate progression to Alzheimer's dementia in mild cognitive impairment patients
- 2022
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Up to now, there are no clinically available minimally invasive biomarkers to accurately identify mild cognitive impairment (MCI) patients who are at greater risk to progress to Alzheimer's disease (AD) dementia. The recent advent of blood-based markers opens the door for more accessible biomarkers. We aimed to identify which combinations of AD related plasma biomarkers and other easily accessible assessments best predict progression to AD dementia in patients with mild cognitive impairment (MCI). Methods: We included patients with amnestic MCI (n = 110) followed prospectively over 3 years to assess clinical status. Baseline plasma biomarkers (amyloid-beta 42/40, phosphorylated tau217 [p-tau217], neurofilament light and glial fibrillary acidic protein), hippocampal volume, APOE genotype, and cognitive tests were available. Logistic regressions with conversion to amyloid-positive AD dementia within 3 years as outcome was used to evaluate the performance of different biomarkers measured at baseline, used alone or in combination. The first analyses included only the plasma biomarkers to determine the ones most related to AD dementia conversion. Second, hippocampal volume, APOE genotype and a brief cognitive composite score (mPACC) were combined with the best plasma biomarker. Results: Of all plasma biomarker combinations, p-tau217 alone had the best performance for discriminating progression to AD dementia vs all other combinations (AUC 0.84, 95% CI 0.75-0.93). Next, combining p-tau217 with hippocampal volume, cognition, and APOE genotype provided the best discrimination between MCI progressors vs. non-progressors (AUC 0.89, 0.82-0.95). Across the few best models combining different markers, p-tau217 and cognition were consistently the main contributors. The most parsimonious model including p-tau217 and cognition had a similar model fit, but a slightly lower AUC (0.87, 0.79-0.95, p = 0 .07). Conclusion: We identified that combining plasma p-tau217 and a brief cognitive composite score was strongly related to greater risk of progression to AD dementia in MCI patients, suggesting that these measures could be key components of future prognostic algorithms for early AD.
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| 19. |
- Pichet Binette, Alexa, et al.
(författare)
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Confounding factors of Alzheimer's disease plasma biomarkers and their impact on clinical performance
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:4, s. 1403-1414
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Plasma biomarkers will likely revolutionize the diagnostic work-up of Alzheimer's disease (AD) globally. Before widespread use, we need to determine if confounding factors affect the levels of these biomarkers, and their clinical utility. Methods Participants with plasma and CSF biomarkers, creatinine, body mass index (BMI), and medical history data were included (BioFINDER-1: n = 748, BioFINDER-2: n = 421). We measured beta-amyloid (A beta 42, A beta 40), phosphorylated tau (p-tau217, p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Results In both cohorts, creatinine and BMI were the main factors associated with NfL, GFAP, and to a lesser extent with p-tau. However, adjustment for BMI and creatinine had only minor effects in models predicting either the corresponding levels in CSF or subsequent development of dementia. Discussion Creatinine and BMI are related to certain plasma biomarkers levels, but they do not have clinically relevant confounding effects for the vast majority of individuals. Highlights Creatinine and body mass index (BMI) are related to certain plasma biomarker levels. Adjusting for creatinine and BMI has minor influence on plasma-cerebrospinal fluid (CSF) associations. Adjusting for creatinine and BMI has minor influence on prediction of dementia using plasma biomarkers.
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| 20. |
- Qiu, Ting, et al.
(författare)
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Structural white matter properties and cognitive resilience to tau pathology
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Ingår i: Alzheimer's and Dementia. - 1552-5260.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We assessed whether macro- and/or micro-structural white matter properties are associated with cognitive resilience to Alzheimer's disease pathology years prior to clinical onset. METHODS: We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid-β/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties. RESULTS: Higher global efficiency of the limbic network, as well as free-water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both networks. DISCUSSION: White matter can influence cognitive resilience against tau pathology, and promoting education and vascular health may enhance optimal white matter properties. Highlights: Aβ and tau were associated with longitudinal memory change over ∼7.5 years. White matter properties attenuated the impact of tau pathology on memory change. Health/risk factors were associated with white matter properties.
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| 21. |
- Salvadó, Gemma, et al.
(författare)
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Disease staging of Alzheimer’s disease using a CSF-based biomarker model
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Ingår i: Nature Aging.
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Tidskriftsartikel (refereegranskat)abstract
- Biological staging of individuals with Alzheimer’s disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort. SuStaIn identified a singular biomarker sequence and revealed that five CSF biomarkers effectively constituted a reliable staging model (ordered: Aβ42/40, pT217/T217, pT205/T205, MTBR-tau243 and non-phosphorylated mid-region tau). The CSF stages (0–5) demonstrated a correlation with increased abnormalities in other AD-related biomarkers, such as Aβ-PET and tau-PET, and aligned with longitudinal biomarker changes reflective of AD progression. Higher CSF stages at baseline were associated with an elevated hazard ratio of clinical decline. This study highlights a common molecular pathway underlying AD pathophysiology across all patients, suggesting that a single CSF collection can accurately indicate the presence of AD pathologies and characterize the stage of disease progression. The proposed staging model has implications for enhancing diagnostic and prognostic assessments in both clinical practice and the design of clinical trials.
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| 22. |
- Smith, Ruben, et al.
(författare)
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Tau-PET is superior to phospho-tau when predicting cognitive decline in symptomatic AD patients
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2497-2507
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials. Methods: We evaluated the ability of tau-PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau-217, neurofilament light (NfL), and amyloid beta (Aβ)42/40 ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER-2 and Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: Baseline tau-PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline. Cortical thickness and NfL provided some additional information. Using a predictive algorithm to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. Discussion: Models including baseline tau-PET and cognition consistently provided the best prediction of change in cognitive function over 2 years in patients with amnestic MCI or mild dementia.
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| 23. |
- St-Onge, Frédéric, et al.
(författare)
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Functional connectome fingerprinting across the lifespan
- 2023
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Ingår i: Network Neuroscience. - 2472-1751. ; 7:3, s. 1206-1227
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Tidskriftsartikel (refereegranskat)abstract
- Systematic changes have been observed in the functional architecture of the human brain with advancing age. However, functional connectivity (FC) is also a powerful feature to detect unique “connectome fingerprints,” allowing identification of individuals among their peers. Although fingerprinting has been robustly observed in samples of young adults, the reliability of this approach has not been demonstrated across the lifespan. We applied the fingerprinting framework to the Cambridge Centre for Ageing and Neuroscience cohort (n = 483 aged 18 to 89 years). We found that individuals are “fingerprintable” (i.e., identifiable) across independent functional MRI scans throughout the lifespan. We observed a U-shape distribution in the strength of “self-identifiability” (within-individual correlation across modalities), and “others-identifiability” (between-individual correlation across modalities), with a decrease from early adulthood into middle age, before improving in older age. FC edges contributing to self-identifiability were not restricted to specific brain networks and were different between individuals across the lifespan sample. Self-identifiability was additionally associated with regional brain volume. These findings indicate that individual participant-level identification is preserved across the lifespan despite the fact that its components are changing nonlinearly.
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| 24. |
- St-Onge, Frédéric, et al.
(författare)
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Tau accumulation and its spatial progression across the Alzheimer’s disease spectrum
- 2024
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Ingår i: Brain Communications. - 2632-1297. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of tau abnormality in sporadic Alzheimer’s disease is believed typically to follow neuropathologically defined Braak staging. Recent in-vivo PET evidence challenges this belief, however, as accumulation patterns for tau appear heterogeneous among individuals with varying clinical expressions of Alzheimer’s disease. We, therefore, sought a better understanding of the spatial distribution of tau in the preclinical and clinical phases of sporadic Alzheimer’s disease and its association with cognitive decline. Longitudinal tau-PET data (1370 scans) from 832 participants (463 cognitively unimpaired, 277 with mild cognitive impairment and 92 with Alzheimer’s disease dementia) were obtained from the Alzheimer’s Disease Neuroimaging Initiative. Among these, we defined thresholds of abnormal tau deposition in 70 brain regions from the Desikan atlas, and for each group of regions characteristic of Braak staging. We summed each scan’s number of regions with abnormal tau deposition to form a spatial extent index. We then examined patterns of tau pathology cross-sectionally and longitudinally and assessed their heterogeneity. Finally, we compared our spatial extent index of tau uptake with a temporal meta-region of interest—a commonly used proxy of tau burden—assessing their association with cognitive scores and clinical progression. More than 80% of amyloid-beta positive participants across diagnostic groups followed typical Braak staging, both cross-sectionally and longitudinally. Within each Braak stage, however, the pattern of abnormality demonstrated significant heterogeneity such that the overlap of abnormal regions across participants averaged less than 50%, particularly in persons with mild cognitive impairment. Accumulation of tau progressed more rapidly among cognitively unimpaired and participants with mild cognitive impairment (1.2 newly abnormal regions per year) compared to participants with Alzheimer’s disease dementia (less than 1 newly abnormal region per year). Comparing the association of tau pathology and cognitive performance our spatial extent index was superior to the temporal meta-region of interest for identifying associations with memory in cognitively unimpaired individuals and explained more variance for measures of executive function in patients with mild cognitive impairments and Alzheimer’s disease dementia. Thus, while participants broadly followed Braak stages, significant individual regional heterogeneity of tau binding was observed at each clinical stage. Progression of the spatial extent of tau pathology appears to be fastest in cognitively unimpaired and persons with mild cognitive impairment. Exploring the spatial distribution of tau deposits throughout the entire brain may uncover further pathological variations and their correlation with cognitive impairments.
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| 25. |
- Strikwerda-Brown, Cherie, et al.
(författare)
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Association of Elevated Amyloid and Tau Positron Emission Tomography Signal with Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment
- 2022
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 79:10, s. 975-985
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Tidskriftsartikel (refereegranskat)abstract
- Importance: National Institute on Aging-Alzheimer's Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD). Objective: To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD. Design, Setting, and Participants: This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years. Exposures: Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T-, A-T+, A-T-). Presence (+) or absence (-) of neurodegeneration (N) was assessed using temporal cortical thickness. Main Outcomes and Measures: Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups. Results: Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable. Conclusions and Relevance: The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years..
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| 26. |
- Wuestefeld, Anika, et al.
(författare)
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Age-related and amyloid-beta-independent tau deposition and its downstream effects
- 2023
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 146:8, s. 3192-3205
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.
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| 27. |
- Wuestefeld, Anika, et al.
(författare)
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Age-related tau-PET uptake and its downstream effects extend beyond the medial temporal lobe in cognitively normal older adults
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyloid-beta (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe (MTL). However, there is evidence that age-related Aβ-independent tau pathology is present outside the MTL (Kaufman et al., Acta Neuropathol, 2018). We examine tau deposition determined by positron emission tomography (PET) in regions typically involved earlier/later in AD and downstream effects on neurodegeneration and cognition in cognitively unimpaired older adults and a low-Aβ subgroup. Methods: We included 488 adults (40-91 years; low-Aβ: n=355, 65.2±11.5 years) from the BioFINDER-2 study. MTL volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex) were obtained, using Automated Segmentation for Hippocampal Subfields packages for T1- and T2-weighted magnetic resonance images. Thickness of early/late neocortical AD-regions (anterior cingulate, precuneus/posterior cingulate (PPC), orbitofrontal, inferior parietal cortex; and middle frontal, lateral occipital, and precentral/postcentral gyrus) was determined using FreeSurfer. [18F]RO948- and [18F]flutemetamol-PET standardized uptake value ratios (SUVRs) were calculated for local tau and global/local Aβ. Aβ status was determined using Aβ-PET or cerebrospinal fluid Aβ-42/40 ratio. Global cognition was measured using delayed word-list recall, trail making test B, and animal fluency. Results: Increasing age was associated with higher tau-PET SUVRs primarily in MTL/frontal/parietal regions. A significant association between age and local tau-PET remained even when including Aβ-PET as a mediator (Fig. 1). Age and local tau-PET, but not Aβ-PET, where negatively associated with structure in most examined regions (Figs. 2-3). Age-structure associations were serially mediated via tau-PET in regions with early AD pathology (SUB/BA35/PPC). Also, in the low-Aβ subgroup, tau-PET mediated the age-structure (SUB/BA35/PPC) associations (Fig. 3D). Finally, the age-global cognition relationship was serially mediated via MTL tau-PET and subiculum volume, even when including global Aβ-PET as additional mediator (Fig. 4). Conclusion: We observe partially Aβ-independent associations between age and tau-PET signal across the neocortex. Interestingly, partially Aβ-independent tau-PET signal appears to mediate the age-structure associations in and outside the MTL (PPC), also in the low-Aβ group, and the age-MTL structure-cognition associations. This potentially provides in vivo support for Primary Age-related Tauopathy downstream effects on structure, beyond the MTL, and cognition.
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- Wuestefeld, Anika, et al.
(författare)
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Medial temporal lobe atrophy patterns in early- versus late-onset amnestic Alzheimer's disease
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfield volumes and drivers of atrophy in amnestic EOAD is lacking.METHODS: BioFINDER-2 participants with memory impairment, abnormal amyloid-β status and tau-PET were included. Forty-one EOAD individuals aged ≤65 years and, as comparison, late-onset AD (LOAD, ≥70 years, n=154) and Aβ-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured.RESULTS: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups, although LOAD showed thinner entorhinal cortices compared to EOAD. EOAD showed lower WMH compared to LOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity was found.CONCLUSIONS: We found in vivo evidence for MTL atrophy in amnestic EOAD and overall similar levels to LOAD of MTL tau pathology and co-pathologies.
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