bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarker analyses from the phase 2, randomized, placebo‐controlled ACT‐AD and open‐label extension clinical trials of fosgonimeton in patients with mild‐to‐moderate Alzheimer’s disease
Authors: Moebius Hans J. , Ooi Kai‐Bin C. , Hale Michael D. , Setti Sharay E. , Kleist Kayla N. , Pan Josh , Church Kevin J. , Sabbagh Marwan 
Published: December 2023

AbstractBackgroundDespite the multifactorial nature of Alzheimer’s disease (AD), research has primarily targeted amyloid‐beta and tau; other approaches are needed. Fosgonimeton, a small‐molecule positive modulator of the hepatocyte growth factor (HGF)/MET system, was evaluated in a randomized, double‐blind, placebo‐controlled, 6‐month, exploratory phase 2 trial (ACT‐AD; NCT04491006)a and an open‐label extension trial (NCT04886063)a.MethodTo evaluate fosgonimeton in participants with mild‐to‐moderate AD, changes from baseline (CFB) in plasma biomarkers were compared with placebo in post hoc analyses. Multifactorial correlations were assessed against the global statistical test (GST), a composite score of cognition (ADAS‐Cog11) and activities of daily living (ADCS‐ADL23) assessments. Blood samples from baseline (n = 59‐61) and week 26 were assessed for biomarkers of neurodegeneration (NfL), neuroinflammation (GFAP; YKL‐40), and proteinopathy (Aβ42/40 ratio; p‐Tau181).ResultBaseline biomarker levels were similar between treatments. An ANOVA, including baseline levels, yielded a statistically significant CFB in NfL (−6.49 pg/mL; SE, 2.79; p = 0.0241) and numerical improvements in GFAP (−35.17 pg/mL; SE, 30.0; p = 0.2469), YKL‐40 (−47.37 ng/L; SE, 27.5; p = 0.0916), Aβ42/40 ratio (0.006; SE, 0.0035; p = 0.0938), and p‐Tau181 (−0.67 pg/mL; SE 0.60; p = 0.2715) were observed in fosgonimeton‐treated participants versus placebo, each without background therapy. APOE4 genotype, baseline Mini‐Mental State Examination score, sex, or age did not affect results. Additional biomarker and correlation analyses are being conducted. The potential association of biomarkers with clinical outcomes is supported by the CFB relative to GST, which significantly correlated with changes in NfL (r = 0.40; p = 0.0023) and GFAP (r = 0.35; p = 0.0408).ConclusionIn this first randomized, placebo‐controlled, 6‐month trial of fosgonimeton, a statistically significant reduction in NfL and numerical improvements in GFAP, YKL‐40, Aβ42/40, and p‐Tau181 plasma concentrations were observed, suggesting a multimodal neuroprotective mechanism of action of fosgonimeton and potential to impact AD‐specific proteinopathies. The significant correlation of NfL and GFAP reduction with the composite endpoint further supports potential clinical relevance.
aThe ACT‐AD trial and open‐label extension thereof are supported by a grant from the National Institute on Aging of the National Institutes of Health (award number R01AG06268). The information presented herein is solely the responsibility of Athira and does not necessarily represent the official views of the National Institutes of Health.
Investigation of neighborhood disadvantage in the context of APOE‐associated amyloid onset age risk
Authors: Irizarry‐Pagan Erica E , Teague Jordan P , Buckingham William R. , Cody Karly Alex , Langhough Rebecca E , De Chavez Elena Ruiz , Navaratna Ruvini , Okonkwo Ozioma , Asthana Sanjay , Johnson Sterling C. , Kind Amy J. , Bendlin Barbara B , Powell W. Ryan , Zuelsdorff Megan , Betthauser Tobey J 
Published: December 2023

AbstractBackgroundExposome social determinants of health (SDoH), such as neighborhood disadvantage, have shown associations with accelerated cognitive decline, brain volume loss, and postmortem AD pathology. However, associations between neighborhood disadvantage and amyloid biomarker positivity (A+) onset remain understudied. This study uses estimated A+ onset age (EAOA) and the Area Deprivation Index (ADI; an exposome SDoH) to investigate associations between neighborhood disadvantage and A+ risk.MethodsParticipants (n = 599, Table 1) from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and the Wisconsin Alzheimer’s Disease Research Center (WADRC) with available amyloid PET, address, and APOE genotype were included. EAOA was estimated using sampled iterative local approximation. Neighborhood disadvantage was categorized by national‐rank 2020 ADI (most disadvantaged ≥80th percentile; least disadvantaged <80th percentile). APOE groups were established based on the number of e4 alleles. Cox proportional hazard models assessed A+ risk associated with APOE, ADI, and their interaction. Secondary Cox models used continuous ADI and a lower 70th ADI percentile for neighborhood groups. Kaplan‐Meier curves were generated to depict A‐ probability vs. age for combinations of APOE and ADI groups. A‐ were right censored.ResultsA significant interaction (p = 0.015) between ADI and APOE groups was observed such that APOE‐e4 homozygotes who resided within a highly disadvantaged neighborhood had higher risk of becoming A+, but this group was limited to two participants. Secondary analyses indicated no significant effect of ADI or interaction with APOE on A+ risk (p>0.49). Plots of A+/‐ and EAOA by ADI and APOE group (Figure 1) and Kaplan‐Meier EAOA curves indicated EAOA overlap of ADI groups within APOE strata. A+ risk was significantly higher for APOE‐e4 homozygotes, followed by APOE‐e4 heterozygotes, and then APOE‐e4 non‐carriers.ConclusionsIn this mostly unimpaired, highly educated sample, higher number of APOE‐e4 alleles was associated with higher A+ risk and earlier A+ onset. APOE‐associated A+ risk was similar for all ADI groups, but representation across APOE genotypes for individuals residing within highly disadvantaged neighborhoods was limited. Further work is needed in more diverse samples to investigate the possible influence of ADI and other exposome SDoH factors on AD biomarker timing and trajectories.
Differential sex associations of regional adiposity with cognition and brain pathology in Israeli older adults with Type II Diabetes
Authors: Boccara Ethel , Golan Sapir , Ganmore Ithamar , Ravona‐Springer Ramit , Ben‐Meir Mery , Livny Abigail , Inbar Yael , Heymann Anthony , Beeri Michal S 
Published: December 2023

AbstractBackgroundAdiposity and Type II diabetes (T2D) are consistently associated with cognitive impairment and dementia. Body mass index (BMI) is the most common measure of global adiposity, but its associations with cognition in old age are inconsistent. BMI does not represent regional fat distribution, which might differ between the sexes. In this study, we examined sex differences in the relationships of regional adiposity with cognition and AD‐related brain volumes in older adults participating in the Israel Diabetes and Cognitive Decline study.MethodsRegional adiposity was measured by abdominal MRI in 89 participants (32.6% women), including hepatic and pancreatic fat, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Participants were assessed for global cognition, episodic memory (EP), working memory (WM), executive function (EF), and language. A subsample (N = 50) underwent brain MRI assessing total gray matter [GM], hippocampus, inferior, middle, and superior frontal gyrus [IFG, MFG, and SFG, respectively]. Linear regressions examined associations of regional adiposity with cognition and AD‐related brain volumes adjusting for age, sex, education, and BMI (and intracranial volume for MRI measures).ResultsIn the whole sample, higher pancreatic fat was associated with lower EF (r = ‐0.369, p = 0.024). In men, high pancreatic fat was associated with lower global cognition (Men: r = ‐0.311; p = 0.048; Women: r = ‐0.122; p = 0.706), EF (Men: r = ‐0.384; p = 0.033; Women: r = ‐0.508; p = 0.661) and language (Men: r = ‐0.309; p = 0.049; Women: r = 0.082; p = 0.798). In the whole sample, no associations were found between pancreatic fat % and AD‐related brain volumes. Surprisingly, in men, higher pancreatic fat was associated with greater GM volume (Men: r = 0.411; p = 0.046; Women: r = ‐0.231; p = 0.521). In women, higher pancreatic fat was associated with smaller IFG (Men: r = ‐0.185, p = 0.386; Women: r = ‐0.642, p = 0.045). Hepatic fat %, VAT, and SAT did not associate with AD‐related brain volumes or cognitive measures.ConclusionIn Israeli older adults with T2D, different regional fat depots are linked to different cognitive and brain outcomes in men and women. Specifically, more pancreatic fat, but not other fat depots, is associated with poorer cognition. These findings highlight the value of examining distinct fat depots rather than global obesity concerning brain and cognition, and the need to account for sex differences in these associations.
Exploring the involvement of oligodendrocytes in Alzheimer’s disease using human iPSCs
Authors: McQuade Courtney A ,   Research Group of Dr. Sarah Jäkel ‐ ISD Munich ‐ Oligodendrocyte Pathology
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a chronic neurodegenerative disease, characterized clinically by cognitive and neuropsychiatric impairments, and pathologically by extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuroinflammation which ultimately leads to neurodegeneration and dementia. Despite extensive research, no effective treatments have been identified to date, and many clinical trials have failed. This is due, in part, to a lack of human‐specific models for evaluating the contribution of non‐neuronal cell types to the disease pathogenesis; an issue we aim to address with our research into the pathogenic contributions of oligodendrocytes to AD.MethodTo investigate the role of OLs in AD, we are analyzing post‐mortem human brain tissue of AD and appropriate control samples to assess OL distribution between cortical areas with different disease burdens within the same patient using transcriptomic and immunohistochemical approaches. To complement our observations in the human brain, we are using human iPSC‐derived oligodendrocyte model systems in 2D and 3D to study how AD‐associated mutations, as well as exposure to AD‐related environmental stress may impact OL physiology.ResultThus far, our analysis of post‐mortem human brain tissue has revealed region and layer‐specific loss of oligodendrocytes in AD. With our in‐vitro models, we have seen morphological differences between human iPSC‐derived OLs carrying AD‐related mutations and isogenic wild‐type controls. We study OL/neuronal interactions in our in‐vitro model systems, as well as in‐vivo via transplantation of iPSC‐derived OL‐precursors into myelin‐deficient mice to allow visualization of their myelination capacity.ConclusionOligodendrocytes (OLs) are known primarily as the myelinating cells of the central nervous system, but have other important functions as well, including providing trophic support to neurons. Accumulating evidence suggests that OLs play an active pathogenic role in AD ‐ historically considered a neuronal disease ‐ but this role has not yet been investigated. The methods we are implementing will help us to identify OL‐mediated mechanisms which may contribute to the pathogenesis and progression of AD, to shed new light on a prevalent neurodegenerative disorder, and to identify novel therapeutic approaches in the future.
Life course exposure to air pollution and the risk of mild cognitive impairment and dementia in the Lothian Birth Cohort 1936
Authors: Jutila Otto‐Emil Ilmari , Welstead Miles , Mullin Donncha S , Tomlinson Samuel , Vieno Massimo , Cox Simon R , Baranyi Gergo , Russ Tom C , Luciano Michelle , Karlsson Ida K 
Published: December 2023

AbstractBackgroundAir pollution has been associated with the risk of pathological cognitive decline and dementia (Chandra et al., 2022). Past research has focused on cross‐sectional associations or short‐term exposure measurement, and there is a lack of studies investigating the impact of air pollution throughout the life course of the individual which examines sensitive periods. In this study, the relationship of air pollution exposure at different periods across the life course and the risk of dementia and mild cognitive impairment (MCI) was investigated.MethodHistoric fine particulate matter (PM2.5) was modeled using the EMEP4UK atmospheric chemistry transport model for several time periods (1935, 1950, 1970, 1980, and 1990) was combined with contemporary data for time period 2001 and 2007 to calculate the lifetime exposure for 576 participants of the Lothian Birth Cohort (LBC) 1936 who had information about lifetime residential history.There were 69 individuals with all‐cause dementia from age 70 years (baseline) onwards were clinically ascertained and 156 individuals with MCI derived at the ages 76, 79, and 82 years according to the NIA‐AA workgroups guidelines. A multivariable Cox proportional hazards model was developed to investigate associations between PM2.5 exposure at each time period with both cognitive outcomes, adjusting for sex, parental occupational social class (OSC) and of Apolipoprotein e4 allele (APOE4) status, childhood smoking (<16 years), years of education, adulthood OSC, smoking status at age 70, and early retirement (<60 years) dependent on time period.ResultHigher exposure (1SD [0.25µg/m3]) of PM2.5 in later life (2007, age 71 years) had a statistically significant (P = 0.0262) association with increased risk of MCI (HR 1.25, 95% CI 1.02‐1.54) and other time periods were positively associated but not statistically significant (P>0.05). There was no statistically significant (P>0.05) association between PM2.5 exposure at any time period and risk of all cause dementia.ConclusionLater life exposure to PM2.5 had a positive association with MCI which could suggest that this is a sensitive period in the life course model. This could indicate that people in later life are more susceptible to the impact of air pollution on cognitive decline and therefore risk of MCI.
Effects of binge alcohol administration on tauopathy and neuroinflammation in PS19 mice
Authors: Colin Samantha , Lee‐Gosselin Audrey , Perkins Abigail , McKinzie David , Oblak Adrian L 
Published: December 2023

AbstractBackgroundIt is estimated that 50 million people worldwide are suffering from dementia, the most common being Alzheimer’s disease (AD). Even as the population ages and the incidence of AD increases, there are limited disease‐modifying treatments to date. Alcohol use disorders (AUD) have been identified as a modifiable risk factors for developing AD. Heavy alcohol intake in elderly individuals is associated with more rapid progression of AD pathology and an elevated neuroinflammatory state. The objective of this study was to investigate the interaction of high ethanol ‘binge’ treatments in a mouse model of tauopathy.MethodPS19 mice, a widely used tauopathy model, were subjected to a 5‐week binge paradigm of IP ethanol administration, 3.0g/kg, three times per week, beginning at 6 months of age. Prior to initiation of the binge ethanol regimen, mice received subcutaneous biotransponder implantations to record body temperature changes in response to ethanol. Blood ethanol concentrations were determined in a subset of mice at 30 minutes following the last ethanol administration. Frailty measures were completed one week after ethanol administration. NanoString unbiased gene expression, MesoScale Discovery ELISA, Western blotting, and Immunohistochemistry were performed to examine neuroimmune changes and markers of tau pathology.ResultOverall, ethanol treatment resulted in reduced body weight, which was further exacerbated in female PS19 mice.. Measures of frailty (i.e. cerebellar ataxia and grip strength) were impaired in PS19 mice, however, female PS19 mice receiving ethanol treatment had the greatest impairments compared to WT controls. Alterations in inflammatory signaling pathways were observed in the PS19 animals receiving alcohol treatment compared to PS19 or WT mice.ConclusionWe have examined the result of intermittent alcohol exposure on tau pathogenesis. In the present study we found that alcohol can induce biometric and behavioral changes in mice, which are further exacerbated by alcohol. Transcriptomic analysis indicated changes in both innate and inflammatory signaling, suggesting a increased inflammatory response in the ethanol treated animals. Taken together, these results suggest that intermittent environmental influences, such as ethanol, can result in more rapid progression of AD pathogenesis.
Screening older adults for potential deficits in IADL using the Menu Task and Medi‐Cog‐R
Authors: Marks Timothy S , Giles Gordon Muir , Kehl‐Floberg Kristen E , Edwards Dorothy F. 
Published: December 2023

AbstractBackgroundThe identification of deficits in functional performance is critical to sustaining the community independence of older adults. Screening for difficulties in the performance of cognitively demanding instrumental activities of daily living (IADL) can facilitate earlier identification of and intervention for people with impairment (Rodakowski et al., 2014). We examined whether two brief performance‐based screening measures ‐ the Menu Task and the Medi‐Cog‐R ‐ can identify those at risk of functional cognitive deficits as indicated by poor performance on the Weekly Calendar Planning Activity (WCPA).MethodUsing a cross‐sectional design we administered the Menu Task, Medi‐Cog‐R, and the WCPA to community dwelling adults 55 years of age and older (N = 280). Using established cut scores, we examined the sensitivity and specificity of the two screening measures to poor performance on WCPA Accuracy (≤ 20th percentile). Known‐group construct validity were examined by comparing impaired and unimpaired groups on the screening measures on subtests of the WCPA.ResultThe sample was 73.57% female and 73.57% white. Mean age was 69.72 (SD = 8.81) and mean education was 15.61 (SD = 3.30) years. The Menu Task demonstrated a sensitivity of .84 and a specificity of .62 and the Medi‐Cog‐R demonstrated a sensitivity of .77 and a specificity of .66 in correctly classifying individuals with potential for impaired IADL as indicated by a score at or below the 20th percentile on the WCPA. The impaired groups on both screening measures scored significantly lower on WCPA subtests of Accuracy, Appointments Entered, Efficiency, Rules, and Strategies than the unimpaired group (p < .001).ConclusionThe Menu Task and the Medi‐Cog‐R could both alert clinicians to the potential for functional cognitive deficits and need for IADL support in community dwelling older adults. Performance‐based screening measures of functional cognition can be used to prompt further assessment and intervention to promote community independence.
Modifications in the perceptions about the use of mobile phones in old people after an interplay program using technological devices
Authors: Sarmiento Elsa Araceli Revollo , Vivas Leticia , Moreno Maria Celeste López 
Published: December 2023

AbstractBackgroundIn the elderly the management of technology has a great impact to nurture their autonomy (Camacho Coronel et al., 2019). In this work, we propose to study whether perceptions change after people´s exposure to the use of technology through a general technology program or a more specific mobile‐phone use program. Sample: 28 elderly people (between 65 and 90 years) without cognitive impairment.MethodAn experimental study was carried out with two groups (experimental GE and active control GC) matched in age (p = .620), educational level (p = .757) and experience in the use of technologies (p = .321). Both groups received training (3 months) through the use of tablets. Subsequently, the GE received an additional two‐week training on the use of cell phones. The Technology Acceptance Questionnaire (Chen & Chan, 2014) oriented to cell phone use was administered before and after the intervention.ResultBy means of the Friedman test, comparisons were established between the pre and post intervention measures with all the participants on the variables of acceptance of the technology. Significant differences were observed in Self‐efficacy (p<0.05), Utility (p<0.05) and Anxiety (p<0.05). Subsequently, the analysis was divided into groups and it was observed that the EG presented significant values in Anxiety (p = 0.03), Utility (p = 0.02) and Self‐efficacy (p = 0.08), while the CG presented significant values in Self‐efficacy (p = 0.08) and values that were not significant, although they were close in usefulness (p = 0.096) and anxiety (p = 0.059). The variables conditions of Facilitation and Attitude toward use did not present significant changes in any group.ConclusionThe results indicate that the measure of Self‐efficacy in the use of technology improves in older people after using a technological product for a while. However, the group that received training in the use of the cell phone also increased the Perceived Utility and Anxiety in the use of technology. In old age, knowing the usefulness of technology and self‐perceiving how effectively it can be used can generate benefits such as greater security and decreased anxiety in the face of technology.
Mechanistic insights into the therapeutic potential of Angiotensin type 2 receptors (AT2R) in shaping behavior of astrocytes and microglia during hypertensive state
Authors: Bhat Shahnawaz A 
Published: December 2023

AbstractBackgroundAstrocytes are the major glial cell type in the central nervous system (CNS) and play a critical role in the pathogenesis of neuroinflammatory and neurodegenerative diseases. In particular, astrocytic activation during neuroinflammatory conditions perpetuates the inflammatory response and brain damage and neurodegeneration. Conversely, Angiotensin type 2 receptor (AT2R) activation is known to promote neuroprotection.MethodTherefore, the present study evaluated the role of AT2R in astrocytic activation in vitro in primary astrocytes and in vivo in hypertensive rats.ResultHere, we demonstrated that Ang II‐induced astrogliosis in primary astrocytes as apparent from increased expression of GFAP and iNOS, ROS generation, inflammatory imbalance and mitochondrial dysfunction in the primary astrocytes. On the contrary, AT2R activation by CGP42112A (CGP) abrogated Ang II induced astrocytic activation by inhibition of ROS production, mitochondrial dysfunction and inflammatory imbalance. However, this anti‐inflammatory action of AT2R activation by CGP was reversed by AT2R antagonist, PD123319 in both in vitro and in vivo conditions. Mechanistically, we found that AT2R via protein phosphatase‐2A (PP2A) activation abrogated the Ang II induced NFкB activation, ROS generation and consequent pro‐inflammatory activation of astrocytes. Importantly, PP2A antagonist, okadaic acid, reversed the anti‐inflammatory action of CGP to the comparable level as that by AT2R antagonist PD123319.ConclusionThus, the present study suggests that AT2R by the activation of PP2A abrogates the NFкB inflammatory signalling and inflammatory activation of astrocytes. Therefore, the therapeutic strategies targeting AT2R might be advantageous for neuroinflammatory or degenerative diseases perpetuated by astrocytic activation.