| 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. |
- Bauckneht, Matteo, et al.
(författare)
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Associations among education, age, and the dementia with Lewy bodies (DLB) metabolic pattern: A European-DLB consortium project
- 2021
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Ingår i: Alzheimer's & Dementia. - : WILEY. - 1552-5260 .- 1552-5279. ; 17:8, s. 1277-1286
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Tidskriftsartikel (refereegranskat)abstract
- Introduction We assessed the influence of education as a proxy of cognitive reserve and age on the dementia with Lewy bodies (DLB) metabolic pattern. Methods Brain 18F-fluorodeoxyglucose positron emission tomography and clinical/demographic information were available in 169 probable DLB patients included in the European DLB-consortium database. Principal component analysis identified brain regions relevant to local data variance. A linear regression model was applied to generate age- and education-sensitive maps corrected for Mini-Mental State Examination score, sex (and either education or age). Results Age negatively covaried with metabolism in bilateral middle and superior frontal cortex, anterior and posterior cingulate, reducing the expression of the DLB-typical cingulate island sign (CIS). Education negatively covaried with metabolism in the left inferior parietal cortex and precuneus (making the CIS more prominent). Discussion These findings point out the importance of tailoring interpretation of DLB biomarkers considering the concomitant effect of individual, non-disease-related variables such as age and cognitive reserve.
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| 4. |
- Bischof, Gérard N., et al.
(författare)
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Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2110-2120
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Forskningsöversikt (refereegranskat)abstract
- Purpose: In 2017, the Geneva Alzheimer’s disease (AD) strategic biomarker roadmap initiative proposed a framework of the systematic validation AD biomarkers to harmonize and accelerate their development and implementation in clinical practice. Here, we use this framework to examine the translatability of the second-generation tau PET tracers into the clinical context. Methods: All available literature was systematically searched based on a set of search terms that related independently to analytic validity (phases 1–2), clinical validity (phase 3–4), and clinical utility (phase 5). The progress on each of the phases was determined based on scientific criteria applied for each phase and coded as fully, partially, preliminary achieved or not achieved at all. Results: The validation of the second-generation tau PET tracers has successfully passed the analytical phase 1 of the strategic biomarker roadmap. Assay definition studies showed evidence on the superiority over first-generation tau PET tracers in terms of off-target binding. Studies have partially achieved the primary aim of the analytical validity stage (phase 2), and preliminary evidence has been provided for the assessment of covariates on PET signal retention. Studies investigating of the clinical validity in phases 3, 4, and 5 are still underway. Conclusion: The current literature provides overall preliminary evidence on the establishment of the second-generation tau PET tracers into the clinical context, thereby successfully addressing some methodological issues from the tau PET tracer of the first generation. Nevertheless, bigger cohort studies, longitudinal follow-up, and examination of diverse disease population are still needed to gauge their clinical validity.
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| 5. |
- Boccalini, Cecilia, et al.
(författare)
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Early-Phase 18F-Florbetapir and 18F-Flutemetamol Images as Proxies of Brain Metabolism in a Memory Clinic Setting
- 2023
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Ingår i: Journal of Nuclear Medicine. - : The Society of Nuclear Medicine and Molecular Imaging. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 64:2, s. 266-273
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer disease (AD) neuropathologic changes are 6-amyloid (A6) deposition, pathologic tau, and neurodegeneration. Dual-phase amy-loid PET might be able to evaluate A6 deposition and neurodegenera-tion with a single tracer injection. Early-phase amyloid PET scans provide a proxy for cerebral perfusion, which has shown good correla-tions with neural dysfunction measured through metabolic consump-tion, whereas the late frames depict amyloid distribution. Our study aimed to assess the comparability between early-phase amyloid PET scans and 18F-FDG PET brain topography at the individual level and their ability to discriminate patients. Methods: One hundred sixty-six subjects evaluated at the Geneva Memory Center, ranging from no cognitive impairment to mild cognitive impairment and dementia, underwent early-phase amyloid PET-using either 18F-florbetapir (eFBP) (n = 94) or 18F-flutemetamol (eFMM) (n = 72)-and 18F-FDG PET. A6 status was assessed. SUV ratios (SUVRs) were extracted to evaluate the correlation of eFBP/eFMM and their respective 18F-FDG PET scans. The single-subject procedure was applied to investigate hypometabolism and hypoperfusion maps and their spatial overlap by the Dice coefficient. Receiver-operating-characteristic analyses were performed to compare the discriminative power of eFBP/eFMM and 18F-FDG PET SUVR in AD-related meta-regions of interest between A6-negative healthy controls and cases in the AD continuum. Results: Positive correlations were found between eFBP/eFMM and 18F-FDG PET SUVR independently of A6 status and A6 radiotracer (R> 0.72, P< 0.001). eFBP/eFMM single-subject analysis revealed clusters of significant hypoperfusion with good correspondence to hypometabo-lism topographies, independently of the underlying neurodegenerative patterns. Both eFBP/eFMM and 18F-FDG PET SUVR significantly dis-criminated AD patients from controls in the AD-related meta-regions of interest (eFBP area under the curve [AUC], 0.888; eFMM AUC, 0.801), with 18F-FDG PET performing slightly better, although not sig-nificantly (all P values higher than 0.05), than others (18F-FDG AUC, 0.915 and 0.832 for subjects evaluated with eFBP and eFMM, respec-tively). Conclusion: The distribution of perfusion was comparable to that of metabolism at the single-subject level by parametric analysis, particularly in the presence of a high neurodegeneration burden. Our findings indicate that eFBP and eFMM imaging can replace 18F-FDG PET imaging, as they reveal typical neurodegenerative patterns or allow exclusion of the presence of neurodegeneration. The findings show cost-saving capacities of amyloid PET and support routine use of the modality for individual classification in clinical practice.
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| 6. |
- Bocchetta, Martina, et al.
(författare)
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The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey.
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 11:2, s. 195-206
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
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| 7. |
- Bollack, Ariane, et al.
(författare)
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Investigating reliable amyloid accumulation in Centiloids : Results from the AMYPAD Prognostic and Natural History Study
- 2024
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Ingår i: Alzheimer's and Dementia. - 1552-5260 .- 1552-5279. ; 20:5, s. 3429-3441
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-β (Aβ) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease–Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aβ-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12–20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.
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| 8. |
- Bos, Isabelle, et al.
(författare)
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The frequency and influence of dementia risk factors in prodromal Alzheimer's disease
- 2017
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 56, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.
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| 9. |
- Buerger, Katharina, et al.
(författare)
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Validation of Alzheimer's disease CSF and plasma biological markers: the multicentre reliability study of the pilot European Alzheimer's Disease Neuroimaging Initiative (E-ADNI).
- 2009
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Ingår i: Experimental gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 44:9, s. 579-85
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alzheimer's Disease Neuroimaging Initiatives ("ADNI") aim to validate neuroimaging and biochemical markers of Alzheimer's disease (AD). Data of the pilot European-ADNI (E-ADNI) biological marker programme of cerebrospinal fluid (CSF) and plasma candidate biomarkers are reported. METHODS: Six academic EADC centres recruited 49 subjects (healthy controls, subjects with mild cognitive impairment (MCI) and AD). We measured CSF beta-amyloid 42 (CSF Abeta42), total tau-protein (t-tau), phosphorylated tau-proteins (P-tau181, P-tau231), plasma beta-amyloid 40 and 42 (Abeta40/Abeta42). Immediate fresh shipment was compared to freezing and later shipment on dry ice. RESULTS: CSF T-tau (fresh samples) was increased in AD versus controls (p=0.049), CSF Abeta42 (frozen samples) was decreased in MCI and AD (p=0.02), as well as plasma Abeta40 (fresh and frozen samples) in AD (p=0.049 and p=0.016). Pooled values of neurochemical parameters and ratios thereof were different between centres (p<0.005). Analysis of frozen samples yielded higher diagnostic accuracy than immediate fresh shipment with 100% (fresh: 100%) correctly classified in control subjects, 100% (78%) in MCI, 91% (91%) in AD. CONCLUSION: The use of frozen rather than fresh samples renders higher diagnostic accuracy within a multicentre context. We confirmed the feasibility of a multicentre AD biomarker programme for future clinical trials.
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| 10. |
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| 11. |
- Caroli, Anna, et al.
(författare)
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Mild cognitive impairment with suspected nonamyloid pathology (SNAP) Prediction of progression
- 2015
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 84:5, s. 508-515
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Tidskriftsartikel (refereegranskat)abstract
- Objectives:The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non-Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI).Methods:We measured markers of amyloid pathology (CSF -amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [F-18]-fluorodeoxyglucose-PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A- and N+/N- based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A-N+ cases.Results:The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A-N-, A+N-, SNAP, and A+N+, respectively; the proportion of APOE epsilon 4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N- and A+N+ groups (p 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A-N-, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N- patients did not (hazard ratio = 1.13, p = 0.771). In A+N- and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073).Conclusions:Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile.
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| 12. |
- Chincarini, Andrea, et al.
(författare)
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Automatic temporal lobe atrophy assessment in prodromal AD: Data from the DESCRIPA study
- 2014
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 10:4, s. 456-467
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the framework of the clinical validation of research tools, this investigation presents a validation study of an automatic medial temporal lobe atrophy measure that is applied to a naturalistic population sampled from memory clinic patients across Europe. Methods: The procedure was developed on 1.5-T magnetic resonance images from the Alzheimer's Disease Neuroimaging Initiative database, and it was validated on an independent data set coming from the DESCRIPA study. All images underwent an automatic processing procedure to assess tissue atrophy that was targeted at the hippocampal region. For each subject, the procedure returns a classification index. Once provided with the clinical assessment at baseline and follow-up, subjects were grouped into cohorts to assess classification performance. Each cohort was divided into converters (co) and nonconverters (nc) depending on the clinical outcome at follow-up visit. Results: We found the area under the receiver operating characteristic curve (AUC) was 0.81 for all co versus nc subjects, and AUC was 0.90 for subjective memory complaint (SMCnc) versus all co subjects. Furthermore, when training on mild cognitive impairment (MCI-nc/MCI-co), the classification performance generally exceeds that found when training on controls versus Alzheimer's disease (CTRL/AD). Conclusions: Automatic magnetic resonance imaging analysis may assist clinical classification of subjects in a memory clinic setting even when images are not specifically acquired for automatic analysis. (C) 2014 The Alzheimer's Association. All rights reserved.
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| 13. |
- Chiotis, Konstantinos, et al.
(författare)
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Clinical validity of increased cortical binding of tau ligands of the THK family and PBB3 on PET as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2086-2096
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Forskningsöversikt (refereegranskat)abstract
- Purpose: The research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s disease (AD). In 2017, the Geneva AD Biomarker Roadmap initiative adapted the framework for the systematic validation of oncological biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. The aim of this work was to assess the validation status of tau PET ligands of the THK family and PBB3 as imaging biomarkers for AD, based on the Biomarker Roadmap methodology. Methods: A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of clinical validity of tau PET ligands of the THK family and PBB3 was assessed based on the 5-phase development framework before the meeting and discussed during the workshop. Results: PET radioligands of the THK family discriminate well between healthy controls and patients with AD dementia (phase 2; partly achieved) and recent evidence suggests an accurate diagnostic accuracy at the mild cognitive impairment (MCI) stage of the disease (phase 3; partly achieved). The phases 2 and 3 were considered not achieved for PBB3 since no evidence exists about the ligand’s diagnostic accuracy. Preliminary evidence exists about the secondary aims of each phase for all ligands. Conclusion: Much work remains for completing the aims of phases 2 and 3 and replicating the available evidence. However, it is unlikely that the validation process for these tracers will be completed, given the presence of off-target binding and the development of second-generation tracers with improved binding and pharmacokinetic properties.
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| 14. |
- Damian, Marinella, et al.
(författare)
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Single-Domain Amnestic Mild Cognitive Impairment Identified by Cluster Analysis Predicts Alzheimer's Disease in the European Prospective DESCRIPA Study
- 2013
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 36:1-2, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). Methods: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e. g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE >= 28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. Results: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (A beta(42), t-tau, APOE epsilon 4, and medial temporal atrophy), compared to SCI or naMCI. Conclusion: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings. Copyright (C) 2013 S. Karger AG, Basel
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| 15. |
- Dubois, Bruno, et al.
(författare)
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Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.
- 2014
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Ingår i: Lancet neurology. - 1474-4465. ; 13:6, s. 614-29
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Forskningsöversikt (refereegranskat)abstract
- In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
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| 16. |
- Etminani, Kobra, 1984-, et al.
(författare)
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A 3D deep learning model to predict the diagnosis of dementia with Lewy bodies, Alzheimers disease, and mild cognitive impairment using brain 18F-FDG PET
- 2022
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - New York : Springer. - 1619-7070 .- 1619-7089. ; 49, s. 563-584
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimers disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimers disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare models performance to that of multiple expert nuclear medicine physicians readers. Materials and methods Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimers disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The models performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention. Results The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6-100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7-100) in AD, 71.4% (51.6-91.2) in MCI-AD, and 94.7% (90-99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders. Conclusion Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.
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| 17. |
- Festari, Cristina, et al.
(författare)
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European consensus for the diagnosis of MCI and mild dementia : Preparatory phase
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:5, s. 1729-1741
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Etiological diagnosis of neurocognitive disorders of middle-old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results. Methods: Using a Delphi consensus method supported by a systematic literature review, 22 delegates from 11 relevant scientific societies defined workflow assumptions. Results: We extracted diagnostic accuracy figures from literature on the use of biomarkers in the diagnosis of main forms of neurocognitive disorders. Supported by this evidence, panelists defined clinical setting (specialist outpatient service), application stage (MCI-mild dementia), and detailed pre-assessment screening (clinical-neuropsychological evaluations, brain imaging, and blood tests). Discussion: The Delphi consensus on these assumptions set the stage for the development of the first pan-European workflow for biomarkers’ use in the etiological diagnosis of middle-old age neurocognitive disorders at MCI-mild dementia stages. Highlights: Rational use of biomarkers in neurocognitive disorders lacks consensus in Europe. A consensus of experts will define a workflow for the rational use of biomarkers. The diagnostic workflow will be patient-centered and based on clinical presentation. The workflow will be updated as new evidence accrues.
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| 18. |
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| 19. |
- Frisoni, Giovanni B., et al.
(författare)
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European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders
- 2024
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Ingår i: The Lancet Neurology. - 1474-4422 .- 1474-4465. ; 23:3, s. 302-312
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Forskningsöversikt (refereegranskat)abstract
- The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries.
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| 20. |
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| 21. |
- Frisoni, Giovanni B, et al.
(författare)
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The pilot European Alzheimer's Disease Neuroimaging Initiative of the European Alzheimer's Disease Consortium.
- 2008
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 4:4, s. 255-64
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In North America, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has established a platform to track the brain changes of Alzheimer's disease. A pilot study has been carried out in Europe to test the feasibility of the adoption of the ADNI platform (pilot E-ADNI). METHODS: Seven academic sites of the European Alzheimer's Disease Consortium (EADC) enrolled 19 patients with mild cognitive impairment (MCI), 22 with AD, and 18 older healthy persons by using the ADNI clinical and neuropsychological battery. ADNI compliant magnetic resonance imaging (MRI) scans, cerebrospinal fluid, and blood samples were shipped to central repositories. Medial temporal atrophy (MTA) and white matter hyperintensities (WMH) were assessed by a single rater by using visual rating scales. RESULTS: Recruitment rate was 3.5 subjects per month per site. The cognitive, behavioral, and neuropsychological features of the European subjects were very similar to their U.S. counterparts. Three-dimensional T1-weighted MRI sequences were successfully performed on all subjects, and cerebrospinal fluid samples were obtained from 77%, 68%, and 83% of AD patients, MCI patients, and controls, respectively. Mean MTA score showed a significant increase from controls (left, right: 0.4, 0.3) to MCI patients (0.9, 0.8) to AD patients (2.3, 2.0), whereas mean WMH score did not differ among the three diagnostic groups (between 0.7 and 0.9). The distribution of both MRI markers was comparable to matched US-ADNI subjects. CONCLUSIONS: Academic EADC centers can adopt the ADNI platform to enroll MCI and AD patients and older controls with global cognitive and structural imaging features remarkably similar to those of the US-ADNI.
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| 22. |
- Hall, Anette, et al.
(författare)
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Predicting Progression from Cognitive Impairment to Alzheimer's Disease with the Disease State Index
- 2015
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Ingår i: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1875-5828 .- 1567-2050. ; 12:1, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the performance of the Disease State Index (DSI) method when predicting progression to Alzheimer's disease (AD) in patients with subjective cognitive impairment (SCI), amnestic or non-amnestic mild cognitive impairment (aMCI, naMCI). The DSI model measures patients' similarity to diagnosed cases based on available data, such as cognitive tests, the APOE genotype, CSF biomarkers and MRI. We applied the DSI model to data from the DE-SCRIPA cohort, where non-demented patients (N=775) with different subtypes of cognitive impairment were followed for 1 to 5 years. Classification accuracies for the subgroups were calculated with the DSI using leave-one-out cross-validation. The DSI's classification accuracy in predicting progression to AD was 0.75 (AUC=0.83) in the total population, 0.70 (AUC=0.77) for aMCI and 0.71 (AUC=0.76) for naMCI. For a subset of approximately half of the patients with high or low DSI values, accuracy reached 0.86 (all), 0.78 (aMCI), and 0.85 (naMCI). For patients with MRI or CSF biomarker data available, they were 0.78 (all), 0.76 (aMCI) and 0.76 (naMCI), while for clear cases the accuracies rose to 0.90 (all), 0.83 (aMCI) and 0.91 (naMCI). The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers. While a specific test or biomarker may confound analysis for an individual patient, combining several different types of tests and biomarkers could be able to reveal the trajectory of the disease and improve the prediction of AD progression.
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| 23. |
- Hampel, Harald, et al.
(författare)
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Biomarkers for Alzheimer's disease therapeutic trials.
- 2011
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Ingår i: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 95:4, s. 579-593
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Forskningsöversikt (refereegranskat)abstract
- The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials.
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| 24. |
- Herukka, Sanna-Kaisa, et al.
(författare)
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Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment.
- 2017
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 13:3, s. 285-295
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Tidskriftsartikel (refereegranskat)abstract
- This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.
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| 25. |
- Homann, Jan, et al.
(författare)
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Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset.
- 2022
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Ingår i: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.
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