bluuebunny/crossref_metadata_2025 huggingface dataset:
Aryl‐Diazonium Salts Offer a Rapid and Cost‐Efficient Method to Functionalize Plastic Microfluidic Devices for Increased Immunoaffinity Capture
Authors: Rabe Daniel C. , Ho Uyen K. , Choudhury Adarsh , Wallace Jessica C. , Luciani Evelyn G. , Lee Dasol , Flynn Elizabeth A. , Stott Shannon L.
Published: June 2023

Microfluidic devices have been used for decades to isolate cells, viruses, and proteins using on‐chip immunoaffinity capture using biotinylated antibodies, proteins, or aptamers. To accomplish this, the inner surface is modified to present binding moieties for the desired analyte. While this approach is successful in research settings, it is challenging to scale many surface modification strategies. Traditional polydimethylsiloxane (PDMS) devices can be effectively functionalized using silane‐based methods; however, it requires high labor hours, equipment, and hazardous chemicals. Manufacture of microfluidic devices using plastics, including cyclic olefin copolymer (COC), allows chips to be mass produced, but most functionalization methods used with PDMS are not compatible with plastic. Herein, this work demonstrates how to deposit biotin onto the surface of a plastic microfluidic chips using aryl‐diazonium. This method chemically bonds biotin to the surface, allowing for the addition of streptavidin nanoparticles to the surface. Nanoparticles increase the surface area of the chip and allow for proper capture moiety orientation. This process is faster, can be performed outside of a fume hood, is very cost‐effective using readily available laboratory equipment, and demonstrates higher rates of capture. Additionally, this method allows for more rapid and scalable production of devices, including for diagnostic testing.
Highly Air Stable Tin Halide Perovskite Photovoltaics using a Bismuth Capped Copper Top Electrode
Authors: Wijesekara Anjana , Han Yisong , Walker David , Huband Steven , Hatton Ross
Published: June 2023

An effective approach is reported to enhance the stability of inverted organo‐tin halide perovskite photovoltaics based on capping the cathode with a thin layer of bismuth. Using this simple approach, unencapsulated devices retain up to 70% of their peak power conversion efficiency after up to 100 h testing under continuous one sun solar illumination in ambient air and under electrical load, which is exceptional stability for an unencapsulated organo‐tin halide perovskite photovoltaic device tested in ambient air. The bismuth capping layer is shown to have two functions: First, it blocks corrosion of the metal cathode by iodine gas formed when those parts of the perovskite layer not protected by the cathode degrade. Second, it sequesters iodine gas by seeding its deposition on top of the bismuth capping layer, thereby keeping it away from the electro‐active parts of the device. The high affinity of iodine for bismuth is shown to correlate with the high polarizability of bismuth and the prevalence of the (012) crystal face at its surface. Bismuth is ideal for this purpose, because it is environmentally benign, non‐toxic, stable, cheap, and can be deposited by simple thermal evaporation at low temperature immediately after deposition of the cathode.
Fast Electrically Switchable Large Gap Quantum Spin Hall States in MGe2Z4
Authors: Islam Rajibul , Hussain Ghulam , Verma Rahul , Talezadehlari Mohammad Sadegh , Muhammad Zahir , Singh Bahadur , Autieri Carmine
Published: June 2023

Spin‐polarized conducting edge currents counterpropagate in quantum spin Hall (QSH) insulators and are protected against disorder‐driven localizations by the time‐reversal symmetry. Using these spin‐currents for device applications requires materials with a large bandgap and fast switchable QSH states. By means of in‐depth first‐principles calculations, this study demonstrates the large bandgap and fast switchable QSH state in a newly introduced 2D material family with 1T′‐MGe2Z4 (M = Mo or W and Z = P or As). These Ge‐based compounds show superior properties with respect to other members of the same family. For the WGe2As4 monolayer it can stabilize the 1T′‐phase, while for the other members of the family, this study needs an appropriate strain. The dynamically stable 1T′‐MGe2Z4 monolayers have a large energy gap up to 237 meV for WGe2As4. These materials undergo a phase transition from a QSH insulator to a trivial insulator with a Rashba‐like spin splitting under the influence of an out‐of‐plane electric field, demonstrating a fast tunability of the bandgap and its band topology for the Ge‐based compounds. Fast topological phase switching in a large gap 1T′‐MGe2Z4 QSH insulators have potential applications in low‐power devices, quantum computation, and quantum communication.
Alternatingly Stacked Low‐ and High‐Resistance PtSe2/PtSe2 Homostructures Boost Thermoelectric Power Factors
Authors: Lee Won‐Yong , Kang Min‐Sung , Choi Jae Won , Kim Si‐Hoo , Park No‐Won , Kim Gil‐Sung , Kim Yun‐Ho , Lee Sang‐Kwon
Published: June 2023

2D transition‐metal dichalcogenide (TMDC) materials are promising candidates with excellent thermoelectric (TE) properties owing to their low dimensionality in electronic and phonon transport. However, the considerable coupling of the Seebeck coefficient and electrical conductivity in such TE materials eventually results in the limit of the TE power factor increase, which severely hinders potential TE device applications. Herein, an alternative approach is demonstrated for breaking the strong coupling between the Seebeck coefficient and electrical conductivity in single TE materials by adopting a novel stacked PtSe2/PtSe2 homostructure. By alternately piling low‐resistance (LR) PtSe2 (3 nm) onto high‐resistance (HR) PtSe2 (2 nm) as one unit, the Seebeck coefficient and electrical conductivity of such stacked homostructures can be greatly enhanced with slightly improved electrical conductivity, ultimately resulting in a TE power factor in three‐unit‐stacked homostructures that is ≈1,648% higher than that of a single PtSe2 (15 nm) layer with the same thickness. This enhancement is attributed to an independent increase in the Seebeck coefficient, which depends on the interface among the LR and HR PtSe2 layers. The findings pave the way for a method that, unlike power factor optimization in conventional thermoelectric materials, can only utilize the Seebeck coefficient and electrical conductivity of each layer in a stacked homostructure.
Lessons learned from local vacant land management organizations for engaging youth in greening
Authors: Rauk Leigh , Rupp Laney , Hohl Bernadette C. , Kondo Michelle C. , Ornelas Lexie , Carter Patrick M. , Zimmerman Marc A.
Published: June 2023

Youth living in areas with high concentrations of vacant properties may be at particular risk for poor health outcomes given the associations between deteriorated vacant properties, poor mental health, and community violence. Vacant lot greening has emerged as a key strategy to mitigate the harms of deteriorated properties. Youth engagement in greening has documented benefits for youth, yet few organizations responsible for managing vacant properties currently engage youth. Further, few researchers have examined the best practices that organizations can employ to effectively engage youth in greening programs. The purpose of this study was to understand how high functioning vacant land management organizations with robust youth engagement capabilities engage youth in their greening work. Based on in‐depth interviews with staff from vacant land management organizations, we explored three research questions: (1) what are their identified best practices for youth engagement?; (2) what are the major challenges that impede their youth engagement work?; (3) what solutions are these organizations employing to address these challenges? Findings from this study emphasize the important themes of engaging youth in vacant lot greening in areas of planning, leadership, and decision‐making. Youth engagement in vacant lot greening may be a key mechanism for preventing violence through cultivating youth empowerment and development.
Ancient mitochondrial genome diversity in South America: Contributions from Quebrada del Toro, Northwestern Argentina
Authors: Russo María Gabriela , Arencibia Valeria , Emery Matthew , Bettera Marcat Gianina , Seldes Verónica , Mercolli Pablo , Soria Silvia , Maldonado Lucas , Kamenetzky Laura , Avena Sergio , Dejean Cristina , Stone Anne C.
Published: June 2023

Objectives

The objective of this study was to enhance our understanding of the population history in South America, specifically Northwestern Argentina, by analyzing complete ancient mitogenomes of individuals from the Ojo de Agua archeological site (970 BP) in Quebrada del Toro (Salta, Argentina).

Materials and Methods

We analyzed teeth from four individuals from the site Ojo de Agua (970 ± 60 BP), located in Quebrada del Toro (Andean region of Northwestern Argentina). DNA extracts were converted to double‐stranded DNA libraries and indexed using unique dual‐indexing primer combinations. DNA libraries were then enriched for the complete mitochondrial genome, pooled at equimolar concentrations, and sequenced on an Illumina® MiSeq™ platform. Reads from high quality libraries were trimmed, merged, and then mapped to the revised Cambridge Reference Sequence. The aDNA damage patterns were assessed and contamination estimated. Finally, variants were called, filtered, and the consensus mitogenome was constructed and used for haplogroup assignment. We also compiled available mitogenome sequences from ancient and present‐day populations from the Southcentral Andes and other surrounding regions in Argentina. Maximum Likelihood and Bayesian phylogenetic reconstructions were obtained using the generated dataset.

Results

We successfully obtained the complete mitogenome sequence from one individual with an average depth coverage of 102X. We discovered a novel haplotype that was assigned to haplogroup D1. Phylogenetic reconstructions suggests that this haplotype falls within the sister branches of the D1j lineage, forming a well‐supported clade. The estimate TMRCA of this clade that includes D1j and its sister branches ranged between 12,535 and 18,669 ya.

Discussion

The sequence analyzed in this study represents the first ancient mitogenome from within the valley region in Northwestern Argentina. We found that a representative of a lineage highly associated with D1j was already present approximately 1000 BP in the region. Our results agree with the proposed origin of D1j in other regions north of Patagonia and independent of the Pacific coast fast migratory route, contrary to what was originally hypothesized. This study highlights the lack of information regarding pre‐Hispanic genetic diversity and contributes to the knowledge about the peopling process in South America.
The cognitive deficit induced by Al nanoparticle ingestion is associated with hippocampal inflammation in mice
Authors: Izadi Sadegh , Abdolrezaei Maryam , Moosavi Maryam
Published: June 2023

Background

Although, both environmental and genetic factors are known as the predispositions to AD development, each of these factors are suggested to acts via increasing the Al content of brain tissue. Al nanoparticles are newer nanomaterials that have been significantly exposed to the human body. When Al reaches the nanosize, it may display different characteristics from natural Al, and its potential influence on body function is an interesting aspect of research as these particles might have more negative impact on human health. Activation of microglia and expression of the inflammatory cytokine IL‐1 (interleukin‐1) in the brain have been used as hallmarks of brain inflammation. Our recent findings suggest that administration of nano‐Al for a short period of 5 days can cause memory impairment. Given the importance of neuroinflammation in Alzheimer’s pathology, the question was whether 5‐day nano‐Al intake could lead to inflammatory changes in the hippocampus.

Method

Adult male NMRI mice were treated with nano‐Al in doses 5 and 10 mg/kg/oral gavage for 5 days. The test session of novel object recognition (NOR) task was performed on day 5. Following the NOR test, the hippocampi were isolated. Considering the key roles of microglia activation and IL‐1β in neuroinflammation, the levels of hippocampal iba‐1 (as the speciefic marker of microglial activation) and IL‐1β were determined using western blot studies.

Result

The results showed that nano‐Al oral gavage in doses of 5 and 10 mg/kg impairs NOR memory in mice. Moreover, the memory impairing effect of nano‐Al coincided with a dose dependent increase in hippocampal iba‐1. It also increased the content of IL‐1 in the hippocampus.

Conclusion

This study showed that nano‐Al in doses as low as 5 and 10 mg/ kg ingested for 5 days impairs memory and induces neuroinflammation in the hippocampus.
A novel approach to quantifying longitudinal white matter hyperintensity morphometrics with Alzheimer disease progression
Authors: Strain Jeremy F. , Phuah Chia‐Ling , Adeyemo Babatunde , Womack Kyle B. , McCarthy John E , Chen Yasheng , Morris John C , Benzinger Tammie L.S. , Lee Jin‐Moo , Ances Beau M. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

Background

The role of cerebrovascular damage in Alzheimer’s Disease (AD) has resulted in inconsistent findings particularly when analyzing longitudinal data. We introduce WMH shape analysis (WSA) that quantifies white matter hyperintensity (WMH) expansion as the distance from lesion voxels to a region of interest boundary. We sought to examine the extent and spatial topography of WMH expansion with progression to AD.

Method

Fluid‐Attenuated Inversion Recovery (FLAIR) images were extracted across two timepoints from ADNI. 275 longitudinal participants were classified into groups based on amyloid and cognitive status: 99 controls (CN), 42 amyloid positive cognitively stable preclinical (PC) AD, and 134 amyloid positive cognitively impaired AD individuals. WSA was performed on 5 WMH clusters (juxtacortical, anterior corona radiata, periventricular, parietal, and occipital/posterior horn). The intensity value for each cluster ROI boundary voxels reflects the Euclidean Distance from a voxel to the closest WMH voxel. The difference in distances (DD) for each timepoint provides a metric of WMH expansion. A voxel‐wise omnibus ANOVA was performed across all three groups followed by subsequent T‐tests. Additionally, we evaluated the relationship between the changes in DD maps with PET amyloid summary values, hypertension, and APOE e4 status.

Result

WMH expansion was found to be significant across three groups (Fig. 1) and was primarily within two WMH clusters (p<0.05 corrected). T‐tests revealed that the AD group had significantly greater expansion in the juxtacortical cluster compared to CN but not the PC group (p<0.05 corrected). However, for the posterior horn that difference was driven by the PC with greater WMH expansion compared to either the AD or CN group (p<0.05 corrected). A significant association was observed with amyloid in the juxtacortical cluster but not with hypertension. A strong trend (p = 0.06 corrected) was observed for APOE e4 status in the juxtacortical cluster associating with more copies of the e4 allele.

Conclusion

This new approach to quantifying and analyzing WMH longitudinal expansion revealed different patterns of expansion with increased AD severity. These results implicate that WMH growth associated with AD progression is spatially specific and grows in distinct ways throughout the disease process.
Longitudinal risk estimation of progression from normal cognition to amnestic mild cognitive impairment: The independent contribution of ATN biomarkers
Authors: Zhao Lei , Shi Lin , Luo Yishan , Mok Vincent C.T. ,   for the Alzheimer Disease Neuroimaging Initiative
Published: June 2023

Background

It is still not clear about the independent contribution of ATN biomarkers (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) on top of neuropsychological tests for risk estimation of amnestic mild cognitive impairment (aMCI) in subjects with normal cognition (NC).

Method

We included 306 NC subjects who underwent neuropsychological tests and were available for ATN biomarkers with cerebrospinal fluid (CSF) examinations, MRI and FDG‐PET at baseline. The involved ATN biomarkers included CSF‐Aβ, CSF‐Ptau, CSF‐Tau, FDG‐PET and an MRI‐based Alzheimer’s disease resemblance atrophy index (AD‐RAI) calculated by AccuBrain. The study cohort was divided into training cohort (n = 204, 19.6% developed aMCI within 4.73±2.83 years) and validation cohort (n = 102, 20.6% developed aMCI within 4.67±2.72 years). All the demographic features and neuropsychological tests (Table 1) were entered into the cox regression model with backward elimination to predict time to incident aMCI (the subscores of FAQ and ADAS‐cog were also entered as candidate predictors), and the resulting model based on the training cohort was treated as the basic model. Individual ATN biomarkers were added on top of the basic model for cox regressions, and the enriched models would be tested in the validation cohort using time‐dependent AUC (t‐AUC) if they presented higher Chi‐squares than the basic model in training cohort.

Result

The features that survived backward elimination for the basic model were shown in Table 2. Only the enriched model with Ptau or AD‐RAI presented higher Chi‐square than the basic model in the training cohort (p<0.05, Table 3). In the validation cohort, the model Basic+(AD‐RAI) presented significantly higher t‐AUC (0.770∼0.859) than the basic model through year 2∼7 and Basic+Ptau through year 1∼4 (p<0.05, Figure 1). The model with Ptau only presented significantly higher t‐AUC than the basic model for year 7 (p = 0.02). Also, adding Ptau on top of Basic+(AD‐RAI) presented no significant increase of t‐AUC for any time point (Figure 1). These findings indicated that Basic+(AD‐RAI) may be used as the optimal model for predicting risk of aMCI (nomogram shown in Figure 2).

Conclusion

AD‐RAI consistently presented independent contribution to predicting aMCI among NC subjects on top of demographic characteristics and neuropsychological tests.
Immunity gene IFITM3 variant: relation to cognition and Alzheimer pathology
Authors: Pyun Jung‐Min , Park Young Ho , Han Moon‐ku , Hodges Angela , Jang Jae‐Won , Bice Paula , Kim SangYun , Saykin Andrew J. , Nho Kwangsik
Published: June 2023

Background

IFITM3, an innate immune response protein and inhibitor of viral infection, was reported to modulate amyloid‐β production in Alzheimer’s disease (AD). We aimed to identify single‐nucleotide polymorphisms (SNPs) in IFITM3 associated with cognition and AD biomarkers.

Method

We used genetic, longitudinal cognition and AD biomarker data from Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 1,565) and AddNeuroMed (N = 633) as discovery and replication samples, respectively. First, we performed gene‐based association analysis of SNPs in IFITM3 with cognitive performance. Second, we performed SNP‐based association analysis in IFITM3 with cognitive decline and AD biomarkers from amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI).

Result

Gene‐based association analysis showed that IFITM3 was significantly associated with cognitive performance (permutation‐corrected p = 1.25×10−3). Particularly, among two SNPs (rs10751647, rs2091850) in IFITM3 significantly associated with cognitive performance, rs10751647 was associated with cognitive decline in ADNI, which was replicated in AddNeuroMed. In addition, rs10751647 was significantly associated with amyloid‐β deposition measured by amyloid PET scan, CSF phosphorylated tau levels, and entorhinal cortical thickness measured by MRI scan in ADNI. The association of rs10751647 with entorhinal cortical thickness was replicated in AddNeuroMed. Participants with minor alleles (C) of rs10751647 have less cognitive decline, less amyloid and tau burden, and less brain atrophy. eQTL analysis showed that rs10751647 is associated with IFITM3 expression levels in blood and brain.

Conclusion

This suggests that rs10751647 in IFITM3 is associated with less vulnerability for cognitive decline and AD biomarkers, providing mechanistic insight regarding involvement of immune activity and infection in AD.
The intrinsic locus coeruleus functional connectivity change in older adults with subjective memory complaint
Authors: Gong Liang , Zhang Bei ,   Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

Background

The locus coeruleus (LC) is critical for late‐lift cognitive processing by modulating the norepinephrine system, which is often the first place Alzheimer’s pathology appears. Previous researches have identified that the LC was associated with late‐life cognitive ability. This study aims to investigate whether the intrinsic LC functional connectivity (LC‐FC) is altered in older adults with subjective memory complaints (SMC).

Method

A total of 199 participants were selected from the Alzheimer’s Disease Neuroimaging Initiative database, including 95 SMC older adults and 104 cognitively normal individuals (CN). Bilateral LCs were selected to construct the LC functional connectivity based on resting‐state fMRI data. The cognitive function was evaluated by using the ADNI composite executive function (ADNI‐EF) and memory (ADNI‐Mem) scores at baseline and 24 months later. Data were analyzed using the voxel‐wise two‐sample t‐test and partial correlation analysis, we utilized permutation testing with threshold‐free cluster enhancement (TFCE) to multiple comparison correction.

Result

There were no significant differences in demographic information and cognitive function between the two groups. In the left LC‐FC network, compared to CN group, the SMC group showed increased LC‐FC in the left salient network (anterior insula, and frontal operculum cortex), hippocampus, and right default mode network(DMN, inferior temporal gyrus), while they had decreased LC‐FC in left inferior temporal gyrus. No significant difference in the right LC‐FC network between the two groups. The altered FC between left LC and right inferior temporal gyrus (DMN) was significantly associated with ADNI‐EF performance in the SMC group, controlled the effect of age, gender, and APOE genotype (r = ‐0.404, p = 0.002), and the FC between LC and right ITG was also associated with executive function performance after 24 months in SMC group.

Conclusion

The present study manifested the abnormal intrinsic LC functional connectivity in elder adults with SMC. In addition, the FC between LC and default mode network was associated with the executive function performance in SMC. These findings might suggest an LC norepinephrine system compensatory mechanism in cognitive processing in older individuals with SMC.
Imaging correlates of premorbid personality in the Frontotemporal Dementia ‐ Amyotrophic Lateral Sclerosis (FTD‐ALS) spectrum
Authors: Gallingani Chiara , Vinceti Giulia , Carbone Chiara , Fiondella Luigi , Zucchi Elisabetta , Martinelli Ilaria , Tondelli Manuela , Salemme Simone , Mandrioli Jessica , Chiari Annalisa , Zamboni Giovanna
Published: June 2023

Background

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) belong to the same neurodegenerative spectrum. Factors determining phenotypic expression are unknown; however, it is common observation that personality differs between phenotypes: ALS patients tend to display a pleasant and nice attitude, while FTD patients frequently exhibit antisocial behaviours and lack of empathy. We therefore aimed at testing if FTD and ALS patients have different premorbid personalities, and, consequently, different organizations in the brain networks involved in social behaviour and motor function.

Method

We recruited FTD and ALS patients presenting to Modena University Hospital Neurology Clinics. Patients’ premorbid personality was assessed through the NEO Personality Inventory 3, which evaluates five main personality factors (Neuroticism, Extraversion, Openness, Agreeableness, Conscientiousness). Brain MRI scan including T1‐weighted and resting state fMRI sequences was performed. Data were analysed with voxel‐based morphometry and probabilistic independent component analysis.

Result

50 patients (30 FTD, 17 ALS, and 3 FTD‐ALS) were recruited. A significant difference in premorbid personality emerged in the Openness and Extraversion domains, meaning that ALS patients – in their premorbid life – showed higher sociability, loquacity and optimism and were more prone to new experience, ideas, and emotions than FTD patients, respectively. Structural imaging analysis showed a positive correlation between premorbid Neuroticism and grey matter density of the hippocampus bilaterally (left>right) across all patients. Group comparisons of fMRI data showed greater functional connectivity (FC) in ALS compared to FTD patients within the Salience Network (SN) in the right insula, putamen, nucleus accumbens, and the left thalamus. FC within the SN positively correlated with premorbid Openness across all patients.

Conclusion

Premorbid personality differs between patients with ALS and FTD, and relates to different degrees of FC within the Salience Network. This suggests that premorbid personality may represent a vulnerability marker to the development of specific phenotypes along the FTD‐ALS spectrum.
Does awareness of condition change over time in people with mild‐to‐moderate dementia? Longitudinal findings from the IDEAL cohort
Authors: Alexander Catherine Maria , Martyr Anthony , Clare Linda ,   in collaboration with the IDEAL programme research team
Published: June 2023

Background

Although awareness is known to vary in people with dementia, little is known about longitudinal trajectories of awareness of condition in people with mild‐to‐moderate dementia. Exploring this could help understand the concepts around awareness, and reasons for apparent impaired awareness, relevant to person‐centered care.

Method

We used longitudinal data from the IDEAL programme for 917 community‐dwelling people diagnosed with mild‐to‐moderate dementia. Using a validated checklist, we assessed awareness of personal difficulties associated with dementia at three timepoints over two years. Changes in awareness from baseline were examined. Focusing on people with low awareness at baseline, we used case‐matching to compare characteristics between people who gained awareness over time, and those who continued with low awareness.

Result

At baseline, 83 people showed low awareness of personal dementia‐related difficulties. Following up this group, after attrition we examined data for 49 people at T2 and 25 people at T3. Most people remaining in the study had gained awareness at T2 and T3. Gains were seen up to four or more years after diagnosis. Five people continued to deny any of the common difficulties associated with dementia at all timepoints. These five reported slightly more comorbid conditions than matched cases. Few other distinguishing features were evident but in comparison, the people who came to acknowledge difficulties showed greater deterioration in cognitive and functional ability by T3.

Conclusion

Over time, self‐reported awareness of dementia‐related difficulties can change in people with mild‐to‐moderate dementia. Awareness gains, seen in most people remaining in the study at T2 and T3, may have been prompted by deteriorating abilities. Reasons for ongoing low awareness were difficult to establish and may relate to individual circumstances including comorbidity. This highlights the individual complexity and dynamic nature of awareness in dementia and challenges the concept of impaired awareness as a fixed disease‐related condition.
Mid‐ to late‐life physical and recreational activities: Associations with late‐life cognition
Authors: Gavett Brandon E , Widaman Keith F. , McKenzie Cathryn , Chooi Cheyenne K , De Leon Fransia S. , Fletcher Evan M , Farias Sarah Tomaszewski , Mungas Dan M.
Published: June 2023

Background

Physical and cognitively stimulating recreational activities are lifestyle factors that may modify risk of late‐life cognitive decline. We sought to examine the role of retrospective ratings of mid‐life (age 40) physical and recreational activity engagement – and change in these activities from age 40 to study entry – in predicting late‐life cognition. We hypothesized that higher self‐reported levels of physical and recreational activities at age 40, and less decline in these activities over time, would be associated with higher levels of late‐life cognition and less rapid cognitive decline.

Method

Data were obtained from 898 participants in the University of California Davis Aging and Diversity Cohort, a longitudinal study of cognitive aging in demographically and cognitively diverse older adults. Participants ranged in age from 49‐93 years (M = 75, SD = 7.19). Self‐reported physical and recreational activity participation at age 40 and at study entry were quantified using the Life Experiences Assessment Form. Confirmatory factor analysis established the unidimensionality and longitudinal measurement invariance of physical and recreational activity levels at age 40 and at study entry. Change in activities was modeled using latent change scores. Cognitive outcomes were obtained annually (range = 0‐17 years) using the Spanish and English Neuropsychological Assessment Scales, which measures episodic memory, semantic memory, visuospatial processing, and executive functioning. Multilevel structural equation modeling was used to regress four cognitive intercepts and one global cognitive slope onto age 40 and change factors for physical and recreational activities, in separate models.

Result

Physical activity engagement at age 40 was strongly associated with cognitive performance in all four domains at study entry and with global cognitive slope. However, change in physical activities was not associated with cognitive outcomes. In contrast, recreational activity engagement – both at age 40 and change after age 40 – was predictive of cognitive intercepts and slope.

Conclusion

Mid‐life physical and recreational activity engagement were strongly associated with late‐life cognition – both level of performance and rate of future decline. However, the data suggest that maintenance of recreational activity engagement (e.g., writing, taking classes, reading, arts & crafts) after age 40 is more strongly associated with late‐life cognition than continued maintenance of physical activity levels.
The significance of the Calbindin‐D in Alzheimer’s disease
Authors: Mroczko Barbara , Kulczynska‐Przybik Agnieszka , Borawska Renata , Dulewicz Maciej , Doroszkiewicz Julia , Karpiuk Magdalena , Slowik Agnieszka
Published: June 2023

Background

Alzheimer’s disease is a heterogeneous, progressive, and devastating neurodegenerative disease. In addition to the accumulation of Aβ and tau, neuropathological processes in the early stage of AD are accompanied by calcium dysregulation, which might cause the loss of synapses and then dysfunctions of the neural network. Calbindin‐D is abundant throughout the central nervous system (CNS) and one of the neuronal protective factors, also involved in calcium homeostasis. It has been reported that the depletion of Calbindin‐D in AD transgenic mice brain elicited significant alterations in apoptosis, synaptic transmission, and cytoskeleton organization. Despite of the reduced Calbindin expression in the brains of mice and patients with AD, still the role of this protein in AD‐related dysfunction is tested. To obtain better insights into the pathological significance of the protein we assesed the concentarion of Calbindin‐D in cerebrospinal fluid of patients with AD and non‐demented controls.

Method

The study group included 34 subjects: patients with AD and controls without cognitive impairments. The cerebrospinal fluid (CSF) concentrations of tested proteins were measured with the use of multiplexing technique.

Result

The CSF concentrations of Calbindin‐D were elevated in AD patients in comparison to non‐demented controls. Additionally, the CSF levels of Calbindin‐D positively correlated with tau as well as phTau181, and negatively with MMSE in the whole study group.

Conclusion

Our preliminary study indicates a potential role of Calbindin‐D in the development of AD, although the question, whether this protein can be useful in clinical practice of dementia requires further examination.
A new BACE‐1 inhibitor peptide from Macrorhynchia philippina
Authors: Renzo Karine Cristie Quaglio Banagouro , Kitahara Marcelo V , Sciani Juliana Mozer
Published: June 2023

Background

Alzheimer’s Disease (AD), the most common cause of dementia, is characterized by the amyloid plaques accumulation, generated after the APP cleavage by enzymes, being the most important the beta‐secretase‐1 (BACE1) (Hardy and Selkoe, 2002). Small‐molecule BACE1 inhibitors reduced the production of amyloid‐β peptide, but clinical trials have demonstrated some adverse effects, although non‐progressive and reversible, which indicates that BACE1 inhibition should be better investigated (McDade et al., 2021). Peptides are molecules few explored in the drug development field, but have several advantages, such as specificity, bioavailability and ability to cross the brain‐blood barrier (BBB) (Craik et al., 2013). Marine animals are a rich source of peptides, some of them already used in the clinics (Malve, 2016). Thus, the objective of this work was to find new BACE1 inhibitor peptides from Macrorhynchia philippina venom, a Brazilian marine animal.

Method

M. philippina venom was obtained by methanol/acetic acid extraction and tested in SH‐SY5Y neurons for toxicity evaluation. The extract was analyzed by mass spectrometry for peptides identification and sequencing, and had their secondary structure determined and prepared for molecular docking with BACE1 (PDB code 2VKM), conducted by MDockPep serve (Xu and Zou, 2020). Results were analyzed by UCSFChimera, and molecules were selected according to their positioning in the enzyme active site, with distance lower than 3 Å between atoms. Selected molecules were also analyzed by ProtParam tool (Gasteiger et al., 2005) for determining physico‐chemical properties, BBB permeability and stability.

Result

Nineteen peptides were obtained, and none of them have already been described, according to similarity analysis by BLAST algorithm. None of them caused significant cytotoxicity for neurons. From that, 10 were positioned in the BACE1 active site after a global docking analysis, in the same place than a known inhibitor (Ki 1.8 nM). One of them was stable, according to algorithms created from known peptides and high aliphatic index. Moreover, the peptide had high hydrophobicity, according to GRAVY index, indicating high BBB permeation.

Conclusion

One new peptide was obtained with potential activity on BACE1 inhibition, with suitable characteristics for a drug. The bioactive peptide represents a good alternative for AD treatment.
The Markers in Neuropsychiatric Disorders Study (The MiND Study): moving neurofilament light and other markers into the clinic to improve care for people with symptoms and illnesses of the mind and brain
Authors: Eratne Dhamidhu , Lewis Courtney , Kang Matthew , Keem Michael H , Dobson Hannah , Santillo Alexander , Li Qiao‐Xin , Stehmann Christiane , Loi Samantha M , Walterfang Mark , Watson Rosie , Yassi Nawaf , Blennow Kaj , Zetterberg Henrik , Janelidze Shorena , Brodtmann Amy , Darby David G , Walker Adam J , Dean Olivia , Kaylor‐Hughes Cath , Gunn Jane , Goranitis Ilias , Pan Tianxin , Fowler Christopher J , Masters Colin L. , Collins Steven J , Berkovic Samuel F , Velakoulis Dennis ,   The MiND Study Group
Published: June 2023

Background

Accurate, timely diagnosis of neuropsychiatric symptoms, in particular distinguishing primary psychiatric from neurological disorders and in younger people, can be challenging. Neurofilament light (NfL) and other blood biomarkers have shown promise to reduce the diagnostic odyssey and improve outcomes. The MiND Study in investigating the diagnostic utility of NfL and other markers, to distinguish neurological/neurodegenerative from psychiatric disorders, to lead to a widely available, routine screening blood test.

Methods

We assessed NfL, p‐tau181 and GFAP in broad cohorts, including: patients assessed for neurocognitive/psychiatric symptoms at Neuropsychiatry and other services, in a wide range of disorders including Alzheimer disease, frontotemporal dementia, schizophrenia, bipolar disorder, depression, functional neurological disorders, Niemann‐Pick Type C, epilepsy.

Results

Updates on the The MiND Study progress and findings that NfL differentiated diverse neurodegenerative from psychiatric disorders, with 90+% accuracy, from over 500 patients/participants, will be presented, with real patient and family stories to demonstrate the challenges and potential clinical impact of The MiND Study. Plasma P‐tau181 levels distinguished Alzheimer disease (mainly younger sporadic), from non‐Alzheimer. As recruitment, sample analysis, data collection is ongoing, the most up to date results including GFAP, cognitive and neuroimaging markers, will be presented.

Conclusions

NfL shows great promise as a diagnostic screening blood test, akin to a “CRP for the brain”. Plasma p‐tau181 shows strong diagnostic utility in younger‐onset Alzheimer disease. NfL could dramatically alter clinical care of patients with neuropsychiatric and neurological symptoms, improving outcomes for patients, their families, the healthcare system, and clinical trials, facilitating precision medicine algorithmic diagnostics incorporating other biomarkers and clinical/cognitive markers, for real‐world clinical settings.
The relationship between the frailty of the older adults and cognitive function, activities of daily living, and life satisfaction
Authors: Lee Gyeong A , Park Ji‐Hyuk
Published: June 2023

Background

Frailty belongs to the pre‐disability stage and is closely related to the transition to disability. It is more fatal when frailty occurs in older adults than in other age groups. By understanding the negative negative outcomes of frailty on the health of older adults, they will be able to manage their own health and prevent disability. This study aims to examine whether the frailty of older adults contributes to cognitive function, activities of daily living, life satisfaction.

Method

The study sample was 9,885 community‐dwelling older adults aged 65 years and older. Data obtained from the 2020 survey of living conditions and welfare needs of older Koreans. Hierarchical regression analysis was used to determine whether frailty and cognitive function, activities of daily living, life satisfaction are significantly related even after controlling for factors influencing dependent variables. Life‐course determinants factors (i.e. age, sex, spouse, education, living environment, life events, lifestyle) were entered in block 1, the number of chronic diseases was entered in block 2, and frailty factors(physical, psychological, social) was entered in block 3.

Result

The analysis results are as follows. First, cognitive function decreased significantly as physical, psychological, and social frailty (β = 0.100, p<0.001; β = 0.104, p<0.001; β = 0.112, p<0.001, respectively) increase. Second, as physical, psychological, and social frailty (β = 0.063, p<0.001; β = 0.283, p<0.001; β = 0.032, p = 0.003, respectively) increase, the basic activities of daily living decreased significantly. Third, as physical, psychological, and social frailty (β = 0.140, p<0.001; β = 0.304, p<0.001; β = 0.028, p = 0.008, respectively) increase, the instrumental activities of daily living decreased significantly. Fourth, as physical, psychological, and social frailty (β = 0.041, p<0.001; β = 0.209, p<0.001; β = 0.076, p<0.001, respectively) increase, life satisfaction decreased significantly.

Conclusion

In this study, it was investigated whether frailty (physical, psychological, and social) contributes to cognitive function, the activities of daily living, and life satisfaction among older adults. This finding suggests that frailty may be related to health‐related variables of older adults.
The neuronal pentraxin receptor (NPTXR) as a candidate biomarker of synaptic dysfunction in mild cognitive impairment
Authors: Dulewicz Maciej , Kulczynska‐Przybik Agnieszka , Borawska Renata , Slowik Agnieszka , Mroczko Barbara
Published: June 2023

Background

Early deficits of cognitive symptoms have molecular background closely related to Alzheimer’s Disease (AD). Before developing full‐blown AD, mild cognitive impairment (MCI) develops. It has been suggested that synaptic pathology is closely associated with memory impairment in the early phase of the disease and may be monitored by assessment of the synaptic proteins in cerebrospinal fluid (CSF), like neuronal pentraxin receptor (NPTXR). The highest expression of NPTXR and involvement in neuronal processes have been observed in the hippocampus and cortex. This candidate biomarker of synaptic dysfunction may have a crucial role in synaptic transmission and modulation of memory processes with other synaptic proteins. The purpose of the our investigation was to assessed the neuronal pentraxin receptor (NPTXR) level in cerebrospinal fluid (CSF) in MCI patients.

Method

The study included 17 patients with MCI and 17 non‐demented controls. The CSF levels of NPTXR and classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, Tau, and pTau181, were assessed by commercially available immunoenzyme assays.

Result

The CSF concentration of NPTXR was significantly lower in MCI patients compared to non‐demented controls. Moreover, NPTXR level was positively correlated with Tau181, Aβ‐42, and total Tau proteins in MCI patients.

Conclusion

Our results suggest that Neuronal Pentraxin Receptor may be one of the biomarker reflecting synaptic dysfunction in MCI patients. These preliminary results seem very promising, particularly for the early diagnosis of Alzheimer’s disease. Future research concerning NPTXR is necessary to understand better the role of the protein in early pathological processes of the disease.
Open RoAD: Design and baseline characteristics of an open‐label rollover study evaluating long‐term safety and tolerability of subcutaneous gantenerumab in participants with early Alzheimer’s disease
Authors: Neve Anuja , Bullain Szofia , Das Bibha , Huang Zhiyue , Watkin Michelle , Delmar Paul , Klein Gregory , Bittner Tobias , Lott Dominik , Smith Janice , Kerchner Geoffrey A. , Fontoura Paulo , Baudler Monika , Doody Rachelle S.
Published: June 2023

Background

Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer’s disease (AD). SCarlet RoAD (SR) (NCT01224106) and Marguerite RoAD (MR) (NCT02051608) were two Phase III trials which assessed the efficacy and safety of subcutaneous (SC), low‐dose gantenerumab in participants with prodromal and mild AD, respectively, for up to 2 years. Following a gap period gantenerumab treatment was continued with uptitration to a dose of 1,200 mg monthly in open‐label extensions (OLE), which demonstrated substantial Abeta removal by positron emission tomography without new or unexpected safety findings. Here, we describe the study design, present baseline characteristics, and safety data from an additional open‐label, multicenter, rollover study, Open RoAD (OR) (NCT04339413), collecting long‐term safety and tolerability data for gantenerumab in participants who completed the SR OLE or MR OLE.

Method

Participants who completed either OLE study and were treated with doses up to 1,200 mg of gantenerumab for up to 5 years continue to receive the same dose of SC gantenerumab (every 4 weeks [q4w]) for 2 additional years in OR. The primary objective is to evaluate long‐term safety and tolerability by assessing adverse events, including amyloid‐related imaging abnormalities, and injection‐site reactions. Exploratory efficacy objectives include Mini‐Mental State Examination (MMSE) total score. The long‐term effect of gantenerumab on pharmacodynamic measures and biomarkers will also be explored.

Result

Baseline characteristics

Fifty‐nine participants from SR OLE and 56 participants from MR OLE received at least one dose of gantenerumab in OR. The median participant age at baseline was 78 years, and the majority of the participants were female (61%). Sixty‐seven percent of participants were apolipoprotein‐E‐e4 (APOE e4) carriers. The median total MMSE score at baseline was 16.

Safety data will be presented.

Conclusion

The RoAD studies are among the longest‐duration OLEs of an anti‐amyloid monoclonal antibody. Data from the OR study demonstrate that gantenerumab at doses of 1,200 mg administered SC q4w is well tolerated, with no new or unexpected safety findings in patients with early AD.
Modifiable dementia risk factors are associated with greater subjective cognitive concerns but not perceived susceptibility to dementia in late middle‐aged adults: Baseline characteristics of the BetterBrains Trial
Authors: Rosenich Emily , Bransby Lisa , Pirotta Stephanie , Ayton Darshini , Buckley Rachel F. , Maruff Paul , Lim Yen Ying ,   BetterBrains Research Group
Published: June 2023

Background

A range of lifestyle factors in midlife can increase risk for developing dementia in late‐life.1 However, it remains unclear whether the presence of such risk factors (RFs) is associated with individuals’ insight into their risk of developing dementia. In a group of middle‐aged adults with a family history of dementia enrolled in a lifestyle prevention trial, we measured associations between modifiable RF prevalence, subjective cognitive concerns, and perceived susceptibility to dementia.

Method

Participants (n = 456) enrolled in BetterBrains (betterbrains.org.au)2 completed a comprehensive self‐report RF assessment at baseline. Modifiable dementia risk was determined across four domains (vascular health, social/cognitive engagement, mood, sleep) and trial eligibility required risk in at least one domain. Participants were grouped according to the number of domains in which they reported high‐risk (ranging from 1‐4). Participants completed the Cognitive Function Instrument, and a brief questionnaire to assess perceived susceptibility to dementia (Motivation to Change Lifestyle/Health Behaviours for Dementia Risk Reduction scale). Linear regressions examined associations between modifiable RF prevalence, subjective cognition, and perceived susceptibility to dementia, adjusting for age, sex, education, negative beliefs about ageing, and beliefs about protective health behaviours on dementia risk.

Result

Participants were mostly female (80%), with an average age of 59.4 years and 15.2 years of education. Of the sample, 29.6% reported risk in all domains (29.6%) and 16.9% in three domains. Risk in a higher number of RF domains was significantly associated with greater subjective cognitive concerns (β(SE) = 0.18(0.06), p = <.001), but not with greater perceived susceptibility to developing dementia (β(SE) = 0.62(0.35), p = .08). Increasingly negative beliefs about ageing and weaker beliefs in the protective effect of health behaviours were the only significant predictors of perceived susceptibility to dementia (both p’s <.05).

Conclusion

In middle‐aged adults, dementia RFs are associated with greater subjective cognitive concerns, but not with an increased perception of susceptibility to dementia. Incongruence between participants’ self‐report of subjective cognitive concerns and susceptibility to dementia may be due in part to poor knowledge on modifiable dementia RFs.3 Perceptions of personal susceptibility to dementia may also be tied more closely to negative ageing stereotypes typically associated with older age and family history of disease.