1. |
- Leffa, D. T., et al.
(author)
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Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults
- 2023
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 28:3, s. 1248-1255
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Journal article (peer-reviewed)abstract
- Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer's Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years). These individuals had baseline amyloid-beta (A beta) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau(181)), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain A beta deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau(181) levels and frontoparietal atrophy in CU A beta-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in A beta-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of A beta pathology.
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2. |
- Bellaver, B., et al.
(author)
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Astrocyte reactivity influences amyloid-beta effects on tau pathology in preclinical Alzheimer's disease
- 2023
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In: Nature Medicine. - 1078-8956. ; 29:7
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Journal article (peer-reviewed)abstract
- Cross-sectional and longitudinal analyses of tau pathology in preclinical Alzheimer's disease reveal that tau tangles accumulate as a function of amyloid-beta burden only in individuals positive for an astrocyte reactivity biomarker. An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-beta (A beta)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash A beta effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of A beta with tau phosphorylation in CU individuals. We found that A beta was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast(+)). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of A beta only in CU Ast(+) individuals. Our findings suggest astrocyte reactivity as an important upstream event linking A beta with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.
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3. |
- Ferrari-Souza, J. P., et al.
(author)
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APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles
- 2023
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In: Science Advances. - 2375-2548. ; 9:14
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Journal article (peer-reviewed)abstract
- Animal studies suggest that the apolipoprotein E epsilon 4 (APOE epsilon 4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOE epsilon 4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomog-raphy for amyloid-beta (A beta; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOE epsilon 4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for A beta and tau deposition. Furthermore, microglial acti-vation mediated the A beta-independent effects of APOE epsilon 4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOE epsilon 4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOE epsilon 4 genotype exerts A beta-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.
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4. |
- Ferrari-Souza, J. P., et al.
(author)
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APOEε4 potentiates amyloid β effects on longitudinal tau pathology
- 2023
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In: Nature Aging. - 2662-8465. ; 3:10
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Journal article (peer-reviewed)abstract
- The mechanisms by which the apolipoprotein E epsilon 4 (APOE epsilon 4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOE epsilon 4 carriership and amyloid-beta (A beta) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for A beta ([F-18]AZD4694) and tau ([F-18]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan. We found that APOE epsilon 4 carriership potentiates A beta effects on longitudinal tau accumulation over 2 years. The APOE epsilon 4-potentiated A beta effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217(+)) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results suggest that the APOE epsilon 4 allele plays a key role in A beta downstream effects on the aggregation of phosphorylated tau in the living human brain.
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5. |
- Ferreira, P. C. L., et al.
(author)
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Plasma p-tau231 and p-tau217 inform on tau tangles aggregation in cognitively impaired individuals
- 2023
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In: Alzheimers & Dementia. - 1552-5260. ; 19:10, s. 4463-4474
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Journal article (peer-reviewed)abstract
- INTRODUCTIONPhosphorylated tau (p-tau) biomarkers have been recently proposed to represent brain amyloid-& beta; (A & beta;) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify A & beta; and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI). METHODSWe assessed 138 CU and 87 CI with available plasma p-tau231, 217(+), and 181, A & beta;42/40, GFAP and A & beta;- and tau-PET. RESULTSIn CU, only plasma p-tau231 and p-tau217(+) significantly improved the performance of the demographics in detecting A & beta;-PET positivity, while no plasma biomarker provided additional information to identify tau-PET positivity. In CI, p-tau217(+) and GFAP significantly contributed to demographics to identify both A & beta;-PET and tau-PET positivity, while p-tau231 only provided additional information to identify tau-PET positivity. DISCUSSIONOur results support plasma p-tau231 and p-tau217(+) as state markers of early A & beta; deposition, but in later disease stages they inform on tau tangle accumulation. HighlightsIt is still unclear how much plasma biomarkers contribute to identification of AD pathology across the AD spectrum beyond the information already provided by demographics (age + sex).Plasma p-tau231 and p-tau217(+) contribute to demographic information to identify brain A & beta; pathology in preclinical AD.In CI individuals, plasma p-tau231 contributes to age and sex to inform on the accumulation of tau tangles, while p-tau217(+) and GFAP inform on both A & beta; deposition and tau pathology.
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6. |
- Ferreira, P. C. L., et al.
(author)
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Potential Utility of Plasma P-Tau and Neurofilament Light Chain as Surrogate Biomarkers for Preventive Clinical Trials
- 2023
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In: NEUROLOGY. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 101:1, s. 38-45
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Journal article (peer-reviewed)abstract
- ObjectiveTo test the utility of longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light chain (NfL) as surrogate markers for clinical trials targeting cognitively unimpaired (CU) populations.MethodsWe estimated the sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers in CU participants from Alzheimer's Disease Neuroimaging Initiative database.ResultsWe included 257 CU individuals (45.5% males; mean age = 73 [6] years; 32% & beta;-amyloid [A & beta;] positive). Changes in plasma NfL were associated with age, whereas changes in plasma p-tau181 with progression to amnestic mild cognitive impairment. Clinical trials using p-tau181 and NfL would require 85% and 63% smaller sample sizes, respectively, for a 24-month than a 12-month follow-up. A population enrichment strategy using intermediate levels of A & beta; PET (Centiloid 20-40) further reduced the sample size of the 24-month clinical trial using p-tau181 (73%) and NfL (59%) as a surrogate.DiscussionPlasma p-tau181/NfL can potentially be used to monitor large-scale population interventions in CU individuals. The enrollment of CU with intermediate A & beta; levels constitutes the alternative with the largest effect size and most cost-effective for trials testing drug effect on changes in plasma p-tau181 and NfL.
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7. |
- Tissot, C., et al.
(author)
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The Association of Age-Related and Off-Target Retention with Longitudinal Quantification of 18F MK6240 Tau PET in Target Regions
- 2023
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 64:3, s. 452-459
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Journal article (peer-reviewed)abstract
- 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F] MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stabil-ity of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off -target retention on the longitudinal quantification of [18F]MK6240 in tar-get regions. Methods: We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzhei-mer disease spectrum with longitudinal [18F]MK6240 SUVs and SUV ratios (SUVRs) (mean +/- SD, 2.25 +/- 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with [18F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 +/- 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-P-negative and tau-negative, 58.50 +/- 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed t testing and Pearson correlation testing were used to determine the difference between groups and associa-tions between changes in region uptake, respectively. Results: Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-P status, cross-sectionally and over time. [18F]MK6240 uptake significantly differed between CUY and CU adults in the puta-men or pallidum (affecting-75% of the region) and in the Braak II region (affecting-35%). Changes in meningeal and putamen or palli-dum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated. Conclusion: Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and sta-ble over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible, [18F]MK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nev-ertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related [18F]MK6240 signal, and in vivo studies should further explore its impact on tracer quantification.
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8. |
- Bellaver, B., et al.
(author)
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Blood-brain barrier integrity impacts the use of plasma amyloid-beta as a proxy of brain amyloid-beta pathology
- 2023
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:9, s. 3815-3825
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Journal article (peer-reviewed)abstract
- INTRODUCTION Amyloid-beta (A beta) and tau can be quantified in blood. However, biological factors can influence the levels of brain-derived proteins in the blood. The blood-brain barrier (BBB) regulates protein transport between cerebrospinal fluid (CSF) and blood. BBB altered permeability might affect the relationship between brain and blood biomarkers.METHODS We assessed 224 participants in research (TRIAD, n = 96) and clinical (BIODEGMAR, n = 128) cohorts with plasma and CSF/positron emission tomography A beta, p-tau, and albumin measures.RESULTS Plasma A beta(42/40) better identified CSF A beta(42/40) and A beta-PET positivity in individuals with high BBB permeability. An interaction between plasma A beta(42/40) and BBB permeability on CSF A beta(42/40) was observed. Voxel-wise models estimated that the association of positron emission tomography (PET), with plasma A beta was most affected by BBB permeability in AD-related brain regions. BBB permeability did not significantly impact the relationship between brain and plasma p-tau levels.DISCUSSION These findings suggest that BBB integrity may influence the performance of plasma A beta, but not p-tau, biomarkers in research and clinical settings.
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