bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence mild cognitive impairment in mexican older adults in a third‐level hospital
Authors: Ruiz‐Castillo Karla Paulina , Chable Adiel Eleazar Dzul , Cuautle Karina Arellano , Silva Itzel Alejandra Hernandez , Reyes Brandon Alexis Reyes
Published: December 2023

Background

Mild Cognitive Impairment (MCI) is a common condition among older adults that refers to cognitive deficits that are not derived from daily activities, this condition that can progress to dementia, therefore it deserves special attention since it is prevalent in populations of older adults and It can coexist with geriatric syndromes. we evaluated the epidemiological characteristics in an older population with mild cognitive impairment.

Method

A descriptive and cross‐sectional study was carried out, evaluating adults 60 years of age or older, from a dementia clinic at a tertiary level hospital in Mexico. The analytical sample consisted of 700 older adults, from whom patients with Mild Cognitive Impairment were selected, using the Petersen criteria. Epidemiological variables were considered, as well as gait disturbance, geriatric syndromes, among others.

Result

The study found that of the total population of 700 patients, 275 participants were diagnosed with mild cognitive impairment, indicating an estimated overall prevalence of 39.42%. Among those with MCI, 54.1% were in the a‐MCI‐s subtype, 22.5% in the a‐MCI‐md subtype, 18.18% in the na‐MCI‐md subtype, and 5 .09% in the na‐MCI‐s subtype. The prevalence of MCI was higher in women (59.6%) and between 60 and 70 years (55.6%). 46.7% had basic education (<6 years), of which 27.2% belonged to the a‐MCI‐s subtype. in patients with MCI, 28% presented depression, 48.3% gait disturbances. Pre‐frailty was present in 40% of patients. Sensory deprivation was found in 88.3% and polypharmacy in 49.1%. The marital status was predominantly married (61.8%) and 32.3% worked and in terms of comorbidities, a relationship with arterial hypertension (61%) was observed.

Conclusion

This study suggests that mild cognitive impairment is common among the elderly population, especially women and people in their 60s and 70s. The a‐MCI‐s subtype was the most common. Mild cognitive impairment was also associated with various comorbidities and geriatric syndromes, including gait disorders, depression, pre‐frailty, sensory deprivation, polypharmacy, and association with arterial hypertension. These findings highlight the importance of identifying and managing mild cognitive impairment and its associated syndromes.
The Roles of Daily Stressor Control and Social Determinants of Health in Executive Function and Episodic Memory Performance
Authors: Cerino Eric S. , McCarthy Michael J. , Horowitz Chloe S. , Almeida David M.
Published: December 2023

Background

Studying modifiable psychosocial contributors to Alzheimer’s disease and related dementias (ADRD) is crucial to inform approaches for ADRD prevention, especially among those with less education, lower neighborhood quality, and heightened discrimination. These three social determinants of health confer increased ADRD risk. Perceived control is an important psychosocial resource for cognitive health. Most prior work, however, focuses exclusively on global aspects of control, ignoring influences of more dynamic aspects of control over specific experiences in daily life, such as daily stressor control.

Method

We used data from the Midlife in the United States study and the National Study of Daily Experiences (N = 1,651, Mage = 62.09, SE = 12.11, 56.65% Female) to address this gap and examine the roles of daily stressor control and social determinants of health in cognitive performance. Over 8 consecutive days in the second and third waves of data collection, respondents reported their perceived control over stressors they had experienced. Respondents also completed assessments of education, neighborhood quality, perceived discrimination, and a telephone‐based battery of tests measuring executive function (EF) and episodic memory (EM). We employed multilevel modeling to assess associations of daily stressor control and social determinants of health with cognitive performance.

Result

EF was higher among people with more education and those with less perceived discrimination (ps<.001), but was not related to daily stressor control (p>.05). Greater daily stressor control, more education, and better neighborhood quality was related to better EM (ps<.05). A stressor control by discrimination interaction showed that greater stressor control was associated with better EM among those with comparatively less perceived discrimination (p<.01).

Conclusion

Daily stressor control may serve as a psychosocial resource for cognitive health, but the strength of its relationship with cognitive performance varied by perceived discrimination. Promoting stressor control may be beneficial for cognitive health among those with comparatively less perceived discrimination, but more research is needed to clarify psychosocial resources that could buffer against the impacts of heightened discrimination on cognitive health disparities in the US. Future work should examine longitudinal relationships to clarify the predictive utility of stressor control for cognitive health and the daily mechanisms that may explain these associations.
Relationship between Arterial Transit Time and Framingham Risk Score in the U.S. POINTER lifestyle intervention trial
Authors: Jung Youngkyoo , Hong Sarah Y. , Kim Donghoon , Vemuri Prashanthi , Borowski Bret J. , Jack Clifford R. , Koeppe Robert , Lockhart Samuel N. , Harrison Theresa M. , Gordineer Leslie , Woolard Nancy , Espeland Mark A. , Harvey Danielle J. , Lovato Laura , Toga Arthur W. , Masdeu Joseph C. , Oh Hwamee , Gitelman Darren R. , Aggarwal Neelum T. , Carrillo Maria C. , Snyder Heather M , Whitmer Rachel A. , Baker Laura D , Decarli Charles , Landau Susan M. ,   U.S. POINTER Study Group
Published: December 2023

Background

The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a two‐year randomized controlled trial designed to evaluate the effects of lifestyle interventions on older adults aged 60‐79 years. The POINTER Imaging ancillary study employs arterial spin labeling (ASL) magnetic resonance imaging (MRI) with two inversion times, enabling the mapping of arterial transit time (ATT) and the investigation of its relationship with dementia risk factors. This study examines the effect of the Framingham Risk Score (FRS) on ATT, which provides hemodynamic information on the cerebral vasculature.

Method

A subset of POINTER Imaging participants (n = 134; F/M = 81/53; age = 68.1±5.1; FRS = 11.3±10.4) from two imaging sites underwent two ASL MRI scans during the baseline session. Two 3D Pulsed ASL scans were obtained with TI1 of 790ms and TI2 values of 2000ms or 2750ms, providing delay times (between labeling and imaging) of 1210ms or 1960ms. ATT, the time required for blood to travel from the neck to the tissue, was estimated in the range of 1210ms and 1960ms using a kinetic model (Figure 1). ATT maps were normalized to a standard space, and a voxel‐wise linear regression (ATT∼age+sex+log(FRS)) was performed on ATT maps in gray matter to assess the effect of FRS on ATT. To control false positives, clusters smaller than 1.4ml were removed based on a simulation with α = 0.05.

Result

Figure 2 depicts three clusters found in the occipital, precuneus and frontal gray matter regions, all of which demonstrate a positive relationship between ATT and log(FRS). Participants with higher FRS exhibit prolonged mean ATT values in the clusters as shown in Figure 3. After stratifying into sex groups, both groups show the same direction.

Conclusion

Although the detectable range of ATT with two ASL scans was limited, the analysis suggests that an increased risk of cardiovascular disease, as quantified by the Framingham Risk Score, can serve as an indicator of potential cerebrovascular disease leading to prolonged ATT, which is associated with arterial stiffness, and vascular resistance. The clusters demonstrating the association between FRS and ATT are the brain regions that may have heightened vulnerability to vascular risk factors, according to previous studies.
Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer’s disease
Authors: Green Gilad Sahar , Yang Hyun‐Sik , Fujita Masashi , Taga Mariko , Regev Aviv , Menon Vilas , Bennett David A. A , Habib Naomi , De Jager Philip L
Published: December 2023

Background

Recent studies have revealed diverse Alzheimer’s disease (AD)‐associated brain cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brain’s cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single‐nucleus RNA‐seq profiles.

Method

We associated glial, vascular and neuronal subpopulations with AD‐related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. Further, to model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities.

Result

We identified two distinct lipid‐associated microglial subpopulations, one contributed to amyloid‐β proteinopathy while the other mediated the effect of amyloid‐β in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. The BEYOND method uncovered two possible trajectories of brain aging, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging.

Conclusion

We provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.
Alzheimer Plasma Biomarkers Distinguish SuperAgers from their Cognitively Average Peers
Authors: Macomber Alyssa J , Gefen Tamar , Ayala Ivan , Weintraub Sandra , Mesulam Marsel , Rogalski Emily J , Geula Changiz
Published: December 2023

Background

SuperAgers are individuals ≥80 years old who were selected for having episodic memory performance that is at least as good as individuals 20‐30 years their junior. We have previously shown that on average SuperAgers show lower neurofibrillary tangle density in the entorhinal cortex than cognitively average controls, which may be one biological factor contributing to superior memory beyond the 8th decade. This preliminary study investigated whether plasma concentrations of Alzheimer and related neurodegenerative biomarkers differ between SuperAgers and their cognitively average peers.

Method

SuperAgers (N = 61) and Cognitively Average Controls (N = 28) were enrolled through the SuperAging Research Program. The plasma biomarkers amyloid β peptide 40 (Aβ40), amyloid β peptide 42 (Aβ42), neurofilament light (NFL), phosphorylated tau‐181 (pTau‐181), and glial fibrillary acidic protein (GFAP) were measured in SuperAgers and Cognitively Average participants using the Quanterix single molecule protein detection (SIMOA) platform. Independent samples t‐tests were used for statistical analyses (significance was set at p<0.05, uncorrected).

Result

There were no significant differences in mean age between SuperAgers and Cognitively Average Controls. Concentrations of Aβ42, Aβ40, the ratio of Aβ42/Aβ40, NFL or GFAP did not significantly differ between groups. On average, SuperAgers and Controls showed pTau‐181 levels that were <16.5 pg/mL, falling within the “Unlikely Alzheimer’s” designation according to Quanterix guidelines. SuperAgers showed significantly lower pTau‐181 levels compared to Cognitively Average Controls [M = 5.42 pg/mL (SD = 2.60) vs M = 7.10 pg/mL (SD = 3.14), respectively].

Conclusion

Plasma phosphotau biomarkers are promising for the assessment of brain integrity versus degeneration across the age‐Alzheimer continuum. The current results provide preliminary support for the contention that the SuperAger brain may be even more removed from the Alzheimer side of the continuum than neurotypical controls.

Emily Rogalski and Changiz Geula contributed equally to this study.
Social determinants of health in Colombian patients with Alzheimer Disease and Frontotemporal Dementia
Authors: Buitrago Carlos Felipe , Garcia Deissy Milena , Giraldo Claudia Irene , Triviño Cristian , Forero Laura Valentina , Moreno Maria Jose , Reyes Pablo A , Matallana Diana
Published: December 2023

Background

There are a series of social, economic, political, and cultural determinants that may impact the course of dementia. Previous studies have found that structural determinants are particularly important as they establish a set of hierarchies derived from socio‐economic position that determine institutional responses in both health and social services, which affect the health outcomes of everyone.

Method

This presentation aims to characterize the socio‐economic factors in a sample of 70 Colombian individuals with dementia (35 with Alzheimer’s Disease and 35 with Frontotemporal Dementia) who participated in the RedLat project. Cluster analysis is proposed for a set of variables that are linked to the socio‐economic determinants of health that are queried from each participant in the framework of the RedLat project, and relates them to the disease progression time, severity, and impact on each person’s functionality.

Result

Overall, it is found that the socio‐economic factors of each individual impact the course of the disease.

Conclusion

These findings justify the need to implement public health programs that address the needs of and improve the living conditions of older adults.

References:

Buitrago, A. F. S., Perdomo, D. C., & Bogota, M. A. M. (2022). Asociación entre el deterioro cognitivo y factores socioeconómicos y sociodemográficos en adultos mayores colombianos. Revista Colombiana de Psiquiatría.

Duran‐Aniotz, C., Sanhueza, J., Grinberg, L. T., Slachevsky, A., Valcour, V., Robertson, I., … & Ibáñez, A. (2022). The Latin American Brain Health Institute, a regional initiative to reduce the scale and impact of dementia.

Hersi, M., Irvine, B., Gupta, P., Gomes, J., Birkett, N., & Krewski, D. (2017). Risk factors associated with the onset and progression of Alzheimer’s disease: A systematic review of the evidence. Neurotoxicology, 61, 143‐187.

Parra, M. A., Baez, S., Sedeño, L., Gonzalez Campo, C., Santamaría‐García, H., Aprahamian, I., … & Ibanez, A. (2021). Dementia in Latin America: paving the way toward a regional action plan. Alzheimer’s & Dementia, 17(2), 295‐313.
Comparison between verbal and visual working memory in subjects with frontotemporal dementia and Alzheimer’s participating in the Redlat study
Authors: Forero Laura Valentina , Garcia Deissy Milena , Moreno Maria Jose , Buitrago Carlos Felipe , Triviño Cristian , Rivera Carlos , Reyes Pablo A , Matallana Diana
Published: December 2023

Background

Alterations in working memory have been reported in people with Alzheimer’s disease and frontotemporal degeneration, and have been associated with executive impairment related to the frontal areas of the brain.

Method

The objective of this work is to compare the capacity of verbal and visual working memory in a sample of 70 Colombian people with dementia (32 with Alzheimer’s Dementia and 30 with Frontotemporal Dementia and 22 healthy controls) participating in the RedLat study. For this, the performance in a digit retention task and the Short Term Memory Binding Test (STMB) are studied.

Result

In general, there is a decrease in the performance of the two groups of patients (AD and FTD). Also AD patients shows worst performance at visual working memory tasks. Results shows differences between dementia groups and controls, but not between AD and FTD.

Conclusion

This converges with what has been reported about the dissociation between verbal and visual working memory, and could suggest alternative strategies for the recall of immediate information. Additionally, both low performances are explained by differents reasons in each neurodegenerative disorder.

References:

Stopford, C. L., Thompson, J. C., Neary, D., Richardson, A. M., & Snowden, J. S. (2012). Working memory, attention, and executive function in Alzheimer’s disease and frontotemporal dementia. Cortex, 48(4), 429‐446.

Giovannetti, T., Lamar, M., Cloud, B. S., Swenson, R., Fein, D., Kaplan, E., & Libon, D. J. (2001). Different underlying mechanisms for deficits in concept formation in dementia. Archives of Clinical Neuropsychology, 16(6), 547‐560.

Della Sala, S., Parra, M. A., Fabi, K., Luzzi, S., & Abrahams, S. (2012). Short‐term memory binding is impaired in AD but not in non‐AD dementias. Neuropsychologia, 50(5), 833‐840.
Evaluation of cognitive profile through Q‐RUDAS: first approach in Quechua Participants
Authors: Zegarra‐Valdivia Jonathan Adrian , Quispe Ruth Diana Mamani , Turpo Jose Chinoapaza , Chino‐Vilca Brenda Nadia , Manrique Carmen Paredes , Malaga Marco , Choquenaira Enrique , Velasquez‐Rimachi Victor , Rodriguez‐Calienes Aaron , Alva‐Díaz Carlos , Benito Oscar Mamani , Montesinos Rosa , Custodio Nilton
Published: December 2023

Background

The Rowland Universal Dementia Assessment Scale (RUDAS) has proven to be one ofthe best instruments of cognitive function evaluation in illiterate and low‐educated participants; it is easyto adapt in different countries, languages, and cultures, showing good validation properties. In Peru, weare working to bring this instrument to Quechua speakers. The present study aimed to obtain the firstapproach to cognitive prevalence in elderly individuals in their native language.

Methods

After an initial pilot study (Malaga in preparation), we use the culturally and language‐adapted Q‐RUDAS in the Peruvian Quechua population of the Puno region (n = 511), with a mean age of65.04 ± 6.73 means (ranging from 59 to 92 years), 80.4% of the sample were females. We obtain socio‐demographic data (educational level, occupation, and precedence residence area) and the Q‐RUDASscores. Additionally, we asked the patients open‐ended questions about the test adaptation. Weexcluded patients with antecedents of pathologies that may interfere with the performance of the test. Verbal and signed consent were obtained. We use the previous RUDAS cut‐off from Peruvian validationstudies to have an initial approach to cognitive prevalence.

Results

We include 502 participants without relevant medical history. Participants understood all Q‐RUDAS items but reported difficulties with visuospatial construction (more than 50% could not draw thecube, more than 25% failed to draw some parts, and around 20% drew it accordingly). The mean scoreof Q‐RUDAS was 26.01 ± 2.71. We found that 448 participants have standard scores (26.67 ± 1.92), 46MCI (21.49 ± 1.92), and 11 participants that meet scores of dementia (17.00 ± 2.71). Besides, differences were found in the total score regarding the precedence area of participants, with Urban´shaving an increased score.

Conclusion

The previously adapted RUDAS test to Quechua (Q‐RUDAS) in Peru was well understoodamong native patients. This culturally sensitive tool is essential for diagnosing dementia in indigenouspopulations, but more studies are needed, such as cross‐validation studies. An initial approach of theprevalence of MCI and dementia is around 10.8% in the native population.
Clinical and biomarker correlates of region‐specific diffusion MRI metrics in a short‐term, Phase 1b clinical trial for XPro1595 in Alzheimer’s disease
Authors: Pope Parris , Ridgway Gerard R , Torso Mario , Chance Steven A , Roy Maggie , Houde Jean‐Christophe , Descoteaux Maxime , Barnum CJ , Tesi RJ
Published: December 2023

Background

XPro1595 is a selective, brain penetrant neutralizer of soluble TNF with potent anti‐neuroinflammatory effects recently assessed for safety and pharmacological activity in a 12‐week, phase‐1b open‐label dose finding study in patients with AD (NCT03943264). An unbiased screen of imaging outcomes revealed signals for target engagement in gray matter (GM) cortices documented in the literature as regions most frequently affected by accumulation of amyloid‐beta (Aβ) in early and late phases of AD (Mattsson et al. 2019). Post‐hoc analyses were conducted to further investigate these signals.

Method

Study results for patients (n = 9; MMSE range: 8‐27) with analyzable dMRIs who completed 12‐weeks of treatment with XPro1595 [0.3 mg/kg; n = 3) or (1.0 mg/kg; n = 6)] met inclusion criteria. Correlation matrices (uncorrected Pearson’s r) were created to compare key secondary and exploratory imaging outcomes to clinical characteristics and CSF biomarkers of AD specific pathology (Roche Elecsys NeuroToolKit). Imaging outcomes included white matter free‐water (WM‐FW) as a prespecified proxy for neuroinflammation, and GM PerpPD+. PerpPD+ represents the diffusion components perpendicular to cortical GM minicolumns and serves as an indicator of worsening GM microarchitecture when increased in AD. Due to the small sample size, the threshold for identification of informative values was set at P<0.05.

Result

At baseline, PerpPD in GM regions associated with early Aβ accumulation (insula, precuneus, isthmus and posterior cingulate, and lateral‐orbitofrontal cortices), and WM‐FW in the cingulum bundle, showed strong associations with CSF biomarkers of neurodegeneration (pTau and tTau), inflammatory gliosis (YKL‐40, GFAP and sTREM2), cognitive status (MMSE scores) and disease duration (Table1). Week‐12 results showed decreased PerpPD+ and WM‐FW in these regions, with a dose‐dependent signal concentrated in the isthmus cingulate GM and cingulum WM. Isthmus cingulate PerpPD+ ∆ (%) correlated positively with baseline Aβ42/40 and MMSE (Figure1), and negatively with duration of disease and cingulum WM‐FW, whereas cingulum WM‐FW ∆ (%) corelated with baseline pTau and tTau (Table 2).

Conclusion

PerpPD+ in isthmus cingulate GM and WM‐FW in cingulum WM represent potential indicators of disease activity sensitive to early treatment effects in small, proof of concept clinical trials for AD. Additional research is warranted to further elucidate these signals.
Deep Brain Stimulation for Alzheimer’s Disease and the Human Memory Circuit
Authors: Howard Calvin W , Horn Andreas , Lyketsos Constantine G. , Lozano Andres M , Fox Michael D ,   ADvance Study Research Group
Published: December 2023

Background

Brain lesions causing amnesia are in a memory circuit centered on the subiculum. Deep brain stimulation (DBS) sites connected to this circuit are linked to cognitive decline in Parkinson’s disease but cognitive improvement in Alzheimer’s Disease (AD). Insight into this paradox may come from directly comparing the topography of lesion and DBS‐induced effects.

Methods

We studied 53 amnesia‐causing lesion locations and 46 patients (92 DBS sites) from Phase 1 and Phase 2 randomized controlled trials of fornix DBS for AD. Connectivity between lesions and DBS sites was computed using a normative atlas of functional connectivity data from 1000 healthy subjects. Baseline cognitive scores were compared to 1‐year post‐DBS activation scores.

Results

Connectivity between AD patients' DBS sites and a subiculum region derived from amnesia‐causing brain lesions correlated with cognitive improvement (Spearman’s rho = 0.33, p = 0.027). There was a difference between sham‐first (Spearman’s rho = 0.33, p = 0.027) and stimulation‐first (Spearman’s rho = 0.25, p = 0.27) cohorts. Whole‐brain connectivity maps of the subiculum region and AD response fingerprints were aligned: 17/19 local maxima appeared in both maps, dice coefficient 0.71 (p<0.00001). Both maps showed data‐driven peaks in an overlapping subiculum region. However, DBS data showed a significant interaction effect between patient age and subiculum connectivity upon outcome in a general linear model (p = 0.031). Randomization status was controlled as a covariate and was not significant. Specifically, higher subiculum connectivity in older patients led to improved cognition, while higher connectivity in younger patients resulted in worsening cognition. The data‐driven inflection point for this interaction effect was at age 65 at any subiculum connectivity value.

Conclusion

Our findings suggest that lesions causing amnesia and DBS sites modulating cognition converge on common neuroanatomy. However, patient age appears to be critical variable in determining whether DBS sites connected to the subiculum result in cognitive improvement or decline. Our results provide insight into the paradox of mixed outcomes across DBS cohorts and support restricting ADvance II enrollment of fornix‐targeted DBS to patients over 65. The underlying mechanisms remain unclear, and this study must be replicated in additional datasets.
Neuropsychological Characteristics of Posterior Cortical Atrophy: A Case Series Study in Participants of the RedLat Study
Authors: Garcia Deissy Milena , Buitrago Carlos Felipe , Forero Laura Valentina , Moreno Maria Jose , Rivera Carlos , Reyes Pablo A , Matallana Diana
Published: December 2023

Background

Posterior cortical atrophy is a neurodegenerative condition characterized by the deterioration of visuospatial skills, associated with the deterioration in the occipital and parietal regions of the brain, and frequently associated with the neuropathology of Alzheimer’s disease.

Method

The objective of this study is to describe the neuropsychological characteristics in a sample of five RedLat study participants diagnosed with this condition. The subjects were evaluated in cognitive areas of language, attention, memory, executive functions, and visuospatial skills with a series of neuropsychological tests.

Result

The obtained data is analyzed in a descriptive manner. The results support that alterations with visual and spatial predominance. However executive dysfunction and language alterations are present aswell.

Conclusion

These findings support the understanding of posterior cortical atrophy as a heterogeneous clinical syndrome.

References:

Yong, K. X., Graff‐Radford, J., Ahmed, S., Chapleau, M., Ossenkoppele, R., Putcha, D., … & Harding, E. (2023). Diagnosis and management of posterior cortical atrophy. Current Treatment Options in Neurology, 1‐21.

Schott, J. M., & Crutch, S. J. (2019). Posterior Cortical Atrophy. Continuum (Minneapolis, Minn.), 25(1), 52‐75. https://doi.org/10.1212/CON.0000000000000696

Carvajal Castrillón, J., Aguirre, D. C., & Lopera, F. (2010). Perfil clínico y cognitivo de la atrofia cortical posterior y sus diferencias con la enfermedad de Alzheimer esporádica tardía y familiar precoz. Acta Neurológica Colombiana, 26(2), 75‐86.

Iacono, L. L., Sarotto, L., & Braccia, M. L. (2022). Atrofia cortical posterior: la “variante visual” de la enfermedad de Alzheimer. Oftalmología Clínica y Experimental, 15(2).
Time saved in disease progression for treatments in AD (including 3 monoclonal antibodies and 2 other promising treatments)
Authors: Hendrix Suzanne B. , Mallinckrodt Craig , Wassom Mitchell , Haaland Benjamin A , O'Keefe Patrick P , Dickson Samuel P.
Published: December 2023

Background

Alzheimer’s disease progression causes worsening on multiple symptoms of disease which can be measured by cognitive, functional and global scales. These scales can be thought of as surrogate outcomes for the true disease progression. The degenerative and therefore progressive nature of the disease indicates that time is a measurable gold standard against which we can assess all other outcomes. Composite endpoints and global statistical tests have been used to approximate this progression outcome since it is not directly measurable. Using time as the gold standard, one can calculate the alignment of any measure against the gold standard using a signal to noise ratio. A combination of the ADAS‐cog, ADCS‐ADL and CDR‐sb aligns more than 90% with the unmeasurable progression outcome.

Method

Converting each of the clinical scales to a time scale allows us to measure progression in “disease progression” time: i.e. months of progression per month of treatment, which should be linear in nature despite any non‐linearity in the clinical scale. A recent meta‐analysis was performed and data from relevant studies have been estimated using an overall progression time metric.

Result

Results for five studies of interest (three monoclonal antibodies and two other treatments) Aducanumab, Donanemab, Lecanemab, AD04, and Souvenaid show time savings range from 2 months per year to 7 months per year. Results for these five studies are presented in Table 1.

Conclusion

Measuring time savings in a degenerative disease reflects the true goal of disease modifying treatments which is to slow down a progressive disease which will result in slowing of progression on all aspects or symptoms of disease. Progressive diseases would cease to be diseases at all if there was no progression of symptoms. Focusing on the clinical meaningfulness of each separate point on each outcome distracts us from this overall goal. Progression time savings is meaningful to patients, caregivers and all stakeholders and can be calculated from meaningful, clinically acceptable outcomes.
Cell cycle dysregulation in iPSC‐derived neurons from C9ORF72 carriers
Authors: Gonzalez Rodrigo Lopez
Published: December 2023

Background

The GGGGCC (G4C2) repeat expansion in the C9ORF72 is the most common genetic form of amyotrophic lateral sclerosis (ALS). We and others have uncovered the role of DNA damage, upregulation of the NHEJ repair pathway and P53 activation in the pathogenesis of C9ORF72‐related ALS. Evidence from other neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease, suggests cell cycle re‐entry of post‐mitotic neurons may be detrimental and contribute to neurodegeneration.

Method

In this study, we used several well characterized induced pluripotent stem cells (iPSC) from C9ORF72 carriers and controls and differentiate into neurons. iPSC‐derived neurons were cultured for up to two months and analyzed at different time points by gene expression and western blot analysis.

Result

We have found an age‐dependent increase in the levels of cell division markers including Ki67 and Geminin (GMNN) as well as Cyclin A2, Cyclin B1, Cyclin B2, CDK1, CDK2 and CDK4 in 2‐month‐old neurons from C9ORF72 carriers as compared to controls. When we analyzed 1‐month‐old neurons as we did not find differences between controls and C9ORD72 neurons. Moreover, we found a decrease in the levels of p21 is a cyclin‐dependent kinase inhibitor that belongs to the CIP/Kip family of CDKs inhibitors and has the ability to arrest cell cycle progression at G1/S and G2/M stages, this data indicate dysregulation of cell cycle in C9ORF72 neurons.

Conclusion

Our data indicates that post‐mitotic neurons from C9ORF72 repeat expansion carriers are aberrantly activating the expression of proteins related to cycle progression.
Biomarker changes and their relationships to clinical efficacy outcomes in Alzheimer’s disease
Authors: Dawson Katherine
Published: December 2023

Background

Biological and clinical evidence points to Alzheimer’s disease (AD) as an amyloid‐beta (Aβ)–driven tauopathy, with Aβ and tau remaining high‐priority targets for therapeutic development. Alterations of fluid and imaging biomarkers are key indicators of underlying Aβ and tau pathological changes in the brain during AD and are important for evaluating investigational agents and assessing clinical effects efficiently (e.g., via shorter trials with fewer participants).

Method

Anti‐Aβ monoclonal antibodies (mAb) and anti‐extracellular tau antibodies, as well as antisense oligonucleotides (ASO) that target intracellular tau, have been evaluated across multiple clinical studies. Outcome measures were broadly consistent across trials and assessed both clinical efficacy and longitudinal effects on fluid and imaging biomarkers of disease (e.g., those detected via cerebrospinal fluid [CSF], plasma, and imaging (positron emission tomography [PET]).

Result

The results presented here show that anti‐Aβ mAb treatment reduced amyloid and tau PET standardized uptake value ratios across multiple brain regions and also impacted CSF Aβ1‐42, CSF phosphorylated tau (p‐tau), total tau (t‐tau), and plasma p‐tau181 biomarkers of disease in a dose‐dependent manner. Relevant biomarker changes generally correlated with positive clinical effects across multiple clinical efficacy scales. Anti‐tau antibody treatment demonstrated robust extracellular tau engagement in CSF but did not show clinical efficacy or any corresponding effect on tau pathology as assessed by PET. A Phase 1b trial evaluating an ASO targeting intracellular tau demonstrated a reduction in CSF t‐tau in a dose‐dependent manner; at the end of a long‐term extension study, this ASO also reduced tau burden as assessed by PET in all brain regions examined.

Conclusion

Results across therapeutic targets and modalities suggest that, with disease modification, relevant changes that occur in proximal and distal fluid and imaging biomarkers are linked to clinical effects. Lessons from the anti‐tau mAb study indicate that these relationships are still maintained even where, without a clinical effect, changes in AD biomarkers are not observed. Ongoing clinical trials will continue to expand our understanding of biomarker changes in AD, the contribution of amyloid and tau to disease pathology, and the temporal dynamics of biomarker changes, and their relationships to clinical efficacy outcomes.
Inhibition of BACE1 in glial cells for enhancing clearance of amyloid plaques
Authors: Yan Riqiang
Published: December 2023

Background

Neuronal BACE1 has been shown to regulate synaptic functions, and deletion of Bace1 in the brain leads to impaired synaptic plasticity. To avoid dramatic inhibition of BACE1, we aimed to understand the role of BACE1 in glial cells and to determine the function of BACE1 in either microglia or astrocytes.

Method

By utilizing the generated Bace1flox mouse model, we specifically deleted Bace1 in either microglia or astrocytes and crossed with Alzheimer’s 5xFAD mice to evaluate the changes in amyloid plaques. We also purified microglia and astrocytes from multiple mouse models to examine the transcriptomic profiles in microglia or astrocytes to determine whether BACE1 regulates cellular functions of microglia or astrocytes.

Result

We showed that targeted deletion of Bace1 in microglia significantly reduced amyloid plaque loads by enhancing clearance. Unbiased RNAseq results revealed that BACE1 facilitates transition of homeostatic microglia to stage 1 disease associated microglia (DAM‐1) while reduces DAM‐2. Mice with Bace1 deletion only in microglia exhibited no defects in synaptic functions as examined by long term potentiation assays. Mice with Bace1 deletion in astrocytes also exhibited reduction in amyloid plaque load in the early stage. Unbiased RNAseq results revealed elevation of clusterin and ApoE, two proteins known for enhancing clearance of amyloid plaques.

Conclusion

Our molecular and mouse genetic studies show that deletion of Bace1 in glial cells appears to have minimal effect on synaptic functions. inhibition of glial BACE1 is a potential alternative strategy for enhancing Aβ clearance for AD treatment.
Highly Ordered Hierarchical Macro–Mesoporous Carbon‐Supported Cobalt Electrocatalyst for Efficient Oxygen Evolution Reaction
Authors: Luo Lanke , Xu Jingshen , Wan Qiuhong , Han Yiting , Li Mingxuan , Cui Dingwei , Chen Runxuan , Tang Zhangrong , Cui Xinjun , Xin Xin , Li Xinchang , Xiang Yulu , Dong Haohai , Lin Liu , Sun Zemin , Sun Genban
Published: December 2023

Metal‐organic frameworks (MOFs) and their derivatives have been extensively employed in Oxygen Evolution Reaction (OER) catalysts due to their significantly larger specific surface areas, distinct metal centers, and well‐organized porous structures. However, the microporous structure of MOFs and their derivatives presents mass transfer resistance, limiting their further development. Drawing inspiration from hierarchical structures allowing for the transport and exchange of substances in the biological world, we designed and fabricated biomimetic layered porous structures within ZIF‐67 and its derivatives. Based on this, we achieved a three‐dimensional ordered layered porous nitrogen‐doped carbon‐coated magnetic cobalt catalyst (3DOLP Co@NDC) with a biomimetic pore structure. It is found that the 3DOLP Co@NDC (352 mV @10 mA cm−1) was better than Co@NDC (391 mV @10 mA cm−1). The introduction of a three‐dimensional ordered layered porous structure is conducive to increasing the specific surface area of the material, increasing the electrochemical active area, and improving the catalytic performance of the material. The introduction of a three‐dimensional ordered layered porous structure would help to build a bionic grade pore structure. The existence of biomimetic grade pore structure can effectively reduce the mass transfer resistance, improve the material exchange efficiency, and accelerate the reaction kinetics.
Water‐based Supercapacitors with Amino Acid Electrolytes: A Green Perspective for Capacitance Enhancement
Authors: D'Alessandro Alessio , Bellani Sebastiano , Gamberini Agnese , Mastronardi Valentina , Zappia Marilena Isabella , Abruzzese Matteo , Thorat Sanjay , Calcagno Elena , Bonaccorso Francesco
Published: December 2023

State‐of‐the art Electrochemical Double‐Layer Capacitors (EDLCs) usually extend their operating electrochemical stability window (ESW) by means of organic electrolytes, or highly concentrated aqueous (water‐in‐salt) electrolytes hindering parasitic water splitting reactions. Unfortunately, organic solvents and high concentrations of ions penalize the dielectric constant of the electrolyte, hence the capacitive performance. We suggest here a new concept of cost‐effective and sustainable aqueous electrolytes based on concentrated amino acid water solutions with a dielectric permittivity much higher than pure water, unlocking the capacitive performance of aqueous EDLC references. Amino acids are natural zwitterionic molecules with a large separation between the positive and negative moiety, leading to huge dipoles with excellent dielectric properties. Some of them (e. g., lysine and proline), have a solubility
10 m at ambient temperature. With an experimental characterization we prove that aqueous EDLCs based on electrolytes obtained with L‐ lysine or L‐proline added to 2 M NaNO3 solution have +50 % of gravimetric capacitance enhancement at low specific currents (0.1 A/g) compared to a reference device based on 2 M NaNO3 electrolyte without amino acids. A theoretical model suggests that this performance may be further enhanced by increasing the ionic accessibility of commercially available active materials, with porosity optimized to the size of amino acid ions.
Mercaptosilane Engineered Interface with Surface‐Preferred Crystal Plane for High‐Performance Zn Anode
Authors: Li Guo‐Xian , Zhao Zhen , Yu Wei , Meng Chui‐Zhou , Guo Shi‐Jie
Published: December 2023

Zn‐ion battery (ZIB) has drawn huge attentions as a prospective energy storage system for the next generation, but dendrite and side reaction issues related to Zn have limited their potential applications. Here, a combined approach involving the modification of surface texture and the implementation of a passivation layer is proposed to tackle the problem. A zinc‐silane composite layer is coated on (002)‐preferred Zn (ZSi@Zn) by selective acid etching, concomitant with the hydrolysis of Mercaptosilane. The preferred (002) crystal plane, in conjunction with the zinc‐silane composite layer, leads in integrated interfacial transport and deposition control. As a result, the ZSi@Zn electrode has dramatically increased stability and uniform Zn deposition behavior. Remarkably, it exhibits a Coulombic efficiency of approximately 99.4 %, a long lifespan of around 3000 hours at the current density of 1 mA cm−2 with a capacity of 0.5 mAh cm−2. The excellent reversibility of zinc persists with current densities of 2, 5, and 10 mA cm−2. Furthermore, Zn‐MnO2 battery constructed with ZSi@Zn also delivers excellent performance, manifesting a capacity retention of 88.4 % after 4000 cycles.
Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma
Authors: Liu Weiren , Wang Huqiang , Zhao Qianfu , Tao Chenyang , Qu Weifeng , Hou Yushan , Huang Run , Sun Zimei , Zhu Guiqi , Jiang Xifei , Fang Yuan , Gao Jun , Wu Xiaoling , Yang Zhixiang , Ping Rongyu , Chen Jiafeng , Yang Rui , Chu Tianhao , Zhou Jian , Fan Jia , Tang Zheng , Yang Dong , Shi Yinghong
Published: December 2023

Background

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA.

Methods

We performed integrated multiomics analysis in 116 iCCA samples, including whole‐exome sequencing, bulk RNA‐sequencing and proteome analysis. Based on the non‐negative matrix factorization method and the protein abundance of metabolic genes in human genome‐scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5‐ethynyl‐2'‐deoxyuridine (EdU) assay, colony formation assay, RNA‐sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells.

Results

Three metabolic subtypes (S1‐S3) with subtype‐specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune‐suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT‐rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype‐specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen‐activated protein kinase (MAPK) signaling.

Conclusion

Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.
Oxidation State‐Based Selectivity Tuning in Transition Metal Catalysis
Authors: Zou Tian‐Yi , Zhang Qing‐Wei
Published: December 2023

Tuning between different selectivity is a challenging yet promising aspect in transition metal catalysis. Traditional methods for the attainment of synthetically relevant products rely on changing the solvent, ligand or additive. Despite the existing examples, outcomes of new catalytic conditions remain elusive. Recently, a novel tuning strategy based on the oxidation state of metal has drawn our attention. This method highlights the difference in reaction pathways, exhibiting great potential for high predictability. Nonetheless, researches within this field are scarcely‐reported in the present literature, and many of which show limitations in the elucidation of mechanism. To fully handle this tactic, more in‐depth investigations are demanded.
One‐pot Construction of Metal Nanoparticles Loaded COF Catalysts for Aqueous Hydrogenation Reactions
Authors: Lin Xiaogeng , Ma Xingyu , He Yasan , Li Shijun , Chen Wangzhi , Li Lei
Published: December 2023

The catalysis performance of metal nanoparticles (NPs) will be significantly deteriorated because of their spontaneous agglomeration during practical applications. Covalent‐organic frameworks (COFs) materials with functional groups and well‐defined channels benefit for the dispersion and anchor of metal ions and the confined growth of metal NPs, working as an ideal platform to compose catalytic systems. In this article, we report a one‐pot strategy for the preparation of metal NPs loaded COFs without the need of post‐modification. During the polymerization process, the pre‐added metal ions were stabilized by the rapidly formed COF oligomers and hardly disturb the construction of COFs. After reduction, metal NPs are uniformly anchored on the COF matrix. Eventually, a wide spectrum of metal NPs, including Au, Pd, Pt, AuPd, CuPd, CuPt and CuPdPt, loaded COFs are successfully prepared. The versatility and metal ions anchoring mechanism are verified with four different COF matrixes. Taking AuPd NPs as example, the resultant AuPd NPs loaded COF materials can selectively decompose ammonium formate and produce hydrogen in‐situ, exhibiting over 99 % conversion of hydrodechlorination for chlorobenzenes and nitro‐reduction reaction for nitroaromatic compounds under ambient temperature in aqueous solution.
Highly sensitive electrochemical determination of chemical oxygen demand by carbon‐capsulated CuOx derived from Cu foam supported Cu‐MOF
Authors: Li Pei , Yan Yu , Sun Yining , Chang Qing , Xie Yuqun , Jiang Guodong
Published: December 2023

Efficient detection of chemical oxygen demand (COD) is crucial for effective pollution prevention. Traditional Cu‐based electrodes, widely utilized for COD sensors suffer from issues related to low activity and stability. This study introduced a novel approach by employing a copper foam‐supported metal‐organic frameworks (Cu‐MOF), synthesized through a solvothermal method, which is subsequently pyrolyzed to yield a carbon‐capsulated CuOx/Cu foam electrode. Cyclic voltammetry analysis demonstrated that the carbon‐capsulated CuOx/Cu foam electrode exhibited superior redox activity, notably generating an increased amount of Cu(III) species. This enhancement significantly contributed to the electrocatalytic oxidation of organic compounds. The developed electrode demonstrated a wide linear detection range of 5–600 ppm, with a low detection limit of 0.96 ppm (S/N=3) for COD sensing. Notably, the sensor exhibited excellent anti‐interference capabilities, desirable reproducibility, and stability. The proposed method was successfully applied to determine COD in real water samples. Comparative analysis with the standard potassium dichromate method revealed high accuracy and a low relative error (2.89 %–6.72 %). This innovative approach holds promise for rapid and accurate COD detection, presenting a valuable contribution to environmental monitoring and water quality assessment.
Role of derivatives market in attenuating underreaction to left‐tail risk
Authors: Saurav Sumit , Agarwalla Sobhesh Kumar , Varma Jayanth R.
Published: December 2023

The anomalous negative relationship between left‐tail risk measures and future returns has recently attracted the attention of finance researchers. We examine the role of the derivatives market in attenuating left‐tail risk anomaly in India, where derivatives trade only for a subset of stocks. We find that the negative association between left‐tail risk measure and future return is absent only in stocks having derivatives, indicating that derivatives trading hastens the diffusion of negative information into the stock prices. We find evidence that the information generation role of derivatives markets plays a primary role compared to investor inattention and limits to arbitrage.