bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering new tau aggregation and spreading mechanism through AD tau‐seed interactome analysis
Authors: Martinez Pablo , You Yanwen , Patel Henika , Garfe Nur Jury , Redding Javier , Troncoso Juan C , Reeves Cristian A Lasagna 
Published: December 2023

AbstractBackgroundPathological tau aggregates are key features of Alzheimer’s disease and other tauopathies. The current research aims to understand how tau aggregates spread in AD patient brains, but the mechanisms remain unclear. Our recent‐published study found that the protein Bassoon plays a key role in tau spreading and pathology in a mouse model for tauopathy using mass spectrometry to identify proteins interacting with tau seeds. Considering our finding enhancing the relevance of tau‐seed interactor on disease pathology, we aim to characterize the interactome of the tau‐seed isolated from AD brains using a similar approach.MethodIn this study, we used Size Exclusion Chromatography (SEC) to separate TBS‐soluble AD and healthy brain extracts into fractions and measured tau seeding activity using a flow cytometry‐based biosensor cell line (n = 3). Then, the fractions with higher seeding activity were subjected to immunoprecipitation to isolate the tau seed and performed a TMT‐tags‐based unbiased quantitative mass spectrometry to uncover the specific tau species involved in tau propagation and identify new tau‐seed interactors.ResultThe strongest seeding activity in AD brains was found in fraction 9, which contains high molecular weight (HMW) proteins (>2,000 kDa), including only 5% of total tau, as assayed by ELISA for tau. Levels of tau were similar in fraction 9 in age‐matched controls but lacked seeding activity. Our bioinformatic analysis revealed that a total of 504 proteins interact with HWM tau without seeding activity isolated from controls and 1192 proteins interact with HWM tau‐seed isolated from AD cases. In addition, a total of 385 interacting proteins were found in both HWM tau from control and tau‐seed from AD cases. Interestingly, DAVID analysis as well as networks and interactions analysis (STRING analysis), revealed enrichment in proteins related to both synaptic and mitochondrial pathways.ConclusionOur findings significantly contribute to our understanding of the mechanisms involved in tau propagation and offer new insights into the potential for targeting tau‐seed interactions as a therapeutic strategy for tauopathies. Previously, we have identified BSN as a key interactor of tau seeds, and our data suggest that inhibiting these interactions could represent a promising new approach to treating these debilitating conditions.
Neuroprotective Potential of Limonene in LPS Induced PD in Rats
Authors: Kapoor Satyan , Deshmukh Rahul Renukadas 
Published: December 2023

AbstractBackgroundParkinson’s disease is 2nd most disabling neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in basal ganglia. There are different pathologies that count for PD like neuro‐inflammation. This study highlights the role of oxidative stress and inflammation in progression of PD where limonene shows antioxidant and anti‐inflammatory response.MethodWistar rats (200‐250gm) of either sex were taken and divided into 6 groups. Animals were treated with three different doses of limonene i.e. (25, 50, 100 mg/kg p.o.) for 21 day, starting 1 day prior to LPS 5μl(1mg/ml PBS) infused stereotaxically into the SN of rats.ResultThe catalepsy technique was used to analyze the clinical signs of Parkinson’s disease in rats. LPS significantly increased oxidative stress indicators in the animals and decreased systemic antioxidant synthesis. Biochemically limonene significantly reduced the oxidative–nitrative stress, as evidenced by decrease in malondialdehyde and nitrite levels, and restored the reduced catalase, glutathione and Superoxide dismutase levels. The observed beneficial effects of limonene in motor defects may be due to its ability reduce oxidative burden.ConclusionLPS is potent inflammatory biomarker but this also has major role in development of oxidative stress. Interaction between reactive oxygen species and dopamine leads to its depletion & considered as one of the major mechanism for dopaminergic degeneration in PD. LPS caused significant elevation in malondialdehyde, nitrite and decline in SOD, catalase & glutathione, indicating development of oxidative‐nitrosative stress. Limonene treatment significantly reduced striatal MDA and nitrite concentration & restored antioxidant enzyme activities.
The Therapeutic Landscape of Tauopathies: Evaluating the Tau Pipeline
Authors: Harris Glenn A. , Cummings Jeffrey L. , Gonzalez Isabel , Pritchard Martyn , Toledo‐Sherman Leticia , May Patrick C. 
Published: December 2023

AbstractBackgroundMany disease modifying therapeutics for neurodegenerative diseases (NDs) have focused on the reduction of amyloid, neuroinflammation and synaptic plasticity. Many NDs include tau pathology either with amyloid deposits or without. These NDs can collectively classified as tauopathies. We have provided an overview of the therapeutic landscape of programs targeting tauopathies covering drug candidates in the clinical development as well as programs still in discovery and the preclinical stages.MethodSearch results from targeted queries and key word searches for MAPT and tau were carried out on GlobalData and SciFinder databases as the principal sources of information. Company websites, PubMed and conference proceedings were also researched for additional information. All data presented here is current to Aug. 31, 2022. All therapeutics in clinical phases I, II and III, as well as in preclinical development and discovery phase were included.ResultThe majority of therapeutic approaches focused on tau by directly targeting Microtubule Associated Protein Tau (MAPT) although indirect mechanisms also afford strategies that may ultimately affect tau. Our search through the end of August 2022 showed that the tau landscape currently contains 160 compounds, of which 38 are in clinical development. Of those, a total of 135 drugs directly target MAPT, with 33 of them combining MAPT with other mechanisms, mostly alpha synuclein (α‐syn) or amyloid protein targets. There is a growing variety of modalities that are being explored in targeting tau, with small molecules remaining dominant accounting for approximately 44% of all molecules in development. There were 18 therapies in both phase I and phase II clinical trials, and only one currently in phase three. There were also two therapies currently with an IND/CTA filing in process.ConclusionThere has been a significant increase in the number of researchers focusing on tau as a main therapeutic approach. The landscape of anti‐tau therapeutic agents is growing but special consideration should be given to primary tauopathies which do not share the amyloid burden of other NDs like Alzheimer’s disease, and do not share in the recent success of approved anti‐amyloid therapeutics.
Functional Brain Activation in Mild Cognitive Impairment With Defined Small Vessel Disease Burden
Authors: Marcolini Sofia , Mondragon Jaime , Ramakers Inez H.G.B. , Biessels Geert Jan , Claassen Jurgen A.H.R. , Bron Esther E , Papma Janne M. , van der Flier Wiesje M. , van der Lugt Aad , Maurits Natasha M. , De Deyn Peter Paul 
Published: December 2023

AbstractBackgroundVascular dysregulations and changes in functional brain network integrity play a fundamental role in the pathogenesis of dementia. While often identified in individuals with dementia, the role of small vessel disease (SVD) in the development of dementia is not completely understood yet. Previously, structural and functional brain connectivity was shown to be different between individuals with and without cerebral SVD, but a comprehensive measure of SVD has not been used consistently. We aim to analyze functional brain activation differences in mild cognitive impairment (MCI) individuals with defined SVD burden.MethodFunctional brain activation differences were analyzed in MCI individuals with absent or low (n = 34) or high (n = 34) SVD burden using data from the Parelsnoer Institute, a multicenter study involving eight Dutch medical centers. SVD burden was characterized using an ordinal scale ranging from 0 to 4 (Klarenbeek et al., 2013) considering the following markers: lacunes; microbleeds; perivascular spaces in the basal ganglia; white matter hyperintensities based on the Fazekas score. Two groups were identified: the absent or low SVD burden group with a score of 0 or 1 and the high SVD group with a score between 2 and 4. Activation differences were calculated using resting state fMRI data acquired using 3Tesla scanners and analyzed with group‐independent component analysis using the CONN toolbox.ResultActivation of two clusters in the high SVD burden group was lower than in the absent or low SVD group: the cerebellum (p‐FDR >. 001, F = 1.49) and the brainstem (p‐FDR >. 001, F = 2.79). The cerebellar cluster (4541 voxels, +20 ‐74 ‐38) consisted of the left cerebellum crus II, right cerebellum crus II, and left cerebellum lobule VIII. The brainstem cluster (218 voxels, +22 ‐28 +20) involved the right thalamus and the right caudate nucleus.ConclusionBrain activation differences between groups of individuals with MCI and absent or low or high SVD burden were found in the cerebellum and brainstem. These brain areas are mainly responsible for motor, attentional and executive functions, domains which were found in previous studies to be mostly associated with SVD markers.
Cognitive and Functional Connectivity Outcomes from a Phase I Trial of Accelerated High‐Dose Repetitive Transcranial Magnetic Stimulation in Amnestic MCI
Authors: Fountain‐Zaragoza Stephanie , McTeague Lisa M , Benitez Andreana 
Published: December 2023

AbstractBackgroundRepetitive transcranial magnetic stimulation (rTMS), most widely used to treat depression, may have secondary benefits for cognition. Accelerated high‐dose protocols such as intermittent theta burst (iTBS)‐rTMS shorten the treatment course by >50%, potentially improving the feasibility of use in patients with cognitive impairments. Here, we present the results of a phase I trial of iTBS‐rTMS for improving cognition in individuals with amnestic mild cognitive impairment (aMCI) and we explore whether functional brain changes relate to improved cognition.MethodTwenty‐two patients with clinically diagnosed aMCI received 24 sessions of open‐label iTBS‐rTMS to left dorsolateral prefrontal cortex (l‐dlPFC) over 3 days. Nineteen had complete brain MRI and cognitive testing pre‐ and immediately post‐treatment. The primary cognitive outcome was the norm‐adjusted fluid cognition composite T‐score from the NIH Toolbox Cognition Battery. Resting‐state functional connectivity was computed from subject‐specific parcellations mapped to each individual’s functional topology. We examined changes in connectivity within and between the FPN (of with the l‐dlPFC is a hub) and networks implicated in cognition (FPN, dorsal and ventral attention, limbic, default mode). We assessed whether connectivity changes (post minus pre) related to change in fluid cognition.ResultWe achieved a high retention rate of 95%. Treatment with iTBS‐rTMS was safe, with no adverse neuroradiological, neuropsychiatric, or neurocognitive effects. Side effects were minimal and acceptability ratings were high. Treatment produced significant, large effect size (d = 0.98) improvements in fluid cognition (Fig. 1A), and we observed preliminary evidence of related changes in functional connectivity. Specifically, there was a numerical increase in within‐FPN connectivity and a marginally significant increase in connectivity between cognitive networks (Fig. 1B). Further, there was a medium‐strength and marginally significant association between increased within‐FPN connectivity and improved fluid cognition (Fig. 1C).ConclusionThis phase I trial demonstrated that iTBS‐rTMS is safe, feasible, and acceptable in aMCI. Although not dosed for efficacy, we observed large improvements in fluid cognition and preliminary evidence of increased functional connectivity in expected brain networks that related to improved cognition. These promising results support iTBS‐rTMS as potentially efficacious in improving cognition in aMCI, directly informing larger, planned follow‐up randomized controlled phase II trials.
Trajectories of plasma biomarkers of Alzheimer’s disease and neurodegeneration in the general population
Authors: Graff‐Radford Jonathan , Lesnick Timothy G. , Mielke Michelle M. , Ramanan Vijay K , Cogswell Petrice M , Algeciras‐Schimnich Alicia , Knopman David S. , Hofrenning Ekaterina I. , Stricker Nikki H. , Jack Clifford R. , Petersen Ronald C. , Vemuri Prashanthi 
Published: December 2023

AbstractBackgroundPlasma biomarkers of Alzheimer’s disease (AD) and neurodegeneration have demonstrated diagnostic utility and associations with AD pathology. Our objective was to map the average trajectories over age of plasma biomarkers and more established biomarkers including cognition, amyloid PET, and hippocampal volume.MethodWe included 1731 cognitively unimpaired (CU) and 226 mild cognitive impairment (MCI) participants from the Mayo Clinic Study of Aging (mean age of 70.3 years; 46.3% female; 14.8 years of mean education) with one or more measurements of amyloid‐PET, MRI with hippocampal volume measurements adjusted for head size (HVa), and plasma biomarkers (Aβ42/40 ratio, p‐tau181, GFAP, and NfL measured using Quanterix Simoa assays). A global cognitive z‐score was created by averaging the z‐scores of memory, language, executive function, and visuospatial domains. Smoothing spline curves were calculated for the values of each variable over age and placed on the same plot. Since each variable has a different scale, the smoothed curves were centered at the predicted value at age 50 and scaled so that a value of 1 would be one standard deviation of the fitted values from ages 50‐80.ResultAt age 50, GFAP and NfL start to increase, and Aβ42/40 was observed to decrease. At age 55, amyloid‐PET and p‐tau181 had a smooth and upward‐curving increase. After age 70, the average values of p‐tau181 increased at a higher rate. Average cognition started declining after 55 years. HVa began to decline after age 60 and then showed a steeper decline at age 72.ConclusionThis study demonstrates that predicted values of plasma GFAP, NfL, and Aβ42/40 across participants begin to change at younger ages than cognitive decline or increases observed in amyloid PET. The changes observed during middle age in GFAP and NfL likely reflect non‐AD pathologies and aging processes, while Aβ42/40 may be a leading indicator of future cerebral amyloidosis. Predicted plasma neurodegenerative biomarkers (GFAP and NfL) begin to change at younger ages than a traditional biomarker of neurodegeneration (HVa). Predicted ptau181 increases were observed in tandem with amyloid PET likely reflecting current amyloid status.
Tangle and neuritic burden from neurofibrillary tangle maturity markers in the hippocampus are differentially correlated to tau‐PET, MRI, and cognitive measures
Authors: Moloney Christina M. , Peng Zhongwei , Wood Ashley C. , Rothberg Darren M. , Rutledge Matthew H. , Hofrenning Ekaterina I. , Machulda Mary M. , Petersen Ronald C. , Jack Clifford R. , Dickson Dennis W. , Nguyen Aivi T. , Reichard Ross R. , Carter Rickey E. , Lowe Val J. , Vemuri Prashanthi , Murray Melissa E. , Murray Melissa E. 
Published: December 2023

AbstractBackgroundThere is a gap in knowledge concerning which tangle maturity levels (Moloney, Alzheimers Dement, 2021) are associated with antemortem measures (tau‐PET, MRI, cognitive testing). We hypothesized antemortem measures would be more strongly correlated with markers recognizing middling to advanced tangle maturity. We additionally sought to assess the strength of the relationship with tangle and neuritic pathology recognized by tangle maturity markers.MethodPosterior hippocampi from n = 30 cases with antemortem measures ≤3 years prior to death were cut (5µm) and immunostained with tau antibodies to evaluate early (AT8), middling (PHF‐1), or advanced (2E9) tangle maturity. GENIE (pattern recognition software) separated tangle from neuritic burden (Figure). Hippocampus, parahippocampus, and fusiform were analyzed to correlate digital pathology with flortaucipir tau‐PET standard uptake value ratio (SUVr, cerebellar crus normalization), MRI volume/thickness, and cognitive measures which included Auditory Verbal Learning Test (AVLT) delayed recall, Mini‐Mental State Exam (MMSE), and Clinical Dementia Rating (CDR).ResultThe strongest relationships observed with flortaucipir were with PHF‐1 and 2E9 burden (Table). AT8 tangle and neuritic burden correlations with flortaucipir were relatively similar in the hippocampus but were stronger with neuritic pathology in parahippocampus and fusiform. PHF‐1 tangle and neuritic burden correlations were relatively similar with flortaucipir. 2E9 correlations were stronger with neuritic pathology in hippocampus. MRI measures were more strongly correlated with PHF‐1 and 2E9 burden. AT8 tangle and neuritic burden were correlated with fusiform thickness. The correlations between MRI measures and 2E9 tangle and neuritic burden were similar. Correlations between cognitive measures were similar between tangle maturity markers. AVLT delayed recall correlated with all tangle maturity markers, but neuritic burden was stronger for AT8 and 2E9 in hippocampus compared to tangle burden. MMSE correlated with neuritic burden for all tangle maturity markers. CDR remained statistically non‐significant.ConclusionInterpretation of the strength of the relationship between tau burden and antemortem measures differed across tangle maturity markers. Neuroimaging measures may be more sensitive to middle/advanced maturity markers with limited differences between tangle and neuritic pathology. These findings may be biologically relevant and imply either a limited recognition of tangles depending on antibody epitope, and/or may represent the clinicoradiologic impact of increasing neuritic burden.
Development of innovative chalcone derivates targeting neuroprotective effects in Alzheimer disease
Authors: Haas Murillo Orsatto , Ruaro Thaís C , Gosmann Grace , Zimmer Aline R. 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a progressive neurodegenerative disturb that has reached global epidemic proportions. As a complex multifactorial disease affecting different cells in CNS, and with no effective treatment, developing new neuroprotective agents is critical (Therriault, J. et al, 2022). Based on that, a series of innovative molecules based on chalcones of natural origin was developed. Their cytotoxicity and neuroprotective effects were evaluated in silico and in vitro experimental platforms. Flavonoid derivatives are known for their anti‐inflammatory and antioxidant potential in AD (DAS, S. et al, 2017), however, there are few studies relating the action of the flavonoids' precursors called chalconoids (GOMES, M.N. et al., 2017).MethodThe research was carried out in two stages. The first stage was performed in silico, where virtual platforms were used to determine and predict the drug‐like characteristics of compounds and their ability to permeate by the blood‐brain barrier (BBB). The second stage evaluated the in vitro cytotoxicity in healthy cell lines (Vero and C6) and the neuroprotective effect against glutamatergic and oxidative insults in astroglial cells. In addition, the in vitro evaluation of cell viability was carried out using colorimetric methods (SRB and MTT). The neuroprotector effect was evaluated after pre‐exposure of cells to molecules under study.ResultRegarding the tested compounds, nineteen in the series presented adequate drug‐like properties and low or no cytotoxicity. Among them, three showed significant neuroprotective potential against both insults (oxidative stress and glutamatergic excitotoxicity) in astroglial cells, keeping the cell viability between 70% and 80%. In addition, these compounds have a high potential to cross the BBB and will proceed to the in vivo pre‐clinical studies phase.ConclusionThe designed chalconoids showed low cytotoxic potential and chemical characteristics compatible with oral use and passage through BBB. These results suggest chalcone derivatives as promising multi‐target agents preventing AD.
Cardio‐autonomic control and cognitive decline in older adults
Authors: Gao Chenlu , Lim Andrew , Yu Lei , Bennett David A. A , Gao Lei , Hu Kun , Li Peng 
Published: December 2023

AbstractBackgroundCardiovascular diseases may be linked to dementia pathogenesis. The cardio‐autonomic control (CAC) plays an important role in the development of cardiovascular diseases and may be implicated by dementia pathophysiology. We tested whether the CAC proxied by the complexity of beat‐to‐beat pulse rate intervals (PRI) predicted longitudinal cognitive decline in older adults.MethodContinuous overnight pulse oximetry (photoplethysmography) data from 594 participants (mean age = 82.76±7.11 at oximetry assessment; 76% female) in the Rush Memory and Aging projects were studied. All participants completed cognitive assessments at oximetry baseline. Eighty‐four participants who had at least one follow‐up cognitive assessment were included in the analyses. After quality control, the feet of pulse waves in the photoplethysmography data were detected, and the consecutive foot‐to‐foot internals (i.e., PRI) time‐series within each 10‐min window were analyzed using the distribution entropy that evaluated the complexity of PRI (i.e., greater distribution entropy means more complex dynamics). To reduce behavioral and circadian effects, we used the mean distribution entropy values during 12AM‐3AM for each individual. Mixed‐effects models were constructed to associate distribution entropy to longitudinal cognitive changes, adjusting for age, sex, and education.ResultAt baseline, distribution entropy was normally distributed (mean = 0.33±0.14). On average, the global cognition score was 0.12 units (SD = 0.60). This score declined at an annual rate of 0.15 units (SE = 0.04; p = 0.0001). The distribution entropy was not associated with global cognition at baseline, but greater distribution entropy predicted slower cognitive decline. Specifically, a 1‐SD increase in distribution entropy correlated with a drop of 0.11 (SE = 0.04; p = 0.005) in the rate of cognitive decline.ConclusionThe nighttime CAC (potentially during sleep) is linked with longitudinal cognitive profiles in older adults. As the CAC is regulated by an internal body clock—the circadian system, in which a dysfunction is involved in Alzheimer’s pathogenesis, it is possible that the CAC underlies the connections of cardiovascular disorders and circadian dysfunction with Alzheimer’s disease and its clinical outcomes. Future studies are warranted to test these hypotheses. Further studies should also investigate whether CAC at different times of the night has different correlations with cognitive changes and whether CAC predicts Alzheimer’s disease.