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- Jack, C. R., et al.
(författare)
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Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2
- 2015
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:7, s. 740-756
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. Methods: We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. Results: Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. Discussion: Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
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| 3. |
- Fockler, J., et al.
(författare)
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Remote blood collection from older adults in the Brain Health Registry for plasma biomarker and genetic analysis
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:12, s. 2627-2636
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Use of online registries to efficiently identify older adults with cognitive decline and Alzheimer's disease (AD) is an approach with growing evidence for feasibility and validity. Linked biomarker and registry data can facilitate AD clinical research. Methods: We collected blood for plasma biomarker and genetic analysis from older adult Brain Health Registry (BHR) participants, evaluated feasibility, and estimated associations between demographic variables and study participation. Results: Of 7150 participants invited to the study, 864 (12%) enrolled and 629 (73%) completed remote blood draws. Participants reported high study acceptability. Those from underrepresented ethnocultural and educational groups were less likely to participate. Discussion: This study demonstrates the challenges of remote blood collection from a large representative sample of older adults. Remote blood collection from>600 participants within a short timeframe demonstrates the feasibility of our approach, which can be expanded for efficient collection of plasma AD biomarker and genetic data. © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
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| 4. |
- Insel, Philip S., et al.
(författare)
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Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology
- 2016
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Ingår i: Neurology. - 0028-3878. ; 86:20, s. 1887-1896
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate. Methods: In 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ 42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression. Results: Rates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline. Conclusions: A considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ 42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline. © 2016 American Academy of Neurology.
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| 5. |
- Insel, P. S., et al.
(författare)
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Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease
- 2015
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 2:5, s. 534-547
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To find the combination of candidate biomarkers and cognitive endpoints to maximize statistical power and minimize cost of clinical trials of healthy elders at risk for cognitive decline due to Alzheimer's disease. Methods: Four-hundred and twelve cognitively normal participants were followed over 7 years. Nonlinear methods were used to estimate the longitudinal trajectories of several cognitive outcomes including delayed memory recall, executive function, processing speed, and several cognitive composites by subgroups selected on the basis of biomarkers, including APOE-epsilon 4 allele carriers, cerebrospinal fluid biomarkers (A beta(42), total tau, and phosphorylated tau), and those with small hippocampi. Results: Derived cognitive composites combining Alzheimer's Disease Assessment Scale (ADAS)-cog scores with additional delayed memory recall and executive function components captured decline more robustly across biomarker groups than any measure of a single cognitive domain or ADAS-cog alone. Substantial increases in power resulted when including only participants positive for three or more biomarkers in simulations of clinical trials. Interpretation: Clinical trial power may be improved by selecting participants on the basis of amyloid and neurodegeneration biomarkers and carefully tailoring primary cognitive endpoints to reflect the expected decline specific to these individuals.
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| 6. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Effects of cerebrospinal fluid proteins on brain atrophy rates in cognitively healthy older adults
- 2014
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 35:3, s. 614-622
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Tidskriftsartikel (refereegranskat)abstract
- Biomarkers associated with Alzheimer's disease (AD)-like brain atrophy in healthy individuals may identify mechanisms involved in early stage AD. Aside from cerebrospinal fluid (CSF) beta-amyloid42 (A beta 42) and tau, no studies have tested associations between CSF proteins and AD-like brain atrophy. We studied 90 healthy elders, who underwent lumbar puncture at baseline, and serial magnetic resonance imaging scans for up to 4 years. We tested statistical effects of baseline CSF proteins (N = 70 proteins related to A beta 42-metabolism, microglial activity, and synaptic/neuronal function) on atrophy rates in 7 AD-related regions. Besides the effects of A beta 42 and phosphorylated tau (P-tau) that were seen in several regions, novel CSF proteins were found to have effects in inferior and middle temporal cortex (including apolipoprotein CIII, apolipoprotein D, and apolipoprotein H). Several proteins (including S100 beta and matrix metalloproteinase-3) had effects that depended on the presence of brain A beta pathology, as measured by CSF A beta 42. Other proteins (including P-tau and apolipoprotein D) had effects even after adjusting for CSF A beta 42. The statistical effects in this exploratory study were mild and not significant after correction for multiple comparisons, but some of the identified proteins may be associated with brain atrophy in healthy persons. Proteins interacting with CSF A beta 42 may be related to A beta brain pathology, whereas proteins associated with atrophy even after adjusting for CSF A beta 42 may be related to A beta-independent mechanisms. (C) 2014 Elsevier Inc. All rights reserved.
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| 7. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Emerging β-amyloid pathology and accelerated cortical atrophy
- 2014
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 71:6, s. 725-734
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood. OBJECTIVE To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons. DESIGN, SETTING, AND PARTICIPANTS Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Aβ42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Aβ42 data and included 13 stable Aβ negative (normal baseline Aβ42 levels, with less than the median reduction over time), 13 declining Aβ negative (normal baseline Aβ42 levels, with greater than the median reduction over time), and 21 Aβ positive (pathologic baseline Aβ42 levels). All 15 patients with AD dementia were Aβ positive. MAIN OUTCOMES AND MEASURES Group effects on regional gray matter volumes at baseline and over time, tested by linear mixed-effects models. RESULTS Baseline gray matter volumes were similar among the CN Aβ groups, but atrophy rates were increased in frontoparietal regions in the declining Aβ-negative and Aβ-positive groups and in amygdala and temporal regions in the Aβ-positive group. Aβ-positive patients with AD dementia had further increased atrophy rates in hippocampus and temporal and cingulate regions. CONCLUSIONS AND RELEVANCE Emerging Aβ pathology is coupled to increased frontoparietal (but not temporal) atrophy rates. Atrophy rates peak early in frontoparietal regions but accelerate in hippocampus, temporal, and cingulate regions as the disease progresses to dementia. Early-stage Aβ pathologymay have mild effects on local frontoparietal cortical integrity while effects in temporal regions appear later and accelerate, leading to the atrophy pattern typically seen in AD. © 2014 American Medical Association.
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| 8. |
- Insel, Philip S., et al.
(författare)
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Assessing risk for preclinical β-amyloid pathology with APOE, cognitive, and demographic information
- 2016
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 4, s. 76-84
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Clinical trials in Alzheimer's disease are aimed at early stages of disease, including preclinical Alzheimer's disease. The high cost and time required to screen large numbers of participants for Aβ pathology impede the development of novel drugs. This study's objective was to evaluate the extent to which inexpensive and easily obtainable information can reduce the number of screen failures by increasing the proportion of Aβ+ participants identified for screening. Methods We used random forest models to evaluate the positive predictive value of demographics, APOE, and longitudinal cognitive rates in the prediction of amyloid pathology, measured by florbetapir PET or cerebrospinal fluid. Results Predicting Aβ positivity with demographic, APOE, and cognitive information yielded a positive predictive value estimate of 0.65 (95% CI, 0.50–0.96), nearly a 60% increase over the reference Aβ+ prevalence in the cohort of 0.41. Conclusions By incorporating this procedure, clinical trial screening costs of 7500 USD per participant may be reduced by nearly 7 million USD total.
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| 9. |
- Mattsson, Niklas, 1979, et al.
(författare)
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CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders
- 2013
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188 .- 2158-3188. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- β-amyloid (Ab) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aβ1-42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Ab metabolism predict the development of Ab plaques, assessed by longitudinal CSF Aβ42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aβ42 from a mean concentration of 211-195 pg ml1 after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Ab metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. The most significant proteins were angiotensinconverting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiveroperating characteristic analysis identified 11 proteins with significant effects on longitudinal Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Ab metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Ab pathology at the earliest stages of AD, prior to widespread development of Aβ plaques. © 2013 Macmillan Publishers Limited All rights reserved.
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