bluuebunny/crossref_metadata_2025 huggingface dataset:
Inverse relationship between education and amyloid burden in individuals with subjective cognitive decline plus and mild cognitive impairment
Authors: Hönig Merle C. , Caprioglio Camilla , Collij Lyduine E. , Frisoni Giovanni B , Barkhof Frederik , Farrar Gill , Scheltens Philip , Delrieu Julien , Molinuevo Jose Luis , Grau‐Rivera Oriol , Walker Zuzana , Nordberg Agneta K , Demonet Jean‐François , Stephens Andrew W. , Battle Mark R , Buckley Christopher , Gispert Juan Domingo , Jessen Frank , Altomare Daniele , Drzezga Alexander ,   the Amypad consortium
Published: June 2023

Background

Higher educated patients with MCI can tolerate more neuropathology than lower educated patients with similar clinical impairment. It is not known whether this observation also accounts for potential preclinical stages of AD, namely subjective cognitive decline plus (SCD+).

Method

Data of 197 SCD+ individuals, 227 MCI and 157 AD patients were included, which were collected as part of the AMYPAD‐DPMS cohort (https://amypad.eu/). First, median education in years was computed across the AD‐spectrum groups for each of the 8 European sites. Next, using a median split, the SCD+, MCI and AD cohort were separately categorized into a higher and lower educated group, excluding subjects with median education. Afterwards, the higher and lower educated AD‐spectrum groups were matched for age, sex and cognitive function (MMSE) using propensity score matching in R, leading to the following sample (low/high education): 54/54 SCD+, 70/81 MCI and 56/65 AD patients. Global amyloid load was compared between education groups using Centiloid (CL) information derived from Flutemetamol and Florbetaben PET scans. To confirm the results of the stringent group comparison, partial correlations between years of education and CL values correcting for age, sex and tracer type were performed for each AD‐spectrum group. All analyses were conducted in SPSS 28 and significance level was set to p < .05.

Result

Higher educated SCD+ subjects presented significantly (p <. 001) lower CL values (M(CL) = 16.48) than lower educated SCD+ subjects (M(CL) = 32.17), whereas the opposite effect (p < .046) was observed in the MCI cohort with higher educated MCI patients presenting greater CL values (M(CL) = 57.08) compared to the lower educated MCI group (M(CL) = 41.74). No difference was found in the AD group. Results were further confirmed by the correlation approach across the unmatched sample yielding a negative association between years of education and CL values in the SCD+ group (r = ‐.159, p = .027) and a positive association in the MCI group (r = .153, p = .022).

Conclusion

These results indicate that sensitivity to early amyloid accumulation may possibly increase with higher education in potential preclinical stages of AD, whereas in clinical stages of AD higher education may support compensatory mechanisms against amyloid burden.
Quantum crystallographic method improves the accuracy of screening of inhibitors: A set of Alzheimer’s disease responsible protein‐ligand complexes
Authors: Kandasamy Saravanan , Srinivasan Sugarthi
Published: June 2023

Background

In drug design and development, identification of lead structure is a crucial step to predict the ligand binding affinity and functional potency with any of target enzyme/protein. The recently developed quantum crystallographic method (fragment‐based approach) has been used as a substitutional way to calculate the interaction energies. This quantum mechanical level information gives a deeper understanding of structural facts with the position of hydrogen atoms and valence electron distributions. It is very much essential to understanding the electronic properties of drug‐receptor interactions. Therefore, the quantum crystallographic based interaction energy calculation is a better alternative method to docking score‐based modelling.

Method

A set of AD responsible protein‐ligand complexes were selected for the quantitative analysis. Molecular docking of selected compounds with four different enzymes (AChE/BChE/BACE1/GSK3β) was carried out and then, all the selected complexes have been subjected to MD simulation. Later, the 3D coordinates of ligand with active site residues (around 4Å from the ligand) were used for quantum crystallographic studies.

Result

The screened molecules are forming strong hydrogen bonding and hydrophobic interactions with active site residues of all four enzymes; particularly, π‐π stacking, π‐cationic, π‐alkyl and π‐σ types of interactions, which are highly stable during dynamic behavior. After the quantum crystallographic studies, the interaction energies of selected compounds with different active site residues of all four enzymes were analyzed; it is ranged from ‐20.83 to ‐3.92 kcal/mol and the total interaction energies of each complex are higher than binding energy gained from MD simulation. And, the RMSD of each molecule was compared with the corresponding geometry of solid‐state and dynamic state; it is found to be significantly low (>0.5Å) and similar. Interestingly, the correlation between experimental IC50 and averaged interaction energies of selected compounds exhibits good agreement.

Conclusion

The in‐silico results revealed conformational flexibility, high stability and compactness, binding affinity and orientation of the target molecules in the active site residues of all enzymes in the physiological nature (water‐medium). Quantum crystallographic method is a novel approach that opens new window to delineate the different type of interactions at electronic level. And, it may allow us to design new drug against target disease.
Testing the brain maintenance and cognitive reserve hypothesis of cognitive aging: Application to vascular and metabolic risk factors
Authors: Neth Bryan J. , Lesnick Timothy G. , Castillo Anna , Przybelski Scott A. , Graff‐Radford Jonathan , Machulda Mary M. , Mielke Michelle M. , Petersen Ronald C. , Lowe Val J. , Jack Clifford R. , Knopman David S. , Vemuri Prashanthi
Published: June 2023

Background

Two pathways that help explain cognitive health are 1) brain maintenance – referring to the relative absence of brain changes over time; 2) cognitive reserve – a property of the brain that allows for sustained cognitive ability in the presence of brain pathology. Both pathways influence cognitive aging and are best understood using longitudinal data. Our goal was to assess the effect of modifiable vascular/metabolic and lifestyle enrichment factors on these pathways using longitudinal brain changes measured on structural magnetic resonance imaging (MRI) and longitudinal cognitive decline. Lastly, we combined these pathways and their relationships in the same model.

Method

We identified 1250 participants from a well‐characterized sample of older adults from the Mayo Clinic Study of Aging with both longitudinal MRI and cognitive data. Linear mixed models were performed to assess the impact of modifiable factors on brain maintenance and cognitive reserve. Latent growth curve models (SEM) were used to assess the impact of brain structure and cognitive reserve on longitudinal cognition.

Result

The mean age of our sample was 78.8 years, with 45.4% female, and 27.1% APOE4 carriers. Mean follow‐up time was 4.0 years with a mean of 3.2 MRI scans per participant. Linear mixed models showed that poorer vascular/metabolic health (presence of vascular/metabolic conditions) was associated with lower cross‐sectional temporal region cortical thickness (‐0.014 (0.003), p<0.001) and lower global cognition (‐0.042 (0.018), p = 0.024). Higher estimated cognitive reserve at baseline as assessed by education/occupation composite (0.103 (0.01), p<0.001) was associated with higher global cognition. Unexpectedly, late‐life physical activities were related to lower global cognition (‐0.05 (0.007), p = 0.004). Our final latent growth curve SEM fit the data well showing temporal associations between unmodifiable characteristics, cognitive reserve, and brain structural pathways, as well as the influence of modifiable vascular/metabolic factors.

Conclusion

We found that brain maintenance and cognitive reserve pathways were related to better cognition over time. We further showed that vascular/metabolic health impacts long‐term cognitive outcomes (i.e. cognitive aging) primarily through the brain maintenance pathway. These data provide a modeling scheme for future studies and can aid in assessing the pathways by which individual factors may influence cognitive aging.
Longitudinal lumbar puncture adherence in the Alzheimer’s Prevention Initiative Autosomal‐Dominant Alzheimer’s Disease Colombia Trial
Authors: Acosta‐Baena Natalia , Ríos‐Romenets Silvia , Giraldo‐Chica Margarita , Espinosa Alejandro , Ramos Claudia , Aguillon David , Aponte Claudia , Leon‐Varela Yudy M , Piedrahita Francisco , Lopez Liliana , Gomez Francisco , Ehrhard Patricia , Sink Kaycee M. , Tariot Pierre N. , Reiman Eric M. , Lopera Francisco ,   API ADAD Colombia Trial Group
Published: June 2023

Background

Cerebrospinal fluid (CSF) biomarkers have potentially important roles in Alzheimer’s disease (AD) treatment and prevention trials. The Alzheimer’s Prevention Initiative Autosomal‐Dominant AD (API ADAD) trial protocol (NCT01998841) includes optional CSF biomarker measurements at baseline, 24 months, and 60 months. We determined the adherence to lumbar puncture (LP) procedures and predictors of dropout rates in trial participants who had a baseline LP.

Method

Available data from cognitively unimpaired 30–60‐year‐old members of the Presenilin 1 E280A kindred were used to characterize LP participation rates at baseline, LP‐related complications and potential factors associated with adherence to 24‐month follow‐up LPs (age, sex, education, place of residence, puncture site, needle gauge, number of attempts, and traumatic puncture). Logistic regression was used to investigate associations.

Result

130 (51.6%) of 252 trial individuals consented to participate in the CSF biomarkers substudy. Consent was not associated with age, sex, education or location of residence. 43 (33.1%) participants had 49 LP‐related complications at baseline. The most frequent complications were headache in 25 (19.2%) participants and low back pain in 14 (10,8%) participants. Other baseline LP‐related events were dizziness, photopsia, and tremor. Complications at baseline were not associated with puncture site (L3‐L4 or L4‐L5), needle gauge (22 or 24 G), number of attempts or traumatic puncture. Ninety‐eight (75.4%) of the eligible participants consented to have the 24‐month follow‐up LP. Absence of any baseline LP‐related complications was associated with less attrition in this subsequent LP consent (0R = 0.25; 95%CI 0.10‐0.61), after controlling for age, sex, years of schooling, rural home and city of residence.

Conclusion

Adherence to 24‐month follow‐up LP in API ADAD trial was 75.4%. This clinical trial is conducted in young people, active at work. Although some participants live far from the city where LP’s are performed or in remote areas, this did not affect their willingness to consent to a second LP. However, the presence of any complication did increase the risk of withdrawal for the subsequent procedure since it impacted ability to work. This information could help to inform the design and statistical power of future AD prevention trials using CSF biomarker endpoints.
Predicting Conversion to Alzheimer Disease using Module‐Based Polygenic Risk Scores Informed by Brain Proteome Profiles
Authors: Hu Junming , Sahelijo Nathan , Priyadarshi Dhawal , Thompson Paul M , Saykin Andrew J. , Davatzikos Christos , Jun Gyungah R ,   Alzheimer’s Disease Neuroimaging Initiative(ADNI),AI4AD Consortium
Published: June 2023

Background

Neuropathologically confirmed Alzheimer disease (AD) patients are heterogeneous in their cognitive functions, brain atrophy patterns, and neuropathological traits. Genetic risk profiles informed by brain proteome signatures may predict the conversion of clinically normal individuals to AD.

Method

We discovered co‐expressed proteome networks using 201 AD brains from the prefrontal cortex area in the Religious Orders Study and Memory and Aging Project (ROSMAP) and validated the findings using 328 AD brains in the Emory study. Of the preserved modules, we selected modules with significant association (P<0.01) between neuropathologically and clinically confirmed AD (symptomatic) and neuropathologically confirmed AD but clinically unimpaired brains. We generated polygenic risk scores of the symptom‐associated modules (mbPRSs) using existing genome‐wide summary statistics for AD (Kunkle, 2019) in 309 AD, 483 mild cognitive impairment (MCI), and 301 cognitively normal (CN) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We investigated relationships between the derived mbPRSs and previously clustered brain atrophy patterns in the ADNI (Yang, 2021). We defined at‐risk CN and MCI subjects in the ADNI for each module if mbPRSs of the subject > the third quantile. Age‐adjusted Cox proportional hazard models were applied for conversion status to AD with at‐risk subjects of the symptom‐associated modules comparing with all CN and MCI subjects as a reference group.

Result

We detected 12 preserved modules that showed significant associations for symptomatic AD (P‐value<0.05). The mbPRSs of the yellow and the lightcyan modules were significantly associated with brain atrophy cluster 3 (P‐value: yellow‐mbPRS = 5.5e‐03; lightcyan‐mbPRS = 7.1e‐05). At the same time, Of the mbPRSs for the 12 symptom‐associated modules, the at‐risk subjects defined by the lightcyan‐mbPRS were also predicted to be earlier conversion from CN or MCI to AD (Hazard ratio = 1.63, P‐value = 3.8e‐02). Lightcyan‐mbPRS shows a good prediction of conversion to AD and also the association with MRI endophenotypes.

Conclusion

This study demonstrates for the first time that PRSs informed by symptom‐associated protein networks may identify at‐risk CN and MCI subjects who will develop clinical symptoms and enable targeted prevention and treatment trials for AD for these at‐risk subjects in preclinical stages of AD.
High plasma Glial Fibrillary Acidic Protein levels are associated with an increased risk of dementia and Alzheimer’s disease over a 13‐year follow‐up period: Results from a prospective population‐based cohort
Authors: Linard Morgane , Martinuzzi Manuela , Samieri Cécilia , Dartigues Jean‐François , Glaichenhaus Nicolas , Féart Catherine , Helmer Catherine
Published: June 2023

Background

Reactive astrogliosis, an activation state that includes morphological, metabolic and functional changes of astrocytes, occurs in neurodegenerative diseases, including Alzheimer’s disease (AD). Increased plasma levels of glial fibrillary acidic protein (GFAP), a reactive astrogliosis biomarker, have been recently reported in the preclinical and symptomatic stages of AD. However, very few works have investigated its ability to predict long‐term AD risk. This study aimed to investigate the association between plasma GFAP levels and future risk of dementia and AD.

Method

Within the Bordeaux‐3C prospective population‐based cohort, we quantified plasma GFAP levels using V‐PLEX immunoassay among 1068 non‐demented participants aged 69 years or over. Dementia was screened over a follow‐up of 13 years. Associations of baseline plasma GFAP levels with the risk of incident AD and dementia were investigated using Cox models adjusted for socio‐demographic characteristics, cardio‐vascular comorbidities and APOE4 status.

Result

The mean age of the participants was 77.6 years (std 4.7) and 64% were women. Median GFAP level was 239 pg/ml [IQR 192‐321]. During the follow‐up (median 8.8 years, up to 14.3 years), 281 dementias occurred, including 120 probable AD. In multivariate models, the middle and high tertiles of GFAP were associated with an increased risk of dementia (aHR = 1.8, 95%CI: 1.3 to 2.5 and aHR = 2.0, 95%CI: 1.5 to 2.8 respectively, compared to the lower tertile, global p‐value<.0001). These risks were higher when considering only probable AD (aHR = 2.7, 95%CI: 1.5 to 4.7 and aHR = 3.0, 95%CI: 1.7 to 5.2 for the middle and high tertiles respectively, global p‐value 0.0004). The association was found regardless of the APOE4 status. There was no interaction with time meaning that baseline GFAP was associated with higher risk of AD at short as at long‐term.

Conclusion

These results suggest that plasma GFAP levels are increased very early in the process of AD. GFAP could represent a useful means to identify people at high risk of AD for both an objective of prevention or to include them in clinical trials. The interest of such a marker, alone or in combination with other plasmatic biomarkers of AD, should be further studied.
Diffusion MRI indices of brain microstructure: Evaluating the Ball‐and‐Stick model in distinguishing Alzheimer’s disease
Authors: Snoussi Haykel , Rashid Tanweer , Seshadri Sudha , Habes Mohamad , Satizabal Claudia L.
Published: June 2023

Background

Diffusion MRI is a valuable tool to assess white matter (WM) microstructure biomarkers of brain aging and Alzheimer’s disease (AD). The most common model used to extract diffusion properties is the diffusion tensor model (DTI). However, DTI cannot resolve complex WM microstructure and suffers from partial volume effects. Further, the majority of multi‐site imaging clinical studies, such as ADNI, are limited to single‐shell acquisitions due to time constraints. Therefore, multi‐compartment models are not feasible to overcome these limitations except multi‐tensor models, such as Ball‐and‐Stick (B&S) under some constraints. B&S offers a novel approach to derive biomarkers for early detection of AD because it splits the diffusion‐weighted MR signal into several anisotropic components (Stick) and a single isotropic component (Ball). This model is implemented in Anima software. Here, we propose a classification approach using four DTI and two B&S indices quantified in various anatomical regions of interest (ROIs) to assess and compare their ability to distinguish AD.

Method

Cross‐sectional data were available for 413 ADNI‐3 participants: 68 AD (age: 76.81±8.3; 50% women) and 345 cognitively normal (CN; age:72.91±7.27; 62% women). We processed T1‐weighted and diffusion sequences following the pipeline in Fig.1. We obtained four DTI maps: fractional anisotropy (FA), axial (AxD), mean (MD), radial (RD) diffusivity; and two B&S maps: free water weight (FWW) and Stick‐axial diffusivity (ST). Diffusion maps were quantified within a set of anatomical ROIs. Then, we performed a high‐dimensional pattern classification approach. For each metric, we consider all brain ROIs jointly and identify a minimal set of regions whose values jointly maximally differentiate between AD and CN.

Result

B&S model with regional FWW and ST measures shows the greatest discrimination between AD and CN (FWW ROCAUC = 0.942; ST ROCAUC = 0.938) compared to DTI (Table 1). Left PHG Parahippocampal Gyrus and Right Hippocampus regions have the highest contribution in the classification (Table 2, Fig.2).

Conclusion

Our results suggest B&S measures are more sensitive to discriminate AD from CN than DTI measures, widely used in clinical research. B&S has the advantage of identifying and separating crossing fibers, and therefore, has the potential to offer greater and novel insights into the underlying pathology of AD.
Normalization methods for RT‐qPCR assessment of circulating microRNAs in Alzheimer’s and other aging‐related diseases
Authors: Wojda Urszula , Want Andrew , Staniak Karolina , Grabowska‐Pyrzewicz Wioleta
Published: June 2023

Background

Circulating miRNAs in blood plasma present significant potential for use as minimally‐invasive biomarkers for diagnosis of aging‐related diseases, such as cancer or Alzheimer’s disease (AD). The most sensitive and inexpensive analysis method of circulating miRNA is RT‐qPCR. However, lack of RT‐qPCR standardisation is one of the major causes of data inconsistency across different studies and it hinders progress towards widespread implementation of miRNA biomarkers in clinical use. Normalisation of RT‐qPCR data to stably expressed miRNAs is a key step in data analysis. Current methods of identifying optimal normalisers are lacking in their evaluation of the stability of normalisers and their combinations in aging populations. To address these needs, we created a novel, transparent, method for selecting optimal normalisers in aging populations, using the Python programming language (v. 3.7.3).

Method

Our method uses the Python packages: pandas (v. 1.2.3), numpy (v. 1.17.1), scipy (v. 1.3.1). The method uses three measures to evaluate the miRNA Cq values for potential normalisers: Kolmogorov‐Smirnov score (KS‐score), average displacement from a mean of zero and mean standard deviation. In each case, the comparators are two distinct biological groups of interest (such as AD and cognitively normal controls). Before comparison, the group of potential normalisers were normalised according to the log2(2−ΔΔCq) method. The miRNA data were collected from Polish subjects including 44 AD patients and 70 similar‐aged, cognitively normal, controls). Circulating miRNA molecules were isolated from plasma, followed by RT‐qPCR with a selection of 7 miRNAs tested as potential normalisers, along with suitable controls for mRNA isolation and reverse transcription.

Result

We provide a novel method for identification of optimal normalisers with the advantages of: assessments of a greater number of combined potential normalisers (7 in this study), transparency of decision making and the ability for end users to weight that decision making according to their judgment of relative importance.

Conclusion

We recommend assessment of plasma miRNA levels in an aging population employing a novel set of normalisers.

Work supported by the Polish National Science Centre grant OPUS 2018/29/B/NZ7/02757and by the EU Horizon2020 FETOPEN grant no 737390 (ArrestAD).
Is depression in those with Alzheimer’s Disease different to depression in those without dementia?
Authors: Sinclair Lindsey I , Lawton Michael , Palmer Jennifer , Ballard Clive G ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

Background

Depression in individuals with Alzheimer’s disease (AD) is common, distressing, difficult to treat, may increase carer burden and is inadequately understood. It occurs more frequently in AD than in older adults without dementia. The reasons why some patients develop depression during AD and others do not remain obscure.

We aimed to identify risk factors for depression in AD using 3 large cohort studies and assess whether these risk factors differed from those for depression in people with normal cognition.

Method

We used data from 3 large dementia focused cohorts: ADNI (n = 665 with AD, 669 normal cognition), NACC (n = 698 with AD, 711 normal cognition) and BDR (n = 757 with AD). Depression ratings were available using the GDS & NPI and in addition for BDR the Cornell. Intermittent depression was defined as one episode above threshold and persistent as ≥ 2 episodes. A cut‐off of ≥8 was used for the GDS and the Cornell Scale for Depression in Dementia, ≥6 for the NPI depression sub‐scale and ≥2 for the NPI‐Q depression sub‐scale.

We used logistic regression and a random‐effects meta‐analysis to examine potential risk factors and an interaction term to look for interactions between each risk factor and the presence of cognitive impairment. Because we aimed to study persistent depression any participants with only study visit were excluded from the analysis, as were those with treated depression who did not meet criteria for caseness at any point.

Result

In individual studies there was no evidence of a difference in risk factors for depression in AD but combining data with meta‐analysis suggested clear differences between risk factors for depression in AD and depression in those without dementia e.g. gender (figure 1). Previous depression increased the risk in the only study with this information (OR 7.78 95%CI 4.03‐15.03).

Conclusion

Risk factors for depression in AD appear to differ to those for depression per se supporting suggestions of a different pathological process. We have identified that a past history of depression is the strongest risk factor for the development of depression in AD, but information on this was only available for one cohort.
Longitudinal associations of emergent and persistent affective dysregulation symptoms with incident dementia in dementia‐free older adults
Authors: Ebrahim Inaara , Ghahremani Maryam , Smith Eric E. , Camicioli Richard , Ismail Zahinoor
Published: June 2023

Background

Neuropsychiatric symptoms (NPS) are risk factors for dementia. Mild behavioral impairment (MBI) is a neurobehavioral syndrome that refines NPS assessment to improve dementia prognostication by identifying later‐life emergent and persistent NPS specifically as the at‐risk group. Affective dysregulation contributes to dementia risk and is an MBI domain characterized by the inability to regulate emotions. Here, we investigate the longitudinal association of MBI‐affective dysregulation with incident dementia in dementia‐free older adults from the National Alzheimer Coordinating Centre (NACC).

Method

NACC participants with no history of psychiatric, neurological, or neurodevelopmental disorders were included. MBI‐affective dysregulation status was determined based on Neuropsychiatric Inventory Questionnaire (NPI‐Q) depression, anxiety, and elation scores at two consecutive visits. The comparator group involved participants with no NPS prior to dementia. Participants with dementia at baseline were excluded from the study. Kaplan‐Meier curves of dementia‐free survival over ten years were generated for MBI‐affective dysregulation versus no NPS. Cox proportional hazard models were implemented to assess the risk of dementia, adjusted for age, sex, years of education, race, APOE e4 status, and clinical cognitive diagnosis. Potential interactions were further explored for relevant model covariates.

Result

The final sample consisted of 3,446 participants with no NPS (mean age 73.1; 63.0% female), and 1,156 with MBI‐affective dysregulation (mean age 75.1; 53.9% female). MBI‐affective dysregulation was associated with lower chance of dementia‐free survival (log rank, p<0.001) and 1.67 times greater risk of dementia compared to no NPS (CI:1.4‐2, p<0.001). Moderation analysis revealed that in participants with normal cognition (NC), those with MBI‐affective dysregulation were at 2.56 times greater risk of dementia than those with no NPS (CI:1.87‐3.49, p<0.001). In mild cognitive impairment (MCI), the risk associated with MBI‐affective dysregulation was 1.4 times greater than no NPS (CI:1.14‐1.72, p = 0.02).

Conclusion

The emergence of persistent affective dysregulation symptoms in dementia‐free older adults is associated with substantial risk for dementia. When emerging in individuals with NC, these persistent affective symptoms represent a greater risk compared to those with no NPS, compared to emergence of these symptoms in MCI. MBI‐affective dysregulation is an important risk factor for dementia and should be considered in clinical assessments.
Normative data for three physical frailty parameters in an aging, rural Indian population
Authors: Sundarakumar Jonas S. , Teja Karru Venkata Ravi , Muniz‐Terrera Graciela , Ravindranath Vijayalakshmi ,   SANSCOG
Published: June 2023

Background

Physical frailty is associated with multiple adverse health outcomes. Since physical characteristics markedly vary with different populations, population‐specific norms for physical frailty parameters are necessary. Such norms are lacking for the Indian population, especially for older, rural Indians. We aimed to develop normative values for three quantitative, frailty parameters – hand grip strength, ‘Timed Up‐and‐Go’ (TUG) time and physical activity in an aging, rural Indian population

Method

The study sample is from an ongoing, prospective, cohort (Srinivaspura NeuoSenescence and COGnition, SANSCOG) comprising of rural, community‐dwelling, cognitively healthy, aging Indians. Subjects are recruited through area sampling strategy, from villages of Srinivaspura, Kolar district, Karnataka state, India. Three physical frailty parameters of Fried’s phenotype – hand grip strength (n = 1787), TUG time (n = 1863) and physical activity (n = 1640) were assessed using digital hand dynamometry, TUG test and General Physical Activity Questionnaire (GPAQ), respectively.

Result

The 10th, 25th, 50th, 75th, 90th percentiles for age groups 45‐55, 56‐65, 66‐75 and >75 years were: right hand grip strength(kg): males–13.90, 18.60, 23.80, 28.70, 33.70 & females–7.80, 10.60, 14.20, 17.90, 21.30; left hand grip strength(kg): males–13.30, 18.30, 23.60, 28.90, 32.86 & females–7.90, 10.53, 14.30, 17.80, 21.20; TUG time(seconds): males–9.05, 10.09, 11.43, 13.38, 15.50 & females–9.51, 10.73, 12.40, 14.50, 16.57; physical activity(MET‐minutes/week): males–1680, 4320, 8880, 15840, 23352 & females–1680, 4320, 9240, 15120, 20160.

Conclusion

Our findings show that from 45 years onwards, overall grip strength decreases and TUG time increases, with women performing significantly poorer than men across all age groups, except >75 years, where no differences were seen. Physical activity did not show any consistent trend according to age or gender. Reference values for this aging, rural Indian population were substantially lower for grip strength and higher for TUG time than aging populations in several Western and other Asian countries
“Neuroprotective Potential of Limonene in LPS Induced Parkinson’s Disease in Rats”
Authors: Dhureja Maanvi
Published: June 2023

Background

Parkinson’s disease is 2nd most disabling neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in basal ganglia. There are different pathologies that count for PD like neuro‐inflammation. This study highlights the role of oxidative stress and inflammation in progression of PD where limonene shows antioxidant and anti‐inflammatory response.

Method

Wistar rats (200‐250gm) of either sex were taken and divided into 6 groups. Animals were treated with three different doses of limonene i.e. (25, 50, 100 mg/kg p.o.) for 21 day, starting 1 day prior to LPS 5μl(1mg/ml PBS) infused stereotaxically into the SN of rats.

Result

The catalepsy technique was used to analyze the clinical signs of Parkinson’s disease in rats. LPS significantly increased oxidative stress indicators in the animals and decreased systemic antioxidant synthesis. Biochemically limonene significantly reduced the oxidative–nitrative stress, as evidenced by decrease in malondialdehyde and nitrite levels, and restored the reduced catalase, glutathione and Superoxide dismutase levels. The observed beneficial effects of limonene in motor defects may be due to its ability reduce oxidative burden.

Conclusion

LPS is potent inflammatory biomarker but this also has major role in development of oxidative stress. Interaction between reactive oxygen species and dopamine leads to its depletion & considered as one of the major mechanism for dopaminergic degeneration in PD. LPS caused significant elevation in malondialdehyde, nitrite and decline in SOD, catalase & glutathione, indicating development of oxidative‐nitrosative stress. Limonene treatment significantly reduced striatal MDA and nitrite concentration & restored antioxidant enzyme activities.
Cognitive control, interference inhibition and ordering of information during working memory in younger and older healthy adults
Authors: Mirjalili Mina , Zomorrodi Reza , Daskalakis Zafiris J. , Hill Sean , Kumar Sanjeev , Blumberger Daniel M. , Fischer Corinne E. , Flint Alastair , Herrmann Nathan , Lanctôt Krista L. , Mah Linda , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. ,   PACt‐MD Study Group
Published: June 2023

Background

Investigating effects of aging on neurophysiological mechanisms underlying working memory provides a better understanding of potential targets for brain intervention to prevent cognitive decline. Theta‐gamma coupling (TGC) indexes the ability to order information processed during working memory tasks. Frontal theta event‐related synchronization (ERS) and parietal alpha event‐related desynchronization (ERD) index cognitive control and interference inhibition, respectively. Relative contributions of TGC, theta ERS and alpha ERD in relation to stimulus presentation are not characterized. Further, differential effect of normal aging on pre or post‐stimulus processes is unknown.

Method

Electroencephalography was recorded in 66 younger and 41 older healthy participants while performing 3‐back working memory task. We assessed relationships between 3‐back task performance and each of post‐stimulus TGC, pre‐stimulus parietal alpha ERD, and pre‐stimulus frontal theta ERS in each age group.

Result

While older adults performed worse on 3‐back task than younger adults. TGC, alpha ERD or theta ERS did not differ between the two groups. TGC was positively associated with 3‐back performance in both age groups; pre‐stimulus alpha ERD was associated with performance among younger adults; and pre‐stimulus theta ERS was not associated with performance in either group.

Conclusion

Our findings suggest that both pre‐stimulus interference inhibition and post‐stimulus ordering of information are important for working memory in younger adults. In contrast, performance in older adults appears to depend only on post‐stimulus ordering of information. These specific contributions of neurophysiological resources may explain the poorer performance of older adults and suggest different targets to enhance working memory in age groups.
Actigraphy sleep patterns in presymptomatic Alzheimer’s Disease: the potential role of neuroinflammation
Authors: Baril Andree‐Ann , Labonté Anne , Sanchez Erlan , Picard Cynthia , Duclos Catherine , Rosa‐Neto Pedro , Breitner John C.S. , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD Research Group
Published: June 2023

Background

Both short and long sleep duration have been associated with increased risk of developing Alzheimer’s Disease (AD). While short sleep has been hypothesized to be a risk factor promoting neurodegenerative processes. Long sleep has been viewed as a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective of the study is to evaluate sleep patterns measured with actigraphy close to expected symptom onset in association with neuroinflammatory biomarkers. We leveraged the PREVENT‐AD cohort in which participants with a parental history of sporadic AD are studied before clinical onset.

Method

203 participants (age: 68.5±5.4 years, 151 women) free of dementia were tested with a week of actigraphy. Nighttime sleep duration, time in bed, sleep latency, sleep efficiency, and number of sleep bouts were calculated using the Actiware scoring algorithm (medium threshold). The standard deviation of these characteristics was calculated across actigraphy days to assess day‐to‐day variability. Years to expected onset was calculated by the number of years remaining before the age of clinical onset of a parent, or the earliest age of clinical onset if both parents developed AD. A subset of 100 participants underwent a lumbar puncture, and IL‐6 and MCP‐1 levels were assessed using OLINK technology in cerebrospinal fluid (CSF). The association between sleep characteristics, years to expected onset and inflammatory markers was assessed using linear regressions adjusted for age, sex, and time interval between measurements.

Result

Being closer to expected onset was associated with longer nighttime sleep duration (b = ‐0.19, p = 0.015) and lower sleep bouts day‐to‐day variability (b = 0.17, p = 0.027). Higher CSF IL‐6 was associated with longer sleep duration and time in bed (b = 0.30, p = 0.006; b = 0.24, p = 0.028), whereas higher MCP‐1 was associated with longer nighttime sleep duration (b = 0.25, p = 0.019). Higher CSF MCP‐1 levels were associated with lower sleep bouts day‐to‐day variability and shorter sleep onset latency only in those within 10 years of expected onset (interaction p = 0.012 and 0.061; b = ‐0.31, p = 0.043; b = ‐0.31, p = 0.047).

Conclusion

Proximity to parental onset of sporadic AD onset was associated with a longer sleep profile that is more consolidated and stable, which may be due to proinflammatory processes.
Genomic assessment of early‐onset AD identifies novel risk loci and an incomplete genetic overlap with late‐onset AD
Authors: da Fonseca Eder Lucio , Jean‐Francois Melissa , Kurup Jiji T. , Yang Chengran , Slifer Susan H. , Martin Eden R. , Kunkle Brian W. , Naj Adam C. , Farrer Lindsay A. , Haines Jonathan L. , Mayeux Richard , Schellenberg Gerard D. , Pericak‐Vance Margaret A. , Fernandez Maria Victoria , Cruchaga Carlos , Reitz Christiane , Beecham Gary W. ,   Alzheimer’s Disease Genetics Consortium (ADGC)
Published: June 2023

Background

Early Onset Alzheimer Disease (EOAD, age at onset [AAO] < = 65) is a severe form of AD, often occurring when patients are still caring for children or adults. Despite this, most genetic studies of EOAD have focused on autosomal dominant forms, and there is little understanding of similarities and differences between early and late onset forms of AD (LOAD, [AAO]>65). To address this, we present a genome‐wide association study of non‐Mendelian EOAD and compare it to LOAD GWAS.

Methods

Primary single‐variant analyses were performed using two additive logistic regression for case‐control models (full: SNPs, PCs, sex and APOE‐ɛ4 dosage as covariates; reduced: SNPs and PCs); secondary models included PCs+sex and PCs+APOE. Models were applied on data derived from the Alzheimer Disease Genetics Consortium (ADGC), composed by unrelated individuals. Samples varied from 1293‐1459 cases and 8894‐9366 controls for EOAD, and 8795‐9508 cases and 9702‐10273 controls for LOAD, depending on the considered model. The SNP heritability (h2) and genetic correlation (rg) were estimated using LD score regression. Gene‐based and pathway analysis (gene sets from Msigdb‐v7.0) were performed using FUMA/MAGMA‐v1.6.

Results

We identified two novel loci associated with EOAD: Chromosome 4 (full model: chr4:102027610, P = 2.98×10−08, near PPP3CA gene) and Chromosome 12 (PCs+sex model: rs117001070, P = 2.11×10−08, intergenic between LINC02444 and LINC02882). We additionally confirmed BIN1 and APOE in the EOAD subset. Several known genes also showed a significant association with LOAD. Heritability analyses showed higher h2 values for EOAD (h2 = 0.29, 0.29, 0.29 and 0.27) than LOAD (h2 = 0.19, 0.16, 0.19, and 0.15), for full, reduced, PCs+sex and PCs+APOE models respectively. Genetic correlation showed moderate but incomplete genetic correlation between EOAD and LOAD. Other than APOE (p = 3.89×10−12), gene‐based tests showed nominal association for EOAD C8orf44‐SGK3 (p = 9.95×10−06), SGK3 (p = 2.01×10−05) and HIST1H2AC (p = 3.04×10−05), and plausible pathways such as HDL remodeling (p = 5.50×10−05) and positive regulation of cholesterol efflux (p = 9.79×10−05). These pathways were nominally associated with LOAD (p = 0.04 and p = 4.05×10−03).

Conclusions

We identified two novel loci associated to EOAD not previously reported by LOAD studies. Heritability and genetic correlation results suggest that the genetic etiology of EOAD has an incomplete genetic overlap with LOAD.
Antifungal and ultraviolet–visible barrier properties in starch films reinforced with CuO nanoparticles
Authors: Malafatti João Otávio Donizette , Domingues Marcelo Ávila , Meirelles Mariana Rodrigues , Peres Laiza Gabriela Sanches , Bresolin Joana Dias , Paris Elaine Cristina
Published: June 2023

Starch materials are subject to loss of initial characteristics due to the retrogradation degenerative effect, high hygroscopicity, and favoring the growth of the microorganisms, which reduces the shelf life of packaging. In this sense, the insertion of nanoparticulated CuO was evaluated for the best performance. CuO is a semiconductor that can improve optical, mechanical, and antimicrobial properties, enabling excellent promotion of starch films. The hot injection precipitation method was used to obtain CuO nanoparticles in the nanometric scale rapidly. The films were carried out from the starch homogenization in water and urea under temperature, followed by thermopressing at 120°C. As a result, the 1% CuO (w w−1) increased tensile strength from 0.87 ± 0.40 to 1.92 ± 0.09 MPa. Furthermore, the films containing nanoparticles showed a barrier property against radiation in the ultraviolet–visible spectrum, not observed for the micrometric scale. Such results were attributed to the superior opacity of the films generated by nanometric reinforcement. Concerning antimicrobial activity, the films containing CuO showed a fungistatic effect (33%) for the Alternaria alternata fungus, a microorganism very susceptible to carbohydrate‐rich sources. Thus, the CuO‐reinforced starch films improved physicochemical and biological properties, making them promissory candidates for commercial application.
Predominant contribution of an endogenous cellulase (OlCel) to the cellulolysis in the digestive system of larvae of banana pseudostem weevil, Odoiporus longicollis (Coleoptera: Curculionidae)
Authors: Bhuvaragavan Sreeramulu , Reshma Thenozhiyil , Hilda Karuppiah , Meenakumari Mani , Sruthi Kannan , Nivetha Ramanathan , Janarthanan Sundaram
Published: June 2023

Insects have evolved with effective strategies to utilize cellulose as an energy source by possessing cellulolytic enzymes which can be used as an optimal resource in the bioenergy sector. The study was aimed at evaluating the cellulolytic enzyme in the larval gut of the banana pseudostem weevil, Odoiporus longicollis Olivier (Coleoptera: Curculionidae). Primarily, cellulase activity was localized along the gut, in which the midgut showed the highest activity (2858 U/mg). The thermo‐tolerance of cellulase activity was found to be up to 80°C (highest at 60°C), and the enzyme was stable at a pH between 5 and 6. Various concentrations of divalent cations (CaCl2, MgCl2, and CuCl2) have differential enhancing and inhibitory effects on cellulase activity. The cellulase (OlCel) was purified using anion exchange chromatography. The molecular weight of the cellulase was determined to be 47 kDa. The physicochemical parameters of the purified enzyme were similar to that of enzyme activity of whole gut extract. Mass spectrometry results identified sequence similarities of purified cellulase to the glycosyl hydrolase family 5 (GHF5) family. The gut microbial cellulase activity as exogenous source showed no competence compared with the endogenous activity.
Utilization of erythrosine B in spectrofluorimetric quenching analysis of amlodipine and perindopril in pharmaceutical and biological matrices
Authors: Badr El‐Din Khalid M. , Salem Hesham , Derayea Sayed , Abdelaziz Amany , Nagy Dalia M.
Published: June 2023

A spectrofluorimetric approach that is sensitive, simple, validated, and cost‐effective has been proposed for the estimation of amlodipine (AML) and perindopril (PER) in their bulk powders, pharmaceutical formulations, and spiked human plasma. The recommended approach utilized the quantitative quenching effect of the two cited drugs on the fluorescence intensity of erythrosine B, as a result of complex binary reactions among each drug with erythrosine B at pH 3.5 (Teorell and Stenhagen buffer). The quenching of erythrosine B fluorescence was recorded at 554 nm after excitation at 527 nm. The calibration curve was detected in the range 0.25–3.0 μg ml−1, with a correlation coefficient of 0.9996 for AML, and 0.1–1.5 μg ml−1, with a correlation coefficient of 0.9996 for PER. The established spectrofluorimetric approach was validated for the estimation of the cited drugs with high sensitivity regarding International Council on Harmonization guidelines. Therefore, the established approach could be utilized for quality control of the cited drugs in their pharmaceutical formulations.
Molecular characterization ofMETfusions from a large real‐world Chinese population: A multicenter study
Authors: Xia Hui , Zhang Junhua , Chen Tong , Wang Mingzhao , Chen Dongna , Si Tongguo , Liu Yutao
Published: June 2023

Purpose

METis a notable driver gene in the diversity of aberrations with clinical relevance, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two,METfusions are severely under‐reported, leaving a series of unanswered questions. In this study, we addressed this gap by characterizingMETfusions in a large, real‐world Chinese cancer population.

Methods

We retrospectively included patients with solid tumors who had DNA‐based genome profiles acquired through targeted sequencing from August 2015 to May 2021.METfusion‐positive (MET+) patients were subsequently selected for clinical and molecular characterization.

Results

We screened 79,803 patients across 27 tumor types and detected 155 putativeMETfusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority ofMET+ patients (92, 75.4%). Prevalence was markedly higher in liver cancer, biliary tract cancer, and renal cancer (range 0.52%–0.60%). It was lower in ovarian cancer (0.06%). A substantial proportion (48/58, 82.8%) of unique partners were reported for the first time. High heterogeneity was observed for partners, withST7,HLA‐DRB1, andKIF5Bas the three most common partners. Mutational landscape analysis of lung adenocarcinoma (n = 32) revealed a high prevalence ofTP53inMET+ alterations,EGFRL858R,EGFRL861Q, andMETamplification.

Conclusion

To our knowledge, this is currently the largest study in characterizingMETfusions. Our findings warrant that further clinical validation and mechanistic study may translate into therapeutic avenues forMET+ cancer patients.
Plasma D‐dimer and interleukin‐6 are associated with treatment response and progression‐free survival in advanced NSCLC patients on anti‐PD‐1 therapy
Authors: Chen Chong , Yin Huaru , Zhang Yu , Chen Huan , Xu Jie , Ren Li
Published: June 2023

Background/Aims

Response to therapy after using immune checkpoint inhibitors (ICIs) is unpredictable due to significant interindividual variation in efficacy among advanced non‐small cell lung cancer (NSCLC) patients. The current study centered on the identification of perivascular blood biomarkers for predicting the effectiveness of anti‐programmed cell death protein 1 (anti‐PD‐1) treatment and progression‐free survival (PFS) in advanced NSCLC patients, that could be applied to help determine how to change treatment plans therapeutic regimens for optimizing clinical benefits.

Methods

A comprehensive review of 100 advanced or recurrent NSCLC patients receiving anti‐PD‐1 therapy (Camrelizumab, pembrolizumab, sintilimab, or nivolumab) was conducted between January 2018 and April 2021 in Tianjin Medical University Cancer Hospital. The cutoff values of D‐dimer were selected from rom our previous study, and interleukin‐6 (IL‐6) was divided according to the median. Using computed tomography, tumor response was evaluated in accordance with the Response Assessment Criteria in Solid Tumors, version 1.1.

Results

High IL‐6 level in advanced NSCLC patients was predictive of low efficacy and a short PFS duration after anti‐PD‐1 therapy. An increased D‐dimer value of 981 ng/mL was significantly predictive of disease progression in NSCLC patients treated with anti‐PD‐1 and high D‐dimer expression predictive of short duration of PFS. Further studies on the correlation between IL‐6, D‐dimer, and anti‐PD‐1 efficacy in NSCLC patients stratified by gender revealed that D‐dimer and IL‐6 levels were significantly associated with the risk of PFS in male patients.

Conclusions

High IL‐6 content in peripheral blood in patients with advanced non‐small cell lung cancer may contribute to poor anti‐PD‐1 efficacy and short duration of PFS through inducing alterations in the tumor microenvironment. D‐dimer in peripheral blood is predictive of hyperfibrinolysis and contributes to the release of tumor‐driven specific factors, leading to poor effects of anti‐PD‐1 therapy.