bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of person recognition deficits in genetic frontotemporal dementia
Authors: Todd Emily G. , Bouzigues Arabella , Foster Phoebe H , Ferry‐Bolder Eve , Peakman Georgia , Bocchetta Martina , Cash David M , Greaves Caroline V , Convery Rhian S , van Swieten John C. , Jiskoot Lize C. , Seelaar Harro , Moreno Fermin , Sanchez‐Valle Raquel , Laforce Robert , Graff Caroline , Masellis Mario , Tartaglia Carmela , Rowe James B. , Borroni Barbara , Finger Elizabeth , Synofzik Matthis , Galimberti Daniela , Vandenberghe Rik , Mendonca Alexandre , Butler Christopher , Gerhard Alexander , Ducharme Simon , Ber Isabelle Le , Tiraboschi Pietro , Santana Isabel , Pasquier Florence , Levin Johannes , Otto Markus , Sorbi Sandro , Rohrer Jonathan D. , Russell Lucy L. ,   Genetic FTD Initiative (GENFI)
Published: December 2023

Background

Semantic and socioemotional knowledge, including person recognition, can be altered in frontotemporal dementia (FTD), and is often associated with the right temporal lobe variant. Using data from the Genetic FTD Initiative, we investigated person recognition deficits in genetic FTD.

Method

901 GENFI participants (279 mutation negative controls, 280 C9orf72 mutation carriers (MCs), 101 MAPTMCs and 241 GRN MCs) were grouped using the Clinical Dementia Rating scale plus National Alzheimer’s Coordinating Centre Frontotemporal Lobar Degeneration (CDR plus NACC FTLD) global score where 0 denotes asymptomatic, 0.5 as prodromal, and 1+ as mild to severe symptoms (C9orf72: 135 = 0, 48 = 0.5, 97 = 1+; GRN: 143 = 0, 35 = 0.5, 63 = 1+; MAPT: 50 = 0, 20 = 0.5, 31 = 1+). Person recognition (PR) was assessed using a single question within a structured clinical questionnaire, scoring the ability to recognise people who should be familiar by face or voice to them, with a value between 0 (absent) to 3 (severe), similar to the CDR scale. The percentage of participants with PR deficits was calculated for each group. Logistic regression with bootstrapping compared the PR score between groups with age, gender, and education as covariates.

Result

16.1% of C9orf72 MCs (0 = 0.7%, 0.5 = 2.1%, 1+ = 44.3%), 7.5% of GRN (0 = 0.0%, 0.5 = 8.6%, 1+ = 23.8%) and 17.8% of MAPT carriers (0 = 2%, 0.5 = 10%, 1+ = 48.4%) showed PR deficits. Mean (standard deviation) severity in each group was: C9orf72 0 = 0.0(0.0), 0.5 = 0.0(0.1), 1+ = 0.6(0.9); GRN 0 = 0.0(0.0), 0.5 = 0.0(0.1), 1+ = 0.2(0.6); MAPT 0 = 0.0(0.2), 0.5 = 0.1(0.3), 1+ = 0.6(0.8). Each of the symptomatic genetic groups had a significantly greater PR deficit than the control group (p<0.001), with the prodromal MAPT (p = 0.006) and GRN (p<0.001) groups also showing a greater impairment than controls. There was a trend to significance in the C9orf72asymptomatic and prodromal groups compared with controls (p = 0.058 and p = 0.059 respectively). Symptomatic C9orf72 and MAPT carriers showed greater impairment than the symptomatic GRN carriers (both p = 0.005).

Conclusion

Person recognition is a key early marker of disease in some individuals with genetic FTD and further imaging analyses will help to reveal the underlying mechanism of this deficit.
Exposure to area disadvantage across the life course and its influence on cognition and neurodegenerative pathology in later life.
Authors: Cartlidge Molly R E , Liu Yiwen , Bakolis Ioannis , Nicholas Jennifer M , Keuss Sarah E , Coath William , Cash David M , Malone Ian B , Sudre Carole H , Schott Jonathan M , Richards Marcus
Published: December 2023

Background

In older adults, exposure to area disadvantage is associated with poorer cognitive performance, smaller whole brain and hippocampal volumes and cardiovascular risk. However, there is little research on the timing, accumulation and change in exposure to area disadvantage. This study aimed to investigate whether exposure to area disadvantage across the life course is associated with cognition and neurodegenerative pathology in late adulthood.

Method

Data from the MRC National Survey of Heath and Development (British 1946 birth cohort; analytical sample: n = 1,762) and a neuroimaging sub‐study (Insight 46; analytical sample: n = 447) were used. Area disadvantage was defined as the percentage of employed individuals in semi‐skilled or unskilled occupations. In the full cohort we assessed the relationship of area disadvantage at 26, 53 and 60‐64 years, cumulative area disadvantage and area disadvantage change score with cognitive performance at 69. In Insight 46 we examined associations between area disadvantage and neuroimaging outcomes (69‐71 years): whole brain, hippocampal, and ventricular volumes, amyloid status, and white matter hyperintensity volume (WMHV). All analyses were adjusted for socio‐economic and lifestyle confounders, with the neuroimaging analyses also adjusted for age at scan and total intracranial volume.

Result

Negative associations were found between exposure to area disadvantage at all ages and cognitive performance, with stronger effects at 53 and 60‐64 (Table 1). These effect sizes remained similar when adjusted for sex, father’s social class and childhood emotional symptoms, but were attenuated when further adjusted for educational attainment and childhood cognition. A negative association was found between cumulative exposure to area disadvantage and cognitive performance (Table 1), and no effect was found from change in area disadvantage. WMHV was the only neurological outcome found to be associated with area disadvantage variables (Table 2).

Conclusion

Living in a disadvantaged area across the life course is associated with poorer cognitive performance at age 69, most of this affect is accounted for by childhood cognition and educational attainment. Living in a disadvantaged area across the life course is also associated with higher WMHV, suggesting presumed cerebrovascular disease, a dementia risk factor. Further research is required to understand the mechanism driving this association.
Education and amyloid load affect posterior lobe function in subjective memory complainers: an EEG‐fMRI study
Authors: Lopez Susanna , Hampel Harald , Chiesa Patrizia Andrea , Percio Claudio Del , Lizio Roberta , Noce Giuseppe , Teipel Stefan , González‐Escamilla Gabriel , Cavedo Enrica , Lista Simone , Vergallo Andrea , Lemercier Pablo , Spinelli Giuseppe , Grothe Michel J. , Babiloni Claudio
Published: December 2023

Background

Indicators of
cognitive reserve
(CR) moderate the effect of brain pathophysiology on cognitive deficits in the Alzheimer’s Disease (AD) continuum. In a previous study on individuals with subjective memory complaint (SMCs), a condition at risk for AD, from the INSIGHT‐preAD cohort, we found that CR using educational attainment (Edu) as a proxy altered the association of amyloid load with neurophysiological mechanisms generating posterior electroencephalographic (EEG) alpha rhythms in quiet wakefulness.

Method

Here, we tested the hypothesis of an interaction between Edu and cerebral amyloid‐b load by analyzing the association between posterior alpha rhythms and functional magnetic resonance imaging connectivity (fMRI), among cholinergic basal forebrain (BF), thalamus, and cortical regions forming the Visual Network (VN).

Result

Results showed a significantly positive association between posterior alpha rhythms and above‐mentioned functional connectivity in the SMC seniors with low brain amyloid accumulation and high education attainment (SMCneg Edu+), characterized by the amplest posterior alpha rhythms. This effect may be related to the neuroprotective effect of CR. On the contrary, SMC seniors with high brain amyloid accumulation and high education attainment (SMCpos Edu+) showed a trend towards the greatest negative association between posterior alpha rhythms and functional connectivity, possibly reflecting the compensatory effect related to high CR and high brain amyloidosis (see Figure).

Conclusion

The present results suggest that, in SMC seniors, high CR affects the relation between cortical neural synchronization mechanisms generating posterior rsEEG alpha rhythms and functional connectivity involving the ascending cholinergic system and the VN. Unfortunately, these CR effects may be annulled at earlier stages of Alzheimer’s amyloid pathophysiology.
More than words: Photovoice as an innovative participatory approach to explore perceptions of rare dementia, a pilot study
Authors: Wood Olivia K
Published: December 2023

Background

There is limited evidence internationally exploring the everyday experiences of people living with rare dementia (PLWRD)– by which we mean atypical, inherited, and young onset forms of dementia– from their own subjective perspectives. Photovoice (Wang and Burris, 1997) is an inclusive, empowering visual research methodology that facilitates collaboration and supports shared understandings. This pilot study presents findings from the first known study where an inclusive research team, including individuals with different rare dementia diagnoses (e.g. Primary Progressive Aphasia, Posterior Cortical Atrophy, Dementia with Lewy bodies) used Photovoice methodology to visually represent experiences and perspectives of living with these conditions.

Method

Drawing on Freire’s empowerment pedagogy, the study aims were consistent with global Photovoice aims: enabling people to visually record critical dialogue about their experiences of dementia through photography. We investigated the benefits and challenges of Photovoice methodology with this population and sought to identify perspectives of rare dementia from eight PLWRD. Data analysis utilised an iterative, participatory approach in which researchers and co‐researchers selected, contextualised, and codified the data. Thematic analyses involved both inductive and realist approaches.

Result

This paper discusses some of the practical challenges associated with using this methodology with PLWRD, as well as issues concerning co‐researcher’s perspectives on the acceptability and utility of Photovoice. We examine the benefits and challenges of using Photovoice and discuss lessons learned relating to the co‐production of topics and outputs, including barriers and facilitators to co‐researcher engagement with the study processes (e.g. use of cameras, photo upload).

Conclusion

This pilot study will help inform a larger scale project where Photovoice and other creative participatory approaches (e.g. graphic elicitation) will be applied within a participatory action research framework that will promote group and individual reflection on dementia perspectives. In turn we hope this will lead to social action on a local and national level by co‐researchers with rare forms of dementia. This study contributes to the existing, if limited, international literature on creative participatory approaches with PLWRD.
Re‐estimation of drug‐specific amyloid removal parameters and the rate constant for pathogenic tau turnover brings the Q‐ATN model into better alignment with recent phase 3 data from gantenerumab and lecanemab
Authors: Mazer Norman A , Lott Dominik , Grimm Hans Peter , Machacek Matthias , Boess Frank , Gieschke Ronald , Klein Gregory , Baudler Monika , Doody Rachelle S.
Published: December 2023

Background

The Q‐ATN model (Mazer et al., Alzheimer’s & Dementia. 2022; https://doi.org/10.1002/alz/12877) is a quantitative semi‐mechanistic representation of the A (amyloid)/T (tau)/N (neurodegeneration) framework for simulating the natural history of Alzheimer’s disease and the effects of anti‐amyloid treatment. The recently reported phase 3 trials of gantenerumab (GRADUATE 1&2) and lecanemab (CLARITY) provide additional data to update model parameters and assess the assumptions of the model.

Method

The drug‐specific amyloid removal parameters (αrem) for gantenerumab and lecanemab were re‐estimated from the mean amyloid PET data in GRADUATE 1&2 and CLARITY. Using the new αrem values, Q‐ATN simulations of the Clinical Dementia Rating – Sum of Boxes (CDR‐SB) and tau PET trajectories were made for each study. The rate constant for pathogenic tau turnover (ktau), which was uncertain due to limited data, was re‐estimated using a sensitivity analysis of the CDR‐SB treatment effects. Results from the aducanumab EMERGE and ENGAGE studies were also included in the analysis.

Result

The simulated increase in amyloid PET agreed well with the mean data from the placebo groups. For GRADUATE 1&2, αrem was 34% and 41% lower, respectively, than the prior value (0.0137 Yr−1/(ug/mL)) estimated from the gantenerumab open‐label extension studies. For CLARITY, αrem was 26% lower than the prior value (0.0109 Yr−1/(ug/mL)) estimated from the lecanemab phase 2 study. For GRADUATE 1&2, the simulated CDR‐SB trajectories for the placebo groups were in good agreement with the observed increases from baseline. For CLARITY, the simulation overestimated the observed increase. The re‐estimated value of ktau (0.2 Yr−1), which corresponds to a 3.5 Yr half‐life, yielded treatment effect sizes on CDR‐SB within the 95% confidence intervals for all treatment arms (N = 7). The prior value (0.5 Yr−1) yielded treatment effect sizes that were too large in three cases (see Figure). Tau PET simulations (with ktau = 0.2 Yr−1) were consistent with medial temporal ROI data from lecanemab and aducanumab; tau PET data from gantenerumab are pending.

Conclusion

The updated αrem and ktau parameters bring the Q‐ATN model into better alignment with recent phase 3 data. Forthcoming data from the Donanemab TRAILBLAZER‐ALZ 2 study could further help assess the model assumptions.
Relationship between Framingham Risk Score and Cognitive Performance among Rural Indian Participants of SANSCOG study
Authors: Lingegodwa Abhishek Mensegere , Malo Palash Kumar , Stezin Albert , Hameed Shafeeq K Shahul , Mallikarjun Divya N , Partha Ajith , M Amitha C , Narayanasamy Rajitha , R Meghana , Menon Meenakshi , Velavarajan Goutham , Arvind Prathima , HS Sunitha , Singh Sadhana , Kommaddi Reddy Peera , Diwakar Latha , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: December 2023

Background

The burden of Cardiovascular risk factors is increasing in India and the rural population is more susceptible due to rapidly changing lifestyle. There cardiovascular risk factors are known to occur in clusters and are implicated in poor cognitive performance. The Framingham risk score (FRS) is a simplified and common tool for the assessment of risk of developing Cardiovascular events over 10 years using six risk factors, such as, age, gender, total cholesterol (TC), high density lipoprotein cholesterol (HDL), smoking habits, and systolic blood pressure. Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) is a longitudinal, prospective cohort study in healthy aging individuals in a town located near Bangalore, India, where participants are recruited from the community.

Method

Our objective was to examine to effect of FRS on cognitive performance measured by COGNITO among SANSCOG cohort participants. We performed separate multiple linear regression analysis to examine to effect of FRS on various COGNITO domains after adjusting for years of education and Geriatric Depression Scale (GDS) scores.

Result

In a sample of 3929 individuals, 2022 (51.5%) were women. The median (IQR) age of the sample was 58 (50,65), the median (IQR) years of education was 4 (0,9) and the median (IQR) GDS was 2 (1,6). Multiple linear regression analysis was used to see the association of FRS with various cognitive tests after adjusting for years of education and GDS revealed that individuals with higher FRS performed poorly in all cognitive domains as shown in Table 1. When we examined this in men and women separately the results remained the same.

Conclusion

We have demonstrated that higher FRS affects cognitive performance among rural elderly Indian individuals of both genders. It is imperative to design and implement strategies for risk‐reduction such as early identification and management of risk factors, a healthy lifestyle, balanced diet and regular physical exercise.
Plasma p‐tau212 is an early biomarker to identify Alzheimer’s Disease pathology in Down Syndrome
Authors: Kac Przemyslaw Radoslaw , Alcolea Daniel , Montoliu‐Gaya Laia , Rodriguez Juan Lantero , Gonzalez‐Ortiz Fernando , Ashton Nicholas J. , Zetterberg Henrik , Karikari Thomas K , Fortea Juan , Blennow Kaj
Published: December 2023

Background

The life‐time risk of Alzheimer´s disease (AD) in people with Down Syndrome (DS) is above 95% by the seventh decade of life. Understanding the strong biological relation between those conditions is important to accelerate progress in diagnostics and treatment. Tau phosphorylation at threonine‐212 (p‐tau212) is very sensitive to Dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A), which is encoded in chromosome 21. Published results showed that p‐tau212 was significantly increased in AD‐DS male brains. This suggests a possible involvement of p‐tau212 in early progression to AD in individuals with DS. Here, we assessed the potential of these biomarker in DS and sporadic AD.

Method

Using SIMOA technology, we tested in‐house developed p‐tau212 immunoassay (n = 245 for plasma, n = 329 for CSF and n = 115 paired samples) and p‐tau181 (n = 459 for plasma, n = 357 for CSF and n = 245 for p‐tau212 paired plasma samples). A subset of participants had amyloid‐PET data. We used AUC‐ROC to examine diagnostic potential and DeLong test for comparison. Spearman correlations were used to establish associations. Age‐related changes of p‐tau212 and p‐tau181 were examined in relation to amyloid positivity in CSF and Amyloid‐PET.

Result

Plasma/CSF p‐tau212 and p‐tau181 showed excellent analytical performances. Plasma p‐tau212 started increasing around 20 years before people were diagnosed as prodromal AD‐DS (pDS) and CSF p‐tau212 approximately 27 years. Paired plasma and CSF p‐tau212 measurements correlated strongly (r = 0.71;p<0.001). Both plasma biomarkers were successful in differentiating asymptomatic DS (aDS) from dementia‐DS (dDS) with an AUC = 91% for p‐tau212 and AUC = 88% for p‐tau181. Plasma p‐tau212 had greater than p‐tau181 magnitude of change in early stages of AD performing 3.4 vs 2‐fold change for pDS and 3 vs 2.1 for vs mild cognitive impairment (MCI‐AD). Pattern remained the same for dDS, AD and CSF measurements. Moreover, plasma p‐tau212 was 2.4‐fold increased in aDS people, when compared to CN. Aside of great discrimination in DS, plasma p‐tau212 had significantly better performance than p‐tau181 for differentiating CN from MCI‐AD (AUC = 84%‐91%;p = 0.026) and CN from MCI‐AD+AD (AUC = 86%‐93%;p = 0.026).

Conclusion

Plasma p‐tau212 is useful for early DS and AD differentiation. Blood‐based p‐tau212 will be a cost‐effective and simple‐to‐implement alternative to in vivo and autopsy‐based evaluations for AD changes in DS and sporadic cases.
Designing EXercise for Cognitive hEalth in depression and anxiety: the EXCEL study
Authors: Curran Eleanor , Ellis Kathryn A , Palmer Victoria J , Cox Kay L , Chong Terence W.H , Rego Thomas W H , Anstey Kaarin J. , Southam Jennifer Amanda , Moorhead Rebecca Anne , Westphal Alissa , Lai Rhoda , Lautenschlager Nicola T
Published: December 2023

Background

Physical inactivity significantly contributes to chronic disease burden, including increasing dementia risk. Physical activity (PA) can benefit cognitive health for groups at high‐risk of dementia, such as people experiencing cognitive concerns (including mild cognitive impairment and subjective cognitive decline), and mental health symptoms. However, understanding how to best enable people with co‐occurring cognitive and mental health concerns to increase PA for dementia risk reduction (DRR) remains challenging for researchers, resulting in lower adherence in clinical trials and limiting the impact of implementation in clinical practice. The EXCEL PA implementation study incorporated design approaches from behavioral science that were novel to DRR, to improve intervention tailoring and engagement. We report findings from the first phase of EXCEL, which aimed to understand PA behavior change needs in this population and identify unique intervention tailoring requirements to enable more effective engagement.

Method

The study used the Capability, Opportunity and Motivation (COM‐B) model of behavior change as an organizing framework. Middle‐aged and older people (aged 45 – 85 years) experiencing subjective cognitive decline (SCD) or mild cognitive impairment (MCI) and mild‐moderate depression or anxiety were interviewed. Themes from semi‐structured interviews examining PA and DRR perspectives were triangulated with findings from published PA intervention trials to identify convergent and complementary themes. Integrated findings were mapped to the study framework to develop a specified, contextualized model of key factors influencing PA behavior change and matched intervention approaches.

Result

Data from 21 interviews and 24 relevant papers were included. Identified areas requiring behavior change support in the target population that have not been emphasized in theory or previous interventions included:

• Emotional regulation

• Turning intentions into action despite distractions or barriers

• Confidence in existing skills, including to overcome barriers and regulate emotion

These aligned with and extended COM‐B and provided a model to guide the EXCEL intervention.

Conclusion

This novel model used behavioral science methods to tailor an intervention for people experiencing cognitive concerns and depression or anxiety, supporting improved PA engagement and impact for an at‐risk population (see Ellis et al. AAIC‐23, submitted, for trial results).
Identifying Social Visitations in a Household of Person Living with Dementia using Movement Sensors and a Sleep Tracking Device
Authors: Su Ting , Jouaiti Melanie , Barnaghi Payam , Vaidyanathan Ravi
Published: December 2023

Background

Social isolation and loneliness are commonly linked to reduced quality of life, neuropsychiatric symptoms, or increased medication usage among people living with dementia (PLwD). Thus, this study aims to monitor the frequency of visitations in households with PLwD, ideally lending insights into these issues. It builds upon the UK Dementia Research Institute and Clinical Research and Technology centre smart home deployment.

Method

We collected activity data from movement sensors and sleep tracking devices, and audio data from a smart chatbot. These devices are deployed to one household where a PLwD is living together with their primary carer. Two scientists listened to all the audio clips captured by the chatbot and manually labelled them as from either carer, PLwD, or visitors (Cohen’s Kappa = 0.96). All the days with audio clips from visitors are labelled as days with visitors, and other days are labelled as days without visitors. A Support Vector Machine (SVM) is trained to classify if the PLwD has had visitors based on sensor data. The cross‐validation (cv = 5) method is used to evaluate the effectiveness of the classification model.

Result

1719 audio clips from 127 days were recorded by the chatbot between 09‐08‐2021 to 31‐05‐2022. We removed 10 days where there were no bed movements recorded, resulting in a total of 117 days in the dataset. Among these days, 11 days were labelled as with visitors and 106 days as without visitors. We observed significantly fewer bed activities when they have visitors (Mann‐Whitney U test, p = 0.0003 for times getting into bed and p = 0.0003 for getting out of bed), but significantly more times entering bedroom (Mann‐Whitney U test, p = 0.0242). Additionally, we observed that the SVM model could classify if the PLWD has had visitors with 0.768 Accuracy, 0.694 Precision, 0.768 Recall, and 0.728 F1 score.

Conclusion

Visitors may influence PLwD’s daily routine, as the PLwD has significantly fewer bed activities and significantly more bedroom activities when having visitors at home. The SVM model can classify if PLwD’s household has had visitors using data from movement sensors and the sleep tracking device as input, with 0.768 Accuracy.
Effect of Adeno‐associated Viral Vector Mediated APOE Protective Variants Expression on Tau Pathology in a Tau Mouse Model
Authors: Chatterjee Madhurima , Zuko Amila , Wattimury Hendrina , Boggiani Lorenzo , Paerels Lieke , Schwarz Lukas , Hentschel Lisa , Kusuma Angga , Bosma Bas , Villamil Javier , Spronck Lisa , Pereira Ines Lopes , Nogueira Ana , Peris Sara Gimeno , de Miguel Elena , Dobrynin Greg , Liu Ying Poi
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by two main pathological hallmarks in the brain, namely, the presence of amyloid plaques and neurofibrillary tangles. However, the underlying mechanisms of AD pathogenesis are still largely unknown. Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late‐onset AD, with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring protection relative to the common APOE*ε3 allele. Previous studies have shown that the presence of APOE*ε4 exacerbates tau pathology in AD patients as well as AD mouse models. uniQure is developing an AAV gene therapy approach which will simultaneously silence the risk‐increasing APOE allele and overexpress the protective APOE variant. Here, our goal is to investigate the effect of AAV‐mediated APOE protective variants expression on tau pathology in a tau mouse model.

Method

Protective APOE‐variants were tested by intra‐striatal delivery of AAV vectors in a humanized tau mouse model. Vehicle or empty AAVs were injected in two separate control groups. Vector DNA, APOE mRNA and human APOE protein levels were measured in different brain areas of these mice. In addition, human tau protein levels were measured.

Result

We successfully expressed protective variants of APOE in a tau mouse model and measured human APOE protein levels in different brain areas. Furthermore, phosphorylated tau protein levels were significantly lower in AAV‐APOE‐protective variants treated tau mice compared to control groups mice indicating reduction in tau pathology in the hippocampus after protective APOE variants expression.

Conclusion

AAV‐mediated overexpression of protective APOE variants results in reduction of tau pathology in mice. Overexpression of protective APOE variants or in combination with a silencing approach using a new generation of therapeutic microRNAs (miRNAs) from our miQURE® platform could be an attractive treatment approach for AD.
Association between anxiety symptoms and Alzheimer’s disease biomarkers in cognitively healthy adults: A systematic review and meta‐analysis
Authors: Demnitz‐King Harriet , Saba Lisa , Lau Yolanda , Munns Lydia , Zabihi Sedigheh , Schlosser Marco , del‐Pino‐Casado Rafael , Orgeta Vasiliki , Marchant Natalie L
Published: December 2023

Background

Anxiety has been identified as both a risk factor and prodromal symptom for Alzheimer’s disease (AD) and related dementias, however, the underlying neurobiological correlates remain unknown. The aim of this systematic review and meta‐analysis was to examine the association between anxiety symptoms and two defining markers of AD neuropathology: amyloid‐beta (Aβ) and tau.

Method

Systematic literature searches were conducted across 5 databases. Studies investigating the relationship between anxiety and AD neuropathology (i.e., Aβ and/or tau) in cognitively healthy adults were eligible. Where possible, effect sizes were combined across studies, for Aβ and tau separately, using random‐effects meta‐analyses. Sensitivity analyses were performed to assess whether results differed according to anxiety type (i.e., state and trait) and biomarker assessment modality (i.e., positron emission tomography and cerebrospinal fluid). Between‐study heterogeneity was quantified using I
2 with 95% confidence intervals (CI), publication bias evaluated by examining funnel plots, and risk of bias assessed via the National Heart, Lung, and Blood Institute Quality Assessment Tool.

Result

Twenty‐seven studies reporting data from 14 unique cohorts met eligibility criteria (Figure‐1). All studies received a quality rating of either ‘good’ (k = 15) or ‘fair’ (k = 12). Random‐effects meta‐analyses revealed no associations between self‐reported anxiety symptoms and either Aβ (13 studies, N = 5141; Fisher’s z = 0.02, 95% CI ‐0.01–0.05, p = 0.194 [Figure‐2]) or tau (4 studies, N = 1126; Fisher’s z = 0.04, 95% CI ‐0.02–0.09, p = 0.235 [Figure‐3]). There was no evidence of publication bias and heterogeneity was low (I
2 = 0.0%). Results remained substantively unchanged across sensitivity analyses assessing the effects of anxiety type and biomarker assessment modality.

Conclusion

In cognitively healthy adults, meta‐analytic syntheses revealed no associations between anxiety symptoms and either Aβ or tau. There is a critical need, however, for larger studies with follow‐up periods to examine the effect of anxiety symptom onset, severity, and chronicity on AD neuropathology. An association between anxiety and dementia‐related neurobiological correlates is also likely complex, underpinned by multiple factors, and not restricted to AD neuropathology. Further research investigating other potential neurobiological correlates is crucial to advance understanding of the relationship between anxiety and dementia.
Virtual‐ and Augmented Reality‐Assisted Screening for Early Detection of Cognitive Impairments
Authors: Draxler Theresa , Christova Monica , Fuchs‐Neuhold Bianca , Guggenberger Bernhard , Loder‐Fink Brigitte , Maas Nina , Nischelwitzer Alexander , Palli Christoph , Pilz René , Schadenbauer Sandra , Simi Helmut , Steiner Anna , Strohmaier Robert , Staubmann Wolfgang
Published: December 2023

Background

A key element in providing future dementia patients with sufficient care is the early detection of cognitive impairment. Using augmented reality (AR) and virtual reality (VR), the project “Smart Cognition & Behaviour Screening powered by Augmented Reality” (SCOBES‐AR) seeks to create a multimodal screening tool (MST) for the early and easy detection of cognitive impairment. The MST focusses on non‐pharmacological prevention by assessing behavioral and lifestyle‐associated risk factors and identifying personal resources.

Methods

First, a validation study was carried out utilizing the established Cognitive Functions Dementia (CFD) test battery to evaluate a set of selected test procedures. The validated test procedures were implemented in an MST prototype based on AR/VR techniques. Using observational summative evaluation and the co‐discovery method, the usability and applicability of the validated test methods for therapists and subjects were further assessed in a subsequent cross‐over study with 98 healthy individuals (age 60‐75 years).

Results

310 people were involved in the validation study (age 60‐75 years). Among other things, the assessment of olfactory performance (r = 0.09, p = 0.003), reaction time (r = ‐0.47, p<0.001), and activities of daily living (r = 0.29, p<0.001) revealed a particularly high agreement with the CFD. Further, the MST prototype, that includes a tablet PC, AR head‐mounted display with smartphone, VR head‐mounted display, and Flic Buttons as input devices, was developed (see fig. 1). It allows the therapist to have control and direction over the screening process (see fig. 2).

Conclusion

The focus of the MST is on non‐clinical cognitive and physical functionalities, as it integrates tests from multiple health professions and is low‐threshold viable. The development of the MST prototype enables the determination of ideal procedures for multimodal AR/VR‐based testing to measure cognitive impairment in older people. To bolster the findings and advance research, clinical trials involving people with cognitive decline and those who already have dementia would be required.
Screening Alzheimer’s genetic risk factors against amyloid‐βeta synaptotoxicity
Authors: Gelle Carla , Siedlecki‐Wullich Dolores , Coulon Audrey , Chapuis Julien , Lambert Jean‐Charles , Kilinc Devrim
Published: December 2023

Background

Synapse degeneration is one of the earliest events in Alzheimer’s disease (AD) and toxic oligomers of amyloid‐beta (Aβ) peptide, cleavage product of APP, plays a major role in this process. Genome‐wide association studies recently reported 75 genomic risk loci for developing AD, but how the potential risk genes contribute to AD remains unknown. This project aims to identify AD genetic risk factors that mediate Aβ‐induced synaptotoxicity.

Method

We conducted a high‐content shRNA screening to assess the impact of ca. 200 AD risk genes on synaptic density and connectivity. Twenty‐four genes expressed in neurons with highest impact on synapses when silenced were shortlisted for a medium‐throughput screening to assess their capacity to block Aβ‐induced synaptotoxicity. Synaptotoxicity was modelled in microfluidic devices that allow primary postnatal rat neurons to be co‐cultured with Chinese hamster ovary cells, that overexpress wild‐type APP or APP with V717I (or London) mutation with increased secretion of Aβ1‐42 oligomers. Microfluidic devices allow the fluidic isolation of neurites from neuronal cell bodies and therefore provide exclusive access to pre‐ and post‐synaptic neurons. Target genes expression will be modulated either in pre‐ or post‐synaptic neurons and its impact on synaptic connectivity will be assessed.

Result

Based on the shRNA screening, we shortlisted 17 detrimental genes, for which we obtained overexpression vectors packed in lentiviruses, and 6 protective genes. We have developed a medium‐throughput co‐culture device that permits screening twelve genes per imaging session using the INCell 6000 automated microscope, as well as an automated image analysis workflow for detecting and assigning presynaptic to postsynaptic puncta based on their relative proximity. Gene expression modulation is validated and the screen is on‐going.

Conclusion

We have developed a microfluidic co‐culture model to rapidly and systematically interrogate genetic risk factors for their impact on synaptic connectivity. This study will help us identify AD genetic risk factors with a potential to block Aβ‐induced synaptotoxicity in vitro. Hit genes will be functionally validated via microelectrode array recordings.
The influence of widowhood on amyloid positivity status in cognitively normal older adults
Authors: Chandra Avinash , Anjum Rifah , Bothongo Phazha LK , Waters Sheena , Uchegbu Ijeoma , Jeraldo Rosario Isabel Espinoza , Byford Michelle , Marshall Charles R
Published: December 2023

Background

Widowhood and associated spousal bereavement is a life event that may lead to stress, loneliness, and depression. Previous research found associations between widowhood and an elevated risk of dementia. However, no direct relationship has been evidenced between widowhood and beta‐amyloid (Aβ) pathology, which is a hallmark of Alzheimer’s disease. Additionally, little is known about whether particular demographic or background factors might contribute to potential influences of widowhood on Aβ levels in older adults. Our objective was to evaluate the relationship between widowhood and Aβ positivity status in older adults, and to determine whether subgroups based on age, gender, educational attainment, or APOE ε4 status are driving effects.

Method

Cognitively normal (CN) subjects (n = 182) who were either widowed (including widows and widowers) or married from the Alzheimer’s Disease Neuroimaging Initiative were included in this study that underwent [18F]Florbetapir PET imaging on the baseline study visit. Multivariable logistic regression interrogated associations between widowhood status and Aβ positivity classification based on a global standardised uptake value ratio threshold of 1.11. This analysis included age, gender, APOE ε4 allele possession, education, and MMSE score as covariates. Regressions were also run in subgroups of CN subjects based on gender (male vs. female), APOE ε4 allele possession (carriers vs. non‐carriers), age (youngest, middle, oldest tertiles), and education (at least an undergraduate degree vs. no undergraduate degree).

Result

In CN subjects, there was overall no significant association between widowhood status and Aβ positivity (p = 0.114). When examining subgroups, widowhood was significantly associated with an increased risk of Aβ positivity in CN individuals with an undergraduate degree or higher (p = 0.025) or in the oldest age tertile (ages ranging from 76.3 to 89) (p = 0.024).

Conclusion

Findings from this cross‐sectional study indicated that a positive relationship between widowhood and in vivo Aβ neuropathology measured by PET exists specifically in those that are highly educated or undergoing advanced ageing. Whereas cognitive reserve is often hypothesised to mediate links between social isolation, depression and dementia risk, these results suggest that there may also be a direct effect on Alzheimer’s disease neuropathology.
Consensus meta‐analysis of genome‐wide association studies for Alzheimer’s disease across the EADB, PGC‐ALZ and IGAP consortia
Authors: Bellenguez Céline
Published: December 2023

Background

A large number of putative genes have been associated with Alzheimer’s disease (AD), in particular by the International Genomics of Alzheimer’s Project (IGAP), the European Alzheimer & Dementia Biobank (EADB), and the Psychiatric Genomics Consortium (PGC). Those genome‐wide association studies (GWAS) showed that increasing the sample size and performing imputation using the largest reference panel available greatly improves statistical power to detect genetic associations with AD. In order to better characterize the genetic architecture and pathophysiology underlying this disease, the three consortia joined to perform a meta‐analysis of GWAS across all their samples of European ancestry, the UK Biobank, and FinnGen.

Method

In a preliminary analysis, 48 studies were considered, totaling 70,276 AD cases, 610,828 controls, 55,960 proxy‐cases and 235,566 proxy‐controls. This represents an effective sample size of 225,605 (97% of the expected final size). Most of the datasets were imputed with the TOPMed reference panel. A GWAS was performed in each study with a logistic regression or a logistic mixed model adjusted on principal components and/or centers, and results were combined across studies with an inverse variance fixed effect meta‐analysis.

Result

More than 23 million variants were analyzed. We identified a genome‐wide significant signal for 92 loci, including 16 novel loci. Lead variants were InDels for two novel loci, and had a frequency below 5% for four other novel loci. We did not identify any genome‐wide significant signals in six previously reported loci: results are borderline significant for SORT1 and ICA1, and further investigations are required for FOXF1, SLC2A4RG, HAVCR2 and NTN5.

Conclusion

This meta‐analysis will provide consensus results for loci previously reported for AD and will identify novel signals. Their robustness will be assessed after exclusion of proxy or biobank samples, and secondary analyses will be performed, such as pathway or functional analyses, to provide further insights into the novel loci.
Predictive value for cerebrospinal fluid Alzheimer’s disease profile of different measures of verbal episodic memory in patients with mild cognitive impairment
Authors: Salvadori Nicola , Chipi Elena , Montanucci Chiara , Marchesiello Marta Sveva Maria , Torrigiani Edoardo Guido , Verderosa Claudio , Paoletti Federico Paolini , Fruttini Daniela , Parnetti Lucilla
Published: December 2023

Background

Episodic memory deficits represent the typical manifestation of prodromal Alzheimer’s disease (AD), namely amnestic Mild Cognitive Impairment (a‐MCI). Current neuropsychological criteria for MCI recommend the use of at least two measures for each cognitive domain. Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) are two widely used verbal episodic memory measures. Our aim was to investigate the value of these measures in predicting cerebrospinal fluid (CSF) AD biomarkers positivity in a retrospective fully characterized consecutive MCI cohort.

Method

One‐hundred and six MCI patients were included. All of them underwent a comprehensive neuropsychological assessment including RAVLT (sub‐measures: RAVLT‐imm, RAVLT‐del, RAVLT‐false_recognitions) and LM. All patients underwent lumbar puncture for the analysis of CSF core AD biomarkers (Aβ42/Aβ40 ratio, phospho‐tau, total tau). By applying the A/T/(N) classification model, patients were classified as AD (A+T+, MCI‐AD, n. 62) and non‐AD (A‐T*, MCI, n. 44). Pearson’s r correlation coefficient was used to assess the relationship of RAVLT and LM sub‐scores with diagnosis. WALD logistic regression model was used to find which memory sub‐measures show the best predictive value on biomarkers positivity. To evaluate the discriminatory power of different sub‐measures for CSF AD profile, receiver‐operating characteristic (ROC) curves were generated.

Result

With respect to non‐AD MCI, MCI‐AD patients showed worse scores on all RAVLT and LM sub‐measures. RAVLT‐del could predict both positivity of each biomarker (p<0.01) and CSF AD‐like profile (p<0.01). The combination of RAVLT‐del with other measures (RAVLT‐imm+RAVLT‐false_recognition+LM) discriminated these groups (AUC: 0.76, 95% CI: 0.67‐0‐85) with a sensitivity of 0.74 and a specificity of 0.66.

Conclusion

Our study shows that the combination of all RAVLT memory sub‐measures and LM reaches the higher diagnostic accuracy in discriminating non‐AD MCI from MCI‐AD patients. Since RAVLT and LM measure different aspects of verbal episodic memory, they should be considered as complementary, rather than interchangeable, tasks. Our findings support the use of different memory measures in the neuropsychological assessment of MCI patients.
Efficacy of transcranial direct current stimulation in mild cognitive impairment – a meta‐analysis
Authors: G Sandhya , Malo Palash Kumar , Issac Thomas Gregor
Published: December 2023

Background

MCI or Mild Cognitive Impairment is a state of cognitive decline which is in between that of normal ageing and dementia. People with MCI have a higher chance of progressing to dementia because of which introducing interventions at this stage becomes increasingly important. Transcranial Direct Current Stimulation (tDCS) is one non‐invasive brain stimulation technique that is considered as an effective intervention strategy for people with MCI to prevent their progression to dementia.

Method

From 221 and 686 results obtained from PubMed and Google Scholar respectively using the search term ‘(“tDCS”) AND (“MCI”) AND (Randomized) AND (sham controlled)’, 8 studies were included for the current meta‐analysis. Among these studies, the most commonly used cognitive tests namely MMSE (Mini Mental State Examination), MoCA (Montreal Cognitive Assessment), TMT (Trail Making Test) A and B, DST (Digit Span Test) forward and backward and Logical Memory Test were considered for the analysis. The standard mean difference between active and sham treatments in different tests were computed.

Result

The standard mean difference and the 95% confidence interval for the test scores are MoCA: 0.37 (‐0.22,0.95), MMSE: 0.26 (‐0.25, 0.77), TMT A: ‐0.01 (‐0.42, 0.40), TMT B: 0.07 (‐0.41, 0.55), DST F: ‐0.09 (‐0.44, 0.25), DST B: ‐0.11 (‐0.54, 0.31) and Logical memory test: 0.80 (‐0.24, 1.83). It is found that there is an improvement in the performance in MoCA, MMSE, TMT A and logical memory test after treatment with active tDCS but the improvement is statistically insignificant.

Conclusion

Although there is an evident clinical effectiveness, the study identified no significant improvement in cognitive performance with active tDCS in comparison with sham tDCS. This might be due to difference in protocols followed among studies, lower duration of stimulation in a few studies and smaller sample size in each.
Health economic evaluations of interventions for the diagnosis of Dementia and Cognitive Impairment from Primary Care: a systematic review
Authors: Almirall‐Sanchez Arianna , Rodriguez‐Velasco Arianne , Rodriguez Juan J Llibre
Published: December 2023

Background

Dementia is a leading global cause of morbidity and mortality. There is evidence that population and community‐based interventions on early diagnosis of Dementia and Cognitive Impairment represent around US$10,000 of net savings per person with dementia across the disease course. They also avoid early or unnecessary admission to a care home or hospital and allows patients and their families to receive timely practical information, advice, and support. Only through receiving a diagnosis can they get access to available drug and non‐drug therapies that may improve their cognition and enhance their quality of life. This study aim is to identify existing evidence concerning the cost of implementing interventions strategies for the early diagnosis of Dementia and Cognitive Impairment from primary Care.

Methods

We systematically reviewed economic studies of community‐based interventions for diagnosing Dementia and Cognitive impairment from primary care. Medline, EMBASE, Web of Science, CINAHL, PsycInfo, Scopus were searched on 05/09/2022. Cost‐effectiveness, cost‐benefit, and cost‐utility studies were included, provided that the direct outcome of the intervention was the diagnosis of Dementia or Cognitive Impairment and was measured empirically. Quality appraisal was completed using the Consensus on Health Economic Criteria checklist. A narrative synthesis was performed.

Results

We included 45 studies, from 2,749 records offering economic evidence on dementia diagnosis. Most of the reviewed studies were cost‐effectiveness analysis (n = 15 34.4%) followed by cost‐utility analysis (n = 8 19.6%). Among 20,330 patients screened, 9555 scored positive for Dementia (47%), 33% had cognitive impairment (CI), and 20% were considered to have no cognitive deficit. The prevalence of dementia was 6.0% (95%CI: 4.8%‐7.3%) and the mean of interventions strategies cost was $120 (95%CI: $112‐$136) per patient screened for dementia and $3798 (95%CI: $3702‐$3823) per patient diagnosed with dementia. Only 19% of patients with confirmed dementia diagnosis had documentation of dementia in their medical record. Most studies (56.1%) didn’t meet the methodological requirements contained in the quality assessment framework.

Conclusions

Overall, interventions were cost‐effective and/or cost‐saving. However, there is a scarcity and low methodological quality of existing studies and the generalization from the available evidence is difficult because of the narrowness of cost measures in the literature.