bluuebunny/crossref_metadata_2025_split huggingface dataset:
The detection of phosphorylated tau in tear fluid
Authors: Molfetta Guglielmo Di , Demleitner Antonia Franziska , Gomes Lucas Arujo Caldi , Jeromin Andreas , Vanmechelen Eugeen , Blennow Kaj , Zetterberg Henrik , Lingor Paul , Ashton Nicholas J. 
Published: December 2023

AbstractBackgroundThe recent development of ultrasensitive immunological methods has allowed for the detection of biomarkers related to neurodegenerative disorders in blood, e.g., phosphorylated tau (p‐tau). This allows for a cost‐effective and scalable assessment of the causes behind cognitive decline. Nevertheless, other biofluids, e.g., tear fluid, have the potential to surpass these metrics. Previously, tear fluid from patients with neurodegenerative conditions has been explored both with mass‐spectrometry and immunoassays. Hereby, we established a method for the detection of p‐tau181, p‐tau217 and p‐tau231 in tear fluid from patients.MethodA total of 40 participants with neurodegenerative diseases (amyotrophic lateral sclerosis [n = 11], dementia [n = 9], Parkinson’s disease [n = 20]) and control subjects without clinical signs of neurodegeneration [n = 20], were recruited at the Department of Neurology at the Klinikum rechts der Isar, München, Germany. Tear fluid from both eyes was collected with Schirmer strips. The strips from both eyes were combined and eluted by centrifugation (16,000g) in sample buffer. The eluate was then analysed for p‐tau181, p‐tau217 and p‐tau231 by Single molecule array (Simoa). Results were normalised to tear fluid running length.ResultAll tear fluid samples were above the lower limit of detection (LLOD) for all p‐tau assays ([mean] p‐tau181, 92.1pg/ml; p‐tau217, 0.398pg/ml; p‐tau231, 52.9pg/ml) improving on previous attempts found in literature. There was a highly significant correlation between all p‐tau biomarkers in tear fluid (r = 0.90–0.98; P<0.001). The normalised concentration of tear fluid p‐tau had a significant positive correlation with age (R
p‐tau181 = 0.28, R
p‐tau217 = 0.27, R
p‐tau231 = 0.39; P<0.05) but there was no association with the corresponding p‐tau in serum. No significant group differences in tear fluid p‐tau were observed but a trend towards increased serum p‐tau181 was found in the neurodegenerative group (6.37pg/ml) compared to controls (4.37pg/ml).ConclusionIn this pilot study, we describe quantifiable levels of p‐tau181, p‐tau217 and p‐tau231 in tear fluid samples. However, the detectable levels of p‐tau in tear fluid do not seem to correlate to p‐tau levels in serum. Further studies will show p‐tau in tear fluid of patients with suspected AD, stratified by CSF biomarkers, and thus establish the relevance of tear fluid as a diagnostic biofluid in AD.
Neuromodulation for Mild Cognitive Impairment: Improvements in Spatial Navigation and Associative Memory with Acute Transcutaneous Vagus Nerve Stimulation: VINCI‐AD
Authors: Dolphin Helena , Dyer Adam H , Dukelow Tim , Commins Sean , Finucane Ciaran , Kennelly Sean 
Published: December 2023

AbstractBackgroundNew therapeutic strategies to treat Mild Cognitive Impairment (MCI) are urgently needed. Transcutaneous Vagus Nerve Stimulation (tVNS) is a neuromodulation technique which uses a handheld device to peripherally stimulate the afferent vagus nerve. tVNS has shown promise in augmenting memory in cognitively healthy populations but data in cognitively impaired populations is sparse.MethodVINCI‐AD is an investigator‐led, single‐blind, sham‐controlled crossover pilot study assessing the effects of tVNS in amnestic MCI. All participants have MCI (CDR global 0.5) with amnestic neuropsychological profile (RBANS delayed memory index <85). Participants are randomised over 3 study visits to baseline (no stimulation) active stimulation (at the CC of left ear) or sham stimulation (earlobe). Cognitive tests include Face‐Name Association Task (FNAT), Sustained Attention Response Test (SART) and Sea Hero Quest Navigation Test (SHQ) among others.ResultInterim data analysis of 28 participants is presented (mean age 71.5 (range 55‐85), 17 male, RBANS DMI 73.3 ±11.1). CSF AD biomarkers were positive for 75% (21/28) (AB‐42 460.4pg/ml (± 83.3pg/ml) and p‐tau181 82.5pg/ml [± 53.2pg/ml]) and 78% (22/28) of participants had a Charleston Comorbidity Index of ≥3. Mean tVNS stimulation time pre‐cognitive assessments was 21.2 minutes, with mean amplitude setting during active stimulation of 2.5mA (1.8‐4.5) and sham of 2.0mA (0.9‐3.1). During FNAT, active tVNS had no effect on facial recognition or reaction times, however recall accuracy was significantly improved (69.2% ±3.13) compared to baseline (44.7% ±3.51 p = 0.016) and sham (50.1% ±3.28 p = 0.021) and during active tVNS spatial navigation (38.94sec [±1.68]) was quicker than baseline (51.49sec (±3.2) p = 0.0164) and sham (51.9sec (±3.15) p = 0 .0038). We noted no significant improvements in SART or other cognitive tests performance during tVNS.ConclusiontVNS may be a useful complementary tool to augment spatial and associative memory in MCI. Further larger studies are needed to delineate precise settings in this population.
The impact of air pollution and pollutants on the progression of dementia
Authors: Li Chien‐Hsun , Tsao Yu‐Hsiang , Ho Pei‐Shan 
Published: December 2023

AbstractBackgroundAir pollution is known to increase the incidence of dementia, but whether dementia in areas with high air pollution likely to get worse is still unclear. We investigate the impact of high air pollution areas on the progression in dementia, and which air pollutants have more obvious influences.MethodA retrospective case‐control study was performed using the data from the Kaohsiung Medical University Hospital Research Database and Environmental Protection and Administration, Taiwan. Clinical data and air pollution data were concatenated with addresses to assess the exposure to each case. Further, divide Kaohsiung into areas with severe air pollution and compare them with general areas. Exacerbation of dementia was defined as detection with use of advanced medications. We constructed conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs).ResultThere were 529 cases in the group of worsening dementia and 2351 cases in the control group. The OR of dementia exacerbation in the general area is significantly lower than that of the high SO2 exposure area (OR: 0.745, 95% CI: 0.616‐0.901). Exposure to SO2 and PM2.5 at all five time points studied were significantly associated with an increased risk of worsening dementia of all types and non‐degenerative types. The maximum total peak ORs (95% CI) were 1.285 (1.154–1.431) in the first year with exposure to high SO2 and 1.111 (1.043–1.183) in the four years with exposure to high PM2.5, respectively. In the dementia of degenerative types, exposure to SO2 were significantly associated with an increased risk of worsening dementia. The maximum total peak ORs (95% CI) were 1.386 (1.174–1.638) in the first year.ConclusionThis study confirms that cumulative exposure in the previous one to five years in high‐exposure areas has a significantly higher risk of all dementia worsening. SO2 pollutant has the obvious effect on the progression of dementia of all types, degenerative and non‐degenerative types. PM2.5 pollutant has the obvious effect on the progression of dementia of all types and non‐degenerative types. The protection from air pollution, especially SO2 and PM2.5 pollutants is very important in the treatment of dementia.
Modeling and Simulation to Inform Potential New Strategies for BACEi in Treatment of Alzheimers Disease
Authors: Stone Julie A 
Published: December 2023

AbstractBackgroundThe β‐secretase‐1 inhibitors (BACEi), including verubecestat, were extensively studied in prodromal to moderate AD and demonstrated early cognitive decline at doses achieving >50% inhibition of amyloid production. Questions remain as to whether BACEi may still have utility, if used earlier in disease, in combination with other therapies, and/or at lower doses. Modeling and simulation approaches were used to maximize learnings from the prior trials and to make predictions around potential alternative therapeutic approaches.MethodTwo models were developed: 1) A joint plaque turnover model, linking drug exposure with amyloid plaque load (PET data in centiloids), to describe natural progression and treatment response to BACEi and amyloid mAb therapies. All plaque data from natural progression (control arms), BACEi and amyloid mAb treatment arms were well described by a joint model, after accounting for differences in baseline plaque load, dosing and titration regimens, and mechanism of action. 2) Disease progression models for the clinical efficacy outcomes (ADAS‐cog11, CDR‐SB) were developed using a methodology similar to Ref. Evidence for BACEi drug effects (on progression rate and/or early detrimental offset) was tested and dependencies on dose, drug exposure and patient characteristics were explored.ResultThe joint plaque turnover model well described natural progression and treatment response to BACEi and amyloid mAb and allows for prediction of alternative regimens and therapeutic approaches. Simulations indicate that 20‐30% inhibition of BACE would be sufficient to stabilize plaque loads in prodromal patients. Disease progression results for ADAS‐cog11 and CDR‐SB identified a verubecestat drug effect of early detrimental offset with no effect on rate of disease progression supported. The magnitude of the early detrimental offset was small relative to the overall progression seen over 18‐24 months and results suggested that this effect may be reduced in advanced AD patients. A simulation engine utilizing the progression model allows for estimation of sample size needed to check for the detrimental effect in future trials.ConclusionModel‐based simulations can help inform future BACEi therapeutic strategies and trial designs.
Reference: Clin Pharmacol Ther. 2015 Mar;97(3):210‐4
Exploring the value of hope in dementia
Authors: Furlano Joyla A , Bandler Zach , Dasgupta Jayashree , Fittipaldi Sol , Canty Alison Jane , McGettrick Grainne , Yasoda‐Mohan Anusha , El‐Jaafary Shaimaa Ibrahim , Ucheagwu Valentine A , la Cruz‐Góngora Vanessa De , Nguyen Kim Huong , Lawlor Brian , Haas Aline Nogueira 
Published: December 2023

AbstractBackgroundTo hope is to be human, and it has been examined in diverse disciplinary perspectives across theology, philosophy and anthropology. However, hope is more than an idea. It has the potential to positively impact people across the life course, particularly those living with conditions like dementia. Hope can be meaningfully experienced at the individual, group and community levels through its potent power to build resilience. Despite this significance, there are sizeable gaps in our knowledge of the brain mechanisms underlying hope.MethodWe explore how understanding hope as a neurobiological entity is an exciting prospect. As a possible key to tackling challenges of dementia, it could buoy the ability for patients and their families to cope with the devastation of diagnosis, as well as the sense of doom, anxiety, loss and despair that follows.ResultsThe literature suggests that hope may be situated in the frontal cortex, although more research in this area is needed. With an understanding of the neurobiological basis of hope, interventions focused on instilling hope to improve quality of life are needed urgently.ConclusionIf hope can be harnessed for brain health, both therapeutically and preventatively, it has the potential to be used as a ‘tool’ to improve patient and family experiences with dementia, as well as that of our greater society.
Association of Gut Microbiome with Diabetes Mellitus and Alzheimer’s Disease in a Puerto Rican Adult Population: A Preliminary Report
Authors: Soler‐Llompart Cecilia Michelle , Godoy‐Vitorino Filipa , Sala‐Morales Ana Cecilia , Santiago‐Berríos Michel , Ruiz‐Adames Javier A. , Olivieri‐Henry Gerianne , Herrero‐Rivera Carlos , Pérez‐Luzunaris Fabián J. , Sepulveda Vanessa 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia, consisting in a highly debilitating disorder, progressing from slight memory impairments to a complete loss of mental function, resulting in significant disability and death. In Puerto Rico, AD is the fourth leading cause of death. Caribbean Hispanics, including Puerto Ricans living on the island have shown a more severe AD symptomatology and disease mortality than any other ethnic group. This disparity may be due to health, diet, lifestyle, socioeconomic risk factors and more prevalent chronic health conditions such as diabetes in Hispanic people. Diabetes Mellitus is nowadays considered a risk factor for AD. Evidence suggests that the gut microbiome plays a role in the pathophysiology of AD through neuroinflammation and amyloid deposition leading to cognitive impairment. Main objective: Study the microbiome composition and diversity of Puerto Ricans with AD compared to cognitive‐intact controls in association with Diabetes Mellitus.MethodFifty‐three participants (n = 53), 28 with AD and 25 controls were evaluated clinically and cognitively with the Montreal Cognitive Assessment (MoCA) to associate the gut microbiome with cognitive impairment. Stool was collected for genomic DNA extractions and microbiome characterization. NextGen Illumina MiSeq was used to sequence 16S rRNA genes (V4 region) and analyzed with standard pipelines.ResultNo statistically significant differences in bacterial diversity and richness between AD vs. controls. We found slight differences in composition, including an abundance of Euryachaeota in AD, while controls had higher levels of Bacteroidetes. Compared to cognitively intact, a decrease in gut microbiome diversity was seen among participants with cognitive decline (p = 0.02). Roseburia (butyrate producing bacteria) seems to decrease with cognitive impairment severity. Diabetics have significantly reduced Anaerostipes and Ruminococcus also butyrate producing bacteria. AD participants with/without Diabetes have predominance of Euryarchaeota. Controls with Diabetes have more Proteobacteria and Bacteroidetes compared to cognitively impaired.ConclusionBoth Diabetes and neurocognitive decline appear to reduce butyrate‐producing bacterias, which may be related to a decrease in the homeostasis of the gut‐brain axis and lead to microbiome dysbiosis in the setting of disease. A better understanding of the gut microbiome will be an invaluable approach for development of modulation‐based therapeutic interventions.
Rate of clinical progression in mixed Limbic‐Predominant Age‐Related TDP‐43 Encephalopathy (LATE) and Alzheimer disease
Authors: Ospina‐Romero Monica , Salamat Shahriar , Betthauser Tobey J , Bendlin Barbara B 
Published: December 2023

AbstractBackgroundLimbic predominant age‐related encephalopathy neuropathologic change (LATE‐NC) is associated with amnestic type dementia. LATE‐NC frequently coexists with Alzheimer disease neuropathologic change (ADNC). It is unclear whether LATE and Alzheimer disease neuropathologic change interact or independently affect clinical disease progression.MethodsData was from 80 autopsied participants with TDP‐43 immunohistochemical studies from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention. We used linear mixed effects models to estimate associations of ADNC and LATE‐NC with rate of progression of Clinical Dementia Rating Sum of Boxes (CDR‐SB) and investigated whether co‐occurrence of these two pathologies would modify these trends.ResultsParticipants in our sample were 42% female with mean age at death of 77.8 years (SD 9.6). Neuropathologic diagnoses were low/intermediate ADNC in 20 (25%), high ADNC in 29 (36%), LATE‐NC in 8 (10%), and LATE‐NC + high ADNC in 23 (29%) participants. Clinical progression of cognitive impairment was faster in participants with high ADNC than in those LATE‐NC (Slopes:1.82 units/year [95% CI: 0.93‐2.71] vs 1.33 units/year [95% CI: 0.29‐2.38]) (Figure). Co‐occurrence of LATE‐NC + high ADNC predicted similar progression than high ADNC alone (Slope: 1.83 units/year [95% CI: ‐0.45 – 4.12]) demonstrating interaction (p = 0.013) between LATE‐NC and high ADNC.ConclusionLATE‐NC and ADNC are independently associated with clinical progression of cognitive impairment. Co‐occurrence of LATE‐NC and high ADNC is expected to have similar clinical progression than ADNC alone. Research is ongoing to examine differences among these groups using T1‐weighted volumetric imaging and CSF glial activation biomarkers.
Using Different Time Operationalizations To Investigate Relationships Among Amyloid PET, White Matter Hyperintensities, And Cognition In A Cognitively Unimpaired Sample
Authors: Langhough Rebecca E , Du Lianlian , Cody Karly Alex , Jonaitis Erin M. , Hermann Bruce P , Chin Nathaniel A. , Rivera‐Rivera Leonardo A. , Cadman Robert V. , Pompa Christian C. , Hudson Sarah , Christian Bradley T. , Eisenmenger Laura B. , Betthauser Tobey J , Johnson Sterling C 
Published: December 2023

AbstractBackgroundAmyloid‐PET and white matter hyperintensities (WMH) associations in older adults have variously been interpreted as separate or dependent processes. In this study, we examine evidence for a temporal relationship between amyloid‐PET and WMH and investigate how both contribute to cognitive decline in a baseline cognitively unimpaired (CU) sample.MethodWe analyzed longitudinal WMH and PACC3 cognition in n = 240 Wisconsin Registry for Alzheimer’s Prevention participants who were CU at cognitive baseline with ≥1 amyloid‐PET and T2‐FLAIR scan. Amyloid burden was assessed using [C‐11]Pittsburgh Compound B (PiB) PET and a multi‐ROI DVR value; DVR>1.19 = PiB+. WMH lesion volume was segmented and summed by the Lesion Segmentation Tool (LST) version 1.2.3 in SPM12 from T1‐weighted and T2‐weighted FLAIR scans; TIV‐adjusted WMH >2.06 = WMH+. Sampled iterative local approximation (SILA) modeling aligned biomarker levels to positivity duration scale (years = 0 at biomarker+ threshold). To investigate how amyloid burden relates to WMH trajectories, time at each WMH scan was operationalized four ways: age, ∼WMH+ duration, years_since_baseline_scan, and ∼PiB+ duration. We compared model fits and interaction effects for the various PiB status*time interactions (mixed effects models; retaining significant quadratic time terms; random slopes and intercepts). We also examined whether PACC3 age‐related trajectories differed by PiB/WMH +/‐ groups (at last scan).ResultMore women were WMH+ and APOE4 was more common among PiB+ (see also Table1). Significant interactions using age or years_since_baseline_scan suggested slightly faster WMH accumulation in PiB+ vs PiB‐ at older ages. In parallel models, WMH+ duration*PiB status and PiB+ duration*PiB status did not show differences between PiB+ and PiB‐ WMH trajectories. Time operationalized as WMH+ duration yielded the best fitting model (see Table2 and Fig1A‐D). PACC3 decline was fastest in the PiB+/WMH+ group, followed by PiB+/WMH‐ (Fig1E). PiB+ was more common than WMH+ and tended to precede it when both were present (Table1; Fig1F).ConclusionIn this baseline CU sample, WMH+ was less common and occurred later in life, on average, than PiB+. Associations between amyloid burden and WMH trajectories were driven by older ages, suggesting potential unidentified age‐related mediators in this relationship. Presence of both amyloid and WMH was associated with fastest preclinical cognitive decline.
AlphaFold 2 predicts opening of the tau hairpin conformation by Mapt mutations and the extent of opening reflects their location
Authors: Chain Daniel G , Margolin Richard A 
Published: December 2023

AbstractBackgroundDozens of Mapt mutations can cause FTD, but the molecular mechanisms involved are poorly understood. We recently reported that Pro301 mutations increase the susceptibility of full‐length tau (FLT) to caspase‐3 cleavage at Asp421, which produces the highly noxious C‐terminal fragment tauC3. We speculated that the increased susceptibility could be caused by exposing the cleavage site through impact on critical hairpin interactions between Ser432 and P301. In another study, we used the AI‐based AlphaFold 2 (AF2) algorithm to predict and compare structural models of FLT and tauC3. This revealed dramatic differences in their conformations: tauC3 has an open conformation while FLT is closed by a hairpin. We postulated that other Mapt mutations may also open the conformation of tau in the same way.MethodWe performed AF2 predictions on FASTA sequences of several 4‐repeat FLT variants: R5H, P301S, P301L, and R406W. We also obtained the predicted intramolecular distances between Ser432 and the MTBR to assess the effect of the mutations on the conformation of tau quantitatively.ResultThere were notable differences in the magnitude of opening across the variants. Rank order for openness (Figure) was tauC3 > P301L > P301S > R406W > R5H ∼ non‐mutated FLT. P301L had a strong effect that approximated the opening in tauC3. P301S and R06W had moderate effects, while R5H has a minimal effect.ConclusionThe finding that P301L’s effect was greater than that of P301S may be explained by leucine’s greater hydrophobicity. The relatively strong effect of both Pro301 mutations reflect this residue being closest to Ser432. The R406W mutation’s intermediate but lesser effect is consistent with its relative proximity to Ser432, while the lack of effect for R5H suggests that the extreme N‐terminus is minimally involved. Collectively, our data shows the power of AF2 to predict effects of sequence alterations. The findings also have important implications for understanding tau biology and the development of therapeutics for tauopathies.