bluuebunny/crossref_metadata_2025_split huggingface dataset:
CenTauRz: A standardized quantification of tau PET scans
Authors: Dore Vincent , Bullich Santiago , Bohorquez Sandra Sanabria , Leuzy Antoine , Shimada Hitoshi , Rowe Christopher C. , Bourgeat Pierrick , Lopresti Brian J. , Huang Kun , Krishnadas Natasha , Fripp Jurgen , Takado Yuhei , Stephens Andrew W. , Weimer Robby , Higuchi Makoto , Hansson Oskar , Villemagne Victor L 
Published: June 2023

AbstractBackgroundOver the past decade, several PET tracers were developed to visualise and quantify tau pathology in vivo. However, all these tracers have distinct off‐target binding, different dynamic ranges and likely different levels of non‐specific binding resulting in large variability in semiquantification. We propose to standardise the sampling and the quantification across all available tau tracers.Method549 participants underwent tau scans with either 18F‐FTP (Cognitively Unimpaired (CU) = 54/AD = 14), 18F‐MK6240 (CU = 186/AD = 89), 18F‐PI2620 (CU = 17/AD = 21), 18F‐PM‐PBB3 (CU = 30/AD = 28), 18F‐GTP1 (CU = 7/AD = 38) or 18F‐RO948 (CU = 35/AD = 30). All CU individuals were Aβ‐ and all AD were Aβ+. The tau scans were spatially normalized using CapAIBL and the cerebellar cortex was used as reference region. We constructed a “universal” tau mask from the intersection of all the specific tau tracer masks, after subtracting AD from CU. All tau PET studies were sampled with a Mesial Temporal (MTL) and a Meta Temporal (MetaT) composites constrained by the universal mask. For each tracer and in composite, the mean and standard deviation of the Aβ‐ CU SUVR for each tau tracer were used to generate z‐scores (CenTauRz).ResultUsing a threshold of 2 CenTauRz in the MetaT regions, all tracers highly discriminated Aβ+ AD from Aβ‐ CU (ACC = [0.94‐1], sens = [0.84‐1], spec = [0.96‐1]) with mean CenTauRz for the different AD cohorts ranging from 8 to 14. Lower accuracy was observed in the MTL (ACC = [0.78‐1]) due to lower sensitivity in some cohorts [0.65‐1] however, the specificity was similar to that in the MetaT composite (spec = [0.94,1]).ConclusionAll tracers exhibited comparably high discriminative power to separate Aβ+ AD from Aβ‐ CU, where AD Aβ+ displayed a consistent range of CenTauRz across tracers. However, there were some differences between cohorts. For example, different PET scanners, with different sensitivities were used. For some cohorts, scans were selected as extreme representative cases, while for others the scans were more representative of clinical settings, with AD patients at early stages (with low or negative tau scans) or with suspected hippocampal sparing subtype that likely explains the lower accuracy in the MTL for some cohorts. Further studies with larger cohorts to validate the universal mask and CenTauRz scale are ongoing.
Elevated CSF GAP43 is driven by tau aggregation rather than β‐amyloid and neurodegeneration in Alzheimer’s disease
Authors: Lan Guoyu , Cai Yue , Li Anqi , Liu Zhen , Guo Tengfei 
Published: June 2023

AbstractBackgroundCerebrospinal fluid (CSF) pre‐synaptic protein growth‐associated protein 43 (GAP43) appears to be closely linked to neurodegeneration and cognitive decline in Alzheimer’s disease (AD). However, it is not well characterized about the associations of CSF GAP43 with β‐amyloid (Aβ), tau, neurodegeneration and cognitive decline.MethodWe identified 790 Alzheimer’s Disease Neuroimaging Initiative participants with concurrent CSF GAP43, Aβ PET, CSF p‐Tau181, residual hippocampal volume (rHCV), 18F‐fluorodeoxyglucose (FDG) PET and cognitive assessments within one year. Among of them, 340 individuals had longitudinal CSF GAP43 measurements. We compared baseline and longitudinal changes of CSF GAP43 among different biological stages defined by Aβ PET (A), CSF p‐Tau181 (T) and rHCV (N) in addition to their associations with Aβ PET, CSF p‐Tau181, rHCV, FDG PET and cognition cross‐sectionally and longitudinally, controlling for age, sex, APOE‐ε4 status and diagnosis.ResultAmong different A/T and A/T/N profiles, we found all CSF p‐Tau181‐positive individuals had significant higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases regardless of Aβ deposition and hippocampal atrophy (Figure 1). Furthermore, increased CSF p‐Tau181 rather than Aβ PET was related to higher baseline CSF GAP43 and faster rates of CSF GAP43 increases regardless of A/T profiles (Figure 2). In the subgroups of individuals with longitudinal MRI, FDG PET and cognition data, we found that higher CSF GAP43 concentrations (n = 377) and faster rates of GAP43 increases (n = 240) were associated with faster hippocampal atrophy, hypometabolism and cognitive decline (Figure 3).ConclusionThese findings imply that tau aggregation rather than Aβ pathology is driving pre‐synaptic loss measured by CSF GAP43, which subsequently contributes to hippocampal atrophy and hypometabolism, resulting in cognitive decline in AD. Altogether, CSF GAP43 may be considered for an extra biomarker beyond A/T/N biomarkers, which can provide new insights into underlying AD pathogenesis prior to neurodegeneration.
Alteration of metabolic profile during the progression of Alzheimer’s disease
Authors: Yu Wuhan , Li Xuebing , Yu Weihua , Lü Yang 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that threatens the population health of older adults. However, the mechanisms of how altered metabolism involves AD pathology are poorly understood. This study intends to provide novel insights into the role of metabolic alteration in the pathology and identify potential metabolic biomarkers for AD diagnosisMethodThe Gas chromatography‐mass spectrometry (GC‐MS) was used to measure the concentrations of serum metabolites in a cohort of subjects with AD (n = 88) and cognitively normal control (CN) (n = 85). The patients were classified as very mild (n = 25), mild (n = 27), moderate (n = 25), and severe (n = 11). Serum metabolic profiles were analyzed by multivariate (principal component analysis) and univariate approaches (t‐tests, false discovery, receiver operating characteristic curves, and correlation analysis). The artificial neural network model (ANN) was applied to identify potential biomarkers of AD. Biofunctional enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes.ResultThe results revealed considerable separation between the AD and CN patients. Edetic acid, (S)‐3,4‐Dihydroxybutyric acid, and arachidonic acid were identified as potential AD diagnostic biomarkers using an ANN model. And the classification model could predict the risk for AD with high accuracy (AUC = 0.93). The most significant changes in the metabolite’s composition occur during the very mild to the mild stage. The metabolic enrichment analysis revealed that carbohydrate metabolism deficiency and disturbance of amino acids, fatty acids, and lipids metabolism are involved in AD progression. Especially, pathway analysis highlighted that l−glutamate participated in four crucial nervous system pathways (including GABAergic synapse, glutamatergic synapse, retrograde endocannabinoid signaling and synaptic vesicle cycle).ConclusionSerum metabolomic analysis demonstrated that the metabolic alterations had already arisen at the very mild stages of dementia. Disrupt energy metabolism may be the core of the vicious cycle in AD, resulting in a wide range of metabolic disorders, including abnormal glucose metabolism, TCA cycle impairments, amino acids, fatty acids, and lipids dysregulation. Furthermore, a metabolic diagnostic model of AD was constructed using ANN, which could robustly differentiate AD patients from CN. Our study identified new markers for AD diagnosis and highlighted the roles of metabolic changes on the progression of AD.
Locus Coeruleus hypopigmentation in frontotemporal lobar degeneration and its relation to cerebrovascular injury biomarkers
Authors: Taheri Saeid 
Published: June 2023

AbstractBackgroundIncreasing evidence suggests that degeneration of Locus Coeruleus (LC) neurons is a common feature of various neurodegenerative diseases. Including patients neuropathologically diagnosed with frontotemporal lobar degeneration (FTLD). Based on the histopathological patterns FTLD has been categorized into three distinct subtypes; FTLD with tau immunoreactivity inclusion (FTLD‐tau), FTLD with TDP‐43 (transactive response DNA‐binding protein 43 kDa) immunoreactivity inclusion (FTLD‐TDP), and FTLD with other than tau and TDP‐43 immunoreactivity inclusion (FTLD‐Others). However, the significance of LC degeneration as a marker of the FTLD subtypes has not been fully explored. The purpose of this study was to investigate if the graded LC hypopigmentation can be used as a biomarker to separate distinct subtypes of FTLD.MethodThe sample included 63 participants from the National Alzheimer’s Coordinating Center’s (NACC) data sets who had ante mortem neuropathological and CSF data. LC pigmentation was graded as 0 = none, 1 = mild, 2 = moderate, and 3 = severe. The relationship between LC gross anatomy (hypopigmentation) and CSF A‐beta and Tau levels was explored. Also, the relationship between LC hypopigmentation and FTLD type was investigated. Moreover, markers of cerebrovascular diseases, including infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy, were investigated for their correlation with LC hypopigmentation.ResultThe hypopigmentation of LC is highly correlated with FTLD‐tau, then with a lower degree with FTLD‐TDP and less correlated with FTLD‐Other. Both LC and Substantia Nigra damage was correlated with CSF tau. We did not find statistically significant correlations between FTLD and cerebrovascular disease markers.ConclusionAnte mortem LC hypopigmentation could be used as a biomarker to differentiate underlying FTLD‐tauopathies from clinically similar FTLD‐TDP proteinopathies.
Lifestyle and pharmacological interventions in South America: Potential barriers for recruitment, implementation, and effectiveness
Authors: de Oliveira Fabricio Ferreira , Smith Marilia Arruda Cardoso , Naffah‐Mazzacoratti Maria da Graça , Bertolucci Paulo Henrique Ferreira 
Published: June 2023

AbstractBackgroundThe study of vascular cognitive impairment and dementia (VCID) risk factors must be reproduced in every community so that disparities may be addressed. In South America, diverse levels of education, mixed ethnicity, genetic and cultural heterogeneity, and the burden of cerebrovascular risk are important features to be investigated for proper interventions.MethodsObservational and interventional VCID studies from South America will be discussed so that issues concerning potential barriers for participant recruitment and research effectiveness may be addressed.ResultsFew South American institutions have studied risk factors for VCID. Older people suffer the effects of restrictions to female education that occurred a century ago. Cross‐sectional studies demonstrated that APOE‐ε4 carrier status predisposes to physical inactivity and has smaller effects over dementia onset than in studies from the Northern Hemisphere, possibly due to ethnical disparities, while the burden of combined cerebrovascular risk factors (and smoking in particular) in this regard is high. Foreigners living in Brazil had later dementia onset, unexplained by common genetic variants. While prevalent in almost half of the older population, and associated with earlier dementia onset particularly in women, depression could be a risk factor or a prodromal symptom. Late life prospective studies verified that cerebrovascular risk factors such as arterial hypertension, hypercholesterolemia and a higher coronary heart disease risk, or increased creatinine clearance for women only, may be neuroprotective against cognitive and functional decline, probably due to enhanced cerebral perfusion. Lifetime sanitary conditions and increasing late life body mass index may protect against frailty, while education is neuroprotective for women and APOE‐ε4 carriers (though associated with faster cognitive decline in some cohorts). Longitudinal pharmacogenetic studies demonstrated that potential benefits of cerebrovascular metabolism modulators such as angiotensin‐converting enzyme inhibitors and lipophilic statins depend upon epistatic interactions among specific genetic variants. Caregiver awareness of the need to control cerebrovascular risk is beneficial for patients.ConclusionsGenomic effects of cognitive reserve, cerebral perfusion, and hormonal changes interact on mechanisms of neurodegeneration. Adherence to lifestyle and pharmacological interventions in South America is highly dependent upon proper funding, public support, harmonization efforts, institutional expertise and leadership, and caregiver education. (Supported by FAPESP grant #2015/10109‐5)
Amyloid‐β and tau imaging in chronic traumatic brain injury
Authors: Hicks Amelia J , Ponsford Jennie L , Spitz Gershon , Dore Vincent , Krishnadas Natasha , Roberts Caroline , Rowe Christopher C. 
Published: June 2023

AbstractBackgroundAmyloid‐β and tau are the pathological hallmarks of Alzheimer’s disease. There is evidence of elevated amyloid‐β and tau immediately following moderate to severe traumatic brain injury (TBI). This suggests TBI may initiate pathological processes that lead to Alzheimer’s disease. It is not clear whether amyloid‐β and tau remain elevated in the chronic post‐injury period. To address this issue, we assessed amyloid‐β and tau burden in long‐term TBI survivors (≥ 10 years post injury) and healthy controls using PET imaging.MethodUsing a cross‐sectional design, we recruited individuals following a single moderate to severe TBI at least 10 years previously from an inpatient rehabilitation program. A demographically similar healthy control group was recruited from the community. PET data were acquired using 18F‐NAV4694 (amyloid‐β) and 18F‐MK6240 (tau) tracers. PET scans were classified as positive or negative using visual assessment. Amyloid‐β deposition was quantified using the Centiloid scale. Tau deposition was quantified using the standardized uptake value ratio (SUVR) in four key composite regions of interest (ROI). We examined PET data in relation to time since injury and age at injury. PET data were analysed in a series of regression analyses controlling for age and sex.ResultThe sample comprised 87 individuals with TBI (71.3% male; M = 57.53 years, SD = 11.53) and 59 controls (59% male; M = 60.34 years, SD = 11.97). Our results showed that individuals with TBI were not more likely than controls to have a positive amyloid‐β or tau scan based on visual assessment. Individuals with TBI did not have significantly higher 18F‐NAV4694 Centiloid values or 18F‐MK6240 tau SUVRs in any ROI. No associations were identified for amyloid‐β or tau burden with time since injury or age at injury.ConclusionA single moderate to severe TBI was not associated with higher burden of amyloid‐β or tau pathologies in the chronic period following injury relative to healthy controls. Amyloid‐β and tau burden did not show a significant increase with years since injury. Likewise, we found no evidence that amyloid‐β and tau burden were greater for those who were older at the time of their injury.
Antibiotics: Treatment for Alzheimer’s diseases
Authors: Chandolia Priyanka , Agrawal Mohit 
Published: June 2023

AbstractBackgroundAlzheimer’s is a specific neurodegenerative disease that accounts for 60‐80% of overall dementia cases. This is the most common type of dementia arises from the deposition of beta‐amyloid plaques and neurofibrillary tangles, in the hippocampal region and the entorhinal cortex tends to cause neuronal death. Currently, available drugs can provide symptomatic relief in patients associated with AD. Recently, it has been reported that antibiotics can exert a variety of biological actions that are independent of their anti‐microbial activity, including anti‐inflammatory, anti‐excitotoxic, anti‐apoptotic, and antioxidant activities.MethodA number of antibiotics are used in the preclinical and clinical studies of Alzheimer’s disease. Among all antibiotics β‐lactam antibiotics and tetracyclines are well reported to reach CSF concentration, targeting Alzheimer’s disease. These two classes well suggest their neuroprotective role in various neurodegenerative disorders. β‐lactam antibiotics (penicillins and cephalosporins) has been demonstrated as protectors against near excitotoxicity. Ceftriaxone posses good BBB penetration thus used for various neurodegenerative disorders and shows the improvement in learning and cognitive functions when studied in transgenic models of AD.ResultThe combination of two well known pharmacokinetically safer antibiotics to synergize their individual effects and develop a newer approach concerning the treatment of AD.ConclusionFurthermore, there is a need to develop the neuroprotective mechanisms in the treatment of Alzheimer’s disease.
Preliminary data on micro errors as a sensitive measure of everyday functioning in older adults
Authors: Holmqvist Sophia L. , Mckniff Moira , Pinsky Emma , Mis Rachel , Simone Stephanie M. , Tassoni Molly , Hackett Katherine , Lloyd Nicole , Giovannetti Tania 
Published: June 2023

AbstractBackgroundMild difficulties with daily tasks are associated with cognitive abilities and future cognitive decline but are difficult to measure objectively. Performance‐based tests with high task demands (e.g., multitasking, prospective memory) have been fruitful in capturing mild functional difficulties, however measuring certain aspects like overt errors or completion time often shows floor effects and thereby fail to discriminate between individuals with subtle functional decline. We propose a different approach that involves coding micro‐error defined as inefficient but not overtly erroneous actions (e.g., mis‐reaching toward the wrong object) during relatively simple, performance‐based tests, such as the Naturalistic Action Test (NAT). We present preliminary findings on the validity of micro‐errors as sensitive measures of cognition in participants with healthy cognition, mild cognitive impairment (MCI), and mild dementia.Method27 older adults (Healthy, MCI, Dementia) completed the NAT, which requires participants to make a breakfast and a lunch using objects presented on a table. Standard cognitive tests (memory, language, etc.) were administered. NAT scores reflecting micro‐errors, total steps accomplished, and completion time were examined across participant groups and included in correlation analyses.ResultWorse performance on the NAT was associated with disease severity (micro errors Mean (SD) ‐ Healthy: M = 3.05 (.79); MCI: M = 8.80 (1.28); Dem: M = 9.33 (4.84); completion time(sec) ‐ Healthy: M = 211.84 (10.70); MCI: M = 352.00 (110.50); Dem: M = 363.00 (36.67); total steps accomplished‐ Healthy: M = 32.79 (0.12); MCI: M = 31.80 (0.73); Dem: M = 30.67 (2.33)). Among those with healthy cognition and MCI, greater micro errors were associated with lower accomplishment scores (r = ‐.422, p = .040) and longer completion times (r = .388, p = .061). Micro‐errors, but not accomplishment scores or completion time, were significantly associated with cognitive tests, who made more micro‐errors obtained a lower overall cognitive composite (r = ‐.434, p = .034) and a lower memory score (r = ‐.438, p = .032).ConclusionSubtle errors and inefficient actions (micro‐errors) during highly familiar everyday tasks are valid indicators of cognitive difficulties in older adults without dementia. Micro‐errors may be more sensitive than time to completion and task accomplishment and may be obtained from 5‐10 minutes of task performance. Micro‐errors have potential to identify risk of decline and as sensitive functional outcomes in clinical trials.
Determinants of cognitive and brain resilience to tau pathology: A longitudinal analysis
Authors: Bocancea Diana I. , Svenningsson Anna L , van Loenhoud Anna C. , Groot Colin , Barkhof Frederik , Strandberg Olof , Smith Ruben , Pontecorvo Michael J. , Rabinovici Gil D. , van der Flier Wiesje M. , Hansson Oskar , Ossenkoppele Rik 
Published: June 2023

AbstractBackgroundMechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease (AD) spectrum are insufficiently understood. Longitudinal data is necessary for revealing which factors contribute to maintaining cognition (cognitive resilience, CR) or preserving brain structure (brain resilience, BR) despite elevated tau, and for clarifying whether these factors provide a baseline advantage and/or moderate rates of brain structural and cognitive change. We therefore investigated whether age, sex, education, APOE‐e4 status, intracranial volume (ICV) and cortical thickness (in CR analysis) moderate the association between baseline tau load and subsequent changes in cognition and cortical thickness.MethodsThe study included 341 amyloid‐β‐positive individuals from a multi‐cohort dataset (BioFINDER‐1/AVID/ADNI/UCSF), diagnosed with MCI or AD dementia at the time of the baseline [18F]flortaucipir tau‐PET scan, who had longitudinal cognitive assessments (CR sample). A subset (n = 133) additionally underwent longitudinal structural MRI (BR sample). We used (separate) linear mixed‐effect models with MMSE as outcome to investigate the association of key baseline variables‐of‐interest (age, sex, APOE‐e4 status, education, ICV and global cortical thickness) with cognitive decline in the presence of tau (covaried for cohort). A three‐way interaction between time, tau and the predictor‐of‐interest was initially assessed. In the absence of a moderation effect, we subsequently assessed models including only the two‐way interaction between each predictor and time. These analyses were repeated with global cortical thinning as an outcome variable.ResultsCharacteristics of the CR sample and BR sub‐sample are described in Table‐1. Models revealed that younger age (βInteraction = ‐0.18, p<0.01), higher education (βInteraction = ‐0.62, p<0.001), larger ICV (βInteraction = ‐8.12, p<0.01) and greater cortical thickness (βInteraction = ‐9.9, p<0.05) were related to higher CR, as these factors moderated the relationship between tau pathology and decline in MMSE (Figure‐1,2). No predictor moderated tau effects on cortical thinning nor explained additional variance (Table‐2).ConclusionThis study indicates that tau pathology affects cognitive decline differently across age, education, ICV and cortical thickness levels. Understanding moderators of prospective cognitive decline and cortical thinning related to tau pathology, as well as their complex interactions, may be relevant for improving prognosis and clinical trial design in AD.