| 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. |
- Collij, L. E., et al.
(författare)
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The amyloid imaging for the prevention of Alzheimer's disease consortium: A European collaboration with global impact
- 2023
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAmyloid-beta (A beta) accumulation is considered the earliest pathological change in Alzheimer's disease (AD). The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and 'Small and Medium-sized enterprises' (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population. The AMYPAD studiesIn the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with [F-18]flutemetamol or [F-18]florbetaben radiotracers was performed and quantified using the Centiloid (CL) method. ResultsAMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BPND), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging A beta burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine. Future stepsThe AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.
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| 3. |
- Bader, I., et al.
(författare)
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Recruitment of pre-dementia participants: main enrollment barriers in a longitudinal amyloid-PET study
- 2023
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Ingår i: Alzheimer's Research & Therapy. - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer's disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies.Methods Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests.Results 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (beta = - 0.22, OR = 0.80, p < .05), more prior study visits (beta = - 0.93, OR = 0.40, p < .001), and positive family history of dementia (beta = 2.08, OR = 8.02, p < .01) resulted in lower odds on study refusal. General study burden was the main enrollment barrier (36.1%), followed by amyloid-PET related burden (PCresearch = 27.4%, PCclinical = 9.0%, X-2 = 10.56, p = .001), and loss of research interest (PCclinical = 46.3%, PCresearch = 16.5%, X-2 = 32.34, p < .001).Conclusions The enrollment rate for the AMYPAD-PNHS was relatively high, suggesting an advantage of recruitment via ongoing studies. In this observational cohort, study burden reduction and tailored strategies may potentially improve participant enrollment into trial readiness cohorts such as for phase-3 early anti-amyloid intervention trials. The AMYPAD-PNHS (EudraCT: 2018-002277-22) was approved by the ethical review board of the VU Medical Center (VUmc) as the Sponsor site and in every affiliated site.
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| 4. |
- Mastenbroek, Sophie E., et al.
(författare)
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Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer’s disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.
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| 5. |
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| 6. |
- Barthélemy, Nicolas R, et al.
(författare)
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Highly Accurate Blood Test for Alzheimer's Disease Comparable or Superior to Clinical CSF Tests
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Ingår i: Nature Medicine. - 1546-170X.
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Tidskriftsartikel (refereegranskat)abstract
- With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. We evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n=1,422) and the US Knight ADRC cohort (n=337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology, respectively, using PET imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aβ PET status, with an area-under-the-curve (AUC) for both between 0.95-0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95-0.98. In cognitively impaired sub-cohorts (BioFINDER-2: n=720; Knight ADRC: n=50), plasma %p-tau217 had an accuracy, positive predictive value and negative predictive value of 89-90% for Aβ PET and 87-88% for tau-PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two cut-off approach. Blood plasma %p-tau217 demonstrated performance clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments.
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| 7. |
- Lorenzini, L., et al.
(författare)
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Eigenvector centrality dynamics are related to Alzheimer's disease pathological changes in non-demented individuals
- 2023
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta accumulation starts in highly connected brain regions and is associated with functional connectivity alterations in the early stages of Alzheimer's disease. This regional vulnerability is related to the high neuronal activity and strong fluctuations typical of these regions. Recently, dynamic functional connectivity was introduced to investigate changes in functional network organization over time. High dynamic functional connectivity variations indicate increased regional flexibility to participate in multiple subnetworks, promoting functional integration. Currently, only a limited number of studies have explored the temporal dynamics of functional connectivity in the pre-dementia stages of Alzheimer's disease. We study the associations between abnormal cerebrospinal fluid amyloid and both static and dynamic properties of functional hubs, using eigenvector centrality, and their relationship with cognitive performance, in 701 non-demented participants from the European Prevention of Alzheimer's Dementia cohort. Voxel-wise eigenvector centrality was computed for the whole functional magnetic resonance imaging time series (static), and within a sliding window (dynamic). Differences in static eigenvector centrality between amyloid positive (A+) and negative (A-) participants and amyloid-tau groups were found in a general linear model. Dynamic eigenvector centrality standard deviation and range were compared between groups within clusters of significant static eigenvector centrality differences, and within 10 canonical resting-state networks. The effect of the interaction between amyloid status and cognitive performance on dynamic eigenvector centrality variability was also evaluated with linear models. Models were corrected for age, sex, and education level. Lower static centrality was found in A+ participants in posterior brain areas including a parietal and an occipital cluster; higher static centrality was found in a medio-frontal cluster. Lower eigenvector centrality variability (standard deviation) occurred in A+ participants in the frontal cluster. The default mode network and the dorsal visual networks of A+ participants had lower dynamic eigenvector centrality variability. Centrality variability in the default mode network and dorsal visual networks were associated with cognitive performance in the A- and A+ groups, with lower variability being observed in A+ participants with good cognitive scores. Our results support the role and timing of eigenvector centrality alterations in very early stages of Alzheimer's disease and show that centrality variability over time adds relevant information on the dynamic patterns that cause static eigenvector centrality alterations. We propose that dynamic eigenvector centrality is an early biomarker of the interplay between early Alzheimer's disease pathology and cognitive decline. Lorenzini et al. demonstrate widespread dynamic functional connectivity impairments in relationship with Alzheimer's disease pathological changes in non-demented individuals. This work suggests that initial amyloid deposition affects eigenvector centrality temporal patterns by reducing the involvement of functional hubs in different network dynamics, therefore reducing functional integration, and promoting cognitive deterioration.
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| 8. |
- Collij, Lyduine E., et al.
(författare)
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Clinical outcomes up to 9 years after [18F]flutemetamol amyloid-PET in a symptomatic memory clinic population
- 2023
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies demonstrated increases in diagnostic confidence and change in patient management after amyloid-PET. However, studies investigating longitudinal outcomes over an extended period of time are limited. Therefore, we aimed to investigate clinical outcomes up to 9 years after amyloid-PET to support the clinical validity of the imaging technique. Methods: We analyzed longitudinal data from 200 patients (M age = 61.8, 45.5% female, M MMSE = 23.3) suspected of early-onset dementia that underwent [18F]flutemetamol-PET. Baseline amyloid status was determined through visual read (VR). Information on mortality was available with a mean follow-up of 6.7 years (range = 1.1–9.3). In a subset of 108 patients, longitudinal cognitive scores and clinical etiological diagnosis (eDx) at least 1 year after amyloid-PET acquisition were available (M = 3.06 years, range = 1.00–7.02). VR − and VR + patients were compared on mortality rates with Cox Hazard’s model, prevalence of stable eDx using chi-square test, and longitudinal cognition with linear mixed models. Neuropathological data was available for 4 patients (mean delay = 3.59 ± 1.82 years, range = 1.2–6.3). Results: At baseline, 184 (92.0%) patients were considered to have dementia. The majority of VR + patients had a primary etiological diagnosis of AD (122/128, 95.3%), while the VR − group consisted mostly of non-AD etiologies, most commonly frontotemporal lobar degeneration (30/72, 40.2%). Overall mortality rate was 48.5% and did not differ between VR − and VR + patients. eDx at follow-up was consistent with baseline diagnosis for 92/108 (85.2%) patients, with most changes observed in VR − cases (VR − = 14/35, 40% vs VR + = 2/73, 2.7%, χ 2 = 26.03, p < 0.001), who at no time received an AD diagnosis. VR + patients declined faster than VR − patients based on MMSE (β = − 1.17, p = 0.004), episodic memory (β = − 0.78, p = 0.003), fluency (β = − 1.44, p < 0.001), and attention scores (β = 16.76, p = 0.03). Amyloid-PET assessment was in line with post-mortem confirmation in all cases; two cases were VR + and showed widespread AD pathology, while the other two cases were VR − and showed limited amyloid pathology. Conclusion: In a symptomatic population, we observed that amyloid-status did not impact mortality rates, but is predictive of cognitive functioning over time across several domains. Also, we show particular validity for a negative amyloid-PET assessment, as these patients did not receive an AD diagnosis at follow-up.
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