| 1. |
- 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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| 2. |
- Grau-Rivera, O., et al.
(författare)
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Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease
- 2021
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRecognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.MethodsThis prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n=2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [F-18]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.ResultsWeight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p=0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p=0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p=0.001) and was greater among participants with an A+T+ profile (p<0.01) at follow-up. Weight change was positively associated with CSF A42/40 ratio (beta =0.099, p=0.032) and negatively associated with CSF p-tau (beta=-0.141, p=0.005), t-tau (beta=-0.147 p=0.004) and neurogranin levels (beta=-0.158, p=0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.ConclusionsWeight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-beta accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.Trial registrationNCT01835717, NCT02485730, NCT02685969.
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| 3. |
- Johnson, S. C., et al.
(författare)
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Identifying clinically useful biomarkers in neurodegenerative disease through a collaborative approach: the NeuroToolKit
- 2023
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Alzheimer's disease (AD) is a complex and heterogeneous disease, which requires reliable biomarkers for diagnosis and monitoring disease activity. Preanalytical protocol and technical variability associated with biomarker immunoassays makes comparability of biomarker data across multiple cohorts difficult. This study aimed to compare cerebrospinal fluid (CSF) biomarker results across independent cohorts, including participants spanning the AD continuum.Methods Measured on the NeuroToolKit (NTK) prototype panel of immunoassays, 12 CSF biomarkers were evaluated from three cohorts (ALFA+, Wisconsin, and Abby/Blaze). A correction factor was applied to biomarkers found to be affected by preanalytical procedures (amyloid-beta(1-42), amyloid-beta(1-40), and alpha-synuclein), and results between cohorts for each disease stage were compared. The relationship between CSF biomarker concentration and cognitive scores was evaluated.Results Biomarker distributions were comparable across cohorts following correction. Correlations of biomarker values were consistent across cohorts, regardless of disease stage. Disease stage differentiation was highest for neurofilament light (NfL), phosphorylated tau, and total tau, regardless of the cohort. Correlation between biomarker concentration and cognitive scores was comparable across cohorts, and strongest for NfL, chitinase-3-like protein-1 (YKL40), and glial fibrillary acidic protein.Discussion The precision of the NTK enables merging of biomarker datasets, after correction for preanalytical confounders. Assessment of multiple cohorts is crucial to increase power in future studies into AD pathogenesis.
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| 4. |
- Mila-Aloma, M., et al.
(författare)
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Cognitively unimpaired individuals with a low burden of A beta pathology have a distinct CSF biomarker profile
- 2021
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-beta (A beta) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of A beta pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile. Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF A beta 42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and alpha-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F-18]-FDG, and [F-18]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of A beta pathology: (1) positive CSF A beta 42/40 and < 30 Centiloids in A beta PET, (2) positive CSF A beta 42/40 and negative A beta PET visual read, and (3) 20-40 Centiloid range in A beta PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding A beta-negative group, adjusted by age and sex. Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the A beta-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2. Conclusions: There are biologically meaningful A beta-downstream effects in individuals with a low burden of A beta pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of A beta pathology for clinical trials.
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| 5. |
- Rodriguez-Fernandez, B., et al.
(författare)
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Genetically predicted telomere length and Alzheimer's disease endophenotypes: a Mendelian randomization study
- 2022
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer's disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-epsilon 4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF A beta and higher levels of CSF NfL only in APOE-epsilon 4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations.
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| 6. |
- Salvado, G., et al.
(författare)
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Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers
- 2019
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts.MethodsA total of 516 participants of the ALFA+ Study (N=205) and ADNI (N=311) underwent amyloid PET imaging ([F-18]flutemetamol and [F-18]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys (R) tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of A(42), tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded.ResultsAll Centiloid cut-offs fell within the range of 25-35, except for CSF A(42) that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/A(42) ratios was higher than that of CSF A(42). Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs.ConclusionsA cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.Trial registrationALFA+ Study, NCT02485730ALFA PET Sub-study, NCT02685969
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| 7. |
- Vilor-Tejedor, N., et al.
(författare)
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Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum
- 2021
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. Objective We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. Methods The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys (R) immunoassays were used to measure CSF A beta 42, A beta 40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and alpha-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by A beta status (positivity defined as A beta 42/40 < 0.071). Results The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of A beta positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in A beta negative participants. Conclusions Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
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