| 1. |
- van der Lee, S. J., et al.
(författare)
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A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 237-250
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Tidskriftsartikel (refereegranskat)abstract
- The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
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| 2. |
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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- Tolboom, N., et al.
(författare)
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The Dopamine Stabilizer (-)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An C-11 Raclopride PET Study in Healthy Human Subjects
- 2015
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 40:2, s. 472-479
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Tidskriftsartikel (refereegranskat)abstract
- (-)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (-)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [C-11] raclopride PET scanning before and 1 h after a single oral dose of (-)-OSU6162 (15-90 mg). Blood samples for determination of (-)-OSU6162 and prolactin plasma levels were collected at T-max. Parametric images of [ 11 C] raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BPND) at baseline and after (-)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [C-11] raclopride BPND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (-)-OSU6162, ranging from 0.01 to 0.9 mu M, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (-)-OSU6162 plasma level of 0.2 mu M, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (-)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (-)-OSU6162.
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| 8. |
- Visser, D., et al.
(författare)
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Tau pathology as determinant of changes in atrophy and cerebral blood flow: a multi-modal longitudinal imaging study
- 2023
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 50:8, s. 2409-19
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Tidskriftsartikel (refereegranskat)abstract
- PurposeTau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF.MethodsWe included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 +/- 7.5 years, 44% female, 57% amyloid-beta positive [A beta +], 26 cognitively impaired [CI]) who underwent dynamic [F-18]flortaucipir PET and structural MRI at baseline and 25 +/- 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [F-18]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [F-18]flortaucipir PET binding potential (BPND) and R-1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R-1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in A beta- cognitively normal (CN) individuals and A beta+ (CN and CI) individuals separately.ResultsIn A beta+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either A beta+ or A beta- individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in A beta + individuals.ConclusionWe showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal.
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| 9. |
- Wolters, E. E., et al.
(författare)
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Tau PET and relative cerebral blood flow in dementia with Lewy bodies : A PET study
- 2020
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 28
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Alpha-synuclein often co-occurs with Alzheimer's disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. Methods: Eighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology (DLB-AD+). Receptor parametric mapping (cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests. Results: Regional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p > 0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p < 0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p < 0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stβ = 0.72) and category fluency (stβ = 0.69) tests. Lower parietal R1 was related to lower delayed (stβ = 0.50) and immediate (stβ = 0.48) recall, VOSP number location (stβ = 0.70) and fragmented letters (stβ = 0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stβ = 0.61), all p < 0.05. Conclusion: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET.
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| 10. |
- Vos, Stephanie J. B., et al.
(författare)
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Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage
- 2015
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 138:5, s. 1327-1338
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Tidskriftsartikel (refereegranskat)abstract
- Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.
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