| 1. |
- Moseby-Knappe, Marion, et al.
(författare)
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Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest
- 2021
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Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 47, s. 984-994
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The majority of unconscious patients after cardiac arrest (CA) do not fulfill guideline criteria for a likely poor outcome, their prognosis is considered "indeterminate". We compared brain injury markers in blood for prediction of good outcome and for identifying false positive predictions of poor outcome as recommended by guidelines. Methods Retrospective analysis of prospectively collected serum samples at 24, 48 and 72 h post arrest within the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Clinically available markers neuron-specific enolase (NSE) and S100B, and novel markers neurofilament light chain (NFL), total tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were analysed. Normal levels with a priori cutoffs specified by reference laboratories or defined from literature were used to predict good outcome (no to moderate disability, Cerebral Performance Category scale 1-2) at 6 months. Results Seven hundred and seventeen patients were included. Normal NFL, tau and GFAP had the highest sensitivities (97.2-98% of poor outcome patients had abnormal serum levels) and NPV (normal levels predicted good outcome in 87-95% of patients). Normal S100B and NSE predicted good outcome with NPV 76-82.2%. Normal NSE correctly identified 67/190 (35.3%) patients with good outcome among those classified as "indeterminate outcome" by guidelines. Five patients with single pathological prognostic findings despite normal biomarkers had good outcome. Conclusion Low levels of brain injury markers in blood are associated with good neurological outcome after CA. Incorporating biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining therapy.
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| 2. |
- Berron, David, et al.
(författare)
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Early stages of tau pathology and its associations with functional connectivity, atrophy and memory
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2771-2783
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Tidskriftsartikel (refereegranskat)abstract
- In Alzheimer's disease, post-mortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with Brodmann area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 amyloid-β- cognitively unimpaired, 81 amyloid-β+ cognitively unimpaired and 87 amyloid-β+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, Brodmann area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease stage-specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.
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| 3. |
- Bjurstrom, M. F., et al.
(författare)
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Preoperative sleep quality and adverse pain outcomes after total hip arthroplasty
- 2021
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Ingår i: Eur J Pain. - : Wiley. ; 25:7, s. 1482-1492
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sleep disturbance is thought to aggravate acute postoperative pain. The influence of preoperative sleep problems on pain control in the long-term and development of chronic postsurgical pain is largely unknown. METHODS: This prospective, observational study aimed to examine the links between preoperative sleep disturbance (Pittsburgh Sleep Quality Index, PSQI) and pain severity (Brief Pain Inventory, BPI) 6 months postoperative (primary outcome), objective measures of pain and postoperative pain control variables (secondary outcomes). Patients (n = 52) with disabling osteoarthritis (OA) pain undergoing total hip arthroplasty (THA) were included. Quantitative sensory testing (QST) was performed preoperatively on the day of surgery to evaluate pain objectively. Clinical data, as well as measures of sleep quality and pain, were obtained preoperatively and longitudinally over a 6-month period. RESULTS: Preoperatively, sleep disturbance (i.e., PSQI score >5) occurred in 73.1% (n = 38) of THA patients, and pain severity was high (BPI pain severity 5.4 +/- 1.3). Regression models, adjusting for relevant covariates, showed that preoperative PSQI score predicted pain severity 6 months postoperative (beta = 0.091 (95% CI 0.001-0.181), p = .048, R(2) = 0.35). Poor sleep quality was associated with increased pressure pain sensitivity and impaired endogenous pain inhibitory capacity (R(2) range 0.14-0.33, all p's < 0.04). Moreover, preoperative sleep disturbance predicted increased opioid treatment during the first 24 hr after surgery (unadjusted beta = 0.009 (95% CI 0.002-0.015) mg/kg, p = .007, R(2) = 0.15). CONCLUSIONS: Preoperative sleep disturbance is prevalent in THA patients, is associated with objective measures of pain severity, and independently predicts immediate postoperative opioid treatment and poorer long-term pain control in patients who have undergone THA. SIGNIFICANCE: Poor sleep quality and impaired sleep continuity are associated with heightened pain sensitivity, but previous work has not evaluated whether preoperative sleep problems impact long-term postoperative pain outcomes. Here, we show that sleep difficulties prior to total hip arthroplasty adversely predict postoperative pain control 6 months after surgery. Given sleep difficulties robustly predict pain outcomes, targeting and improving sleep may have salutary effects on postoperative pain reports and management.
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| 4. |
- Cicognola, Claudia, et al.
(författare)
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Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment
- 2021
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Plasma glial fibrillary acidic protein (GFAP) is a marker of astroglial activation and astrocytosis. We assessed the ability of plasma GFAP to detect Alzheimer’s disease (AD) pathology in the form of AD-related amyloid-β (Aβ) pathology and conversion to AD dementia in a mild cognitive impairment (MCI) cohort. Method: One hundred sixty MCI patients were followed for 4.7 years (average). AD pathology was defined using cerebrospinal fluid (CSF) Aβ42/40 and Aβ42/total tau (T-tau). Plasma GFAP was measured at baseline and follow-up using Simoa technology. Results: Baseline plasma GFAP could detect abnormal CSF Aβ42/40 and CSF Aβ42/T-tau with an AUC of 0.79 (95% CI 0.72–0.86) and 0.80 (95% CI 0.72–0.86), respectively. When also including APOE ε4 status as a predictor, the accuracy of the model to detect abnormal CSF Aβ42/40 status improved (AUC = 0.86, p = 0.02). Plasma GFAP predicted subsequent conversion to AD dementia with an AUC of 0.84 (95% CI 0.77–0.91), which was not significantly improved when adding APOE ε4 or age as predictors to the model. Longitudinal GFAP slopes for Aβ-positive and MCI who progressed to dementia (AD or other) were significantly steeper than those for Aβ-negative (p = 0.007) and stable MCI (p < 0.0001), respectively. Conclusion: Plasma GFAP can detect AD pathology in patients with MCI and predict conversion to AD dementia.
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| 5. |
- Cullen, Nicholas C., et al.
(författare)
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Accelerated inflammatory aging in Alzheimer’s disease and its relation to amyloid, tau, and cognition
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- It is unclear how pathological aging of the inflammatory system relates to Alzheimer’s disease (AD). We tested whether age-related inflammatory changes in cerebrospinal fluid (CSF) and plasma exist across different stages of AD, and whether such changes related to AD pathology. Linear regression was first used model chronological age in amyloid-β negative, cognitively unimpaired individuals (Aβ− CU; n = 312) based on a collection of 73 inflammatory proteins measured in both CSF and plasma. Fitted models were then applied on protein levels from Aβ+ individuals with mild cognitive impairment (Aβ+ MCI; n = 150) or Alzheimer’s disease dementia (Aβ+ AD; n = 139) to test whether the age predicted from proteins alone (“inflammatory age”) differed significantly from true chronological age. Aβ− individuals with subjective cognitive decline (Aβ− SCD; n = 125) or MCI (Aβ− MCI; n = 104) were used as an independent contrast group. The difference between inflammatory age and chronological age (InflammAGE score) was then assessed in relation to core AD biomarkers of amyloid, tau, and cognition. Both CSF and plasma inflammatory proteins were significantly associated with age in Aβ− CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the Aβ− SCD and validation Aβ− CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in Aβ− MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the Aβ+ MCI and Aβ+ AD groups, with varying degrees of change compared to Aβ− CU and Aβ− SCD groups. Finally, CSF inflammatory changes were highly correlated with amyloid, tau, general neurodegeneration, and cognition, while plasma changes were mostly associated with amyloid and cognition. Inflammatory pathways change during aging and are specifically altered in AD, tracking closely with pathological hallmarks. These results have implications for tracking AD progression and for suggesting possible pathways for drug targeting.
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| 6. |
- Cullen, Nicholas C., et al.
(författare)
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Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations
- 2021
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Ingår i: Nature Aging. - : Springer Science and Business Media LLC. - 2662-8465. ; 1, s. 114-123
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Tidskriftsartikel (refereegranskat)abstract
- We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of β-amyloid (Aβ), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outcomes were longitudinal cognition and conversion to Alzheimer’s disease (AD) dementia. A model combining tau phosphorylated at threonine 181 (P-tau181) and neurofilament light (NfL), but not Aβ42/Aβ40, had the best prognosis performance of all models (area under the curve = 0.88 for 4-year conversion to AD in BioFINDER, validated in ADNI), was stronger than a basic model of age, sex, education and baseline cognition, and performed similarly to cerebrospinal fluid biomarkers. A publicly available online tool for individualized prognosis in MCI based on our combined plasma biomarker models is introduced. Combination of plasma biomarkers may be of high value to identify individuals with MCI who will progress to AD dementia in clinical trials and in clinical practice.
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| 7. |
- Cullen, Nicholas C., et al.
(författare)
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Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ± 1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in cognition (Pre-Alzheimer’s Clinical Composite; R2 = 0.14, 95% CI [0.12–0.17]; P < 0.0001) and subsequent AD dementia (AUC = 0.82, 95% CI [0.77–0.91], P < 0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54–81]; P < 0.001) with cognition as trial endpoint, and by 63% (95% CI [53–70], P < 0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.
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| 8. |
- Gertje, Eske Christiane, et al.
(författare)
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Association of Enlarged Perivascular Spaces and Measures of Small Vessel and Alzheimer Disease
- 2021
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Ingår i: Neurology. - 1526-632X. ; 96:2, s. 193-202
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the relationship between enlarged perivascular spaces (EPVS) and measures of Alzheimer disease (AD), small vessel disease (SVD), cognition, vascular risk factors, and neuroinflammation, we tested associations between EPVS and different relevant neuroimaging, biochemical, and cognitive variables in 778 study participants. METHODS: Four hundred ninety-nine cognitively unimpaired (CU) individuals, 240 patients with mild cognitive impairment, and 39 patients with AD from the Swedish Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study were included. EPVS with diameter >1 mm in centrum semiovale (CSO), basal ganglia (BG), and hippocampus (HP); hippocampal volume; white matter lesions (WML); and other SVD markers were determined from MRI. CSF levels of β-amyloid42 (Aβ42), phosphorylated tau, total tau, and neuroinflammatory markers; amyloid accumulation determined with [18F]-flutemetamol PET; and vascular risk factors and results from cognitive tests were determined and collected. RESULTS: EPVS in CSO, BG, and HP were associated with WML volume and Fazekas score in individuals without dementia. No associations were found between EPVS and CSF Aβ42, total tau and phosphorylated tau, neuroinflammatory markers, vascular risk factors, and cognitive tests. EPVS in HP were associated with hippocampal atrophy. In a matched group of individuals with AD and CU, EPVS in HP were associated with AD diagnosis. CONCLUSIONS: EPVS are related to SVD, also in early disease stages, but the lack of correlation with cognition suggests that their importance is limited. Our data do not support a role for EPVS in early AD pathogenesis.
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| 9. |
- Hansson, Oskar, et al.
(författare)
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Plasma phosphorylated tau181 and neurodegeneration in Alzheimer’s disease
- 2021
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 8:1, s. 259-265
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Tidskriftsartikel (refereegranskat)abstract
- We examined if plasma phosphorylated tau is associated with neurodegeneration in Alzheimer’s disease. We investigated 372 cognitively unimpaired participants, 554 mild cognitive impairment patients, and 141 Alzheimer’s disease dementia patients. Tau phosphorylated at threonine 181, regional cortical thickness (using magnetic resonance imaging) and hypometabolism (using fluorodeoxyglucose positron emission tomography) were measured longitudinally. High plasma tau was associated with hypometabolism and cortical atrophy at baseline and over time, and longitudinally increased tau was associated with accelerated atrophy, but these associations were only observed in Aβ-positive participants. Plasma phosphorylated tau may identify and track processes linked to neurodegeneration in Alzheimer’s disease.
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| 10. |
- Insel, Philip S., et al.
(författare)
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Association between Apolipoprotein e ϵ2 vs ϵ4, Age, and β-Amyloid in Adults without Cognitive Impairment
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:2, s. 229-229
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Although the most common recent approach in Alzheimer disease drug discovery is to directly target the β-amyloid (Aβ) pathway, the high prevalence of apolipoprotein E ϵ4 (APOE ϵ4) in Alzheimer disease and the ease of identifying ϵ4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow Aβ accumulation. Objective: To determine whether the ϵ2 allele is protective against Aβ accumulation in the presence of the ϵ4 allele and evaluate how age and the APOE genotype are associated with emerging Aβ accumulation and cognitive dysfunction. Design, Setting, and Participants: This cross-sectional study used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study) collected from April 2014 to December 2017 and analyzed from November 2019 to July 2020. Of the 6943 participants who were a part of the multicenter clinical trial screening visit, 4432 were adults without cognitive impairment aged 65 to 85 years who completed a fluorine 18-labeled (18F)-florbetapir positron emission tomography scan, had APOE genotype information, and had a Clinical Dementia Rating of 0. Participants who were taking a prescription Alzheimer medication or had a current serious or unstable illness that could interfere with the study were excluded. Main Outcomes and Measures: Aβ pathology, measured by 18F-florbetapir positron emission tomography and cognition, measured by the Preclinical Alzheimer Cognitive Composite. Results: A total of 4432 participants were included (mean [SD] age, 71.3 [4.7] years; 2634 women [59.4%]), with a mean (SD) of 16.6 (2.8) years of education and 1512 (34.1%) with a positive Aβ level. APOE ϵ2 was associated with a reduction in both the overall (standardized uptake value ratio [SUVR], ϵ24, 1.11 [95% CI, 1.08-1.14]; ϵ34, 1.18 [95% CI, 1.17-1.19]) and the age-dependent level of Aβ in the presence of ϵ4, with Aβ levels in the APOE ϵ24 group (n = 115; ϵ24, 0.005 SUVR increase per year of age) increasing at less than half the rate with respect to increasing age compared with the APOE ϵ34 group (n = 1295; 0.012 SUVR increase per year of age; P =.04). The association between Aβ and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOE genotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE ϵ4 carriers compared with noncarriers was completely mediated by Aβ (unadjusted difference in composite scores between ϵ4 carriers and noncarriers = -0.084, P =.005; after adjusting for 18F-florbetapir = -0.006, P =.85; after adjusting for 18F-florbetapir and cardiovascular scores = -0.009, P =.78). Conclusions and Relevance: These findings suggest that the protective outcome of carrying an ϵ2 allele in the presence of an ϵ4 allele against Aβ accumulation is important for potential treatments that attempt to biochemically mimic the function of the ϵ2 allele in order to facilitate Aβ clearance in ϵ4 carriers. Such a treatment strategy is appealing, as ϵ4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia. This strategy could represent an early treatment option, as many ϵ4 carriers begin to accumulate Aβ in early middle age..
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| 11. |
- Insel, Philip S., et al.
(författare)
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Time between milestone events in the Alzheimer's disease amyloid cascade
- 2021
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119. ; 227
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Estimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer's disease. Methods: In a cohort of 335 older adults, ranging in cognitive functioning, we estimated the time of initial changes of Aβ, tau, and decreases in cognition with respect to the time of Aβ-positivity. Results: Small effect sizes of change in CSF Aβ42 and regional Aβ PET were estimated to occur several decades before Aβ-positivity. Increases in CSF tau occurred 7–8 years before Aβ-positivity. Temporoparietal tau PET showed increases 4–5 years before Aβ-positivity. Subtle cognitive dysfunction was observed 4–6 years before Aβ-positivity. Conclusions: Increases in tau and cognitive dysfunction occur years before commonly used thresholds for Aβ-positivity. Explicit estimates of the time for these events provide a clearer picture of the time-course of the amyloid cascade and identify potential windows for specific treatments.
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| 12. |
- Janelidze, Shorena, et al.
(författare)
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Associations of Plasma Phospho-Tau217 Levels with Tau Positron Emission Tomography in Early Alzheimer Disease
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:2, s. 149-149
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Tidskriftsartikel (refereegranskat)abstract
- Importance: There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes. Objective: To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology. Design, Setting, and Participants: This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans. Main Outcomes and Measures: Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures. Results: Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P =.02). Conclusions and Relevance: In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.
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| 13. |
- Johansson, Maurits, et al.
(författare)
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Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Mild behavioral impairment (MBI) is suggested as risk marker for neurodegenerative diseases, such as Alzheimer's disease (AD). Recently, pathologic tau deposition in the brain has been shown closely related to clinical manifestations, such as cognitive deficits. Yet, associations between tau pathology and MBI have rarely been investigated. It is further debated if MBI precedes cognitive deficits in AD. Here, we explored potential mechanisms by which MBI is related to AD, this by studying associations between MBI and tau in preclinical AD. In all, 50 amyloid-beta -positive cognitively unimpaired subjects (part of the BioFINDER-2 study) underwent MBI-checklist (MBI-C) to assess MBI, and the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) delayed word recall (ADAS-DR) to assess episodic memory. Early tau pathology was determined using tau-PET ([F-18]RO948 retention in entorhinal cortex/hippocampus) and cerebrospinal fluid (CSF) P-tau(181). Regression models were used to test for associations. We found that higher tau-PET signal in the entorhinal cortex/hippocampus and CSF P-tau(181) levels were associated with higher MBI-C scores (beta =0.010, SE=0.003, p=0.003 and beta =1.263, SE=0.446, p=0.007, respectively). When MBI-C and ADAS-DR were entered together in the regression models, tau-PET (beta =0.009, p=0.009) and CSF P-tau(181) (beta =0.408, p=0.006) were predicted by MBI-C, but not ADAS-DR. We conclude that in preclinical AD, MBI is associated with tau independently from memory deficits. This denotes MBI as an important early clinical manifestation related to tau pathology in AD.
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| 14. |
- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 15. |
- Kumar, Atul, et al.
(författare)
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Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer’s disease
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence, and educational attainment) to predict longitudinal cognitive change (measured by mini-mental state examination (MMSE) [primary outcome] and other cognitive tests) over a mean of 4.2 years. We included 260 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 121 Aβ-positive CU (preclinical AD), 50 Aβ-negative mild cognitive impairment (MCI) patients, and 127 Aβ-positive MCI patients (prodromal AD). Statistical significance was determined at Bonferroni corrected p value < 0.05. The PGS for intelligence (beta = 0.1, p = 2.9e−02) was protective against decline in MMSE in CU and MCI participants regardless of Aβ status. The polygenic risk score for AD (beta = − 0.12, p = 9.4e−03) was correlated with the rate of change in MMSE and was partially mediated by Aβ-pathology (mediation effect 20%). There was no effect of education PGS on cognitive measures. Genetic variants associated with intelligence mitigate cognitive decline independent of Aβ-pathology, while effects of genetic variants associated with AD are partly mediated by Aβ-pathology.
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| 16. |
- Kumar, Atul, et al.
(författare)
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Genetic influence during the early phases of Alzheimer's disease on longitudinal cognitive impairment
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The rate of cognitive decline in the early stages of Alzheimer's disease (AD) is variable, which may be partly due to genetic factors. We therefore investigated genetic predictors of longitudinal cognitive decline in AD. METHOD: In the Swedish BioFINDER study, we used polygenic scores (PGS) (of AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal change in cognition (measured by MMSE) over a mean of 4.2 years. We included 555 b-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Mixed-effect models were fitted with longitudinal MMSE data as dependent variable. Random slopes and intercepts were extracted and were rank-based inverse normal transformed (INT) to be used as dependent variables in linear regression models. RESULT: AD polygenic risk score (PRS) and intelligence PGS (but not education PGS) were associated with rate of cognitive decline (Figure 1). The AD PRS was only associated with decline in Ab-positive individuals, but the intelligence PGS was protective irrespective of Ab-status (Figure 2). The model containing only the APOE burden (ε4 and ε2 counts) was associated with cognitive decline with a nominal level of significance, whereas this was not found for the early-stage AD cohort (Figure 1 and 2). Our GWAS identified 8 genes (out of which 3 genes independent of Aβ-status) associated with rate of cognitive decline at a p-value ≤ 5e-05 (Table 1). CONCLUSION: An a priori defined genetic risk score for AD was only associated with rate of cognitive decline in early stage AD (Aβ+ CU and Aβ+ MCI) and not in an unselected population, while a polygenic score for intelligence was protective irrespective of Aβ status. Together with novel genetic associations for rate of cognitive decline in AD, this may provide new insights into the pathophysiology of AD and new therapeutic development targets.
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| 17. |
- Kumar, Atul, et al.
(författare)
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Genetic interaction study of Alzheimer's disease quantitative biomarkers : A polygenic risk score analysis and evaluation
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Relationship between genetic factors and pathological features of Alzheimer's disease (AD) may be studied with biomarker, using both polygenic risk scores (PRSs), as well as individual genetic variants in genome-wide association studies (GWAS). METHOD: In the Swedish BioFINDER study, we used a priori PRS for AD based on findings in recent GWAS, and AD related biomarkers in cerebrospinal fluid (CSF) in cognitively unimpaired individuals (n = 751), Mild Cognitive Impairment (n = 212), and AD (n = 150) patients. AD related biomarkers were rank-based inverse normal transformed to be used as dependent variables in linear regression models adjusted for age, gender, education, APOE ε4, ε2 count and significant principal components. We also tested individual genetic variants in GWAS for each biomarker. Analyses were performed in the total sample, and after stratification on MMSE results. RESULT: The PRS was associated with higher CSF P-tau 181 (p ≤1.2e-05) and T-tau (p ≤ 8.14e-05) and lower CSF Aβ42/40 (p ≤ 0.006) and Aβ42 (p ≤ 0.04) (Figure 1, 2). Gene Enrichment of PRS 5 genes [containing 1850 genetic variants mapped to 1607 genes] for Tau biomarker showed 13 Gene Ontology (GO) Biological Process (BP) terms at p-value < e-03 ("Dendrite Morphogenesis": top hit; p-value ≤ 9.20e-06) and 16 KEGG pathway term enriched for genes of PRS 5 ("Phosphatidylinositol signaling system": top hit; p-value ≤ 5.5e-06) (Figure 3, 4). Gene enrichment of PRS 7 [containing 62 genetic variants mapped to 58 genes] for Aβ biomarker returned 12 GO terms ("Integrin-Mediated Signaling Pathway": top hit; p-value ≤1.20e-03) and 1 term enriched for KEGG pathway (Hematopoietic cell lineage). In our predefined list of genes interacting with MAPT (22 genes) and APP (69 genes) we found 3 genes from MAPT and APP set that were involved in PRS 5 and PRS 7 respectively. We also found 9 genes from APP set that was involved in PRS 5. CONCLUSION: Elevated levels of AD related biomarkers are associated with polygenic risk scores in AD. These findings further strengthens the link between genetic and biomarker disease predictors and indicate a potential role for these markers in disease prediction and patient stratification in AD.
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| 18. |
- Lagebrant, Alice, et al.
(författare)
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Brain injury markers in blood associate with generalised oedema on computed tomography after cardiac arrest
- 2021
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Ingår i: - : Springer Science and Business Media LLC. ; , s. 203-204
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Konferensbidrag (refereegranskat)abstract
- Introduction. According to the 2021 ERC/ESICM guideline recommen-dations, elevated neuron-specific enolase [NSE] levels as well as diffuseand extensive anoxic damage on neuroimaging are predictors of poorneurological outcome after cardiac arrest.(1) We previously describedthat NSE is elevated in patients with generalised oedema on com-puted tomography [CT]. (2).Objectives. In this study, we aim to examine the novel brain injurymarkers serum neurofilament light [NFL], glial fibrillary acidic protein[GFAP] and total-tau [tau] to predict the presence of generalised brainoedema.Methods. Retrospective analysis of patients examined with CT onclinical indication within the Target Temperature Management afterout-of-hospital cardiac arrest [TTM] trial. (2,3) Serum samples fromthe biobank sub study were prospectively collected at 48 h post arrestand analysed after trial completion as published. (4–7) The neuronalmarker NSE, the neuroaxonal injury markers NFL and tau and theastrocytic injury marker GFAP were correlated with the presence ofgeneralised oedema on CT, assessed by local radiologists through vis-ual evaluation. The prognostic accuracy of NSE ≥ 60 ug/l for predictinggeneralised oedema was also analysed.Results. 192 patients had data available on all four biomarkers at 48 hand were examined with CT < 168 h post arrest. Brain injury markerswere significantly higher in patients with generalised oedema as com-pared to patients without oedema on CT scans performed 24–168 hafter ROSC (p < 0.001) (Fig. 1A–D). For CT scans performed < 24 h, onlyNSE levels showed a significant correlation (p < 0.05). Biomarkers pre -dicted generalised oedema with area under the receiver operatingcharacteristics curve [AUC] 67.5–73.2% for CT scans performed < 24 h(n = 111), with no statistically significant difference between themarkers ( Fig. 2A). For scans performed 24–168 h (n = 81) AUC for pre -dicting generalised oedema was 78.1%-82.9%, with no statisticallysignificant difference between the markers. NSE ≥ 60 ug/l at 48 h, asrecommended by guidelines, predicted generalised oedema with 81%(95%CI 67–90%) sensitivity and 77% (95%CI 62–87%) specificity.Conclusion. Concentrations of all evaluated brain injury markerswere significantly higher in patients with generalised oedema on CTperformed after the first 24 h post arrest. Biomarker concentrationsindicate whether generalised oedema on CT is likely and may thus beclinically useful for deciding if a CT scan is sufficient for prognostica-tion or if a MRI is more appropriate.
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| 19. |
- Leuzy, Antoine, et al.
(författare)
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A multicenter comparison of [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2295-2305
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer’s disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases. Methods: A total of 1755 participants underwent tau PET using either [18F]flortaucipir (n = 975), [18F]RO948 (n = 493), or [18F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively. Results: Comparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926–0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI. Conclusion: The temporal meta-ROI can be used for differential diagnosis of dementia patients with [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.
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| 20. |
- Leuzy, Antoine, et al.
(författare)
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Comparing the Clinical Utility and Diagnostic Performance of Cerebrospinal Fluid P-Tau181, P-Tau217 and P-Tau231 Assays
- 2021
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Ingår i: Neurology. - 1526-632X. ; 97:17, s. 1681-1694
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Phosphorylated tau (P-tau) in cerebrospinal fluid (CSF) is considered an important biomarker in Alzheimer's disease (AD) and has been incorporated in recent diagnostic criteria. Several variants exist, including P-tau at threonines 181 (P-tau181), 217 (P-tau217) and 231 (P-tau231). However, no studies have compared their diagnostic performance or association to amyloid-β (Aβ) and Tau positron emission tomography (PET). Understanding which P-tau variant to use remains an important yet answered question. We aimed to compare the diagnostic accuracy of P-tau181, P-tau217 and P-tau231 in CSF for AD and their association with Aβ and Tau-PET.METHODS: 629 subjects from the Swedish BioFINDER-2 study were included (cognitively unimpaired, n=334; Aβ-positive mild cognitive impairment, n=84; AD dementia, n=119; and non-AD disorders, n=92). In addition to P-tau181 and P-tau217 measured using assays with the same detector antibodies from Eli Lilly (P-tau181Lilly, P-tau217Lilly) and P-tau231, we also included P-tau181 measurements from two commonly used assays (Innotest and Elecsys).RESULTS: Though all P-tau variants increased across the AD continuum, P-tau217Lilly showed the greatest dynamic range (13-fold-increase vs 1.9-5.4-fold-increase for other P-tau variants for AD dementia vs non-AD). P-tau217Lilly showed stronger correlations with Aβ- and Tau-PET (P<0.0001). P-tau217Lilly exhibited higher accuracy than other P-tau variants for separating AD dementia from non-AD (AUC, 0.991vs 0.906-0.982, P<0.0001) and for identifying Aβ- (AUC, 0.951 vs 0.816-0.924, P<0.0001) and Tau-PET positivity (AUC, 0.957 vs 0.836-0.938, P<0.0001). Finally, P-tau181Lilly generally performed better than the other P-tau181 assays, (e.g., AD dementia vs non-AD, AUC, 0.976 vs 0.923, P<0.0001).DISCUSSION: CSF P-tau217Lilly seem to be more useful than other included P-tau assays in the work-up of AD. Varied results across P-tau181 assays also highlights the importance of anti-tau antibodies for biomarker performance.CLASSIFICATION OF EVIDENCE: This study provides class II evidence that phosphorylated tau at threonine 217 provides higher diagnostic accuracy for diagnosis of AD dementia than P-tau at threonine 181 or 231.
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| 21. |
- Leuzy, Antoine, et al.
(författare)
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Current advances in plasma and cerebrospinal fluid biomarkers in Alzheimer's disease
- 2021
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Ingår i: Current Opinion in Neurology. - 1473-6551. ; 34:2, s. 266-274
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: This review provides a concise overview of recent advances in cerebrospinal fluid (CSF) and blood-based biomarkers of Alzheimer's disease lesions. RECENT FINDINGS: Important recent advances for CSF Alzheimer's disease biomarkers include the introduction of fully automated assays, the development and implementation of certified reference materials for CSF Aβ42 and a unified protocol for handling of samples, which all support reliability and availability of CSF Alzheimer's disease biomarkers. Aβ deposition can be detected using Aβ42/Aβ40 ratio in both CSF and plasma, though a much more modest change is seen in plasma. Tau aggregation can be detected using phosphorylated tau (P-tau) at threonine 181 and 217 in CSF, with similar accuracy in plasma. Neurofilament light (NfL) be measured in CSF and shows similar diagnostic accuracy in plasma. Though total tau (T-tau) can also be measured in plasma, this measure is of limited clinical relevance for Alzheimer's disease in its current immunoassay format. SUMMARY: Alzheimer's disease biomarkers, including Aβ, P-tau and NfL can now be reliably measured in both CSF and blood. Plasma-based measures of P-tau show particular promise, with potential applications in both clinical practice and in clinical trials.
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| 22. |
- Lindh-Rengifo, Magnus, et al.
(författare)
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Perceived walking difficulties in Parkinson’s disease – predictors and changes over time
- 2021
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Ingår i: BMC Geriatrics. - : Springer Science and Business Media LLC. - 1471-2318. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: People with Parkinson’s disease (PD) have described their walking difficulties as linked to activity avoidance, social isolation, reduced independence and quality of life. There is a knowledge gap regarding predictive factors of perceived walking difficulties in people with PD. Such knowledge could be useful when designing intervention studies. This study aimed to investigate how perceived walking difficulties evolve over a 3-year period in people with PD. A specific aim was to identify predictive factors of perceived walking difficulties. Methods: One hundred forty-eight people with PD (mean age 67.9 years) completed the Generic Walk-12 (Walk-12G) questionnaire (which assesses perceived walking difficulties) at both baseline and the 3-year follow-up. Paired samples t-test was used for comparing baseline and follow-up mean scores. Multivariable linear regression analyses were used to identify predictive factors of perceived walking difficulties. Results: Perceived walking difficulties increased after 3 years: mean Walk-12G score 14.8 versus 18.7, p < 0.001. Concerns about falling was the strongest predictor (β = 0.445) of perceived walking difficulties, followed by perceived balance problems while dual tasking (β = 0.268) and pain (β = 0.153). Perceived balance problems while dual tasking was the strongest predictor (β = 0.180) of a change in perceived walking difficulties, followed by global cognitive functioning (β = − 0.107). Conclusions: Perceived walking difficulties increase over time in people with PD. Both personal factors (i.e. concerns about falling) and motor aspects (i.e. balance problems while dual tasking) seem to have a predictive role. Importantly, our study indicates that also non-motor symptoms (e.g. pain and cognitive functioning) seem to be of importance for future perceived walking difficulties. Future intervention studies that address these factors need to confirm their preventative effect on perceived walking difficulties.
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| 23. |
- Macdonald-Dunlop, Erin, et al.
(författare)
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Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
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| 24. |
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| 25. |
- Mattsson-Carlgren, Niklas, et al.
(författare)
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Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau
- 2021
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer’s disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations correlated with β-amyloid PET (but not tau PET) in early disease stages and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 concentration is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.
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| 26. |
- Nilsson, Maria H, et al.
(författare)
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The effects of tau, amyloid and white matter lesions on mobility, dual tasking and balance in older people
- 2021
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Ingår i: Journals of Gerontology. Series A: Biological Sciences & Medical Sciences. - : Oxford University Press (OUP). - 1758-535X. ; 76:4, s. 683-691
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This study aimed to investigate whether white matter lesions (WML), β-amyloid- and tau pathologies are independently associated with mobility, dual tasking and dynamic balance performance in older non-demented individuals.METHODS: We included 299 older people (mean, SD, age: 71.8, 5.6 years) from the Swedish BioFINDER study, whereof 175 were cognitively unimpaired and 124 had mild cognitive impairment (MCI). In multivariable regression analyses, dependent variables included mobility (Timed Up & Go, TUG), dual tasking (TUG with a simultaneous subtraction task, i.e. TUG-Cog, as well as dual task cost), and balance (Figure-of-eight). The analyses were controlled for age, sex, education, diagnosis (i.e. MCI) and comorbidity (stroke, diabetes, and ischemic heart disease). Independent variables included WML volume, and measures of β-amyloid (abnormal CSF Aβ42/40 ratio) and tau pathology (CSF phosphorylated tau, p-tau).RESULTS: Multivariable regression analyses showed that an increased WML volume was independently associated with decreased mobility, i.e. TUG (standardized β=0.247; p<0.001). Tau pathology was independently associated with dual tasking both when using the raw data of TUG-Cog (β=0.224; p=0.003) and the dual task cost (β= -0.246; p=0.001). Amyloid pathology was associated with decreased balance, i.e. Figure-of-eight (β= 0.172; p=0.028). The independent effects of WML and tau pathology were mainly observed in those with MCI, which was not the case for the effects of amyloid pathology on balance.CONCLUSIONS: Common brain pathologies have different effects where WML are independently associated with mobility, tau pathology has the strongest effect on dual tasking and amyloid pathology seems to be independently associated with balance. Although these novel findings need to be confirmed in longitudinal studies, they suggest that different brain pathologies have different effects on mobility, balance and dual tasking in older non-demented individuals.
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| 27. |
- Ossenkoppele, Rik, et al.
(författare)
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Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease : A Head-to-Head Comparison against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:8, s. 961-971
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P <.001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P <.001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P <.001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P =.71). Age (t = -2.28; P =.02), but not sex (t = 0.92; P =.36) or APOE genotype (t = 1.06; P =.29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
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| 28. |
- Ossenkoppele, Rik, et al.
(författare)
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Tau PET correlates with different Alzheimer’s disease-related features compared to CSF and plasma p-tau biomarkers
- 2021
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)-related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n=400) and ADNI (n=371). All had tau-PET ([18F]RO948 in BioFINDER-2, [18F]flortaucipir in ADNI) and CSF p-tau181 biomarkers available. Plasma p-tau181 and plasma/CSF p-tau217 were available in BioFINDER-2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p-tau181 and p-tau217 levels were independently of tau PET associated with higher age, and APOEɛ4-carriership and Aβ-positivity, while increased tau-PET signal in the temporal cortex was associated withworse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p-tau181 and p-tau217 levels being more tightly linked with early markers of AD (especially Aβ-pathology), while tau-PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.
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| 29. |
- Ossenkoppele, Rik, et al.
(författare)
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The impact of demographic, clinical, genetic, and imaging variables on tau PET status
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2245-2258
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) are tau PET–negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET–positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status. Methods: We included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model. Results: Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan. Conclusion: We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.
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| 30. |
- Palmqvist, Sebastian, et al.
(författare)
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Prediction of future Alzheimer's disease dementia using plasma phospho-tau combined with other accessible measures
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27, s. 1034-1042
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Tidskriftsartikel (refereegranskat)abstract
- Plasma P-tau, in combination with clinical measures, predicts future Alzheimer's disease dementia in two independent cohorts with high accuracy and is superior to the clinical diagnostic predictions of specialists. A combination of plasma phospho-tau (P-tau) and other accessible biomarkers might provide accurate prediction about the risk of developing Alzheimer's disease (AD) dementia. We examined this in participants with subjective cognitive decline and mild cognitive impairment from the BioFINDER (n = 340) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 543) studies. Plasma P-tau, plasma A beta 42/A beta 40, plasma neurofilament light, APOE genotype, brief cognitive tests and an AD-specific magnetic resonance imaging measure were examined using progression to AD as outcome. Within 4 years, plasma P-tau217 predicted AD accurately (area under the curve (AUC) = 0.83) in BioFINDER. Combining plasma P-tau217, memory, executive function and APOE produced higher accuracy (AUC = 0.91, P < 0.001). In ADNI, this model had similar AUC (0.90) using plasma P-tau181 instead of P-tau217. The model was implemented online for prediction of the individual probability of progressing to AD. Within 2 and 6 years, similar models had AUCs of 0.90-0.91 in both cohorts. Using cerebrospinal fluid P-tau, A beta 42/A beta 40 and neurofilament light instead of plasma biomarkers did not improve the accuracy significantly. The clinical predictions by memory clinic physicians had significantly lower accuracy (4-year AUC = 0.71). In summary, plasma P-tau, in combination with brief cognitive tests and APOE genotyping, might greatly improve the diagnostic prediction of AD and facilitate recruitment for AD trials.
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| 31. |
- Pereira, Joana B., et al.
(författare)
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Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:11, s. 3505-3516
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Tidskriftsartikel (refereegranskat)abstract
- Although recent clinical trials targeting amyloid-β in Alzheimer's disease have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid-β metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in Alzheimer's disease. However, so far, no studies have assessed whether astrocytosis is independently related to either amyloid-β or tau pathology in vivo. To address this question, we determined the levels of the astrocytic marker GFAP in plasma and CSF of 217 amyloid-β-negative cognitively unimpaired individuals, 71 amyloid-β-positive cognitively unimpaired individuals, 78 amyloid-β-positive cognitively impaired individuals, 63 amyloid-β-negative cognitively impaired individuals and 75 patients with a non-Alzheimer's disease neurodegenerative disorder from the Swedish BioFINDER-2 study. Participants underwent longitudinal amyloid-β (18F-flutemetamol) and tau (18F-RO948) PET as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all amyloid-β-positive groups compared with participants without amyloid-β pathology (P < 0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-β-PET signal in all amyloid-β-positive groups, but also in cognitively normal individuals with normal amyloid-β values (P < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-β-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, soluble TREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for amyloid-β-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-Alzheimer's disease patients compared to other groups (P < 0.05) and correlated with amyloid-β-PET only in amyloid-β-positive cognitively impaired individuals (P = 0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-β-PET and cognitive decline, and mediated the effect of amyloid-β-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid-β aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid-β pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid-β status. This suggests that plasma GFAP should be incorporated in current hypothetical models of Alzheimer's disease pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to amyloid-β pathology.
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| 32. |
- Pereira, Joana B., et al.
(författare)
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Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2826-2836
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Tidskriftsartikel (refereegranskat)abstract
- It is currently unclear whether plasma biomarkers can be used as independent prognostic tools to predict changes associated with early Alzheimer's disease. In this study, we sought to address this question by assessing whether plasma biomarkers can predict changes in amyloid load, tau accumulation, brain atrophy and cognition in non-demented individuals. To achieve this, plasma amyloid-β 42/40 (Aβ42/40), phosphorylated-tau181, phosphorylated-tau217 and neurofilament light were determined in 159 non-demented individuals, 123 patients with Alzheimer's disease dementia and 35 patients with a non-Alzheimer's dementia from the Swedish BioFINDER-2 study, who underwent longitudinal amyloid (18F-flutemetamol) and tau (18F-RO948) PET, structural MRI (T1-weighted) and cognitive testing. Our univariate linear mixed effect models showed there were several significant associations between the plasma biomarkers with imaging and cognitive measures. However, when all biomarkers were included in the same multivariate linear mixed effect models, we found that increased longitudinal amyloid-PET signals were independently predicted by low baseline plasma Aβ42/40 (P = 0.012), whereas increased tau-PET signals, brain atrophy and worse cognition were independently predicted by high plasma phosphorylated-tau217 (P < 0.004). These biomarkers performed equally well or better than the corresponding biomarkers measured in the CSF. In addition, they showed a similar performance to binary plasma biomarker values defined using the Youden index, which can be more easily implemented in the clinic. In addition, plasma Aβ42/40 and phosphorylated-tau217 did not predict longitudinal changes in patients with a non-Alzheimer's neurodegenerative disorder. In conclusion, our findings indicate that plasma Aβ42/40 and phosphorylated-tau217 could be useful in clinical practice, research and drug development as prognostic markers of future Alzheimer's disease pathology.
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| 33. |
- Pereira, Joana B., et al.
(författare)
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Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer's disease.
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 144:1, s. 310-324
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Tidskriftsartikel (refereegranskat)abstract
- It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer's disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.
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| 34. |
- Provost, Karine, et al.
(författare)
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Comparing ATN-T designation by tau PET visual reads, tau PET quantification, and CSF PTau181 across three cohorts
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2259-2271
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer’s Disease (AD) Research Framework derived from [18F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181). Methods: We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/mL). Results: FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181. Conclusion: The choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.
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| 35. |
- Simrén, Joel, 1996, et al.
(författare)
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The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease
- 2021
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:7, s. 1145-1156
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-β (Aβ42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.
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| 36. |
- Thijssen, Elisabeth H, et al.
(författare)
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Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study.
- 2021
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Ingår i: The Lancet. Neurology. - 1474-4465 .- 1474-4422. ; 20:9, s. 739-752
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Tidskriftsartikel (refereegranskat)abstract
- Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes.In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test.Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau217, AUC=0·97 [0·94-0·99] for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92-1·00] for p-tau217, AUC=0·91 [0·82-1·00] for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91-0·96] for p-tau217, AUC=0·91 [0·88-0·94] for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88-0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86-0·93]; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230).Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology.US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.
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