bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic‐based Biological Aging Clock and MRI Markers of Cerebrovascular Disease: Atherosclerosis Risk in Community Study
Authors: Sedaghat Sanaz , Wang Shuo , Liu Jialing , Hughes Tim M. , Sabayan Behnam , Tang Weihong , Coresh Josef , Pankow James , Walker Keenan A. , Lutsey Pamela L. , Guan Weihua , Prizment Anna 
Published: December 2023

AbstractBackgroundBiological aging state can be quantified by composite metrics called aging clocks using proteomics. Proteomic aging clocks (PACs) are accurate, easily measured, and are associated with age‐related diseases including Alzheimer’s Disease and Related Dementias. We aim to investigate whether an accelerated biological aging (a discrepancy between chronological age and PAC) is associated with subclinical cerebrovascular structural changes.Method1494 participants from the Atherosclerosis Risk in Communities (ARIC) Study with proteomics and 3T brain MRI data at ARIC visit 5 in 2011‐13 (mean age 76, 59% female, 25% Black) were included. Nearly 5000 plasma proteins were measured using the SomaScan assay. PAC was developed using elastic net regression model and was internally validated. Age acceleration was calculated as residuals after regressing PAC on chronological age (positive value indicates biological age is higher than the person’s chronological age). Linear and logistic regression models were used to assess the associations of age acceleration with white matter hyperintensity volume (in cm3, log2 transformed, median [IQR]: 11[6‐20]) and the presence of: subcortical (n = 281), lacunar (n = 263), and cortical infarcts (n = 150), and microbleeds (n = 355).ResultAccelerated age (median [IQR]:‐0.04[‐1.4,1.3]; correlation with chronological age = 0) was associated with MRI markers of cerebrovascular disease after adjusting for demographic, cardiovascular risk factors, education, and kidney function. Every five years higher age acceleration was associated with larger white matter hyperintensity volume (Difference:0.34[95%CI 0.19,0.49]), higher odds of lacunar (OR:1.61[1.13,2.30]), subcortical (OR:1.63[1.15, 2.32]), and cortical infarcts (OR:1.72[1.11,2.67]). There was no association with presence of microbleeds (OR:1.25[0.91,1.73]) (Figure). Findings were consistent after excluding participants with clinical stroke and there was no difference between APOEe4+ and APOEe4‐ participants.ConclusionHigher accelerated age is cross‐sectionally associated with a greater prevalence of MRI markers of cerebrovascular disease. Understanding this relation has potential to help with risk stratification and personalized prevention and treatment strategies to promote brain health.
Examining longitudinal changes of disease severity scores in familial forms of frontotemporal dementia within the GENFI cohort
Authors: Foster Phoebe H , Ferry‐Bolder Eve , Peakman Georgia , Bouzigues Arabella , Greaves Caroline V , Convery Rhian S , van Swieten John C. , Jiskoot Lize C. , Seelaar Harro , Moreno Fermin , Sanchez‐Valle Raquel , Laforce Robert , Graff Caroline , Masellis Mario , Tartaglia Carmela , Rowe James B. , Borroni Barbara , Finger Elizabeth , Synofzik Matthis , Galimberti Daniela , Vandenberghe Rik , Mendonca Alexandre , Butler Christopher , Gerhard Alexander , Ducharme Simon , Ber Isabelle Le , Tiraboschi Pietro , Santana Isabel , Pasquier Florence , Levin Johannes , Otto Markus , Sorbi Sandro , Rohrer Jonathan D. , Russell Lucy L. 
Published: December 2023

AbstractBackgroundThe CDR®+NACC FTLD Sum of Boxes (SB) score is a well‐established measure of disease severity in frontotemporal dementia (FTD), however, few studies have assessed longitudinal changes in score within familial forms of FTD.Method343 participants from the Genetic FTD Initiative (77 mutation‐negative controls, 109 C9orf72 expansion carriers, 105 GRN mutation carriers, and 52 MAPT mutation carriers), with available scores on the CDR®+NACC FTLD‐SB and the FTD Rating Scale (FRS) at baseline and follow‐up, were examined. Using the baseline FRS percentage scores, mutation carriers were stratified into four groups: asymptomatic/very mild (100‐97%), mild (96‐80%), moderate (79‐41%), and severe (40‐0%). Linear regression models with bootstrapping were used to assess annualised change in CDR®+NACC FTLD‐SB scores across genetic groups between participants' first and follow‐up visit.Result
C9orf72 and GRN mutation carriers in the moderate and severe groups, as well as mild GRN carriers, showed significantly greater change than controls (p < 0.050). No significant differences in change scores were observed between MAPT mutation carriers and controls. Comparisons within genetic groups revealed that both the moderate and severe GRN and C9orf72 expansion carriers showed larger annualised change relative to their asymptomatic/very mild counterparts (p < 0.001 and p = 0.037; p = 0.028 and p < 0.001, respectively). The moderate GRN and severe C9orf72 groups also demonstrated greater annualised score changes than their respective mild counterparts (p < .001; p = 0.001). For MAPT mutation carriers, no significant changes were observed. Between genetic group comparisons revealed significant change score differences between the moderate individuals, with GRN mutation carriers showing a greater change than the C9orf72 and MAPT groups (both p < 0.001), and the C9orf72 group showing a larger annualised change than the MAPT mutation carriers (p = 0.041).ConclusionThe CDR®+NACC FTLD‐SB detects significant changes in disease severity from baseline to a first follow‐up visit in familial forms of FTD, with GRN mutation carriers showing the greatest annualised change.
Monoaminergic Disfunctions and Misfolded Proteins levels in the Alzheimer’s Disease Continuum
Authors: Orso Beatrice , Peira Enrico , Arnaldi Dario , Girtler Nicola , Brugnolo Andrea , Mattioli Pietro , Biassoni Erica , Donniaquio Andrea , Massa Federico , Uccelli Antonio , Bauckneht Matteo , Morbelli Silvia , Pardini Matteo 
Published: December 2023

AbstractBackgroundMonoaminergic systems are pharmacologically modulable and therefore both a target for symptomatic therapies and a window for the study of disease progression. Although these mechanisms are unclear. We explore the progression and the distribution of monoaminergic deficits in the Alzheimer’s Disease (AD) continuum, along with the accumulation of misfolded pathological proteins.MethodWe included 50 patients with Alzheimer’s Disease (AD) and 42 Healthy Controls (HC). We acquired brain [18F]FDG‐PET images as a marker of neurodegeneration and MMSE as a measure of global cognitive functioning. We performed voxel‐based analysis between AD vs. HC. Using JuSpace toolbox we explored the correlation between [18F]FDG‐PET images and PET maps of dopamine (DAT), serotonin (SERT), noradrenaline (NAT) and choline vesicular (VAChT) transporters cortical distribution. Moreover, we evaluated relative hypometabolism in the main cholinergic nucleus (Meynert nucleus). We divided in two groups the AD patients based on MMSE score (AD Dementia ‐ADD‐ <24; MCI ≥24), to explore the association between monoaminergic disfunction and pathological proteins burden, across the AD continuum.ResultSample characteristics are provided in Table 1. Results from voxel‐based analysis are shown in Figure 1. In the whole AD group, the distribution of relative cortical hypometabolism was associated with a significant reduction of VAChT availability (p = 0.018). This association remained significant when considering the ADD (p = 0.006), but not the MCI group. Figure 2.β‐amyloid42 levels and β‐amyloid42/40 ratio were inversely correlated with VAChT in the ADD group (p = 0.003; p = 0.038, respectively). No correlation was observed in the MCI group. Lastly, there was no correlation between Meynert nucleus relative hypometabolism and misfolded proteins levels in all groups.ConclusionIn the ADD phase we showed a significant damage in the cortical regions targeted by the cholinergic system. This result was not evident among the other systems studied, nor in the MCI phase. This provides an explanation of the reduction of the cholinesterase inhibitors efficiency in the dementia phase. Moreover, we showed that β‐amyloid accumulation was not associated with Meynert Nucleus degeneration, but that impacted on cholinergic function via damage accumulation in the cortical areas targeted by the cholinergic system.
Optimizing brain health after a Traumatic Brain Injury: application of dementia prevention programs regarding neuroprotective lifestyles to the field of TBI care
Authors: Bayen Eleonore , de Langavant Laurent Cleret , Cotter Eoin , Lawlor Brian , Cotter Agnès Weill‐Chounlamountry 
Published: December 2023

AbstractOutcome after a Traumatic Brain Injury is multi‐determined and depends on the interaction of factors, including injury severity, pre‐injury (e.g. level of education) and post‐injury factors (e.g. access to health care resources including neuro‐cognitive rehabilitation, but also environmental factors such as family/socio‐economic support, follow‐up of comorbidity conditions, physical activity, healthy sleep and diet…). Some of these modifiable risk and neuroprotective factors have been shown to have an impact on brain health and on outcomes post‐TBI. Additionally, patients with moderate to severe TBI have an increased risk of developing dementia (Gardner, Yaffe 2014), reinforcing the need for secondary prevention post‐injury. Yet, primary‐secondary prevention regarding brain health modifiable factors remains insufficiently developped during TBI care management. We describe here the building of a hospital‐based psycho‐educational program promoting brain health in the Neuro‐Rehabilitation Center of Pitié‐Salpêtrière hospital (Paris, France): it includes raising awareness about neuroprotective lifestyles and managing modifiable risk factors that have been studied in dementia prevention (Norton, Yaffe, 2014; Livingston 2017) to the field of post‐TBI care. Indeed, detection and management of modifiable risk factors help to prevent neurodegeneration that participate to cognitive decline and clinical dementia later in life. The brain health program takes place during the out‐patient rehabilitation. It engages a transdisciplinary group of health professionals (physicians, rehabilitation professionals) that support and educate patients about easy steps towards healthy lifestyles and behavioral changes. The implementation includes 1) a medical interview about lifestyles and daily life environment (social support, physical activity, diet, sleep habits), and clinical check/follow‐up of comorbidities distinct from the TBI (cardiometabolic/vascular diseases, epilepsia, mood, addictions, sensory loss); 2) a targeted customized psychoeducation regarding modifiable risk factors. This entails recommendations regarding: cognitive stimulation, diet, physical fitness, secondary prevention of TBI, therapeutic observance for comorbidity conditions, sleep habits, the benefits of social interactions, follow‐up of mood disorders, prevention of tabacco/drug/excessive alcohol intake. Pre‐ post‐ evaluations (satisfaction, lifestyles, propensity to change behaviors and associated factors) are assessed. The TBI event stands as an opportunity to increase patients’ awareness about the importance of brain health. This program supports patients’ education regarding possible changes in patients’ daily life activities and behaviors.
Regional amyloid‐β is linked to disruptions in connected speech in amnestic mild cognitive impairment
Authors: Chou Chia‐Ju , Chang Chih‐Ting , Lee Chia‐Ying , Liu Yi‐Chien 
Published: December 2023

AbstractBackgroundSpeech changes in amnesic mild cognitive impairment (aMCI) are potential markers for the early detection of Alzheimer disease (AD). However, few studies investigate the relationship between speech and amyloid‐β burden. The focus of this study was to examine the relationship between the linguistic features and the distribution of amyloid‐β load in aMCI.MethodThis study recruited 25 aMCI patients (52% female, aged 70‐85 years) and 25 healthy elders (44% female, aged 68‐80 years) from the memory clinic of Cardinal Tian Hospital in Taiwan. All participants received [18F] florbetaben PET and standardized cognitive tests. Amyloid‐β load using a standardized uptake value ratio (SUVr) was estimated from 5 cortical regions (parietal, frontal, cingulate, temporal, and occipital). Spontaneous speech was recorded using the picture description task (three Taiwanese culture‐related pictures) and transcribed verbatim. Linguistic features were extracted, including lexical richness (total words, unique words, type‐token‐ratio, lexical density, and frequency), syntactic complexity (mean length of utterance/sentence, ratio of verbs/pronouns/passive sentence), and speech fluency (ratio of long pauses/ fillers).ResultEighteen subjects with high amyloid burden (SUVr > 1.21) progressed (defined as CDR‐SB change≧1) within 1 year. We performed linear regression analyses between linguistic features (dependent variables, separate models) and amyloid‐β load in brain regions. Analyses were adjusted for age and education. The data revealed that a high amyloid‐β burden in the frontal region was associated with fewer unique words, less lexical density, and an increased proportion of long pauses and fillers. Reduced passive sentence, short mean length of utterance and lower scores on episodic memory tests related to increased amyloid‐β burden in the parietal region.ConclusionLexical richness and speech fluency was associated with amyloid‐β burden in the frontal region, indicating that voluntary lexical retrieval may require the additional recruitment of frontal lobe. Less syntactic complexity related to increased amyloid‐β burden in the parietal region. In conclusion, regional amyloid‐β is linked to subtle spontaneous speech deficits in aMCI.
Reduction in tau‐pathology induced with two novel tau aggregation inhibitors in Alzheimer mice
Authors: Drapich Patrycja , Zadrozny Maciej , Mironczuk Sandra , Gasiorowska Anna , Melis Valeria , Riedel Gernot , Harrington Charles R , Niewiadomska Grazyna , Niewiadomski Wiktor 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a common neurodegenerative disorder for which tau pathology is implicated. Abnormal forms of tau, which trigger neuronal dysfunction, can offer a therapeutic target. The main purpose of this study was to determine the effect of two new tau aggregation inhibitors here termed A and B, synthesised by TauRx Therapeutics Ltd., on tau pathology in a transgenic mouse model of AD.MethodThe research was conducted using the Line 1 (L1) transgenic mouse model with mild Alzheimer’s disease‐like tauopathy and the control wild‐type NMRI mice. L1 mice express a fragment of 945 amino acids fragment (296‐390) of the longest human tau CNS isoform (2N4R; htau40).Experiments were carried out on 20‐25 weeks old animals. Compounds A and B were administered orally at daily dose 1.5 and 7.5 mg/kg for six weeks. Level of tau pathology was examined immunohistochemically using mAb7/51. Images of stained brain sections were collected and analysed using ImageJ software. Tau staining was assessed using the relative optical intensity (ROI) in three areas of interest (AoI): dorsal CA1 and CA3 subfields of hippocampus and primary motor cortex. Three measures were applied: (i) overall mean ROI of all pixels within AoI; (ii) specific mean ROI calculated only for pixels within AoI, whose ROI was below a threshold, which was set manually, and (iii) %Area – ratio of number of all pixels in AoI with ROI below manually set threshold relative to the number of all pixels in AoI.ResultTau labelling was significantly enhanced in overall and specific mean ROI between NMRI and L1 mice (both untreated and treated) in all structures scrutinised. Drug efficacy was strongest in cortex where a clear reduction of tau immunolabelling was revealed, followed by CA3 subfield of the hippocampus. No efficacy was obtained for CA1 independent of analysis method. The analysis of % Area affected by tau was particularly sensitive for drug efficacy in both CA3 and cortex, but there was yet again no effect in CA1.ConclusionTwo new tau aggregation inhibitors A and B both reduced the level of pathological tau deposits in L1 mice.
Use of Chair Exercises in Increasing Heart Rate during Pilot Testing of mPACT app
Authors: Smith Lenora W , O'Brien Charles 
Published: December 2023

AbstractBackgroundThe mPACT app is a mobile application that integrates physical activity (through chair exercises) and cognitive training in one application. The aim of this study was to explore the exercise dose required to obtain target heart rates in older adults using chair exercises.MethodThe mPACT app was designed for our target population with the use of chair exercises to prevent injury and to allow older adults to complete physical activity even though they may have limitations. Chair exercises provide a less strenuous method for physical activity while still allowing for an increase in heart rate, which results in more oxygenation to the brain. The various exercises were videos that were looped to be 40 seconds, 60 seconds, and 90 seconds long, resulting in 30 minutes of physical activity. FitBit(R) inspire watches were used to monitor heart rate through the dashboard on the FitBit(R) website.ResultAlthough the greatest increases in heart rate were seen during the final series of 90‐second exercises, this was likely a result of the marching and T‐pose exercises in sequences. The average heart rate displayed by the FitBit app, however, make the data inconclusive.ConclusionOur chair exercises in general can reach target heart rate, but the exact sequence and whether one causes a drop in heart rate is inconclusive due to more sedentary adults having small rest periods during each sequence. Using heart monitors to obtain more accurate data rather than FitBits(R) would be beneficial. Further research is needed for sequencing of specific chair exercises in order to adequate show the amount of exercise needed for the mPACT app.
Development and characterization of a robust in vitro disease cell line to study tauopathies
Authors: Ritsma Laila , Bsibsi Malika , Buti Ludovico , Stevenhagen Fleur , Sancerni Sara Compte , de Kraa Esther , Popalzij Abeera , Iovino Mariangela , Oosterveen Tony , Turner Amanda , Fisher David F , Vlaming Marijn 
Published: December 2023

AbstractBackgroundTauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s dimentia (AD), are neurodegenerative diseases characterized by the pathological aggregation of paired helical filaments (PHFs) or neurofibrillary tangles (NFTs) within neurons and glia, leading to cell death1. PHFs and NFTs are formed by aggregation of hyperphosphorylated tau1. Mutations in the microtubule‐associated protein tau (MAPT) gene result in tauopathies. Moreover, FTD is a common clinical syndrome of 4 repeat (4R) tauopathies, as defined by aggregation of tau protein isoforms with four microtubule binding domains2. Here, we aimed to develop and characterize a physiologically relevant and robust in vitro FTD model, to aid the future development of FTD disease therapeutics.MethodUsing CRISPR‐Cas9 gene editing technology, familial mutations MAPT P301S and N279K underlying AD/FTD3 were engineered into an iPSC line that carries the opti‐oxTM technology and can rapidly be reprogrammed into glutamatergic neurons4. By means of immunocytochemistry we characterized b‐amyloid oligomer treated neurons, and neurons with the MAPT mutations to assess tau hyperphosphorylation.ResultThe CRISPR‐edited MAPT neurons can mature and show a healthy morphology. b‐amyloid oligomers (dose dependently) induce tau hyperphosphorylation in wild type glutamatergic neurons. Total tau expression is reduced in MAPT P301S homozygous and N279K heterozygous cells when compared to wild type cells. The MAPT P301S cells also show hyperphosphorylation for p‐tau 217, p‐tau202/205, and p‐tau404, and the N279K cells show hyperphosphorylation for p‐tau202/205, and p‐tau404.ConclusionThe elevated p‐tau to total tau ratio measured by the immunocytochemistry assay indicates the potential of at least two cell lines as possible disease models to aid future research into developing AD/FTD disease therapeutics.References:1. Silva MC, eLife, 20192. Seward ME, et al, 2013. Journal Cell Sci 126(5):1278‐12863. Hutton M, et al, 1998, Nature 393:702‐7054. PawlowskiM, et al, 2017. Stem cell reports 8(4), 803‐812
Cap‐Independent Translation as a Physiological Process Linking Amyloid and Tau Pathology in Alzheimer’s Disease
Authors: Murphy Michael Paul , Kohler Katharina , Webb Robin 
Published: December 2023

AbstractBackgroundNeurodegenerative diseases are complex entities that are driven by multiple pathophysiological processes. Alzheimer’s disease (AD) is no exception, with both a multifaceted etiology, and varied pathologies that interact in overlapping ways. Although AD is the most common form of dementia found in the elderly, it is typically encountered with multiple age‐related co‐morbidities that are indicative of other disease processes that likely contribute to the overall neurologic disease state, such as cerebrovascular pathology. A well known connection exists between type 2 diabetes (T2D), or metabolic dysfunction in general, and risk of dementia later in life. Our data indicate that a significant contributing factor that connects these processes may be the increased utilization of cap‐independent translation (CIT), an alternative form of eukaryotic protein manufacture that is more active during various forms of physiologic stress.MethodThrough an investigation of AD cases and controls, multiple cell lines (N2A, CHO, HEK293T, H4), rat primary neurons, cell free transcription / translation assays, and mouse models, we demonstrate that changes in CIT may drive both amyloid and tau pathology.ResultWe found that increased BACE1 protein in AD cases, as well as in vitro, was directly connected to an increase in an mRNA binding protein (ZNF9) responsible for controlling cap‐independent translation. Up and down regulation of ZNF9 produced corresponding changes in BACE1 protein (but not BACE1 mRNA), as well as BIN1, a key driver in the development of tau pathology. Cell free in vitro transcription / translation assays, mRNA binding in vitro and in vivo (both gel shift and RNA immunoprecipitation), and fluorescent reporter assays using a variety of constructs confirmed that ZNF9 is controlling CIT and likely not acting via typical cap‐dependent translation, or by affecting transcription. Additional studies in cell lines, as well as in a mouse model of metabolic dysfunction and amyloid pathology, demonstrated that this process can be driven by metabolic stress.ConclusionIn addition to any direct connection between the development of amyloid‐beta and tau neuropathologies, these data indicate that these two primary pathologic hallmarks of AD could share an upstream connection through a basic, yet underappreciated, biological process.