bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co‐Developing Awareness Video Campaign for People Living with Dementia with Lewy Bodies
Authors: Green Kit , Booi Laura 
Published: December 2023

AbstractBackgroundAlthough Dementia with Lewy Bodies (DLB) is the second most common form of neurodegenerative dementia, information about DLB is often scarce and fragmented. Corresponding with this, the lived experience of DLB involves high rates of misinformation, social isolation, loneliness, and stigma. There is a need to develop outputs in which the expertise of those living with DLB, care‐partners and clinicians focused on DLB is shared.MethodsFunded by a UKRI Catalyst Award, and after receiving ethical approval from Leeds Beckett University, this project implemented consulting workshops with key informants including: (i) people living with DLB; (ii) care‐partners of those living with DLB; (iii) Third Sector organizations and; (iv) clinicians focused on supporting those with DLB. The consulting workshops discussed the key issues surrounding DLB, from the perspective of the attendees. The outcome of these workshops highlighted the most salient topics for individuals who have recently come into the DLB community (either as a newly diagnosed person or care‐partner).ResultsFindings from the consulting workshops highlight the importance of peer‐support in DLB, including the topics of: hallucinations, sleep and peer‐support. Clinically, the subjects of early diagnoses, Capgras Syndrome and specific care needs were identified as key topics. Six short films are currently being developed based on the findings from the consulting workshops. The Creative Team, Research Team and lived‐experience experts will co‐develop the script for these videos. Each video will be one minute long in duration. The videos will offer a gentle, general introduction to the topic from an expert (mostly with lived experience), with the aim of removing fear and stigma.ConclusionThese videos will offer guidance for shared experiential learning so that the person living with DLB and their CP will be better educated and equipped to support themselves and each other through the care pathway. The solution offered via the Lewy Video Campaign will contributes to improving access to information in an affordable, personable venue, supporting individuals into becoming integrated into the wider DLB community of both clinical and peer‐support.
Synaptic Marker NPTX2 Predicts Risk of MCI Clinical Symptom Onset
Authors: Pettigrew Corinne , Na Chan‐Hyun , Oh Sungtaek , Soldan Anja , Zhu Yuxin , Moghekar Abhay , Albert Marilyn S. , Worley Paul F 
Published: December 2023

AbstractBackgroundNeuronal pentraxin 2 (NPTX2) is a synaptic protein involved in the homeostatic regulation of cortical network dynamics and synaptic plasticity. Prior cross‐sectional studies suggest that NPTX2 levels decline across the spectrum of Alzheimer’s disease (AD), and that NPTX2 levels can distinguish individuals with normal cognition vs. mild cognitive impairment (MCI) and AD dementia. Less is known about how levels of NPTX2 among individuals with normal cognition relate to future clinical outcomes. To address this, we examined whether baseline levels of NPTX2 predicted time to onset of clinical symptoms of MCI, both alone and in combination with AD biomarkers, among individuals who were cognitively normal at baseline and have undergone 16.3y of follow‐up, on average.MethodCerebrospinal fluid (CSF) was collected at baseline from 269 cognitively normal BIOCARD Study participants (M baseline age = 57.7y), including 77 (29%) who subsequently progressed to MCI or dementia (Table 1). Baseline NPTX2 levels were measured from three highly correlated peptides using quantitative parallel reaction monitoring mass spectrometry. NPTX2 peptide levels were standardized and averaged to create an NPTX2 composite score. Baseline levels of Aβ42/Aβ40, p‐tau181, and t‐tau were measured using Lumipulse automated electrochemiluminescence assays.ResultIn Cox regression models, lower NPTX2 levels were significantly associated with earlier time to MCI clinical symptom onset (HR = 0.76, 95% CI (0.601, 0.962), p = 0.02; Figure 1a). After accounting for CSF AD biomarkers (i.e., Aβ42/Aβ40 and tau), the association between NPTX2 levels and MCI symptom onset appeared stronger (Table 2; Figure 1b). Importantly, NPTX2 did not interact with AD biomarker levels (all p > 0.11) or APOE‐ε4 genetic status (p = 0.71) in relation to MCI symptom onset.ConclusionCSF levels of the synaptic marker NPTX2 predict time to progress to MCI among individuals with normal cognition, suggesting that NPTX2 may be an early prognostic biomarker of synaptic dysfunction. Moreover, this association appears to be additive and independent of AD biomarker levels. Future work is underway to determine if NPTX2 provides resilience to cognitive impairment in the presence of AD pathology, and if there is a differential relationship with markers of amyloid vs. tau.
An Epigenome‐wide association study of psychosis in Alzheimer’s disease dorsolateral prefrontal cortex
Authors: Kouhsar Morteza P , Weymouth Luke Stephen , Creese Byron , Bergh Sverre , Wedatilake Yehani , Torkamani Ali , Smith Adam R. , Selbæk Geir , Sweet Robert , Ballard Clive G , Mill Jonathan , Kofler Julia , Pishva Ehsan , Lunnon Katie 
Published: December 2023

AbstractBackgroundPsychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving aetiology. In this study, we performed an epigenome‐wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of post‐mortem brain samples.MethodBrain samples were obtained from the University of Pittsburgh Alzheimer’s disease Research Centre (PITT‐ADRC). AD pathology was assessed and classified using CERAD neurotic plaque density score, Braak neurofibrillary tangle stages and NIA‐RI criteria. We used the presence or absence of delusions and hallucinations, Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) to categorise our samples into AD with Psychosis (AD+P) and AD without Psychosis (AD‐P) groups. DNA was extracted, bisulfite‐treated and profiled on the Illumina Methylation EPIC Array and genotyping was carried out on the Illumina Global Screening Array (GSA).ResultAfter data quality control, 153 samples (40 AD‐P, 113 AD+P) remained for further analysis. The normalized beta values and the effect estimate values were used to extract Differentially Methylated positions (DMP) and differentially methylated regions (DMRs), respectively. To identify methylation quantitative trait loci (mQTLs) in both cis and trans, SNP‐CpG pairs with a p‐value threshold of <1e‐5 were calculated. We performed a colocalization analysis for the most significant DMPs and mQTLs, using publicly available summary statistics of relevant genome‐wide association studies (GWAS).ConclusionThe development of effective therapies for AD+P is an urgent priority and requires a better understanding of the molecular mechanisms underlying this syndrome. To address this, we have collated a well‐powered study cohort to interrogate the epigenetic basis of AD+P in the brain and have identified several loci of interest that require further study.
Tau‐PET signal in Alzheimer’s disease is related to immune activation and synaptic signaling measured with CSF proteomics
Authors: Rikken Roos M. , Vromen Eleonora M. , Coomans Emma M. , Visser Denise , Barkhof Frederik , Boellaard Ronald , Golla Sandeep S.V. , van Berckel Bart N.M. , Ossenkoppele Rik , den Braber Anouk , Vijverberg Everard G.B. , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Teunissen Charlotte E. , Visser Pieter Jelle , van de Giessen Elsmarieke , Tijms Betty M. 
Published: December 2023

AbstractBackgroundTau tangles are one of the pathological hallmarks of Alzheimer’s disease (AD) and can be quantified using PET. It remains unclear which molecular processes are related to tau aggregation. Protein levels in CSF can be used to study such underlying processes. This study aims to identify biological processes related to tau‐PET using unbiased CSF proteomics in participants along the AD continuum.MethodWe included 89 participants with CSF proteomic and [18F]flortaucipir (tau)‐PET data available from the Amsterdam Dementia Cohort and the EMIF‐preclin AD study (N = 68 with abnormal CSF Aβ42 [64.7% cognitively impaired, 67.6% tau‐PET visual read positive] and N = 21 controls [normal cognition and normal CSF AD biomarkers]) (table 1). [18F]flortaucipir BPND was quantified in the temporal meta‐ROI (Braak I, Braak III, Braak IV). CSF proteomics was measured using untargeted LC‐MS/MS based on TMT labelling. We included proteins available in the whole sample (n = 1421 proteins). Protein concentrations were normalized to the control group. We determined the relationship between tau‐PET BPND (outcome) with protein levels (determinant) using linear regressions with sex and age as covariates, stratified for group. GO database was used for biological pathway enrichment analyses within the AD group for proteins thresholded at p<0.05 for positive and negative associations separately.ResultHigher CSF tau levels were associated with higher tau‐PET BPND (β = 0.092, p = 0.002). In total, 458 proteins were associated with tau‐PET BPND in AD. A higher tau‐PET BPND was related to higher levels of 140 proteins and lower levels of 318 proteins. Proteins that showed higher levels with increasing tau‐PET BPND were mainly involved in immune system processes (figure 1), while the proteins with lower levels were predominantly related to synaptic processes and cell signaling (figure 2). No significant associations were found within controls.ConclusionUsing CSF proteomics, we identified 458 proteins associated with tau‐PET in AD. Higher tau burden was associated with increased levels of proteins involved in immune activation suggesting a role of the immune system in tau accumulation. Furthermore, higher tau burden was associated with lower levels of proteins related to synaptic process hinting at a role for tau in synaptic degeneration.
Investigating enhancement of TIE2 activation as a means of preserving blood‐brain barrier integrity and preventing cerebral amyloid angiopathy in Alzheimer’s Disease
Authors: Marola Olivia J , Onos Kristen D , Maclean Michael , Keezer Kelly J , Howell Gareth R 
Published: December 2023

AbstractBackgroundCerebral amyloid angiopathy (CAA) co‐occurs with cognitive impairment and neurodegeneration in Alzheimer’s disease (AD). We have shown wild‐derived WSB/EiJ (WSB) mice transgenic for APP/PS1 robustly developed CAA and are thus a useful tool to investigate the mechanisms driving CAA. It has been hypothesized that loss of blood brain barrier (BBB) integrity causes improper amyloid clearance and vascular deposition. One mechanism by which this is possible is the deactivation (loss of phosphorylation) of endothelial cell TIE2. TIE2 phosphorylation is negatively regulated by endogenous antagonists ANGPT2 and VE‐PTP, which can be manipulated to potentially bolster BBB integrity and prevent CAA. Here, we fully characterize CAA pathogenesis in WSB.APP/PS1 mice and explore the efficacy of enhancing TIE2 phosphorylation to protect from BBB dysfunction and CAA.MethodMale and female WSB mice harboring the APP/PS1 transgene were aged to 4, 6, 8, 14, and 18 months. Brains were histologically assessed for parenchymal plaque deposition and CAA. To investigate the importance of TIE2 inactivation in driving BBB dysfunction in WSB mice, adult WSB and B6 mice were treated with 5mg/kg lipopolysaccharide (LPS; known to induce BBB leakage) or vehicle control. Brains were harvested 16 hours later and bulk RNA‐seq was performed to investigate modulation of Angpt2 expression.ResultMale and female WSB.APP/PS1 mice exhibited significant parenchymal plaque deposition and CAA by 8 months, which was further increased by 14 and 18 months. Furthermore, while expression of Angpt2 was significantly upregulated after LPS treatment in both B6 and WSB compared to vehicle‐treated counterparts, WSB showed a significantly greater increase compared to B6.ConclusionWSB.APP/PS1 mice develop progressively severe CAA, which may be driven by unique susceptibility to BBB dysfunction. The enhanced elevation of WSB Angpt2 upon LPS treatment may reflect susceptibility of WSB vasculature to BBB degradation and therefore CAA development. Thus, TIE2 phosphorylation will be experimentally elevated in WSB.APP/PS1 mice through Angpt2 heterozygosity and VE‐PTP pharmacological inhibition with AKB‐9778 to determine whether protecting the BBB is a viable strategy to prevent CAA. Furthermore, B6 and WSB.APP/PS1 F2 gene mapping studies will be utilized to identify WSB‐associated alleles driving CAA pathogenesis.
Resting state brain networks activity and association with transfer of cognitive training gains
Authors: Faraza Sofia , Dyrba Martin , Wolf Dominik , Fischer Florian U , Knaepen Kristel , Kollmann Bianca , Binder Harald , Mierau Andreas , Riedel David , Tüscher Oliver , Fellgiebel Andreas , Teipel Stefan ,   German AgeGain study group
Published: December 2023

AbstractBackgroundAge‐related cognitive decline increases the need for cognitive interventions to maintain cognitive function. Cognitive training is considered an effective non‐pharmacological intervention. Transfer of training gains to untrained tasks is a key indicator for the effectiveness of cognitive training. However, the underlying brain mechanisms need to be further investigated. We implemented a cognitive training study to assess functional connectivity determinants of transfer of training gains.MethodA sample of 181 healthy older adults (mean age: 68 years) underwent a 4‐week cognitive training across three sites. The control group consisted of 54 older adults. To evaluate transfer and training effects, participants underwent a neuropsychological assessment before and after the training. A second follow‐up assessment was applied 12 weeks after the training. The training group was divided in subjects who had and who did not have successful transfer, which was defined as higher improvement in cognitive tasks than the control group. We used composite scores representing working memory, memory and executive functions to assess transfer and training effects. Baseline resting‐state functional magnetic resonance imaging was used to investigate the functional connectivity of brain networks associated with cognitive functions. We extracted brain resting state networks using the Independent Component Analysis (ICA) approach.ResultWe observed successful transfer of cognitive training gains in most of the participants. Our results demonstrated spatially restricted effects (p<.01 uncorrected) for the association of transfer of gains with the resting‐state connectivity of brain networks, such as the Default Mode Network and Central Executive Network.ConclusionTransfer of training gains in aging is possible. A strong association between transfer of gains and resting‐state functional connectivity was not identified.
Relationship of structural and functional visual biomarkers with measures of amyloid, tau, and neurodegeneration across the AD continuum
Authors: Mathew Sunu , WuDunn Darrell , Mackay Devin , Vosmeier Aaron , Tallman Eileen F. , Deardorff Rachael , Dage Jeff L. , Clark David G. , Farlow Martin R. , Brosch Jared R. , Gao Sujuan , Apostolova Liana G. , Saykin Andrew J. , Risacher Shannon L 
Published: December 2023

AbstractBackgroundThe eye often reflects changes seen in the brain in neurodegenerative diseases. This study sought to examine the relationship of contrast sensitivity measured using frequency doubling technology (FDT) and retinal thickness measured using optical coherence tomography (OCT) with temporal lobe neurodegeneration, cerebral tau deposition, and mean plasma ptau181 in older adults along the Alzheimer’s disease (AD) continuum.MethodParticipants included 28 individuals with subjective cognitive decline (SCD), 18 mild cognitive impairment (MCI), 4 with AD, and 30 age‐matched cognitive normal (CN) from the Indiana Memory and Aging Study at the Indiana ADRC. Participants were excluded from the study if they had significant eye disease determined to interfere with OCT, FDT, non‐AD dementia, or exclusion for MRI or PET. Mean deviation (MD) and pattern standard deviation (PSD) from FDT were used as measures of contrast sensitivity. OCT scans from each eye to measure retinal thickness in the retinal nerve fiber layer (RNFL) and macula. MRI scans were processed using Freesurfer v6 to measure medial (MTL) and lateral temporal lobe (LTL) volumes. LTL SUVR values were extracted from [18F]flortaucipir PET scans. Plasma ptau 181 was measured using a SIMOA assay. Finally, the association between contrast sensitivity, average RNFL thickness, macular volumes with temporal lobe volumes, LTL tau, and mean plasma ptau181 was assessed using a partial Pearson correlation, covaried for age, sex, and diagnosis. p<0.05 was considered significant.ResultRNFL thickness was decreased in patients with AD. Hippocampal volume correlated with RNFL thickness and macular volume in both eyes and with PSD in the left eye. The inferior temporal volume correlated with MD in both eyes, while mean plasma ptau181 with PSD in both eyes. Finally, lateral temporal lobe tau was correlated with the inner retinal layers of ganglion cell layer plus inner plexiform layer thickness.ConclusionContrast sensitivity correlates with temporal lobe volumes and mean plasma ptau181. RNFL thinning and macular volumes are associated with hippocampal atrophy, and inner retinal nuclear layers correlate with lateral temporal tau. Imaging of the eye may represent a useful biomarker to screen patients at risk for AD prior to more invasive and prolonged testing.
Evaluation of locus coeruleus changes during aging by post‐mortem brain MRI contrast
Authors: Marinho Pedro Burlacchini , Rodriguez Roberta Diehl , Carreira Luzia Lima , Heinsen Helmut , Chaim Khallil Taverna , Grinberg Lea T. , Leite Claudia da Costa , Otaduy Maria Concepción Gracía 
Published: December 2023

AbstractBackgroundNeuropathological studies have pointed to the importance of neurodegeneration in the locus coeruleus (LC) as a possible early biomarker of Alzheimer’s Disease (AD). The aim of this study is to explore a non‐invasive MRI technique to evaluate normal and pathological changes in the LC during aging.MethodsSubjects were recruited from our Capital’s Death Verification Service. After obtaining written consent from family members, 24 individuals (55‐94 yrs) were submitted for post‐mortem brain in situ MRI with a 7T scanner. Post‐mortem interval ranged from 7 to 20 hours and body temperature varied from 14.8°C to 26°C. MRI protocol included acquisition of multi‐echo gradient‐echo axial images with 2 mm thickness and 0.4 mm in‐plane resolution. LC signal intensity was evaluated from a single gradient‐echo image presenting the brightest signal for the LC. In the same slice normalized values for the left and right LC were quantified (LNV and RNV) by selecting a ROI on the brightest spot of the LC (one‐pixel sized) and dividing it by the signal intensity measured in the left and right pons, respectively (ROI of approx. 50mm2) (Figure1). Subject’s Clinical Dementia Rating (CDR) was obtained by interviewing a close family member. A two‐tailed paired t‐test was performed between the RNV and the LNV, and dependence with age was analyzed by Pearson correlation.ResultsCDR was 0 (n = 17); 0,5 (n = 2); 1 (n = 1), 2 (n = 1), and 3 (n = 3). LNV was higher than RNV (t(23) = 3.9; p< 0.001 (Figure2). The mean of LNV and RNV (MNV) was higher in individuals with CDR = 0 than in subjects with CDR >0, but subjects with CDR>0 were also significantly elder, and there was a significant effect of age on the MNV (r = ‐ 0,49, p = 0,015), Figure 3.ConclusionMRI LC contrast was able to depict LC changes as a function of age, whereby subjects with symptons seemed to present lower LC intensity. The left LC was consistently brighter than the right LC endorsing results observed in other studies (Betts et al.2019 https://doi.org/10.1016/j.dadm.2019.02.001). Future histopathological analysis will help to elucidate the origin for this signal difference.
Distinct effects of cholesterol profile components on amyloid and vascular burdens
Authors: Kim Jun Pyo , Yoo Heejin , Cheon Bo Kyoung , Park Yu Hyun , Kim Soo‐Jong , Ham Hongki , Jang Hyemin , Kim Hee Jin , Koh Seong‐Beom , Na Duk L , Seo Sang Won 
Published: December 2023

AbstractBackgroundCholesterol plays important roles in β‐amyloid (Aβ) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aβ and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aβ and CSVD burdens in a large, non‐demented Korean cohort.MethodWe enrolled 1,175 non‐demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aβ PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low‐density lipoprotein cholesterol [LDL‐c], high‐density lipoprotein cholesterol [HDL‐c], and triglyceride) level as a predictor and each image marker (Aβ uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders.ResultIncreased LDL‐c levels (β = 0.014 to 0.115, p = 0.013) were associated with greater Aβ uptake, independent of the APOE e4 allele genotype and lipid‐lowering medication. Decreased HDL‐c levels (β = −0.133 to −0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL‐c levels were also associated with decreased hippocampal volume (direct effect β = −0.053, p = 0.040), which was partially mediated by Aβ uptake (indirect effect β = −0.018, p = 0.006).ConclusionOur findings highlight that increased LDL‐c and decreased HDL‐c levels are important risk factors for Aβ and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL‐c and HDL‐c levels is a potential strategy to prevent dementia.