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1.
  • Jansen, Willemijn J, et al. (author)
  • Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
  • 2015
  • In: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 313:19, s. 1924-38
  • Journal article (peer-reviewed)abstract
    • Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.
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2.
  • Mattsson, Niklas, et al. (author)
  • Prevalence of the apolipoprotein E epsilon 4 allele in amyloid beta positive subjects across the spectrum of Alzheimers disease
  • 2018
  • In: Alzheimer's & Dementia. - : ELSEVIER SCIENCE INC. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
  • Journal article (peer-reviewed)abstract
    • Introduction: Apolipoprotein E (APOE) epsilon 4 is the major genetic risk factor for Alzheimers disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta(A beta) pathology. Methods: We included 3451 A beta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon 4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE epsilon 4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in A beta+ cognitively normal and A beta+ mild cognitive impairment (P amp;lt;.05) but not in A beta+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE E4 prevalence in AD was higher than that in previous studies, which did not require presence of A beta pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location. (C) 2018 the Alzheimers Association. Published by Elsevier Inc. All rights reserved.
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3.
  • Mattsson, Niklas, et al. (author)
  • Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease
  • 2018
  • In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
  • Journal article (peer-reviewed)abstract
    • Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology. Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P <.05) but not in Aβ+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
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4.
  • Jansen, Willemijn J, et al. (author)
  • Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
  • 2018
  • In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
  • Journal article (peer-reviewed)abstract
    • Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P=.16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P<.001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P<.001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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6.
  • Jansen, Iris E, et al. (author)
  • Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
  • 2022
  • In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
  • Journal article (peer-reviewed)abstract
    • Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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7.
  • Jansen, Willemijn J, et al. (author)
  • Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
  • 2022
  • In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
  • Journal article (peer-reviewed)abstract
    • One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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8.
  • Coenen, Mirthe, et al. (author)
  • Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts
  • 2023
  • In: NeuroImage. Clinical. - 2213-1582. ; 40
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. METHODS: Individual participant data (N=3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. RESULTS: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DISCUSSION: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.
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9.
  • Coomans, Emma M., et al. (author)
  • Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia with Lewy Bodies
  • 2023
  • In: Neurology. - 0028-3878 .- 1526-632X. ; 101:19, s. 1850-1862
  • Journal article (peer-reviewed)abstract
    • Background and ObjectivesRecently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables.MethodsWe included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen . To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE).ResultsWe included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent ( = 0.95, CI 0.91-0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β =-0.52, CI-0.74 to-0.30, p < 0.001) and participants with AD (β =-0.30, CI-0.58 to-0.02, p = 0.04).DiscussionThe excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population.Classification of EvidenceThis study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-Tracer binding from those with high tau-Tracer binding and is associated with amyloid positivity and cognitive decline.
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10.
  • Verfaillie, Sander C.J., et al. (author)
  • Amyloid-β load is related to worries, but not to severity of cognitive complaints in individuals with subjective cognitive decline : The science project
  • 2019
  • In: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 11:JAN
  • Journal article (peer-reviewed)abstract
    • Objective: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer's Disease (AD). Early disease processes, such as amyloid-β aggregation measured with quantitative PET, may help to explain the phenotype of SCD. The aim of this study was to investigate whether quantitative amyloid-β load is associated with both self- and informant-reported cognitive complaints and memory deficit awareness in individuals with SCD. Methods: We included 106 SCD patients (mean ± SD age: 64 ± 8, 45%F) with 90 min dynamic [ 18 F]florbetapir PET scans. We used the following questionnaires to assess SCD severity: cognitive change index (CCI, self and informant reports; 2 × 20 items), subjective cognitive functioning (SCF, four items), and five questions “Do you have complaints?” (yes/no) for memory, attention, organization and language), and “Does this worry you? (yes/no).” The Rivermead Behavioral Memory Test (RBMT)-Stories (immediate and delayed recall) was used to assess objective episodic memory. To investigate the level of self-awareness, we calculated a memory deficit awareness index (Z-transformed (inverted self-reported CCI minus episodic memory); higher index, heightened self-awareness) and a self-proxy index (Z-transformed self- minus informant-reported CCI). Mean cortical [ 18 F]florbetapir binding potential (BPND) was derived from the PET data. Logistic and linear regression analyses, adjusted for age, sex, education, and depressive symptoms, were used to investigate associations between BPND and measures of SCD. Results: Higher mean cortical [ 18 F]florbetapir BPND was associated with SCD-related worries (odds ratio = 1.76 [95%CI = 1.07 ± 2.90]), but not with other SCD questionnaires (informant and self-report CCI or SCF, total scores or individual items, all p > 0.05). In addition, higher mean cortical [ 18 F]florbetapir BPND was associated with a higher memory deficit awareness index (Beta = 0.55), with an interaction between BPND and education (p = 0.002). There were no associations between [ 18 F]florbetapir BPND and self-proxy index (Beta = 0.11). Conclusion: Amyloid-β deposition was associated with SCD-related worries and heightened memory deficit awareness (i.e., hypernosognosia), but not with severity of cognitive complaints. Our findings indicate that worries about self-perceived decline may reflect an early symptom of amyloid-β related pathology rather than subjective cognitive functioning.
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11.
  • Schoonhoven, Deborah N., et al. (author)
  • Tau protein spreads through functionally connected neurons in Alzheimer's disease : a combined MEG/PET study
  • 2023
  • In: Brain. - 0006-8950. ; 146:10, s. 4040-4054
  • Journal article (peer-reviewed)abstract
    • Recent studies on Alzheimer's disease (AD) suggest that tau proteins spread through the brain following neuronal connections. Several mechanisms could be involved in this process: spreading between brain regions that interact strongly (functional connectivity); through the pattern of anatomical connections (structural connectivity); or simple diffusion. Using magnetoencephalography (MEG), we investigated which spreading pathways influence tau protein spreading by modelling the tau propagation process using an epidemic spreading model. We compared the modelled tau depositions with 18F-flortaucipir PET binding potentials at several stages of the AD continuum. In this cross-sectional study, we analysed source-reconstructed MEG data and dynamic 100-min 18F-flortaucipir PET from 57 subjects positive for amyloid-β pathology [preclinical AD (n = 16), mild cognitive impairment (MCI) due to AD (n = 16) and AD dementia (n = 25)]. Cognitively healthy subjects without amyloid-β pathology were included as controls (n = 25). Tau propagation was modelled as an epidemic process (susceptible-infected model) on MEG-based functional networks [in alpha (8-13 Hz) and beta (13-30 Hz) bands], a structural or diffusion network, starting from the middle and inferior temporal lobe. The group-level network of the control group was used as input for the model to predict tau deposition in three stages of the AD continuum. To assess performance, model output was compared to the group-specific tau deposition patterns as measured with 18F-flortaucipir PET. We repeated the analysis by using networks of the preceding disease stage and/or using regions with most observed tau deposition during the preceding stage as seeds. In the preclinical AD stage, the functional networks predicted most of the modelled tau-PET binding potential, with best correlations between model and tau-PET [corrected amplitude envelope correlation (AEC-c) alpha C = 0.584; AEC-c beta C = 0.569], followed by the structural network (C = 0.451) and simple diffusion (C = 0.451). Prediction accuracy declined for the MCI and AD dementia stages, although the correlation between modelled tau and tau-PET binding remained highest for the functional networks (C = 0.384; C = 0.376). Replacing the control-network with the network from the preceding disease stage and/or alternative seeds improved prediction accuracy in MCI but not in the dementia stage. These results suggest that in addition to structural connections, functional connections play an important role in tau spread, and highlight that neuronal dynamics play a key role in promoting this pathological process. Aberrant neuronal communication patterns should be taken into account when identifying targets for future therapy. Our results also suggest that this process is more important in earlier disease stages (preclinical AD/MCI); possibly, in later stages, other processes may be influential.
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12.
  • Timmers, Tessa, et al. (author)
  • Amyloid PET and cognitive decline in cognitively normal individuals : the SCIENCe project
  • 2019
  • In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 79, s. 50-58
  • Journal article (peer-reviewed)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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13.
  • Ahmad, Shahzad, et al. (author)
  • CDH6 and HAGH protein levels in plasma associate with Alzheimer’s disease in APOE ε4 carriers
  • 2020
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
  • Journal article (peer-reviewed)abstract
    • Many Alzheimer’s disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (β = 0.638, P = 3.33 × 10−4) and HAGH (β = 0.481, P = 7.20 × 10−4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10−3) and HAGH proteins (β = 0.506, P = 9.31 × 10−7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10−3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10−9). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.
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14.
  • Coomans, Emma M., et al. (author)
  • A Head-to-Head Comparison Between Plasma pTau181 and Tau PET Along the Alzheimer’s Disease Continuum
  • 2023
  • In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 64:3, s. 437-443
  • Journal article (peer-reviewed)abstract
    • Both plasma tau phosphorylated at threonine-181 (pTau181) and tau PET show potential for detecting Alzheimer’s disease (AD) pathology and predicting clinical progression. In this study, we performed a head-to-head comparison between plasma pTau181 and tau PET along the AD continuum. Methods: We included participants from the Amsterdam Dementia Cohort who underwent 18F-flortaucipir (tau) PET and had a plasma sample biobanked within 12 mo from tau PET. Fifty subjective cognitive decline (SCD) participants (31 Ab-negative and 19 Ab-positive) and 60 Ab-positive participants with mild cognitive impairment (MCI) or dementia due to AD were included. A subset had 2-y longitudinal plasma pTau181 and tau PET available (n 5 40). Longitudinal neuropsychological test data covering 3.2 6 2.7 y from both before and after tau PET were available. Plasma pTau181 and tau PET were compared in their accuracies in discriminating between cognitive stage (MCI/AD vs. SCD) and preclinical Ab status (SCD Ab-positive vs. SCD Ab-negative), their associations with cross-sectional and longitudinal neuropsychological test performance, and their longitudinal changes over time. Results: When discriminating between preclinical Ab status, the area under the curve (AUC) for plasma pTau181 (0.83) and tau PET (entorhinal, 0.87; temporal, 0.85; neocortical, 0.67) were equally high (all DeLong P . 0.05), but tau PET outperformed plasma pTau181 in discriminating MCI/AD from SCD (AUC for plasma pTau181: 0.74; AUCs for tau PET: entorhinal, 0.89; temporal, 0.92; neocortical, 0.89) (all P, 0.01). Overall, tau PET showed stronger associations with cognitive decline and was associated with a wider variety of cognitive tests than plasma pTau181 (plasma pTau181, 20.02 . b, 20.12; tau PET, 20.01 . b, 20.22). Both plasma pTau181 and tau PET increased more steeply over time in MCI/AD than in SCD (P, 0.05), but only tau PET annual changes were associated with cognitive decline. Conclusion: Our results suggest that plasma pTau181 and tau PET perform equally well in identifying Ab pathology but that tau PET better monitors disease stage and clinical progression.
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15.
  • Eikelboom, Willem S., et al. (author)
  • Neuropsychiatric and Cognitive Symptoms Across the Alzheimer Disease Clinical Spectrum: Cross-sectional and Longitudinal Associations
  • 2021
  • In: Neurology. - 1526-632X. ; 97:13, s. 1276-1287
  • Journal article (peer-reviewed)abstract
    • BACKGROUND AND OBJECTIVES: To investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid-positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum. METHODS: In this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (MMSE). We examined trajectories including model-based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time points (subsample n = 520, mean 1.8 [SD 0.7] years follow-up). RESULTS: We included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β = -0.18 to -0.11, false discovery rate [FDR]-adjusted p < 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = -0.32 to 0.36, all FDR-adjusted p > 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = -0.13 to 0.44, all FDR-adjusted p > 0.05). DISCUSSION: NPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease.
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16.
  • Singleton, Ellen H., et al. (author)
  • Social cognition deficits and biometric signatures in the behavioural variant of Alzheimer’s disease
  • 2023
  • In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 146:5, s. 2163-2174
  • Journal article (peer-reviewed)abstract
    • The behavioural variant of Alzheimer’s disease (bvAD) is characterized by early predominant behavioural changes, mimicking the behavioural variant of frontotemporal dementia (bvFTD), which is characterized by social cognition deficits and altered biometric responses to socioemotional cues. These functions remain understudied in bvAD. We investigated multiple social cognition components (i.e. emotion recognition, empathy, social norms and moral reasoning), using the Ekman 60 faces test, Interpersonal Reactivity Index, empathy eliciting videos, Social Norms Questionnaire and moral dilemmas, while measuring eye movements and galvanic skin response. We compared 12 patients with bvAD with patients with bvFTD (n = 14), typical Alzheimer’s disease (tAD, n = 13) and individuals with subjective cognitive decline (SCD, n = 13), using ANCOVAs and age- and sex-adjusted post hoc testing. Patients with bvAD (40.1 ± 8.6) showed lower scores on the Ekman 60 faces test compared to individuals with SCD (49.7 ± 5.0, P < 0.001), and patients with tAD (46.2 ± 5.3, P = 0.05) and higher scores compared to patients with bvFTD (32.4 ± 7.3, P = 0.002). Eye-tracking during the Ekman 60 faces test revealed no differences in dwell time on the eyes (all P > 0.05), but patients with bvAD (18.7 ± 9.5%) and bvFTD (19.4 ± 14.3%) spent significantly less dwell time on the mouth than individuals with SCD (30.7 ± 11.6%, P < 0.01) and patients with tAD (32.7 ± 12.1%, P < 0.01). Patients with bvAD (11.3 ± 4.6) exhibited lower scores on the Interpersonal Reactivity Index compared with individuals with SCD (15.6 ± 3.1, P = 0.05) and similar scores to patients with bvFTD (8.7 ± 5.6, P = 0.19) and tAD (13.0 ± 3.2, P = 0.43). The galvanic skin response to empathy eliciting videos did not differ between groups (all P > 0.05). Patients with bvAD (16.0 ± 1.6) and bvFTD (15.2 ± 2.2) showed lower scores on the Social Norms Questionnaire than patients with tAD (17.8 ± 2.1, P < 0.05) and individuals with SCD (18.3 ± 1.4, P < 0.05). No group differences were observed in scores on moral dilemmas (all P > 0.05), while only patients with bvFTD (0.9 ± 1.1) showed a lower galvanic skin response during personal dilemmas compared with SCD (3.4 ± 3.3 peaks per min, P = 0.01). Concluding, patients with bvAD showed a similar although milder social cognition profile and a similar eye-tracking signature to patients with bvFTD and greater social cognition impairments and divergent eye movement patterns compared with patients with tAD. Our results suggest reduced attention to salient facial features in these phenotypes, potentially contributing to their emotion recognition deficits.
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17.
  • van Assema, Danielle M. E., et al. (author)
  • Blood-brain barrier P-glycoprotein function in Alzheimer's disease
  • 2012
  • In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 135, s. 181-189
  • Journal article (peer-reviewed)abstract
    • A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-beta in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-beta from the brain may lead to these elevated amyloid-beta levels. One of the clearance pathways of amyloid-beta is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-beta. P-glycoprotein function can be assessed in vivo using (R)-[C-11]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[C-11]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 +/- 7 years, Mini-Mental State Examination 23 +/- 3), global (R)-[C-11]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 +/- 4 years, Mini-Mental State Examination 30 +/- 1). Global (R)-[C-11]verapamil binding potential values were 2.18 +/- 0.25 for patients with Alzheimer's disease and 1.77 +/- 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[C-11]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[C-11]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic Alzheimer's disease and suggests that decreased P-glycoprotein function may be involved in the pathogenesis of Alzheimer's disease.
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18.
  • van Assema, Danielle M. E., et al. (author)
  • No evidence for additional blood-brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds
  • 2012
  • In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 32:8, s. 1468-1471
  • Journal article (peer-reviewed)abstract
    • Decreased blood-brain barrier P-glycoprotein (Pgp) function has been shown in Alzheimer's disease (AD) patients using positron emission tomography (PET) with the radiotracer (R)-[C-11] verapamil. Decreased Pgp function has also been hypothesized to promote cerebral amyloid angiopathy (CAA) development. Here, we used PET and (R)-[C-11] verapamil to assess Pgp function in eighteen AD patients, of which six had microbleeds (MBs), presumably reflecting underlying CAA. No differences were found in binding potential and nonspecific volume of distribution of (R)-[C-11] verapamil between patient groups. These results provide no evidence for additional Pgp dysfunction in AD patients with MBs.
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19.
  • Verberk, Inge M.W., et al. (author)
  • Combination of plasma amyloid beta(1-42/1-40)and glial fibrillary acidic protein strongly associates with cerebral amyloid pathology
  • 2020
  • In: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
  • Journal article (peer-reviewed)abstract
    • Background: Blood-based biomarkers for Alzheimer's disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta(1-42/1-40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity. Methods: We included individuals with a positive (n = 176: 63 ± 7 years, 87 (49%) females) or negative (n = 76: 61 ± 9 years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET-), mild cognitive impairment (26 PET+, 24 PET-), or AD-dementia (132 PET+). Plasma Abeta(1-42/1-40), GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald's backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman's correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA). Results: Abeta(1-42/1-40) and GFAP independently associated with amyloid PET status (p = 0.009 and p < 0.001 respectively), and GFAP and NfL independently associated with syndrome diagnosis (p = 0.001 and p = 0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta(1-42/1-40) and GFAP, alongside age and APOE (AUC = 88% (95% CI 83-93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized β (sβ) = - 0.40 to - 0.26; NfL: range sβ = - 0.35 to - 0.18; all: p < 0.002), whereas Abeta(1-42/1-40) associated with global cognition, memory, attention, and executive functioning (range sβ = 0.22 - 0.11; all: p < 0.05) but not language. GFAP and NfL showed moderate positive correlations with MTA (both: Spearman's rho> 0.33, p < 0.001). Abeta(1-42/1-40) showed a moderate negative correlation with MTA (Spearman's rho = - 0.24, p = 0.001). Discussion and conclusions: Combination of plasma Abeta(1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.
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20.
  • Altomare, Daniele, et al. (author)
  • Applying the ATN scheme in a memory clinic population : The ABIDE project
  • 2019
  • In: Neurology. - 1526-632X. ; 93:17, s. 1635-1646
  • Journal article (peer-reviewed)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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21.
  • de Wilde, Arno, et al. (author)
  • Assessment of the appropriate use criteria for amyloid PET in an unselected memory clinic cohort : The ABIDE project
  • 2019
  • In: Alzheimer's and Dementia. - : Wiley. - 1552-5260.
  • Journal article (peer-reviewed)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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22.
  • Eikelboom, Willem S., et al. (author)
  • The reporting of neuropsychiatric symptoms in electronic health records of individuals with Alzheimer’s disease : a natural language processing study
  • 2023
  • In: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
  • Journal article (peer-reviewed)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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23.
  • Groot, Colin, et al. (author)
  • Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease
  • 2018
  • In: Neurology. - 1526-632X. ; 91:20, s. 1851-1859
  • Journal article (peer-reviewed)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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24.
  • Luo, Jiao, et al. (author)
  • Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease
  • 2023
  • In: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 6:5
  • Journal article (peer-reviewed)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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25.
  • Visser, Denise, et al. (author)
  • Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer’s disease
  • 2022
  • In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 49:6, s. 1951-1963
  • Journal article (peer-reviewed)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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26.
  • Visser, Denise, et al. (author)
  • Longitudinal Tau PET Using 18F-Flortaucipir : The Effect of Relative Cerebral Blood Flow on Quantitative and Semiquantitative Parameters
  • 2023
  • In: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505. ; 64:2, s. 281-286
  • Journal article (peer-reviewed)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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27.
  • Visser, Denise, et al. (author)
  • Tau pathology and relative cerebral blood flow are independently associated with cognition in Alzheimer’s disease
  • 2020
  • In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 47:13, s. 3165-3175
  • Journal article (peer-reviewed)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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28.
  • Vos, Stephanie J. B., et al. (author)
  • Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage
  • 2015
  • In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 138:5, s. 1327-1338
  • Journal article (peer-reviewed)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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29.
  • Wolters, Emma E., et al. (author)
  • Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer’s disease
  • 2020
  • In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 47:12, s. 2866-2878
  • Journal article (peer-reviewed)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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30.
  • Bos, Isabelle, et al. (author)
  • Cerebrovascular and amyloid pathology in predementia stages : the relationship with neurodegeneration and cognitive decline
  • 2017
  • In: Alzheimer's Research & Therapy. - : BioMed Central. - 1758-9193. ; 9:1
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Cerebrovascular disease (CVD) and amyloid-β (Aβ) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aβ on neurodegenerative markers and cognition in patients without dementia.METHODS: We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aβ1-42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aβ and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (-) of Aβ and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics.RESULTS: MTA and t-tau were elevated in the Aβ - WMH+, Aβ + WMH-, and Aβ + WMH+ groups. MTA was most severe in the Aβ + WMH+ group compared with the groups with a single pathology. Both WMH and Aβ were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline.CONCLUSIONS: In the present study, we found an additive association of Aβ and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up.
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31.
  • Bos, Isabelle, et al. (author)
  • Correction to : Cerebrovascular and amyloid pathology in predementia stages
  • 2018
  • In: Alzheimer's Research & Therapy. - : BioMed Central. - 1758-9193. ; 10:56
  • Journal article (peer-reviewed)abstract
    • Upon publication of this article [1], it was noticed that there were some inconsistencies in Tables 1, 2 and 3. Some of the superscript letters were incorrectly assigned. Please see below the correct tables.
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32.
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33.
  • Collij, Lyduine E., et al. (author)
  • Clinical outcomes up to 9 years after [18F]flutemetamol amyloid-PET in a symptomatic memory clinic population
  • 2023
  • In: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
  • Journal article (peer-reviewed)abstract
    • Background: Previous studies demonstrated increases in diagnostic confidence and change in patient management after amyloid-PET. However, studies investigating longitudinal outcomes over an extended period of time are limited. Therefore, we aimed to investigate clinical outcomes up to 9 years after amyloid-PET to support the clinical validity of the imaging technique. Methods: We analyzed longitudinal data from 200 patients (M age = 61.8, 45.5% female, M MMSE = 23.3) suspected of early-onset dementia that underwent [18F]flutemetamol-PET. Baseline amyloid status was determined through visual read (VR). Information on mortality was available with a mean follow-up of 6.7 years (range = 1.1–9.3). In a subset of 108 patients, longitudinal cognitive scores and clinical etiological diagnosis (eDx) at least 1 year after amyloid-PET acquisition were available (M = 3.06 years, range = 1.00–7.02). VR − and VR + patients were compared on mortality rates with Cox Hazard’s model, prevalence of stable eDx using chi-square test, and longitudinal cognition with linear mixed models. Neuropathological data was available for 4 patients (mean delay = 3.59 ± 1.82 years, range = 1.2–6.3). Results: At baseline, 184 (92.0%) patients were considered to have dementia. The majority of VR + patients had a primary etiological diagnosis of AD (122/128, 95.3%), while the VR − group consisted mostly of non-AD etiologies, most commonly frontotemporal lobar degeneration (30/72, 40.2%). Overall mortality rate was 48.5% and did not differ between VR − and VR + patients. eDx at follow-up was consistent with baseline diagnosis for 92/108 (85.2%) patients, with most changes observed in VR − cases (VR − = 14/35, 40% vs VR + = 2/73, 2.7%, χ 2 = 26.03, p < 0.001), who at no time received an AD diagnosis. VR + patients declined faster than VR − patients based on MMSE (β = − 1.17, p = 0.004), episodic memory (β = − 0.78, p = 0.003), fluency (β = − 1.44, p < 0.001), and attention scores (β = 16.76, p = 0.03). Amyloid-PET assessment was in line with post-mortem confirmation in all cases; two cases were VR + and showed widespread AD pathology, while the other two cases were VR − and showed limited amyloid pathology. Conclusion: In a symptomatic population, we observed that amyloid-status did not impact mortality rates, but is predictive of cognitive functioning over time across several domains. Also, we show particular validity for a negative amyloid-PET assessment, as these patients did not receive an AD diagnosis at follow-up.
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34.
  • De Wilde, Arno, et al. (author)
  • Discordant amyloid-β PET and CSF biomarkers and its clinical consequences
  • 2019
  • In: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
  • Journal article (peer-reviewed)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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35.
  • Le Guen, Yann, et al. (author)
  • Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
  • 2023
  • In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
  • Journal article (peer-reviewed)abstract
    • Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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36.
  • Ossenkoppele, Rik, et al. (author)
  • Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline
  • 2022
  • In: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 28:11, s. 2381-2387
  • Journal article (peer-reviewed)abstract
    • A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T- and A-T- groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1-26.4) and A+T- (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A-T- (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4-10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T- group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A+TMTL+ (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A+T- (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T- (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T- group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.
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37.
  • Reimand, Juhan, et al. (author)
  • Why Is Amyloid-β PET Requested After Performing CSF Biomarkers?
  • 2020
  • In: Journal of Alzheimer's disease : JAD. - 1387-2877. ; 73:2, s. 559-569
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Amyloid-β positron emission tomography (PET) and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer's disease. OBJECTIVE: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. METHODS: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. RESULTS: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n = 53, 74%), followed by incongruent MRI (n = 16, 22%), unusual clinical presentation (n = 11, 15%) and young age (n = 8, 11%). An amyloid-β PET scan was rarely (n = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. CONCLUSION: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results.
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38.
  • Salvadó, Gemma, et al. (author)
  • The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals
  • 2022
  • In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:7, s. 1383-1395
  • Journal article (peer-reviewed)abstract
    • Introduction: Harboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described. Methods: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3). Results: Carrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging. Discussion: In addition to the known resistance against amyloid-β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD-related cognitive decline.
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39.
  • Teunissen, Charlotte E, et al. (author)
  • Blood-based biomarkers for Alzheimer's disease: towards clinical implementation.
  • 2022
  • In: The Lancet. Neurology. - 1474-4465 .- 1474-4422. ; 21:1, s. 66-77
  • Journal article (peer-reviewed)abstract
    • For many years, blood-based biomarkers for Alzheimer's disease seemed unattainable, but recent results have shown that they could become a reality. Convincing data generated with new high-sensitivity assays have emerged with remarkable consistency across different cohorts, but also independent of the precise analytical method used. Concentrations in blood of amyloid and phosphorylated tau proteins associate with the corresponding concentrations in CSF and with amyloid-PET or tau-PET scans. Moreover, other blood-based biomarkers of neurodegeneration, such as neurofilament light chain and glial fibrillary acidic protein, appear to provide information on disease progression and potential for monitoring treatment effects. Now the question emerges of when and how we can bring these biomarkers to clinical practice. This step would pave the way for blood-based biomarkers to support the diagnosis of, and development of treatments for, Alzheimer's disease and other dementias.
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40.
  • Timmers, Tessa, et al. (author)
  • Associations between quantitative [18F]flortaucipir tau PET and atrophy across the Alzheimer's disease spectrum
  • 2019
  • In: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1
  • Journal article (peer-reviewed)abstract
    • Background: Neuropathological studies have linked tau aggregates to neuronal loss. To describe the spatial distribution of neurofibrillary tangle pathology in post-mortem tissue, Braak staging has been used. The aim of this study was to examine in vivo associations between tau pathology, quantified with [18F]flortaucipir PET in regions corresponding to Braak stages, and atrophy across the Alzheimer's disease (AD) spectrum. Methods: We included 100 subjects, including 58 amyloid-β positive patients with mild cognitive impairment (MCI, n = 6) or AD dementia (n = 52) and 42 controls with subjective cognitive decline (36% amyloid-β positive). All subjects underwent a dynamic [18F]flortaucipir PET to generate non-displaceable binding potential (BPND) maps. We extracted average [18F]flortaucipir BPND entorhinal, Braak III-IV (limbic) and Braak V-VI (neocortical) regions of interest (ROIs). T1-weighted MRI was used to assess gray matter (GM) volumes. We performed linear regression analyses using [18F]flortaucipir BPND ROIs as independent and GM density (ROI or voxelwise) as dependent variable. Results: In MCI/AD subjects (age [mean ± SD] 65 ± 8 years, MMSE 23 ± 4), [18F]flortaucipir BPND was higher than in controls (age 65 ± 8, MMSE 29 ± 1) across all ROIs (entorhinal 0.06 ± 0.21 vs 0.46 ± 0.25 p < 0.001, Braak III-IV 0.11 ± 0.10 vs 0.46 ± 0.26, p < 0.001, Braak V-VI 0.07 ± 0.07 vs 0.38 ± 0.29, p < 0.001). In MCI/AD, greater [18F]flortaucipir BPND in entorhinal cortex was associated with lower GM density in medial temporal lobe (β - 0.40, p < 0.001). Greater [18F]flortaucipir BPND in ROI Braak III-IV and Braak V-VI was associated with smaller GM density in lateral and inferior temporal, parietal, occipital, and frontal lobes (range standardized βs - 0.30 to - 0.55, p < 0.01), but not in medial temporal lobe (β - 0.22, p 0.07). [18F]Flortaucipir BPND in ROI Braak I-II was not associated with GM density loss anywhere. When quantifying [18F]flortaucipir BPND across brain lobes, we observed both local and distant associations with GM atrophy. In controls, there were no significant associations between [18F]flortaucipir BPND and GM density (standardized βs ranging from - 0.24 to 0.02, all p > 0.05). Conclusions: In MCI/AD patients, [18F]flortaucipir binding in entorhinal, limbic, and neocortical regions was associated with cortical atrophy.
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41.
  • Timmers, Tessa, et al. (author)
  • Test–retest repeatability of [18F]Flortaucipir PET in Alzheimer’s disease and cognitively normal individuals
  • 2020
  • In: Journal of Cerebral Blood Flow and Metabolism. - 0271-678X. ; 40:12, s. 2464-2474
  • Journal article (peer-reviewed)abstract
    • The aim of this study was to investigate the test–retest (TRT) repeatability of various parametric quantification methods for [18F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer’s disease and six cognitively normal subjects. All underwent two 130-min dynamic [18F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40–60, 80–100 and 110–130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest–test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68–2.15) to 6.84% (2.99–11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78–3.58) vs. SUVr80–100: 3.05% (1.28–5.52), p < 0.001. Furthermore, for SUVr80–100 and SUVr110–130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.
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42.
  • Toledo, Jon B, et al. (author)
  • Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects.
  • 2015
  • In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 138:Pt 9, s. 2701-15
  • Journal article (peer-reviewed)abstract
    • In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.
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43.
  • Tuncel, Hayel, et al. (author)
  • Effect of Shortening the Scan Duration on Quantitative Accuracy of [18F]Flortaucipir Studies
  • 2021
  • In: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 23:4, s. 604-613
  • Journal article (peer-reviewed)abstract
    • Purpose: Dynamic positron emission tomography (PET) protocols allow for accurate quantification of [18F]flortaucipir-specific binding. However, dynamic acquisitions can be challenging given the long required scan duration of 130 min. The current study assessed the effect of shorter scan protocols for [18F]flortaucipir on its quantitative accuracy. Procedures: Two study cohorts with Alzheimer’s disease (AD) patients and healthy controls (HC) were included. All subjects underwent a 130-min dynamic [18F]flortaucipir PET scan consisting of two parts (0–60/80–130 min) post-injection. Arterial sampling was acquired during scanning of the first cohort only. For the second cohort, a second PET scan was acquired within 1–4 weeks of the first PET scan to assess test-retest repeatability (TRT). Three alternative time intervals were explored for the second part of the scan: 80–120, 80–110 and 80–100 min. Furthermore, the first part of the scan was also varied: 0–50, 0–40 and 0–30 min time intervals were assessed. The gap in the reference TACs was interpolated using four different interpolation methods: population-based input function 2T4k_VB (POP-IP_2T4k_VB), cubic, linear and exponential. Regional binding potential (BPND) and relative tracer delivery (R1) values estimated using simplified reference tissue model (SRTM) and/or receptor parametric mapping (RPM). The different scan protocols were compared to the respective values estimated using the original scan acquisition. In addition, TRT of the RPM BPND and R1 values estimated using the optimal shortest scan duration was also assessed. Results: RPM BPND and R1 obtained using 0–30/80–100 min scan and POP-IP_2T4k_VB reference region interpolation had an excellent correlation with the respective parametric values estimated using the original scan duration (r2 > 0.95). The TRT of RPM BPND and R1 using the shortest scan duration was − 1 ± 5 % and − 1 ± 6 % respectively. Conclusions: This study demonstrated that [18F]flortaucipir PET scan can be acquired with sufficient quantitative accuracy using only 50 min of dual-time-window scanning time.
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44.
  • Tuncel, Hayel, et al. (author)
  • Head-to-head comparison of relative cerebral blood flow derived from dynamic [18F]florbetapir and [18F]flortaucipir PET in subjects with subjective cognitive decline
  • 2023
  • In: EJNMMI Research. - 2191-219X. ; 13:1
  • Journal article (peer-reviewed)abstract
    • Background: Dynamic PET imaging studies provide accurate estimates of specific binding, but also measure the relative tracer delivery (R1), which is a proxy for relative cerebral blood flow (rCBF). Recently, studies suggested that R1 obtained from different tracers could be used interchangeably and is irrespective of target tissue. However, the similarities or differences of R1 obtained from different PET tracers still require validation. Therefore, the goal of the current study was to compare R1 estimates, derived from dynamic [18F]florbetapir (amyloid) and [18F]flortaucipir (tau) PET, in the same subjects with subjective cognitive decline (SCD). Results: Voxel-wise analysis presented a small cluster (1.6% of the whole brain) with higher R1 values for [18F]flortaucipir compared to [18F]florbetapir in the Aβ-negative group. These voxels were part of the hippocampus and the left middle occipital gyrus. In part of the thalamus, midbrain and cerebellum, voxels (2.5% of the whole brain) with higher R1 values for [18F]florbetapir were observed. In the Aβ-positive group, a cluster (0.2% of the whole brain) of higher R1 values was observed in part of the hippocampus, right parahippocampal gyrus and in the left sagittal stratum for [18F]flortaucipir compared to [18F]florbetapir. Furthermore, in part of the thalamus, left amygdala, midbrain and right parahippocampal gyrus voxels (0.4% of the whole brain) with higher R1 values for [18F]florbetapir were observed. Despite these differences, [18F]florbetapir R1 had high correspondence with [18F]flortaucipir R1 across all regions of interest (ROIs) and subjects (Aβ−:r 2 = 0.79, slope = 0.85, ICC = 0.76; Aβ+: r 2 = 0.87, slope = 0.93, ICC = 0.77). Conclusion: [18F]flortaucipir and [18F]florbetapir showed similar R1 estimates in cortical regions. This finding, put together with previous studies, indicates that R1 could be considered a surrogate for relative cerebral blood flow (rCBF) in the cortex and may be used interchangeably, but with caution, regardless of the choice of these two tracers.
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45.
  • Ulugut, Hulya, et al. (author)
  • The natural history of primary progressive aphasia : beyond aphasia
  • 2022
  • In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 269:3, s. 1375-1385
  • Journal article (peer-reviewed)abstract
    • Introduction: Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes. Methods: In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1–6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed. Results: Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4). Discussion: Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration.
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46.
  • van Maurik, Ingrid S., et al. (author)
  • Biomarker testing in MCI patients—deciding who to test
  • 2021
  • In: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
  • Journal article (peer-reviewed)abstract
    • Background: We aimed to derive an algorithm to define the optimal proportion of patients with mild cognitive impairment (MCI) in whom cerebrospinal fluid (CSF) testing is of added prognostic value. Methods: MCI patients were selected from the Amsterdam Dementia Cohort (n = 402). Three-year progression probabilities to dementia were predicted using previously published models with and without CSF data (amyloid-beta1-42 (Abeta), phosphorylated tau (p-tau)). We incrementally augmented the proportion of patients undergoing CSF, starting with the 10% patients with prognostic probabilities based on clinical data around the median (percentile 45–55), until all patients received CSF. The optimal proportion was defined as the proportion where the stepwise algorithm showed similar prognostic discrimination (Harrell’s C) and accuracy (three-year Brier scores) compared to CSF testing of all patients. We used the BioFINDER study (n = 221) for validation. Results: The optimal proportion of MCI patients to receive CSF testing selected by the stepwise approach was 50%. CSF testing in only this proportion improved the performance of the model with clinical data only from Harrell’s C = 0.60, Brier = 0.198 (Harrell’s C = 0.61, Brier = 0.197 if the information on magnetic resonance imaging was available) to Harrell’s C = 0.67 and Brier = 0.190, and performed similarly to a model in which all patients received CSF testing. Applying the stepwise approach in the BioFINDER study would again select half of the MCI patients and yielded robust results with respect to prognostic performance. Interpretation: CSF biomarker testing adds prognostic value in half of the MCI patients. As such, we achieve a CSF saving recommendation while simultaneously retaining optimal prognostic accuracy.
  •  
47.
  • Willemse, Eline A J, et al. (author)
  • Neurogranin as Cerebrospinal Fluid Biomarker for Alzheimer Disease: An Assay Comparison Study.
  • 2018
  • In: Clinical chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 64:6, s. 927-937
  • Journal article (peer-reviewed)abstract
    • Neurogranin in cerebrospinal fluid (CSF) correlates with cognitive decline and is a potential novel biomarker for Alzheimer disease (AD) dementia. We investigated the analytical and diagnostic performance of 3 commonly used neurogranin assays in the same cohort of patients to improve the interpretability of CSF neurogranin test results.The neurogranin Singulex assay from Washington University, St. Louis, MO (WashU); ELISA from ADx Neurosciences; and ELISA from Gothenburg University, Mölndal, Sweden (UGot), were compared using silver staining and Western blot after gel electrophoresis. Clinical performance of the 3 assays was compared in samples from individuals diagnosed with subjective cognitive decline (n = 22), and in patients with AD (n = 22), frontotemporal dementia (n = 22), dementia with Lewy bodies (n = 22), or vascular dementia (n = 20), adjusted for sex and age.The assays detected different epitopes of neurogranin: the WashU assay the N-terminal part of neurogranin (S10-D23) and a C-terminal part (G49-G60), the ADx assay C-terminal neurogranin truncated at P75, and the UGot assay the C-terminal neurogranin with intact ending (D78). Spearman ρ was 0.95 between ADx and WashU, 0.87 between UGot and WashU, and 0.81 between UGot and ADx. ANCOVA (analysis of covariance) showed group differences for ranked neurogranin concentrations in each assay (allP< 0.05), with specific increases in AD.Although the 3 assays target different epitopes on neurogranin and have different calibrators, the high correlations and the similar group differences suggest that the different forms of neurogranin in CSF carry similar diagnostic information, at least in the context of neurodegenerative diseases.
  •  
48.
  • Wolters, Emma E., et al. (author)
  • Hippocampal [18F]flortaucipir BPND corrected for possible spill-in of the choroid plexus retains strong clinico-pathological relationships
  • 2020
  • In: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 25
  • Journal article (peer-reviewed)abstract
    • Background: Off-target [18F]flortaucipir (tau) PET binding in the choroid plexus causes spill-in into the nearby hippocampus, which may influence the correlation between [18F]flortaucipir binding and measures of cognition. Previously, we showed that partial volume correction (combination of Van Cittert iterative deconvolution and HYPR denoising; PVC HDH) and manually eroding the hippocampus resulted in a significant decrease of the choroid plexus spill-in. In this study, we compared three different approaches for the quantification of hippocampal [18F]flortaucipir signal using a semi-automated technique, and assessed correlations with cognitive performance across methods. Methods: Dynamic 130 min [18F]flortaucipir PET scans were performed in 109 subjects (45 cognitively normal subjects (CN) and 64 mild cognitive impairment/Alzheimer's disease (AD) dementia patients. We extracted hippocampal binding potential (BPND) using receptor parametric mapping with cerebellar grey matter as reference region. PVC HDH was performed. Based on our previous study in which we manually eroded 40% ± 10% of voxels of the hippocampus, three hippocampal volumes-of-interest (VOIs) were generated: a non-optimized 100% hippocampal VOI [100%], and combining HDH with eroding a percentage of the highest hippocampus BPND voxels (i.e. lowering spill-in) resulting in optimized 50%[50%HDH] and 40%[40%HDH] hippocampal VOIs. Cognitive performance was assessed with the Mini-Mental State Examination (MMSE) and Rey auditory verbal learning delayed recall. We performed receiver operating characteristic analyses to investigate which method could best discriminate MCI/AD from controls. Subsequently, we performed linear regressions to investigate associations between the hippocampal [18F]flortaucipir BPND VOIs and MMSE/delayed recall adjusted for age, sex and education. Results: We found higher hippocampal [18F]flortaucipir BPND in MCI/AD patients (BPND100%=0.27±0.15) compared to CN (BPND100%= 0.07±0.13) and all methods showed comparable discriminative effects (AUC100%=0.85[CI=0.78–0.93]; AUC50%HDH=0.84[CI=0.74–0.92]; AUC40%HDH=0.83[CI=0.74–0.92]). Across groups, higher [18F]flortaucipir BPND was related to lower scores on MMSE (standardized β100%=-0.38[CI=-0.57−0.20]; β50%HDH= -0.37[CI=-0.54−0.19]; β40%HDH=-0.35[CI=-0.53−0.17], all p<0.001) and delayed recall (standardized β100%=-0.64[CI=-0.79−0.49]; β50%HDH= -0.61[CI=-0.76−0.46]; β40%HDH=-0.59[CI=-0.75−0.44]; all p<0.001), with comparable effect sizes for all hippocampal VOIs. Conclusions: Hippocampal tau load measured with [18F]flortaucipir PET is strongly associated with cognitive function. Both discrimination between diagnostic groups and associations between hippocampal [18F]flortaucipir BPND and memory were comparable for all methods. The non-optimized 100% hippocampal VOI may be sufficient for clinical interpretation. However, proper correction for choroid plexus spillover and may be required in case of smaller effect sizes between subject groups or for longitudinal studies.
  •  
49.
  • Altomare, Daniele, et al. (author)
  • Prognostic value of Alzheimer’s biomarkers in mild cognitive impairment : the effect of age at onset
  • 2019
  • In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 266:10, s. 2535-2545
  • Journal article (peer-reviewed)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.
  •  
50.
  • Bayoumy, Sherif, et al. (author)
  • Clinical and analytical comparison of six Simoa assays for plasma P-tau isoforms P-tau181, P-tau217, and P-tau231.
  • 2021
  • In: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
  • Journal article (peer-reviewed)abstract
    • Studies using different assays and technologies showed highly promising diagnostic value of plasma phosphorylated (P-)tau levels for Alzheimer's disease (AD). We aimed to compare six P-tau Simoa assays, including three P-tau181 (Eli Lilly, ADx, Quanterix), one P-tau217 (Eli Lilly), and two P-tau231 (ADx, Gothenburg).We studied the analytical (sensitivity, precision, parallelism, dilution linearity, and recovery) and clinical (40 AD dementia patients, age 66±8years, 50%F; 40 age- and sex-matched controls) performance of the assays.All assays showed robust analytical performance, and particularly P-tau217 Eli Lilly; P-tau231 Gothenburg and all P-tau181 assays showed robust clinical performance to differentiate AD from controls, with AUCs 0.936-0.995 (P-tau231 ADx: AUC=0.719). Results obtained with all P-tau181 assays, P-tau217 Eli Lilly assay, and P-tau231 Gothenburg assay strongly correlated (Spearman's rho>0.86), while correlations with P-tau231 ADx results were moderate (rho<0.65).P-tau isoforms can be measured robustly by several novel high-sensitive Simoa assays.
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