| 1. |
- Altomare, Daniele, et al.
(författare)
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Applying the ATN scheme in a memory clinic population : The ABIDE project
- 2019
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Ingår i: Neurology. - 1526-632X. ; 93:17, s. 1635-1646
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To apply the ATN scheme to memory clinic patients, to assess whether it discriminates patient populations with specific features. METHODS: We included 305 memory clinic patients (33% subjective cognitive decline [SCD]: 60 ± 9 years, 61% M; 19% mild cognitive impairment [MCI]: 68 ± 9 years, 68% M; 48% dementia: 66 ± 10 years, 58% M) classified for positivity (±) of amyloid (A) ([18F]Florbetaben PET), tau (T) (CSF p-tau), and neurodegeneration (N) (medial temporal lobe atrophy). We assessed ATN profiles' demographic, clinical, and cognitive features at baseline, and cognitive decline over time. RESULTS: The proportion of A+T+N+ patients increased with syndrome severity (from 1% in SCD to 14% in MCI and 35% in dementia), while the opposite was true for A-T-N- (from 48% to 19% and 6%). Compared to A-T-N-, patients with the Alzheimer disease profiles (A+T+N- and A+T+N+) were older (both p < 0.05) and had a higher prevalence of APOE ε4 (both p < 0.05) and lower Mini-Mental State Examination (MMSE) (both p < 0.05), memory (both p < 0.05), and visuospatial abilities (both p < 0.05) at baseline. Non-Alzheimer profiles A-T-N+ and A-T+N+ showed more severe white matter hyperintensities (both p < 0.05) and worse language performance (both p < 0.05) than A-T-N-. A linear mixed model showed faster decline on MMSE over time in A+T+N- and A+T+N+ (p = 0.059 and p < 0.001 vs A-T-N-), attributable mainly to patients without dementia. CONCLUSIONS: The ATN scheme identified different biomarker profiles with overlapping baseline features and patterns of cognitive decline. The large number of profiles, which may have different implications in patients with vs without dementia, poses a challenge to the application of the ATN scheme.
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| 2. |
- Altomare, Daniele, et al.
(författare)
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Prognostic value of Alzheimer’s biomarkers in mild cognitive impairment : the effect of age at onset
- 2019
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Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 266:10, s. 2535-2545
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study is to assess the impact of age at onset on the prognostic value of Alzheimer’s biomarkers in a large sample of patients with mild cognitive impairment (MCI). Methods: We measured Aβ42, t-tau, hippocampal volume on magnetic resonance imaging (MRI) and cortical metabolism on fluorodeoxyglucose–positron emission tomography (FDG-PET) in 188 MCI patients followed for at least 1 year. We categorised patients into earlier and later onset (EO/LO). Receiver operating characteristic curves and corresponding areas under the curve (AUCs) were performed to assess and compar the biomarker prognostic performances in EO and LO groups. Linear Model was adopted for estimating the time-to-progression in relation with earlier/later onset MCI groups and biomarkers. Results: In earlier onset patients, all the assessed biomarkers were able to predict cognitive decline (p < 0.05), with FDG-PET showing the best performance. In later onset patients, all biomarkers but t-tau predicted cognitive decline (p < 0.05). Moreover, FDG-PET alone in earlier onset patients showed a higher prognostic value than the one resulting from the combination of all the biomarkers in later onset patients (earlier onset AUC 0.935 vs later onset AUC 0.753, p < 0.001). Finally, FDG-PET showed a different prognostic value between earlier and later onset patients (p = 0.040) in time-to-progression allowing an estimate of the time free from disease. Discussion: FDG-PET may represent the most universal tool for the establishment of a prognosis in MCI patients and may be used for obtaining an onset-related estimate of the time free from disease.
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| 3. |
- de Wilde, Arno, et al.
(författare)
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Assessment of the appropriate use criteria for amyloid PET in an unselected memory clinic cohort : The ABIDE project
- 2019
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260.
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort. Methods: We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post–positron emission tomography diagnosis and management change between “AUC-consistent” and “AUC-inconsistent” patients. Results: Almost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post–positron emission tomography diagnosis (28%–21%) and management (32%–17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%). Discussion: The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not.
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| 4. |
- De Wilde, Arno, et al.
(författare)
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Discordant amyloid-β PET and CSF biomarkers and its clinical consequences
- 2019
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: In vivo, high cerebral amyloid-β load has been associated with (i) reduced concentrations of Aβ42 in cerebrospinal fluid and (ii) increased retention using amyloid-β positron emission tomography. Although these two amyloid-β biomarkers generally show good correspondence, ~ 10-20% of cases have discordant results. To assess the consequences of having discordant amyloid-β PET and CSF biomarkers on clinical features, biomarkers, and longitudinal cognitive trajectories. Methods: We included 768 patients (194 with subjective cognitive decline (SCD), 127 mild cognitive impairment (MCI), 309 Alzheimer's dementia (AD), and 138 non-AD) who were categorized as concordant-negative (n = 315, 41%), discordant (n = 97, 13%), or concordant-positive (n = 356, 46%) based on CSF and PET results. We compared discordant with both concordant-negative and concordant-positive groups on demographics, clinical syndrome, apolipoprotein E (APOE) ϵ4 status, CSF tau, and clinical and neuropsychological progression. Results: We found an increase from concordant-negative to discordant to concordant-positive in rates of APOE ϵ4 (28%, 55%, 70%, Z = - 10.6, P < 0.001), CSF total tau (25%, 45%, 78%, Z = - 13.7, P < 0.001), and phosphorylated tau (28%, 43%, 80%, Z = - 13.7, P < 0.001) positivity. In patients without dementia, linear mixed models showed that Mini-Mental State Examination and memory composite scores did not differ between concordant-negative (β [SE] - 0.13[0.08], P = 0.09) and discordant (β 0.08[0.15], P = 0.15) patients (P interaction = 0.19), while these scores declined in concordant-positive (β - 0.75[0.08] patients (P interaction < 0.001). In patients with dementia, longitudinal cognitive scores were not affected by amyloid-β biomarker concordance or discordance. Clinical progression rates from SCD to MCI or dementia (P = 0.01) and from MCI to dementia (P = 0.003) increased from concordant-negative to discordant to concordant-positive. Conclusions: Discordant cases were intermediate to concordant-negative and concordant-positive patients in terms of genetic (APOE ϵ4) and CSF (tau) markers of AD. While biomarker agreement did not impact cognition in patients with dementia, discordant biomarkers are not benign in patients without dementia given their higher risk of clinical progression.
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| 5. |
- Eikelboom, Willem S., et al.
(författare)
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Early recognition and treatment of neuropsychiatric symptoms to improve quality of life in early Alzheimer's disease : Protocol of the BEAT-IT study
- 2019
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuropsychiatric symptoms (NPS) are very common in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and are associated with various disadvantageous clinical outcomes including a negative impact on quality of life, caregiver burden, and accelerated disease progression. Despite growing evidence of the efficacy of (non)pharmacological interventions to reduce these symptoms, NPS remain underrecognized and undertreated in memory clinics. The BEhavioural symptoms in Alzheimer's disease Towards early Identification and Treatment (BEAT-IT) study is developed to (1) investigate the neurobiological etiology of NPS in AD and (2) study the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) approach to structure and standardize the current care of NPS in AD. By means of the DICE method, we aim to improve the quality of life of AD patients with NPS and their caregivers who visit the memory clinic. This paper describes the protocol for the intervention study that incorporates the latter aim. Methods: We aim to enroll a total of 150 community-dwelling patients with MCI or AD and their caregivers in two waves. First, we will recruit a control group who will receive care as usual. Next, the second wave of participants will undergo the DICE method. This approach consists of the following steps: (1) describe the context in which NPS occur, (2) investigate the possible causes, (3) create and implement a treatment plan, and (4) evaluate whether these interventions are effective. Primary outcomes are the quality of life of patients and their caregivers. Secondary outcomes include NPS change, caregiver burden, caregivers' confidence managing NPS, psychotropic medication use, the experiences of patients and caregivers who underwent the DICE method, and the cost-effectiveness of the intervention. Conclusions: This paper describes the protocol of an intervention study that is part of the BEAT-IT study and aims to improve current recognition and treatment of NPS in AD by structuring and standardizing the detection and treatment of NPS in AD using the DICE approach. Trial registration: The trial was registered on the Netherlands Trial Registry (NTR7459); registered 6 September 2018.
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| 6. |
- 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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| 7. |
- Mattsson, Niklas, et al.
(författare)
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Predicting diagnosis and cognition with 18F-AV-1451 tau PET and structural MRI in Alzheimer's disease
- 2019
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:4, s. 570-580
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The relative importance of structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) to predict diagnosis and cognition in Alzheimer's disease (AD) is unclear. Methods: We tested 56 cognitively unimpaired controls (including 27 preclinical AD), 32 patients with prodromal AD, and 39 patients with AD dementia. Optimal classifiers were constructed using the least absolute shrinkage and selection operator with 18F-AV-1451 (tau) PET and structural MRI data (regional cortical thickness and subcortical volumes). Results: 18F-AV-1451 in the amygdala, entorhinal cortex, parahippocampal gyrus, fusiform, and inferior parietal lobule had 93% diagnostic accuracy for AD (prodromal or dementia). The MRI classifier involved partly the same regions plus the hippocampus, with 83% accuracy, but did not improve upon the tau classifier. 18F-AV-1451 retention and MRI were independently associated with cognition. Discussion: Optimized tau PET classifiers may diagnose AD with high accuracy, but both tau PET and structural brain MRI capture partly unique information relevant for the clinical deterioration in AD.
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| 8. |
- Ossenkoppele, Rik, et al.
(författare)
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Associations between tau, Aβ, and cortical thickness with cognition in Alzheimer disease
- 2019
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Ingår i: Neurology. - 1526-632X. ; 92:6, s. 601-612
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the cross-sectional associations between regional tau, β-amyloid (Aβ), and cortical thickness and neuropsychological function across the preclinical and clinical spectrum of Alzheimer disease (AD). METHODS: We included 106 participants from the Swedish Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study, of whom 33 had preclinical AD (Aβ-positive cognitively normal individuals), 25 had prodromal AD (Aβ-positive mild cognitive impairment), and 48 had probable AD dementia. All underwent [18F]flortaucipir (tau) and structural MRI (cortical thickness), and 88 of 106 underwent [18F]flutemetamol (Aβ) PET. Linear regression models adjusted for age, sex, and education were performed to examine associations between 7 regions of interest and 7 neuropsychological tests for all 3 imaging modalities. RESULTS: In preclinical AD, [18F]flortaucipir, but not [18F]flutemetamol or cortical thickness, was associated with decreased global cognition, memory, and processing speed (range standardized β = 0.35-0.52, p < 0.05 uncorrected for multiple comparisons). In the combined prodromal AD and AD dementia group, both increased [18F]flortaucipir uptake and reduced cortical thickness were associated with worse performance on a variety of neuropsychological tests (most regions of interest survived correction for multiple comparisons at p < 0.05), while increased [18F]flutemetamol uptake was specifically associated with lower scores on a delayed recall memory task (p < 0.05 uncorrected for multiple comparisons). The strongest effects for both [18F]flortaucipir and cortical thickness on cognition were found in the lateral and medial parietal cortex and lateral temporal cortex. The effect of [18F]flutemetamol on cognition was generally weaker and less region specific. CONCLUSION: Our findings suggest that tau PET is more sensitive than Aβ PET and measures of cortical thickness for detecting early cognitive changes in preclinical AD. Furthermore, both [18F]flortaucipir PET and cortical thickness show strong cognitive correlates at the clinical stages of AD.
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| 9. |
- Pereira, Joana B., et al.
(författare)
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Amyloid and tau accumulate across distinct spatial networks and are differentially associated with brain connectivity
- 2019
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Ingår i: eLife. - 2050-084X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The abnormal accumulation of amyloid-β and tau targets specific spatial networks in Alzheimer’s disease. However, the relationship between these networks across different disease stages and their association with brain connectivity has not been explored. In this study, we applied a joint independent component analysis to18F-Flutemetamol (amyloid-β) and18F-Flortaucipir (tau) PET images to identify amyloid-β and tau networks across different stages of Alzheimer’s disease. We then assessed whether these patterns were associated with resting-state functional networks and white matter tracts. Our analyses revealed nine patterns that were linked across tau and amyloid-β data. The amyloid-β and tau patterns showed a fair to moderate overlap with distinct functional networks but only tau was associated with white matter integrity loss and multiple cognitive functions. These findings show that amyloid-β and tau have different spatial affinities, which can be used to understand how they accumulate in the brain and potentially damage the brain’s connections.
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| 10. |
- Timmers, Tessa, et al.
(författare)
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Amyloid PET and cognitive decline in cognitively normal individuals : the SCIENCe project
- 2019
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 79, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- We examined the relationships between amyloid-β PET and concurrent and longitudinal cognitive performance in 107 cognitively normal individuals with subjective cognitive decline (age: 64 ± 8 years, 44% female, Mini-Mental State Examination score 29 ± 1). All underwent 90-minute dynamic [ 18 F]florbetapir PET scanning and longitudinal neuropsychological tests with a mean follow-up of 3.4 ± 3.0 years. Receptor parametric mapping was used to calculate [ 18 F]florbetapir binding potential (BP ND ), and we performed linear mixed models to assess the relationships between global [ 18 F]florbetapir BP ND and neuropsychological performance. Higher [ 18 F]florbetapir BP ND was related to lower concurrent Mini-Mental State Examination (β ± SE: −1.69 ± 0.63 p < 0.01) and to steeper rate of decline on tasks capturing memory (Rey Auditory Verbal Learning Task immediate [β ± SE −1.81 ± 0.81, p < 0.05] and delayed recall [β ± SE −1.19 ± 0.34, p < 0.01]), attention/executive functions (Stroop II [color] [β ± SE −0.02 ± 0.01, p < 0.05], Stroop III [word-color] [β ± SE −0.03 ± 0.02, p < 0.05]), and language (category fluency [β ± SE −0.04 ± 0.01, p < 0.01]). These findings suggest that higher amyloid-β load in cognitively normal individuals with subjective cognitive decline from a memory clinic is associated with lower concurrent global cognition and with faster rate of decline in a variety of cognitive domains.
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