| 1. |
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| 2. |
- Jansen, Willemijn J, et al.
(author)
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
- 2018
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
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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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| 3. |
- Mattsson, Niklas, et al.
(author)
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Prevalence of the apolipoprotein E epsilon 4 allele in amyloid beta positive subjects across the spectrum of Alzheimers disease
- 2018
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In: Alzheimer's & Dementia. - : ELSEVIER SCIENCE INC. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
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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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| 4. |
- Mattsson, Niklas, et al.
(author)
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Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease
- 2018
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
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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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| 5. |
- Coomans, Emma M., et al.
(author)
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Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia with Lewy Bodies
- 2023
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In: Neurology. - 0028-3878 .- 1526-632X. ; 101:19, s. 1850-1862
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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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| 6. |
- Eikelboom, Willem S., et al.
(author)
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Neuropsychiatric and Cognitive Symptoms Across the Alzheimer Disease Clinical Spectrum: Cross-sectional and Longitudinal Associations
- 2021
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In: Neurology. - 1526-632X. ; 97:13, s. 1276-1287
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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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| 7. |
- Schoonhoven, Deborah N., et al.
(author)
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Tau protein spreads through functionally connected neurons in Alzheimer's disease : a combined MEG/PET study
- 2023
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In: Brain. - 0006-8950. ; 146:10, s. 4040-4054
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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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| 8. |
- Timmers, Tessa, et al.
(author)
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Amyloid PET and cognitive decline in cognitively normal individuals : the SCIENCe project
- 2019
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 79, s. 50-58
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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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| 9. |
- van Assema, Danielle M. E., et al.
(author)
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Blood-brain barrier P-glycoprotein function in Alzheimer's disease
- 2012
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 135, s. 181-189
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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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| 10. |
- van Assema, Danielle M. E., et al.
(author)
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No evidence for additional blood-brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds
- 2012
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 32:8, s. 1468-1471
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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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| 11. |
- Verfaillie, Sander C.J., et al.
(author)
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Amyloid-β load is related to worries, but not to severity of cognitive complaints in individuals with subjective cognitive decline : The science project
- 2019
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In: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 11:JAN
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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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| 12. |
- Vos, Stephanie J. B., et al.
(author)
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Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage
- 2015
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In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 138:5, s. 1327-1338
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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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| 13. |
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| 14. |
- Coomans, Emma M., et al.
(author)
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A Head-to-Head Comparison Between Plasma pTau181 and Tau PET Along the Alzheimer’s Disease Continuum
- 2023
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 64:3, s. 437-443
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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. |
- Coomans, Emma M., et al.
(author)
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Genetically identical twins show comparable tau PET load and spatial distribution
- 2022
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 145:10, s. 3571-3581
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Journal article (peer-reviewed)abstract
- Tau accumulation starts during the preclinical phase of Alzheimer's disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in (i) tau load; and (ii) spatial distribution of tau, measured with 18F-flortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6 years), enriched for amyloid-β pathology and APOE ε4 carriership, who underwent dynamic 18F-flortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial 18F-flortaucipir distribution compared to non-twin pairs, and whether the participant's co-twin could be identified solely based on the spatial 18F-flortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in 18F-flortaucipir BPND. On visual inspection, Alzheimer's disease-like 18F-flortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. 18F-flortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; P = 0.01), neocortical (r = 0.59; P < 0.01) and global (r = 0.56; P < 0.01) regions, but not in the temporal region (r = 0.20; P = 0.10). The 18F-flortaucipir distribution pattern was significantly more similar between twins of the same pair [mean r = 0.27; standard deviation (SD) = 0.09] than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (P < 0.01), also after correcting for proxies of off-target binding. Based on the spatial 18F-flortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in 18F-flortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37 < β < 0.56), physical activity (-0.41 < β < -0.42) and social activity (-0.32 < β < -0.36) (all P < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer's disease pathological processes, which may be of interest for future prevention strategies.
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| 16. |
- De Wilde, Arno, et al.
(author)
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Discordant amyloid-β PET and CSF biomarkers and its clinical consequences
- 2019
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In: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
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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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| 17. |
- Groot, Colin, et al.
(author)
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Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease
- 2018
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In: Neurology. - 1526-632X. ; 91:20, s. 1851-1859
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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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| 18. |
- Ossenkoppele, Rik, et al.
(author)
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Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline
- 2022
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 28:11, s. 2381-2387
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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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| 19. |
- Reimand, Juhan, et al.
(author)
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Why Is Amyloid-β PET Requested After Performing CSF Biomarkers?
- 2020
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In: Journal of Alzheimer's disease : JAD. - 1387-2877. ; 73:2, s. 559-569
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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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| 20. |
- Timmers, Tessa, et al.
(author)
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Associations between quantitative [18F]flortaucipir tau PET and atrophy across the Alzheimer's disease spectrum
- 2019
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In: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1
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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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| 21. |
- Timmers, Tessa, et al.
(author)
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Test–retest repeatability of [18F]Flortaucipir PET in Alzheimer’s disease and cognitively normal individuals
- 2020
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In: Journal of Cerebral Blood Flow and Metabolism. - 0271-678X. ; 40:12, s. 2464-2474
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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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| 22. |
- Tuncel, Hayel, et al.
(author)
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Effect of Shortening the Scan Duration on Quantitative Accuracy of [18F]Flortaucipir Studies
- 2021
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In: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 23:4, s. 604-613
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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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| 23. |
- Tuncel, Hayel, et al.
(author)
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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
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In: EJNMMI Research. - 2191-219X. ; 13:1
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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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| 24. |
- Ulugut, Hulya, et al.
(author)
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The natural history of primary progressive aphasia : beyond aphasia
- 2022
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 269:3, s. 1375-1385
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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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| 25. |
- van Assema, Danielle M. E., et al.
(author)
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P-Glycoprotein Function at the Blood-Brain Barrier : Effects of Age and Gender
- 2012
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In: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 14:6, s. 771-776
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Journal article (peer-reviewed)abstract
- PurposeP-glycoprotein (Pgp) is an efflux transporter involved in transport of several compounds across the blood–brain barrier (BBB). Loss of Pgp function with increasing age may be involved in the development of age-related disorders, but this may differ between males and females. Pgp function can be quantified in vivo using (R)-[11C]verapamil and positron emission tomography. The purpose of this study was to assess global and regional effects of both age and gender on BBB Pgp function.ProceduresThirty-five healthy men and women in three different age groups were included. Sixty minutes dynamic (R)-[11C]verapamil scans with metabolite-corrected arterial plasma input curves were acquired. Grey matter time–activity curves were fitted to a validated constrained two-tissue compartment plasma input model, providing the volume of distribution (V T) of (R)-[11C]verapamil as outcome measure.ResultsIncreased V T of (R)-[11C]verapamil with aging was found in several large brain regions in men. Young and elderly women showed comparable V T values. Young women had higher V T compared with young men.ConclusionsDecreased BBB Pgp is found with aging; however, effects of age on BBB Pgp function differ between men and women.
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