bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative amyloid PET in the AMYPAD diagnostic and patient management study
Authors: Buckley Christopher , Gispert Juan Domingo , Altomare Daniele , Moro Christian , Bullich Santiago , Caprioglio Camilla , Scheltens Philip , Van Berckel Bary N.M. , Collij Lyduine E. , Alves Isadora Lopes , Berkhof Johannes , Garibotto Valentina , Delrieu Julien , Molinuevo Jose , Drzezga Alexander , Jessen Frank , Nordberg Agneta K. , Walker Zuzana , Demonet Jean‐François , Gismondi Rossella , Battle Mark R. , Farrar Gill , Stephens Andrew W. , Barkhof Frederik , Frisoni Giovanni ,   AMYPAD Consortium
Published: December 2021

AbstractBackgroundAMYPAD‐DPMS is a European, multicenter, prospective, interventional, randomized controlled study. It aims to assess clinical utility and cost‐effectiveness of amyloid‐PET. It recruited individuals with Subjective Cognitive Decline plus (SCD+), and syndromic diagnosis of Mild Cognitive Impairment (MCI) and dementia. Here, we describe the quantitative results of the basal amyloid PET performed in these participants.MethodUntil end of recruitment on October 30th, 2020, 844 participants were included in AMYPAD‐DPMS from 8 clinical sites. Of those, 186 are from the Geneva site, 143 from Amsterdam, 130 from Toulouse, 101 from Barcelona, 94 from Cologne, 73 from Stockholm, 64 from London and 53 from Lausanne. Amyloid PET was performed with either 18F‐florbetaben or 18F‐flutemetamol and analysed with AmyPype, a PET‐only Centiloid‐calibrated pipeline running on a GE Advantage Workstation, to render comparable estimates of global amyloid load for both tracers. The standard Global Cortical Average region of interest was used as target region and the whole cerebellum as reference. Distributions as well as Mean and Standard Deviations (SD) of CL values by tracer, site and by diagnostic groups were computed.ResultFrom the 844 recruited participants, 245 (29%) were SCD, 341 (40%) MCI and 258 (31%) dementia. By January 19th, 2021, 661 scans had been analyzed with AmyPype and had passed quality control. Of them, 308 (47%) were scanned using 18F‐florbetaben and 353 (53%) with 18F‐flutemetamol. The global mean (SD) [range] of Centiloid (CL) values was 45.0 (49.0) [ ‐52.4, 221.9] CL. By clinical group, the average (SD) CL values were 25.5(39.1) for SCD+, 45.8(47.9) for MCI, and 66.3(51.1) for dementia patients. CL distributions by clinical group are shown in Figure 1, and per‐site and tracer in Figures 2‐3 for the MCI and Dementia groups.ConclusionQuantitative amyloid PET in AMYPAD‐DPMS shows a very well‐balanced tracer use. As expected, CL values increased with increasing disease severity. The consistent distribution of the majority of CL values within/across clinical groups suggest that the Centiloid transformation implemented in AmyPype allowed the direct comparison of estimates of amyloid burden across the two tracers used in this trial.
CSF and PET biomarkers for noradrenergic dysfunction in neurodegenerative disease: A systematic review and meta‐analysis
Authors: Lancini Elisa , Bartl Franziska , Haag Lena , Rühling Maren , Ashton Nicholas J , Zetterberg Henrik , Düzel Emrah , Hämmerer Dorothea , Betts Matthew 
Published: December 2021

AbstractBackgroundAlterations to the noradrenergic system may occur in the early stages of Alzheimer’s disease (AD) and Parkinson’s disease (PD) and could contribute to clinical symptoms. The aim of this study was to conduct a meta‐analysis of noradrenergic differences in AD and PD assessed using cerebrospinal fluid (CSF) and positron emission tomography (PET) measuresMethodCSF noradrenaline (NA) and its metabolite 3‐Methoxy‐4‐hydroxyphenylglycol (MHPG) as well as NA transporter availability (PET MeNER) levels in controls, AD and PD patients were pooled across studies. Differences between controls and patients were calculated with Hedge’s g and combined using a random‐effects model meta‐analysis. A random‐effect meta‐regression was conducted using the volume of the CSF samples, the sample sizes, the years post diagnosis, the severity of the diseases as covariates using laboratory analysis technique as a between‐study factor.ResultTwenty‐seven studies met the inclusion criteria. Seven studies with extreme effect sizes influencing between‐study heterogeneity were identified as outliers and subsequently removed from further analyses. In PD patients, significant reductions in CSF NA (n= 132, g= ‐0.26, p=0.01) and MHPG (n=257, g = ‐0.27, p<0.01), in addition to reduced PET MeNER binding in the hypothalamus (n=29, g = ‐0.87, p<0.05), were observed compared with control subjects (n=166 for NA, n=227 for MHPG respectively). In AD patients, no significant difference in CSF NA levels (n=194, g= ‐0.06, p= 0.78) and only a trend for increased MHPG levels (n=208, g= 0.24, p= 0.07) were observed compared with controls (n=196 for NA, n=218 for MHPG respectively), see Figure 1. The number of articles addressing PET MeNER in AD was not sufficient to conduct a meta‐analysis. The hypothesized explanatory variables, namely the volume of CSF samples, the sample size, the years post diagnosis and the severity of the disease, were not significant (p>0.05) in any of the investigated groups.ConclusionOur results indicate that noradrenergic dysfunction in neurodegenerative diseases can be detected using CSF or PET measures and may be more pronounced in PD compared to AD. Further studies using longitudinal CSF and PET measures are required to elucidate the relationship between noradrenergic dysfunction and the progression of neurodegenerative diseases.
Longitudinal examination and validation of the latent dementia phenotype factor in 10 harmonized cohort studies
Authors: Lam Ben CP , Crawford John D , Lipnicki Darren M , Mewton Louise , Sachdev Perminder S 
Published: December 2021

AbstractBackgroundPrevious studies have developed a latent continuous indicator of dementia phenotype, referred to as delta (δ), capturing the overlap of cognition and functional status in dementia (Royall & Palmer, 2012. J Neuropsy Clin Neurosci; Gravett et al., 2015. Neuropsy). To investigate this as a potential tool for harmonizing cognitive test and function data and identifying dementia cases in heterogeneous samples of older adults across studies, the current research constructed and examined the latent dementia factor (LDF) in 10 longitudinal population‐based studies from the Cohort Studies of Memory in an International Consortium (COSMIC).MethodA total sample of 19,208 older individuals (mean age = 73 years; 58% females) with a median follow‐up of 6 years was analysed. Longitudinal confirmatory factor analysis was first conducted to establish measurement invariance of LDF constructed by available neuropsychological tests and instrumental activity measures in each study (see Figure 1). The LDF scores were then standardised at common values of age, sex, and education to ensure comparability. Latent growth curve analysis was then conducted to estimate the initial level of and per year change in LDF. Measures for examining validity included dementia diagnosis, the Mini‐Mental State Examination (MMSE), and the Clinical Dementia Rating Scale Sum of Boxes (CDR‐SOB).ResultA significant linear increase in LDF in the overall sample was observed (an increase of 0.13 standard deviation per year). Mixed effects cox regression revealed significant associations between initial level of and change in LDF and incident. Further, one standard deviation increase in LDF was associated with 0.72 point decrease in MMSE and 0.34 point increase in CDR‐SOB over time. Change in LDF accurately discriminated diagnosed dementia cases in all except two studies with limited neuropsychological data (average ROC area under the curve = 0.84).ConclusionThis research shows the validity of a latent dementia indicator with dementia risk in a geographically and ethnoculturally diverse sample of older adults. This supports the utility of this approach to harmonise studies with different cognitive and functional measures to identify cases at risk of dementia (based on cutoffs of LDF).
Developments in clinical testing of cerebrospinal fluid biomarkers of Alzheimer’s disease in the UK
Authors: Keshavan Ashvini , Chapman Miles D. , Hart Melanie , Lunn Michael P. , Zetterberg Henrik , Schott Jonathan M. 
Published: December 2021

AbstractBackgroundGuidance from the UK National Institute for Health and Care Excellence now incorporates CSF biomarkers in certain circumstances when a diagnosis of Alzheimer’s disease (AD) is considered. To improve testing speed and reliability, we validated the fully‐automated Lumipulse platform against existing Innotest ELISAs, by measuring amyloid‐β 1‐42 and 1‐40 (Aβ42 and Aβ40), tau and phospho‐tau181 (p‐tau181), and deriving cut‐points for reporting all routine clinical tests in the UK.MethodIn a prospectively‐collected cognitive clinic cohort, 56 samples were tested using Innotest ELISAs for Aβ42 and total tau, and the Lumipulse platform for Aβ42 and Aβ40. The Lumipulse Aβ42/Aβ40 cut‐point that gave the best concordance with an Innotest definition of AD‐like CSF (Aβ42<630 pg/ml and tau/Aβ42≥0.88) was selected and compared to values derived in the Insight 46 cohort by concordance with 18F‐florbetapir PET (Keshavan et al. 2020, Alz Dem (Amst.) doi:10.1002/dad2.12097). A subset of 20 samples from the clinic cohort assayed on both platforms for p‐tau181, and a further 42 samples from routine clinical testing, were also examined for concordance of Lumipulse p‐tau181 with Aβ42/Aβ40.ResultA Lumipulse Aβ42/Aβ40 cut‐point of 0.065 gave 95% sensitivity and 89% specificity for distinguishing AD‐like from non‐AD‐like CSF (area under the curve (AUC) 0.959). Applying this cut‐point to data from Insight 46, where the Lumipulse Aβ42/Aβ40 AUC for amyloid PET was 0.966, yielded 85% sensitivity and 94‐96% specificity. Innotest and Lumipulse measurements of p‐tau181 were highly correlated (r=0.897, β=1.261, intercept=‐1.001). Applying the manufacturer's recommended Lumipulse p‐tau181 cut‐point of 56.5 pg/ml to the clinical samples gave 72% sensitivity and 86% specificity for distinguishing those with Lumipulse Aβ42/Aβ40≤0.065.ConclusionClinical testing of AD CSF biomarkers in the UK has now moved to the Lumipulse platform, reducing the result turnaround time from 20‐25 to 10 working days. As certified reference materials for each biomarker become available, future cut‐point refinements may allow for standardisation across laboratories and even countries.
Mass spectrometric measurement of six site‐specific tau phosphorylations in CSF and blood of Alzheimer's disease patients
Authors: Montoliu‐Gaya Laia , Ashton Nicholas J. , Benedet Andréa Lessa , Rodriguez Juan Lantero , Brinkmalm Gunnar , Karikari Thomas K. , Kern Silke , Rosa‐Neto Pedro , Zetterberg Henrik , Blennow Kaj , Gobom Johan 
Published: December 2021

AbstractBackgroundHyperphosphorylation of tau is responsible for its loss of normal physiological function, gain of toxicity and its aggregation to form NFTs. Increased phosphorylated tau is detected in Alzheimer´s disease (AD) CSF and blood, and changes in the tau phosphorylation pattern may reflect different stages of the disease progression. A better understanding on how the levels of site‐specific phosphorylations are modulated across the AD continuum in these biofluids may help to provide with a more accurate diagnosis.MethodWe developed an LC‐MS method based on parallel reaction monitoring (PRM) using Orbitrap MS to measure tau phosphorylations at positions pT181, pS199, pT205, pT217 and pT231 in CSF and plasma, and additionally p396 in CSF. Tau enrichment prior to LC‐MS differed between biofluids. For CSF, 250 µl of sample were prepared by performing partial PCA protein precipitation, followed by SPE and tryptic digestion. For plasma, 1 ml samples were subjected to immunoprecipitation using a combination of several tau antibodies, followed by tryptic digestion and SPE.ResultThe performance of the method was first evaluated by analysis of CSF from neurochemically characterized AD patients and controls (n=40). All measured phosphorylations showed significant separation between groups (p<0.001) (Fig. 1). In addition, pT181, pT217 and pT231 showed good correlations with SIMOA immunoassays. In plasma, a set of AD patients and controls (n=26) were analysed. All phosphorylations showed an increase in AD, and most significantly pT205 (p=0.003) and pT231 (p=0.008) (Fig 2). Interestingly, these two phosphorylations were the ones that showed higher correlation with p‐tau CSF (Spearman r=0.52 and r=0.63, respectively). Plasma values were also compared to the respective SIMOA immunoassays. Finally, the method was used to measure samples from the Translational biomarker In Aging and Dementia (TRIAD) cohort (n=209), consisting of young individuals (<30 years old), cognitive unimpaired, mild cognitive impairment (MCI) and AD patients.ConclusionWith our LC‐MS method to quantify site‐specific p‐tau levels, we have established the tau phosphorylation pattern in AD biofluids. Our data indicates that phosphorylation at position T231 is the one that shows a higher fold change between AD and controls both in CSF and blood.
A novel regional centiloid atlas to investigate the relationship between the quantification of [18F]flutemetamol amyloid PET and CSF Aβ42/40 in patients with SCD or MCI
Authors: Battle Mark R , Buckley Chris J , Farrar Gill , Pillay Lovena Chedumbarum , Ossenkoppele Rik , Smith Ruben , Hansson Oskar 
Published: December 2021

AbstractBackgroundVisual assessment of [18F]flutemetamol amyloid PET images, performed regionally (frontal, lateral temporal, posterior cingulate/precuneus, temporo‐parietal, striatum), is recommended, with a positive (abnormal) classification if any one of these regions is clearly positive. Changes in the striatum, known to contain extensive fibrillar amyloid deposits in AD, could identify likely converters in Subjective Cognitive Decline (SDC) or Mild Cognitive Impairment (MCI) subjects. CSF biomarkers are proven to detect abnormal amyloid metabolism in early stages of AD, with Aβ42/40 more reliable than Aβ42 alone. We applied a novel regional Centiloid Atlas, based on standard Centiloid (CL) cortical VOIs with additional striatal , aiming to better stratify amyloid abnormalities. Correlation between CL and Aβ42/40 was also investigated.MethodsThe regional Centiloid atlas, developed by overlaying standard CL cortical VOI on AAL atlas and incorporating additional striatal regions, was applied to 394 [18F]flutemetamol subjects from the Swedish BioFINDER I study following the methods of Klunk et.al. (Alzheimer’s & Dementia, 2015). In total, 387 Subjects with CSF Aβ42/40 information from the ADx analysis platform available, were included for analysis.ResultsAverage Aβ42/40 and CL values are presented (Table 1). Statistically significant differences in Aβ42/40 between control and MCI (p=0.0004), and SCD and MCI (p=0.0031) were observed (Fig. 1). Statistically significant differences in CL were also found in the cortical (p=0.007 or less) and striatal (p=0.028 or less) regions across all groups. Correlation between CL and Aβ42/40 for controls was moderate in both cortical (R2=0.35, Fig. 1) and striatal (R2=0.33, Fig. 2) regions. Similar correlations were found for SCD (Cortical: R2=0.52, Striatal: R2=0.48) and MCI (Cortical: R2=0.52, Striatal: R2=0.54).ConclusionsStandard Centiloid PET quantification provides global values across the cortical region. Identifying combined striatal differences in [18F]flutemetamol retention may provide additional information, aiding . Detecting these abnormalities and understanding their relationship to CSF biomarker changes may be useful in identifying those subjects for progression to AD. Further work to identify differences between cortical and striatal uptake in within subjects is ongoing.
An analysis of the study participant and study coordinator experience utilizing an electronic consent (eConsent) in REDCap
Authors: Chin Erin , Suver Christine , Lah James J , Goldstein Felicia C , Manzanares Cecelia , Cobb Nichelle L , Blazel Hanna , Edwards Dorothy Farrar 
Published: December 2021

AbstractBackgroundThe informed consent (IC) process offers an opportunity for researchers to promote participant autonomy and facilitate decision making. However, the traditional IC experience is often tedious, requiring study coordinators to present information in long IC documents. Paper IC documents can be difficult to understand and do not necessarily meet the needs of participants or study coordinators. The COVID‐19 pandemic underscores the need to provide an alternative to the in‐person, paper‐based IC process to minimize person‐to‐person contact. We worked with IRBs to revise how we engage and consent people in Alzheimer’s Disease Research Centers at the University of Wisconsin‐Madison and Emory University.MethodIn an ongoing effort to improve the IC process for adults at risk of developing memory and cognitive deficit, our team has been building and testing an electronic IC experience. We interviewed a total of 63 participants with a median age of 72. Participants underwent both the eConsent prototype and the paper consent. Seventy (70) percent of those participants preferred the eConsent over the traditional paper copy. We adapted into REDCap the electronic IC experience (eConsent). We collected input on the project from IRBs and study coordinators, and measured participant’s understanding of key elements of the IC through questions distributed throughout the eConsent.ResultsEach interested study participant received a unique link to the eConsent in REDCap. We observed which participants selected to review the eConsent information on their own, and which ones preferred to be guided remotely with the Study coordinators. We evaluated level of engagement with the eConsent and scored comprehension. The insights provided by this informed consent approach were used to determine whether it would be well suited for at‐home self‐administration across a diverse population.ConclusionStudy participants and study coordinators alike prefer an electronic consent process and participants retain information better as opposed to the typical paper consent form. While the REDCap consent survey is a temporary solution for our study team, it is a cost‐effective solution that facilitates a better experience for the participants. We believe that this REDCap eConsent could be a beneficial solution for the virtual recruitment and consent process at other ADRC sites.
[11C]PiB and [18F]AV45 PET radiotracers show different rates of amyloid‐β clearance
Authors: Chen Charles D. , McCullough Austin A. , Gordon Brian A. , Joseph‐Mathurin Nelly , Wang Guoqiao , Li Yan , Xiong Chengjie , Pontecorvo Michael J. , Klein Gregory , Shcherbinin Sergey , Higgins Ixavier A. , Masters Colin L , Clifford David B. , van Dyck Christopher H , Masellis Mario , Hsiung Ging‐Yuek Robin , Gauthier Serge , Bateman Randall J. , McDade Eric , Salloway Stephen P. , Benzinger Tammie L.S. 
Published: December 2021

AbstractBackgroundResults from the first Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) clinical trial showed Gantenerumab reduces amyloid‐β deposition in autosomal dominant Alzheimer disease individuals. However, it is uncertain whether these initial findings from [11C]PiB PET generalize to other amyloid‐β PET radiotracers.MethodWe acquired [11C]PiB and [18F]AV45 PET in mutation positive DIAN‐TU participants in the gantenerumab (n=30) and placebo drug arms (n=19). Participants were assessed at baseline and Year 4; at each visit, [11C]PiB and [18F]AV45 PET were acquired, with at most 28 days between imaging sessions. Regional standardized uptake value ratios (SUVRs) were quantified using the PET Unified Pipeline. Annualized SUVR percent change between baseline and Year 4 for both radiotracers in both drug arms were calculated. Differences in SUVR change between radiotracers/drug arms were assessed using the Wilcoxon signed‐rank/rank‐sum test. Each test statistic is reported as a rank‐biserial correlation r accompanied by p‐values adjusted for false discovery control by the Benjamini‐Hochberg procedure at level q=0.20.ResultWe observed a decrease from baseline to Year 4 SUVR in the gantenerumab arm, which was larger when studied with [11C]PiB than with [18F]AV45 PET in several regions, including the striatum and cingulate gyrus (r=[‐0.79,‐0.31], FDR‐adjusted p‐values=[0.00086,0.19], Figure 1). In contrast, we observed an increase in SUVR in the placebo arm, comparable in magnitude between [11C]PiB and [18F]AV45 PET (r=[‐0.15,0.68], FDR‐adjusted p‐values=[0.29,0.86]).ConclusionDifferences seen between the effects of gantenerumab in [11C]PiB versus [18F]AV45 PET suggest several regions, such as the striatum and cingulate gyrus, may be inappropriate for radiotracer harmonization in studies involving gantenerumab. More practically, the finding that anti‐amyloid‐β therapies may have different effects on signal across radiotracers suggests multi‐site studies of anti‐amyloid‐β treatments should agree on a single radiotracer for best results. Follow‐up postmortem studies will be conducted to determine the binding affinity of various amyloid‐β radiotracers to amyloid‐β plaques in this cohort.
Functional connectivity measurements in APP/PS‐1 mice revealed hypo‐connectivity with transient hyper‐connectivity
Authors: Cover Christopher G , Klunk William E , Vazquez Alberto L 
Published: December 2021

AbstractBackgroundChanges in brain functional connectivity (FC) have gained traction as an early event in Alzheimer’s disease (AD), especially reports of hyper‐connectivity preceding hypo‐connectivity.1 In the present study, we characterized changes in neuronal and hemodynamic connectivity in AD mice from 3‐12 months of age.MethodAmyloid precursor protein/presenlin‐1 (APP/PS‐1) mice (n=8) were injected with AAV‐Syn‐GCaMP6f into cortical regions. Mice were head‐fixed and imaged monthly from 3‐12 months of age. Simultaneous neuronal and hemodynamic signals were measured using wide‐field optical imaging (Fig 1a). Plaque characterization was performed via methoxy‐04 labelled images (Fig 1b). Resting‐state connectivity was calculated via Pearson correlation derived from the average timeseries of functionally clustered brain regions using a K‐means algorithm (Fig 2). Repeated measures Wilcoxon Rank Sum was used to assess statistical differences. Findings were considered significant for p<0.05.ResultAmyloid plaques were predominately seen after 6 months old (mo) and increased linearly till 12‐mo (Fig 3). The average neuronal connectivity (Fig 4a) steadily declined between 3‐ to 12‐mo, with the steepest decrease occurring around 6‐mo (r=0.65 ± 0.01 @ 3‐mo to r=0.57 ± 0.01 @ 6‐mo; p=0.01). The exception being around 9‐mo, connectivity spiked (r=0.63 ± 0.01; p=0.94, compared to 3‐mo) before returning to r=0.55 ± 0.03 (p = 0.005, 10‐mo compared to 9‐months). Hemodynamic connectivity decreased between 3‐ to 12‐mo to r= 0.43 ± 0.01 (p=0.32; compared to 3‐mo; Fig 4b) with a trough around 9‐mo r=0.41 ± 0.02 (p=0.28; compared to 3‐mo). Average correlation between neuronal and hemodynamic activity remained stable but spiked around 9‐mo, though the transient hyper‐connectivity was not significant (Fig 5).ConclusionThe observed neuronal transient hyper‐connectivity coincides with an acceleration in insoluble amyloid plaque deposition. Though insoluble amyloid continues to accumulate in the form of plaque and around blood vessels as the mouse ages, the steepest change in regional hypo‐connectivity seemed to occur around 6‐mo. We are currently exploring the decline in hemodynamic FC overtime and the detection of hemodynamic changes around the transient neuronal hyper‐connectivity at 9‐mo.Reference: Schultz et al., J Neurosci. 2017 Apr 19; 37(16): 4323–4331.