| 51. |
- Groot, Colin, et al.
(författare)
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A biomarker profile of elevated CSF p-tau with normal tau PET is associated with increased tau accumulation rates on PET in early Alzheimer’s disease
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Different tau biomarkers become abnormal at different stages of Alzheimer’s disease (AD), with CSF p-tau typically being elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we selected a group of amyloid-β-positive (A+) individuals with elevated CSF p-tau levels but negative tau-PET scans and assessed longitudinal changes in tau-PET, cortical thickness and cognitive decline. Method: Individuals without dementia (i.e., cognitively unimpaired (CU) or mild cognitive impairment, n=231) were selected from the BioFINDER-2 study. These subjects were categorized into biomarker groups based on Gaussian mixture modelling to determine cut-offs for abnormal CSF Aβ42/40 (A; <0.078), CSF p-tau217 (P; >110 pg/ml) and [18F]RO948 tau-PET SUVR within a temporal meta-ROI (T; SUVR >1.40). Resulting groups were: A+P-T- (concordant, n=30), A+P+T- (discordant, n=48) and A+P+T+ (concordant, n=18). We additionally used 135 A- CU individuals (A- CU) as a reference group (Tables 1 and 2). Differences in annual change in regional tau-PET SUVR, cortical thickness and cognition between the A+P+T- group and the other groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures) education. Result: Longitudinal change in tau-PET was faster in the A+P+T- group than in the A- CU and A+P-T- groups across medial temporal and neocortical regions, with the medial temporal increases being more pronounced. The A+P+T- group showed slower rate of increases in tau-PET compared to the A+P+T+ group, primarily in neocortical regions (Figures 1 and 2). We did not detect differences in yearly change in cortical thickness (Figure 3) or in cognitive decline (Figure 3) between the A+P+T- and A+P-T- groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Conclusion: These findings suggest that the A+P+T- biomarker profile is associated with early tau accumulation, and with relative sparing of cortical thinning and cognitive decline compared to A+P+T+ individuals. Therefore, the A+P+T- group represents an interesting target-group for early anti-tau interventions and for examining the emergence of tau aggregates in early AD.
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| 52. |
- Groot, Colin, et al.
(författare)
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Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease
- 2018
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Ingår i: Neurology. - 1526-632X. ; 91:20, s. 1851-1859
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the clinical phenotype, gray matter atrophy patterns, and small vessel disease in patients who developed prodromal or probable Alzheimer disease dementia, despite carrying the protective APOEε2 allele. METHODS: We included 36 β-amyloid-positive (by CSF or PET) APOEε2 carriers (all ε2/ε3) with mild cognitive impairment or dementia due to Alzheimer disease who were matched for age and diagnosis (ratio 1:2) to APOEε3 homozygotes and APOEε4 carriers (70% ε3/ε4 and 30% ε4/ε4). We assessed neuropsychological performance across 4 cognitive domains (memory, attention, executive, and language functions), performed voxelwise and region of interest analyses of gray matter atrophy on T1-weighted MRI, used fluid-attenuated inversion recovery images to automatically quantify white matter hyperintensity volumes, and assessed T2*-weighted images to identify microbleeds. Differences in cognitive domain scores, atrophy, and white matter hyperintensities between ε2 carriers, ε3 homozygotes, and ε4 carriers were assessed using analysis of variance analyses, and Pearson χ2 tests were used to examine differences in prevalence of microbleeds. RESULTS: We found that ε2 carriers performed worse on nonmemory domains compared to both ε3 homozygotes and ε4 carriers but better on memory compared to ε4 carriers. Voxelwise T1-weighted MRI analyses showed asymmetric (left > right) temporoparietal-predominant atrophy with subtly less involvement of medial-temporal structures in ε2 carriers compared to ε4 carriers. Finally, ε2 carriers had larger total white matter hyperintensity volumes compared to ε4 carriers (mean 10.4 vs 7.3 mL) and a higher prevalence of microbleeds compared to ε3 homozygotes (37.5% vs 18.3%). CONCLUSION: APOEε2 carriers who develop Alzheimer disease despite carrying the protective allele display a nonamnestic clinical phenotype with more severe small vessel disease.
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| 53. |
- 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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| 54. |
- 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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| 55. |
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| 56. |
- Groot, Colin, et al.
(författare)
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Latent atrophy factors related to phenotypical variants of posterior cortical atrophy
- 2020
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Ingår i: Neurology. - 1526-632X. ; 95:12, s. 1672-1685
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether atrophy relates to phenotypical variants of posterior cortical atrophy (PCA) recently proposed in clinical criteria (i.e., dorsal, ventral, dominant-parietal, and caudal) we assessed associations between latent atrophy factors and cognition. METHODS: We employed a data-driven Bayesian modeling framework based on latent Dirichlet allocation to identify latent atrophy factors in a multicenter cohort of 119 individuals with PCA (age 64 ± 7 years, 38% male, Mini-Mental State Examination 21 ± 5, 71% β-amyloid positive, 29% β-amyloid status unknown). The model uses standardized gray matter density images as input (adjusted for age, sex, intracranial volume, MRI scanner field strength, and whole-brain gray matter volume) and provides voxelwise probabilistic maps for a predetermined number of atrophy factors, allowing every individual to express each factor to a degree without a priori classification. Individual factor expressions were correlated to 4 PCA-specific cognitive domains (object perception, space perception, nonvisual/parietal functions, and primary visual processing) using general linear models. RESULTS: The model revealed 4 distinct yet partially overlapping atrophy factors: right-dorsal, right-ventral, left-ventral, and limbic. We found that object perception and primary visual processing were associated with atrophy that predominantly reflects the right-ventral factor. Furthermore, space perception was associated with atrophy that predominantly represents the right-dorsal and right-ventral factors. However, individual participant profiles revealed that the large majority expressed multiple atrophy factors and had mixed clinical profiles with impairments across multiple domains, rather than displaying a discrete clinical-radiologic phenotype. CONCLUSION: Our results indicate that specific brain behavior networks are vulnerable in PCA, but most individuals display a constellation of affected brain regions and symptoms, indicating that classification into 4 mutually exclusive variants is unlikely to be clinically useful.
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| 57. |
- Groot, Colin, et al.
(författare)
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Mesial temporal tau is related to worse cognitive performance and greater neocortical tau load in amyloid-β–negative cognitively normal individuals
- 2021
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 97, s. 41-48
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Tidskriftsartikel (refereegranskat)abstract
- We examined whether mesial temporal (Me) tau relates to cognitive performance in 47 amyloid-β (Aβ)-negative, cognitively normal older adults (>60 years old). Me-tau was measured using [18F]flortaucipir–positron emission tomography standardized uptake value ratio. The effect of continuous and categorical (stratified at standardized uptake value ratio = 1.2 [21% Me-positive]) Me-tau on cognition (mini-mental state examination, pre-Alzheimer's cognitive composite, a memory composite, and a nonmemory composite score) was examined using general linear models, and associations between Me-tau and [18F]flortaucipir signal in the neocortex were assessed using voxelwise regressions (continuous) and voxelwise contrasts (categorical). In addition, we assessed the effect of age and Aβ burden on Me-tau. Both continuous and categorical Me-tau was associated with worse cognitive performance across all tests and with higher lateral temporal and parietal [18F]flortaucipir signal. Furthermore, we observed a marginal association between Me-tau and age, whereas there was no association with Aβ burden. Our findings indicate that Me-tau in Aβ-negative cognitively normal individuals, which is likely age-related (i.e., primary age-related tauopathy), might not be as benign as commonly thought.
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| 58. |
- Groot, Colin, et al.
(författare)
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Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals
- 2023
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 146:4, s. 1580-1591
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Tidskriftsartikel (refereegranskat)abstract
- Different tau biomarkers become abnormal at different stages of Alzheimer's disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in Tau-PET, cortical thickness and cognitive decline in amyloid-β-positive (A+) individuals with elevated CSF P-tau levels (P+) but subthreshold Tau-PET retention (T-). To this end, individuals without dementia (i.e., cognitively unimpaired or mild cognitive impairment, N = 231) were selected from the BioFINDER-2 study. Amyloid-β-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF P-tau217 and [18F]RO948 (Tau) PET, yielding groups of tau-concordant-negative (A + P-T-; n = 30), tau-discordant (i.e., A + P+T-; n = 48) and tau-concordant-positive (A + P+T+; n = 18) individuals. In addition, 135 amyloid-β-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional Tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was ∼2 years. Longitudinal increase in Tau-PET was faster in the A + P+T- group than in the control and A + P-T- groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A + P+T- group showed a slower rate of increases in tau-PET compared to the A + P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A + P+T- and A + P-T- groups. The A + P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A + P+T- biomarker profile in persons without dementia is associated with an isolated effect on increased Tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring effects of interventions with disease modifying agents on tau accumulation in early Alzheimer's disease, and for examining the emergence of tau aggregates in Alzheimer's disease. Further, we suggest to update the AT(N) criteria for Alzheimer's disease biomarker classification to APT(N).
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| 59. |
- Groot, Colin, et al.
(författare)
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Tau PET Imaging in Neurodegenerative Disorders
- 2022
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505. ; 63, s. 20-26
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Tidskriftsartikel (refereegranskat)abstract
- The advent of PET ligands that bind tau pathology has enabled the quantification and visualization of tau pathology in aging and in Alzheimer disease (AD). There is strong evidence from neuropathologic studies that the most widely used tau PET tracers (i.e., 18F-flortaucipir, 18F-MK6240, 18F-RO948, and 18F-PI2620) bind tau aggregates formed in AD in the more advanced (i.e., ≥IV) Braak stages. However, tracer binding in most non-AD tauopathies is weaker and overlaps to a large extent with known off-target binding regions, limiting the quantification and visualization of non-AD tau pathology in vivo. Off-target binding is generally present in the substantia nigra, basal ganglia, pituitary, choroid plexus, longitudinal sinuses, meninges, or skull in a tracer-specific manner. Most cross-sectional studies use the inferior aspect of the cerebellar gray matter as a reference region, whereas for longitudinal analyses, an eroded white matter reference region is sometimes selected. No consensus has yet been reached on whether to use partial-volume correction of tau PET data. Although an increased neocortical tau PET signal is rare in cognitively unimpaired individuals, even in amyloid-β-positive cases, such a signal holds important prognostic information because preliminary data suggest that an elevated tau PET signal predicts cognitive decline over time. Also, in symptomatic stages of AD (i.e., mild cognitive impairment or AD dementia), tau PET shows great potential as a prognostic marker because an elevated baseline tau PET retention forecasts future cognitive decline and brain atrophy. For differential diagnostic use, the primary utility of tau PET is to differentiate AD dementia from other neurodegenerative diseases, as is in line with the conditions for the approval of 18F-flortaucipir by the U.S. Food and Drug Administration for clinical use. The differential diagnostic performance drops substantially at the mild-cognitive-impairment stage of AD, and there is no sufficient evidence for detection of sporadic non-AD primary tauopathies at the individual level for any of the currently available tau PET tracers. In conclusion, while the field is currently addressing outstanding methodologic issues, tau PET is gradually moving toward clinical application as a diagnostic and possibly prognostic marker in dementia expert centers and as a tool for selecting participants, assessing target engagement, and monitoring treatment effects in clinical trials.
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| 60. |
- Hahn, Andreas, et al.
(författare)
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Association Between Earliest Amyloid Uptake and Functional Connectivity in Cognitively Unimpaired Elderly
- 2019
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1460-2199 .- 1047-3211. ; 29, s. 2173-2182
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in cognitive performance have been noted in nondemented subjects with elevated accumulation of amyloid-β (Aβ) fibrils. However, it is not yet understood whether brain function is already influenced by Aβ deposition during the very earliest stages of the disease. We therefore investigated associations between [18F]Flutemetamol PET, resting-state functional connectivity, gray and white matter structure and cognitive performance in 133 cognitively normal elderly that exhibited normal global Aβ PET levels. [18F]Flutemetamol uptake in regions known to accumulate Aβ fibrils early in preclinical AD (i.e., mainly certain parts of the default-mode network) was positively associated with dynamic but not static functional connectivity (r = 0.77). Dynamic functional connectivity was further related to better cognitive performance (r = 0.21-0.72). No significant associations were found for Aβ uptake with gray matter volume or white matter diffusivity. The findings demonstrate that the earliest accumulation of Aβ fibrils is associated with increased functional connectivity, which occurs before any structural alterations. The enhanced functional connectivity may reflect a compensatory mechanism to maintain high cognitive performance in the presence of increasing amyloid accumulation during the earliest phases of AD.
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