bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meta‐analysis of age‐related cognitive decline reveals a novel locus for the attention domain and implicates a COVID‐19 related gene for global cognitive function
Authors: Acharya Vibha , Fan Kang‐Hsien , Snitz Beth E , Ganguli Mary , DeKosky Steve , Lopez Oscar L. , Feingold Eleanor , Kamboh M. Ilyas 
Published: December 2022

AbstractBackgroundCognition is a highly complex polygenic trait. A limited number of studies have explored the genetic basis of cognitive decline in aging populations using cognitive domain specific measures.MethodTo identify genetic markers for cognitive decline, we conducted a genome‐wide association meta‐analysis and gene‐based tests on five different cognitive domains (attention, language, executive function, visuospatial abilities, memory) and global cognition on 3,068 older individuals (≥65 years) of European ancestry derived from three prospective cohorts: Gingko Evaluation Memory Study (GEMS), Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). All subjects completed a comprehensive neuropsychological battery of tests covering the examined domains. A linear mixed effects model was used to estimate the longitudinal decline in cognitive scores after adjusting for sex, baseline age and education. Global cognitive decline was defined as a decline in average performance in neuropsychological tests across the five domains.ResultGenome‐wide significant association of APOE*4 was observed with decline in the memory domain (p= 8.93E‐09) and global cognitive function (p= 2.69E‐08).We identified a novel locus for decline in the attention domain on chromosome 9 in an intergenic region between RASEF/FRMD3 (p = 3.17E‐08). Gene‐based analysis identified TMPRSS11D as the top gene for decline in global cognition (Bonferroni corrected p= 2.48E‐06). TMPRSS11D plays a role in host‐defense system and recent studies have shown that it activates spike protein of SARS‐CoV‐2 and facilitates viral entry to cell (Viruses 2021;13:384; J Biol Chem 2021; 296:100135).ConclusionWe have identified a novel locus for longitudinal decline in the attention domain, replicated the association of APOE*4 with the global and memory domains, and potentially implicated the role of TMPRS11D in cognitive decline through gene‐based analysis. The association of TMPRSS11D with cognitive decline might help to explain cognitive impairment observed in some patients after COVID‐19 infection (Br J Anaesth 2021; 25:e54; JAMA Netw Open 2021; 4(10):e2130645 ). While functional studies might help to understand the underlying molecular mechanism of the associated loci, cognitive decline studies with larger samples are essential to establish these findings.
Biological characterization of the therapeutic role of Rab10 modulation in the development of Alzheimer’s disease
Authors: Murcia Josue D Gonzalez , Mollard Alexis , Bearss David 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia in the elderly. The continuous genetic research done on this disease demonstrates the vast complexity of the genetic architecture. The most recent whole‐genome sequence analysis (GWAS)included 1.1 million individuals and identified 38 loci associated with AD status with seven novel loci. However, there is no reliable therapeutics to combat the late stages of AD as of late. The identified rare variants in the RAB10 gene show protective effects against developing AD. This work demonstrates that inhibition of the expression of RAB10 yields better outcomes in terms of the amyloid‐beta ratio and cognition. In addition, we demonstrated that RAB10 modulates the NLRC4 inflammasome complex and their derived products IL‐1‐beta, IL‐18, and TNF‐alpha.MethodIn‐vitro experiments were carried out using human neuroblastoma (N2A) cell lines transfected with a mammalian plasmid to overexpress the APP gene and the immortalized microglia HMC3 cell line. We used the compound reference MLi2 and house compounds HT4253 and HT4403 to inhibit the expression of the RAB10. We used ELISA protocols to test the amyloid‐beta 40 and 42 ratios, IL‐1‐beta, IL‐18, and TNF‐alpha secretion. Western blots immunocytochemistry allowed us to determine the phosphorylation of RAB10 and LRRK2, LAMP1, and ASC. In‐vivo behavioral experiments were done using APP/PS1 mice. Hippocampus tissue was collected to run RNA sequence and total proteomics analysis.ResultA higher dosage of compound HT4253 and HT4403 inhibits phosphorylation of RAB10 with an IC50 of 82 nM and 63 nM, respectably. The inhibition of RAB10 and LRRK2 activates a higher expression of the LAMP1 protein. The incubation with a high compound dosage improved the secretion of the amyloid‐beta 42/40 ratio. The additional experiments and results will be presented at the conference.ConclusionThis work provides insights into the protective role of RAB10 against AD and neuroinflammation. RAB10 could be a promising therapeutic target for AD prevention.
Efficacy evaluation of a novel vectorized anti‐tau antibody, targeting a C‐terminal phospho‐tau epitope, using systemic dosing of a blood brain barrier penetrant AAV capsid in mouse models of tauopathies.
Authors: Liu Wencheng , Paranjpe Maneesha , Holth Jerrah , Clarke Blaise , Thompson Jeffery , Clement Joe , Knoll Elisabeth , Chung Charlotte , Adeluyi Adewale , Powers Alex , Kurella Vinodh , Kavanagh Dillon , Ezell Brian , Fiore Timothy , Grant Kyle , Hou Jay , Bales Kelly R. , Paul Steven M. , Carter Todd 
Published: December 2022

AbstractBackgroundAnti‐tau immunotherapy has become a promising therapy for Alzheimer’s disease (AD) and tauopathies. With the hypothesis that tau pathology spreads via cell‐to‐cell transmission, including trans‐synaptic propagation, success of anti‐tau immunotherapy relies, in part, on the identification of efficacious antibodies and their delivery to affected or vulnerable brain regions with sufficient or enhanced exposure in the CNS. We have previously demonstrated broad distribution and expression of vectorized anti‐tau antibodies in the mouse brain using a blood brain barrier penetrant capsid, VOY101, administered intravenously (IV).MethodSeveral novel anti‐tau antibodies that met the target profile have been generated and are being evaluated in vivo (Liu et al, submitted as a separated abstract in AAIC 2022).ResultOne of the antibodies discovered, antibody 1, exhibits strong affinity for PHF‐tau, demonstrates specific binding to tau pathology on brain sections of AD and PSP patients, and potently prevents PHF seeding and propagation in vitro and in vivo. This antibody recognizes a phospho‐specific epitope in the C‐terminal region of tau and shows significant reduction of tau pathology in an AD‐PHF induced P301S hippocampal seeding and propagation model. Furthermore, we have vectorized antibody 1 into an AAV expression vector with by BBB penetrant capsid and are evaluating it in two independent mouse models of tauopathy.ConclusionThis gene therapy‐based approach has potential advantages over traditional passive immunization, including 1) continuous expression of antibody in the central nervous system (CNS) after a single gene therapy administration compared to repetitive administrations of high dose of antibody by passive immunotherapy; 2) increased CNS exposure of tau antibody relative to passive immunotherapy; and 3) the potential to target intracellular tau aggregates which are less effectively accessed by passively delivered antibody. These results add to accumulating evidence that systemic dosing of a vectorized anti‐tau antibody using a BBB‐penetrant AAV capsid results in reduced tau pathology and may represent a new single‐dose therapeutic strategy for treating various tauopathies.
Soluble TREM2 drives earliest amyloid‐related p‐tau increase in Alzheimer’s disease but attenuates neurodegeneration in advanced disease
Authors: Biel Davina , Ewers Michael , Suárez‐Calvet Marc , Hager Paul , Rubinski Anna , Dewenter Anna , Steward Anna , Roemer Sebastian Niclas , Haass Christian , Brendel Matthias , Franzmeier Nicolai 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is characterized by Aβ and tau accumulation, microglial activation, metabolic brain changes, neurodegeneration, and cognitive decline. Studies found both detrimental and protective effects of microglial activation on AD progression, hence neuroinflammation may be a double‐edged sword in AD, which is critical for clinical trials aiming to modulate microglial activation. Here, we used CSF sTREM2 as a proxy of microglial activation to investigate disease stage‐dependent drivers of microglial activation in AD and its associations with the development of tau, metabolic brain changes, and neurodegeneration.MethodsWe included 271 ADNI participants, including cognitively normal (n=71) and mild cognitively impaired (n=200) participants with available CSF Aβ1‐42, p‐tau181, sTREM2, as well as amyloid‐PET and FDG‐PET. To determine disease stage, we stratified patients into Aβ CSF+/PET‐ (early Aβ‐accumulators, n=70) and Aβ CSF+/PET+ (late Aβ‐accumulators, n=201). A subset of 21/75 early/late Aβ‐accumulators had available longitudinal p‐tau181 and sTREM2 assessments, based on which we calculated annual sTREM2 and p‐tau181 change rates. Using linear models and mediation analyses we tested disease stage‐specific associations between amyloid‐PET (centiloid), p‐tau181 and sTREM2, and between sTREM2 and metabolic brain changes (FDG‐PET) or neurodegeneration (grey matter volume), controlling for age, sex, education, and diagnosis.ResultsWe found that higher centiloid was associated with cross‐sectional and longitudinal increases in p‐tau181 and sTREM2 in early Aβ‐accumulators, while in late Aβ‐accumulators, only a cross‐sectional association between centiloid and p‐tau181 was observed (Fig.1A+B). In early Aβ‐accumulators, sTREM2 fully mediated the association between centiloid and p‐tau181 (55% mediation) as well as longitudinal p‐tau181 increase (71% mediation) (Fig.1C+D). Higher sTREM2 was associated with higher FDG‐PET in early Aβ‐accumulators but with lower FDG‐PET in late Aβ‐accumulators (Fig.2A+B), in line with our previous findings that activated microglia consume glucose. In exploratory analyses, sTREM2 attenuated effects of higher p‐tau181 on hippocampal atrophy in late Aβ‐accumulators (n=155, T=2.215, p=0.031).ConclusionEarliest Aβ accumulation is associated with elevated sTREM2‐related microglial activation ensuing increases in p‐tau181 and glucose metabolism, whereas higher microglial activation in late Aβ‐accumulators attenuates hippocampal atrophy. Our findings have clinical implications as they suggest that targeting enhancement of microglial activation may have opposing effects on disease progression, depending on disease stage.
On the origin of a potential clearance marker: The contribution of enlarged perivascular fluid diffusion to an MRI derived proxy of interstitial fluid
Authors: van der Thiel Merel M. , Roos Nathalie A. , Drenthen Gerhard S. , Voorter Paulien H.M. , Feiweier Thorsten , Ramakers Inez H.G.B. , Backes Walter H. , Jansen Jacobus F.A. 
Published: December 2022

AbstractBackgroundIntraVoxel Incoherent Motion (IVIM) MRI can detect the diffusion of cerebral interstitial fluid (ISF) (D
int) and its volume fraction (f
int), which has the potential as a proxy of cerebral waste clearance. fint has been suggested to both be driven by fluid diffusivity within enlarged perivascular spaces (ePVS) ‐ transporting fluid from the subarachnoid space into the parenchyma ‐ and the ISF between the parenchymal cells. Both factors play a crucial role in soluble protein clearance, e.g., Amyloid‐Beta (Aβ).This study simultaneously aims to verify the contribution of ePVS fluid diffusivity to fint and highlights the ability to specifically assess ePVS fluid diffusion in the cerebrum using a non‐invasive MR method.MethodTwenty neurotypical elderly subjects (Table 1) underwent ultra‐high field MRI (7T research system, Siemens Healthcare GmbH, Erlangen, Germany) (Table 2).The intermediate diffusion components (Dint) in the range 1.5*10‐3< Diffusivity<4.0*10‐3 mm2/s were calculated using spectral analysis (Fig.1). The relative signal contribution of Dint was quantified by fint.ePVS were segmented from the enhanced perivascular contrast images (Fig.2). Median fint values were extracted from ePVS and non‐ePVS voxels within the basal ganglia (BG).fint and Dint values from within the ePVS mask were compared with values from surrounding non‐ePVS voxels in the BG using Wilcoxon Signed Ranks Tests.ResultFigure 3 contains a graphic summary of the statistical comparison of Dint and fint values from the ePVS and non‐ePVS voxels in the BG. Higher Dint and fint values are observed in the ePVS compared to the non‐ePVS tissue.ConclusionThe current study identified a higher IVIM‐derived proxy of ISF within the ePVS compared to surrounding non‐ePVS tissue, confirming that ePVS indeed contribute to the waste clearance marker fint.ePVS are fluid‐filled spaces surrounding cerebral blood vessels, in which ISF diffusivity is less restricted. This explains the higher Dint values in ePVS compared to non‐ePVS.Furthermore, this study suggests a potential method to investigate diffusivity within the microscopic ePVS, independent of the ISF diffusivity between parenchymal cells. In patients with Alzheimer’s disease, this method could be applied to investigate alterations in ISF diffusivity which could be representative of potential Aβ blockages in ePVS.
A new approach for estimating and quantifying disease‐modification in Alzheimer’s disease clinical trials
Authors: Raket Lars Lau 
Published: December 2022

AbstractBackgroundThe standard methodology for estimating treatment effects in Alzheimer’s disease clinical trials has remained unchanged for decades. With an increasing focus on disease‐modifying treatments, there are opportunities for developing more powerful methods for detecting such types of treatment effects and quantifying them in more interpretable ways.MethodsThe Progression Model for Repeated Measures (PMRM) was developed as an alternative to the Mixed Model for Repeated Measures (MMRM). The assumptions and flexibility of the PMRM are like the MMRM except treatment effects are handled differently (Figure 1). The PMRM estimates treatment effects as time‐delays/slowing of progression relative to the control group while the MMRM estimates treatment effects as point differences/reduction in decline on the outcome scale at a given visit. Because the unit of the treatment effect is shared with the time variable, PMRMs can simultaneously handle multiple outcomes in a natural and efficient manner. The power and interpretability of the PMRM was compared to the MMRM and other methods in a range of scenarios based on simulated and historical clinical trial data.ResultsThe PMRM was found to produce accurate and interpretable estimates of treatment effects across a range of simulated scenarios. Using CDR‐SB as an outcome, the PMRM produced the overall highest power to detect treatment effects across all simulated scenarios compared to all studied approaches. When treatment effects were simulated as time delays or slowing of progression, the PMRM offered substantial power gains compared to the MMRM. Using CDR‐SB, ADAS‐cog and ADCS‐ADL as multivariate outcomes, the PMRM was found to outperform models that combined the information in the outcome using the global test statistic and iADRS.ConclusionThe PMRM offers advantages in terms of interpretation and meaningful quantification of treatment effects, also in situations where the average decline observed in the control group is small. PMRMs can seamlessly include multiple outcome measures to estimate a single treatment effect and it was found that PMRMs offered substantially increased power to detect slowing of disease progression compared to conventional methods using both single and multiple outcome measures.
A predictive coding framework of allostatic interoceptive overload to comprehend frontotemporal dementia
Authors: Migeot Joaquín , Signorelli Camilo Miguel , Duran‐Aniotz Claudia , Piguet Olivier , Ibáñez Agustin 
Published: December 2022

AbstractBackgroundRecent allostatic‐interoceptive predictive coding theories propose that efficient regulation of the internal milieu is necessary to correctly anticipate the needs required to overcome environmental challenges before they arise. These theories are based on neurocognitive models of allostatic load and interoceptive processes, dimensions convergently affected in behavioral variant frontotemporal dementia. Nevertheless, this neurodegenerative disease has not been previously framed within such framework.MethodWe propose the hypothesis that behavioral variant frontotemporal dementia may be characterized by an imbalance of the predictive allostatic‐interoceptive system, with manifestations across psychological, cerebral, cardiocerebral and peripheral dimensions. Further, we propose a set of theory‐driven predictions in behavioral variant frontotemporal dementia, which could be subsumed into a dimensional framework integrating neurocognitive and physiological markers into a multimodal assessment of allostatic interoceptive priors.ResultUnder such framework, cognitive and behavioral impairments of behavioral variant frontotemporal dementia would be predicted by structural and connectivity deficits among critical allostatic interoceptive brain’ hubs, altered electrophysiological activity, and allostatic overload, jointly yielding meaningful associations with clinical manifestations.ConclusionSuch framework could help to further understand the hallmarks behavioral and physiopathological dysregulations of behavioral variant frontotemporal dementia within a predictive coding account, strengthening clinical models integrating its neurological and psychiatric manifestations.
Heterogeneity in normal aging: longitudinal trajectories of grey matter
Authors: Lorenzon Giulia , Poulakis Konstantinos , Mohanty Rosaleena , Kivipelto Miia , Eriksdotter Maria , Ferreira Daniel , Westman Eric 
Published: December 2022

AbstractBackgroundIn dementia research, the role of aging is usually de‐trended as a confounder, implying implicit assumptions on the nature of controls. In fact, normal aging brings about structural and functional damage, possibly reflecting brain resistance and resilience, unrelated to overt cognitive impairment (1). The aim of this exploratory study is to predict longitudinal trajectories of brain change in healthy elderly, based on their heterogeneous patterns at baseline, to uncover potentially lost information and link brain, cognitive and biological profiles. To our knowledge, it´s the first study investigating this in healthy aging.MethodCortical volumes and subcortical thickness were assessed through MRI from 307 healthy elderly from ADNI, JADNI and AIBL initiatives. We applied cross‐sectional clustering using unsupervised random forest (2), followed by multivariate mixture of generalized mixed effect model (3) to predict individual trajectories and group them based on similarities. The longitudinal clustering was replicated in the separate cohorts for validity check.Result4 different clusters were identified, which statistically differ for musculoskeletal comorbidities. Cluster 1 shows the healthiest brain and cognitive profile at the age of 60, but it deteriorates the most across time. Conversely, cluster 3 presents the worst grey and white matter profiles at 60, and the greatest cognitive decline over time. However, showing only minimal brain change, cluster 3 resembles brain resistance, whereas cluster 1 seems compatible with cognitive resilience.ConclusionThese different trajectories suggest the possibility of identifying resilient and resistant individuals already from healthy aging. Clinically, this promotes environmental protective factors and early diagnosis. Methodologically, this warns on the heterogeneity of healthy “controls” in experimental designs.
Pilot Randomized‐Controlled Trial of Social Ballroom Dancing in Dementia‐At‐Risk Older Adults
Authors: Blumen Helena M , Ayers Emmeline , Wang Cuiling , Ambrose Ann F , Jayakody Shanika Oshadi , Verghese Joe 
Published: December 2022

AbstractBackgroundExecutive functions (EF) such as planning, problem‐solving, and organization are often impaired in Alzheimer’s disease (AD). This pilot trial examined the safety and efficacy of social ballroom dancing for improving EF in older adults at increased risk for AD and related dementias. We hypothesized that the added social and cognitive demands of ballroom dancing would lead to greater intervention‐related changes in EF than a traditional aerobic activity (treadmill‐walking) – because it furthers neuroplasticity.MethodA single‐blind pilot randomized controlled trial (clinicaltrials.gov: NCT03475316) contrasted 6‐months (90 minutes twice a week) of social ballroom dancing with 6 months (90 minutes twice a week) of treadmill walking in dementia‐at‐risk older adults. Dementia‐at‐risk was defined as a memory impairment screen score of ≥3 and ≤6, and/or an AD‐8 dementia screening interview score of ≥1. A composite EF score generated from digit‐symbol substitution (DSST), flanker interference, and walking‐while‐talking tasks was the primary outcome. Functional neuroplasticity during fMRI‐adapted versions of these EF tests were secondary outcomes. The intention‐to‐treat principle was applied to all linear‐mixed effects analyses.ResultTwenty‐five participants were randomized between June 2019 and March 2020. The mean age was 76.45 years. 66% were women, 48% White/Caucasian, 24% Black/African‐American and 20% Hispanic/Latino. Sixteen participants (8 in each study arm) completed the intervention prior to study termination due to COVID‐19. The most common (mild) adverse event was falls (social dancing = 4; treadmill walking = 1), but no falls occurred during intervention sessions. No serious study‐related adverse events were reported. No between‐group differences were observed on the composite EF measure – although social dancing generated greater improvements on DSST than treadmill walking (6.57 correct items more; SE = 2.77, 95% CI = .46; 12.67, p = .02. No between‐group differences were observed in functional activation/deactivation patterns during EF tasks. Hippocampal volume, however, showed less atrophy following social dancing arm than treadmill walking (SE = 109.42; 95% CI = 58.29; 487.22, p = .01).ConclusionSocial ballroom dancing is a safe intervention for dementia‐at‐risk older adults. This clinical trial provides preliminary evidence that social dancing improves performance on one test of EF (DSST), and promotes hippocampal neuroplasticity – but these findings need to be confirmed in larger clinical trials.