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- Knutsson, Linda, et al.
(author)
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Dynamic susceptibility contrast MRI with a prebolus contrast agent administration design for improved absolute quantification of perfusion.
- 2014
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In: Magnetic Resonance in Medicine. - : Wiley. - 1522-2594 .- 0740-3194. ; 72:4, s. 996-1006
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Journal article (peer-reviewed)abstract
- Arterial partial-volume effects (PVEs) often hamper reproducible absolute quantification of cerebral blood flow (CBF) and cerebral blood volume (CBV) obtained by dynamic susceptibility contrast MRI (DSC-MRI). The aim of this study was to examine whether arterial PVEs in DSC-MRI data can be minimized by rescaling the arterial input function (AIF) using a sagittal-sinus venous output function obtained following a prebolus administration of a low dose of contrast agent.
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| 4. |
- Salvadó, Gemma, et al.
(author)
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The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals
- 2022
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:7, s. 1383-1395
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Journal article (peer-reviewed)abstract
- Introduction: Harboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described. Methods: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3). Results: Carrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging. Discussion: In addition to the known resistance against amyloid-β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD-related cognitive decline.
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| 5. |
- Ahmadi, Khazar, et al.
(author)
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Fixel-Based Analysis Reveals Tau-Related White Matter Changes in Early Stages of Alzheimer’s Disease
- 2024
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In: Journal of Neuroscience. - 0270-6474. ; 44:18
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Journal article (peer-reviewed)abstract
- Several studies have shown white matter (WM) abnormalities in Alzheimer’s disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD (N = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aβ-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aβ-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics.
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| 6. |
- Ahmadi, Khazar, et al.
(author)
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Gray matter hypoperfusion is a late pathological event in the course of Alzheimer's disease
- 2023
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In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - 1559-7016. ; 43:4, s. 565-580
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Journal article (peer-reviewed)abstract
- Several studies have shown decreased cerebral blood flow (CBF) in Alzheimer's disease (AD). However, the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, PET, and CSF biomarkers, we investigated the associations between gray matter (GM)-CBF and the key mechanisms in AD including amyloid-β (Aβ) and tau pathology, synaptic and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in temporo-occipito-parietal cortex in the Aβ-positive cognitively impaired compared to both Aβ-negative and Aβ-positive cognitively unimpaired individuals. In participants along the AD spectrum, GM-CBF was associated with tau, synaptic and axonal dysfunction, but not Aβ in similar cortical regions. Axonal degeneration was further associated with hypoperfusion in cognitively unimpaired individuals. Disease progression modeling revealed that GM-CBF disruption Followed the abnormality of biomarkers of Aβ, tau and brain atrophy. These findings indicate that tau tangles and neurodegeneration are more closely connected with GM-CBF changes than Aβ pathology. Although subjected to the sensitivity of the employed neuroimaging techniques and the modeling approach, these findings suggest that hypoperfusion might not be an early event associated with the build-up of Aβ in preclinical phase of AD.
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| 8. |
- Baumeister, Hannah, et al.
(author)
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A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
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In: Brain : a journal of neurology. - 1460-2156. ; 147:7, s. 2400-2413
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Journal article (peer-reviewed)abstract
- Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.
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| 9. |
- Berron, David, et al.
(author)
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Medial temporal lobe connectivity and its associations with cognition in early Alzheimer's disease
- 2020
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:3, s. 1233-1248
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Journal article (peer-reviewed)abstract
- Human episodic memory critically depends on subregions of the medial temporal lobe, which are part of functional brain systems such as the anterior-temporal and the posterior-medial system. Here we analysed how Alzheimer's pathology affects functional connectivity within these systems. Data from 256 amyloid-b-negative cognitively unimpaired, 103 amyloid-b-positive cognitively unimpaired, and 83 amyloid-b-positive individuals with mild cognitive impairment were analysed. Amyloid-b and tau pathology were measured using the CSF amyloid-b42/40 ratio and phosphorylated tau, respectively. We found that amyloid-b-positive cognitively unimpaired individuals were mainly characterized by decreased functional connectivity between the medial temporal lobe and regions in the anterior-temporal system, most prominently between left perirhinal/entorhinal cortices and medial prefrontal cortex. Furthermore, correlation analysis in this group revealed decreasing functional connectivity between bilateral perirhinal/entorhinal cortices, anterior hippocampus and posterior-medial regions with increasing levels of phosphorylated tau. The amyloid-b-positive individuals with mild cognitive impairment mostly exhibited reduced connectivity between the medial temporal lobe and posterior-medial regions, predominantly between the anterior hippocampus and posterior cingulate cortex. In addition, they showed hyperconnectivity within the medial temporal lobe and its immediate proximity. Lower medial temporal-cortical functional connectivity networks resulting from the group comparisons of cognitively unimpaired individuals were associated with reduced memory performance and more rapid longitudinal memory decline as shown by linear mixed-effects regression analysis. Finally, we found that reduced medial temporal-cortical connectivity in mildly cognitively impaired individuals was related to reduced entorhinal thickness and white matter integrity of the parahippocampal cingulum and the fornix. No such relationships were found in cognitively unimpaired individuals. In conclusion, our findings show that the earliest changes in preclinical Alzheimer's disease might involve decreased connectivity within the anterior-temporal system, and early changes in connectivity might be related to memory impairment, but not to structural changes. With disease progression and increased tau pathology, medial temporal functional connectivity with posterior-medial regions seems to be increasingly impaired. In individuals with mild cognitive impairment, reduced functional connectivity is associated with structural brain changes as well as the emergence of locally increased connectivity patterns. Thus, functional connectivity between the medial temporal lobe and the anterior-temporal and posterior-medial system could serve as stage-specific functional markers in early Alzheimer's disease.
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| 10. |
- Borland, Emma, et al.
(author)
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The age-related effect on cognitive performance in cognitively healthy elderly is mainly caused by underlying AD pathology or cerebrovascular lesions : implications for cutoffs regarding cognitive impairment
- 2020
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In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: As research in treatments for neurocognitive diseases progresses, there is an increasing need to identify cognitive decline in the earliest stages of disease for initiation of treatment in addition to determining the efficacy of treatment. For early identification, accurate cognitive tests cutoff values for cognitive impairment are essential. METHODS: We conducted a study on 297 cognitively healthy elderly people from the BioFINDER study and created subgroups excluding people with signs of underlying neuropathology, i.e., abnormal cerebrospinal fluid [CSF] β-amyloid or phosphorylated tau, CSF neurofilament light (neurodegeneration), or cerebrovascular pathology. We compared cognitive test results between groups and examined the age effect on cognitive test results. RESULTS: In our subcohort without any measurable pathology (n = 120), participants achieved better test scores and significantly stricter cutoffs for cognitive impairment for almost all the examined tests. The age effect in this subcohort disappeared for all cognitive tests, apart from some attention/executive tests, predominantly explained by the exclusion of cerebrovascular pathology. CONCLUSION: Our study illustrates a new approach to establish normative data that could be useful to identify earlier cognitive changes in preclinical dementias. Future studies need to investigate if there is a genuine effect of healthy aging on cognitive tests or if this age effect is a proxy for higher prevalence of preclinical neurodegenerative diseases.
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