bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive value of a plasma p‐tau181‐specific assay for amyloid accumulation in asymptomatic Alzheimer’s Disease
Authors: De Meyer Steffi , Vanbrabant Jeroen , Luckett Emma S. , Schaeverbeke Jolien , Stoops Erik , Van Laere Koen , Dupont Patrick , Vanmechelen Eugeen , Poesen Koen , Vandenberghe Rik
Published: December 2022

Background

Plasma phosphorylated tau‐181 (p‐tau181) is one of the most reliable blood‐based biomarkers for Alzheimer’s Disease (AD), yet has been consistently quantified with assays employing an antibody cross‐reacting with p‐tau175. We investigated the ability of a novel phospho‐specific plasma p‐tau181 assay to predict longitudinal amyloid accumulation in cognitively unimpaired (CU) elderly.

Methods

Plasma p‐tau181 was quantified with a novel Simoa‐based assay using a p‐tau181 specific antibody (ADx252) in a prospective longitudinal cohort of 78 CU elderly (baseline age[mean] = 70 years, 47% female, 51% APOE‐ε4 carriers). Plasma sampling, amyloid‐β (Aβ)‐PET ([18F]flutemetamol or [11C]PiB) and episodic memory tests (average Buschke Selective Reminding total retention /12) were performed at baseline and Aβ‐PET was repeated on average 5 years later (SD: 2, range 1‐10 years). Longitudinal amyloid accumulation was modelled through calculation of Aβ‐PET rate of change by dividing the difference between baseline and follow‐up tracer uptake (in Centiloids) by the time interval between scans (in years). A Spearman correlation matrix between longitudinal amyloid accumulation, plasma p‐tau181, baseline amyloid load, age and baseline episodic memory was calculated. Z‐scores of all variables were entered into a hierarchical regression analysis in a stepwise manner based on correlation strength and finally sex and APOE were added.

Results

Baseline plasma p‐tau181 correlated with longitudinal amyloid accumulation (ρ = 0.28, Figure 1A) as well as age (ρ = 0.31, Figure 1B). A negative correlation was found between age and baseline episodic memory scores (ρ = ‐0.33), and between p‐tau181 and baseline episodic memory scores (ρ = ‐0.19), although the latter did not reach significance. Apart from plasma p‐tau181, none of the other baseline variables correlated significantly with longitudinal amyloid accumulation (Figure 2). Hence, plasma p‐tau181 was entered into the base regression model. This base model (F(1,76) = 7.78, p = 0.007) explained 27% of the variance (R2) in longitudinal amyloid accumulation. Including additional predictors like demographics, clinical data or baseline amyloid load, did not further improve the model.

Conclusion

Plasma p‐tau181 measured with the novel phospho‐specific Simoa assay best reflects longitudinal amyloid accumulation in asymptomatic Alzheimer’s Disease with no additional predictive value of the other baseline factors included.
Risk of all‐cause dementia, Alzheimer’s disease, and vascular dementia among breast cancer survivors: Evidence from Swedish population data
Authors: Wennberg Alexandra MV , Ding Mozhu , Talbäck Mats , Feychting Maria , Modig Karin
Published: December 2022

Background

Cancer incidence and survival rates are increasing, and, as of 2020, two‐thirds of cancer survivors are over the age of 65; however, there is a paucity of evidence investigating their long‐term health. Cancer survivors may be at increased risk of cognitive impairment, even at younger ages. This risk may be associated with both the cancer and the cancer treatment, though very little research has been done using population datasets.

Method

In this matched cohort study, we examined risk of dementia among breast cancer survivors (n = 34900) compared to age‐matched comparison subjects (n = 290063). Women born 1935‐1975 registered in the Swedish Total Population Register between January 1st, 1991 and December 31st, 2015 were eligible for inclusion in the study. Survivors were women with a first breast cancer diagnosis between 1991 and 2005 who survived for at least 5 years after their initial diagnosis. All‐cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were assessed using ICD codes in the National Patient Register. Date of death was determined by record linkage to the National Cause of Death Registry until December 31st, 2015.

Result

In subdistribution hazard models accounting for competing risk of death and adjusted for age, among all individuals in the analyses, there was no association between breast cancer survivorship and risk of all‐cause dementia, AD, or VaD. However, when stratified by age of cancer diagnosis, there was a higher risk of all‐cause dementia (subdistribution hazard ratio (SHR) = 1.28, 95% CI 1.05, 1.57) and VaD (SHR = 1.68, 95% CI 1.15, 2.45) among those diagnosed with breast cancer after age 65. Examining AD risk, the point estimate indicated an elevated risk, but the result was not statistically significant (SHR = 1.31, 95% CI 0.98, 1.76).

Conclusion

Our findings suggest that breast cancer survivors who were diagnosed with cancer after age 65 are at higher risk of developing dementia compared to women without a history of cancer. This suggests that late‐life but not mid‐life breast cancer may be a risk factor for dementia. However, more work needs to be done to further investigate potential differences between types of dementia and mediating effects.
Diabetes and hypertension are associated with elevated beta‐amyloid burden: evidence from the prospective population‐based Rotterdam Study
Authors: van Arendonk Joyce , Neitzel Julia , Steketee Rebecca M.E. , van Assema Daniëlle , Segbers Marcel , Ikram M. Arfan , Vernooij Meike W.
Published: December 2022

Background

Higher vascular risk increases the likelihood of developing dementia. Better understanding the association between vascular risk and Alzheimer’s disease (AD) pathology at the pre‐dementia stage is critical for developing effective strategies to delay cognitive decline. In this work, we estimated the impact of vascular risk on the presence and severity of in‐vivo measured brain beta‐amyloid (Aβ) plaques in participants from the population‐based Rotterdam Study.

Methods

Vascular risk factors (hypertension, hypercholesterolemia, diabetes, obesity, physical inactivity, and smoking) were assessed twelve and seven years prior to 18F‐florbetaben positron emission tomography (PET) in 506 dementia‐free participants. Vascualr risk factors were associated with binary amyloid PET status or continuous PET readouts (SUVr values) using logistic and linear regression models respectively, adjusted for age, sex, education, APOE4 risk allele count, and time between vascular risk and PET assessment.

Results

Participants’ mean age at time of amyloid PET was 68 years (range: 60‐90), 262 (51.8%) were women and 158 (31.2%) carried at least one APOE4 risk allele (Figure 1). The adjusted prevalence estimates of an amyloid‐positive PET status markedly increased with age (12% in 60‐69y vs. 45.5% in 80‐89y age‐groups) and APOE4 allele count (8.3% in non‐carriers vs. 34.8 to 58.8% in carriers of one or two risk allele(s); Figure 2). A diagnosis of diabetes seven years prior to PET assessment was associated with a higher risk of a positive amyloid status (OR[95%CI]=4.07[1.66–9.71], P=0.002; Figure 3) and higher SUVr values, indicating more severe Aβ pathology (standardized beta=0.478[0.205–0.750], P=0.001; Figure 4). We found evidence for an association between hypertension and higher SUVr values in APOE4 carriers, but not in non‐carriers (interaction: standardized beta=0.425[0.092–0.758], P=0.013; Figure 5). Hypercholesterolemia, obesity, physical inactivity and smoking were not related to amyloid PET measures.

Conclusion

The current findings suggest a contribution of diabetes and hypertension to the pathophysiology of AD. Since both conditions respond well to lifestyle modification and drug treatment, further research should be conducted to examine the preventative effect of early risk management on the development of AD neuropathology.
Investigating neurodegenerative heterogeneity in cognitively unimpaired A4 pre‐randomization cohort
Authors: Shand Cameron , Donohue Michael C. , Oxtoby Neil P
Published: December 2022

Background

The heterogeneous nature of Alzheimer’s disease and uncertainty of determining disease severity and subtype can confound treatment effects in clinical trials. Computational methods for subtyping can assist in trial enrichment. This study investigates the latent heterogeneity and severity (including absence) of neurodegeneration in the cognitively unimpaired A4 cohort enriched for elevated amyloid.

Method

Baseline 3T T1‐weighted MRI data from ADNI (N=687) and A4 pre‐randomization (N=1240, all Aβ+ [Sperling et al. 2020, DOI:10.1001/jamaneurol.2020.0387]) studies were included. FreeSurfer was used to estimate regional brain volumes, of which 13 features were input to SuStaIn (Young et al., 2018, DOI:10.1038/s41467‐018‐05892‐0) to train two cohort‐specific models of neurodegeneration subtypes. Volumes were first adjusted for age, sex, education, and intracranial volume, and z‐scored relative to controls (Aβ– in A4; cognitively normal in ADNI). For each feature, z‐score events of z=1 (subtle abnormality) and z=2 (atrophy) were used. The number of subtypes was determined using cross‐validation.

Result

Figure 1 shows our SuStaIn model for ADNI, replicating the three‐subtype finding of Young et al. (2018). Figure 2 shows our SuStaIn model for A4, which estimated a similar three‐subtype model: typical, cortical, subcortical (named for the earliest atrophy events). Notable differences between the models are in the subtle abnormality (z=1) events in A4 that might, or might not, develop into more prominent atrophy (z=2), such as with the caudate which stalls at z=1 (Figure 2, top‐left). Our results indicate the presence of AD‐like heterogeneity in the A4 cohort. Figure 3 shows boxplots of amyloid PET SUVr — there are no statistically significant differences between subtypes (Mann‐Whitney U test), suggesting amyloid PET screening is insufficient to detect neurodegeneration heterogeneity. There were no statistically significant subtype differences in cognitive measures nor demographics (Table 1).

Conclusion

Our results show that neurodegeneration heterogeneity exists in the A4 cohort, despite amyloid PET screening. This heterogeneity could have ramifications on the potential success of the A4 trial, particularly if it correlates with different rates of cognitive decline and confounds anti‐amyloid therapeutic effects on trial endpoints. Our results support the use of more holistic, multimodal, data‐driven screening for clinical trials in Alzheimer’s disease to reduce cohort heterogeneity.
High anticholinergic burden in patients referred from primary care to a tertiary memory care.
Authors: Castilhos Raphael Machado , Formoso Carolina Rodrigues , Strelow Matheus Zschornack , Borelli Wyllians Vendramini , Chaves Marcia L Fagundes
Published: December 2022

Background

The anticholinergic burden (ACB) quantifies the cumulative anticholinergic drug exposure. Although a high ACB is associated with a greater risk of functional/cognitive decline, its usage is frequent in clinical practice. We aim to quantify the ACB and polypharmacy in referrals to a dementia tertiary outpatient clinic.

Method

A retrospective analysis was performed including medical records of referrals from primary care to the tertiary outpatient dementia clinic of the Hospital de Clínicas de Porto Alegre from 2014 to 2021. All medications were evaluated and ACB was measured with the Brazilian Anticholinergic Activity Drug (BAAD) score. It classified drugs according to its central anticholinergic activity from 1 to 3, with higher values indicating greater anticholinergic activity. BAAD score is the sum of anticholinergic activity of each drug, with scores above 3 meaning high ACB. Polypharmacy was defined as the use of > 3 drugs. A logist regression was performed using age, sex, dementia etiology, and Mini Mental State Examination (MMSE) as covariates.

Result

Among 398 referrals, 238 had a diagnosis of dementia: Alzheimer’s disease (AD) (34.4%), mixed type dementia (10.9%), vascular dementia (VD) (9.6%) and others (Frontotemporal, Lewy bodies, alcohol and others 26.9%). A total of 43 (18%) individuals had severe dementia, named unspecified dementia. Polypharmacy was frequent (277, 74.5%) and VD presented an increased number of medications when compared with other groups (7.2+‐3.1, p<0.002 for all). A third of patients with dementia were classified as high ACB (119, 32%), though dementia etiologies were not associated with BAAD (p = 0.13). In the regression analysis BAAD were associated with VD (OR 3.6, IC 95%: 1.34‐9.9) and other types of dementia (OR 2.4, IC 95%: 1.19‐5). BAAD had a significant correlation with Geriatric Depression Scale (GDS) (r = 0.23, p = 0.0002), but not MMSE (p = 0.07).

Conclusion

Most patients presented polypharmacy at arrival to a tertiary memory clinic, and a third presented a high ACB. VD was a predictor of ACB score, and they may be at a greater risk of cognitive and functional worsening.
Investigation of relationship between tau PET SUVR and an indicator of post‐translational modification of tau in human blood plasma using electrochemical assay
Authors: Yoon Hyosang , Kwon SunSang , Jeong Seongeun , Hwang Bo Song , Seo Sang Won , Lee Soo Hyun
Published: December 2022

Background

Human tau protein is a well‐known biomarker to predict and diagnose the progress of Alzheimer’s disease [1]. The tau protein undergoes various post‐translational modificiation (PTM) of tau such as phosphorylation, O‐glycosylation, nitration, and glycation. Recently, abnormal phosphorylation of tau protein is observed in AD patients, while the level of O‐GlcNAcylation on tau protein is relatively elevated in brains of normal controls [2]. Reference: [1] L.M. Ittner et al. Nature Reviews Neuroscience, 12 (2011) 67. [2] C. Alquezar et al. Frontiers in Neurology, 11 (2021) 595532:

Method

(Figure 1) To investigate tau protein in human blood plasma and its PTM, a novel type of electrochemical sensor demonstrated and obtained Taumeter, an indicator as relative impedance changes of phosphorylated tau and O‐glycosylated tau, using secondary antibodies Finally, the as‐obtained Taumeter and PET SUVR were investigated for a relationship.

Result

We investigated the clinical relationship between Taumeters for AT8 and AT270 and tau PET SUVR, respectively, obtained from human blood plasma from normal control (NC, n=9), mild cognitive impairment (MCI, n=14), and Alzheimer’s disease (AD, n=13). In the case of AT8, it was observed that average Taumeters in MCI and AD were 2.86 and 4.73 times higher than those in NC (p=0.078 between NC and AD) (Figure 2a). In the case of AT270, average Taumeters in MCI and AD were 1.84 and 4.24 times higher than those in NC (p=0.057 between NC and AD) (Figure 2b). In further study, Taumeters for AT8 and AT270 correlated with tau PET SUVR (r=0.151, p=0.384 and r=0.575, p<0.001) (Figure 2c‐d).

Conclusion

In this study, we investigated Taumeter reflecting PTM of tau proteins using secondary antibodies (O‐GlcNAc antibody, AT8, and AT270) in human blood and tau PET scan to investigate the relationship of Taumeter and tau PET SUVR in NC, MCI, and AD. As a result, it can be carefully implied that Taumeter has the relationship with the progress of AD.
A longitudinal study on quality of life along the spectrum of Alzheimer’s disease
Authors: Mank Arenda , Rijnhart Judith J.M. , van Maurik Ingrid S. , Jönsson Linus , Handels Ron , Bakker Els D. , Teunissen Charlotte E. , van Berckel Bart NM , van Harten Argonde C. , Berkhof Johannes , van der Flier Wiesje M.
Published: December 2022

Background

Quality of life (QoL) is an important outcome from the perspective of patients and their caregivers, in both dementia and pre‐dementia stages.1 Yet, little is known about the long‐term changes in QoL over time.2 We aimed to compare the trajectories of the QoL between amyloid‐positive and amyloid‐negative patients along the Alzheimer’s disease (AD) continuum of cognitively normal to dementia.

Method

In this longitudinal study, we included n = 447 (age 61.6±6.6, n(40%)F, Mini Mental State Examination (MMSE) 29(27‐29), 23% amyloid‐positive) patients with Subjective Cognitive Decline (SCD), n = 276 (age 64.6±7.0, n(33%F), MMSE 27(25‐28), 52% amyloid‐positive) patients with Mild Cognitive Impairment (MCI) and n = 417 (age 64.4±7.0, n(51%F), MMSE 23 (19‐25), all amyloid‐positive) with AD dementia from the Amsterdam Dementia Cohort. We used linear mixed‐effect models (LMM) to compare QoL trajectories of the European Quality of Life‐5 Dimensions (EQ‐5D‐3L and EQ‐5D‐5L) and Visual Analogue Scale (VAS) between 1) amyloid‐positive and amyloid‐negative SCD or MCI patients and 2) amyloid‐positive SCD, MCI, and dementia patients. The models were adjusted for age, sex, Charlson Comorbidity Index (CCI), education and EQ‐5D scale (3 or 5 level).

Result

In SCD, amyloid‐positive participants had a higher VAS at baseline, but showed a steeper decline over time in EQ‐5D and VAS than amyloid‐negative participants (figure 1). Also in MCI, amyloid‐positive patients had higher QoL at baseline, but subsequently showed a steeper decline in QoL over time compared to amyloid‐negative patients. When we compared amyloid‐positive patients along the Alzheimer continuum, we found no difference between SCD, MCI or dementia in baseline QoL, but QoL decreased at a faster rate in the dementia stage compared with the pre‐dementia stages of SCD and MCI (figure 2). When we additionally adjusted for covariates in model 2, the effects remained.

Conclusion

QoL decreased at a faster rate over time in amyloid‐positive SCD or MCI patients than amyloid‐negative patients. QoL decreases over time along the entire continuum of AD of SCD, MCI and dementia, with the strongest decrease in dementia patients.
Higher dietary intake of advanced glycation end products is associated with faster cognitive decline in community dwelling older adults
Authors: Beeri Michal Schnaider , Lotan Roni , Uribarri Jaime , Leurgans Sue E. , Bennett David A , Buchman Aron S
Published: December 2022

Background

Dietary‐derived advanced glycation end products (AGEs) may contribute to chronic diseases. The goal of this study was to investigate the associations of dietary AGEs (dAGEs) with cognitive decline in older adults.

Method

Non‐demented older adults (N = 684) underwent annual testing with 19 cognitive tests summarized as a global cognitive score based on five cognitive domains. We modified a previously validated food frequency questionnaire designed to assess dAGE. The modified questionnaire assessed portion size and frequency of consumption of six food groups (meat, poultry, fish, cheese, spreads and processed foods), as well as the method of their preparation (e.g. grilling, boiling). dAGE was the sum of the scores of the six food groups. Linear mixed‐effect models were used to examine the association of baseline dAGE with cognitive decline. All models controlled for age, sex, education, race and BMI.

Result

Average follow‐up was 3.0 years. Higher baseline dAGEs was associated with a faster rate of global cognitive decline (Estimate = ‐0.003 (standard error = 0.001, p‐value = 0.015). This association was driven by declines in the episodic memory (‐0.004 (0.002, 0.013) and perceptual speed (‐0.003 (0.001, 0.049) but not by semantic memory, working memory and visuospatial domains. These associations were not attenuated by controlling for cardiovascular risk factors and diseases, including diabetes. Levels of dAGE of the specific food groups were not associated with cognitive decline.

Conclusion

Higher levels of dietary AGE levels in older adults are associated with faster cognitive decline. These data lend further support for the importance of diet and that its modification may slow or prevent late‐life cognitive impairment. Further clinical studies will be needed and the molecular mechanisms underlying these associations will need to be identified.
Changes in modifiable risk factors for Alzheimer´s disease and dementia during the COVID‐19 pandemic in Swedish older adults: a population‐based digital survey
Authors: Rocha Ana Sabsil Lopez , Mangialasche Francesca , Thunborg Charlotta , Levak Nicholas , Aspö Malin , Rydström Anders , Lehtisalo Jenni , de Jager Celeste A , Price Geraint J , Hall Anette , Solomon Alina , Ngandu Tiia , Kivipelto Miia
Published: December 2022

Background

Older adults have a higher risk of Alzheimer´s disease (AD) and dementia. In terms of morbidity and mortality, they also represent the group most severely affected by the SARS‐CoV‐2 (COVID‐19) pandemic. Since February 2020, the Swedish government recommended different general measures limiting mobility and social contact, to contain the spread of infection. Pandemic‐related changes in lifestyle and access to healthcare could have a negative impact on modifiable factors for AD and dementia.

Methods

A digital survey was distributed to the general population (multiple distribution channels, voluntary participation) during the last waves of the COVID‐19 pandemic in Sweden (May/2021 – December/2021). Participants were people aged 60+ years, free of dementia, and living in Sweden. The survey aimed to measure changes in lifestyle (e.g., diet, physical activity), care of vascular/metabolic risk factors (e.g., diabetes, hypertension), as well as psychosocial factors (e.g., depressive symptoms, sleep quality, social isolation) relevant for AD and dementia. The survey is part of the World‐Wide‐FINGERS‐SARS‐CoV‐2 initiative.

Results

6,918 participants completed the survey, mean age was 67.9 (5.11 SD), 58% were female, 71.6% were from urban areas. Preliminary results showed that, during the pandemic, 27% of participants decreased their physical activity, 26.3% increased intake of unhealthy snacks, 25.7% experienced increased sleep problems. Also, 58.7% had less contact with family, 40.4% experienced loneliness, 24.7% experienced worsening of memory, and 26.8% rated their health worse than before the pandemic. On the other hand, the reported increase in consumption of vegetables and fruits was 14.1% and 15.7%, respectively, and 65.2% of people had increased the use of digital services to keep in contact with family and friends. Also, 2.6% of participants decreased smoking, and 11.2% reduced their alcohol consumption. The occurrence of chronic vascular and metabolic diseases and related disruption in access to healthcare is presented in Table 1.

Conclusion

The COVID‐19 pandemic has had an effect on modifiable factors for AD and dementia in Swedish older adults. These changes can affect future AD/dementia occurrence and should be addressed in forthcoming interventions for AD/dementia risk reduction and prevention. The survey can also be used for pre‐screening participants for prevention trials.
LatAm Fingers Initiative: Challenges and opportunities of launching a multicultural trial in pandemic times
Authors: Calandri Ismael Luis , Crivelli Lucia , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Ortiz Ana Luisa Sosa , Suemoto Claudia Kimie , Salinas‐Contreras Rosa Maria , Velilla Lina M , Yassuda Monica Sanches , Sevlever Gustavo , Allegri Ricardo Francisco , Initiative LatAm FINGERS
Published: December 2022

Background

The Latin American FINGERS initiative gathers 12 countries, including Spanish and Portuguese‐speaking populations. We aim to describe challenges and opportunities related to launching a multi‐country trial during the Covid‐19 pandemic. Identified challenges included. a) To train personnel from the different teams in trial procedures b) To assess the training results c) To provide support regarding the trial set‐up on the different sites.

Method

The challenges were approached with multiple online networking strategies. a) Training was provided online in workgroup meetings led by specialists from the different interventions. Furthermore, because our project includes English, Spanish and Portuguese speakers, the training sessions were recorded, and subtitles in the alternate language were provided. b) To assess training, a web‐based campus with educational sessions and questionnaires with different educational paths for each role in the intervention was set up. Additionally, we created different certifications, and a medal system to reward the training completion was included. c) Two innovative platforms provided support. We created a WhatsApp Chatbot to assist investigators 24/7, automatically answering questions, sending resources required for visits, and reporting difficulties. The Chatbot includes a database system to register adverse events reports and report them immediately to the clinical core. Finally, a LatAm FINGERS Consulting Room was built to provide weekly online sessions led by the executive committee. Members can connect without a prior appointment and discuss any questions.

Result

Hitherto, 16 in‐vivo online sessions were provided to 203 trainees, 15 multilingual videos summarizing essential aspects of intervention, and six tutorials solving frequent problems were uploaded in the web‐based campus with multiple language subtitles. A total of 93 participants received certification for the trial. 9 meetings have been carried out so far regarding the Consulting Room, and more than 30 conflicts have been solved. Chatbot has answered a mean of 12 daily questions since its implementation.

Conclusion

We present successful tools to implement an intervention in multicultural centers separate by more than 10000 km and 5 time zones where travel was banned. Finally, this trial also brought up the opportunity to increase the spirit of the scientific community and strengthen the network ties.
Maintain Your Brain: a 3‐year online randomized controlled trial to reduce cognitive decline in 55‐77 year olds
Authors: Brodaty Henry , Heffernan Megan , Singh Maria A. Fiatarone , Valenzuela Michael , Lautenschlager Nicola T , Anstey Kaarin J. , Sachdev Perminder S. , Jorm Louisa , McNeil John , Maeder Anthony , Ginige Jeewani Anupama , Chau Tiffany , Jose Juan Carlo San , Millard Michael , Welberry Heidi ,   Maintain Your Brain Research Group
Published: December 2022

Background

Technology and web‐based approaches potentially provide scalable population‐based interventions to reduce modifiable risk factors for dementia such as physical inactivity, suboptimal nutrition and low cognitive activity. Our aim was to reduce cognitive decline with ageing using an online package of interventions delivered intensively for 12 months followed by monthly boosters for 24 months. The trial was completed in November 2021.

Method

Invitations were sent to people aged 55‐77 years from the 45 and Up study, a population‐based cohort study of one in ten people aged 45 years and older in New South Wales, Australia (n = 267,000). Participants were required to be eligible for at least two of four modules. The modules addressed physical inactivity and health risks associated with inactivity (Physical Activity), adherence to a Mediterranean‐type diet and health risks associated with poor nutrition (Nutrition), cognitive activity (Brain Training) and mental well‐being (Peace of Mind). All participants received modules based on their risks, with randomized allocation to active personalised coaching modules (intervention) or static information‐based modules (control). The primary outcome was change in an online combined multi‐domain cognitive score measured using COGSTATE and Cambridge Brain Sciences tests. Secondary outcomes included ANU‐ADRI risk score, specific cognitive domain scores and diagnoses of dementia.

Result

From 96,418 invitations, 14,064 (14%) consented; 12,281 (13%) were eligible. Of these, 6,236 (6%) completed all 10 baseline assessments and were enrolled in the trial. Nearly 70% or 4,365 participants provided follow‐up data. At final 36‐months’ follow‐up, 3,482 (55.8%) completed the primary outcome and 2594 (41.6%) had returned informant‐rated Amsterdam‐Instrumental Activities of Daily Living Scale questionnaires.

Conclusion

Online strategies to prevent cognitive decline in 55‐77 year olds are feasible and appear acceptable for more than half of participants. Analysis of group*time effects will be presented.
The effects of locus coeruleus stimulation on the BOLD global signal in TgF344‐AD rats
Authors: Anumba Nmachi , Kelberman Michael , Smith Corrie , Pan Wen Ju , Clavijo Perrin G , Marriott Alexia , Kim Ellen , Weinshenker David , Keilholz Shella
Published: December 2022

Background

Functional connectivity of the brain as measured by the blood oxygen level dependent (BOLD) signal in fMRI is altered during Alzheimer’s disease (AD) progression. Common practice during preprocessing of fMRI data is removal of the global signal, defined as the averaged brain signal, by regression, removing major sources of noise while risking loss of neural activity. The locus coeruleus (LC), one of the first brain regions to accumulate hyperphosphorylated tau, contributes to brainwide neuromodulatory regulation. Therefore, we combined optogenetics and fMRI to study how LC activity affects the global signal in the TgF344‐AD rat model of AD, which overexpresses mutant human amyloid precursor protein and presenilin‐1.

Methods

At 2 months of age, TgF344‐AD rats and WT littermates received intra‐LC infusions of a ChR2‐mCherry virus under the noradrenergic specific PRSx8 promoter. 2‐4 weeks prior to fMRI, rats were implanted with an optic ferrule targeting the LC. Functional ChR2 expression and LC activation were confirmed by pupil dilation following optogenetic LC stimulation. At ∼6 months of age, rats underwent 10‐minute fMRI scans at baseline and during 2 Hz optogenetic stimulation. During scanning, rats were anesthetized with 1.3% isoflurane, intubated, and administered pancuronium (1.5 mg/kg*hr, s.c.). fMRI scans were gradient echo EPI (TR = 1.25 s) and obtained using a 9.4T Bruker Animal MRI scanner. Data were preprocessed using a customized pipeline. The voxel‐wise analysis was performed by correlating each voxel timecourse with the global signal via Pearson’s linear correlation.

Results

In general, there were levels of slightly higher correlation to the global signal in the anterior medial region of the brain and bilaterally in the posterior region of the brain (Figure 1). The highest levels of correlation to the global signal were observed in the WT rats at baseline, but differences between groups were negligible.

Conclusion

Neither genotype nor optogenetic simulation profoundly affected global signal. These negative results may be explained by (1) the lack of profound forebrain AD‐like neuropathology in 6‐month TgF344‐AD rats, and (2) the 2 Hz optogenetic stimulation being insufficient to drive changes in global signal above the 1‐2 Hz baseline activity of LC neurons.
Differences in the measurement of cognition for the assessment of dementia across geographic contexts: Recommendations for cross‐national research
Authors: Nichols Emma , Deal Jennifer A , Langa Kenneth M , Ng Derek , Gross Alden L
Published: December 2022

Background

Although 71% of individuals with dementia are projected to live and low‐ and middle‐income countries by 2050, most dementia research to‐date has been conducted in high‐income countries. Cross‐national studies are needed to understand how the causes and consequences of dementia may differ by country. However, factors such as urbanicity, language of administration or race/ethnicity, which vary across countries, affect the measurement of cognition. A better understanding of which cognitive items perform well across countries or within specific countries will allow researchers to optimize dementia measurement in future cross‐national and international studies.

Method

We used data from the Harmonized Cognitive Assessment Protocol surveys in the US, Mexico, India, England, and South Africa (combined N = 11,364). To define cognitive impairment consistently across countries, we compared participants’ cognitive performance with robust neuropsychological norms within each country. For each HCAP country, we assessed item performance by estimating associations between each cognitive item and cognitive impairment using logistic regression models, controlling for age and gender. We avoided circularity in the analysis by using an iterative quasi‐leave‐one‐out approach. We compared patterns of associations across countries using median odds ratios, and visually, using heatmaps.

Result

The associations between cognitive items and cognitive impairment were stronger in the US (Median Odds Ratio [OR] = 0.17) and England (Median OR = 0.19), in comparison to South Africa (Median OR = 0.23), India (Median OR = 0.29), and Mexico (Median OR = 0.28). Memory items, notably delayed recall tasks, had the most consistent associations of the largest magnitudes across countries. In comparison, there was variability in performance between settings for many language items (e.g. naming a hammer). Items requiring numeracy, including the Trail‐making test, did not perform well in countries with low educational attainment.

Conclusion

The performance of cognitive items for the classification of cognitive impairment was not consistent across countries. Although items performing well in a single country could be used to improve measurement precision in specific settings, transporting items between countries without prior validation warrants caution. However, we did identify items that performed well across a range of countries (i.e. delayed recall, animal naming); these items may be of particular utility in future cross‐national research.
The SYNERGIC Trial: A Randomized Controlled Trial Assessing Multimodal Interventions to Improve Cognition in Mild Cognitive Impairment in Older Adults
Authors: Montero‐Odasso Manuel , Almeida Quincy J , Burhan Amer M. , Camicioli Richard , Li Karen , Liu‐Ambrose Teresa , Middleton Laura E , Doyon Julien , Fraser Sarah , Hunter Susan W , McIlroy Bill , Morais José A , Pieruccini‐Faria Frederico , Shoemaker Kevin , Speechley Mark R. , Vasudev Akshya , Zou G Y , Berryman Nicolas , Lussier Maxime , Vanderhaeghe Leanne , Bherer Louis
Published: December 2022

Background

Older adults with Mild Cognitive Impairment (MCI) have increased risk of dementia. Physical exercise, cognitive training, and vitamin D supplementation are emerging interventions for improving cognition. However, the potential synergism of combining them to improve cognition in MCI has not been yet tested.

Methods

The SYNERGIC trial (SYNnchronizing Exercises, Remedies in Gait and Cognition)— a multi‐site, double‐blinded, controlled, quasi‐factorial trial—assessed the efficacy and synergistic effect of combining bi‐modal exercises (aerobic + progressive resistance training = E), cognitive training (CT) and, vitamin D supplementation (D = 10000IU 3xweekly) to improve cognition in MCI. Personalized interventions were delivered for 20 weeks in 5 arms: Arm 1 received 3 active interventions (E+CT+D), Arm 2 received E+CT+placebo D, Arm 3 received E+ sham CT+ D, Arm 4 received E+ sham CT and placebo D, and Arm 5 received all control interventions (Control E‐balance and toning‐, sham CT and placebo D). Change in ADAS‐Cog‐13 was the primary outcome assessed with linear mixed effects models adjusting for age, sex, education, and number of comorbidities.

Results

170 MCI participants were randomized. As compared to the control group (Arm 5), multimodal intervention (Arm 1) had significant improvements in ADAS‐Cog‐13 scores (difference = ‐2.3 ADAS‐Cog‐13 points; 95% CI: ‐1.06 ‐3.54). Following analyses guidelines for factorial trials, interactions of intervention across arms were analyzed and no significant interactions were found for vitamin D supplementation. Therefore, we collapsed Arms 1 and 2 (combined E + CT), and we collapsed Arms 3 and 4 (E), and compared them to Arm 5 (control). Relative to the control group (Arm 5), the combined exercise and cognitive intervention (Arms 1+2) had significantly improved cognitive function (difference = ‐2.2 ADAS‐Cog‐13 points; 95% CI: ‐0.70, ‐3.72). In contrast, the exercise only intervention (Arms 3+4) did not have significantly improved cognition as compared to the control group (difference = ‐1.24 ADAS‐Cog‐13 points; 95% CI: ‐0.21, 2.69).

Conclusion

A synergistic effect of combined bi‐modal exercise with sequential computerized cognitive training was found to improve cognition in older adults with MCI with a large effect size = 0.62. Addition of vitamin D supplementation did not improve the effect.
Pandemic‐Related Stress, Coping, and Wellbeing in an International and Multi‐Ethnic Cohort of Older Adults
Authors: Medina Luis D , Franco Idalid , Thumala Daniela , Miranda‐Castillo Claudia , Acosta Daisy M , Aguero Cinthya , Aguilar‐Navarro Sara Gloria , Baena Ana Y. , Brucki Sonia , Bustin Julian , Duque Lissette , Velazquez Ivonne Z. Jimenez , Marquine Maria J. , Slachevsky Andrea , Soto‐Añari Marcio , Quiroz Yakeel T.
Published: December 2022

Background

The COVID‐19 pandemic has impacted the wellbeing of older adults. Pandemic‐related stress has implications on cognitive status, including decline due to Alzheimer’s disease and related dementias. Yet, evidence suggests that COVID‐19 has impacted culturally and linguistically diverse communities differently. We sought to examine the role of COVID‐19 on coping and wellbeing in an international, multi‐ethnic sample of older adults.

Method

Data from 955 older adults (age = 66.7±7.9 years; education = 15.2±5.9 years; 71% female; 41% Hispanic/Latino) were pulled from a larger, international sample examining the response of older adults to COVID‐19. All participants completed demographic questionnaires, measures of psychological distress, the Brief‐COPE – a 28‐item self‐report questionnaire used to measure respondent’s efforts to minimize distress from a stressful life event – and the Epidemic‐Pandemic Impacts Inventory (EPII) – a 92‐item inventory of pandemic related experiences across several life domains. Using linear regression, we examined relationships between Brief‐COPE scores, ethnicity, and select EPII items controlling for several covariates (age, sex, education, marital status, number of children, employment status, household income, and history of COVID‐19 symptoms) in all analyses.

Result

Hispanic/Latino (H/L) ethnicity was associated with slightly higher scores on the approach‐focused coping subscale compared to the non‐Hispanic White (NHW) group (Approach: 27.3±6.6 vs 26.1±6.1; B = 1.205, p = 0.015, CI: 0.238, 2.172). There was no effect of ethnicity on Brief‐COPE Total or Avoidance subscale scores (both ps>0.050). Notably, review of covariates suggested increased age was associated with lower scores on Approach (B = ‐0.065, p = 0.041, CI: ‐0.128, ‐0.003), Avoidance (B = ‐0.054, p = 0.034, CI: ‐0.104, ‐0.004), and Total scores (B = ‐0.136, p = 0.028, CI: ‐0.257, ‐0.015). Higher Approach scores were associated with greater endorsement of Positive Life Changes in both ethnic groups (NHW: partial r = 0.298, p<0.001; H/L: partial r = 0.249, p<0.036), but with endorsement of Mental Health Problems in NHWs only (NHW: partial r = 0.144; p = 0.001; H/L: partial r = ‐0.019, p>0.050).

Conclusion

Findings suggest cross‐cultural differences in the stress coping response of older adults during the pandemic, even after controlling for symptomatic history and other relevant covariates. Moreover, coping may be differentially related to positive and negative outcomes across cultural groups. These results support the need to consider cultural background when considering coping and wellbeing in older adults.
The Functional Role of Amyloid Precursor Protein at Mitochondria
Authors: Strope Taylor A. , Troutwine Benjamin R , Lysaker Colton R , Wilkins Heather M
Published: December 2022

Background

Aβ is generated from amyloid precursor protein (APP) via sequential proteolytic processing. While APP processing and its localization are well understood, the functional role of APP is largely unknown. APP is expressed almost ubiquitously but is concentrated in neuronal synapses and localizes to mitochondria. The functional consequence of mitochondrial APP localization is not well understood. We leveraged a mutant APP construct which does not localize to mitochondria to interrogate the functional role of APP at mitochondria.

Methods

We used a mutant form of APP (3M APP) which harbors mutations at amino acids +41, +44, and +52 (His to Asp). SH‐SY5Y cells were transfected for 24‐48 hours with either WT or 3M APP plasmids. Following transfection, mitochondrial function was analyzed using Seahorse Technology or Vmax spectrophotometric assays of electron transport chain (ETC) function. Mitophagy was examined by qPCR against mitochondrial DNA content. A co‐localization assay using an adenovirus expressing EGFP‐Cox8 was used as a separate measure of mitophagy. To activate mitophagy, cells were either treated with deferiprone (DFP), starvation (glucose and amino acid deprivation), or PINK1 was overexpression. Mitochondrial biogenesis and turnover were measured using an adenoviral vector (MitoTimer). We further assessed the ability of APP to interact with known mitophagy proteins using immunoprecipitation.

Results

Compared to WT APP, cells expressing 3M APP showed a decrease in mitochondrial localization as expected. 3M APP led to a significant decrease in complex II and IV flux of the ETC with decreased in complex IV Vmax. 3M APP showed significantly lower mitochondrial mass and biogenesis. Finally, 3M APP expressing cells appeared to have reduced mitophagy when compared to WT APP. We further found that APP interacts with PINK1 and p62 under conditions of enhanced mitophagy.

Conclusions

APP localization to mitochondria alters ETC function, mitochondrial mass, and mitophagy. Further studies are in progress to elucidate the mechanisms of APP localization at mitochondria, bioenergetic changes, and mitophagy.
Feasibility of a 3‐Dimensional Exergame to Promote Integrated Cognitive and Physical Activity in Aging Adults
Authors: Carlson Michelle C , Moored Kyle D. , Crane Breanna M , Ahmad Ohmar , Chan Thomas , Krakauer John
Published: December 2022

Background

Evidence suggests that bi‐directional associations exist between cognition and mobility that magnify with increasing age. Both cognition and mobility are important to maintaining independent function in daily life. These and other findings suggest that cognition and mobility may share common neural substrates that can be trained simultaneously through real‐world simulations that safely promote navigation through complex virtual environments. However, few interventions explicitly train on cognition and mobility simultaneously. We optimized an immersive, 3‐Dimensional (3‐D) exergame to simultaneously train cognitive and motor functions in a community‐based setting for older adults.

Method

We recruited 16 older adults from an independent living community, with varying levels of physical function. Participants completed one‐hour sessions three times each week for five weeks for a total of 15 sessions. The customized game provides an immersive virtual oceanic environment in which the participants control a simulated dolphin (“Bandit”) that responds to the participant’s desired direction in 3‐D space and amid other oceanic fish, including sharks, orcas and small pods of fish. Participants used their dominant hand, tracked by motion sensors, to navigate this world to help “Bandit” eat fish, avoid being bitten by sharks, and jump out of the water. Players advanced in levels after mastering the preceding level. After completing all 110 game levels, participants switched to their non‐dominant hand to remaster all levels of the exergame again.Before and after the program, participants completed tests of memory, executive function, and speed of processing.

Result

All participants successfully completed the intervention, with the exception of one participant, with a vestibular disorder. In adjusted models (age, sex, education), post‐intervention improvement in processing speed was marginally significant (p = 0.06). No other cognitive improvements were found.

Conclusion

Our feasibility study demonstrated that we can effectively use this innovative exergame platform as a clinic‐ or community‐ based tool for individuals to safely practice and promote integrated skills related to complex, real‐world navigation.
Natural Killer Cells Improve Cognitive Function and Support to Induce Amyloid Beta Clearance by Functional Recovery of Impaired Microglia in Natural Killer Cell‐treated Alzheimer’s Diseases Mouse Model
Authors: Hwang Do Won , Sohn Dae‐Hee , Ki Young Wook , Kim Shin‐Il , Choi Yoori , Ko Min Kyung , Lee Sung Chang
Published: December 2022

Background

Dysfunction of microglia that plays a pivotal role in amyloid beta clearance is recognized to be involved in pathological progression of the Alzheimer’s diseases. Natural killer (NK) cells participate in homeostatic immune‐modulation and immune‐surveillance by secreting immune‐boosting signaling molecules. These molecules can serve as cell‐based therapeutics for AD. In this study, we found that the activated NK cells eliminated Aβ plaques, resulting in a marked improvement in behavior in mice with AD. This improvement may be associated with the recovery in microglial function due to the upregulation of phagocytic activity and autophagy genes.

Method

NK cells were isolated, using a negative selection process, from the spleens of BALB/c mice and subsequently expanded to 1×108 cells.

Result

The cultured NK cells were intravenously administered into APP/PS1 mutant mice. There was dramatic reduction of Aβ deposition in the cortex and dentate gyrus areas of the brain in these mice following the NK cell treatment. While phosphate‐buffered saline APP/PS1 control mice exhibited learning deficits in the escape platform, the NK cell‐treated mice showed reduced escape latency in the Morris water maze test. Mouse microglia, in the AD model, were isolated using CD11b positive magnetic activated cell sorting method. RNA sequencing was performed using total RNA isolated from mouse brain hippocampus tissue, to explore differential gene expression levels. Hierarchical cluster heat maps revealed the recovered gene populations in the NK‐treated microglial group. The percentage of genes upregulated in the total gene ontology groups were significantly altered in NK treated/sham ratio group (i.e., 171 upregulated immune response‐related genes). The homeostatic and disease‐associated microglia (DAM)‐related genes that were increased in microglia isolated from APP/PS1 mouse brain were downregulated after NK treatment. KEGG pathway analysis projected the autophagy signaling pathways as critical pathways associated with amyloid beta clearance. Our analysis showed that treatment of mice with NK cells recovered gene signatures involved in phagocytic activity.

Conclusion

These findings show that NK cells, which are known to have low in vivo toxicity, could be a potential therapeutic option for AD that could be rapidly translated to the clinic.