bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Mild Behavioral Impairment trajectories and AD biomarkers in adults with Mild Cognitive Impairment. Results from the CompAS study
Authors: Mallo Sabela Carme , Fernández Miguel Ángel Rivas , Vázquez‐Vázquez Laura , Galdo‐Álvarez Santiago , Lindín Mónica , Nieto‐Vieites Ana , Juncos‐Rabadán Onésimo , Aldrey Jose M. , Díaz Fernando , Ismail Zahinoor , Pereiro Arturo X
Published: December 2023

Background

Our aim was to investigate the association of the NPS trajectories in time measured by MBI‐C for MCI patients with the CSF biomarkers and temporal lobe atrophy detected at baseline.

Method

CSF biomarkers at baseline were obtained from 71 patients with MCI belonging to Compostela Aging Study (CompAS) (Spain). Positivity for A (β‐amyloid), T (p‐Tau), and N (t‐Tau) was defined by cut‐off levels. Structural MRI was employed to evaluate cortical thickness and volume. Mild behavioral impairment was assessed using the validated Spanish‐language MBI‐C (Mallo et al., 2018) at baseline, 24 months, and 60 months follow‐up. Spearman correlations were performed to evaluate the relationships between CSF biomarkers at baseline and MBI‐C scores for the three evaluations. Logistic regressions were used to test the predictive value of the MBI‐C scores at each evaluation on the biomarkers’ positivity at baseline, and linear regression analyses to test the relationships between cortical thickness and volume at baseline and the three MBI‐C scorings.

Results

Spearman correlations showed no significant relations between MBI‐C and β‐amyloid, pTau, tTau and tTau/β‐amyloid ratio at baseline. However, significant positive correlations appeared between MBI‐C at 24‐month follow‐up and pTau (rho = .371), tTau (rho = .282) and tTau/β‐amyloid ratio at baseline but not with β‐amyloid. MBI‐C scores at the 60‐month follow‐up only significantly correlated with tTau/β‐amyloid ratio (rho = ‐.418). MBI‐C at 24 months and at 60 months were respectively predicted by pTau and tTau (Table 1). Linear regression analyses showed that MBI‐C at 24 months was predicted by cortical thickness of entorhinal, fusiform, inferior temporal, inferior parietal, middle and supramarginal gyri. MBI‐C at 24 and 60 months were predicted by Volume of entorhinal, inferior temporal, precuneus and whole hippocampus (Table 2).

Conclusion

The markers of atrophy in structures of the medial temporal lobe and the lateral and parietal temporal lobe, and pTau+ or tTau+ in MCI patients at baseline were associated with worsening of neuropsychiatric symptoms at 24 and/or 60 months.
Integrating population neuroscience and syndemics frameworks to better understand global sex and gender‐based risk in Alzheimer’s disease and related dementias
Authors: Shaaban C. Elizabeth , Trani Jean‐Francois , Babulal Ganesh M. ,   the Sex and Gender Special Interest Group of the ISTAART Diversity and Disparities Professional Interest Area
Published: December 2023

Aging populations in low‐ and middle‐income countries (LMICs) are growing more rapidly than those in high income countries (HICs). Thus, globally, the burden of Alzheimer’s disease and related dementias (ADRD) profoundly impacts LMICs, with greater burden and risk for late‐life women than men. LMICs are unable to meet diagnostic challenges with underfunded healthcare infrastructure, low numbers of clinicians with training and expertise in ADRD, and a lack of culturally and linguistically sensitive screening assessments. Emerging social and societal factors that are important risk and protective factors for later life ADRD and are differentially experienced by gender/sex are relatively understudied, yet essential in LMICs. Typical samples in neuroscience studies have been small and highly selected. They have been biased toward Western, Educated, Industrialized, Rich, and Democratic (WEIRD) samples and do not apply well to target populations in LMICs. In addition, levels‐of‐analysis across social/societal and biological determinants of disease are not typically integrated, and social/societal factors such as sociocultural (e.g., culture, religion, gender norms, access to education, discrimination, social aspects of pandemics, disability), political (e.g., governments and policies; migrants and displaced persons; war and conflict; reproductive health, justice, and agency), environmental (e.g., climate change and pollution), and economic factors (e.g., poverty), and their co‐occurrence, have been minimally considered for their role and impact on ADRD. To better understand gender/sex differences in ADRD in LMICs, we review how these social and societal factors may be important to ADRD using an integrated Population Neuroscience and Syndemics framework. Population neuroscience considers the brain in context using multiple levels of analyses, a life course perspective, and tools to enhance internal and external validity, while Syndemics suggest that diseases and social conditions may cluster and interact in populations with syndemic risk factors—sociocultural, political, economic, and environmental factors which promote stress pathways. We lay out a model in which syndemic risk and protective factors contribute to or protect from stress and biological aging and ultimately ADRD risk, both directly and indirectly through physical and mental health conditions. We close with recommendations for future aging and ADRD research based on this integrated Population Neuroscience‐Syndemics of ADRD framework.
Genome‐wide CRISPR knockout screening to identify key regulators of phagocytosis in induced pluripotent stem cell derived microglia
Authors: Washer Sam J , Perez‐Alcantara Marta , Navarro‐Guerrero Elena , Steer Juliette , Chen Yixi , McWilliam Joe , Cowley Sally A , Ebner Daniel , Bassett Andrew R
Published: December 2023

Background

A whole genome knockout CRISPR screen in human induced pluripotent stem cell (hiPSC) derived microglia was undertaken to identify regulators of phagocytosis. The secondary objective was to cross reference these genes to Alzheimer’s Disease genome‐wide association studies to provide potential therapeutic targets for drug development.

Method

HiPSC‐derived microglia precursor cells were transduced with the TKOv3 genome‐wide CRISPR/Cas9 knockout library and differentiated for two weeks to microglia in our recently published media. hiPSC‐microglia were then fed dead GFP/mCherry fluorescent labelled SH‐SY5Y neuronal cells as phagocytic meal. Phagocytosis proceeded for 6 hours before washing away non‐phagocytosed SH‐SY5Y, harvesting and fixing the hiPSC‐microglia. hiPSC‐microglia were sorted into high and low levels of phagocytosis by fluorescent activated cell sorting (FACS) for single mCherry‐positive cells as GFP is quenched due to a low pH environment. Genomic DNA was extracted from sorted cell populations and the integrated guide RNA were sequenced by Illumina Novoseq.

Result

Microglia were successfully transduced at a multiplicity of infection at 0.7 to maximize single guide integration. Successful phagocytosis was observed via FACS, with over 60% of hiPSC‐microglia phagocytosing dead neurons after 6 hours. Four populations of varying levels of phagocytosis were harvested and genomic DNA extracted and sequenced.

Conclusion

We have developed a pipeline for the first successful genome‐wide CRISPR knockout screening in hiPSC‐microglia and have used this to identify regulators of phagocytosis.
The association between air pollution and dementia: results from the Cognitive Function and Ageing Study II and Wales
Authors: Wu Yu‐Tzu , Prina Matthew , Zied Eman , Matthews Fiona E
Published: December 2023

Background

Air pollution has been recognised as one of the key modifiable risk factors for dementia. In the UK, there is a lack of evidence from population‐based cohort studies including older people from different backgrounds and living environments. Using two multicentre ageing cohorts in England and Wales, the aim of this study is to investigate the potential impact of air pollution on dementia in later life.

Method

This study was based on the Cognitive Function and Ageing Study (CFAS) II (2008‐2011) and Wales (2011‐2013), two longitudinal studies of people aged 65 or above across five centres in England (Cambridgeshire, Newcastle upon Tyne, Nottingham) and Wales (Gwynedd, Neath Port Talbot). A two‐year follow‐up wave was carried out for both studies. Dementia was identified using the Geriatric Mental State and its diagnostic algorithm, Automated Geriatric Examination for Computer Assisted Taxonomy (GMS‐AGEACT). Based on the participants’ postcodes at the baseline, exposure to four air pollutants in 2012, including nitrogen dioxide (NO2), ozone (O3), particulate matter with a diameter ≤10 microns (PM10) and ≤2.5 microns (PM2.5), was estimated using the Community Multiscale Air Quality pollution modelling at a resolution of 20×20 m. Multistate modelling was used to investigate the effects of air pollution exposure on risk of developing dementia over the follow‐up period, incorporating mortality (from national death certification) and adjusting for age, sex, education, study centre and area deprivation.

Result

Among the 11329 participants in CFAS II (N = 7753) and Wales (N = 3576), the median exposure was 17.7 (IQR = 11.6) µg/m3 for NO2, 43.8 (IQR = 11.1) µg/m3 for O3, 15.5 (IQR = 3.1) µg/m3 for PM10 and 10.1 (IQR = 2.8) µg/m3 for PM2.5 and large variation was observed across the five centres. Per unit increase in NO2 exposure was associated with a higher risk of dementia in CFAS II (HR: 1.07; 95%CI: 1.03, 1.12) but not the Welsh cohort (HR: 0.93; 95%CI: 0.86, 1.00) after adjustment. For the other air pollutants, the associations were unclear.

Conclusion

Our study suggests limited evidence for the impacts of air pollution on dementia. Other environmental factors may influence individual exposure to air pollution and altogether have a complex effect on cognitive health in later life.
Challenges of Dementia care in times of COVID. Change and survive or Perish
Authors: Kremer leonardo Janus
Published: December 2023

Background

The COVID era forced dementia centers to reshaped their strategies in order to keep providing care to patients and to their families

Method

Adaptation of simple social media tools as a telemedicine system

Result

Very useful

Conclusion

Our Institute faced the same challenges that all other institutions, having to deal with isolation, fear, decreased income and uncertainty. Patients and caregivers suffered enormously these facts.We developed a complex system of telemedicine in order to keep being responsible for the continuing care. Our country was not adapted in technology by that time and most the families belonged to low income sector. Most of them (65% approximately) did not have even a personal computer at home.We adapted neuropsychiatric consultations, neuropsychological evaluations and cognitive training using simple tools such as Instagram, Zoom, Meet and mainly Whatsapp.We were able not only to provide the very same standard of care to patients but also the hold the needs of the caregivers.This rudimentary structure created during the sanitary emergency was the basis for a larger, more complex and sophisticated web platform that we developed and today we are using as a virtual Alzheimer Institute, being able to reach patients and caregivers worldwide.
Healthy Dietary Intake Reduces Longitudinal Brain Iron Accumulation in Older Adults
Authors: Zachariou Valentinos , Bauer Christopher E. , Seago Elayna R. , Gold Brian T.
Published: December 2023

Background

Brain iron, which tends to accumulate with normal aging, negatively affects cognitive performance. However, the impact of brain iron on cognition appears modifiable. In a recent study from our group [1], we demonstrated that those older adults with high dietary intake of antioxidants, iron chelating nutrients and polyunsaturated fatty acids (Factor 2 in [1]), tended to have lower brain iron and better working memory performance than expected for their age. Here, we extend our previous work by evaluating associations between baseline consumption of Factor 2 nutrients and longitudinal brain iron accumulation, evaluated three years after baseline.

Methods

Forty‐three, cognitively normal, older adults (26 women, age range 63‐88 years) underwent MRI‐based structural brain imaging and quantitative susceptibility mapping for assessment of brain iron concentration at two time points: baseline (T1) and three years after baseline (T2). Additionally, at T1, nutritional‐intake was assessed via a validated questionnaire. Nutrients were grouped into nutrition factors based on previous literature and factor analysis. Factor 2, comprised vitamin E, lysine, DHA omega‐3 and LA omega‐6, representing antioxidants, iron chelating nutrients and polyunsaturated fatty acids.

Results

Voxelwise, whole‐brain, linear mixed‐effects models (qFDR < 0.05), controlling for longitudinal gray matter volume alterations, age, gender and education, revealed brain iron accumulation within several subcortical and cortical brain regions. Importantly, a significant time point by nutrition interaction was also observed. Specifically, those participants who consumed higher amounts of Factor 2 nutrients at baseline exhibited lower longitudinal brain iron accumulation within the left middle frontal gyrus, left superior parietal lobule, left insular cortex, right inferior temporal cortex, and bilateral hippocampus. Time point by nutrition interactions were not observed for other nutrition factors discussed in [1], such as those comprised of nutrients found in fruits and vegetables, or in green tea.

Conclusion

Our results indicate that dietary patterns rich in oxidative stress‐reducing antioxidants, iron chelating nutrients and polyunsaturated fatty acids may slow down age‐related, brain iron accumulation in older adults.

References:

[1] V. Zachariou et al., “Healthy dietary intake moderates the effects of age on brain iron concentration and working memory performance,” Neurobiol Aging, vol. 106, pp. 183‐196, Oct. 2021
A Clinical Cognitive Resilience Score Based on Residual Approach in Alzheimer’s Disease Continuum
Authors: Ersoezlue Ersin , Rauchmann Boris‐Stephan , Perneczky Robert ,   Alzheimer’s Disease Imaging Initiative (ADNI)
Published: December 2023

Background

Highly varying cognitive abilities among individuals facing pathological alterations, e.g. in Alzheimer’s disease (AD), is conceptualized by the cognitive reserve (CR) hypothesis[1]. The growing interest in prevention and intervention methods brings many new challenges for precision medicine[2]. Hereby, studies on the residual approach for estimating CR, i.e. cognitive resilience, are emerging[1], while the employed methods are highly variable among studies. We aim to develop a standardized and simplified clinical score that predicts CR individually.

Method

Cognitively normal (CN) and β‐amyloid(Aβ)‐negative n = 86 participants and n = 707 individuals with Aβ+ from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort ‐ADNI‐1/GO and 2‐ were included in the study. The Aβ+ group was stratified as CN+, mild cognitive impairment (MCI+) and AD dementia (ADD+) subgroups. A residual factor score (CR‐Factor) using principal component analyses was derived, including cognitive composite scores and continuous CSF‐Aβ and CSF‐phosphorylated‐tau. We predicted a CR‐Score through multinomial regression analysis on CR‐Factor, including the modified‐Preclinical‐Alzheimer‐Cognitive‐Composite score and CSF‐Aβ and CSF‐phosphorylated‐tau categories (normal, intermediate range ‐10% borderline towards abnormal values‐ and abnormal) as predictors (Figure‐1). The associations of the CR‐Score with baseline characteristics and longitudinal change in cognition were tested.

Result

Multinomial regressions revealed that CR‐Score was positively associated with higher years of education in the entire cohort and subgroups, except ADD+. Moreover, higher CR‐Score was associated with younger age and female sex in CN+, younger age in MCI+ and inversely with Afro‐American race in the entire cohort (Table‐1). In linear mixed models, higher CR‐Scores predicted a slower increase of Clinical Dementia Rating‐sum of boxes in MCI+ and ADD+ and of AD‐Assessment‐Scale cognitive‐subscale‐13 in MCI+ (Figure‐2).

Conclusion

The framework to derive a formula that operationalizes CR on an individual level might provide a simplified and yet effective method for clinical studies with patients in AD‐continuum, especially prodromal AD, where intervention is emphasized as appropriate[3]. Furthermore, a standardized marker among studies can promote the replicability and comparison of studies on residual methods.

[1] Stern Y et al. Alzheimers Dement 2020;16:1305‐11.

[2] Livingston G et al. Lancet 2020;396:413‐46.

[3] Cummings J & Fox N. J Prev Alzheimers Dis 2017;4:109‐15.
Precision of clinical diagnosis in neurodegenerative diseases: an investigation of 455 autopsied cases
Authors: Vöglein Jonathan , Kostova Irena , Arzberger Thomas , Herms Jochen , Roeber Sigrun , Danek Adrian , Höglinger Günter , Giese Armin , Levin Johannes
Published: December 2023

Background

Accuracy of clinical diagnosis in neurodegenerative diseases is critically important for patient care and study recruitment. We aimed to investigate the precision of clinical diagnosis of various neurodegenerative conditions using neuropathological diagnosis for reference.

Method

All 1310 autopsy cases between 1993 and 2017 from the Neurobiobank München (Munich, Germany) were screened for neurodegenerative diagnoses. Neuropathological diagnoses that occurred in at least five cases were included in the study. Real world clinical diagnoses were extracted from medical records of admitting hospitals in Germany and correlated with neuropathological diagnoses. Sensitivity, specificity and accuracy (using receiver operating characteristic (ROC) curves and area under the curve (AUC) analysis) of clinical diagnoses were calculated.

Result

The study included 455 cases with neuropathologically diagnosed Alzheimer’s disease (AD, n = 132), argyrophilic grain disease (AGD, n = 6), corticobasal degeneration (CBD, n = 20), frontotemporal lobar degeneration (FTLD, n = 47), Huntington’s disease (HD, n = 22), Lewy body disease (LBD, n = 104), motor neuron disease (MND, n = 10), multiple system atrophy (MSA, n = 37) and progressive supranuclear palsy (PSP, n = 77). Clinical diagnoses in these cases comprised AD (n = 136), CBD (n = 17), Creutzfeldt‐Jakob disease (CJD, n = 6), dementia with Lewy bodies (DLB, n = 11), frontotemporal dementia (FTD, n = 44), HD (n = 23), MND (n = 20), MSA (n = 36), Parkinson’s disease (PD, n = 92), PSP (n = 60) and vascular dementia (VD, n = 10). Figure 1 illustrates the relationship between clinical (left) and neuropathological diagnoses (right). Figure 2 shows sensitivity, specificity, ROC curves, AUCs including standard errors (SE) and 95% confidence intervals (CI) and p‐values for testing the null hypothesis AUC = 0.5 for clinical diagnoses.

Conclusion

Clinical diagnoses of neurodegenerative diseases exhibited a wide span of sensitivity depending on the particular disease (0‐100%) while specificity was high for all clinical diagnoses (89.5‐100%). Accuracy of clinical diagnoses as determined with AUC analysis was very good (AUC>0.9) for HD, MND and MSA, good (AUC = 0.8‐0.9) for AD, DLB/PD and PSP, moderate (AUC = 0.7‐0.8) for FTD, poor (AUC = 0.51‐0.7) for CBD and bad/no discrimination capacity (AUC = 0.5) for AGD. Based on these findings, an increase of sensitivity of clinical diagnoses may be key to improve correct identification of neurodegenerative diseases. This may be possible through development and clinical implementation of molecular biomarkers that are able to indicate the causal proteinopathies of neurodegenerative diseases.
Living without a diagnosis: Quality of life differences between those who screen positive and negative for dementia in rural Kenya
Authors: Farina Nicolas , Musyimi Christine W. , Muyela Levi A. , Masila Joe , Mutunga Elizabeth Kasimu , Ndetei David
Published: December 2023

Background

Within Kenya, dementia is commonly under‐recognised and under‐diagnosed. As a result, many people living with dementia do so without any formal support. The DEM‐SKY project seeks to address this gap by implementing a dementia screening program in Kenya using Community Health Volunteers. The aim of this study is to understand some of the consequences of living with cognitive and functional impairment.

Methods

Older adults (aged 60 years and older) were opportunistically screened for dementia using the Brief Community Screening Instrument for Dementia (CSID) within Makueni County, Kenya. Secondary outcomes included Quality of life (EUROHIS‐8) and loneliness (UCLA). Regression models were created to understand how quality of life and loneliness outcomes differ between those who screen positive and negative for dementia.

Results

Of the 672 older adults screened, 31.1% (n = 209) screened positive for dementia. People who screen positive for dementia reported to have poorer quality of life (p = 0.01) and were also lonelier (p = 0.03) than those who screened negative. Quality of life (b = ‐0.93, 95%CIs = ‐1.83 to ‐0.02; p = 0.04) and loneliness (b = 0.34, 95%CIs = 0.03 to 0.65; p = 0.03) outcomes remained statistically significant after controlling for age, sex, ethnicity, geographic location, and social status.

Conclusion

The findings indicate that people who experience cognitive and functional impairment (indicative of dementia) in Kenya are more likely to be lonely and have poorer quality of life. Further research is needed to understand the underlying mechanisms within a Kenyan context, but our findings are indicative that even without a diagnosis the impact of dementia can be felt by people living with it.
Genome‐wide analysis identifies APOE4 as a strong mitophagy modifier in Lewy body disease
Authors: Hou Xu , Heckman Michael G. , Fiesel Fabienne C , Tiemann Savannah J , Koga Shunsuke , Beasley Alexandra I. , Watzlawik Jens O , Zhao Jing , Johnson Patrick W. , White Launia J , Quicksall Zachary , Zhao Na , Bu Guojun , Dickson Dennis W. , Ross Owen A. , Springer Wolfdieter
Published: December 2023

Background

Loss of function mutations in PINK1 and PRKN are the most common causes of early‐onset Parkinson disease (PD). The encoded ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN together regulate the autophagic degradation of dysfunctional mitochondria, termed mitophagy. During this cytoprotective process, PINK1 and PRKN identify and jointly decorate damaged mitochondria with phosphorylated Ub (pS65‐Ub) that serves as the mitophagy tag. Accumulating evidence suggest a pathogenic role for impaired mitophagy in PD and related neurodegenerative conditions. This is in line with our previous finding of increased levels of the mitophagy marker pS65‐Ub in the hippocampus of postmortem Lewy body disease (LBD) brain.

Method

We performed a genome‐wide association study (GWAS) of hippocampal pS65‐Ub level to identify novel regulators of the PINK1‐PRKN‐directed mitophagy in LBD. In our two‐stage GWAS, we obtained 1,012 autopsy confirmed LBD samples (754 discovery stage, 258, replication stage) from Caucasian participants of European ancestry. Using an established, mostly automated workflow, hippocampal sections were immunostained for pS65‐Ub, scanned, and quantified with unbiased algorithms.

Result

Our findings identified that APOE rs429358 (β: 0.50, 95% CI: 0.41 to 0.69, p = 8.67×10−25) was very strongly associated with pS65‐Ub levels in LBD brain. The APOE4 genotype is known to exacerbate Aβ and tau deposition. We did observe strong correlations of pS65‐Ub levels with both tau tangle and senile plaque density in the entire LBD cohort. Nevertheless, the increased pS65‐Ub levels in APOE4‐carrying LBD brains were also independent of Aβ and tau deposition in a subgroup (N = 175) with medium levels of these pathologies. To further explore APOE4 effects on mitophagy outside disease context, this observation was also confirmed in APOE‐targeted replacement mice and in induced pluripotent stem cell‐derived astrocytes.

Conclusion

Our findings nominate a novel mitophagy regulator in LBD brain and highlight a strong association of APOE4 with mitophagy alteration. Our results suggested that APOE4 may mediate mitophagy defects through two mechanisms, by aggravating Alzheimer’s‐type pathologies and also independent of them. With APOE4 being the strongest known risk factor for Alzheimer’s disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.
The NeuGRID Workflow: a “Swiss Army knife” for MRI processing
Authors: De Francesco Silvia , Archetti Damiano , Redolfi Alberto
Published: December 2023

Background

The advent of big data and artificial intelligence has energized the neuroimaging community with powerful processing tools and the need for large‐scale computational resources for data analysis has increased. Not all neuroscientists have access to extensive resources or have sufficient expertise to configure these libraries, making them difficult to use.

Method

A collection of popular MRI scan processing software, (i.e.: Fsl, FreeSurfer, Ants, SPM, Adaboost, Neuromorphometrics, LPA, Tracula) was selected as a proof of concept to be included in the NeuGRID Workflow to produce an advanced tool for group analysis and biomarkers assessment.

Result

The NeuGRID Workflow was designed to allow the user to build a custom MRI processing pipeline by means of a layered structure (Fig.1) available for users at the URL https://neugrid2.eu/index.php/workflowgroup. In the first layer, the user must upload a compressed file containing T13D, FLAIR, and DWI scans of subjects. In the second layer, the user selects which kind of MRI sequence to process. If DICOMs were uploaded, the third layer provides tools to convert DICOMs into NIFTI, the default format for all subsequent workflow processes. All DICOMs are anonymized upon upload. The fourth layer allows the user to choose how images are preprocessed, and the preprocessing pipelines can be customized for different modalities. In the final layer, the user can choose how to analyze the images to calculate volume, thickness, area and curvature of brain regions, quantify white‐matter lesions and reconstruct major white‐matter pathways. The triggered job is efficiently parallelized using a Sun Grid Engine scheduler to reduce computation time. After the scans are processed in the NeuGRID cluster (450 CPUs, 2.5TB memory, 400TB storage), the user is notified by email that the job is finished and the results can be downloaded.

Conclusion

The NeuGRID Workflow is a practical tool that allows researchers without computational resources and/or expertise to design a custom pipeline to process large amounts of data from anywhere using a traditional laptop or personal computer. The collection of heterogeneous tools provides a high degree of freedom in pipeline design, making NeuGRID Workflow a Swiss Army knife for MRI processing
Characterization of Novel Antioxidant VANL‐100 on Akt and GSK3B Protein Activity and Expression
Authors: Pfeifer Julia Anne , Saleh Tarek M , Kalisch Bettina E
Published: December 2023

Background

Strong evidence suggests antioxidant therapies modulate Akt and glycogen synthase 3 beta (GSK3B) signalling pathways–molecular mechanisms tightly correlated with the pathophysiology of Alzheimer’s disease (AD).

Method

The effects of VANL‐100, a novel antioxidant co‐drug, were characterized on Akt and GSK3B signalling in the SH‐SY5Y human neuroblastoma cell line. Cells were treated with varying doses of VANL‐100 and the effects compared to its parent compounds, naringenin (NGN) and alpha‐lipoic acid (ALA) alone or in combination without a chemical link. After 24 hours of treatment, activation and total protein levels of Akt and GSK3B were assessed by Western blot analysis.

Result

VANL‐100 was 100‐fold more potent at increasing the phosphorylation of Akt (Ser473) (p<0.05) than its parent compounds alone or in combination without being conjugated to one another. Furthermore, VANL‐100 was more effective at inhibiting the activity of GSK3B (Ser9) than either of the parent compounds alone or in combination at a dose of 50uM (p<.05), 100uM (p<.01) and 200uM (p<.05).

Conclusion

These findings suggest that the novel co‐drug VANL‐100 is more effective at modulating Akt and GSK3B activity than its parent compounds, even when they are administered in combination but not chemically‐linked. Since disruptions in Akt and GSK3B signalling pathways are linked to AD, elucidation of compounds such as VANL‐100 that modulate these pathways supports the use of antioxidant conjugates as potential novel therapeutic strategies.
Investigation of plasma β‐synuclein levels in different stages of Alzheimer´s disease and relation to amyloid and tau‐PET
Authors: Oeckl Patrick , Janelidze Shorena , Halbgebauer Steffen , Stomrud Erik , Palmqvist Sebastian , Otto Markus , Hansson Oskar
Published: December 2023

Background

Synaptic degeneration is a major hallmark of Alzheimer´s disease (AD). Easily accessible biomarkers are needed to study its role in AD pathogenesis and to detect positive effects on synaptic dysfunction in clinical drug trials. β‐Synuclein is an emerging synaptic blood biomarker for AD but changes of β‐synuclein levels in preclinical AD and its associations with amyloid and tau pathology have not yet been studied.

Method

We measured plasma β‐synuclein levels using immunoprecipitation‐mass spectrometry in the Swedish BioFINDER‐2 study (N = 230) including cognitively unimpaired individuals (CU) with positive Aβ‐PET (CU Aβ+
, i.e. preclinical AD, N = 48) or negative Aβ‐PET (CU Aβ−
, N = 61), Aβ‐positive patients with mild cognitive impairment (MCI Aβ+, N = 36) and Aβ‐positive AD dementia (N = 85). Amyloid (A) and tau (T) pathology were assessed by [18F]Flutemetamol and [18 F]RO948 PET, cortical thickness by MRI and cognitive performance using the Mini‐Mental State Examination (MMSE) and modified Preclinical Alzheimer’s Cognitive Composite (mPACC).

Result

Plasma β‐synuclein levels were increased in CU Aβ+ (p = 0.033) and further increased in MCI Aβ+ (p = 0.007) and AD patients with dementia (p<0.001) compared with CU Aβ−. Furthermore, β‐synuclein levels were higher in AD dementia than in CU Aβ+ (p = 0.002) and MCI Aβ+ (p = 0.037). Stratification according to Aβ‐ and tau‐PET status revealed increased β‐synuclein levels in both A+T− (p = 0.014) and A+T+ (p<0.001) subjects compared with A−T− and further increased in the A+T+ group compared with A+T– group (p<0.001). Plasma β‐synuclein levels significantly correlated with Aβ‐PET SUVR (β = 0.279; p<0.001) and tau‐PET SUVR (β = 0.308; p<0.001) and were associated to temporal cortical thinning (β = ‐0.135; p = 0.044) and worse performance on MMSE (β = ‐0.252; p<0.001) and mPACC (β = ‐0.254; p<0.001).

Conclusion

Our data indicate that plasma β‐synuclein levels rise early in AD during the preclinical phase, preceding tau pathology, which supports that synaptic degeneration belongs to the very early events in sporadic AD. The results support plasma β‐synuclein as an easily accessible and scalable biomarker that can be used to detect positive effects of novel disease‐modifying therapies on synaptic dysfunction in AD and to further study synaptic degeneration in the pathophysiology of AD.
A novel drug‐free intervention to improve cognitive performance in unimpaired older participants: the power of affective touch
Authors: Frau Loredana , Cazzato Valentina , Macglone Francis , Bruno Davide
Published: December 2023

Background

Affective and emotional symptoms (i.e., anxiety, depressions) are common neuropsychiatric symptoms in pre‐clinical dementia. Affective touch (AT),—a pleasant interoceptive stimulus which is signalled by the C‐Tactile system, has been shown to regulate stress responses, physical pain, and negative affect. However, to date, no study has examined if AT also may improve cognitive performance. Here,we investigated whether AT affected inhibitory control (IC; i.e., the ability to inhibit irrelevant information and select more appropriate behaviours)in unimpaired older adults.

Method

Thirty‐six unimpaired older adults (Mean age = 68.12, SD = 5.90) performed two computerised Stroop tasks (classic and emotional version). Before performing each task, participants in the experimental group received brush stroking on the forearm at CT‐optimalvelocity(3 cm/s) while participants in the control group did not receive any touch stimulation (No Touch). To estimate changes in the affective state we used a self‐rating questionnaire (PANAS) and physiological measures (Heart Rate variability‐HRV). To estimate cognitive performance we analysed response time and interference in both tasks. For analyses of HRVsignals, three‐time windows were examined: resting state pre‐task and, before each cognitive task. A repeated measure design was used at baseline and follow‐up.

Result

Participants in the AT group displayed improved response time in the Stroop tasks and greater physiological arousal (i.e., HRV) before performing both tasks compared to controls.

Conclusion

To the best of our knowledge, this is the first study highlighting the role of the touch‐induced physiological arousal in inhibitory control. Beyond regulating emotion and arousal, gentle touch appears to enhance the cognitive processes underlying the suppression of goal‐irrelevant stimuli. Overall, current data seem to suggest that a multi‐modal affective‐cognitive intervention integrating AT may be a promising tool for delaying the natural effects of aging on cognition. Future research should extend this paradigm to individuals with impaired cognition and dementia.
Can escapees of familial AD help identify protective factors? A case report of an extremely resilient PSEN1 carrier
Authors: Smulders Michelle N.C.A. , Dijkstra Janna I.R. , Visser Denise , Vermunt Lisa , Giessen Elsmarieke , Pijnenburg Yolande A.L. , Holstege Henne , van der Flier Wiesje M. , Ossenkoppele Rik , van der Lee Sven J
Published: December 2023

Background

Carriers of mutations in PSEN1, PSEN2 or APP develop early‐onset Alzheimer’s dementia around a certain age depending on the specific mutation. However, some individuals “escape their fate”, meaning they remain asymptomatic far beyond their expected age at onset (EAO). We call these individuals “escapees”. A well‐known example is the resilient PSEN1 carrier that led to the identification of the protective APOEε3‐Christchurch mutation (Arboleda‐Velasquez et al., 2019). Here we present an extremely resilient PSEN1‐P264L mutation carrier where the cause of resilience has not yet been identified.

Method

Carriers of PSEN1‐P264L have an EAO of 47 (SD = 4.3 years; Ryman et al., 2014). Our patient remains asymptomatic at age 58, which less than 0.6% of mutation carriers are expected to reach unaffected. We characterized this individual over the course of eight years with neuropsychological tests (n = 9), MRI scans (n = 5), amyloid (n = 3, [18F]florbetapir) and tau (n = 3, [18F]flortaucipir) PET scans and cerebrospinal fluid (CSF; n = 1). Genetic analysis of APOE and polygenic risk score (PRS) is described.

Result

Neuropsychological test scores were within normal range at baseline and no significant cognitive decline was observed from age 50 to 58. On five consecutive MRI scans, no abnormalities or evidence of neurodegeneration was observed with visual read. At age 50, the patient was amyloid‐positive and tau‐positive in CSF (table 1). The patient was also amyloid‐positive on their first PET at age 51 (fig. 1). Widespread amyloid‐PET binding was observed, which increased over time. On tau‐PET, the patient was negative at age 51 and 53 (fig. 1), but positive at age 56, with an atypical binding pattern that shows high occipital load with relative sparing of the temporal and parietal cortex. This tau pattern and progression are remarkably similar to that seen in the escapee with the APOEε3‐Christchurch mutation. The APOE status of the patient is APOE ε3ε3 and the patient had an average PRS (+0.2SD from population average). Whole genome sequencing is ongoing.

Conclusion

We describe an “escapee” of a PSEN1 mutation in which we have not yet identified the protective factor(s). Escapees represent rare but potent resilience phenotypes that should be studied systematically.
Mid‐life APOE4 to APOE2 ‘Switching’ Alters the Cerebral Transcriptome and Lipidome in a Transgenic Mouse Model
Authors: Golden Lesley R , MacLean Steven M , Smith Cathryn T , Lee Sangderk , L'Italien Nicholas , Whitus Callie M , Goulding Danielle S. , Chen Jing , Zhu Haining , Pandya Kumar , Gordon Scott , Morganti Josh M. , Johnson Lance A
Published: December 2023

Background

Compared to the ‘neutral’ E3, the E4 allele of Apolipoprotein E (APOE) confers up to a 15‐fold increase in Alzheimer’s Disease (AD) risk. Conversely, the neuroprotective E2 allele decreases AD risk by a similar degree. APOE’s strong risk profile and multitude of effects make it a promising therapeutic target. Here, we aimed to assess the therapeutic potential of allelic ‘switching’ by investigating the physiological changes associated with an inducible, in vivo APOE4 to APOE2 transition in a novel transgenic mouse model.

Method

The APOE “switch mouse” (APOE4s2) uses the Cre‐loxP system to allow for inducible APOE allele switching from APOE4 to APOE2. These mice express a floxed human APOE4 coding region followed by the human APOE2 coding region. To study the effects of full body APOE switching, APOE4s2 mice were crossed to ubiquitous ROSA26‐CreERT1
mice. Gene expression and proteomic analyses were used to validate that the model worked as expected. Untargeted lipidomics and single‐cell RNAseq were used to measure physiological changes following the APOE4 to APOE2 allele switch.

Result

mRNA and protein analyses confirm that APOE4s2 mice synthesize full‐length human APOE4/ApoE4 pre‐switch and that the inducible switch results in successful and efficient recombination and expression of human APOE2/ApoE2. Single‐cell RNAseq shows that global, genetic replacement of APOE4 with APOE2 results in distinct alterations to glial cell transcriptomes affecting pathways involved with lipid and mitochondrial metabolism, inflammation, blood‐brain barrier integrity, and amyloid beta. Excitingly, differentially expressed genes associated with an E4 to E2 ‘switch’ included several AD GWAS, and both aging‐ and AD‐associated pathways. Additionally, nontargeted lipidomics reveals changes to several lipid classes in the brain, in particular glycerophospholipids.

Conclusion

Together, these data suggest that a successful transition from APOE4 to APOE2 has broad impact on the cerebral transcriptome as well as peripheral and cerebral metabolism. Ongoing studies aim to determine whether cell‐specific replacement of APOE4 with APOE2 will rescue E4‐associated metabolic dysfunction, disease‐associated gene signatures, and AD pathology.
Reduced pace of biological aging explains the association of diet with dementia: results from the Framingham Offspring Study
Authors: Thomas Aline , Belsky Daniel W , Gu Yian
Published: December 2023

Background

Substantial evidence supports the benefice of healthy diet for brain aging; however, the underlying pathways remain largely unknown. Leveraging a unique cohort design with assessment of long‐term dietary habits, DNA methylation data, and 10‐year follow‐up for dementia, we evaluated the mediating role of pace of biological aging on the relationship of diet with dementia. We investigated the specificity of this pathway for brain aging, as compared to overall aging, by investigating the same mediation for the risk of all‐cause mortality.

Method

We included 1,644 participants (≥60 years‐old) from the Framingham Offspring Cohort, who were free of dementia at baseline examination (exam 8 [2005‐2008]). We evaluated long‐term adherence to a Mediterranean diet (MeDi) by averaging dietary scores across four assessments (validated food frequency questionnaire at exams 5 [1991‐1995], 6 [1995‐1998], 7 [1998‐2001], and 8). Using DNA methylation data collected at baseline, we measured the pace of biological aging through the DunedinPACE epigenetic clock, which was the DNA methylation measure the most strongly associated with dementia in prior studies. Incidence of dementia and mortality was adjudicated from baseline until 2018 by expert committees. We performed mediation analyses to estimate the role of pace of biological aging on the relationship between diet and dementia or all‐cause mortality.

Result

Over the follow‐up (maximum, 13.8 years), 140 (8.5%) participants developed dementia, and 471 (28.6%) died. Participants with a higher adherence to MeDi had a slower pace of biological aging, and lower risks of dementia and of all‐cause mortality (Figure). A faster pace of aging was associated with increased risks of dementia and mortality. Biological aging mediated 13% [95% CI, 0.06; 0.43] of the association between diet and dementia, and 43% [0.23; 1.08] of the association of diet with mortality.

Conclusion

Part of the association of healthier diet with lower risk of dementia is mediated by a slowing of global processes of biological aging. However, this pathway does not fully explain the association of diet and dementia and the proportion mediated was three times smaller than what was observed for mortality, suggesting that other mechanisms, especially brain‐specific mechanisms, need to be further described.
Associations between Distinct Trajectories of Cardiometabolic Risk Factors (Hypertension, Hypercholesterolemia, and Diabetes) over 15 Years Preceding Dementia and Incidence of Dementia
Authors: Ren Dianxu , Lopez Oscar L. , Lingler Jennifer H , Conley Yvette
Published: December 2023

Background

Cardiometabolic Risk Factors (Hypertension, Hypercholesterolemia, and Diabetes) have been reported inconsistently to associate with dementia, with both increased and decreased risks. The purpose of this study was to examine longitudinal distinct trajectories of cardiometabolic risk factors over 15 years preceding dementia with incident dementia using the large national dataset from National Alzheimer’s Coordinating Center (NACC).

Method

We used NACC dataset from 2005 to December 2020 and performed a nested case‐control study (up to 1 to 5 match). The sample included 720 cases of all‐causes dementia with at least 5–years follow‐up time preceding dementia diagnosis, and 2526 non‐dementia controls matched on age, sex, race, education and baseline cognitive status. Group‐based trajectory models were applied to identify longitudinal distinct trajectory groups of binary status measures (absent/inactive vs. recent/active) of hypertension, hypercholesterolemia and diabetes among this sample. Conditional logistic regression models were used to evaluate the effect of distinct trajectories of each cardiometabolic risk factor, APOE genotype and the interaction between them with incident dementia.

Result

For the case group (n = 720), mean age at enrollment was 75.5 years and average education in years was 15.6, participants were more female (58.7%), non‐Hispanic white (87.1%) and healthy cognitive status at initial visit (61.9%). All three binary outcome trajectory models identified similar three trajectory groups over 15 years preceding dementia: “low‐flat,” “low‐to‐high,” and “high‐flat”. Conditional logistic regression model revealed no significant main effects of hypercholesterolemia and hypertension as well as no interaction between them and APOE genotype on the incidence of dementia. However, there is borderline significant effect of diabetes trajectory group on the incidence of dementia. Comparing to “low‐flat” diabetes trajectory group, “high‐flat” group were more likely to develop dementia [OR = 1.32, 95% CI (0.99‐1.76), P = 0.056] after controlling APOE genotype.

Conclusion

Our findings suggest the existence of distinct trajectories of cardiometabolic risk factors preceding incident dementia. Active diabetes status may play an important role for developing dementia especially those who are with long‐term diabetes are with greater risk for the incidence of dementia.
Mitochondrial Localized Amyloid Precursor Protein Alters Mitochondrial Function and Mitophagy
Authors: Wilkins Heather M
Published: December 2023

Background

Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer’s disease (AD). Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), from which Aβ is generated, is found in mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. How these interactions contribute to AD pathology and progression are unknown. Here we interrogated the association of full‐length APP with mitochondria, mitochondrial function, and AD pathological hallmarks.

Method

ND (n = 5, without DS) and DS with dementia (DSD, n = 5) postmortem brain tissue was obtained from the University of California Irvine. A human iPSC line underwent Crispr/Cas9 genome editing to mutate three amino acids in APP and generate a 3M APP model, with reduced mitochondrial APP localization. We also leveraged a human iPSC line with triplication of the APP gene. iPSC models were differentiated into neurons using StemCell Technologies reagents and protocols. We examined mitochondrial function using a Seahorse XF analyzer. We measured full‐length APP protein levels in whole cell extracts and mitochondrial fractions via Western Blotting. We measured Aβ levels with ELISA kits from ThermoFisher. Mitophagy and mitochondrial mass/biogenesis was measured using MitoTimer and EGFP‐Cox8 adenoviral constructs.

Result

iPSC derived neurons showed alterations to Aβ production. 3M APP models had reduced Aβ production while APP triplication models had increased production. 3M APP models had reduced mitochondrial APP levels and APP triplication models had increased mitochondrial APP levels. 3M APP models had reduced mitophagy, increased mitochondrial biogenesis, and increased mitochondrial mass. APP triplication models had increased mitophagy and reduced mitochondrial mass. Mitochondrial respiratory function was reduced in both 3M APP and APP triplication models. DSD postmortem brain tissue had reduced mitochondrial function in females. Full‐length APP levels were significantly higher in mitochondrial fractions in DSD brain tissue. Full‐length APP levels in mitochondrial fractions correlated with mitochondrial function. Higher mitochondrial APP (full‐length) levels associated with lower mitochondrial function.

Conclusion

We describe a relationship between mitochondrial APP accumulation, mitochondrial function, and Aβ. These data support a centralized role for mitochondrial function in APP physiology and APP may play a role in modulating mitophagy.