| 1. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)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 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (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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| 2. |
- Mattsson, Niklas, et al.
(författare)
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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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Ingår i: Alzheimer's & Dementia. - : ELSEVIER SCIENCE INC. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
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Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
- 2018
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
- 2015
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Ingår i: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 313:19, s. 1924-38
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Alakurtti, Kati, et al.
(författare)
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Long-term test-retest reliability of striatal and extrastriatal dopamine D-2/3 receptor binding : study with [C-11]raclopride and high-resolution PET
- 2015
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 35:7, s. 1199-1205
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Tidskriftsartikel (refereegranskat)abstract
- We measured the long-term test-retest reliability of [C-11]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [C-11]raclopride assessments, with a 5-week retest interval. D-2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test-retest studies of [C-11]raclopride binding in the striatum. A novel finding is the relatively low variability of [C-11]raclopride binding, providing suggestive evidence that extrastriatal D-2/3 binding can be studied in vivo with [C-11]raclopride PET to be verified in future studies.
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| 7. |
- Konki, Mikko, et al.
(författare)
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Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer's disease.
- 2019
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Ingår i: Clinical Epigenetics. - : BioMed Central. - 1868-7083 .- 1868-7075. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alzheimer's disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs.RESULTS: Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ≤ 0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer's disease and becomes differentially methylated after disease onset.CONCLUSIONS: DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer's disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.
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| 8. |
- Rinne, Juha O, et al.
(författare)
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11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study.
- 2010
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Ingår i: Lancet neurology. - 1474-4465. ; 9:4, s. 363-72
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimer's disease. METHODS: Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in (11)C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. FINDINGS: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014) in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo group. Estimated mean difference in (11)C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2.0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. INTERPRETATION: Treatment with bapineuzumab for 78 weeks reduced cortical (11)C-PiB retention compared with both baseline and placebo. (11)C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-beta load in vivo. FUNDING: Elan Pharmaceuticals and Wyeth Research.
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| 9. |
- Wolk, David A., et al.
(författare)
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Use of flutemetamol F18-labeled positron emission tomography and other biomarkers to assess risk of clinical progression in patients with amnestic mild cognitive impairment
- 2018
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 75:9, s. 1114-1123
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Patients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were β-amyloid positive vs those who were β-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression. Objective: To evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD. Design, Setting, and Participants: In this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18-labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018. Interventions: Flutemetamol F 18-labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures. Main Outcomes and Measures: Time from PET to probable AD or last follow-upwas plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD. Results: Of 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients), 53.6%(52 of 97) for patients with positive results detected on PET scan, and 22.8% (29 of 127) for patients with negative results detected on PET scan. Hazard ratios for association with progression were 2.51 (95% CI, 1.57-3.99; P < .001) for a positive β-amyloid scan alone (primary outcome measure), 5.60 (95%CI, 3.14-9.98; P < .001) with additional low hippocampal volume, and 8.45 (95%CI, 4.40-16.24; P < .001) when poorer cognitive status was added to the model. Conclusions and Relevance: A combination of positive results of flutemetamol F 18-labeled PET, low hippocampal volume, and cognitive status corresponded with a high probability of risk of progression from aMCI to probable AD within 36 months.
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