bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychometric evaluation of the A‐NKS – a diagnostic instrument to assess impairment of activities of daily living in mild and severe Neurocognitive Disorder according to DSM‐5
Authors: Grothe Jessica , Kropidlowski Adam , Elgner Melanie , Luppa Melanie , Pabst Alexander , Schomerus Georg , Funke Katja , Dietzel Jens , Saur Dorothee , Luck Tobias , Riedel‐Heller Steffi G.
Published: December 2023

Background

Activities of daily living functioning (ADL) are relevant in the diagnosis of neurocognitive disorders (NCD). Currently, however, there has been no standardized and validated instrument based on DSM‐5 diagnosis criteria. Our aim was to psychometrically evaluate the differentiated assessment of ADL impairments due to NCD (A‐NKS).

Method

We interviewed 92 dyads of individuals with either mild NCDs, major NCDs, or cognitively healthy individuals and a relative each and examined reliability, validity, and acceptability of the A‐NKS.

Result

Both versions had excellent internal consistency and are correlated with other (I)ADL instruments (patient [informant]: Barthel Index: rs = ‐0.26, p ≤ .05 [rs = ‐0.30, p ≤ .01]; Amsterdam IADL: rs = 0.59, p ≤ .01 [rs = 0.48, p ≤ .01]; SIDAM ADL: rs = 0.46, p ≤ .001 [rs = 0.47, p ≤ .001]). Aditionally, there are correlations with the scale autonomy of the WHOQOL‐OLD (rs = ‐0.50, p ≤ .001 [rs = ‐0.37, p ≤ .001]) and physical, as well as cognitive activities (rs = ‐0.39, p ≤ .001 [rs = ‐0.50, p ≤ .001]). All participants found the questionnaire acceptable.

Conclusion

The A‐NKS shows promise as a valid, reliable and acceptable measure to assess ADL due to neurodegenerative decline in healthy individuals, individuals with mild NCDs and those with major NCD.
Cognitive trajectories in prevalent and incident hearing impairment: A 12‐year follow‐up of the Maastricht Ageing Study (MAAS)
Authors: Soons Lion M. , Deckers Kay , van Boxtel Martin P.J. , Köhler Sebastian
Published: December 2023

Background

Hearing impairment (HI) is a common and often treatable condition that is associated with increased risk of cognitive impairment and dementia. However, little is known about the cognitive course of individuals with incident HI. The objective of this study was to investigate the temporal association between prevalent and incident HI and change in cognition over 12 years.

Method

Data was used from the Maastricht Ageing Study (MAAS), a Dutch cohort of 1823 cognitively healthy individuals aged 24‐82 years. Individuals were repeatedly assessed at baseline, 6 and 12 years. Hearing acuity was assessed using pure‐tone audiometry thresholds in decibel (dB). Prevalent (baseline) HI was categorized into no HI (average acuity <20 dB), mild HI (≥ 20 and <35 dB) and moderate to profound HI (≥35 dB). The presence of incident HI was defined by an average threshold of 20 dB at 6‐ or 12‐years in those without HI at baseline and follow‐up data (n = 1071). Verbal memory, information processing speed, and executive function were assessed. Linear mixed models were used to test the association between HI and change in cognitive function over time, adjusted for age, sex, education, and a composite score of 11 modifiable dementia risk factors.

Result

Participants with mild prevalent HI (n = 322; 17.8%) and moderate to profound prevalent HI (n = 198; 10.9%) showed more decline over time in verbal memory, information processing speed, and executive function than participants without prevalent HI, independently of the other demographical and risk factors in the model. Likewise, participants with incident HI (n = 360; 33.6%) showed more decline over time in all cognitive domains than those with normal hearing at follow‐up. Comparing slopes across time showed a steady cognitive decline across all time points for prevalent HI, while for incident HI, a more time‐delayed pattern of increasing decline from 6 to 12 years was observed.

Conclusion

Prevalent and incident HI predict cognitive decline in adults aged between 24‐82 years. This association is already present in individuals with mild HI. Findings for incident HI suggest that cognitive decline evolves gradually over time and after the onset of HI, possibly opening a window for risk management.
Age‐related cognitive decline and prevalence of MCI in the Iwaki Health Promotion Project
Authors: Kawarabayashi Takeshi , Nakahata Naoko , Nakamura Takumi , Takatama Masamitsu , Shoji Mikio
Published: December 2023

Background

The Iwaki Health Promotion Project (IHPP) is a community‐based study for the prevention of lifestyle‐related diseases and improvement of quality of life.

Method

Between 2014 and 2017, a total of 4,442 Iwaki town residents from 19 to 93 years of age participated in annual surveys to clarify the natural course of age‐related cognitive decline and mild cognitive impairment (MCI). Modified OLD and SED‐11Q questionnaires, MMSE, Logical Memory II, educational history, and APOE genotypes were examined at the first screening. MCI and dementia were diagnosed at the second examination by detailed neurological examination, CDR, and MRI, and followed for 3 years. Spline regression analyses based on a linear mixed model was adopted for statistical analysis.

Result

MMSE scores declined with age from 55 to 64 years. There was also interaction between levels of education and ages. At the second examination, 56 MCI and 5 dementia patients were identified. None of the MCI cases progressed to dementia during the 3 years. During follow‐up examinations, 13 cases showed improved MMSE scores (0.95 point/year), 5 remained stable, and 7 deteriorated (‐0.83 point/year). Five cases showed improved CDR‐SOB scores (‐0.28 point/year), 9 remained stable, and 6 deteriorated (0.3 point/year).

Conclusion

IHPP revealed that age‐ and education‐related cognitive decline began and advanced from 55 years of age. The prevalence of MCI and dementia was estimated to be 5.9% in the Iwaki town cohort over 60 yeas of age. About 30% of MCI cases showed progression of cognitive decline.
The mediating effect of HbA1c levels on the relationship between education and cognitive function
Authors: Reinke Constantin , Aretz Benjamin , Fink Anne , Doblhammer Gabriele
Published: December 2023

Background

Higher education has been shown to be positively associated with cognitive performance. However, the pathways, through which education is related to cognitive performance, have not been sufficiently explored. Higher levels of glycated hemoglobin (HbA1c) can lead to deterioration in cognitive performance. Part of the association with education may operate via the HbA1c level.

Method

To evaluate if the HbA1c level mediates the association of education with cognitive performance, we used longitudinal data from the Dutch Lifelines Cohort study (2006‐2015). Lifelines is a multi‐disciplinary prospective population‐based cohort study examining the health and health‐related behaviors of 167,729 persons living in the north of the Netherlands. The analyzed sample contained 19,878 persons observed at the baseline and the follow‐up, who were 50+ at baseline. We measured cognitive function using age‐standardized reaction time from the psychomotor function and attention tasks measured by the Cogstate Brief Battery at follow‐up. Higher reaction times indicate weaker cognitive function. The HbA1c level was measured at baseline by using participants’ blood samples. Linear Structural Equation Models were applied to estimate total, direct and indirect effects of education on cognitive function. We controlled for sex, age, income, physical activity, comorbidities and individual task accuracy.

Result

Higher education was associated with faster reaction time respectively better cognitive performance (low: ref; middle: b = ‐0.125 p<0.01; high: b = ‐0.268 p<0.01). An increase in the HbA1c level (%) was associated with slower reaction time respectively poorer cognitive performance (b = 0.031 p = 0.02). Education had a significant effect on the HbA1c level (low: ref; middle: b = ‐0.023 p<0.01; high: b = ‐0.035 p<0.01). Most importantly, we found a significant indirect effect for education (low: ref; middle: b = ‐0.0007 p = 0.06; high: b = ‐0.001 p = 0.03) on cognitive function via the HbA1c level.

Conclusion

The education effect of on cognitive performance was partially mediated by HbA1c levels. Early monitoring and regulation of blood glucose levels may be a potential prevention strategy to tackle cognitive impairments and mitigate the disadvantages in cognitive function of lower‐educated people.
Role of brain‐derived extracellular vesicles in bone‐fat imbalance in Alzheimer’s disease
Authors: Shen Lu , Liu Xixi , Chen Chunyuan , Jiao Bin , Wang Zhenxing , Xie Hui
Published: December 2023

Background

Inadequate osteogenesis and excessive adipogenesis of bone marrow mesenchymal stem cells (BMSCs) are key factors in the pathogenesis of osteoporosis. Patients with Alzheimer’s disease (AD) have a higher incidence of osteoporosis than healthy adults, but the underlying mechanism is not clear. The aim of this study was to investigate the role of brain‐derived extracellular vesicles (EVs) from AD mice on the regulation of bone metabolism.

Method

Brain‐derived EVs from AD or wide‐type mice was injected into C57BL/6 mice intravenously once a week for two months.

Result

Here, we show that brain‐derived EVs from adult AD or wild‐type mice can cross the blood‐brain barrier to reach the distal bone tissue, while only AD brain‐derived EVs (AD‐B‐EVs) significantly promote the shift of the BMSC differentiation fate from osteogenesis to adipogenesis and induce a bone‐fat imbalance. MiR‐483‐5p is highly enriched in AD‐B‐EVs, brain tissues from AD mice, and plasma‐derived EVs from AD patients. This miRNA mediates the anti‐osteogenic, pro‐adipogenic, and pro‐osteoporotic effects of AD‐B‐EVs by inhibiting Igf2.

Conclusion

This study identifies the role of B‐EVs as a promoter of osteoporosis in AD by transferring miR‐483‐5p.
Diagnostic utility of culture/language‐specific normative data on the Version 3 of the Uniform Data Set Neuropsychological Battery for differentiating stages of cognitive impairment among Latinos in the United States
Authors: Marquine Maria J. , Kamalyan Lily , Parks Adam , Perales Jaime , Gonzalez David A. , Rosado‐Bruno Mónica , North Rebecca , Amy Werry E , Kiselica Andrew M , Reyes Marcos , Chapman Silvia , Dodge Hiroko H , Rascovsky Katya
Published: December 2023

Background

Accurate detection of neurocognitive disorders of aging among Latinos in the United States (U.S.) is an important step towards addressing disparities in Alzheimer’s disease and related dementias (ADRDs) and promoting health equity in this group. Federally‐funded Alzheimer’s Disease Research Centers (ADRCs) in the U.S. have utilized the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set Version 3 Neurobehavioral Battery (UDS3‐NB) since 2015. Normative data on this battery adjusted for age, education and sex were published for English‐speakers in 2018 (Weintraub et al., 2018) and expanded to consider differences among non‐Hispanics White and Black people in 2020 (Sachs et al., 2020). We aimed to determine whether the use of newly developed culture/language‐specific neuropsychological normative data for Spanish‐ and English‐speaking Latinos in the U.S. improved diagnostic accuracy of the UDS3‐NB in this group.

Method

Participants included 1,018 Latino adults age 50+ enrolled in ADRCs. Table 1 presents participant demographics by global Clinical Dementia Rating (CDR) score, as indicative of stage of neurocognitive impairment (0 = normal, 0.5 = questionable impairment, 1 = mild impairment, 2‐3 = moderate‐to‐severe impairment). Individual test raw scores were converted to demographically‐adjusted z scores utilizing normative data on the UDS3‐NB developed for Latinos and for other culture/language groups. Individual tests z scores were converted to deficit scores and averaged to compute global deficit scores and determine global neurocognitive impairment (NCI). Rates of NCI based on culture/language specific normative data were compared across the four CDR groups via Chi‐Square tests. Sensitivity and specificity were computed for differentiating participants with CDR = 0 (normal) and CDR = 1 (mild impairment) based on different sets of normative data.

Results

Utilizing culture/language‐specific normative data significantly differentiated CDR groups (p<.001; Figure 1). These culture/language specific normative data performed better in differentiating between CDR = 0 and 1, than utilizing normative data developed for non‐Hispanic English speakers (Table 2).

Conclusion

Culture/language‐specific normative data improve diagnostic accuracy for neurocognitive impairment among Latinos in the U.S. relative to existing normative data developed for other groups. These culture/language‐specific norms can be used in research and clinical practice to enhance ADRD diagnosis among Latinos and represent an important step towards addressing ADRD disparities in this group.
Understanding sex‐specific molecular mechanisms in preclinical and Alzheimer’s disease through brain proteomics and transcriptomics
Authors: Sadeghi Iman , Rodríguez‐Fernández Blanca , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia
Published: December 2023

Background

Sex‐specific molecular mechanisms active during the transition from the preclinical stage to clinically evident Alzheimer’s disease (AD) pathobiology are not yet fully understood. In this study, we used large‐scale multi‐omics data integration of brain proteomics, brain transcriptomics, and genomics to study sex‐specific co‐expression changes related to the AD continuum.

Methods

The study included postmortem brain proteomics samples from the dorsolateral prefrontal cortex (DLPFC) of cases with AD dementia (N = 200, 55% female), cognitively unimpaired individuals with amyloid‐beta pathology (CU A+, N = 206, 70% female), and without (CU A‐, N = 110, 50% female) from the ROSMAP and Banner studies [Figure 1]. Additionally, RNAseq data was obtained from cases with AD dementia (N = 203, 70% female), CU A+ (N = 204, 63% female), and Cu A‐ (N = 125, 56% female) from ROSMAP. We performed co‐expression network analysis to identify functional sex‐specific molecular modules that differentially behave in AD different stages along the AD continuum (AD dementia vs. CU A‐, CU A+ vs. CU A‐). We assessed the preservation of these modules in the brain transcriptome. Additionally, brain protein quantitative trait loci (pQTLs) enrichment analysis was performed to characterize significant modules enriched for AD risk variants. Finally, we assessed the association of sex‐specific modules with AD traits.

Results

Proteomic network analysis showed modules significantly associated with pathological traits differentially by sex [Figure 2]. For instance, a module related to cellular localization showed upregulation in AD and CU A+ compared with CU A‐ [Figure 3A]. Association with pathological traits showed a positive correlation with global pathology and a negative correlation with global cognition only in female [Figure 3B]. In males, two modules related to ubiquitin proteolysis were changed in AD dementia and CU A+. Brain transcriptome showed preservation of the cellular localization module in female [Figure 3C]. This module was enriched for AD pQTLs in the brain, including variants from SYN3, FLOT2 and PACSIN2, which are involved in processing of amyloid and vesicle trafficking
[Figure 3D]

Conclusions

This multi‐omics system network analysis reveals changes of a cellular localization‐related module, specifically in the females AD brain proteome and transcriptome, which could be used as potential therapeutic targets.
Recruitment and Retention Strategies Adopted in TATA Longitudinal Study of Aging Study: A prospective Cohort Study on Aging in Urban India
Authors: HS Sunitha , Lingegodwa Abhishek Mensegere , Arvind Prathima , Hameed Shafeeq K Shahul , Stezin Albert , Malo Palash Kumar , Velavarajan Goutham , Mallikarjun Divya N , Narayanasamy Rajitha , R Meghana , Singh Sadhana , Menon Meenakshi , Partha Ajith , M Amitha C , Diwakar Latha , Kommaddi Reddy Peera , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: December 2023

Background

Recruitment and retention of participants is a crucial step in any longitudinal study. The TATA Longitudinal Study for Aging (TLSA) is an urban cohort study to gather long term data to identify risk and protective factors for dementia in India.

Method

We have recruited more than 1000 individuals with age ≥ 45 years for the study. Our recruitment strategies centered around existing urban community centers in Bangalore, India, where we have conducted more than 50 awareness programs to inform the participants about the healthy aging and our study. We maintain the periodic contact with participants through telephone, in person visits and mental health awareness programs. Though we do not offer any treatment the clinical team provides brief feedback on participants blood test reports, ECG and MRI and makes appropriate referrals to the health system if necessary. To emphasize participant convenience and reduce burden, our study team has a mobile unit that conducts clinical and cognitive sessions at the participant’s location. Transportation is also offered for each participant to attend the sessions at the study center. During the COVID 19 pandemic period, all participants were given special attention in terms of enquiring about their well‐being and using standard methods to assess their anxiety and depression. To keep the participants engaged during COVID 19 pandemic, we had shared the links for virtual museums, materials to read and offered psychosocial support.

Result

We have approached 2225 individuals out of which 52% consented and able to complete the baseline assessment for them. It is been observed that good support and willingness to contribute to the study with the notion of potentially helping their future generations. Currently up to 50% of the participants completed first follow‐up sessions.

Conclusion

The recruitment and retention of participants in the longitudinal clinical studies is a challenging task. However, TLSA study provides the unique insights on recruitment approaches that can be tailored and adopted for increasing the study enrolment and retaining in the urban cohorts of developing countries like India.
Supporting elderly people with cognitive impairment during and after hospital stays with Intersectoral Care Management – results of a randomized controlled trial
Authors: Boekholt Melanie , Nikelski Angela , Schumacher‐Schönert Fanny , Kracht Friederike , Chikhradze Nino , Vollmar Horst Christian , Hoffmann Wolfgang , Kreisel Stefan , Thyrian Jochen René
Published: December 2023

Background

There is a need to examine whether evidence based collaborative care management can be beneficial to people with cognitive impairment transitioning from hospital to primary care.

Method

We conducted a longitudinal multisite randomized controlled trial with two arms (care as usual and care as usual + intersectoral care management) and two follow‐ups 3 and 12 months after hospital discharge. The sample under analysis consists of n = 401 participants from 3 different hospitals in Germany who were at least 70 years old, cognitively impaired and community‐dwelling.

A comprehensive assessment of medical, nursing and psychosocial data at time of admission was analyzed using pre‐specified algorithms to develop an individualized treatment and care plan. After discharge, care managers visited participants at home, aligned the plan and supported participants for up to 3 months afterwards.

Primary outcomes were the rate of re‐admission to hospital, and physical and instrumental functionality (activities of daily living, ADL) after 3 months and rate of institutionalization and ADL after 12 months. Secondary outcomes of interest were: health related quality of life, depressive symptoms, cognitive status and frailty. Statistical analyses include regression models controlled for various factors.

Result

There was no statistically significant effect on the re‐admission rate after 3 months, the activities of daily living, or the institutionalization rate. However, analyses show a significant effect of collaborative care management on health related quality of life 3 as well as 12 months after hospital discharge. Furthermore, depressive symptoms were significantly less likely in the intervention group 3 months after discharge. No effects on cognition or frailty were shown.

Conclusion

Dementia care management has a positive effect on cognitively impaired older people during and after their hospital stay. There is an effect on quality of life and mental wellbeing. It is arguable why there is none on ADL. There is a need to discuss whether it is an appropriate primary outcome measure for a complex care intervention, as the intervention is targeting the needs associated with impaired functionality rather than functionality directly. Further limitations are discussed in more detail.
Evaluation of APOE ε4 allele association with Depression and Anxiety among Elderly Individuals from India.
Authors: Arvind Prathima , Lingegodwa Abhishek Mensegere , Stezin Albert , Hameed Shafeeq K Shahul , Malo Palash Kumar , Mallikarjun Divya N , M Amitha C , Partha Ajith , R Meghana , Narayanasamy Rajitha , HS Sunitha , Menon Meenakshi , Singh Sadhana , Diwakar Latha , Sundarakumar Jonas S. , Issac Thomas Gregor , Kommaddi Reddy Peera
Published: December 2023

Background

Depression and Anxiety are the most widespread forms of psychiatric disorders. Studies on families and twins indicate that genetic variations can be a risk factor. Apolipoprotein ε4 gene is one such gene (APOE ε4). Studies on both humans and animals indicate that APOE ε4 may be a susceptibility gene in depression and anxiety disorders mean while the contradictory observations also reported. The purpose of the study was to investigate the effects of APOE isoforms on depression and anxiety among two aging Indian cohorts.

Method

The study participants are from ongoing Srinivaspura Aging Neuro Senescence and COGnition (SANSCOG) (n = 4913) and TATA Longitudinal Study for Aging (TLSA) (n = 1089) study which are longitudinal, observational studies on aging from rural and urban India respectively. Depression and Anxiety were assessed using the Geriatric Depression Scale (GDS‐30) and Generalized Anxiety Disorder Assessment (GAD‐7). APOE gene polymorphism was determined by polymerase chain reaction (PCR). We performed the Chi‐square test to examine the relationship between prevalence of depression and anxiety in APOE ε4 homozygous, heterozygous and, non‐carriers.

Result

The basic socio demographic characteristics of both cohorts are escribed in Table 1. There was no significant association between APOE ε4 isoforms and prevalence of depression and anxiety in both cohorts as described in Table 2.

Conclusion

APOE ε4 did not show any association with depression or anxiety in both cohorts. There may be other factors are predominant in modulating the depression and anxiety. Moreover, ethnicity plays a significant role in the prevalence of APOE ε4 gene and its modulation effects.
Quantification of encephalic transcripts of the APOE allele specific gene of European and African ancestry
Authors: Nascimento Santos Gabriel , Suemoto Claudia Kimie , Ferretti‐Rebustini Renata Eloah de Lucena , Rodriguez Roberta Diehl , Grinberg Lea T. , Pasqualucci Carlos Augusto , Brito Luciano Abreu , Scliar Marília Oliveira , Leite Renata Elaine Paraizo , Araujo Nathalia Matta , Borda Victor , Tarazona‐Santos Eduardo , Jacob‐Filho Wilson , Nitrini Ricardo , Yaffe Kristine , Zatz Mayana , Haddad Luciana Amaral , Naslavsky Michel S
Published: December 2023

Background

The APOE gene is identified as a major risk factor for late onset Alzheimer’s disease and has three alleles, ε2, ε3 and ε4, related to two non‐synonymous substitutions. The presence of the ε4 allele confers an increased risk for the disease in a dose dependent manner (odds ratio 12.9 for homozygous individuals and between 3.2 and 4.2 for heterozygous individuals). The most prevalent form of Alzheimer’s disease has a multifactorial etiology, where several genetic and environmental factors influence its pathology. Factors such as age and sex are relevant in determining the risk for APOE, recent studies point out that the ancestry around the APOE gene is also relevant to the risk for the disease. Individuals of African‐American ancestry have a reduced risk of developing the disease compared to European and Asian whites. These regions may act in a cis‐regulatory manner in modulating gene expression. The Brazilian population results from miscegenation between indigenous, African and European populations, offering an opportunity to study the effects of different ancestries on the risk of Alzheimer’s disease, fill the lack of genetic information about admixed groups and characterize the differential patterns of APOE’s expression in Brazilian population.

Method

This project aims to quantitatively characterize the role of different local ancestry in the different APOE genotypes using 36 post‐mortem brain tissue, with distinct genotypes and local ancestries combinations (33,34,44, European‐European, African‐African, European‐African, African‐European) and associating them with the expression of this gene through molecular marker genotyping and RT‐qPCR techniques. It is expected that the mRNA expression is differentially increased when European local ancestry is shown to be present, compared to non‐European ancestry and may explain, in part, the difference in risks observed in populations of different ancestries.

Result

ongoing research

Conclusion

ongoing research
Lower blood levels of miR‐29b‐3p in healthy middle‐aged AD risk gene carriers
Authors: Dzianok Patrycja , Grabowska‐Pyrzewicz Wioleta , Staniak Karolina , Wojda Urszula , Kublik Ewa
Published: December 2023

Background

A number of late‐onset Alzheimer’s disease (AD) risk genes have been discovered, among which the most studied but not fully explored is the apolipoprotein E gene (APOE). PICALM (coding Phosphatidylinositol Binding Clathrin Assembly Protein) is another well‐recognized risk‐gene, shown to interact with the APOE gene in conferring AD risk. MicroRNAs (miRNAs) are post‐transcriptional regulators of mRNAs, some of which are known to be involved in AD pathology. The purpose of this study was to investigate in middle‐aged, healthy participants the association between AD risk‐genes (APOE and PICALM) and circulating miRNAs that were previously identified as altered in AD patients.

Method

Blood samples were collected from 76 healthy individuals (36 F, 36 M; age: 56.38±3.16), assigned to three groups: A+P+ (APOE/PICALM risk), A+P‐ (APOE risk, PICALM neutral alleles) and N group (APOE/PICALM neutral alleles). RT‐qPCR was used to compare the levels of 11 microRNA identified by us in previous studies as candidate early AD biomarkers in blood plasma (hsa‐miR‐29b‐3p, hsa‐miR‐34a‐5p, hsa‐miR‐125b, hsa‐miR‐146a, hsa‐miR‐135a, hsa‐miR‐30b‐5p, hsa‐miR‐142‐3p, hsa‐miR‐200a‐3p, hsa‐miR‐483‐5p, hsa‐miR‐486‐5p, hsa‐miR‐502‐3p) [1, 2]. We followed standard procedures of blood assays.

Result

Single gene risk (APOE) carriers had lower levels of miR‐29b‐3p than non‐carriers and double risk carriers (F(2,73) = 12.75, p < 0.001 with Welch homogeneity correction; post‐hoc with Tukey correction: p < 0.01 for A+P‐ versus N, p < 0.001 for A+P‐ versus A+P+). No other changes in miRNA panels were discovered.

Conclusion

Downregulation of miR‐29b‐3p in blood was detected repeatedly before in patients with AD, in 4 independent studies [1]. Here we show the same effect in a subpopulation of middle‐age, healthy individuals with APOE related genetic risk for AD. Further research is needed to understand the interaction reversing this effect in PICALM risk carriers. Longitudinal follow‐up may validate this blood‐based miRNA not only as an easy‐to‐access diagnostic biomarker, but also as a risk‐assessment biomarker for AD prevention.

Funding: This work was funded by the Polish National Science Centre (NCN) grant no. 2018/31/N/HS6/03551, 2016/20/W/NZ4/00354 and 2018/29/B/NZ7/02757.

[1], [2] https://doi.org/10.1016/j.arr.2018.10.008; 10.18632/oncotarget.15109.
RESTING‐STATE ELECTROENCEPHALOGRAPHIC RHYTHMS UNDERPINNING VIGILANCE ARE ABNORMAL IN POST COVID‐19 PATIENTS EXPERIENCING FATIGUE
Authors: Noce Giuseppe , Cacciola Elio Gentilini , Vassalini Paolo , Jakhar Dharmendra , Tucci Federico , Musat Andreea Maria , D'Ettorre Gabriella , Babiloni Claudio
Published: December 2023

Background

Previous evidence showed that persons experiencing post‐COVID‐19 with “brain fog” were characterized by abnormal resting‐state electroencephalographic (rsEEG) rhythms reflecting vigilance dysfunctions. In the present exploratory study, we tested the hypothesis that in post‐COVID persons with normal cognitive status, abnormalities in those rhythms (and vigilance function) may be related to fatigue.

Method

We enrolled post‐COVID participants about one year after their infection, which claimed “brain fog.” They underwent clinical/neuropsychological assessment and 61‐channel‐EEG recordings. Matched controls (never COVID‐19 affected) were included. Using eLORETA freeware, regional neural current densities were estimated in the rsEEG cortical sources at individual delta, theta, and alpha bands and at beta and gamma fixed bands. Clinical and instrumental data were evaluated in the long COVID‐19 patients as a function of fatigue symptoms over the controls.

Result

The post‐COVID patients had no cognitive deficits at the group level. Those patients showed lower posterior rsEEG alpha source activities than the controls. Notably, this effect was more significant with the long COVID‐19 patients experiencing fatigue symptoms than those without (Fig. 1).

Conclusion

In post‐COVID patients with normal cognition, abnormal rsEEG alpha source activation may indicate a significant relationship between vigilance dysfunction and fatigue.
Novel Small‐Molecular Ligands for Prolyl Oligopeptidase to Combat Tauopathies
Authors: Eteläinen Tony , Pätsi Henri , Uhari‐Väänänen Johanna , Aikkila Hannes , Cui Hengjing , De Lorenzo Francesca , Kilpeläinen Tommi , Julku Ulrika , Wallén Erik A.A. , Myöhänen Timo T
Published: December 2023

Background

Tauopathies that include e.g. frontotemporal dementia and Alzheimer’s disease, are neurodegenerative diseases characterized by accumulation of hyperphosphorylated Tau in the brain. Tau is a tempting drug target for tauopathies but no Tau‐targeting therapies are in clinical use. We have recently shown that small‐molecular inhibitors of prolyl oligopeptidase (PREP) can activate protein phosphatase 2A (PP2A) by regulating PREP‐PP2A interaction. PP2A is the main phosphatase regulating Tau, and therefore, we decided to test the efficacy of a reference PREP inhibitor, KYP‐2047, and novel PREP ligands on cellular and animal models of tauopathies.

Method

The compounds, KYP‐2047 and HUP‐46, 55 and 59 (1, 5 and 10 μM), were first screened in the GFP‐2N4R‐Tau transfected HEK‐293 cells where the Tau aggregation was induced by small‐dose okadaic acid (OA; 10 nM), a PP2A inhibitor. The results were verified by using 2N4R‐Tau transfected HEK‐293 cells with 10 nM OA. After the treatment the cells were fractioned to RIPA soluble and SDS‐fractions, and total Tau and S262 phosphorylated Tau (pS262 Tau) levels were studied by Western blot (WB). Finally, KYP‐2047 and HUP‐46 were tested in PS19 Tau transgenic mouse. PS19 mice were treated with the ligands for 4 weeks (10 mg/kg/day, Alzet minipump i.p.) starting from 5.5 months old when the behavioral deficits were observed. After the treatment, the mice behavior was tested by Barnes Maze and locomotor activity assay, and total Tau, pS262 Tau and PP2A levels were studied.

Result

In the GFP‐Tau aggregation assay, all compounds decreased the GFP signal as an indicative of Tau aggregation with 10 mM concentration but HUP‐46 was the most effective (Fig. 1). WB that showed that PREP ligands had the most significant effect on total Tau and pS262 Tau in the SDS‐fraction. In the PS19 mice, KYP‐2047 restored normal behavior in Barnes maze and locomotor activity assay. HUP‐46 had similar effect but did not reach significance (Fig. 2). However, both compounds reduced significantly total Tau and pS262 Tau levels in mouse hippocampus and cortex, and activated PP2A (Fig. 3).

Conclusion

Small‐molecular PREP ligands, such as KYP‐2047 and HUP‐46 have disease‐modifying effects on cellular and animal models of tauopathies.
India ENIGMA Initiative for Global Aging & Mental Health–A globally coordinated study of brain aging and Alzheimer’s Disease
Authors: John John P , Joshi Himanshu , Sinha Preeti , Harbishettar Vijaykumar , Tripathi Ravikesh , Cherian Anish V , Purushottam Meera , Viswanath Biju , Thennarasu Kandavel , Dhinagar Nikhil J , Chattopadhyay Tamoghna , Rajagopalan Priya , Jahanshad Neda , Benegal Vivek , YC Janardhana Reddy , Jain Sanjeev , Varghese Mathew , PT Sivakumar , Venkatasubramanian Ganesan , Thompson Paul M
Published: December 2023

Background

There is a “diversity” crisis in brain research, as most brain research is conducted in Caucasian populations. This lack of ethnic diversity means that we do not know if predictors of health (and disease) generalize to other ethnic groups.

We have recently launched the India ENIGMA Initiative for Global Aging & Mental Health ‐ a globally coordinated study of brain aging and Alzheimer’s disease (AD), funded by the NIA/NIH, USA. Our overall goal is to identify predictive markers in the blood, genome, and epigenome that influence brain aging in India, to better understand prognosis, and to support personalized risk evaluations on each continent. To do this, we will leverage our global consortium, ENIGMA (http://enigma.ini.usc.edu), creating new links between international biobanks, and building research capacity.

Method

Aim 1. Create Lifespan Charts of brain aging Trajectories in India using MRI, DWI and Resting State Functional MRI. Aim 2. Identify Blood and Epigenetic Markers that Predict Brain Aging and AD in India. Aim 3. Using a combination of multimodal imaging, blood markers, and clinical data to predict clinical decline in India. We test structural equation models that hypothesize how brain aging depends on lifestyle and psychosocial factors (diet, family support, drug abuse, literacy, sleep, and depression), as well as sex, education, and AD genetic risk.

Result

We test structural equation models that hypothesize how brain aging depends on lifestyle and psychosocial factors (diet, family support, drug abuse, literacy, sleep, and depression), as well as sex, education, and AD genetic risk. With novel machine learning methods, we will analyze blood markers and plasma proteomic analytes, to define processes that are harmful to brain aging.

Conclusion

The data emerging from this study is expected to help in personalized risk evaluations as well as identify etiological pathways to resilience across genetically and psychosocially diverse populations. This collaborative India‐US initiative will also enable future science initiatives, and equip the team from India with the necessary tools to train new scientists and independently conduct high impact research in the field of disorders of brain aging.
“I would constantly watch myself”: Individual Attitudes and Needs towards Dementia Risk Prediction and Risk Disclosure in Interviews (PreTAD)
Authors: Baumeister Annika , Hübner Constanze , Schwegler Carolin , Gerards Michelle , Cantero‐Fortiz Yahveth , Marquié Marta , Ribaldi Federica , Wittrock Julia , Boada Mercè , Frisoni Giovanni B , Jessen Frank , Rostamzadeh Ayda , Schmitz‐Luhn Björn , Woopen Christiane
Published: December 2023

Background

Research on medical risk profiles and early detection progresses rapidly. With the early knowledge of individual health risks comes, so the hope, the possibility of tailored prevention. Potential users and healthcare providers are facing new challenges in terms of decision‐making for risk prediction, education and counselling, as well as dealing with the risk information obtained. If, as in the case of Alzheimer’s disease, there are hardly any therapy and no healing options so far, risk prediction has an existential relevance and social impact, the extent of which has been little investigated yet. Therefore, supporting a self‐determined decision for or against dementia risk prediction, taking into account individual attitudes, needs and expectations, is of major importance. As part of the PreTAD‐project (The Predictive Turn in Alzheimer’s Disease: Ethical, Clinical, Linguistic and Legal Aspects), we aim to explore the attitudes, needs and expectations regarding early dementia prediction and risk disclosure in the general population, first‐degree relatives of persons with Alzheimer’s dementia or APOE4 allele carriers, and individuals with subjective cognitive decline (SCD).

Method

In the work package ethics, we (1) conduct an online‐survey within the general population and (2) carry out 40 narrative interviews with a) individuals from the general population, b) individuals with AD family history, and individuals diagnosed with SCD (either c) ≤ 4 weeks or d) > 4 weeks ago) to get an in‐depth view of individual attitudes and needs regarding early dementia prediction, the reasons for its approval or rejection, and to examine whether personal characteristics play a role in the decision‐making process. We analyze the interviews using type‐building qualitative content analysis (Kuckartz & Rädiker 2022).

Result

Preliminary results of the first interviews (n = 5), accompanying the quantitative study, showed that participants tended to confuse the terms prediction and diagnosis in the context of Alzheimer’s. The driving reasons for or against prediction were 1) the anticipated impact on self‐determination and 2) self‐awareness, and 3) the anticipated psychological burden of risk knowledge.

Conclusion

Healthcare providers should carefully consider individual attitudes and expectations regarding dementia risk prediction as risk disclosure may have serious implications on individuals’ self‐determination, self‐awareness and mental health.
iPSC‐derived hindbrain spheroids to evaluate drug responses targeting neuropsychiatric symptoms in Alzheimer’s disease
Authors: Zivko Cristina , Sagar Ram , Xydia Ariadni , Lyketsos Constantine G. , Machairaki Vasiliki
Published: December 2023

Background

Alzheimer’s disease (AD), a neurodegenerative disorder, is the most common cause of dementia. The gradual deterioration of brain function eventually leads to death. Almost all AD patients eventually suffer from neuropsychiatric symptoms (NPS; e.g., agitation, depression) whose emergence correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain spheroids containing serotonergic neurons using induced Pluripotent Stem Cells (iPSCs) from healthy volunteers or AD patients with and without NPS. The spheroids can be used to study AD, NPS, and to evaluate individual differences in disease progression, NPS development, and/or pharmacological treatment response.

Method

Human peripheral blood mononuclear cells from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain spheroids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of serotonin (5‐HT) secreted in the extracellular environment. To assess patient‐specific treatment effects, spheroids were treated with different concentrations of escitalopram oxalate, a medication widely prescribed for the treatment of NPS.

Result

Hindbrain spheroids containing serotonergic neurons were successfully generated and characterized from these 6 individual iPSC lines. Changes in 5‐HT levels before and after treatment with escitalopram were dose‐dependent and variable across patients.

Conclusion

It is possible to generate hindbrain spheroids from human iPSCs to study inter‐patient variability using a precision medicine approach. Since hindbrain spheroids from different people respond differently to the application of escitalopram in vitro this may reveal subgroups of AD patients who may be more or less likely to benefit from the drug in vivo. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment with escitalopram.
Amyloid‐beta (Aβ) load in the post‐mortem brain correlates with APOE genotype and ante‐mortem cognitive performance in centenarians
Authors: Rohde Susan K , Fierro‐Hernández Patricia , Rozemuller Annemieke J.M. , Bank Netherlands Brain , Lorenz Linda M.C. , Sikkes Sietske A.M. , Hoozemans Jeroen , Holstege Henne
Published: December 2023

Background

The prevalence of amyloid‐beta (Aβ) pathology increases at higher ages in non‐demented individuals1. With anti‐amyloid‐beta therapies on the horizon and the growing number of elderly in our population, a clear perception of the association between accumulated Aβ pathology, APOE genotype and cognitive performance in the oldest‐old is warranted.

Methods

In 93 post‐mortem brains donated by participants of the Dutch 100‐plus Study, who self‐reported to be cognitively healthy at inclusion, we evaluated: 1) the spatiotemporal Aβ spread using Thal phases2; and 2) Aβ load in frontal, parietal, temporal and occipital cortices using a quantitative image analysis method. Spread and load of Aβ pathology were compared between different APOE groups (ɛ2/2 and ɛ2/3 (n = 20); ɛ3/3 (n = 65); ɛ2/4 and ɛ3/4 (n = 8)). Post‐mortem Aβ measurements were correlated to ante‐mortem test scores on a comprehensive neuropsychological test battery3 and a composite z‐score for global cognitive performance. Median age at death was 103.3 (interquartile range (IQR): 102.3‐104.9) and median time between neuropsychological assessment and brain donation amounted 0.61 years (IQR: 0.28‐0.93).

Results

Notably, only 10% of the centenarians had not accumulated Aβ pathology. APOE ɛ2/2 and ɛ2/3 carriers had lower Aβ load (median frontal AB load = 0.30%, IQR: 0.02‐6.15), but not spread, compared to APOE ɛ2/4 and ɛ3/4 carriers (median frontal AB load = 5.08%, IQR: 2.13‐30.71) (p = 0.041), but not compared to ɛ3/3 carriers (median frontal AB load = 2.19%, IQR:0.23‐7.54) (p = 0.245). Higher Aβ load in all four analyzed regions associated with lower performance on the Digit Span Backward test (rfrontal = ‐0.29, rparietal = ‐0.29, rtemporal = ‐0.28, roccipital = ‐0.32, FDR corrected p<0.05) and the Clock Drawing test (rfrontal = ‐0.40, rparietal = ‐0.29, rtemporal = ‐0.29, roccipital = ‐0.33, FDR corrected p<0.05), which assess executive‐ and visuospatial‐functioning. Moreover, higher Aβ load in the frontal cortex correlated with lower performance on the Mini Mental State Examination (MMSE) (r = ‐0.24, p = 0.049) and a seperate composite score of global cognitive performance (r = ‐0.28, p = 0.019).

Conclusion

Although Aβ pathology seems nearly inevitable at extreme ages, our results suggest that Aβ load, rather than Aβ spread, affects cognitive performance in the oldest‐old

1 https://doi.org/10.1002/alz.12899

2 https://doi.org/10.1212/wnl.58.12.1791

3 https://doi.org/10.1007/s10654-018-0451-3
APOE4 impairs microglia‐astrocyte response in Alzheimer’s disease by inducing TGFβ‐mediated checkpoints
Authors: Butovsky Oleg , Yin Zhuoran , Rosenzweig Neta , Kleemann Kilian , Zhang Xiaoming , Brandao Wesley N , Margeta Milica , Schroeder Caitlin M , Silveira Sebastian , Gauthier Christian , Mallah Dania , Pitts Kristen , Durao Ana , Herron Shawn , Shorey Hannah , Cheng Yiran , Barry Jen‐Li , Wakelin Sam , Rhee Jared , Yung Anthony , Aronchik Michael , Wang Chao , Jain Nimansha , Bao Xin , Gerrits Emma , Brouwer Nieske , Deik Amy , Tenen Daniel G. , Ikezu Tsuneya , Santander Nicolas G. , McKinsey Gabriel L. , Baufeld Caroline , Sheppard Dean , Krasemann Susanne , Eggen Bart , Clish Clary , Tanzi Rudolph E. , Madore Charlotte , Arnold Thomas D. , Holtzman David M.
Published: December 2023

Background

APOE ε4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD).

Method

Generation of CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl: APP/PS1 and APOE‐KI(E3 and E4)fl/fl: P301S mice. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq. Crosstalk between cells was determined using the NichenetR database and validated using 1) recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI, and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Validation in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles.

Result

Here we show, in mice and in humans, a negative role of microglial APOE4 in the induction of MGnD response to neurodegeneration. Deletion of microglial APOE4 restores MGnD phenotype, associated with neuroprotection in P301S tau transgenic mice, and decreases pathology in APP/PS1 mice. MGnD‐astrocyte crosstalk associated with b‐amyloid (Ab) plaque encapsulation and clearance is mediated via Lgals3 signaling following microglial APOE4 deletion. In the brain of AD donors carrying the APOE ε4 allele, we found a sex‐dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, as compared to APOE ε3/3 carriers. Mechanistically, APOE4‐mediated induction of ITGB8‐TGFb signaling impairs MGnD response via upregulation of TGFb‐mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5d restores MGnD‐astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8‐TGFb signaling enhanced MGnD response associated with increased plaque clearance in AD mice.

Conclusion

We identify the microglial APOE4‐ITGB8‐TGFb pathway as a negative regulator of microglia‐astrocyte response to AD pathology, and restoring MGnD phenotype via blocking ITGB8‐TGFb signaling may provide new molecular targets to modulate and restore functional microglia in AD.
RNA‐seq study on the effect of MAPT rs242557 deletion in HMC3 cells
Authors: Das Rueben , Kuska Pavel P. , Lee Wan‐Ping , Choi Eirene , Jiang Ming , Dombroski Beth A. , Schellenberg Gerald D.
Published: December 2023

Background

Microtubule associated protein tau (MAPT) is associated with neurodegenerative diseases including Frontotemporal dementia (FTD), Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Multiple GWAS on AD, PD, PSP and CBD have identified strong signal in MAPT intronic region (SNP, rs242557). Being part of FANTOM5 enhancer in eye and brain, we are interested in the effect of this region in HMC3 (human microglial clone 3) cell line.

Method

Using CRISPR‐Cas9 genome editing, a clone was isolated having homozygous 309 bp deletion encompassing rs242557 and its flanking sequences in HMC3. Sanger sequencing confirmed the deletion while whole genome sequencing corroborated the same and also confirmed no off‐target effects. To identify gene transcripts whose expression was altered due to the deletion, paired‐end RNA‐seq was performed using total RNA extracted from rs242557 KO and wild type (WT) clones.

Result

There were 272 up‐ and 861 down‐regulated transcripts (p< = 0.01) between WT and KO cells. Down‐regulated transcripts include AD risk genes ICA1, EPDR1, PTK2B, SORL1, DOC2A, and TSPOAP1, and PD candidate gene, SNCA. Notable among up‐regulated transcripts was AD risk gene, CASS4. Enrichment analyses revealed biological processes and pathways that are related to structural constituents and organization of neurons and synapses. Currently, we are validating the transcript data.

Conclusion

Our preliminary data suggests that the genomic region encompassing rs242557 might affect multiple AD risk genes.