bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seeding human tau knock‐in neurons with human derived pathological tau results in the formation of pathogenic conformations of tau
Authors: Mueller Rebecca L , Kanaan Nicholas M 
Published: December 2022

AbstractBackgroundOne of the pathological hallmarks of Alzheimer’s disease (AD) is the accumulation of pathological tau inclusions. Conformational exposure of an N‐terminal motif in tau known as the phosphatase‐activating domain (PAD) occurs early in AD and other tauopathies and aberrant exposure of this motif disrupts axonal transport. Tau is capable of seeding aggregation in cells; however, the extent to which disease‐associated pathogenic conformations can be effectively seeded remains an area of active investigation. To help address this gap, we seeded aggregation in primary neurons and assessed known pathogenic tau conformations.MethodPrimary hippocampal neurons from human tau knock‐in mice were treated with pathological tau aggregates from human AD‐brain (AD‐tau) according to methods described in Narasimhan and Lee, 2017. The same purification protocol was used with non‐demented human brain tissue (CO) as a control. The AD‐tau and CO samples were characterized by transmission electron microscopy and biochemical assays that measure total tau and pathological modifications, such as phosphorylation (PHF1) and a conformation specific antibody (TNT1) that labels display of PAD. Neurons treated at 5 days in vitro were maintained for up to 28 days post‐treatment. Markers of pathological species of tau (PAD exposed and phospho‐tau) were used to assess the formation of disease‐associated forms of tau and changes in the numbers of neurons (MAP2) and astrocytes (GFAP) were measured.ResultThe AD‐derived material showed morphologies consistent with small pieces of the characteristic paired helical filaments of AD, phosphorylation at the PHF1 site, and the presence of oligomeric tau and PAD‐exposed tau species. We observed a robust dose and time‐dependent increase in TNT1 in AD‐tau‐treated neurons and ongoing studies are evaluating the presence of other pathological tau species. There were no significant effects on cell number in seeded cultures out to 28 days post‐treatment.ConclusionOur results suggest that primary neurons seeded with AD‐tau form inclusions consisting of PAD‐exposed tau, but overt degeneration does not occur within 28 days of seeding. The presence of PAD‐exposed tau but lack of cell loss could indicate that more time is needed and/or that the consequences of these tau species are more subtle.
Comparing the longitudinal progression of CSF biomarkers with PET Amyloid biomarkers for Alzheimer’s disease
Authors: Cox Timothy , Bourgeat Pierrick , Dore Vincent , Doecke James D , Fripp Jurgen , Chatterjee Pratishtha , Schindler Elizabeth E. , Benzinger Tammie L.S. , Rowe Christopher , Villemagne Victor L , Weiner Michael W. , Morris John C. , Masters Colin L. 
Published: December 2022

AbstractBackgroundCerebrospinal fluid (CSF) soluble biomarkers are useful at detecting pre‐clinical levels of Alzheimer’s disease (AD) biomarkers of b‐amyloid (Ab) and tau. Disease progression times for participants in longitudinal studies can be estimated for different biomarkers. Utilizing a new technique, this work compared the disease progression times between CSF and PET biomarkers.MethodsFour hundred and ten participants from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) including participants form ACS/OASIS, ADNI and AIBL with three or more data points of longitudinal CSF Ab42 and pTau181 (pTau) and Ab PET were selected. PET results were expressed in Centiloid (CL), (299 cognitively unimpaired, 107 mild cognitively impaired, 4 AD dementia; aged 69±9; 216 females (NAIBL=30, NADNI=252, NOASIS=128). Disease trajectory curves for individual biomarkers and the pTau/Ab42 ratio were created by: 1) Fitting a function to the rates of change of the variable of interest versus its mean value), 2) integrating the fit to obtain longitudinal trajectory curves as a function of disease progression time for each of the variables. The participants’ disease progression time along each curve were estimated. Threshold values for Ab PET and pTau/Ab42 ratios were calculated using a gaussian mixture model. Estimates of age of onset were calculated using the progression times. The participants’ disease progression times for each of the different variables were compared using rank correlations.ResultsRank correlations for the progression times were: r(Ab42, Ab PET) = 0.75, r(pTau, Ab PET)=0.62, and r(pTau/Ab42, Ab PET)=0.83. The estimated ages at which participants’ reach Ab PET and the pTau/Ab42 ratio thresholds are compared in Fig 1, the average age at which were estimated to reach the threshold values were 55 yr for pTau/Ab42 (threshold of 0.021) and 61 yr for Ab PET (threshold of 22 CL).ConclusionsThe high correlation between pTau/Ab42 and Ab PET, indicates that pTau/Ab42 captures the progression of AD pathology better than the individual CSF biomarkers. On average participants’ reach abnormal levels of pTau/Ab42 earlier than Ab PET. Further work is required to understand individual variations in progression times.
Handgrip Strength is Related to Regional Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden
Authors: Meysami Somayeh , Raji Cyrus A. , Popa Emily S. , Ganapathi Aarthi S. , Bookheimer Tess , Slyapich Colby B. , Pierce Kyron P. , Richards Casey J. , Gill Jaya M. , Lampa Melanie G. , Rapozo Molly K. , Hodes John F. , Glatt Ryan M. , Tongson Ynez M. , Wong Claudia L. , Kim Mihae , Porter Verna R. , Kaiser Scott A. , Panos Stella E. , Dye Richelin V. , Miller Karen J. , Bookheimer Susan Y. , Martin Neil A. , Kesari Santosh , Kelly Daniel F. , Siddarth Prabha , Bramen Jennifer E. , Merrill David A. 
Published: December 2022

AbstractBackgroundHandgrip strength is important for performing activities of daily living[1]. In older adults, weaker handgrip strength and asymmetry are associated with poorer cognition. o better understand mechanisms, we sought to quantify the relationship between handgrip strength and regional volumes quantified on brain MR imaging.MethodWe selected 32 participants (mean age=70.8±7.3 [range 57‐89] years, 53.1% female, 90.6% right‐handed, mean body mass index BMI=23.9±4.1) from the Pacific Brain Health Center at Providence St. John’s Health Center, with Alzheimer dementia biomarker evidence of amyloidosis[2]. Mean Montreal Cognitive Assessment score for all participants was 21.3±3.8 points. Handgrip strength on dominant and non‐dominant hands was measured using the NIH Motor Toolbox[3] as part of a cognitive fitness assessment using a hydraulic hand dynamometer. The resulting scores included handgrip strength and percentile comparisons to normative data. Asymmetry scores were calculated. Regional brain volumes, including lobar structures and the hippocampus, were measured from T1‐weighted MR images using Neuroreader[4]. Partial correlations (rp), adjusting for age, sex, BMI and total intracranial volume modeled handgrip strength, asymmetry, and brain volumes with a significance threshold of p<0.05.ResultIn the dominant hand, higher handgrip strength scores and percentiles were associated with larger volumes in the left frontal lobe (rp=+0.51, p=0.007; rp =+0.47, p=0.01) and right parietal lobe (rp=+0.40, p=0.03; rp=+0.39, p=0.04). In the non‐dominant hand, higher handgrip strength score and percentiles were associated with smaller total cerebral spinal fluid (CSF) volume (rp =‐0.55, p=0.004; rp =‐0.52, p =0.006) and larger volumes within the left hippocampus (rp=+0.45, p=0.01; rp=+.43, p=0.02), right hippocampus (rp=+0.47, p=0.01; rp=+0.43, p=0.02), and right parietal lobe (rp=+0.39, p=0.04; rp=+0.44, p=0.02). Handgrip strength asymmetry was inversely related to right hippocampal volume (rp=‐0.58, p=0.002) and positively correlated to CSF volume (rp=+0.39, p=0.04).ConclusionGreater handgrip strength was related to larger regional brain volumes. A higher number of brain regions were related to the non‐dominant hand. Asymmetry was associated with lower right hippocampal volume and higher CSF volume. Interventions focused on improving handgrip strength may seek to include quantified brain volumes on MR imaging as endpoints.
A longitudinal analysis of depressive symptoms in relation to repeated measurements of regional tau
Authors: Munro Catherine E , Buckley Rachel F. , Vannini Patrizia , Hanseeuw Bernard , Quiroz Yakeel T. , Farrell Michelle E. , Rentz Dorene M. , Blacker Deborah , Sperling Reisa A. , Johnson Keith A. , Amariglio Rebecca E. , Marshall Gad A , Gatchel Jennifer R 
Published: December 2022

AbstractBackgroundDepressive symptoms are commonly observed early in Alzheimer’s disease (AD), but their temporal association with progression along the AD continuum is less clear. We sought to determine if initial measurements of regional tau were predictive of increasing depressive symptoms, and if changes in depressive symptoms predicted later tau levels. We examined these relationships in a region of early tau accumulation (i.e., entorhinal cortex (EC)), and in regions of later neocortical tau spread commonly involved in affective regulation (amygdala and medial and lateral orbitofrontal cortex (mOFC, lOFC)).MethodParticipants (n=257; mean age=70.7; 61% female) came from the Harvard Aging Brain Study, a longitudinal observational cohort of cognitively unimpaired adults with no/low depression at baseline (mean years of follow‐up=7.2). All participants completed the self‐reported 30‐item Geriatric Depression Scale (GDS) annually and tau PET imaging (Flortaucipir‐FTP) every 3 years. On average, initial tau PET scans occurred 2.3 years after enrollment and the latest available scan occurred 5.1 years after enrollment. Separate linear mixed effects models investigated relationships between longitudinal GDS and cross‐sectional regional tau (FTP PET SUVr), at initial scan and at the latest scan available, in the following regions of interest: EC, amygdala, mOFC, and lOFC. Covariates included age, sex, and education.ResultHigher initial FTP levels were associated with significant increases in GDS score over time in temporal cortex (amygdala: b=0.29,p=0.0002; EC: b=0.21,p=0.0006) and mOFC (b=0.30,p=0.004), with marginal significance in lOFC (b=0.21,p=0.07). However, the reverse temporal sequence was only observed between GDS scores over all time points and later measurement of amygdala FTP, such that increasing depressive symptoms over time preceded higher final amygdala tau levels (b=0.15,p=0.02).ConclusionHigher tau in EC, amygdala and OFC regions predicted increasing depressive symptoms over time in older adults. Only for the amygdala did we also observe the converse relationship: increasing depressive symptoms predicting higher final tau. These results suggest early tau proliferation in affective regions is associated with increased depressive symptoms, though the question of causality is still unclear. Further work is needed to dissect possible temporal relationships across whole brain voxels to better understand depressive symptoms in AD progression.
The effects of age and sex on plasma p‐tau181 concentrations in Alzheimer’s Disease
Authors: Kumar Pankaj , Vanbrabant Jeroen , Encarnacion Mary , Mousavi Ali , Hsiung Ging‐Yuek Robin , Stoops Erik , Vanmechelen Eugeen , Frykman Hans 
Published: December 2022

AbstractBackgroundQuantifying levels of phosphorylated tau in plasma is a highly promising and specific marker for Alzheimer’s disease (AD), but limited data are available on the effect of age on plasma p‐tau181 concentrations in specific clinical groups and especially control subjects. Similarly, the effect of sex on concentration of plasma ptau‐181 levels are unclear.MethodA total of 343 samples of EDTA plasma from patients examined at the UBC Hospital Alzheimer Clinic between 2008 – 2018 included.The patients had been referred with complaint of cognitive impairment and were assessed for dementia and they sorted into four diagnostic groups: Non‐Cognitive Impairment (NCI), non‐ AD neurodegenerative diseases, possible AD, and probable AD, according to US National Institute on Aging (NIA) and the Alzheimer’s Association (AA) criteria diagnosis. The concentrations of their plasma p‐tau181 was measured by a homebrew ADX assay on SIMOA HD‐X platform. We analysed the effect of age and sex on the concentrations of plasma p‐tau181 among and within clinically defined groups. We also assessed p‐tau181 levels in a separate group of healthy individuals (n=60).ResultThere was no significant sex difference in p‐tau181 levels across and between the diagnostic categories (p=0.426). We also confirmed there was not any correlation between age and p‐tau181 levels in healthy controls. Moreover, we did not find any correlation between the age and plasma concentrations of p‐tau181 within each diagnostic group separately. Further with two model linear regression, age was not found to be a significant contributor of plasma p‐tau181 variations (F (3, 429) = 109.04, B=.16, t= 1.42, p<0.16).Interestingly, there was a correlation between average of plasma p‐tau181 with age among the spectrum from NCI to AD.ConclusionWe did not detect any sex difference in plasma p‐tau181 levels. Our findings about the age‐effect of plasma p‐tau181 levels especially within and among diagnostic groups might be described by the intricate dynamics, and kinetics of p‐tau181 in brain and plasma and it needs to investigate with larger healthy control population and multicenter clinical studies.
CSF proteomics analysis to investigate the pharmacodynamic response of the S2R modulator CT1812 in Alzheimer’s disease patients from the SPARC clinical trial
Authors: Pandey Kiran , Waybright Lora , Duong Duc M. , Malagise Evi , Blennow Kaj , Zetterberg Henrik , Mecca Adam P , van Dyck Christopher H , Caggiano Anthony O , Seyfried Nicholas T. , Hamby Mary E 
Published: December 2022

AbstractBackgroundCT1812 is an investigational therapeutic that can displace toxic amyloid‐beta oligomers from neuronal receptors and is currently in development for Alzheimer’s disease (AD). SPARC (COG0105; NCT03493282), was a randomized double‐blinded placebo‐controlled clinical trial designed to test the impact of the small molecule sigma‐2 receptor (S2R) modulator CT1812 on safety and synaptic density. Exploratory analyses included discovery proteomics for pharmacodynamic biomarker identification and to understand the impact of CT1812 on CSF proteins detected in mild to moderate AD patients.MethodUnbiased quantification, using tandem‐mass tag mass spectrometry (TMT‐MS), of proteomes from AD patients given the S2R modulator CT1812 or placebo (N=18) was performed on baseline and end of study CSF to test two doses (100 mg, 300 mg) of CT1812 given once daily for 6 months in participants with mild‐moderate AD. Individual CSF proteomes were compared to within‐study pooled AD and non‐demented control CSF reference standards from the Emory ADRC to benchmark protein levels in SPARC participant CSF at baseline and to assess treatment effects, via differential expression analysis (one‐way ANOVA; p<0.05) and pathway analyses.ResultA total of 2,760 CSF proteins were detected across all CSF samples. Strong correlations (r>|0.70|) between TMT‐MS values and clinically validated ELISAs for canonical AD biomarker levels (Tau, NFL) were observed across participants and timepoints, confirming previous findings of TMT‐MS as a quantitative method. Differential expression analyses identified 327 proteins altered (one‐way ANOVA; p<0.05) in CT1812 vs placebo CSF. From a curated list of previously published AD biomarkers representing distinct pathways, a subset of proteins were found to be significantly altered by treatment with CT1812 compared to placebo (p<0.05), and included some proteins known to be genetically linked to AD. Pathway analysis identified statistically significant pathways (p<0.05) altered by CT1812, including that tied to inflammation, amyloid biology, and synaptic function.ConclusionThis study enabled the identification of candidate pharmacodynamic biomarkers that may reflect target/pathway engagement or disease modification, and extends proteomics CSF learnings from previous clinical trials with CT1812. Overall, this data suggest CT1812 may impact key proteins and pathways in AD and provides additional support for CT1812 to be further evaluated as a promising therapy for AD.
Antemortem‐postmortem correlates of 4D‐Flow MRI in cerebral vessels
Authors: Schroeder Brooke E , Rivera Leonardo A , Romero Monica Ospina , Johnson Kevin M , Wieben Oliver , Asthana Sanjay , Johnson Sterling C. , Eisenmenger Laura , Salamat Shahriar , Betthauser Tobey J 
Published: December 2022

AbstractBackgroundCerebrovascular disease (CVD) is associated with increased dementia risk and often co‐occurs with Alzheimer’s disease (AD). Non‐invasive quantitative 4D‐Flow MRI can be used to characterize cerebrovascular hemodynamics and study CVD/AD interactions during life, but has not been validated against postmortem pathological assessment. This study compares antemortem 4D‐Flow metrics with postmortem pathological assessment in cerebral arteries to inform the interpretation of 4D‐Flow MRI.MethodsThree participants from the Wisconsin ADRC underwent antemortem 4D‐Flow and postmortem pathological examination. Subjects had MCI or dementia before death with suspected AD etiology (Table 1). Antemortem 4D‐Flow was acquired on a 3.0T system (GE Healthcare). Vessel cross‐sections from 4D‐Flow angiograms of cerebral arteries were used to estimate blood flow, pulsatility index (PI), and luminal area. Upon death, brain extraction and neuropathological examination were performed according to NIA‐AA guidelines. Sampled cerebral arteries included left anterior (A1) and middle (M1) cerebral, and left internal carotid arteries, basilar artery, and left and right posterior cerebral (P1 and P2) and vertebral arteries. Mason’s trichrome stained sections of the arteries were captured using an Aperio Digital Slide Scanner. QuPath software was used to delineate the intima, media and functional luminal area of the vessels. A pixel classifier measured the area of smooth muscle cells (SMC) and fibrous tissue (Figure 1). The percentage of stenosis (%stenosis) was calculated as the area of atherosclerotic plaque divided by the area encompassed by the elastica. The percentage of media fibrosis (%fibrosis) was calculated as the area of fibrotic tissue divided by the sum of the SMC and fibrotic areas within the media. Spearman correlations were used to compare antemortem and postmortem vascular measures without correction for multiple comparisons.ResultsImaging‐postmortem correlates were highest for PI vs. %fibrosis (ρSpearman=0.42), mean flow vs. %stenosis (ρSpearman=0.40), and comparisons of luminal area (ρSpearman=0.43) (Table 2, Figure 2). Correlations between other imaging and pathology measures were low (|ρSpearman|<0.21).ConclusionThese data provide preliminary evidence that 4D‐Flow metrics correlate with underlying arterial vessel stenosis and fibrosis. Future work is ongoing to investigate antemortem‐postmortem associations in more cases.
Preoperative Cerebrospinal Fluid and Plasma Markers of Inflammation and Neurodegeneration Predict Mortality Eight Years Later in an Observational Cohort Study of Postoperative delirium in an Older Elective Arthroplasty Populatio
Authors: Sweeney Aoife , Passmore Anthony Peter , Beverland David , McGuinness Bernadette , McAuley Daniel F , Mawhinney Tim , O'Brien Seamus , Schott Jonathan M , Heslegrave Amanda , Zetterberg Henrik , Cunningham Emma L 
Published: December 2022

AbstractBackgroundBetween 2012‐2014, an observational cohort study of postoperative delirium (POD) in an elective arthroplasty population recruited 315 individuals aged over 65, without a diagnosis of dementia. We are now conducting a follow‐up study to determine what effect POD has on cognition years later.MethodIn the baseline study, neuropsychological testing was undertaken preoperatively, cerebrospinal fluid (CSF) was sampled at the time of spinal anaesthesia and delirium was assessed daily on days 1‐3 postoperatively. Stored CSF (n = 270) was analysed for markers of inflammation and neurodegeneration. In 2020, all surviving participants were invited to take part in the follow‐up study.ResultThe average age of the cohort at baseline was 74.4 (5.8) years. Eight years later, 84% (n=264) of the observational study participants are still alive. Mortality rates in the intervening years are higher in those who developed POD (14/44, 32%) than those who did not (37/271, 14%), but is not statistically significant (p=0.13). Significant predictors of mortality in all participants included multi‐morbidity (p=0.007), age at surgery (p<0.001), performance on Colour Trails 2, a test of executive function(p<0.001); CSF glial fibrillary acidic protein (GFAP), a marker of inflammation (p=0.01); CSF neurofilament light (NFL), a marker of axonal degeneration (p=0.019); CSF interleukin‐8 (IL‐8), a marker of inflammation (p=0.007) and CSF triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of age‐related neuroinflammation and tau‐related neurodegeneration (p=0.002).ConclusionThe majority of participants in this elective arthroplasty observational cohort are still alive eight years later. Older age at time of surgery, multimorbidity, lower neuropsychological performance and increased preoperative CSF measures of inflammation and neurodegeneration were associated with mortality in adults eight years following elective orthopaedic surgery.