bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary nitrate intake and the risk of dementia: a population‐based study
Authors: de Crom Tosca O.E. , Vernooij Meike W , Ikram M. Kamran , Voortman Trudy , Ikram M. Arfan , Blekkenhorst Lauren
Published: December 2023

Background

Nitric oxide is a free radical that can be produced from dietary nitrate and positively affect cardiovascular health. With cardiovascular health playing an important role in the etiology of dementia, we hypothesized a link between dietary nitrate intake and the risk of dementia. We therefore aimed to evaluate the association of total, vegetable and non‐vegetable dietary nitrate intake with the risk of dementia and to explore underlying mechanisms involving imaging markers of vascular brain health, i.e. cerebral perfusion, total brain volume, white matter hyperintensity volume, microbleeds, and lacunar infarcts.

Method

Dietary nitrate intake was assessed using food frequency questionnaires in 9,543 dementia‐free participants (mean age 64 years, 58% women) from the prospective population‐based Rotterdam Study. All participants were followed for the incidence of dementia, and 3,949 of the participants underwent a magnetic resonance imaging scan of the brain during a maximum of three consecutive examination rounds (average interval between scans 4.6 years). We used Cox models to determine the association between dietary nitrate intake and incident dementia. We further used linear mixed models and logistic regression models to assess the association of dietary nitrate intake with changes in imaging markers over time.

Result

Participants consumed on average 102.9 (standard deviation: 66.7) grams of dietary nitrate per day, which came on average for 81% from vegetable sources. During a mean follow‐up of 14.5 years, 1,472 participants developed dementia among whom 1,078 had Alzheimer’s disease. A higher intake of total and vegetable dietary nitrate intake was associated with a lower risk of dementia (hazard ratio (HR) [95% confidence interval (CI)] per 50 mg/day increase: 0.92 [0.87‐0.98] and 0.92 [0.86‐0.97], respectively), but no association between non‐vegetable dietary nitrate intake and the risk of dementia was observed (HR [95% CI]: 1.15 [0.64‐2.07]). Results were similar for Alzheimer’s disease. Dietary nitrate intake was also not associated with brain imaging markers.

Conclusion

A higher dietary nitrate intake from vegetable sources is associated with a lower risk of dementia. We found no evidence that this association was driven vascular brain health.
Blood‐brain barrier permeability measured with arterial spin labeling as potential cerebrovascular biomarker over the lifespan
Authors: Padrela Beatriz E. , Tee Mervin , Markus Sneve H , Geier Oliver , Mahroo Amnah , Grydeland Håkon , Fladby Tormod , Eickel Klaus , Günther Matthias , Barkhof Frederik , Hilal Saima , Mutsaerts Henk‐Jan , Petr Jan
Published: December 2023

Background

Blood‐brain barrier (BBB) dysfunction is considered a hallmark of Alzheimer’s disease (AD), making non‐invasive imaging of BBB with arterial spin labeling (ASL) MRI a potential imaging biomarker (BBB‐ASL). However, the normal BBB development over the lifespan is unknown. Here, we created population‐based BBB‐ASL permeability reference maps, and aimed to investigate associations between BBB‐ASL, chronological age, and biological cerebrovascular age – expressed as white matter hyperintensities (WMH) volume.

Method

Cognitively‐unimpaired (CU) participants were included from Center for Lifespan Changes in Brain and Cognition (LCBC) (n = 28, age 58.9±16.1y) and University of Singapore (n = 30, age 55.8±6.1y). The Singapore cohort is known to be vascularly compromised and thus expected to have early cerebrovascular pathology in the form of WMH. Multi‐echo, multi‐post‐labeling‐delay pseudo‐continuous ASL images were acquired at two identical Siemens 3T scanners and analyzed with ExploreASL. Gray matter (GM) BBB water time‐of‐exchange (Tex) was quantified with and without partial‐volume correction (PVC). For Singapore data, WMH were segmented on 3D FLAIR. Linear regression models were used to investigate associations of Tex with age and WMH volume, with and without covarying for sex and site.

Result

Both site population‐averages (Figure 1) show similar Tex patterns, with slightly higher posterior variability in the Singapore data. GM Tex was negatively associated with age (Figure 2A) irrespective of PVC, and after covarying for sex and site (Table 1). GM Tex was also negatively associated with WMH volume (β = ‐0.005, p = 0.012), although the association became non‐significant if both PVC and sex and site corrections were applied (β = ‐0.005, p = 0.068).

Conclusion

Our findings support the hypothesis of increased BBB permeability with aging and there are signs of association with increased cerebrovascular age assessed with WMH volume. We aim to further increase our sample size and also investigate associations with other AD biomarkers.
Using real‐world general practitioner data to study the diagnosis and management of dementia: rationale and design
Authors: Baak Brenda N. , Swart Karin M.A. , van Maurik Ingrid S. , Nooralishahi Mahsa , van der Flier Wiesje M. , Herings Ron M.C.
Published: December 2023

Background

General practitioners (GPs) play a critical role in the early recognition of cognitive deficits and management of dementia. Timely diagnosis is important in light of potential disease‐modifying therapies and the potential to improve patient outcomes. We aimed to establish a real‐world data cohort utilizing data from GPs on individuals with dementia as a starting point, with the goal of gaining valuable insights into trajectories and management of dementia and patient outcomes. Here we describe the rationale and design.

Method

We selected individuals with dementia using Dutch GP data from the PHARMO Data Network, which includes diagnoses, symptoms, examinations, prescriptions, and communication between GPs and specialists. Diagnosis of dementia was defined as a diagnosis code or prescription of anti‐dementia drugs between January 1, 2011 and December 31, 2020. Persons were included if they had one year of history prior to dementia diagnosis. We described the cohort in terms of demographics and screening tests for cognitive impairment.

Result

A total of 52,911 individuals with dementia were selected from a source population of 4.7 million persons. The mean age was 81 years (standard deviation [SD] = 8.65) and 31,343 (59%) were female (Table 1). On average, patients have 8.6 years (SD = 4.09) of data available prior to dementia diagnosis and can be followed‐up for 2.8 years (SD = 2.19) after diagnosis. The reason for end of follow‐up was death for 16,978 persons (32%), end of data availability for 21,314 persons (40%), and 14,699 (28%) reached December 31, 2020 and are still registered (i.e., active). We found the Mini‐Mental State Examination (MMSE) in GP records of 31,759 persons (60%), and the Montreal Cognitive Assessment (MoCA) and Rowland Universal Dementia Assessment Scale (RUDAS) for only 1,777 (3%), and 29 persons (<0.5%), respectively.

Conclusion

We created a cohort of 52,991 individuals with dementia, providing a starting point for further research on trajectories and management of AD in primary care and patient outcomes. Next steps include matching the cohort with dementia‐free controls, enriching the cohort by established linkages to other data sources (e.g. hospital data), and examining healthcare resource utilization, indicators of cognitive decline, treatment, and young‐onset dementia.
Where is my hand? Proprioceptive disturbances in posterior cortical atrophy and typical Alzheimer’s disease
Authors: Yong Keir X X , Bancroft Matthew J , Bai Yuhan , Hayes Oliver S , Mahendran Sharveena , Ocal Dilek , Brotherhood Emilie V , Hoe Juanita , Kaski Diego , Pisella Laure , Crutch Sebastian J , Day Brian L
Published: December 2023

Background

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome most commonly caused by Alzheimer’s disease (AD) pathology. PCA is often considered the canonical ‘visual dementia’, characterised by the progressive loss of visual and posterior cortical functions corresponding to parieto‐occipital and occipito‐temporal atrophy. However, patient reports of difficulties finding sleeves of clothes, transferring between postures and determining heading direction imply non‐visual disturbances, consistent with the multisensory role of the posterior parietal cortex. Such reports raise questions regarding AD clinical heterogeneity, representing a substantial challenge to patients' independence and management of PCA and typical AD (tAD).

Method

Patient (total n = 39; PCA n = 23; tAD n = 16) and control (n = 19) participants repeatedly reached to a proprioceptive target (their non‐dominant thumb) (Fig.A) with and without vision and tactile feedback (n = 40 trials per participant). The target was positioned passively behind a screen apparatus at five positions using an adjustable foam handrest. The primary outcome measure was absolute (medio‐lateral) error determined using whole‐body motion capture data (Fig.B).

Result

Absolute error was greater without than with vision across groups. However, the effect of removing vision on absolute error was smallest in the control group (estimated mean error with vision [95%CI]: 15mm [6,25]; without vision: 23mm [14,32]), greatest in PCA (with vision: 39mm [30,49]; without vision: 76mm [67,86]) and intermediate in the tAD group (with vision: 26mm [16,37]; without vision: 49mm [39,60]) (vision‐by‐group interaction: p<.001; Fig.C). For ∼5% of trials, absolute error exceeded 200mm in PCA and 120mm in tAD participants (Fig.B; control range: 0.01‐80mm). There was no evidence of an effect of tactile feedback in any group.

The effect of target location differed between groups (location‐by‐group interaction: p<.001). Patient reaching errors were particularly apparent under postures where the target arm crossed the body midline (e.g. left arm in right hemispace); this effect was notably evident in the PCA group even with available vision (Fig.C).

Conclusion

Findings emphasise disturbed spatial awareness in PCA and tAD in the absence of vision, consistent with diminished body position sense‐ proprioception ‐ which may be mediated centrally through posterior parietal vulnerability. Findings suggest implications for assessment and management of disabling dressing, mobility, navigation and balance difficulties.
The Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA): Harmonised Cognitive Assessment Protocol (HCAP) dress rehearsal review.
Authors: McAlinden Michael , Neville Charlotte , O'Hara Leeanne , Marr Calum , Langa Kenneth M , Ryan Lindsay H , Weir David R , McGuinness Bernadette
Published: December 2023

Background

NICOLA, the largest public health cohort study of ageing in Northern Ireland, commenced in 2013 with a representative sample of ∼8500 individuals aged 50 years and over living across Northern Ireland.

HCAP is a National Institute on Ageing (NIA) funded sub‐study designed to assess prevalence of cognitive impairment and dementia in a sample of 1000 participants aged 65 years and older.

A dress rehearsal was carried out prior to the main study to implement the study as per the HCAP study protocol. This, ensured any issues could be identified prior to the main phase and the Standard Operating Procedures (SOP) could be amended accordingly.

Method

14 participant interviews and 14 informant interviews were completed between December 2021 and January 2022.

The HCAP dress rehearsal sample was selected from the NICOLA research advisory panel, which included NICOLA participants and individuals from the charity group AgeNI.

The study consisted of a face‐to‐face participant interview, comprising nineteen different measures of memory and thinking.

During the informant interview a family member or friend was asked about participant’s ability to perform daily tasks and their social and cognitive activities.

During the HCAP dress rehearsal, fieldwork staff conducted home visits in pairs: one conducting the interview while the other observed. Staff completed feedback forms which provided opportunities to comment on the use of computer software, consent processes and the administration of memory and thinking assessments.

Result

Several areas for improvement were highlighted:

Pre‐Visit Documentation: Fieldwork staff reflected on the complexities of test administration and the transition between computer and paper assessments. Pre‐visit protocols were revised to include preparation processes.

Test Administration: Queries were raised on the logistics of test administration and scoring. These were resolved through contact with the Health and Retirement Study (HRS) team.

Study Administration Processes: Additional administration databases were created and SOPs amended to ease the flow of recruitment and home visit bookings.

Conclusion

The HCAP dress rehearsal highlighted the importance of pre‐visit preparation and staff training, combined with clear procedures and protocols to allow for the collection of high quality data and enhancement of the study experience for participants and researchers.
Underlying mechanisms, clinical manifestation, and methodological considerations of functional connectivity in Dementia with Lewy Bodies
Authors: Kucikova Ludmila , Kalabizadeh Hoda , Su Li
Published: December 2023

Background

Functional connectivity disturbances are potential disease mechanisms related to observable symptoms in Dementia with Lewy Bodies (DLB). Despite several existing theories, the exact relationship between functional connectivity, underlying mechanisms of the DLB, and symptomatology is yet not clear. The present review addresses this gap by summarising research findings of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) research while considering the impact of different methodological choices causing mixed findings.

Method

We performed a systematic literature review of resting‐state functional connectivity in DLB following PRISMA. We searched multiple databases from January 2000 to November 2022. Keywords included “DLB”, “connectivity”, “EEG”, and “fMRI”, their synonyms and acronyms, and related terms of network analysis. The final sample contained 6 EEG and 14 fMRI studies.

Result

The main methodological choices of fMRI articles included a data‐driven approach (i.e., Independent Component Analysis or Graph Theory; 43%), seed‐based or regions of interest (50%), or their combination (7%) with most studies focusing on large‐scale resting‐state networks (71%). The overall trend of connectivity findings showed a decrease, yet more subtle changes in the directionality of connectivity were observed when using a hypothesis‐driven approach (Fig 1A). The Default Mode Network (DMN) was the most studied network with 75% of relevant articles reporting decreased connectivity. Other networks with a consistent decrease in connectivity included Executive and Sensorimotor Networks (80% and 100% of relevant studies respectively). The inter‐network connectivity revealed the mixed relationship between the DMN, executive, attentional and visual networks (VN; Fig 1B). EEG studies showed a consistent decrease in connectivity on alpha and beta bands (100% and 66% of relevant studies respectively) and disorganisation in graph properties in regions overlapping with findings from large‐scale networks.

Conclusion

Dysfunctions in large‐scale networks likely contribute to progressive degenerative mechanisms and are consistent with visual attention and perception processing theories of psychotic symptoms in the DLB. Hence, connectivity measures can capture brain disturbances in the DLB and remain crucial in uncovering underlying relationships between the networks’ disorganisation and disease mechanisms resulting in psychotic, motor, and cognitive symptoms in DLB. The choice of analytical approach might contribute to the directionality and mixed findings in the literature.
Retention of Study Partners in Longitudinal Studies of Alzheimer Disease
Authors: Edwards Dorothy F.
Published: December 2023

Background

Alzheimer Disease Research Centers (ADRCs) require study partners (SPs) for all participants. SPs accompany participants to study visits, ensure protocol compliance and serve as informants for outcomes and adverse event reporting. Their attitudes and beliefs may therefore affect longitudinal data collection and retention for AD studies. However, little research has examined barriers and facilitators to SP participation in longitudinal AD investigations.

Objective

A random sample of study partners (N = 212) of participants who had no or mild symptoms (global Clinical Dementia Rating [CDR]≤1) at four ADRCs were surveyed to examine facilitators and barriers to continued participation in AD studies.

Methods

Reasons for participation were analyzed with factor analysis and regression analysis. Effects of complaints and goal fulfillment on attendance were estimated with fractional logistic models.

Results

Study partners most often participated in ADRC research for personal benefit and altruism. A majority of study partners rated ADRC participation as positive and meeting their goals. Although half reported at least one complaint, few regretted participating. When the participants had a CDR>0, spouse study partners (p<.01) and sibling study partners (p<.01) were more likely to emphasize personal benefits than were children of participants (p<.01) Spousal caregivers of participants with CDR>0, cited personal benefit as their primary motivation to participate while adult children of cognitively normal participants (CDR = 0) cited personal benefit. Respondents whose personal goals were met had fewer complaints and were more likely to have perfect attendance. More feedback about test results and study findings and better management of study visits were the most common recommendations.

Conclusion

Study partners are motivated by both personal and altruistic goals. The salience of each goal depends on study partner type and the participant’s cognitive status. Fulfilling these goals may improve retention and reduce study partner complaints.
Effects of re‐training sessions in RUDAS assessment in a cohort of evaluators
Authors: Montesinos Rosa , Chambergo‐Michilot Diego , Unaucho‐Pilalumbo Maria M , Russo Griselda , Custodio Nilton
Published: December 2023

Background

The RUDAS scale has been widely used in cohorts and trials, nevertheless this tool is complex and there are no guidelines for using it. Since the RUDAS may be prone to mistakes, even when medical staff is trained once, we aimed to determine the number of correct assessments per each evaluator of a large cohort of adults regarding dementia risk factors after sessions of re‐training.

Method

This was a longitudinal study of 22 evaluators of a large study on dementia risk factors in Antofagaste (Chile) and Quito (Ecuador). Use of RUDAS was established in the study protocol, so all evaluators were trained once to use this tool before study initiation. In order to ensure accuracy between evaluators, they were scheduled for five video‐sessions of re‐training leaded by an expert Neurologist. This sessions lasted 2.5 hours and the aim was to identify mistakes and doubts when performing RUDAS. After each session evaluators had a written test. The content was a simulation of a typical dementia case to be assessed by RUDAS. We collected the number of correct answers by domain.

Result

We assessed the mean number of correct answers by domain and the changes from baseline to the fifth test (visuospatial orientation: 4.25 → 4.89, praxis: 0.25 → 1.05, visuo‐constructional drawing: 0.05 → 2.68, judgement: max. 1.8 → 3, memory recall: 0.2 → 0, language: 5.7 → 8). Re‐training had a significant increase of correct answers in all domains. Despite the majority showed an increase in score from baseline to the fifth test, the mean score in fifth test was higher than in the prior tests only in judgement, memory recall and visuo‐constructional drawing domains. In the other domains we found that the fourth test scored higher than the fifth one, nevertheless the difference was not clinically important.

Conclusion

Training and re‐training are important steps in the approach and use of an assessment tool in trials and cohorts. RUDAS is a complex tool that may be prone to mistakes, therefore we recommend at least five sessions of re‐training to identify mistakes and doubts among evaluators.
Primer: MIND at Home Alzheimer’s and Dementia Care Coordination Program
Authors: Samus Quincy M
Published: December 2023

Background

People living with dementia (PLWD) represent some of the highest‐need and highest‐cost individuals living in the community. The complexity and range of needs (including medical, behavioral, and social needs) make dementia one of the most expensive chronic conditions in the U.S., and a strong candidate for improving care and reducing costs through care management support.

Method

The Maximizing Independence (MIND) at Home dementia care program, developed and implemented in a variety of settings and contexts over the last 15 years, is an advanced care coordination program for community‐living persons with dementia and cognitive impairment and their informal caregiver. The program is delivered through an interdisciplinary, dementia capable collaborative team. Developed by researchers at Johns Hopkins University, the MIND program consists of a comprehensive set of assessments, tools and staff trainings designed to increase individual longevity in the home/community; reduce unmet care needs and improve quality of care; improve person‐centered outcomes; reduce costly acute health care utilization; and reduce caregiver burden.

Result

The MIND at Home program model builds on three prior trials (two RCTs, one quasi‐experimental design) of the MIND at Home dementia care coordination model. These have included a philanthropically‐funded parallel group randomized controlled single blind trial (RCT) (MIND‐RCT‐1 n = 303; 2007‐2012), an NIA‐funded RCT (MIND‐RCT‐2; n = 302; 2014‐2020), and a CMS Health Care Innovation Award Round 2 demonstration project (MIND‐HCIA; n = 342; 2014‐2018). The program has been embedded into 3 types of real world practice settings to date: managed care health plans, primary care, home health care.

Conclusion

The research findings to date for in development of the MIND model show that community‐living older persons with dementia and cognitive impairment experience substantial unmet, yet modifiable care needs among community‐living PWD and caregivers, and that MIND at Home can benefit persons living with dementia and their family caregivers. Benefits include delay in transition from home and nursing home placement; reductions in use of acute and institutional care and total Medicaid spending; and improvement in care quality, behavior, and high program satisfaction. Individuals with lower income may benefit more.
Sex‐specific plasma markers of cholesterol‐metabolism and plant sterols predict cognitive decline in older people – a ten years follow‐up study
Authors: Spinedi Matteo , Lütjohann Dieter , Clark Christopher , Popp Julius
Published: December 2023

Background

Multiple studies in clinical settings show that there is a link between a dysregulation of cholesterol metabolism and neurodegenerative pathologies and dementia. Diet‐based plant sterols may also interfere with neurodegeneration and cognitive decline through cholesterol‐lowering properties. In this study, we investigate whether circulating levels of cholesterol, its precursors, and metabolites, as well as triglycerides, and phytosterols predict cognitive decline ten years later in the general population. As a secondary objective we address the role of sex and the APOE genotype on these relationships.

Method

We considered 206 individuals aged 65 and older from a population‐based prospective study from Lausanne, Switzerland. A comprehensive cognitive assessment was performed at baseline and after ten years. We quantified the plasma levels of cholesterol, high‐density lipoprotein (HDL‐) cholesterol, triglyceride, cholesterol precursors (lathosterol, lanosterol, desmosterol, dihydrolanosterol), cholesterol derivatives (cholestanol), oxysterols (24S‐hydroxycholesterol [24S‐OHC], 7α‐hydroxycholesterol, 27‐hydroxycholesterol), and phytosterols (campesterol, campestanol, stigmasterol, sitosterol, sitostanol and brassicasterol) at baseline and after five years. Regression analysis (considering several possible confounder including APOE‐genotype) determined the relationship between baseline sterol levels, and their changes between baseline and five‐year follow‐up, with measures of cognitive decline (i.e. changes in Clinical Dementia Rating (CDR), Mini‐Mental State Exam and CDR Sum of Boxes) at ten years. Analyses were performed in the whole cohort, and in males and females independently.

Result

Higher levels of baseline HDL‐cholesterol and lanosterol were associated with cognitive decline after ten years in the whole cohort. Decrease over time of 24S‐OHC was also associated with cognitive decline. In males, several cholesterol‐related sterols (cholestanol, lathosterol, lanosterol, 7α‐hydroxy‐cholesterol) and the phytosterol sitosterol were associated with cognitive decline. In females, only cholesterol and campestanol were associated with cognitive decline. The APOE genotype did not affect these associations.

Conclusion

In this cohort of older people from the general population, plasma markers of cholesterol synthesis and metabolism and as well as phytosterols are associated with cognitive decline after ten years. These findings have potential relevance for sex‐specific risk assessment and prevention of cognitive decline in older people.
Modelling the impact of social isolation on the rate of cognitive decline of dementia patients
Authors: Myers James A C
Published: December 2023

Background

The current study looked to model the impact of social isolation (SI), using marital status as a proxy, on the rate of cognitive decline of dementia patients. It was hypothesised that patients with higher levels of SI (whose marital statuses reflected less socially connected living conditions) would exhibit steeper rates of cognitive decline over time than patients with lower levels of SI, and patients with higher levels of SI would have lower intercept cognitive scores compared to patients with lower levels of SI.

Method

Patient demographic, diagnosis, cognitive assessment (Mini‐Mental State Examination [MMSE]/Montreal Cognitive Assessment [MoCA]) and marital status data were collated from electronic health records. Linear mixed‐effects models were used to explore the main effects and interaction effects of SI on the rate of cognitive decline of 4,137 patients from date of diagnosis to up to five years after (17,131 total observations).

Result

Comparisons for the MMSE and MoCA models showed the main effect models significantly outperformed null models testing the fixed effect of only diagnosis duration. The models revealed a similar rate of cognitive decline across all marital statuses. Excluding divorced patients, average intercept scores for less isolated marital statuses (married, civil‐partnership cohabiting) were higher than more isolated marital statuses (single, separated, widowed) for the MMSE models, but not the MoCA models. Interestingly, divorced patients had the highest average intercept scores in both the MMSE and MoCA models.

Conclusion

Future research should look to develop the SI proxy using data from the COVID‐19 pandemic to explore the implications of isolation through enforced social restrictions on cognitive decline in dementia patients.
Adaptation and Modification of Digital Cognitive Assessments for Smartphone‐based and Unsupervised Conduct
Authors: Edgar Chris J.
Published: December 2023

Background

Remote and decentralized approaches to clinical outcome assessments in clinical trials can reduce patient and trial burden, improve recruitment and retention, and lower barriers to trial participation. Remote assessment may be facilitated through smartphone‐based cognitive assessment, especially in Bring‐Your‐Own‐Device (BYOD) trials, and can also enable novel designs, for example, the use of high frequency ‘burst’ assessments. Application of such digital assessments in remote or unsupervised settings requires understanding of potential error from test administration and delivery platform (e.g., smartphones vs. computer).

Method

A series of studies explored the modification of the well‐validated Cogstate Brief Battery (CBB) to include practice trials with dynamic feedback to support unsupervised cognitive assessment, and adaptations for smartphone delivery. Data were drawn from healthy populations in (1) the Healthy Brain Project, where middle‐aged adults (n = 1,594) completed unsupervised cognitive assessments on a computer, (2) a pilot study of young adults (n = 60) who completed both smartphone and computer administration, and (3) a large (n = 35,000) study of adults who completed unsupervised smartphone‐based cognitive assessments in a BYOD context.

Result

Data from middle‐aged adults enrolled in the Healthy Brain Project indicated that adaptation of the CBB for unsupervised computer‐based assessment had high levels of acceptability (98% complete data) and usability (95%), with data meeting criteria for low error rates and ease of understanding). In young adults, rates of test completion were high and comparable (>98%), and performance accuracy (d’s <0.2) was equivalent between smartphone and computer administration. Performance was systematically slower (d’s >0.4) on smartphone than computer. Smartphone usability was high (e.g., >85% found text and button size to be ‘just right’), but there was not a strong preference for smartphone versus computer (56% preferred smartphone) and different issues of fatigue, distraction, and use of keyboard input were raised for the platforms. Similar findings of outcome consistency across platform were observed in the large BYOD sample (N>35,000).

Conclusion

These results indicate that smartphone assessment has high acceptability, good reliability, and that accuracy of performance is equivalent between smartphone and computer versions. The data also raise important issues for the successful adaptation and modification of cognitive tasks for smartphone administration.
Digital is the New Blood: Enabling the Present and the Future
Authors: Au Rhoda , Popp Zachary T , Low Spencer , Hwang Phillip H , De Anda‐Duran Ileana , Li Stephanie , Rahman Salman , Ding Huitong , Igwe Akwaugo , Karjadi Cody , Ang Ting Fang Alvin , Devine Sherral A. , Gurnani Ashita S , Mez Jesse B. , Farrer Lindsay A. , Sunderaraman Preeti , Lin Honghuang , Kolachalama Vijaya B.
Published: December 2023

Background

Digital is the new blood, where collection, use, and storage of raw digital data streams enabled by technology‐embedded sensors are replacing analog methods. Analyses of digital data extend beyond current applications, analogous to previously stored blood currently be used for omics/biomarker research. Today digital technologies are used to measure Alzheimer’s disease (AD)‐related clinical symptoms (e.g., cognition, function, and behavior), but future possibilities remain to be determined. Importantly, digital data collection can go beyond current intermittent sampling by employing internet‐connected applications and devices that allow real‐time monitoring and accurate detection of changes, even within a widely heterogeneous spectrum.

Method

Beginning in 2005, the Framingham Heart Study (FHS) began digitally recording participants’ spoken responses to neuropsychological (NP) test questions, and in 2011 extended to a digital pen to record written responses. The emergence of wearable devices and smartphone applications has led to an expanded use of digital technologies beyond recordings during NP assessments. The Boston University Alzheimer’s Disease Research Center (BU ADRC) leverages digital sensors in multiple internet‐connected devices that longitudinally collect digital data, in both in‐person and remote settings.

Result

The first publication involving FHS digital data was in 2016; the remaining (n> 17) have been from 2020‐current. Digital data measuring cognition, function and behavior are being collected through the BU ADRC, where results to date indicate nearly 100% and 75% uptake of active and passive engagement applications, respectively, and 95% uptake for wearable devices (n = 60). Longitudinal assessments include > 3 months for ∼50 participants; > 1 year for n∼21 participants.

Conclusion

Opportunities for improved trial outcome measurement are evident in the broad range of outcomes digital sensors capture beyond traditional research methodologies. Digital tools are being deployed for rapid screening for clinical trial inclusion, but more transformative opportunities are still to come. Replacing the sporadic and highly heterogeneous measures of cognition and related behaviors with more accurate measures that track treatment impact in real‐time at the individual level will shift the concept of clinically meaningful outcomes from group indicators to personalized ones. Digital is central to the realization of virtual clinical trial monitoring for precision treatment effects.
Review of the impact of menopause symptoms on longevity
Authors: Andrews Robin , Lacey Arron , Bache Kate , Kidd Emma J
Published: December 2023

Background

Emerging evidence suggests that experiencing specific symptoms during menopause can heighten risks of developing conditions which can impact lifespan and long‐term vitality including dementia, cardiovascular disease, psychiatric conditions and cancer. In addition, it is now recognised that, while women live on average about 5 years longer than men, they often have poorer health which could be linked to this increased risk. The aim of the present review was to assess past literature to understand how distinct menopausal symptom presentations can impact lifespan and propensity for developing life‐limiting conditions.

Method

The following databases were searched: Google Scholar, EMBASE, MEDLINE, Cochrane Library, Scopus, PubMed, and Web of Science. Keys words aimed to capture factors relating to menopause, menopausal symptoms, mortality, and life limiting conditions such as Alzheimer’s disease, dementia, cardiovascular disease, stroke, cancer, liver disease, and suicide susceptibility.

Result

Findings suggested that cognitive symptoms experienced during menopause were related to heightened risks of developing Alzheimer’s disease, mild cognitive impairment, dementia, and premature mortality. Vasomotor symptoms were related to increased risks of stroke and cardiovascular disease mortality. Psychological symptoms during the menopause transition were related to increased suicide risks and cardiovascular disease. Sleeping problems during menopause were related to heightened risks of cardiovascular mortality, cancer‐related mortality, and premature death from all causes.

Conclusion

These findings warrant further investigation through robust analyses of public health data, to evaluate whether these outcomes are replicated within the general population. Should these findings endure, these outcomes suggest a need to improve the health of women during midlife, as doing so may prolong wellness in later life and also have consequences for socioeconomic costs. Furthermore, clarifying these associations may enable women and their health providers to recognise whether they are at risk of developing life‐limiting conditions, thus enhancing their vitality by increasing their likelihood of accessing preventative or early interventions and treatments.
Precision and Accuracy of a Novel Cognitive Battery for Use in Alzheimer’s Disease Clinical Trials: The NOMAD Study
Authors: Goldberg Terry E.
Published: December 2023

Background

Many of the established measures used in current AD trials were developed for use in dementia populations. They may lack sensitivity to more subtle declines in earlier stages of the disease, be prone to practice effects (sometimes called learning effects), cause misalignment of biomarker and cognitive scores, have unknown or suboptimal psychometrics, may be prone to ceiling effects, and do not map onto neural systems. Informant based measures of function may increase uncertainty around bias, if the informant is inaccurate in report, biased, or if there is “functional unblinding” of the study drug. Here we address these problems and offer solutions to improve precision and accuracy of these outcome measures using a novel cognitive test battery and a novel performance‐based test of everyday function in the NIA funded multi‐site NOMAD study.

Methods

Design: Using a clinical trials structure one randomized group received novel measures (N Back, Brown Peterson, Fluency, Recognition Memory, Letter‐Number Span, Symbol Digit) and the other group received established measures (PACC, ADAS Cog) to reduce interference. Participants: 145 cognitively unimpaired or early MCI in each group. Serial assessments were conducted at baseline, 3 months, and 12 months.

Results

Baseline data revealed that the novel tests did not have ceiling effects, had excellent test‐reliability, had an interpretable factor structure, and were associated with AD related risk factors and biomarkers, including age, early MCI, APOE e4, and cortical volume. Additionally, they were sensitive to educational level but not sex. Examination of longitudinal data from 3 serial assessments over a 12‐ month period suggested markedly attenuated practice effects when compared to more established measures such as the PACC and ADAS‐ Cog.

Conclusion

Novel measures demonstrated high test‐retest reliability, sensitivity to important AD related biomarkers and demographics, and attenuated practice effects. These results suggest that we met important aims having to do with precision and accuracy— test measurements were reproducible and measured what they were designed to measure, based on factor structure, associations with AD risk factors, and reduced practice effects that would otherwise confound measurement accuracy.
user experience and redesign of a cognitive stimulation web lab for older people with and without mild cognitive impairment
Authors: Moreno Maria Celeste López , Vivas Leticia , Sarmiento Araceli Elsa Revollo
Published: December 2023

Background

LABPSI is a cognitive stimulation web laboratory (labpsi.mdp.edu.ar/ejercicioscognitivos). We present here the results of the redesign process based on user experience (UX).

Method

Sample comprised 40 older adults with an average age of 73 years, from the city of Mar del Plata, Argentina, with and without cognitive impairment, who used the LABPSI on tablets and cell phones. Within the framework of the Mobile Goal Questions metrics (Hussein, 2012) we registered the participants´ performance in three activities. We recorded the correct steps achieved, the mistakes made, and, for tasks 2 and 3, the correct steps in a specific time frame, obtaining 13 measures. These measures were registered before and after the lab´s redesign with different participants in order to avoid learning effect.

Result

A Mann Whitney U test was performed. First, we compared the performance before and after the redesign for both groups.

The MCI group showed significant results in almost all the measures except for the completion of task 3, whose result was very close to the value of significance (p = .064).

The group of people without MCI showed significant results in 10 measures, indicating that they improved their performance in the majority of the tasks with the exception of task 3 where they maintained the same amount of errors (p = .386), correct steps (p = .064) and steps in 5 minutes (p = .164).

Then we compared the performance between people with MCI and without MCI in the redesigned version of the lab and we only observed differences in three measures: number of steps achieved in task 1 (p<.05); number of steps achieved and errors in task 2 (p<.05).

Conclusion

The results show the importance of the UX analysis in the design of cognitive stimulation web labs for elderly people. In the case of the modifications implemented in the LABPSI, the laboratory´s current version proved to be accurate and improve performance for older people with and without MCI.
Anticholinergic burden and polypharmacy in primary care referrals to tertiary outpatient clinics in Brazil
Authors: Castilhos Raphael Machado , Formoso Carolina Rodrigues , Borelli Wyllians Vendramini , Teixeira Elaine Calumby , Dousseau Gabriella , Chaves Marcia L Fagundes , Brucki Sonia Maria Dozzi
Published: December 2023

Background

Anticholinergic burden (ACB) and polypharmacy are associated with cognitive/functional impairment in the elderly and their frequency in primary care has been poorly studied in Brazil. We aimed to evaluate the frequency ACB/polypharmacy and association with cognitive impairment in two large tertiary care outpatients memory clinics in Brazil.

Methods

We retrospectively analyzed records of referrals from primary care to two tertiary outpatients memory clinics in Brazil (Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre and Hospital Santa Marcelina (HSM), São Paulo) from 2014 to 2022. Sociodemographic, clinical and medications in use in the first appointments were recorded. The ACB was calculated using the Brazilian Anticholinergic Activity Drug (BAAD) score, which classified drugs according to their central anticholinergic activity from 1 to 3, with higher values indicating greater anticholinergic activity. The BAAD score was dichotomized as = 0 or ≥ 1. Polypharmacy was defined as ≥ 5 drugs. A logistic regression was performed using age, sex, education, disease duration, dementia etiology, center and Mini Mental State Examination (MMSE) as covariates.

Results

Among 980 referrals (HCPA = 429; HSM = 551), 602 (64.9%) had a final diagnosis of dementia, HCPA = 226 (56.1%); HSM = 376 (71.8%); p<0.001. Alzheimer’s disease, 93 (21.7%) and multifactorial dementia, 109 (19.8%), was the most common dementia diagnosis in HCPA and HSM, respectively. Most patients, 666 (74%), had BAAD ≥ 1 and nearly half 438 (48.7%) had polypharmacy, with no difference between centers (Table 1). BAAD was not different between diagnoses, but polypharmacy was more frequent in vascular (71, 63.4%) and multifactorial (82, 59.9%) dementia. BAAD was associated with MMSE (OR 0.95, IC 95% 0.93‐0.97) and polypharmacy (OR 3.71, IC 95% 2.66‐5.24). In addition to BAAD, polypharmacy was also associated with female sex (OR 1.45, IC 95% 1.09‐1.91) and age (OR 1.01, IC 95% 1‐1.02).

Conclusion

Most patients referred from primary care were using some drug with anticholinergic activity and almost half had polypharmacy, which suggests liberality in the prescription of medications in this context.
Value of hope in dementia care: what if hope is an omitted benefit in economic evaluation?
Authors: Nguyen Kim Huong
Published: December 2023

Quality of life has been perceived as the ultimate outcome of dementia treatment and care, from patient, family, clinical and policy perspectives. Increasingly, there emerges evidence that the utility gain/loss from quality of life changes might not capture a critical function of dementia care: hope. Hope may be an important missing value from utility estimate, which is the key outcome measure in determining whether or not an intervention entails valued care.

Most standard quality of life (EQ5D, HUI) and dementia‐specific measures (QoL‐AD, DEMQoL) do not directly capture hope. They might indirectly capture an aspect of hope that is correlated with self‐reported anxiety, depression or despair. Quality of life reflects the static state of health and immediate satisfaction derived from a particular health state. It does not cover the “forward looking” aspect that is embedded in hope. Furthermore, quality of life does not contain the dynamic nature of hope as a way of thinking ‐ a cognitive process.

The ISPOR task force recently proposed to include hope as a novel element in the evaluation framework in decision making and health technology assessment [Lakdawalla2018]. Here, hope was framed around the risk‐aversion aspect, following two studies of cancer patients [Lakdawalla2014, Hauber2020]. This is a narrow understanding of hope, and strongly links to the prospect of being cured and/or prolonging life until a cure is found.

In this study, we hypothesize that hope in dementia carries a weak link to “risk preference” yet strong association with the cognitive process underlying agency, resilience, and independence. Through the human rights lens, we apply the capability framework [Amartya Sen] to bring out the cognitive process aspect of hope, and propose a dementia‐specific measure of hope. This will also capture the lived experience of patients and families throughout care and when the care outcome is realized.

From both economic and policy perspectives, if the lived experience of hope in dementia could be captured through utility measures, then “hope” will no longer be a missing source of value when evaluating dementia care. This will lead to improved efficiency of resource allocation in favour of novel approaches to care.
Microstructure of White Matter, Probed With Diffusion MRI Modeling, Reveals Distinct Correlations Between Intra‐ vs Extra‐Cellular Spaces and Tau Load
Authors: Pavan Tommaso , Ribaldi Federica , Pievani Michela , Jovicich Jorge , Garibotto Valentina , Frisoni Giovanni B , Jelescu Ileana O
Published: December 2023

Background

In Alzheimer’s disease, pathological phosphorylation of tau protein destabilizes microtubules affecting the neural cytoskeleton organization (Kolarova et al., 2012). In this study, we investigated correlates of Alzheimer’s tau pathology and white matter (WM) microstructure using diffusion MRI (dMRI) advanced models to detect tau‐related tissue changes and their trends across brain regions.

Method

Ten cognitively impaired subjects (age:70±7,M/F:6/4,MMSE:27.8,CI) and 11 cognitive unimpaired (age:62.4±9,M/F:1/10,CU) were recruited in the context of the COSCODE research project (Ribaldi et al., 2021). Tau standardized uptake value ratio (SUVR) was assessed from 18F‐flortaucipir PET in entorhinal, lateral‐occipital, inferior‐temporal cortex, and amygdala (reference: cerebellar crus; Mishra et al., 2017). dMRI scans were collected at 7T. WM microstructure analysis included: diffusion tensor (DTI), kurtosis tensor imaging (DKI, Jensen and Helpern, 2010), and a biophysical model of WM microstructure (WMTI‐Watson, Fig.1, Jespersen, et al., 2018). Mean values for each diffusion metric were calculated in WM ROIs of the JHU atlas (Mori et al. 2005) and correlated to tau across CI subjects (statistical significance: p<0.05).

Result

Correlation analysis showed a systematic disconnect between diffusion metrics parallel and perpendicular to the axons: RD (and MD) correlated positively with tau, while AD negatively. Similarly, RK (and MK) correlated negatively, while AK positively (Fig. 2). Higher diffusivities and lower kurtosis (perpendicular to axons) are associated with less complex tissue, while lower diffusivities and higher kurtosis (parallel to axons) are associated with a more tortuous and heterogeneous environment. The biophysical model showed that higher diffusivity in the extra‐cellular space (De,//, De,

⊥
) was associated with higher tau, while axonal density (f) and within‐axon diffusivity (Da) correlated negatively.

Conclusion

The significant correlations between tau and FA, RD, MD, RK and MK, are consistent with neurodegeneration. The positive correlation of De,//, De,

⊥
and negative correlation of f to tau confirms the axonal loss and the increase of extracellular diffusivity. Interestingly, the negative correlation of tau to water diffusivity within the axons (Da) could be explained by microtubules breakdown and intra‐axonal deposition of neurofibrillary tangles that impede water diffusion. These evidences of dMRI microstructure correlation with tau SUVR may be useful to detect the in‐vivo neurodegeneration.