| 21. |
- 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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| 22. |
- 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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| 23. |
- Eikelboom, Willem S., et al.
(författare)
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The reporting of neuropsychiatric symptoms in electronic health records of individuals with Alzheimer’s disease : a natural language processing study
- 2023
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuropsychiatric symptoms (NPS) are prevalent in the early clinical stages of Alzheimer’s disease (AD) according to proxy-based instruments. Little is known about which NPS clinicians report and whether their judgment aligns with proxy-based instruments. We used natural language processing (NLP) to classify NPS in electronic health records (EHRs) to estimate the reporting of NPS in symptomatic AD at the memory clinic according to clinicians. Next, we compared NPS as reported in EHRs and NPS reported by caregivers on the Neuropsychiatric Inventory (NPI). Methods: Two academic memory clinic cohorts were used: the Amsterdam UMC (n = 3001) and the Erasmus MC (n = 646). Patients included in these cohorts had MCI, AD dementia, or mixed AD/VaD dementia. Ten trained clinicians annotated 13 types of NPS in a randomly selected training set of n = 500 EHRs from the Amsterdam UMC cohort and in a test set of n = 250 EHRs from the Erasmus MC cohort. For each NPS, a generalized linear classifier was trained and internally and externally validated. Prevalence estimates of NPS were adjusted for the imperfect sensitivity and specificity of each classifier. Intra-individual comparison of the NPS classified in EHRs and NPS reported on the NPI were conducted in a subsample (59%). Results: Internal validation performance of the classifiers was excellent (AUC range: 0.81–0.91), but external validation performance decreased (AUC range: 0.51–0.93). NPS were prevalent in EHRs from the Amsterdam UMC, especially apathy (adjusted prevalence = 69.4%), anxiety (adjusted prevalence = 53.7%), aberrant motor behavior (adjusted prevalence = 47.5%), irritability (adjusted prevalence = 42.6%), and depression (adjusted prevalence = 38.5%). The ranking of NPS was similar for EHRs from the Erasmus MC, although not all classifiers obtained valid prevalence estimates due to low specificity. In both cohorts, there was minimal agreement between NPS classified in the EHRs and NPS reported on the NPI (all kappa coefficients < 0.28), with substantially more reports of NPS in EHRs than on NPI assessments. Conclusions: NLP classifiers performed well in detecting a wide range of NPS in EHRs of patients with symptomatic AD visiting the memory clinic and showed that clinicians frequently reported NPS in these EHRs. Clinicians generally reported more NPS in EHRs than caregivers reported on the NPI.
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| 24. |
- 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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| 25. |
- Luo, Jiao, et al.
(författare)
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Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease
- 2023
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 6:5
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).CONCLUSIONS AND RELEVANCE This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
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| 26. |
- Visser, Denise, et al.
(författare)
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Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer’s disease
- 2022
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 49:6, s. 1951-1963
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [18F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD. Methods: Seventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n = 35, age-at-PET = 59 ± 5, MMSE = 23 ± 4; LOAD: n = 44, age-at-PET = 71 ± 5, MMSE = 23 ± 4) underwent a 130-min dynamic [18F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BPND) and R1 (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital, and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language, and executive functioning. We first examined differences between EOAD and LOAD in BPND or R1 using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BPND/R1 on cognition. Results: Both region-of-interest and voxel-wise contrasts showed higher [18F]flortaucipir BPND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R1 values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipitoparietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BPND − 0.76 ≤ stβ ≤ − 0.48 vs LOAD − 0.18 ≤ stβ ≤ − 0.02; EOAD R1 0.37 ≤ stβ ≤ 0.84 vs LOAD − 0.25 ≤ stβ ≤ 0.16). Conclusions: Compared to LOAD, the degree of lateral temporal and occipitoparietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.
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| 27. |
- Visser, Denise, et al.
(författare)
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Longitudinal Tau PET Using 18F-Flortaucipir : The Effect of Relative Cerebral Blood Flow on Quantitative and Semiquantitative Parameters
- 2023
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505. ; 64:2, s. 281-286
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Tidskriftsartikel (refereegranskat)abstract
- Semiquantitative PET measures such as SUV ratio (SUVr) have several advantages over quantitative measures, such as practical applicability and relative computational simplicity. However, SUVr may potentially be affected by changes in blood flow, whereas quantitative measures such as nondisplaceable binding potential (BPND) are not. For 18F-flortaucipir PET, the sensitivity of SUVr for changes in blood flow is currently unknown. Therefore, we compared semiquantitative (SUVr) and quantitative (BPND) parameters of longitudinal 18F-flortaucipir PET scans and assessed their vulnerability to changes in blood flow. Methods: Subjects with subjective cognitive decline (n = 38) and Alzheimer disease patients (n = 24) underwent baseline and 2-y follow-up dynamic 18F-flortaucipir PET scans. BPND and relative tracer delivery were estimated using receptor parametric mapping, and SUVr at 80-100 min was calculated. Regional SUVrs were compared with corresponding distribution volume ratio (BPND + 1) using paired t tests. Additionally, simulations were performed to model effects of larger flow changes in different binding categories. Results: Results in subjective cognitive decline and Alzheimer disease showed only minor differences between SUVr and BPND changes over time. Relative tracer delivery changes were small in all groups. Simulations illustrated a variable bias for SUVr depending on the amount of binding. Conclusion: SUVr provided an accurate estimate of changes in specific binding for 18F-flortaucipir over a 2-y follow-up during which changes in flow were small. Notwithstanding, simulations showed that large(r) flow changes may affect 18F-flortaucipir SUVr. Given that it is currently unknown to what order of magnitude pharmacotherapeutic interventions may induce changes in cerebral blood flow, caution may be warranted when changes in flow are potentially large(r), as in clinical trials.
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| 28. |
- Visser, Denise, et al.
(författare)
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Tau pathology and relative cerebral blood flow are independently associated with cognition in Alzheimer’s disease
- 2020
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 47:13, s. 3165-3175
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We aimed to investigate associations between tau pathology and relative cerebral blood flow (rCBF), and their relationship with cognition in Alzheimer’s disease (AD), by using a single dynamic [18F]flortaucipir positron emission tomography (PET) scan. Methods: Seventy-one subjects with AD (66 ± 8 years, mini-mental state examination (MMSE) 23 ± 4) underwent a dynamic 130-min [18F]flortaucipir PET scan. Cognitive assessment consisted of composite scores of four cognitive domains. For tau pathology and rCBF, receptor parametric mapping (cerebellar gray matter reference region) was used to create uncorrected and partial volume-corrected parametric images of non-displaceable binding potential (BPND) and R1, respectively. (Voxel-wise) linear regressions were used to investigate associations between BPND and/or R1 and cognition. Results: Higher [18F]flortaucipir BPND was associated with lower R1 in the lateral temporal, parietal and occipital regions. Higher medial temporal BPND was associated with worse memory, and higher lateral temporal BPND with worse executive functioning and language. Higher parietal BPND was associated with worse executive functioning, language and attention, and higher occipital BPND with lower cognitive scores across all domains. Higher frontal BPND was associated with worse executive function and attention. For [18F]flortaucipir R1, lower values in the lateral temporal and parietal ROIs were associated with worse executive functioning, language and attention, and lower occipital R1 with lower language and attention scores. When [18F]flortaucipir BPND and R1 were modelled simultaneously, associations between lower R1 in the lateral temporal ROI and worse attention remained, as well as for lower parietal R1 and worse executive functioning and attention. Conclusion: Tau pathology was associated with locally reduced rCBF. Tau pathology and low rCBF were both independently associated with worse cognitive performance. For tau pathology, these associations spanned widespread neocortex, while for rCBF, independent associations were restricted to lateral temporal and parietal regions and the executive functioning and attention domains. These findings indicate that each biomarker may independently contribute to cognitive impairment in AD.
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| 29. |
- Vos, Stephanie J. B., et al.
(författare)
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Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage
- 2015
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 138:5, s. 1327-1338
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Tidskriftsartikel (refereegranskat)abstract
- Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.
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| 30. |
- Wolters, Emma E., et al.
(författare)
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Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer’s disease
- 2020
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 47:12, s. 2866-2878
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In vivo Alzheimer’s disease (AD) biomarkers for tau pathology are cerebrospinal fluid (CSF) phosphorylated tau (p-tau) and [18F]flortaucipir positron emission tomography (PET). Our aim was to assess associations between CSF p-tau with [18F]flortaucipir PET and the associations of both tau biomarkers with cognition and atrophy. Methods: We included 78 amyloid positive cognitively impaired patients (clinical diagnoses mild cognitive impairment (MCI, n = 8) and AD dementia (n = 45) and 25 cognitively normal subjects with subjective cognitive decline (SCD) (40% amyloid-positive)). Dynamic 130 min [18F]flortaucipir PET scans were acquired to generate binding potential (BPND) images using receptor parametric mapping and standardized uptake values ratios of 80–100 min (SUVr80-100min) post injection. We obtained regional BPND and SUVr from entorhinal, limbic, and neocortical regions-of-interest (ROIs), closely aligning to the neuropathological tau staging schemes. Cognition was assessed using MMSE and composite scores of four cognitive domains, and atrophy was measured using gray matter volume covering the major brain lobes. First, we used linear regressions to investigate associations between CSF p-tau (independent variable) and tau PET (dependent variable). Second, we used linear regressions to investigate associations between CSF p-tau, tau PET (separate independent variables, model 1), and cognition (dependent variable). We then assessed the independent effects of CSF p-tau and tau PET on cognition by simultaneously adding the other tau biomarker as a predictor (model 2). Finally, we performed the same procedure for model 1 and 2, but replaced cognition with atrophy. Models were adjusted for age, sex, time lag between assessments, education (cognition only), and total intracranial volume (atrophy only). Results: Higher [18F]flortaucipir BPND was associated with higher CSF p-tau (range of standardized betas (sβ) across ROIs, 0.43–0.46; all p < 0.01). [18F]flortaucipir BPND was more strongly associated with cognition and atrophy than CSF p-tau. When [18F]flortaucipir BPND and CSF p-tau were entered simultaneously, [18F]flortaucipir BPND (range sβ = − 0.20 to – 0.57, all p < 0.05) was strongly associated with multiple cognitive domains and atrophy regions. SUVr showed comparable results to BPND. Conclusion: Regional [18F]flortaucipir BPND correlated stronger with cognition and neurodegeneration than CSF p-tau, suggesting that tau PET more accurately reflects disease severity in AD.
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