bluuebunny/crossref_metadata_2025_split huggingface dataset:
An update and baseline data from the phase 2/3 GAIN trial of COR388 (atuzaginstat), a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s disease
Authors: Detke Mike 
Published: December 2021

AbstractBackgroundThe novel mechanism of action of atuzaginstat is based on the discovery of gingipains, toxic protease virulence factors from the bacterial pathogen Porphyromonas gingivalis (Pg), in >90% of Alzheimer’s disease (AD) brains. Gingipain levels correlated with AD diagnosis and tau and ubiquitin pathology, and oral infection of mice with Pg results in classic AD pathology that can be blocked by atuzaginstat, an irreversible lysine‐gingipain inhibitor. Pg is best known for its role in periodontal disease. Atuzaginstat was well tolerated in phase 1, including trends of efficacy on clinical scales, and significant improvement on a computerized speech assessment and two relevant biomarkers.MethodsThe Phase 2/3 GAIN trial, designed to be potentially pivotal, completed enrollment in November 2020. 642 subjects (aged 55‐80; mild‐moderate AD with MMSE 12‐24) were randomized to one of two doses of atuzaginstat (40mg or 80mg BID) or placebo. The co‐primary endpoints are mean change in ADAS‐Cog 11 and ADCS‐ADL from baseline to 48 weeks. Additional endpoints include change in CDR‐SB, MMSE, NPI, Winterlight Speech Assessment, CSF and oral biomarkers, MRI and other measures.ResultsBaseline data show that the 642 randomized subjects are: 56.9% female, 64.3% ApoE4 positive, 49.5% mild (MMSE = 19‐24) and 50.5% moderate (12‐18). 73.2% of subjects received symptomatic AD co‐medications. New baseline biomarker data from the full set of subjects in the study will be shared, including anti‐Pg IgG, amyloid‐β peptide ratio 42/40, and phospho tau. 233 GAIN trial patients are also participating in a dental sub‐study, and while not selected for periodontal disease, approximately 90% have moderate ‐ severe periodontitis.ConclusionsEnrollment of the GAIN trial was completed in November 2020, and top‐line efficacy data are expected December Q4 2021. An interim analysis in December 2020 indicated that the study should continue as planned without sample size adjustment. Subjects enrolled exhibit baseline characteristics consistent with AD and with Pg infection, indicating an appropriate population to test the efficacy and safety of atuzaginstat in mild‐moderate AD. The high correlations of AD, periodontal disease, and Pg infections observed in GAIN replicates findings by others and supports a causal role of Pg in AD.
Technology‐driven dyadic interaction in caregiving
Authors: Hoel Viktoria , Ambugo Eliva Atieno , Steinert Lars , Schultz Tanja , Wolf‐Ostermann Karin 
Published: December 2021

AbstractBackgroundDue to the ongoing pandemic and the resulting community lockdowns, people with dementia and their family might be at risk of social deprivation and increased relationship strains. Technological means have the potential to engage participants in meaningful positive interactions. The tablet‐based activation system I‐CARE offers social activities specifically designed for people with dementia and their caregivers, by offering user‐specific contents adapted to their needs and sensitivities. Little is known about the impact of Covid‐19 on social health for this population. The ongoing study, presented as a part of the Marie‐Curie Innovative‐Training‐Network action, H2020‐MSCA‐ITN, grant agreement 813196, assesses how COVID‐19 has impacted community‐dwelling dementia caregiving dyads. Contextual factors of technology use and motivations for inviting technology into social interactions is explored.MethodAs a part an ongoing pre‐post mixed‐methods feasibility study, baseline assessments through semi‐structured interviews were conducted and subjected to inductive thematic statement analysis by two independent researchers.ResultParticipants differed in how COVID‐19 restrictions impacted their lives and how they coped with dementia, revealing different motivations for inviting technology into their lives. Dyads who were socially active pre‐COVID‐19, and who managed use technology to maintain social participation during COVID‐19, reported to have been less negatively impacted by COVID‐19 restrictions. Four subthemes within “Social technology during COVID‐19” were identified.ConclusionDuring and beyond this pandemic, social technology is a valuable tool to promote social participation in this population. Successful uptake of technology is dependent on customizing to individuals’ needs and conditions.
Correspondence of CSF biomarkers measured by Lumipulse assays with amyloid PET
Authors: Volluz Katherine E. , Schindler Suzanne E. , Henson Rachel L. , Xiong Chengjie , Gordon Brian A. , Benzinger Tammie L.S. , Holtzman David M. , Morris John C. , Fagan Anne M. 
Published: December 2021

AbstractBackgroundTraditional plate‐based assays for cerebrospinal fluid (CSF) biomarkers have been limited by relatively high assay variance that reduces the accuracy of individual measurements. Next generation automated assay platforms for CSF biomarkers reduce the variability of measurements, including across sample runs. In the current study, we utilized the Lumipulse G1200 (Fujirebio; Malvern, PA), a fully‐automated assay platform to compare CSF biomarkers to brain amyloid burden as determined by positron emission tomography (PET) imaging.MethodParticipants (n=758) were enrolled in studies of memory and aging at the Knight ADRC in St. Louis, Missouri. Concentrations of CSF amyloid‐beta 40 (Aβ40), amyloid‐beta 42 (Aβ42), total tau (tTau) and phosphorylated tau‐181 (pTau) were measured using the Lumipulse G1200 automated assay system. Brain amyloid burden was measured via amyloid PET imaging using Florbetapir or Pittsburgh compound B (PIB). The correspondence of CSF biomarkers with amyloid PET status based on established cut‐offs for each radiotracer was evaluated.ResultFor pooled CSF controls representing a range of three values (low, medium, high), coefficients for inter‐day variability ranged from 2‐4%. CSF collected within two years of an amyloid PET scan was evaluated from 521 amyloid PET‐negative and 237 amyloid PET‐positive individuals. Correspondence with amyloid PET by receiver operating characteristic (ROC) area under the curve (AUC) was highest for ratios including Aβ42: pTau/Aβ42 (0.97, 95% confidence intervals 0.96‐0.99), Aβ42/Aβ40 (0.97, 0.95‐0.98), and tTau/Aβ42 (0.96, 0.94‐0.97). A CSF pTau/Aβ42 value of >0.0649 had the highest combined positive and negative percent agreement (PPA of 0.91, 0.86‐0.94; NPA of 0.96, 0.93‐0.97) with amyloid PET status. The CSF value for Aβ42/Aβ40 with highest combined PPA and NPA was slightly more sensitive but less specific: <0.0673 had a PPA of 0.97 (0.94‐0.99) and NPA of 0.91 (0.88‐0.93) with amyloid PET status.ConclusionMeasurement of CSF biomarkers with the Lumipulse G1200 automated assay system was highly precise, with low variability over multiple runs. Values for pTau/Aβ42, Aβ42/Aβ40, and tTau/Aβ42 were highly concordant with amyloid PET status.
Survey in people with dementia and their care partners on post‐diagnostic care in memory clinics: Data from the COGNISANCE study
Authors: Hevink Maud , Verhey Frans R.J. , Brodaty Henry , Low Lee‐Fay , Vedel Isabelle , Rymaszewska Joanna , Rait Greta , Robinson Louise ,   the COGNISANCE study group
Published: December 2021

AbstractBackgroundRecent literature calls for a focus on providing quality post diagnostic dementia care (Wong & Knapp, 2020). There is dissatisfaction among people with dementia (PwD) and care partners (CP) with post diagnostic dementia support (Hagan, 2020). To improve experiences of post diagnostic support for PwD and CP, it is vital to understand what factors influence their experience of post diagnostic support. Differences between PwD and CP could be used to tailor support to their respective needs and wishes. The aim of the present study is twofold. First, to determine which factors predict the satisfaction with post‐diagnostic support for PwD and CP. Second, to compare factors of PwD and CP that shape experiences of post diagnostic support.MethodAs part of the COGNISANCE project, a survey was developed and distributed among PwD and CP in five countries: Australia, Canada, the Netherlands, Poland, and the United Kingdom. The survey consisted of mostly closed questions on demographics, experiences of the diagnostic process, and post diagnostic support.ResultThe average age of the PWD respondents (N=91) was 74.3 (+‐ 10.0) and 60.1 (+‐ 14.4) that of the CP respondents (N=209). The majority of the PWD (57.1%) and CP (71.3%) were female. Support after a diagnosis was deemed helpful by 57.4% of the PWD and 62% of the CP. There is a significant association between whether PWD and CP were satisfied with support and their satisfaction with the diagnostic process, satisfaction with information on dementia and information on strategies to live well with dementia. For PWD, satisfaction with support is associated with the waiting time for a first appointment in the diagnostic process, the satisfaction with the waiting time, confidence in asking for help, confidence in handling future challenges and living positively with dementia.For CP, the satisfaction with support was associated with the presence of a care plan, their satisfaction with information on prognosis and information on services.ConclusionA significant minority of PwD and CP is not satisfied with the support following a diagnosis. Results suggest that information aspects and experiences in the diagnostic process impact on the satisfaction with dementia support.
Improved comparability between measurements of mean cortical amyloid plaque burden derived from different PET tracers using multiple regions‐of‐interest and machine learning
Authors: Chen Kewei , Ghisays Valentina , Luo Ji , Chen Yinghua , Lee Wendy , Benzinger Tammie L.S. , Wu Teresa , Reiman Eric M. , Su Yi 
Published: December 2021

AbstractBackgroundThe conversion of standard uptake value ratios (SUVRs) to Centiloid units using previously described methods has partially but not completely improved the ability to compare measurements of mean cortical amyloid plaque burden, classify positive versus negative amyloid PET scans, assess changes over time, and evaluate amyloid‐modifying treatment effects using different radiotracers. Here, we demonstrate improved harmonization between PiB and florbetapir (FBP) PET measurements of mean cortical SUVRs (mcSUVRs) using multiple regions‐of‐interest (ROIs) and machine learning algorithms.MethodsPiB and FBP PET image pairs from 91 subjects in the Open Access Series of Imaging Studies (https://www.oasis‐brains.org/) were used as the training set to optimize the algorithms to generate each subject’s pseudo‐PiB mcSUVR measurements from his or her FBP multi‐ROI SUVRs . PiB and FBP image pairs from 46 subjects in the Avid‐related Centiloid Project (www.gaain.org/centiloid‐project) were then used as the test set to compare Pearson’s correlation coefficients (r) between the pseudo and actual PiB mcSUVR measurements using our approach to that used in the Centiloid method. SUVRs with cerebellar reference were extracted from multi‐ROIs using FreeSurfer with partial volume correction. Pseudo mcSUVRs were generated using ensemble regression, partial least square regression (PLSR) and artificial neural network (ANN) separately, and their correlations with the actual PiB mcSUVR were compared to the PiB‐FBP correlation on Centiloid in both training and test sets.ResultsIn the training set, the Centiloid based PiB‐FBP correlation was r=0.904. An ANN with 7/6 neurons in the 1st/2nd hidden layers improved it to 0.987 (p≤8.3e‐12) and PLSR to 0.973 (p≤3.8e‐5). In the independent test set, ANN improved r to 0.981 from 0.927 (p≤6.6e‐4) and PLSR to 0.964 (p=0.011). Ensemble regression did not improve r.ConclusionThe ANN and PLSR algorithms mapping multi‐ROI FBP SUVRs to PiB mcSUVR appear to increase the comparability between measurements of mean cortical amyloid plaque burden using different PET tracers. Additional studies are needed to demonstrate the generalizability to other amyloid PET tracers, clarify its comparability in distinguishing between positive and negative amyloid PET scans, demonstrate its value in longitudinal studies and clinical trials, and extend our approaches to different tau PET ligands.
Age‐stratified, sex‐specific differences in cognitive performance based on risk of obstructive sleep apnea and systemic inflammation: A cross‐sectional analysis of the Canadian Longitudinal Study of Aging
Authors: Legault Julie , Thompson Cynthia , Moullec Gregory , Martineau‐Dussault Marie‐Ève , Baltzan Marc , Cross Nathan , Dang‐Vu Thien Thanh , Gervais Nicole J , Einstein Gillian , Hanly Patrick , Ayas Najib , Lorrain Dominique , Kaminska Marta , Gagnon Jean‐François , Lim Andrew , Carrier Julie , Gosselin Nadia 
Published: December 2021

AbstractBackgroundGrowing evidence supports associations between cognitive impairment and obstructive sleep apnea (OSA). Our study aimed at determining the age and sex‐specific, independent relationship between risk of having OSA and cognitive performance, and the influence of systemic inflammation on this relationship.MethodOur sample included 25,712 participants from the Canadian Longitudinal Study of Aging (CLSA) comprehensive cohort aged 45 to 85 years (M = 63 years; 51% women; 78% with post‐secondary degree). Exclusion criteria included Alzheimer’s and Parkinson’s disease and history of stroke and of traumatic brain injury. Participants were classified as high‐ or low‐risk of having OSA based on the STOP questionnaire (high‐risk = ≥ 2/4), considering signs and symptoms associated with OSA including snoring (S), tiredness (T), observation of apneas (O), and high blood pressure (P). Neuropsychological tests assessed memory, executive functioning and psychomotor speed. Levels of high‐sensitivity C‐reactive protein (hs‐CRP) were obtained through blood samples. We conducted sex‐ and age‐specific (45‐59; 60‐69; ≥70) General Linear Models between cognitive scores and risk of OSA, and moderation and mediation analyses with levels of hs‐CRP. Analyses were adjusted for socio‐demographic, lifestyle and medical comorbidities.ResultIn the fully adjusted model, 45‐59 years old women at high‐risk of OSA presented poorer short‐term memory and learning (Rey Auditory Verbal Learning Test, immediate recall, p=0.040), and executive functioning (Animal Fluency test, p=0.011; Mental Alternation test, p=0.006; Stroop Test, inhibition condition, p=0.047; low‐interference index, p=0.027 and high‐interference index, p=0.022) compared to those at low‐risk of OSA. These associations were not found in women aged ≥60 and in men of all age groups. The association between OSA risk and cognition was not moderated by education nor consistently moderated or mediated by the level of hs‐CRP.ConclusionThese findings suggest that OSA might represent a modifiable risk factor of early cognitive impairment in women aged 45‐59. We suggest clinicians systematically screen for cognitive impairment when patients of this group present suspected or diagnosed OSA. Furthermore, it is important to track changes in cognitive profile of women aged 45‐59 in the CLSA cohort to identify those at risk of long‐term cognitive decline.
The perception of professionals in the socio‐health field about the support services provided for families with a member with neurodegenerative disease
Authors: Montes‐López Estrella , del Álamo‐Gómez Nuria , Yurrebaso‐Macho Amaia , Valverde Eva María Picado ,   NEUROQUALYFAM group
Published: December 2021

AbstractBackgroundIn the Spanish case, the social organization of care is characterized by being family oriented. This means that the involvement of the family in the care of its members is high in relation to the participation of other social actors, such as the State, the market, or the community. Neurodegenerative diseases (ND) significantly affect the quality of life of the person, but also that of their family, precisely because of their high involvement in care. Families require support services to increase their well‐being, and several studies have shown the impact that the absence of support services has on the Family Quality of Life (FQoL). Considering this, the main objective of this study is to find out the perception of professionals working in the socio‐health field about the adequacy and sufficiency of the services available to people with ND and their families in the Spain‐Portugal cross‐border area.MethodThis research has been developed through qualitative methodology. Three focus groups were held. They involved: 1) public social services personnel; 2) public health services staff; 3) workers in the services offered by private initiatives. All of them carried out their work in the cross‐border area studied. With the support of the Atlas.ti software and following a deductive coding model, the data obtained were systematically coded and interpreted.ResultsInitial research results suggest that professionals in the socio‐health field agree on their perceptions of the adequacy and sufficiency of support services provided for families with a member with ND. They consider that:1) most support services are aimed solely at the needs of the person with a ND and therefore contribute little to improving the FQoL;2) support services considered very adequate for the improvement of the FQoL are very insufficient; 3) the characteristics of the environment (small population, geographical dispersion, etc.) significantly limit support services in rural areasConclusionThe support services provided for families with a member with ND are scarce and inadequate, and therefore contribute little to improving the FQoL. There is a need to improve access and adapt support services to the needs of families.
Association of blood‐based epigenetic age acceleration with cognitive impairment and brain outcomes by cardiovascular disease among women
Authors: Shadyab Aladdin H. , McEvoy Linda K. , Horvath Steve , Whitsel Eric A. , Rapp Stephen R. , Espeland Mark A. , Resnick Susan M. , Chen Jiu‐Chiuan , Chen Brian H. , Li Wenjun , Hayden Kathleen M. , Manson JoAnn E. , Bao Wei , Kusters Cynthia D.J. , LaCroix Andrea Z. 
Published: December 2021

AbstractBackgroundDNA methylation‐based epigenetic age acceleration (AgeAccel), an aging biomarker indicating faster biological aging relative to chronological age, is associated with many age‐related phenotypes. Blood‐based AgeAccel has been associated with lower cognitive function in several studies. However, there are limited data on associations of AgeAccel with mild cognitive impairment (MCI), dementia, and brain structure. Further, no prior study investigated whether associations of AgeAccel with cognitive and brain outcomes vary by cardiovascular disease (CVD), despite evidence linking vascular pathologies to both AgeAccel and dementia.MethodParticipants were 615 older women from a case‐cohort study of CVD in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study who also enrolled in the WHI Memory Study (n=327 with incident CVD during follow‐up and n=288 without incident CVD). AgeAccel was measured in blood collected at baseline when women had no CVD or cognitive impairment. Women were followed for up to 25 years to determine centrally adjudicated diagnoses of MCI and dementia according to DSM‐IV criteria. A subset (n=90) had structural brain MRI scans performed ∼8 years after baseline. Associations between four measures of AgeAccel (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) and risks for MCI/dementia incidence were estimated using Cox proportional hazards regression models. Associations of AgeAccel with brain volumes were examined using multiple linear regression models. Models were stratified by incident CVD status and adjusted for chronological age and other sociodemographic characteristics, lifestyle behaviors, and clinical factors.ResultAmong women who developed CVD, a 1‐year increase in IEAA was associated with higher risk of MCI (HR=1.10; 95% CI=1.03‐1.18), higher risk of combined MCI/dementia (HR=1.07; 95% CI=1.01‐1.13), and higher ventricular volume (in cm3; β=1.04; 95% CI=0.15‐1.94). A 1‐year increase in AgeAccelPheno was associated with higher risk of combined MCI/dementia (HR=1.05; 95% CI=1.00‐1.10) in women with incident CVD. The other two measures of AgeAccel were not associated with any outcome among women with incident CVD. No associations of AgeAccel with cognitive impairment or brain volumes were observed among women who did not develop CVD.ConclusionBlood‐based AgeAccel may be a marker of cognitive and brain health among women with underlying vascular pathologies.
Glitter in the darkness? Non‐fibrillar β‐amyloid plaque components significantly impact the β‐amyloid PET signal
Authors: Biechele Gloria , Monasor Laura Sebastian , Wind Karin , Blume Tanja , Parhizkar Samira , Arzberger Thomas , Sacher Christian , Beyer Leonie , Eckenweber Florian , Gildehaus Franz Josef , von Ungern‐Sternberg Barbara , Willem Michael , Bartenstein Peter , Cumming Paul , Rominger Axel , Herms Jochen , Lichtenthaler Stefan F , Haass Christian , Tahirovic Sabina , Brendel Matthias 
Published: December 2021

AbstractBackgroundβ‐amyloid PET (Aβ‐PET) is an important tool for quantification of amyloidosis in the brain of suspected Alzheimer’s disease (AD) patients and transgenic AD mouse models. Despite the excellent correlation of Aβ‐PET with gold standard immunohistochemical assessments, the relative contributions of fibrillar and non‐fibrillar Aβ components to the in vivo Aβ‐PET signal remain unclear. Thus, we obtained two murine cerebral amyloidosis models that present with distinct Aβ plaque compositions and performed regression analysis between immunohistochemistry and Aβ PET to determine the biochemical contributions to Aβ‐PET signal in vivo.MethodWe investigated groups of AppNL‐G‐F
and APPPS1 mice three, six and 12 months of age by longitudinal [18F]‐florbetaben Aβ‐PET and with immunohistochemical analysis of the fibrillar and total Aβ burdens. We then applied group level inter‐modality regression models using age and genotype matched sets of fibrillar/ non‐fibrillar Aβ data (predictors) and Aβ‐PET results (outcome) for both transgenic models. An independent group of double‐hit APPPS1 mice with dysfunctional microglia due to knock‐out of triggering receptor expression on myeloid cells 2 (Trem2‐/‐) served for validation and evaluation of translational impact.ResultNeither fibrillar nor non‐fibrillar Aβ content alone sufficed to explain the Aβ‐PET findings in either transgenic AD model (Figure 1). A regression model compiling fibrillar and non‐fibrillar Aβ together with the estimate of individual heterogeneity and age at scanning could explain a 93% of variance of the Aβ‐PET signal (p<0.001; Figure 2). Fibrillar Aβ burden had a 16‐fold higher contribution to the Aβ‐PET signal when compared to non‐fibrillar Aβ. However, given the relatively greater abundance of non‐fibrillar Aβ, we estimate that non‐fibrillar Aβ produced 79±25% of the net in vivo Aβ‐PET signal in AppNL‐G‐F
mice, and 25±12% in the APPPS1 mice. Corresponding results in groups of APPPS1/Trem2‐/‐ and APPPS1/Trem2+/+ mice validated the calculated regression factors and revealed that the altered fibrillarity due to Trem2 knockout impacts the Aβ‐PET signal (Figure 3).ConclusionTaken together, the in vivo Aβ‐PET signal derives from the composite of fibrillar and non‐fibrillar Aβ plaque components. While fibrillar Aβ has inherently higher PET tracer binding, the greater abundance of non‐fibrillar Aβ plaque in AD model mice contributes importantly to the PET signal.