| 1. |
- Chong, Joyce R, et al.
(författare)
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Plasma P-tau181 to Aβ42 ratio is associated with brain amyloid burden and hippocampal atrophy in an Asian cohort of Alzheimer's disease patients with concomitant cerebrovascular disease.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:10, s. 1649-1662
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Tidskriftsartikel (refereegranskat)abstract
- There is increasing evidence that phosphorylated tau (P-tau181) is a specific biomarker for Alzheimer's disease (AD) pathology, but its potential utility in non-White patient cohorts and patients with concomitant cerebrovascular disease (CeVD) is unknown.Single molecule array (Simoa) measurements of plasma P-tau181, total tau, amyloid beta (Aβ)40 and Aβ42, as well as derived ratios were correlated with neuroimaging modalities indicating brain amyloid (Aβ+), hippocampal atrophy, and CeVD in a Singapore-based cohort of non-cognitively impaired (NCI; n = 43), cognitively impaired no dementia (CIND; n = 91), AD (n = 44), and vascular dementia (VaD; n = 22) subjects.P-tau181/Aβ42 ratio showed the highest area under the curve (AUC) for Aβ+ (AUC = 0.889) and for discriminating between AD Aβ+ and VaD Aβ- subjects (AUC = 0.903). In addition, P-tau181/Aβ42 ratio was associated with hippocampal atrophy. None of the biomarkers was associated with CeVD.Plasma P-tau181/Aβ42 ratio may be a noninvasive means of identifying AD with elevated brain amyloid in populations with concomitant CeVD.
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| 2. |
- Coenen, Mirthe, et al.
(författare)
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Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts
- 2023
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Ingår i: NeuroImage. Clinical. - 2213-1582. ; 40
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. METHODS: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. RESULTS: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DISCUSSION: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.
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| 3. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 4. |
- Tanaka, Tomotaka, et al.
(författare)
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Head-to-head comparison of amplified plasmonic exosome Aβ42 platform and single-molecule array immunoassay in a memory clinic cohort
- 2021
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 28:5, s. 1479-1489
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Various blood biomarkers reflecting brain amyloid-β (Aβ) load have recently been proposed with promising results. However, to date, no comparative study amongst blood biomarkers has been reported. Our objective was to examine the diagnostic performance and cost effectiveness of three blood biomarkers on the same cohort. Methods: Using the same cohort (n = 68), the performances of the single-molecule array (Simoa) Aβ40, Aβ42, Aβ42/Aβ40 and the amplified plasmonic exosome (APEX) Aβ42 blood biomarkers were compared using amyloid positron emission tomography (PET) as the reference standard. The extent to which these blood tests can reduce the recruitment cost of clinical trials was also determined by identifying amyloid positive (Aβ+) participants. Results: Compared to Simoa biomarkers, APEX-Aβ42 showed significantly higher correlations with amyloid PET retention values and excellent diagnostic performance (sensitivity 100%, specificity 93.3%, area under the curve 0.995). When utilized for clinical trial recruitment, our simulation showed that pre-screening with blood biomarkers followed by a confirmatory amyloid PET imaging would roughly half the cost (56.8% reduction for APEX-Aβ42 and 48.6% for Simoa-Aβ42/Aβ40) compared to the situation where only PET imaging is used. Moreover, with 100% sensitivity, APEX-Aβ42 pre-screening does not increase the required number of initial participants. Conclusions: With its high diagnostic performance, APEX is an ideal candidate for Aβ+ subject identification, monitoring and primary care screening, and could efficiently enrich clinical trials with Aβ+ participants whilst halving recruitment costs.
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| 5. |
- Özel, Faith, et al.
(författare)
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Associations of neuroimaging markers with depressive symptoms over time in middle-aged and elderly persons
- 2023
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Ingår i: Psychological Medicine. - : Cambridge University Press. - 0033-2917 .- 1469-8978. ; 53:10, s. 4355-4363
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Tidskriftsartikel (refereegranskat)abstract
- Background Cerebrovascular disease is regarded as a potential cause of late-life depression. Yet, evidence for associations of neuroimaging markers of vascular brain disease with depressive symptoms is inconclusive. We examined the associations of neuroimaging markers and depressive symptoms in a large population-based study of middle-aged and elderly persons over time.Methods A total of 4943 participants (mean age = 64.6 +/- 11.1 years, 55.7% women) from the Rotterdam Study were included. At baseline, total brain volume, gray matter volume, white matter volume, white matter hyperintensities volume, cortical infarcts, lacunar infarcts, microbleeds, white matter fractional anisotropy, and mean diffusivity (MD) were measured with a brain MRI (1.5T). Depressive symptoms were assessed twice with the Center for Epidemiologic Studies Depression scale (median follow-up time: 5.5 years, IQR = 0.9). To assess temporal associations of neuroimaging markers and depressive symptoms, linear mixed models were used.Results A smaller total brain volume (beta = -0.107, 95% CI -0.192 to -0.022), larger white matter hyperintensities volume (beta = 0.047, 95% CI 0.010-0.084), presence of cortical infarcts (beta = 0.194, 95% CI 0.047-0.341), and higher MD levels (beta = 0.060, 95% CI 0.022-0.098) were cross-sectionally associated with more depressive symptoms. Longitudinal analyses showed that small total brain volume (beta = -0.091, 95% CI -0.167 to -0.015) and presence of cortical infarcts (beta = 0.168, 95% CI 0.022-0.314) were associated with increasing depressive symptoms over time. After stratification on age, effect sizes were more pronounced at older ages.Conclusions Neuroimaging markers of white matter microstructural damage were associated with depressive symptoms longitudinally in this study of middle-aged and elderly persons. These associations were more pronounced at older ages, providing evidence for the role of white matter structure in late-life depressive symptomatology.
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