bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential synaptic marker involvement in the different genetic forms of frontotemporal dementia
Authors: Esteve Aitana Sogorb , Nilsson Johanna , Swift Imogen J. , Heller Carolin , Russell Lucy L. , Peakman Georgia , Convery Rhian S. , van Swieten John C. , Seelaar Harro , Borroni Barbara , Galimberti Daniela , Sanchez‐Valle Raquel , Laforce Robert , Moreno Fermin , Synofzik Matthis , Graff Caroline , Masellis Mario , Tartaglia Maria Carmela , Rowe James B. , Vandenberghe Rik , Finger Elizabeth , Tagliavini Fabrizio , de Mendonca Alexandre , Santana Isabel , Butler Christopher , Ducharme Simon , Gerhard Alexander , Danek Adrian , Levin Johannes , Otto Markus , Sorbi Sandro , Le Ber Isabelle , Pasquier Florence , Zetterberg Henrik , Rohrer Jonathan D. ,   GENetic FTD Initiative
Published: December 2021

Background

Approximately a third of frontotemporal dementia (FTD) is genetic with mutations in three genes accounting for the majority of the inheritance: C9orf72, GRN and MAPT. Synaptic dysfunction is a common mechanism in all of them and the use of fluid biomarkers could be helpful to improve the diagnostic accuracy and useful as a readout of cellular dysfunction within therapeutic trials.

Method

A total of 193 cerebrospinal fluid samples from the GENetic FTD Initiative including 77 presymptomatic (31 C9orf72, 23 GRN, 23 MAPT), 55 symptomatic mutation carriers (26 C9orf72, 17 GRN, 12 MAPT) and 61 mutation‐negative controls were measured using a microflow LC PRM‐MS set‐up targeting 15 synaptic proteins: 14‐3‐3 proteins (eta, zeta/delta and epsilon), AP‐2 complex subunit beta, beta‐synuclein, gamma‐synuclein, complexin‐2, neurogranin, neuronal pentraxin receptor (NPTXR), neuronal pentraxin 1 (NPTX1), neuronal pentraxin 2 (NPTX2), phosphatidylethanolamine‐binding protein 1 (PEBP‐1), rab GDP dissociation inhibitor α (rab GDIα), syntaxin‐1B and syntaxin‐7. Mutation carrier groups were compared to each other and to controls using a bootstrapped linear regression model, adjusting for age and sex.

Result

Eight proteins were increased only in symptomatic MAPT mutation carriers (compared with controls) and not in symptomatic C9orf72 or GRN mutation carriers: 14‐3‐3‐eta, beta‐synuclein, gamma‐synuclein, neurogranin, PEBP‐1, rab GDIα, syntaxin‐1B and syntaxin‐7. In contrast, NPTX1 and NPTX2 were affected in all three genetic groups (decreased compared to controls), with NPTXR being affected in C9orf72 and GRN mutation carriers only (decreased compared to controls). No changes were seen in presymptomatic mutation carriers in these proteins. Figure 1 contains p‐values for all significant changes.

Conclusion

Differential involvement of synaptic markers is seen in the genetic forms of FTD, with impairment particularly in those with MAPT mutations, with only the neuronal pentraxins affected in GRN and C9orf72 mutation carriers. Further work is needed to explore correlations with clinical and imaging biomarkers, whether there are changes in the late presymptomatic period, and how these markers change over time.
When is more better? Modeling the effect of dose on the efficacy of the MAPT multidomain intervention as a function of individual characteristics
Authors: Belleville Sylvie , Cloutier Simon , Mellah Samira , Willis Sherry L , Vellas Bruno , Coley Nicola , Andrieu Sandrine , Ngandu Tiia ,   MAPT/DSA Group
Published: December 2021

Background

Dose is a critical factor examined in pharmacological treatment. However, little is known about the optimal dosage for non‐pharmacological multidomain interventions as well as the function that relates dose to improvement. These gaps have been assessed in this present study in interaction with individual characteristics, which may moderate the effect of dose. Magnification models predict that healthier individuals will benefit more from prolonged practice, whereas reserve models predict that training will reduce cognitive disadvantage.

Method

The data from the Multidomain Alzheimer Preventive Trial (MAPT) was used to determine the relationship between cognitive training dose and cognition, and its interaction with sex, age, education, entry criteria, CAIDE risk score, frailty and Apoe4 status. The MAPT is a three‐year randomized controlled trial, which includes cognitive training, physical activity, nutrition and omega‐3 polyunsaturated fatty acids in at‐risk individuals. The number of hours of cognitive training attended (max.=28) was used as a measure of dose in the 749 participants randomized to the multidomain intervention.

Result

First, polynomial regression analysis modelled cognitive performance over time on memory, verbal fluency and composite cognitive score. Mixed model analyses measured the effect of dose on expected scores, and interaction with individual factors were assessed. A cubic function explained the relationship between dose and performance indicating benefits up to 12‐14 training hours followed by a plateau. Interactions were found with individual characteristics. Older participants and those with a higher CAIDE score reached their plateau more rapidly. Individuals with lower education and frail individuals benefited more from increased exposure.

Conclusion

A non‐linear dose‐response function indicates that more is not necessarily better. Here, the optimal dose was found to be 12‐14 hours of training, about half of what was potentially available to participants. A magnification effect is found for age and vascular risk factors as younger and healthier participants show larger benefit. However, a reserve effect is found in frail or less educated participants as they benefitted more from additional training experience than their more privileged counterparts.
Late‐onset epileptic seizures in adults with Down syndrome are linked to Alzheimer’s disease
Authors: Altuna Miren , Fernandez Susana , Carmona‐Iragui Maria , Barroeta Isabel , Simon‐Talero Manuel , Benejam Bessy , Videla Laura , Valldeneu Sílvia , Pegueroles Jordi , Illán‐Gala Ignacio , Garzón Diana , Gironell Alexandre , Escola Concepción , Giménez Sandra , Estellés Teresa , Iulita M. Florencia , Padilla Concepción , Blesa Rafael , Lleó Alberto , Fortea Juan
Published: December 2021

Background

Individuals with Down syndrome have a high risk of epilepsy and this risk increases with age. We aimed to determine the prevalence and characteristics of epileptic seizures and their link with symptomatic Alzheimer’s disease (AD).

Method

Population‐based observational longitudinal study from the Down Alzheimer Neuroimaging Initiative. All adults with Down syndrome underwent a neurological and neuropsychological evaluation that included a structured questionnaire on epilepsy. Participants were classified as asymptomatic, prodromal AD or AD dementia patients. A subgroup had an electroencephalogram performed.

Result

We recruited 810 adults with Down syndrome, of whom 66.9% were asymptomatic, 7.2% had prodromal AD and 25.9% AD dementia. 143 (17.65%) had a history of epileptic seizures with a median age of onset of 41.20 years and a bimodal distribution (modes at 1 and 51 years). Clinical AD was associated with a higher risk of epileptic seizures: prevalence of 9.4% in asymptomatic individuals vs 28.04% in prodromal AD and 53.40% in AD dementia patients. Generalized tonic‐clonic seizures and myoclonic seizures were the most frequent seizure type, especially in patients with symptomatic AD. Epilepsy was associated with an earlier AD dementia diagnosis (p=0.016) and lower age at death (p=0.025).

Conclusion

Symptomatic AD is associated with a high risk of epileptic seizures in DS. Epilepsy in the context of Down syndrome associated Alzheimer´s disease shortens survival.
Can engagement in socially and cognitively stimulating leisure activities compensate for other dementia risk factors? A prospective cohort study
Authors: Duffner Lukas , Deckers Kay , Cadar Dorina , Steptoe Andrew , de Vugt Marjolein , Koehler Sebastian
Published: December 2021

Background

With the projected surge in global dementia cases, research is increasingly focusing on lifestyle factors as preventive measure. Social and cognitive leisure activities are promising targets, but have thus far received relatively little attention. This study investigates whether cognitive and social activities contribute to dementia risk, and whether engagement in these activities moderates the association between other known risk factors (education, wealth & lifestyle factors).

Method

We used data of the English Longitudinal Study of Ageing (ELSA) on engagement in social and cognitive activities in 6346 participants, followed up from 2008/2009 until 2014/2015. Dementia prevalence was assessed until up to 7 years after baseline. Self‐reported cognitive (e.g. “reading the newspaper”) and social (e.g. being a member of a social club) activities and social participation (e.g. “going to the cinema”) were clustered into high and low based on a median split. We then assessed their individual contribution to dementia‐risk as well as their interaction with the other risk factors, using Cox regression models, controlling for age, sex, education, wealth and lifestyle risk factors

Result

We found that higher engagement in cognitive (HR=0.476; 95% CI=0.27‐0.84) and social activities (HR=0.60; 95% CI=0.42‐0.87) as well as social participation (HR=0.59; 95% CI=0.38‐0.90) were associated with lower dementia risk, independently of the other risk‐factors in the model. We also found an interaction between the level of engagement in social activities and level of education with regard to dementia risk, but not with other risk factors.

Conclusion

Cognitive and social leisure activities and social participation may be beneficial for overall dementia risk. The benefits of social activities may be larger for people with low education. Both should be taken into account when designing dementia prevention measures.
Tailoring recruitment message content to reach diverse communities for AD research participation
Authors: Edwards Dorothy Farrar , Dykema Jennifer
Published: December 2021

Background

COVID19 forced cessation of in‐person recruitment accelerating reliance on social media and other communication strategies. New strategies are needed to reach healthy controls who are typically recruited outside of clinical settings. Engaging diverse communities is also a priority given the disproportionate burden of AD and related dementias. Understanding the general and differential appeal of recruitment messaging to diverse groups will facilitate more effectively tailored messaging.

Methods

The Voices Heard Survey designed to identify factors associated with willingness to participate in biomedical research requesting biospecimens was administered to a diverse sample of 406 Wisconsin residents. Respondents include White (n=100), African American (n=105), Latino (n=100) and American Indian (n=101) adults. The 96 item survey assessed trust in medical research, along the continuum of study complexity and invasiveness relevant to AD studies, factors positively or negatively affecting willingness to participate in biomedical studies and clinical trials. Response frequencies indicated likelihood of participation were calculated for the full sample and by racial/ethnic group. Chi‐Square analyses were computed to determine significant differences across groups.

Results

Sample characteristics are presented in Table 1. The factors most highly associated with willingness to volunteer for a study for the total sample were: Invited to Participate (85%), Research Goal (83%), Family Member with Disease (74%) and factors less likely to promote participation were: Share Results (48%), Paid for Participation (35%) and Transportation (34%) (see Figure 1). Significant differences were observed between the White and minority groups for the following factors: Black, Latino and American Indian respondents were: Significantly more likely to volunteer if asked by a a person of the same race (p<.0001), and more concerned than Whites about Disruption of work and family responsibilities (p< .001),Availability of transportation(p<.01), and If the results are used to help others (p<.01), and Childcare (p<.02). Remuneration for participation (p<.06) and sharing results with community (p<.07) approached significance. Specific priorities by racial and ethnic group will be presented.

Conclusion

AD study recruitment requires strategic communication and innovative methods of reaching groups traditionally underrepresented in biomedical research. We identified information opportunities for tailored messaging designed to increase awareness of the value and opportunities afforded of research participation.
Staying Sharp: A case study in virtual health education for aging brain health
Authors: Lazarus Rachel Carly , Rodman Zack
Published: December 2021

Background

AARP's Staying Sharp program is a digital platform dedicated to educating users on how to learn, practice, and apply holistic, lifestyle‐based behaviors that may impact cognitive aging. The Staying Sharp program has been active for several years, and currently has a userbase of over 800,000 members. This past year, COVID necessitated a massive shift in the way we live our lives; this particularly impacted older adults, who are especially vulnerable to COVID. Consequently, Staying Sharp pivoted in several ways in order to best serve as a valuable health education tool. Here, we will (1) discuss the lessons learned during this COVID‐driven pivot; and (2) present preliminary data analyses of the impact of COVID / social distancing on measures of behaviors in the domains of sleep, stress, and social interaction.

Method

A retrospective analysis of >200,000 self‐reported lifestyle surveys from the platform evaluated responses regarding sleep hygiene, social isolation, and stress management. Responses were categorized across three periods: prior to April 1, 2020 (pre‐social distancing), from April 1 ‐ August 1 2020 (acute social distancing), and from August 1 2020 ‐ January 1 2020 (chronic social distancing). Demographic factors were also analyzed for potential correlation with self‐reported changes in lifestyle behaviors.

Result

Preliminary results indicate age‐associated changes in sleep hygiene habits and stress management over the chronological progression of pandemic‐driven social distancing. Furthermore, changes in self‐reported habits of social media use and contact with family / friends were associated with total time elapsed since April 1; these behavior changes were also associated with age.

Conclusion

The Staying Sharp platform carried out a significant pivot at the beginning of the COVID pandemic in order to best serve its userbase. With a cultural shift towards virtual health education, the digital Staying Sharp platform became positioned as an optimal source for health education related to cognitive aging. A preliminary analysis of retrospective data indicates pandemic‐associated shifts in self‐reported habits in sleep, stress, and social interaction as a function of age. These findings may represent an interesting line of future investigation in older populations, who are particularly affected by social distancing during the COVID era.
The shift to virtual, Part 2: Implications for neuropsychological health and well‐being in older populations
Authors: McGuire Lisa C
Published: December 2021

Background

2020 brought a pandemic that placed older adults at risk for severe illness and outcomes.

Method

Because of their increased risk, older adults were advised to limit interactions as much as possible with other people and consider avoiding activities where taking protective measures may be difficult, such as activities where social distancing can’t be maintained.

Results

The result for many older adults was feelings of social isolation, loneliness, and depression. Through the pandemic, there has been a shift from face‐face interactions to virtual interactions as a delivery mechanism for medical interactions and also social ones.

Conclusion

This presentation will explore outcomes of this virtual shift with respect to physical health and well‐being utilizing the latest CDC data.
Bilingualism is associated with lower cognitive decline and with lower levels of AD biomarkers in a cognitively unaffected cohort
Authors: Dauar Marina Tedeschi , Picard Cynthia , Rosa‐Neto Pedro , Breitner John , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD
Published: December 2021

Background

Speaking two or more languages has been shown to contribute to cognitive reserve and to delay the onset of Alzheimer’s disease (AD). However, little is known about the effect of bilingualism on the progression of AD biomarkers. In this study, we intended to investigate the effect of bilingualism on cognitive scores and on AD biomarkers in a cohort of cognitively unaffected individuals.

Method

We analyzed data from participants of the PREVENT‐AD cohort. This cohort comprises cognitively normal participants over the age of 55 who have a first degree relative with AD. Cognition was assessed with the RBANS scale, Tau burden was measured with [18F]‐AV1451 PET, and CSF biomarkers were measured with Innotest’s enzyme‐linked immunosorbent assay kit (Fujirebio, Ghent, Belgium). Analyses were performed comparing participants who speak one, two or three languages and comparing participants who speak one or more than one language.

Result

A total of 327 participants were included, with 89 that speak one language, 195 that speak two languages, and 43 that speak three languages. We found that participants who speak more than one language have significantly higher attention scores (p=0.041) (Fig. 1a) and total RBANS scores (p=0.021) (Fig 1b) than participants who speak only one language. Participants who speak two languages have a lower tau burden in the entorhinal cortex than participants who speak one language (p=0.047) (Fig. 2). For total Tau, participants who speak more than one language have lower CSF levels than participants who speak one language. This difference increases over time and becomes statistically significant on follow up visits 36 months (p=0.049) and 48 months (p= 0.031) (Fig 3a). Participants who speak more than one language have lower CSF levels of phospho‐Tau (p= 0.017) (Fig 3b), and neurofilament light (p=0.041)(Fig 3c) compared to participants who speak one language.

Conclusion

Our results show that bilingualism is associated not only with less cognitive decline, but also with lower levels of AD biomarkers in pre‐symptomatic AD.
Can a digital scientific conference function as a platform for facilitating two‐way learning between researchers and participants?
Authors: Walter Sarah , Wheaton Bonnie , Hummel Cynthia Huling , Tyrone Jamie , Chan Dennis , Ziolkowski Jaimie , Shaffer‐Bacareza Elizabeth , Aggarwal Neelum T
Published: December 2021

Background

Responding to requests from research participants, we piloted a program to facilitate two‐way learning between researchers and participants through the platform of a digital scientific conference.

Method

Participants were invited to attend the Alzheimer’s Association International Conference (AAIC), through a digital platform, and were offered daily small group discussions. Support was provided in the form of daily emails, navigation tips, and a glossary of frequently used terms and acronyms.

Result

The digital conference was well attended, with participants attending a broad spectrum of talks. Convening daily small group discussions was critical in creating a space where two‐way learning could occur by allowing participants to interact and share with each other as well as with research professionals. Participants provided input on research design, recruitment, outcomes, and approaches, as well as applicability of research to clinical settings.

Conclusion

Conferences that are remotely accessible offer a unique opportunity to support the engagement and participation of individuals with limited mobility or time. Future conferences should offer research participants either free or reduced registration, and allow them to select the topics they are most interested in. We recommend providing support and a glossary of frequently used acronyms and terms. Future work is needed to replicate this approach in a more diverse group of research‐naïve participants.
Distinct patters of associations between cognitive performance and Alzheimer’s disease biomarkers in a multinational cohort of clinically normal older adults
Authors: Tsoy Elena , Brugulat‐Serrat Anna , Vandevrede Lawren , Erlhoff Sabrina J , Casaletto Kaitlin B , Rankin Katherine P , Kramer Joel H , Possin Kate L ,   EPAD Consortium
Published: December 2021

Background

There is growing evidence of early cognitive changes associated with Alzheimer’s disease (AD) biomarker burden. While changes in CSF phosphorylated tau (p‐tau) and Aβ42 levels have been shown to precede onset of clinical symptoms by 15‐20 years, preclinical cognitive changes remain poorly understood, particularly in multinational cohorts. In this study, we leveraged the data from the multisite European Prevention of Alzheimer’s Dementia (EPAD) consortium (France, Netherlands, Spain, United Kingdom) to investigate cross‐sectional and longitudinal associations between cognitive performance and gold standard AD CSF biomarkers (p‐tau/Aβ42 ratio).

Method

Participants were 811 clinically normal older adults (age: 65.1±6.8; education: 14.4±3.7; 57% female) who completed a battery of digital cognitive tests of working memory, inhibitory control, and associative memory (TabCAT, University of California San Francisco) in addition to CSF Aβ42 and p‐tau‐181 (Roche Elecsys®). Additionally, 114 of these participants completed both cognitive and biomarker studies at 1‐year follow‐up (age: 65.4±5.9; education: 13.2±3.5; 54% female). Cross‐sectional associations between p‐tau/Aβ42 ratio and cognitive performance were examined using multiple linear regression models, and longitudinal associations were examined using linear mixed effects models. All analyses covaried for age, sex, education, hippocampal volume, and APOE ε4 status. Longitudinal analyses additionally covaried for time since baseline.

Result

At baseline, greater p‐tau/Aβ42 ratio was related to poorer performance on tasks of working memory (B=‐0.57, SE= 0.24, t=‐2.31, P=.02) and inhibitory control (B=‐0.45, SE=0.25, t=‐1.82, P=.06), but not on a task of associative memory (B=‐0.30, SE=0.26, t=‐1.13, P=.23). Longitudinal analyses showed that increases in p‐tau/Aβ42 ratio were significantly associated with decline in associative memory performance only (B=‐1.14, SE=0.52, t=‐2.20, P=.03).

Conclusion

In summary, we found that greater AD biomarker burden was cross‐sectionally associated with poorer executive performance, while longitudinal increase in biomarker burden was related to greater decline in memory. Our findings contribute to the growing literature on the cognitive characteristics of preclinical AD and provide support for the hypothesis of an early impairment in attentional/executive processes, followed by a breakdown in memory functions as the pathological changes progress. A particular strength of our results is their potential generalizability in international cohorts and global studies of preclinical AD.
Visual memory scores are associated with lateralization of tau in the medial temporal lobe
Authors: Arias Jaime Fernandez , Lussier Firoza Z , Therriault Joseph , Mathotaarachchi Sulantha , Tissot Cécile , Wang Yi‐Ting , Benedet Andréa Lessa , Pascoal Tharick A. , Stevenson Jenna , Rahmouni Nesrine , Bezgin Gleb , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2021

Background

Aggie Figures Learning Test (AFLT) is a visual memory test that was conceived as an analogue of the widespread Rey Auditory Verbal Learning Test (RAVLT), which tests verbal memory. Previous research has indicated that performance may rely on the left medial temporal lobe (lMTL) for RAVLT and on the right medial temporal lobe (rMTL) for AFLT, although evidence is inconclusive. The present study looks into the association between delayed recall (DR) scores in both tests and tau binding in the brain.

Method

Tau PET ([18F]‐MK6240) was acquired for 130 individuals for analysis involving AFLT, and 139 for analysis involving RAVLT. Demographic data is shown on Tables 1 and 2. MRI were segmented into probabilistic grey (GM) and white (WM) maps, non‐linearly registered to the ADNI template using Dartel and smoothed with an 8mm FWHM gaussian kernel. Voxel‐wise linear regression models were applied, using VoxelStats, with either DR AFLT or DR RAVLT as dependent variables and tau as a predictor. We corrected for age, diagnosis, and amyloid load. All other variables that were tested did not significantly contribute to predict DR scores.

Results

We found negative associations between tau binding and DR RAVLT in the MTL bilaterally. Interestingly, we found a negative correlation between tau binding and DR AFLT scores that is remarkable in the rMTL and barely reaches significance in the lMTL.

Conclusion

Our findings provide evidence in support of the lateralization of memory in the brain based on the learning modality. This dissociation is in line with previous findings; namely, that the rMTL is responsible for visual memory. However, these findings are not entirely in line with previous research since associations with RAVLT are found bilaterally. Of note, most of the previous research has been made in the context of epilepsy and/or patients with anterior MTL lesions. Here, however, we are investigating a totally different population and we are looking at a parameter that is specific to this population.
Addressing dementia challenges through international networks: Evidence from the Latin American and Caribbean Consortium on Dementia (LAC‐CD)
Authors: Parra Mario A , Garcia Adolfo M , Ibanez Agustin ,   LAC‐CD
Published: December 2021

Background

LAC‐CD has recently reported that challenges faced by LAC countries are very similar to those experienced by HIC, and that regional networks will be needed to bridge gaps. ReDLat is a US‐LAC multi‐partner consortium aimed at expanding dementia research in LAC. The UK‐Latin America Brain Connectivity Research Network (UL‐BCRN) focuses on developing new affordable EEG‐based biomarkers for dementia. The Language and Brain Health Network (LBHN) integrate international multidisciplinary efforts to reveal linguistic markers of neurodegenerative diseases.

Methods

ReDLat is collecting genomic, neuroimaging, clinical, cognitive, and socioeconomic data from a first‐in‐class cohort anchored in six LAC (Argentina, Chile, Colombia, Brazil, Mexico, and Peru) and will compare these to US data (> 4200 participants, including 2100 controls, 1050 AD patients, and 1050 FTD patients). The 5‐year project will develop innovative, harmonized, and cross‐nation approaches on two of the most prevalent neurodegenerative diseases, Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD). The UL‐BCRN currently links seven EEG labs from Colombia, Argentina, Chile, Brazil and the UK. The network’s vision is to forge strong relationships between labs through which new methodologies, EEG plus multidimensional datasets, and experience will be developed and shared. The LBHN will analyze speech samples from massive AD, FTD, and control cohorts across LAC, Spain, and the US. This effort aims to identify low‐cost disease‐specific markers in diverse Latino and English‐speaking patients.

Results

ReDLat will aims to reveal unique risk factors for AD and FTD in LAC compared to US populations. Data collection strategies have been adapted to face the challenges brought by the COVID‐19 pandemic. The UL‐BCRN has now standardised recording protocols across LAC and UK labs and is collecting data from longitudinal cohorts of patients at risk of dementia relying on novel culture‐free cognitive paradigms. Preliminary LBHN data shows that, automated speech analyses can identify Latinos with AD and FTD, with good generalization across socio‐biological profiles, dialects, and languages.

Conclusion

By broadening our understanding of dementia phenotypes, risk factors, and affordable diagnostic approaches in LAC, adding new evidence on variability across HIC and LMIC, the above networks will contribute unique knowledge that will help enhance future global dementia strategies.
The BIN1 rs744373 Alzheimer’s disease risk SNP is associated with faster Aβ‐associated tau accumulation and cognitive decline
Authors: Franzmeier Nicolai , Ossenkoppele Rik , Brendel Matthias , Rubinski Anna , Smith Ruben , Kumar Atul , Mattsson‐Carlgren Niklas , Strandberg Olof , Duering Marco , Buerger Katharina , Dichgans Martin , Hansson Oskar , Ewers Michael ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)*,   the Swedish BioFINDER study
Published: December 2021

Background

The BIN1 rs744373 SNP is a key risk locus for Alzheimer’s disease (AD). Cross‐sectional studies showed BIN1 rs744373 to be associated with higher tau pathology, i.e. a key AD pathological hallmark that is associated with Aβ. Whether carriage of the BIN1 rs744373 risk SNP accelerates the association between Ab and the rate of tau accumulation is unclear. Here, we examined whether BIN1 rs744373 risk‐allele‐carriers show faster Aβ‐related tau accumulation and thus faster cognitive decline.

Method

We included two independent samples (ADNI, n=153; BioFINDER, n=63) characterized with longitudinal 18F‐Flortaucipir tau‐PET (mean follow‐up ∼2years), Aβ‐biomarkers (i.e. Ab‐PET in ADNI vs. cerebrospinal fluid Aβ1‐42 in BioFINDER) and longitudinal cognitive assessments (i.e. ADNI only). We assessed whether BIN1 rs744373 was associated with faster tau accumulation at a given level of Aβ and whether BIN1 rs744373‐associated tau accumulation mediated faster cognitive decline.

Result

BIN1 rs744373 risk‐allele‐carriers showed faster global tau‐PET accumulation (ADNI/BioFINDER, p<0.001/p<0.001, Fig. 1A&B). We found significant Aβ by rs744373 interactions on global tau‐PET accumulation rates (ADNI: b/SE=0.42/0.14, p=0.002; BioFINDER: b/SE=‐0.35/0.15, p=0.021, Fig. 1C&D), showing accelerated tau accumulation in BIN1 risk‐allele‐carriers at higher Aβ‐levels. In ADNI, rs744373‐effects on cognitive decline were mediated by faster global tau‐PET accumulation (b/SE=0.20/0.07, p=0.005, Fig. 2).

Conclusion

BIN1 rs744373 risk‐allele carriers show accelerated Aβ‐related tau accumulation rates and cognitive decline. These findings suggest that BIN1‐associated risk for AD dementia is specifically driven by accelerated tau accumulation, suggesting that BIN1 may be specifically involved in the progression of tau pathology.
Engagement with a preventive eHealth intervention in older adults (the HATICE trial): Predictive factors and associations with dementia and cardiovascular risk
Authors: Coley Nicola , Andre Laurine , Hoevenaar‐Blom Marieke P , Ngandu Tiia , Beishuizen Cathrien , Barbera Mariagnese , van Wanrooij Lennard , Kivipelto Miia , Soininen Hilkka , Brayne Carol , van Charante Eric P Moll , Richard Edo , Andrieu Sandrine
Published: December 2021

Background

Engagement with digital health tools ihas not been well‐studied in older populations. We aimed to describe engagement with a preventive eHealth intervention designed to reduce dementia and cardiovascular risk, identify factors associated with engagement, and examine associations between engagement and changes in dementia and cardiovascular risk factors.

Method

We analyzed data from the 18‐month randomized controlled ‘Healthy Ageing Through Internet Counselling in the Elderly’ (HATICE) trial. Participants, enrolled in Finland, France, and the Netherlands, were aged 65+ with at least basic computer literacy and either ≥2 cardiovascular risk factors or history of cardiovascular disease/diabetes. The intervention group (N=1389) received access to an interactive Internet platform, designed to encourage lifestyle changes, with remote support from a lifestyle coach. The control group (N=1335) received access a static Internet platform containing basic health information. Engagement with the intervention platform was assessed via number of logins, lifestyle goals set, messages sent to the coach, monitoring measurements entered, and amount of advice and education materials read. These metrics were combined into a composite engagement score.

Result

Most intervention group participants engaged with the platform to some extent: 90% set ≥1 goal, 86% sent ≥1 message and 80% entered ≥1 measurement. The median (IQR) number of logins per participant during follow‐up was 29 (16‐48). Regular computer use was the strongest baseline predictor of engagement. Those already working on or with short‐term plans for lifestyle improvement, and better cognition also engaged more. Compared to the control group, after adjustment, intervention group participants who engaged more with the platform showed significantly more improvement over 18‐months in systolic blood pressure, BMI, physical activity, Mediterranean diet score, and cardiovascular/dementia risk scores. Intervention group participants with a low engagement score showed no improvement compared to the control group.

Conclusion

Engaging older people in a digital lifestyle self‐management intervention was feasible. Better engagement led to more improvement in dementia and cardiovascular risk factors. Older adults who are infrequent computer users, have poorer cognition, and no concrete plans to change their lifestyle may need extra support for digital lifestyle interventions. Disparities in engagement may be further emphasized in real‐world settings.
Effects of APOE genotype, age and sex on cerebrospinal fluid biomarkers measured with NeuroToolKit in the Longitudinal Swedish Biofinder Cohort
Authors: Cicognola Claudia , Janelidze Shorena , Palmqvist Sebastian , Suridjan Ivonne , Kollmorgen Gwendlyn , Mattsson‐Carlgren Niklas , Hansson Oskar
Published: December 2021

Background

The exploratory NeuroToolKit (Roche Diagnostics International Ltd.) is a panel of automated robust prototype assays measuring cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers. NeuroToolKit includes core AD biomarkers Aβ42, Aβ40, p‐tau181 and t‐tau, markers of synaptic dysfunction (α‐synuclein and neurogranin), astrocytosis (S100b, YKL‐40, glial fibrillary acidic protein [GFAP]), microglial activation and inflammation (sTREM2, IL‐6) and axonal injury (neurofilament light [NfL]). In this study, we investigated additional effects of APOE e4 genotype, age and sex on the change of the biomarkers over time in CSF samples from the longitudinal Swedish BioFINDER cohort.

Method

CSF samples were collected at baseline and then at 2‐, 4‐, 6‐, 8‐ and 10‐years’ follow‐up from 1324 patients who were cognitively unimpaired (CU, n=801) or had mild cognitive impairment (n=265) or non‐AD dementias (n=258). Groups were stratified as Aβ positive (Aβ+) or negative (Aβ‐) according to CSF Aβ42/40 ratio (cut‐off<0.07). Linear mixed‐effect models were used to assess interaction between time and APOE e4 genotype (no e4 allele, heterozygous e4, homozygous e4), sex and age stratified by cognitive status (CU<65 years, CU≥65 years; cognitively impaired [CI] <65 years, CI≥65 years).

Result

APOE e4 homozygous genotype was associated with a significant increase in Aβ42 and YKL‐40 levels in the Aβ+ group over time (versus subjects with no e4 allele) (Table 1A, Figure 1A‐B). In the Aβ‐ group, male sex was associated with a significant increase in IL‐6 and sTREM2 levels over time (Table 1B, Figure 1C‐D). Regardless of Aβ status, increased age was associated with increase in neurogranin, p‐tau181 and T‐tau over time and decrease in sTREM2 in the cohort as a whole (Table 2A). However, when stratified for age and clinical diagnosis, there was an increase in sTREM2 levels in the CI group (versus CU<65 years) over time (Table 2B, Figure 1E). No significant effects of age, sex and APOE genotype were observed in the other biomarkers.

Conclusion

The longitudinal change in most biomarkers in the NeuroToolKit is not affected by APOE e4 genotype, age and sex; however, significant effects of these factors on the measurement of some biomarkers warrant adjustment in such studies.
Serum‐based inflammatory biomarker profiles and structural brain measures in older adults without dementia
Authors: Gu Yian , Guo Jing , De Jager Philip L. , Schupf Nicole , Manly Jennifer J. , Mayeux Richard , Brickman Adam M.
Published: December 2021

Background

Inflammatory markers may play a crucial role in early stages of Alzheimer’s disease (AD). We previously found C‐reactive protein (CRP) was associated with reduced brain volumes. Whether systemic inflammation profiles using multiple inflammatory biomarkers are associated with brain measures remains unclear.

Method

The study included 662 older (mean age=75.6 years) participants without dementia from the community‐based, multiethnic Washington Heights‐Inwood Columbia Aging Project. Thirty‐six cytokines in serum collected at baseline were quantified with multiplex technology. High‐resolution structural MRI was collected approximately 4 years later. Global brain volumetric measurements, including total brain volume (TBV), total gray matter volume (TGMV), and total white matter volume (TWMV), were quantified from T1‐weighted images via Freesurfer and adjusted for intracranial volume in the analyses. Mean cortical thickness was estimated by the average cortical thickness of 68 regions of interest. Principal component analyses were run to derive cytokine patterns (CPs). Multivariable linear regression models were used to assess the association between cytokines and brain MRI measures, adjusted for demographic and clinical factors.

Result

Eight different cytokine patterns were derived. The CP8, characterized by high (>0.3) positive loadings of α2‐Macroglobulin (A2MG) (loading=0.55), CRP (0.76), and IP‐10 (0.32), was positively correlated with increasing age (r=0.11, p=0.005). In adjusted model, the CP8 was associated with reduced TBV [β (95% confidence interval), p‐value: ‐6.88 (‐13.17, ‐0.58), 0.032], TGMVR [‐5.34 (‐8.61, ‐2.07), 0.001], and TWMV [‐4.69 (‐8.62, ‐0.76), 0.019]. Other CPs were not associated with any of the brain measures. In secondary analyses on individual cytokines, we found CRP was associated with reduced brain volumetric measures and reduced cortical thickness, but no association with brain was found for A2MG or IP‐10. Additionally, compared to the lowest tertile, moderate level (middle tertile) of platelet‐derived growth factor (PDGF‐AB/BB) was associated with larger TGMV; moderate level of macrophage inflammatory protein 1‐alpha was associated with smaller TBV and TWMV; and moderate level of PDGF‐AA was associated with smaller TWMV.

Conclusion

In this cross‐sectional study of non‐demented older adults, we found a cytokine pattern characterized by high CRP, A2MG, and IP‐10 was associated with reduced brain volume, which seemed to be mainly driven by CRP.
At‐home assessment of cognitive performance: Establishing norm scores for the Cognitive Online Self‐Test Amsterdam (COST‐A)
Authors: Visser Leonie N.C. , Dubbelman Mark A. , Verrijp Merike , Wanders Lisa , Pelt Sophie , Zwan Marissa D. , Thijssen Dick H.J. , Wouters Hans , Sikkes Sietske A.M. , Hout Hein PJ , van der Flier Wiesje M
Published: December 2021

Background

Increased public awareness of cognitive decline among older adults increases the need for reliable self‐testing of cognitive performance at home. In this study, we aimed to assess the usability of unsupervised, at‐home cognitive testing using the Cognitive Online Self‐Test Amsterdam (COST‐A). We established norm scores in a reference sample and validated them in an independent sample of cognitively normal individuals. In a clinical sample of individuals diagnosed with mild cognitive impairment (MCI) or dementia, we validated the capacity of COST‐A to distinguish normal from impaired cognitive functioning.

Method

We recruited adults who self‐reported to be cognitively normal through the Dutch Brain Research Registry (reference sample), and invited them to complete and evaluate the COST‐A. We computed expected COST‐A scores based on age, sex and education level using multiple linear regression, to obtain demographically‐adjusted, standardized norm scores. We applied ‐1.5 SD units as a cut‐off for (ab)normal performance.

Result

Out of 3529 participants who started, 3088 participants (60.6±12.1 years old, 70% women, 68% highly educated) successfully completed the COST‐A (Figure 1). These participants considered COST‐A to be of adequate difficulty and duration (±17 minutes), with clear instructions. Based on the norm scores (Figure 2), and corresponding with our cut‐off definition, 242 participants (7.8%) in the reference sample scored below ‐1.5. Results from the independent validation cohort (N=2444, 58.9±12.1 years old, 42% female, 54% highly educated) corroborated this finding: 186 (7.6%) scored below the cut‐off. In the clinical sample, 75% of MCI and 82% of dementia patients scored below ‐1.5.

Conclusion

COST‐A is an easy‐to‐use online test of cognitive performance for individuals worried about their memory that can be used in the comfort of their own home. This is especially relevant in light of the COVID‐19 pandemic, where digital care is increasingly the norm. Moving forward, optimizing user experiences is key to overcome challenges regarding successful completion of the COST‐A at home, even in cognitively normal individuals. With a high accuracy for distinguishing normal from impaired cognition, COST‐A can serve as a screening tool to identify those individuals who require formal assessment by a healthcare professional and/or for research studies.
Examination of cognitive performance and mild behavioral impairment domains of apathy, mood, impulse dyscontrol, social inappropriateness and psychosis in cognitively normal adults aged 50 and over
Authors: Sun Nianqi , Ismail Zahinoor , Aarsland Dag , Brooker Helen , Corbett Anne , Ballard Clive , Creese Byron
Published: December 2021

Background

Mild Behavioral Impairment describes a spectrum of later‐life onset sustained neuropsychiatric symptoms which are a risk state for dementia. Symptoms which constitute MBI can be grouped into apathy, mood, impulse dyscontrol, social inappropriateness and psychosis. While previous studies have shown the presence of any MBI symptoms (i.e. a global measure) to be associated with worse cognitive performance over one‐year, little is known about the individual constituent domains. In this study we examined the cognitive correlates of each of the five MBI domains over two years in a cognitively normal sample.

Method

Data from 8,001 participants aged 50 or over taking part in the PROTECT study were analysed. Cognitive performance was assessed at baseline and after two years via completion of a battery of four tests broadly assessing working memory and elements of executive function (paired associates learning, digit span, self‐ordered search and verbal reasoning). MBI status was ascertained at baseline using the MBI‐C at the same time as performance on the first cognitive test. Change in cognitive performance was calculated was a difference score (year 2‐baseline) and analysed in a regression model with MBI domain score as the predictor and controlling for relevant medical and demographics covariates.

Result

The mean age of the sample was 62 and ∼75% were women. Apathy, mood and impulse dyscontrol were associated with worse cognitive performance across all four cognitive tests, the largest effects were observed for impulse dyscontrol on self‐ordered search and verbal reasoning (β= ‐0.05, p=<0.001; β= ‐0.12, p=0.005 respectively). Social inappropriateness was only associated with worse performance on digit span and self‐ordered search (β= ‐0.08, p=0.005; β= ‐0.11, p=0.018) while there were no cognitive changes associated with psychotic symptoms.

Conclusion

We present the first longitudinal analysis of the relationship between individual MBI domains and cognition. The worse cognitive performance over two years associated with impulse dyscontrol and social inappropriateness highlight the importance of non‐affective symptomology in later life.
Low‐dose lithium treatment of behavioral complications in Alzheimer’s disease: Lit‐AD randomized clinical trial
Authors: Devanand Davangere P , Crocco Elizabeth , Forester Brent P. , Husain Mustafa , Lee Seonjoo , Huey Edward D. , Pelton Gregory H
Published: December 2021

Background

To evaluate low‐dose lithium treatment of agitation in Alzheimer’s disease (AD).

Method

In a four‐site trial, patients with AD and agitation/aggression on the Neuropsychiatric Inventory (NPI) were randomized, double‐blind, to lithium carbonate 150‐600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response defined by 30% reduction in NPI combined score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved. Somatic, cognitive, metabolic, and neurological side effects were assessed.

Result

Fifty‐eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium did not differ from placebo in agitation/aggression change scores. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p=0.26). Moderate or marked improvement on global CGI change, which incorporated behavior, cognition, and function, was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher’s exact test p<0.001). In exploratory analyses, improvement on lithium was greater than placebo on NPI delusions and irritability/lability (p’s<0.05). Lithium showed greater reduction than placebo in patients with high Young Mania Rating Scale scores (β=5.06; 95%CI, 1.18 to 8.94, p=0.01). Oral dose and serum lithium levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on any safety outcome.

Conclusion

Low dose lithium was not efficacious in treating agitation but was associated with global clinical improvement and excellent safety. A larger trial may be warranted with precision pharmacological targeting of likely lithium‐responsive behavioral symptoms that overlap with mania.