| 1. |
- Hibar, Derrek P., et al.
(author)
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Novel genetic loci associated with hippocampal volume
- 2017
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 2. |
- Satizabal, Claudia L., et al.
(author)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Journal article (peer-reviewed)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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| 3. |
- Pemberton, Hugh G., et al.
(author)
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Automated quantitative MRI volumetry reports support diagnostic interpretation in dementia : a multi-rater, clinical accuracy study
- 2021
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In: European Radiology. - : Springer. - 0938-7994 .- 1432-1084. ; 31:7, s. 5312-5323
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Journal article (peer-reviewed)abstract
- Objectives We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists' accuracy and confidence in detecting volume loss, and in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone. Methods Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52-81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, 'non-clinical image analysts') assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as 'normal' or 'abnormal' and if 'abnormal' as 'AD' or 'FTD'. Results The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group's accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters' agreement (Cohen's kappa) with the 'gold standard' was not significantly affected by the QReport; only the consultant group improved significantly (kappa(s) 0.41 -> 0.55, p = 0.04*). Cronbach's alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from 'good' to 'excellent'. Conclusion Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses.
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| 4. |
- Haller, Sven, et al.
(author)
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Cerebral Microbleeds : Imaging and Clinical Significance
- 2018
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In: Radiology. - : Radiological Society of North America (RSNA). - 0033-8419 .- 1527-1315. ; 287:1, s. 11-28
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Research review (peer-reviewed)abstract
- Cerebral microbleeds (CMBs), also referred to as microhemorrhages, appear on magnetic resonance (MR) images as hypointense foci notably at T2*-weighted or susceptibility-weighted (SW) imaging. CMBs are detected with increasing frequency because of the more widespread use of high magnetic field strength and of newer dedicated MR imaging techniques such as three-dimensional gradient-echo T2*-weighted and SW imaging. The imaging appearance of CMBs is mainly because of changes in local magnetic susceptibility and reflects the pathologic iron accumulation, most often in perivascular macrophages, because of vasculopathy. CMBs are depicted with a true-positive rate of 48%–89% at 1.5 T or 3.0 T and T2*-weighted or SW imaging across a wide range of diseases. False-positive “mimics” of CMBs occur at a rate of 11%–24% and include microdissections, microaneurysms, and microcalcifications; the latter can be differentiated by using phase images. Compared with postmortem histopathologic analysis, at least half of CMBs are missed with premortem clinical MR imaging. In general, CMB detection rate increases with field strength, with the use of three-dimensional sequences, and with postprocessing methods that use local perturbations of the MR phase to enhance T2* contrast. Because of the more widespread availability of high-field-strength MR imaging systems and growing use of SW imaging, CMBs are increasingly recognized in normal aging, and are even more common in various disorders such as Alzheimer dementia, cerebral amyloid angiopathy, stroke, and trauma. Rare causes include endocarditis, cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy, and radiation therapy. The presence of CMBs in patients with stroke is increasingly recognized as a marker of worse outcome. Finally, guidelines for adjustment of anticoagulant therapy in patients with CMBs are under development.
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| 5. |
- Haller, Sven, et al.
(author)
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Neuroimaging in Dementia : More than Typical Alzheimer Disease
- 2023
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In: Radiology. - : Radiological Society of North America (RSNA). - 0033-8419 .- 1527-1315. ; 308:3
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Journal article (peer-reviewed)abstract
- Alzheimer disease (AD) is the most common cause of dementia. The prevailing theory of the underlying pathology assumes amyloid accumulation followed by tau protein aggregation and neurodegeneration. However, the current antiamyloid and antitau treatments show only variable clinical efficacy. Three relevant points are important for the radiologic assessment of dementia. First, besides various dementing disorders (including AD, frontotemporal dementia, and dementia with Lewy bodies), clinical variants and imaging subtypes of AD include both typical and atypical AD. Second, atypical AD has overlapping radiologic and clinical findings with other disorders. Third, the diagnostic process should consider mixed pathologies in neurodegeneration, especially concurrent cerebrovascular disease, which is frequent in older age. Neuronal loss is often present at, or even before, the onset of cognitive decline. Thus, for effective emerging treatments, early diagnosis before the onset of clinical symptoms is essential to slow down or stop subsequent neuronal loss, requiring molecular imaging or plasma biomarkers. Neuroimaging, particularly MRI, provides multiple imaging parameters for neurodegenerative and cerebrovascular disease. With emerging treatments for AD, it is increasingly important to recognize AD variants and other disorders that mimic AD. Describing the individual composition of neurodegenerative and cerebrovascular disease markers while considering overlapping and mixed diseases is necessary to better understand AD and develop efficient individualized therapies.
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| 6. |
- van der Velpen, Isabelle F., et al.
(author)
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Psychosocial health modifies associations between HPA-axis function and brain structure in older age
- 2023
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In: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 153
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Journal article (peer-reviewed)abstract
- Background: Dysregulation of the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis may have damaging effects on the brain, potentially under influence of psychosocial health factors. We studied associations between functioning of the negative feedback loop of HPA-axis, measured with a very low-dose dexamethasone suppression test (DST), and brain structure in middle-aged and older adults, and whether these associations were modified by psychosocial health.Methods: From 2006 to 2008, 1259 participants (mean age 57.6 +/- 6.4, 59.6 % female) of the population-based Rotterdam Study completed a very low-dose DST (0.25 mg) and underwent magnetic resonance imaging (MRI) of the brain. Self-reported psychosocial health (depressive symptoms, loneliness, marital status, perceived social support) were assessed in the same time period. Multivariable linear and logistic regression were used to study cross-sectional associations between cortisol response and brain volumetrics, cerebral small vessel disease markers and white matter structural integrity. To assess the effect of psychosocial health on these associations, analyses were further stratified for psychosocial health markers.Results: Cortisol response was not associated with markers of global brain structure in the overall study sample. However, in participants with clinically relevant depressive symptoms, a diminished cortisol response was associated with smaller white matter volume (mean difference: - 1.00 mL, 95 %CI = - 1.89;- 0.10) and smaller white matter hyperintensity volume (mean difference: - 0.03 mL (log), 95 %CI = - 0.05;0.00). In participants with low/moderate perceived social support compared to those with high social support, a diminished cortisol response was associated with larger gray matter volume (mean difference: 0.70 mL, 95 %CI = 0.01;1.39) and higher fractional anisotropy (standardized mean difference 0.03, 95 %CI = 0.00;0.06).Conclusion: Diminished function of the HPA-axis is differently associated with brain structure in communitydwelling middle-aged and older adults with clinically relevant depressive symptoms or suboptimal social support, but not in adults without depressive symptoms or with optimal social support.
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| 7. |
- Özel, Faith, et al.
(author)
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Associations of neuroimaging markers with depressive symptoms over time in middle-aged and elderly persons
- 2023
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In: Psychological Medicine. - : Cambridge University Press. - 0033-2917 .- 1469-8978. ; 53:10, s. 4355-4363
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Journal article (peer-reviewed)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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