| 1. |
- Alosco, Michael L, et al.
(författare)
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Cerebrospinal fluid tau, Aβ, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration.
- 2018
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 14:9, s. 1159-1170
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) protein analysis may facilitate detection and elucidate mechanisms of neurological consequences from repetitive head impacts (RHI), such as chronic traumatic encephalopathy. We examined CSF concentrations of total tau (t-tau), phosphorylated tau, and amyloid β1-42 and their association with RHI in former National Football League (NFL) players. The role of microglial activation (using sTREM2) was examined as a pathogenic mechanism of chronic traumatic encephalopathy.Sixty-eight former NFL players and 21 controls underwent lumbar puncture to quantify t-tau, p-tau181, amyloid β1-42, and sTREM2 in the CSF using immunoassays. The cumulative head impact index estimated RHI.No between-group differences for CSF analytes emerged. In the former NFL players, the cumulative head impact index predicted higher t-tau concentrations (P=.041), and higher sTREM2 levels were associated with higher t-tau concentrations (P=.009).In this sample of former NFL players, greater RHI and increased microglial activation were associated with higher CSF t-tau concentrations.
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| 2. |
- Choi, Seo Eun, et al.
(författare)
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Development and validation of language and visuospatial composite scores in ADNI
- 2020
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Ingår i: Alzheimer's and Dementia: Translational Research and Clinical Interventions. - : Wiley. - 2352-8737. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Composite scores may be useful to summarize overall language or visuospatial functioning in studies of older adults. Methods:We used item response theory to derive composite measures for language (ADNI-Lan) and visuospatial functioning (ADNI-VS) from the cognitive battery administered in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We evaluated the scores among groups of people with normal cognition, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) in terms of responsiveness to change, association with imaging findings, and ability to differentiate between MCI participants who progressed to AD dementia and those who did not progress. Results: ADNI-Lan andADNI-VSwere able to detect change over time and predict conversion fromMCI toAD. Theywere associated with most of the pre-specified magnetic resonance imaging measures. ADNI-Lan had strong associations with a cerebrospinal fluid biomarker pattern. Discussion: ADNI-Lan and ADNI-VS may be useful composites for language and visuospatial functioning in ADNI.
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| 3. |
- Crane, Paul K., et al.
(författare)
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Cognitively defined Alzheimer's dementia subgroups have distinct atrophy patterns
- 2024
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Ingår i: Alzheimer's and Dementia. - 1552-5260. ; 20:3, s. 1739-1752
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging-defined subgroups. METHODS: We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid-negative controls. We used voxel-based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD-Memory. RESULTS: There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD-Memory, lower left hemisphere GMV for AD-Language, anterior lower GMV for AD-Executive, and posterior lower GMV for AD-Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD-Language group than any other group (p = 1.15 × 10−10). For overlap between imaging-defined and cognitively defined subgroups, AD-Memory matched up with an imaging-defined limbic predominant group. DISCUSSION: MRI findings differ across cognitively defined AD subgroups.
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| 4. |
- Frank, Brandon, et al.
(författare)
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Cognition Mediates the Association Between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms
- 2024
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Ingår i: JOURNAL OF ALZHEIMERS DISEASE. - 1387-2877 .- 1875-8908. ; 100:3, s. 1055-1073
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. Objective: We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (A beta(1-42), p-tau(181)), cognitive function, and NPS. Methods: Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR (R)) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOE epsilon 4. Results: The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau(181)/A beta(1-42) ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau(181)/A beta(1-42) ratio and CDR global impairment. With dementia excluded, p-tau(181)/A beta(1-42) ratio was no longer associated with the NPI-Q. Conclusions: NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia.
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| 5. |
- Frank, Brandon, et al.
(författare)
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Plasma p-tau181 shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau.
- 2022
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 18:8, s. 1523-1536
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Tidskriftsartikel (refereegranskat)abstract
- We examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL).Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables.Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM.These results support plasma p-tau181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.
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| 6. |
- Groot, Colin, et al.
(författare)
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Differential patterns of gray matter volumes and associated gene expression profiles in cognitively-defined Alzheimer's disease subgroups
- 2021
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 30
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Tidskriftsartikel (refereegranskat)abstract
- The clinical presentation of Alzheimer's disease (AD) varies widely across individuals but the neurobiological mechanisms underlying this heterogeneity are largely unknown. Here, we compared regional gray matter (GM) volumes and associated gene expression profiles between cognitively-defined subgroups of amyloid-β positive individuals clinically diagnosed with AD dementia (age: 66 ± 7, 47% male, MMSE: 21 ± 5). All participants underwent neuropsychological assessment with tests covering memory, executive-functioning, language and visuospatial-functioning domains. Subgroup classification was achieved using a psychometric framework that assesses which cognitive domain shows substantial relative impairment compared to the intra-individual average across domains, which yielded the following subgroups in our sample; AD-Memory (n = 41), AD-Executive (n = 117), AD-Language (n = 33), AD-Visuospatial (n = 171). We performed voxel-wise contrasts of GM volumes derived from 3Tesla structural MRI between subgroups and controls (n = 127, age 58 ± 9, 42% male, MMSE 29 ± 1), and observed that differences in regional GM volumes compared to controls closely matched the respective cognitive profiles. Specifically, we detected lower medial temporal lobe GM volumes in AD-Memory, lower fronto-parietal GM volumes in AD-Executive, asymmetric GM volumes in the temporal lobe (left < right) in AD-Language, and lower GM volumes in posterior areas in AD-Visuospatial. In order to examine possible biological drivers of these differences in regional GM volumes, we correlated subgroup-specific regional GM volumes to brain-wide gene expression profiles based on a stereotactic characterization of the transcriptional architecture of the human brain as provided by the Allen human brain atlas. Gene-set enrichment analyses revealed that variations in regional expression of genes involved in processes like mitochondrial respiration and metabolism of proteins were associated with patterns of regional GM volume across multiple subgroups. Other gene expression vs GM volume-associations were only detected in particular subgroups, e.g., genes involved in the cell cycle for AD-Memory, specific sets of genes related to protein metabolism in AD-Language, and genes associated with modification of gene expression in AD-Visuospatial. We conclude that cognitively-defined AD subgroups show neurobiological differences, and distinct biological pathways may be involved in the emergence of these differences.
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| 7. |
- Groot, Colin, et al.
(författare)
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Differential trajectories of hypometabolism across cognitively-defined Alzheimer's disease subgroups
- 2021
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 31
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Tidskriftsartikel (refereegranskat)abstract
- Disentangling biologically distinct subgroups of Alzheimer's disease (AD) may facilitate a deeper understanding of the neurobiology underlying clinical heterogeneity. We employed longitudinal [18F]FDG-PET standardized uptake value ratios (SUVRs) to map hypometabolism across cognitively-defined AD subgroups. Participants were 384 amyloid-positive individuals with an AD dementia diagnosis from ADNI who had a total of 1028 FDG-scans (mean time between first and last scan: 1.6 ± 1.8 years). These participants were categorized into subgroups on the basis of substantial impairment at time of dementia diagnosis in a specific cognitive domain relative to the average across domains. This approach resulted in groups of AD-Memory (n = 135), AD-Executive (n = 8), AD-Language (n = 22), AD-Visuospatial (n = 44), AD-Multiple Domains (n = 15) and AD-No Domains (for whom no domain showed substantial relative impairment; n = 160). Voxelwise contrasts against controls revealed that all AD-subgroups showed progressive hypometabolism compared to controls across temporoparietal regions at time of AD diagnosis. Voxelwise and regions-of-interest (ROI)-based linear mixed model analyses revealed there were also subgroup-specific hypometabolism patterns and trajectories. The AD-Memory group had more pronounced hypometabolism compared to all other groups in the medial temporal lobe and posterior cingulate, and faster decline in metabolism in the medial temporal lobe compared to AD-Visuospatial. The AD-Language group had pronounced lateral temporal hypometabolism compared to all other groups, and the pattern of metabolism was also more asymmetrical (left < right) than all other groups. The AD-Visuospatial group had faster decline in metabolism in parietal regions compared to all other groups, as well as faster decline in the precuneus compared to AD-Memory and AD-No Domains. Taken together, in addition to a common pattern, cognitively-defined subgroups of people with AD dementia show subgroup-specific hypometabolism patterns, as well as differences in trajectories of metabolism over time. These findings provide support to the notion that cognitively-defined subgroups are biologically distinct.
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| 8. |
- Ly, Monica T, et al.
(författare)
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Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players.
- 2024
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Ingår i: Neurology. - 1526-632X. ; 102:2
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Tidskriftsartikel (refereegranskat)abstract
- Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health.Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid β1-42, p-tau181, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI.In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau181: B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau181 (158%), and FA (287%) than the unexposed men.Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.
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| 9. |
- Montoliu-Gaya, Laia, et al.
(författare)
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Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study.
- 2024
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Ingår i: Acta neuropathologica. - 1432-0533. ; 147:1
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Tidskriftsartikel (refereegranskat)abstract
- Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD=69, non-AD=54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC=89.8), p-tau231 (AUC=83.4), and p-tau205 (AUC=81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR<1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (ORp-tau217=15.29, ORp-tau205=5.05 and ORp-tau231=3.86) and Braak staging (ORp-tau217=14.29, ORp-tau205=5.27 and ORp-tau231=4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.
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