bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative analytical performance of multiple plasma amyloid‐beta assays and their relationship to amyloid PET
Authors: Zicha Stephen , Bateman Randall J. , Shaw Leslie M. , Bannon Anthony W. , Zetterberg Henrik , Horton Wesley A. , Baratta Michael , Kolb Hartmuth C. , Dobler Iwona ,   Emmanouil (Manos) Spanakis, Wang Wenting , Raunig David L. , Saad Ziad S. , Mordashova Yulia , Li Yan , Bjorklund Nicole L. , Edelmayer Rebecca M. , Martone Robert L. , Rubel Carrie E. , Mawuenyega Kwasi G. , Bollinger James G. , Weber Christopher J. , Meyers Emily A. , Potter William Z. ,   BC‐NSC Plasma Abeta Project Team
Published: December 2021

AbstractBackgroundThe National Institute on Aging and the Alzheimer’s Association framework for classifying Alzheimer’s disease (AD) utilizes measures of pathology for amyloid, tau, and neurodegeneration (ATN), that can identify participants for clinical trials. Currently, amyloid pathology is determined by costly PET or invasive CSF measurements. When applied to participant selection, these measures are associated with high screen failure rates and contribute to the high costs and long duration of recruitment of AD clinical trials. Recent reports indicate plasma amyloid beta (Aβ) peptides correlate highly with PET and CSF amyloid measures. This study aims to characterize novel assays as a screening tool that can quantify plasma Aβ peptides in a robust and reproducible manner.MethodThe project team consists of representatives from pharmaceutical industry, nonprofit/patient advocacy, and academic institutions. Six plasma Aβ assays were selected to be part of the comparison: three liquid chromatography–mass spectrometry (LC‐MS/MS) assays and three immunoassays. Plasma samples with corresponding amyloid PET data were selected from ADNI n=130 (50% Aβ+): cognitively normal n=54 (37% Aβ+), mild cognitive impairment n=54 (46% Aβ+), and AD n=22 (91% Aβ+). Each participant’s sample was tested in a blinded fashion on all six assays with analytical controls. Statistical tests were performed to identify which assays can significantly improve the Area Under the Receiver Operating Characteristic (AUROC) curve for predicting amyloid PET status compared to age and APOE ε4 status alone.ResultThe project tested 130 samples across assays with comparison to amyloid PET. Initial results from assay providers show AUROCs to predict amyloid status at levels consistent with performance in earlier publications. A comparison of results for the various assays will be presented with respect to their ability to classify amyloid PET status and whether they add significantly to the prediction of amyloid positivity beyond age and genotype.ConclusionMeasurement of Aβ in plasma contributes to addressing the amyloid component of the ATN framework and can be a pre‐screen or a substitute for PET or CSF screening. Further clinical validation of these assays is planned to assess amyloidosis detection performance in a cognitively normal population.
Animal fluency improvements and confrontation naming declines over 6 months are associated with differential conversion from MCI to AD in ADNI
Authors: Foldi Nancy S. , Tommet Douglas , Rabin Laura , Lamar Melissa , Jones Richard N , Mungas Dan M. , Choi Seo‐Eun , Grandoit Evan , Mukherjee Shubhabrata , Jutten Roos J. , Sikkes Sietske A.M. , Zhu Ryoui , Crane Paul K. 
Published: December 2021

AbstractBackgroundNot everyone with mild cognitive impairment (MCI) progresses to Alzheimer’s dementia (AD). Predicting who will decline is important. We previously reported that 6‐months change scores for language, but not for memory, executive functioning, or visuospatial functions, identified a high‐risk subgroup. Here we consider more specific language processes and consider AD fluid and imaging biomarkers.MethodsWe used longitudinal data from 764 ADNI participants enrolled with MCI and still had MCI at 6 months, which was our baseline for Cox proportional hazards modeling of conversion to AD. We derived scores for four aspects of language: confrontation naming, animal fluency, letter fluency tests, and other language tests. We evaluated changes from enrollment to month 6 for each of these scores. We also adjusted models for APOE genotype, entorhinal thickness and hippocampal volume, and CSF amyloid and tau biomarkers.ResultsThe sample’s mean age was 73.2 years, and 59% were male. From over 2918 total follow‐up years (mean 3.8), there were 287 conversions to AD. Cox models controlling for demographic characteristics, showed improvements in animal fluency scores associated with lower risk (HR=0.58, p=.005), but declines in confrontation naming were associated with higher risk (HR=1.74, p<.001). The animal fluency finding was somewhat attenuated when further controlling the Cox model for hippocampal volume (HR=0.64, p=0.10) and CSF biomarker findings (HR=0.61, p=0.12). Confrontation naming was not impacted by any of the imaging or fluid biomarkers we considered.ConclusionsIn MCI, the association between six‐month changes in language, and the AD risk appears to be driven by animal fluency improvements and confrontation naming declines. Improvement in animal fluency may reflect still functional access to semantic networks. The attenuation of this signal when controlling for hippocampal volume and CSF biomarkers suggests inability to improve animal fluency may reflect processes associated with hippocampal volumes and CSF biomarkers. Declines in confrontation naming may represent impaired lexical access. The independence of this signal from hippocampal volumes and CSF biomarkers suggests declines in this network may act independently of these biomarkers. These findings suggest intriguing lines of research to further understand the importance of language abilities among people with MCI.
Discrepancy between plasma pTau181 and tau‐PET statuses
Authors: Tissot Cécile , Kunach Peter , Therriault Joseph , Lussier Firoza Z. , Benedet Andréa Lessa , Chamoun Mira , Pascoal Tharick A. , Servaes Stijn , Bezgin Gleb , Arias Jaime Fernandez , Wang Yi‐Ting , Stevenson Jenna , Rahmouni Nesrine , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2021

AbstractBackgroundAssessments of tau usually come from cerebrospinal fluid or Positron Emission Tomography (PET). However, those methods are expensive and not readily available. Current research is focusing on cost‐effective blood‐based biomarkers, and a novel immunoassay for plasma pTau181 has been created. Even though there are strong associations between plasma pTau181 and PET, no study has yet investigated whether plasma pTau181 can be used to detect early AD‐pathology. Does the status of plasma pTau181 always correlate with tau‐PET status?MethodWe assessed 269 individuals from the TRIAD cohort (164 CU, 60 MCI and 45 AD) that underwent plasma pTau181 assessment, [18F]MK6240 tau‐PET scan, [18F]AZD4694 amyloid‐PET scan to assess their amyloid status, an MRI and a neuropsychological evaluation. We conducted statistical analyses using R, first to calculate the threshold values for positivity in both tau assessing methods and to make comparisons between the groups. For tau‐PET, we used [18F]MK6240 SUVR in the temporal meta‐ROI.ResultUsing Receiver Operating Characteristic (ROC) curves, we established that the cut‐off for positivity for plasma pTau181 was 11.1060 pg/mL, while for tau‐PET, it was 1.1827 SUVR. 182 individuals had concordant statuses for both plasma pTau181 and tau‐PET, while 87 were discrepant. 64 were plasma+/PET‐, with a majority cognitively unimpaired (CU) and 23 were plasma‐/PET+, with values close to the thresholds, and mostly MCI or AD (Figure1). Moreover, concomitant plasma/PET statuses were usually accompanied by a similar Ab status (Figure2). CU Ab+ individuals were found in high proportion in the plasma+/PET‐ group (Figure3).ConclusionMost of the participants had concordant statuses for plasma pTau181 and tau‐PET, which correlate well with memory scores and diagnoses. However, there was a significant portion of discordant individuals, which were predominantly plasma+/PET‐. This corroborates findings from comparisons between CSF pTau181 and tau‐PET, with CSF positivity coming before PET. Plasma pTau181 is also a great tool to assess Ab status, even before the onset of tau‐PET abnormalities. Assessing tau through plasma or PET is thought to suggest different stages of pathological progression.
Family stories: Subjective cognitive decline profile associated with a familial history of Alzheimer’s disease
Authors: Robertson Frank , Marx Hannah , Jacova Claudia 
Published: December 2021

AbstractBackgroundSubjective Cognitive Decline (SCD) designates a self‐experienced worsening of cognition before that decline becomes detectable by objective cognitive assessment. SCD has been examined as an early stage of Alzheimer’s disease (AD), but the evidence linking self‐reported SCD features to clinical progression is inconsistent and the predictive validity of SCD presence and symptom burden remains uncertain. More nuanced measures of SCD which differentiate between domains of cognitive decline are needed. This study examined SCD across the domains of Memory, Language and Executive function to identify a pattern of decline associated with well‐established risk factors for AD: family history of AD, female gender, and older age.MethodCommunity‐dwelling participants aged >50 years (M age=64, n=483) were recruited via the crowdsourcing website Amazon Mechanical Turk and completed a survey including demographic questions and the Subjective Cognitive Decline Questionnaire (SCD‐Q MyCog). Risk factors were binary (family history yes/no, female/male, age <70/=>70). Multivariate analysis of variance (MANOVA) was then performed for each risk factor grouping, with the three domains of SCD serving as dependent variables. Follow‐up discriminant analysis was performed on significant relationshipsResultThe sample included 27% of participants with a positive family history, 66.5% female, and 14.5% aged >70 years. Those with a positive family history differed on a combination of SCD domain scores from those without family history, Pillai’s trace=‐.0.023, p=.011 (Memory M=2.6 vs. 1.8, Language M=2.0 vs. 1.4, Executive Function M=1.4 vs. 1.1). No other group differences reached statistical significance. Discriminant function coefficients showed that the memory domain was the strongest contributor (0.984), followed by language (0.849), and finally executive function (0.583).ConclusionA positive family history is a reliable predictor of future AD. We found that those with a positive family history reported a greater amount of subjectively experienced memory and language decline. Memory and language concerns may be helpful in assessing risk of AD in those endorsing SCD.
Plasma glial fibrillary acidic protein is an early and specific marker of amyloid‐β pathology in Alzheimer’s disease
Authors: Pereira Joana B. , Janelidze Shorena , Smith Ruben , Mattsson‐Carlgren Niklas , Palmqvist Sebastian , Zetterberg Henrik , Stomrud Erik , Ashton Nicholas J. , Blennow Kaj , Hansson Oskar 
Published: December 2021

AbstractBackgroundGlial fibrillary acidic protein (GFAP) is a marker of astrogliosis, which is often observed surrounding amyloid‐β (Aβ) plaques in the brains of patients with Alzheimer’s disease (AD). GFAP can be measured both in plasma and cerebrospinal fluid (CSF). The aim of this study was to assess whether plasma and CSF GFAP are independently related to Aβ or tau burden in cognitively unimpaired (CU) and cognitively impaired (CI) individuals.MethodWe measured plasma GFAP and CSF GFAP using the Single molecule array (Simoa) and NeuroToolKit robust prototype assays (Roche Diagnostics) in a sample of 217 CU individuals without Aβ pathology, 71 CU individuals with Aβ pathology, as well as 78 CI subjects with Aβ pathology from the Swedish BioFINDER‐2 cohort. Aβ pathology was defined using CSF Aβ42/40 with a cutoff of < 0.752 determined using mixture modeling. All subjects underwent Aβ (18F‐flutemetamol) and tau (18F‐RO948) positron emission tomography (PET). Differences between groups in GFAP markers were assessed using an analysis of covariance, adjusting for age and sex. Linear regression analyses were performed within each group to assess the relationship between GFAP markers with neocortical Aβ‐PET and temporal tau‐PET.ResultPlasma GFAP was significantly elevated in all Aβ‐positive groups compared to subjects without Aβ pathology (p<0.01). In addition, this marker was associated with higher Aβ‐PET burden in CU individuals (p<0.001), even in the subgroup with normal CSF Aβ42/40 values (p=0.022). Plasma GFAP was also associated with Aβ‐PET in the CI group (p<0.001). All of these associations remained significant after controlling for tau‐PET burden. Further, plasma GFAP could predict Aβ‐PET outcome in the CU and CI groups with an area under the curve of 71%. In contrast, although correlations were also observed between tau‐PET and GFAP, these were no longer significant after controlling for Aβ‐PET. CSF GFAP did not show any differences between groups and correlated with Aβ‐PET only in CI individuals (p=0.005).ConclusionThese findings suggest that plasma GFAP is an early and specific marker associated with brain Aβ but not tau aggregation, even in cognitively normal individuals with normal CSF Aβ42/40.
Toward higher‐sensitivity, shorter‐interval MRI measures of atrophy in neurodegenerative dementias
Authors: Brickhouse Michael , Hanford Lindsay , Carvalho Nicole , Eldaief Mark C. , Mair Ross , Nielsen Jared , Touroutoglou Alexandra , Buckner Randy , Dickerson Brad C. 
Published: December 2021

AbstractBackgroundConventional single acquisition T1w structural MRI can detect significant change in brain structure given ample latency between scans; most contemporary studies of neurodegenerative dementias collect MRI scans at one‐year intervals and calculate annualized rates of atrophy. MRI methods to detect atrophy over shorter (3‐ or 6‐month) intervals would be extremely valuable for basic human neuroscience research about neurodegenerative disease mechanisms as well as for translation into clinical trials. Measurement of change over short intervals would allow neurodegeneration to be monitored in smaller, early‐phase therapeutic trials—potentially even as a marker of target engagement in trials of disease‐modifying interventions.MethodOur pilot cohort consisted of 5 patients: 4 with primary progressive aphasia (2 semantic variant likely due to FTLD, 2 logopenic variant likely due to AD), 1 with posterior cortical atrophy likely due to AD. We collected 32 accelerated 1mm T1w scans in four 30‐minute blocks across two days for each of 3 timepoints (baseline, 3 months, 6 months). We used the FreeSurfer longitudinal processing stream to make robust estimates of the cortex and subcortical structures for each T1w volume. For each timepoint, cortical thickness and volume and subcortical volume estimates were derived from all 32 reconstructed scans. Rates of change were calculated from ROI measures. In addition, a cortical atrophy map was calculated for each subject at each timepoint in comparison with a group of age‐matched controls (N=32).ResultEach of the patients exhibits a typical pattern of atrophy for their clinical syndrome. Cortical atrophy maps are highly reliable between timepoints, and for each subject show visibly apparent but small changes in the magnitude and spread of atrophy. ROI measures demonstrate a slight but observable decrease in the size of many brain structures, even across a 3‐month interval. Cortical thickness changes in regions implicated in the patient’s individual clinical syndrome show the greatest magnitude of change over time—detectable in each individual at 3‐month intervals.ConclusionThis novel approach to MRI acquisition and analysis can sensitively measure neurodegeneration in individuals over shorter intervals of time, which could lead to substantial changes in methods for measuring disease mechanisms and in clinical trial design.
COVID‐19 and cognitive impairment in the elderly: A literature review
Authors: Veerapaneni Seshagiri , Raji Mukaila 
Published: December 2021

AbstractBackgroundCOVID‐19 was declared a pandemic by the World Health Organization on the 11th of March 2020, and it represents an unprecedented immediate and persistent threat to our health care systems. Emerging data reveals neurological symptoms and subclinical cognitive dysfunction and the development of dementia or worsening of it coming to light in the elderly.MethodAn exhaustive search of scientific publications, which included original articles and reports was conducted using the online search databases like Pub Med, with search terms used being neurologic manifestations of COVID‐19, neurological complications of novel coronavirus 2019, with relevant articles analyzed for a possible neurological syndrome related to COVID‐19. Based on specific selection criteria the relationship between COVID‐19 and the nervous system was established and a brief narrative literature review was done.ResultThere has been convincing evidence that SARS‐CoV‐2, the etiologic agent of COVID‐19 can affect the nervous system with consequent damage and neurologic alterations with causation of cognitive decline and worsening of dementia in the elderly survivors.ConclusionBased on evidence gathered from scientific literature, this review raises a possibility of nervous system involvement in COVID‐19 with progression to dementia or worsening of existing Dementia especially in the elderly patients. Longitudinal neurological assessments of patients after recovery will be crucial in understanding the natural History of COVID‐19 in the CNS and monitoring for potential neurologic sequalae and long‐term effects on causation and worsening of dementia. The literature review also states the need to start investigating the mechanistic link between Alzheimer's disease and COVID‐19 for further follow up.
Clock‐drawing center estimation varies with age and Alzheimer's disease
Authors: Chapin Benjamin Albert , Formanski Erin , Amini Shawna , Davoudi Anis , Emrani Sheina , Matusz Emily , Wasserman Victor , Price Catherine C. , Libon David J , Heilman Kenneth 
Published: December 2021

AbstractBackgroundHealthy, young adults deviate leftward when bisecting horizontal lines and upward when bisecting vertical lines, a phenomenon termed “pseudoneglect”. With aging, there is a reduction in this leftward bias. Alzheimer’s disease (AD) can be associated with neglect. Our research assessed directional bias in healthy controls, patients with amnestic mild cognitive impairment (aMCI), and AD with the digital Clock Drawing Test (dCDT) command test condition.MethodThe sample included 68 cognitively normal older adults (M= 72.08, SD= 5.1), 16 younger healthy adults (M= 31.34, SD= 5.83), 13 patients with aMCI (M= 72.56, SD= 6.00), and 24 patients with AD (M= 80.34, SD= 5.97). dCDT protocols were selected for correct number placement within 30 degrees of ideal and hands directed toward the correct digits. The estimated center of the clock face was determined by the point where clock hands converged. Horizontal and vertical deviations of this estimated center from the actual center in each group were normalized as percentages of the clock face diameter.ResultHorizontal deviation: Younger adults deviated leftward(M= 3.55%, SD = 2.82%) and differed from older controls (p= 0.003) who were near center with leftward deviation (0.31%, SD 2.58%). AD patients deviated leftward (M= 3.77%, SD = 4.58%) relative to older controls (p= 0.008). aMCI patients also deviated leftward (M= 2.18%, SD=2.36%) and differed from older controls (p= 0.047).Vertical deviation: Every group deviated upward relative to center (M= 1.82%, SD= 5.09%; p< 0.001).ConclusionOn average, clock center estimation deviates upward similarly across age and AD related neurodegeneration. Leftward “pseudoneglect” was present in younger clocks and decreased with age. AD and aMCI were associated with greater leftward deviation compared to healthy older adults. Leftward deviation on the dCDT may be a useful marker predicting cognitive impairment in otherwise “normal” clocks.
PET imaging biomarkers: What is the outlook for their role in research, trials, and practice?
Authors: Landau Susan M. 
Published: December 2021

AbstractBackgroundPositron emission tomography (PET) imaging is an increasingly widespread tool for the identification of Alzheimer’s disease (AD) pathophysiology. PET biomarkers of Aβ and tau pathology, together with fluid biomarkers and ex vivo pathology validation, have enabled detection of early regional changes and identification of individuals who are unimpaired but on the AD pathway. This presentation will address the changing and complementary role of PET biomarkers in relation to fluid biomarkers in AD clinical trials, research, and practice.MethodRecent PET imaging work from natural history studies targeting Aβ and tau pathology will be reviewed, with an emphasis on early detection of dynamic regional changes in unimpaired individuals in relation to fluid biomarkers and cognition. Relationships between Aβ and tau PET measurements to other biomarkers and pathology will be discussed, as well as the status of emerging PET markers of inflammation and synaptic integrity.ResultA key unique feature of PET imaging is that it offers a regionally‐specific view of fibrillar Aβ and paired helical filament (PHF) tau pathology in vivo. Initial Aβ and tau changes are detectable over a decade before the onset of clinically‐relevant cognitive symptoms. There is a predictable time course of Aβ and tau change over the course of disease, and regional tau accumulation predicts local neurodegenerative changes. In symptomatic individuals, inferolateral temporal tau accumulation is sensitive to AD and useful for differential diagnosis. However, tau accumulation is also highly variable even among symptomatic Aβ+ individuals, likely due to co‐pathology and the influence of poorly understood factors such as age, sex, genetics, and cardiovascular risk. There are a number of technical and cost considerations for successful implementation of PET relative to other biomarkers in research, trials, and clinical practice.ConclusionEarly, regionally‐specific Aβ and tau PET measurements predict downstream neurodegeneration and cognitive decline. Such early changes represent an opportunity for therapeutic intervention, but identification of individuals who are unimpaired but at risk remains challenging. Additional longitudinal research and development of PET biomarkers for other disease targets will address open questions about how AD develops.