| 1. |
- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 2. |
- Wang, Li-San, et al.
(författare)
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Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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| 3. |
- Shahid, Syed Salman, et al.
(författare)
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Hippocampal-subfield microstructures and their relation to plasma biomarkers in Alzheimer's disease.
- 2022
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 145:6, s. 2149-2160
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Tidskriftsartikel (refereegranskat)abstract
- Hippocampal subfields exhibit differential vulnerabilities to Alzheimer's disease (AD)-associated pathology including abnormal accumulation of beta-amyloid deposition and neurofibrillary tangles. These pathological processes extensively impact on the structural and functional interconnectivities of the subfields and may explain the association between hippocampal dysfunction and cognitive deficits. In the present study, we investigated the degree of alterations in the microstructure of hippocampal subfields across the clinical continuum of AD. We applied a gray matter (GM) specific multi-compartment diffusion model (Cortical-NODDI) to understand the differential effects of AD pathology on the hippocampal subfield microstructure. A total of 119 participants were included in this cross-sectional study. Participants were stratified into three categories, cognitively normal (CN; N=47), mild cognitive impairment (MCI; N=52), and AD (N=19). Diffusion MRI, plasma biomarkers, and neuropsychological test scores were used to determine the association between the microstructural integrity and AD associated molecular indicators and cognition. For AD-related plasma biomarkers, we studied amyloid beta (Aβ), total tau (T-tau), and neurofilament light (NfL); for AD-related neuropsychological tests, we included the Trail Making Test (TMT), Rey Auditory Verbal Learning Test (RAVLT), Digit Span, and Montreal Cognitive Assessment (MoCA). Comparisons between CN and MCI showed significant microstructural alterations in the hippocampal cornu ammonis (CA) 4 and dentate gyrus (DG) region, whereas CA1-3 was the most sensitive region for the later stages in the AD clinical continuum. Among imaging metrics for microstructures, the volume fraction of isotropic diffusion for interstitial free water demonstrated the largest effect size in between-group comparisons. Regarding the plasma biomarkers, NfL appeared to be the most sensitive biomarker for associations with microstructural imaging findings in CA4-DG. CA1-3 was the subfield which had stronger correlations between cognitive performance and microstructural metrics. Particularly, poor performance in RAVLT and MoCA was associated with decreased intracellular volume fraction. Overall, our findings support the value of tissue-specific microstructural imaging for providing pathologically relevant information manifesting in the plasma biomarkers and neuropsychological outcomes across various stages of AD.
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| 4. |
- Sims, John R., et al.
(författare)
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Donanemab in Early Symptomatic Alzheimer Disease : The TRAILBLAZER-ALZ 2 Randomized Clinical Trial
- 2023
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Ingår i: JAMA. - 0098-7484. ; 330:6, s. 512-527
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Tidskriftsartikel (refereegranskat)abstract
- Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of.04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P <.001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P <.001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P <.001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P <.001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511.
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