bluuebunny/crossref_metadata_2025 huggingface dataset:
MRI Statistical region of interest best differentiates impaired from non‐impaired in the Study of Latinos‐Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI)
Authors: Fletcher Evan M , Gallo Linda C , Talavera Gregory A , Isasi Carmen R , Kaplan Robert , Lipton Richard B. , Daviglus Martha L , Schneiderman Neil , Gellman Marc D , Stickel Ariana M , Tarraf Wassim , González Hector M , DeCarli Charles S.
Published: December 2022

Background

We developed a statistical region of interest (sROI) of gray matter (GM) for which cortical thickness (CT) significantly differed in a “training set” of 100 cognitively normal and 100 individuals with incident dementia in the Framingham Heart Study. sROI significantly predicts incident cognitive impairment and dementia in both FHS and the highly diverse UC Davis Alzheimer’s disease longitudinal cohort. Here we describe a similar analysis of participants of Study of Latinos‐Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI).

Methods

Hispanics/Latinos (n=6,377 ages 50‐86) were enrolled in the Study of Latinos ‐ Investigation of Neurocognitive Aging (SOL‐INCA) of which 1,143 also participated in SOL‐INCA‐MRI ancillary study. Cognitive impairment (CI) was defined as any cognitive domain score falling below (<‐1.0 SD) the SOL‐INCA robust internal normative mean and significant cognitive decline (‐0.055 SD/yr), self‐reported cognitive decline and no or minimal functional impairment over 7 years. Participants with dementia were excluded.

MRI CT was computed by the DiReCT method. sROI was derived from statistically significant (via 1,000 non‐parametric permutations) clusters of GM voxels having CT group difference t > 2 over the training set (Fig. 1). Extents of sROI overlap with standard atlas GM regions appear in Table 3.

Group differences in variables were assessed by t‐test. Logistic regression assessed the impact on cognitive status of MRI factors: total brain, hippocampal, white matter hyperintensities (WMH), sROI volumes and infarction occurrence, controlling for age, sex, education, and background.

Results

The cohort was 64.4 + 7 years of age, 69% female. Nearly 60% with high school or less education, and 21% CI. Table 1 summarizes demographic and MRI measures for CI and cognitively normal (CN). CI individuals were older, had less education, smaller brains, and greater amounts of WMH. Table 2 summarizes results of logistic regression. Education and sROI mean CT were the only significant predictors of cognitive status.

Conclusion

Cortical thickness within the sROI was strongly associated with cognitive status, even when other commonly used MRI measures were not. sROI may therefore be a sensitive indicator of incipient CI within SOL‐INCA‐MRI where more traditional measures of Alzheimer’s pathology and vascular disease appear insensitive.
IN‐VIVO EVALUATION OF APN‐1808, A TAU SMALL MOLECULE THERAPEUTIC
Authors: Tempest Paul , Lin Yih‐Shyan , Lai Yen‐Ting , Tai Chin‐Yin , Ma Haou‐Tzong , Huang Sheng‐Chieh , Margolin Richard A , Wu Chia‐Lin , Jang Ming‐Kuei
Published: December 2022

Background

The high value for Alzheimer’s Disease and other taupathies of a small molecule treatment that can alter disease course is widely acknowledged. We aim to investigate such a therapeutic by leveraging our small molecule CNS aggregated protein discovery platform.

Method

Our small molecule discovery platform consists of our proprietary small molecule collection, unique PET imaging biomarkers and cryoEM structures. Our proprietary collection of CNS‐focused aggregated protein binding agents, previously developed by APRINOIA to map the structure‐activity relationship of its tau PET tracer programs, was screened for tau binding and further interrogated for other desirable properties such as selectivity and oral availability. Further efforts derived guidance from the cryoEM structure of our lead compound bound to Tau aggregates. These efforts resulted in our small molecule lead compound APN‐1808.

Using rTg4510 mice, which over express 4R tau, we first investigated dose‐response by using in‐vivo PET imaging to measure percent occupancy of APN‐1808. Upon selecting an appropriate dose range, we engaged in 90 day, twice a day dosing of APN‐1808 in rTg4510 mice.

Result

Mice dosed with APN‐1808 showed improvements both biochemically and phenotypically over vehicle controls. Improvements included increase in synaptic protein level, reduction in overall tau burden, reduction in weight loss and other behavioral observations.

Conclusion

Several readouts showed improvement in the dosed groups compared to controls, including increase of synapse level, reduction of weight loss and reduction of total tau. Further investigations are ongoing.
Exploring mechanisms of synaptic vulnerability and resilience in Primary Age Related Tauopathy
Authors: Kadamangudi Shrinath , Tumurbaatar Batbayar , Taglialatela Giulio
Published: December 2022

Background

Primary Age Related Tauopathy (PART) is a sporadic dementia‐related illness, characterized by pathological tau accumulation limited to the hippocampal‐entorhinal region in the absence of Aβ plaques. Studying PART thus presents a unique opportunity to 1) characterize toxic tau species, namely oligomeric (tauO) tau, and to 2) explore molecular mechanisms underlying regional synaptic vulnerability (i.e. hippocampus) and resilience (i.e. neocortex) within a singular tauopathy—such as low‐density lipoprotein receptor 1 (LRP1), recently uncovered as a key mediator of tau uptake and trans‐synaptic spreading.

Methods

We compared levels of tauO, total tau, and LRP1 between the hippocampus and superior medial temporal cortex (SMT) in 7 post‐mortem PART patients. Total homogenate and synaptosomal fractions were prepared for Western Blot; both fractions were probed for total tau (Tau13), and LRP1. TauO were ascribed to high molecular weight tau bands using the total tau probe. p‐tau (AT180) and paired helical filaments (PHF13.6) were also probed in the total homogenate fraction to assess PART neuropathology. The Wilcoxon matched‐pairs signed rank test was utilized to compare regional differences.

Results

We found elevated levels of p‐tau and PHF in the hippocampus vs. SMT (total homogenate), thus validating previously reported PART neuropathology. We observed a trend towards increased tauO in the hippocampus vs. SMT in PART total homogenate (p=0.11) and synaptosome fractions (p=0.06). Of note, no regional differences were found in total tau levels in either the fractions. In the total homogenate, we found no statistically significant regional differences in LRP1 (p=0.30). Interestingly however, we observed decreased LRP1 in the hippocampus vs. SMT in 6 out of 7 PART patients. On the orher hand, we found no significant differences or notable trends in LRP1 between the hippocampus vs. SMT in the synaptosomal fraction.

Conclusions

This investigation of PART neuropathology is the first to demonstrate accumulation of tauO, restricted to the hippocampus and its synapses. We further report lower levels of LRP1 in the hippocampus of PART patients, a seemingly extra‐synaptic phenomenon, that could potentially mediate regional vulnerability to pathological tau species. Further biochemical and functional assays to characterize tau toxicity and spread are currently under investigation.
Robust prediction of memory and neuroticism in men and women using connectome‐based predictive modeling
Authors: Ju Suyeon , Horien Corey , Constable Todd , Fredericks Carolyn A
Published: December 2022

Background

Alzheimer’s disease (AD) disproportionately impacts women, yet we have little understanding of the differences in brain circuitry that underlie this vulnerability. We explored aspects of brain connectivity that robustly predict memory performance (measured by RAVLT performance) and neuroticism (measured by NEO‐N) in healthy women vs men by leveraging data‐driven machine learning to model the brain connectome in the Lifespan Human Connectome Project Aging (HCP‐A) dataset.

Method

We used functional MRI scans to create whole‐brain connectivity matrices based on 268 regions‐of‐interest for 725 healthy subjects (319 men, 406 women) aged 36 to 100 enrolled in HCP‐A. Before and after separating the subjects by sex, connectome‐based predictive modeling (CPM) was used with a p‐value threshold of 0.01 and split‐half cross‐validation to identify and implement edges that significantly predicted the neurobehavioral scores to train a predictive model for each group. The models were applied to test sets within each group, outputting the predicted behavioral measures and Pearson correlations between predicted and observed scores.

Result

As anticipated, overall performance in HCP‐A was higher for women than men in RAVLT (p < 1x10‐7) and NEO‐N (p = 0.12). Our model predicted the RAVLT measure (Fig. 1) with accuracies ranging from R = 0.2154 (p < 1x10‐4) to R = 0.4293 (p < 1x10‐4). Our sex‐based models also predicted a high variance in the RAVLT measure between sexes (σ2 = 0.015, Fig. 2). While neuroticism predictors were not as robust for short‐term memory, the models were still able to predict a significant amount of variance (σ2 = 0.023, Fig. 2).

Conclusion

We successfully implemented CPM to derive robust brain‐based predictors of memory performance and neuroticism. Models derived separately for each sex differ in their ability to explain variance in these measures. Future analyses will pinpoint specific edges within the connectivity matrices that explain variance in memory performance or neuroticism in men vs women. We anticipate these will yield important insights into why women are at higher risk of developing AD.
Higher body mass and fat composition are related to 1‐year cerebral amyloid accumulation in individuals with elevated risk for Alzheimer’ disease
Authors: Smith Aaron N. , Taylor Matthew K , Sullivan Debra K , Keller Jessica E , Burns Jeffrey M.
Published: December 2022

Background

Amyloid‐β is a classical hallmark and risk factor for development of Alzheimer’s disease (AD). Observational data suggest that having higher body mass index (BMI) is associated with lower cerebral amyloid burden in cognitively normal adults. However, the influence of body composition on cerebral amyloid deposition has not been investigated. We investigated whether baseline body composition influences 1‐year change in cerebral amyloid in a sample enriched with older adults with elevated amyloid.

Method

Data from 103 cognitively normal adults with high normal or elevated cerebral amyloid that participated in a 1‐year exercise RCT were analyzed. Cerebral amyloid burden was quantified in 6 cortical regions of interest by Florbetapir F18 PET. Global amyloid burden was calculated by averaging the 6 regions. Total lean body mass and fat mass percentages were measured using DXA. We constructed ordinary least squares regression models to investigate the relationship between our baseline measures of body composition and 1‐year change in regional and global amyloid. All models included age, APOE4 carrier status, study arm, sex, and baseline regional amyloid standard uptake value ratios as covariates.

Result

Participants were 67% female with a mean age of 72.4 ± 5.0 years. Mean BMI was 28.0 ± 5.4, lean body mass percentage was 61% ± 7.5%, and fat mass percentage was 38% ± 7.1%. Higher BMI was related to less 1‐year amyloid accumulation in 5 regions (anterior cingulate gyrus, precuneus, inferior medial frontal gyrus, lateral temporal lobe, and superior parietal lobe) and globally (β range = ‐0.003 to ‐0.004, p<0.03 for all). Higher fat mass percentage was related to less amyloid accumulation in all 6 brain regions and the global average (β range = ‐0.25 to ‐0.34, p<0.03 for all). Higher lean body mass percentage was related to less amyloid accumulation in the lateral temporal lobe (β = ‐0.003, p = 0.01).

Conclusion

In this study, having larger body stature and higher fat mass percentage were related to less amyloid accumulation in individuals with elevated risk for AD. Further studies are necessary to explore these relationships in greater detail and to ascertain if these findings are modulated by other biological variables.
PROGRESS IN DEVELOPING A LIGHT‐STABLE 4R TAU PET IMAGING AGENT: APN‐1701 FIH
Authors: Tempest Paul , Lin Yih‐Shyan , Tai Chin‐Yin , Ono Maiko , Russell David S , Sandiego Christine M , Gunn Roger N , Carroll Vincent , Margolin Richard A , Kao Tzu‐Huei , Higuchi Makoto , Jang Ming‐Kuei
Published: December 2022

Background

The need for a light stable 4R tau PET tracer for use in diverse tauopathies is widely appreciated. We aimed to assess the initial human imaging profile of [18F]APN‐1701 as such a tracer and to compare its imaging profile to the well‐established but light‐sensitive tracer [18F]‐APN‐1607 that can detect 4R aggregates as well as 3R and mixed 3R/4R aggregates. [18F]APN‐1607 has progressed to a multicenter Phase 2 clinical trial for Alzheimer’s disease (AD); therefore, prior imaging data with it was considered valuable for comparison.

Method

One cognitively normal (CN) subject (male, 73yo) and one AD subject (female, 58 yo), who had undergone prior amyloid profiling using [18F]florbetapir PET and subsequent imaging with [18F]APN‐1607 in a proof‐of‐concept study and a test‐retest study, respectively, participated in the current study. Dynamic imaging with [18F]APN‐1701 was performed over 180 min to obtain kinetic data.

Result

Overall, for both subjects [18F]APN‐1701 generally matched [18F]APN‐1607 findings, i.e., peak SUV values reached similar levels. The CN subject, who was amyloid negative, had slight, uniform cortical [18F]‐APN‐1701 uptake and more substantial uptake in the pallidum, pons and midbrain. SUVr images for the AD subject showed retention in similar brain regions for both tau tracers with the same rank order of regional SUV/SUVr. Notably, for this subject [18F]APN‐1701 continued to accumulate up to the end of image acquisition.

Conclusion

[18F]APN‐1701 demonstrates cortical uptake generally similar to [18F]APN‐1607 but its slow kinetics are unfavorable for further development.
Body mass index and 2‐year change of in vivo Alzheimer's disease pathologies in cognitively normal older adults
Authors: Lee Seunghoon
Published: December 2022

Background

Multiple studies supported that low body mass index (BMI) or underweight status in late‐life was associated with increased risk of dementia. We tried to test the hypothesis that lower late‐life BMI is related with greater increase of in vivo AD pathology including Aβ and tau deposition for two years in cognitively healthy individuals. Additionally, we explored the same relationship in each sex separately, considering previous reports that showed prominent sex differences for the relationship between BMI and AD dementia risk.

Method

Total 194 cognitive normal older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent comprehensive clinical assessment including BMI measurement, [11C] Pittsburg compound B and [18F] AV‐1451 PET at baseline. The same brain imaging scans were repeated at a year follow‐up assessment. The association of baseline BMI with longitudinal changes of AD biomarkers were analyzed using linear mixed effect models.

Result

Lower BMI at baseline was significantly associated with greater increase of tau deposition in AD‐signature region for 2 years. In contrast, BMI was not related with 2‐year change of global Aβ deposition. In additional exploratory analysis for each sex, lower baseline BMI was associated with greater increase of both Aβ and tau deposition in male, whereas neither Aβ nor tau change was not related with baseline BMI in female.

Conclusion

The present study suggest that lower late‐life BMI may accelerate the accumulation of AD pathology in the brain, especially in male. To prevent AD, more attention is needed to be paid to avoiding underweight in old age and maintaining an appropriate BMI status.
Amyloid‐ß aggregation, APOE‐e genotype, and the trajectory of cognitive decline in persons without dementia
Authors: Janssen Olin , Jansen Willemijn J. , Oomens Julie Elisabeth , Tijms Betty M. , Maserejian Nancy Nairi , Ossenkoppele Rik , Vos Stephanie J. B. , Visser Pieter Jelle ,   the Amyloid Biomarker Study group
Published: December 2022

Background

The association of amyloid abnormality with cognitive decline in persons with normal cognition (NC) and mild cognitive impairment (MCI) is important to guide AD trial design and understand prognoses. We examined the relation between amyloid abnormality and decline over time in several cognitive domains, and tested whether apolipoprotein (APOE)‐e genotype modified this association.

Method

We included 3,820 persons (2,599 NC, 1,221 all‐cause MCI) from 22 Amyloid Biomarker Study cohorts, with baseline PET (n = 846) or CSF (n = 2,974) amyloid measurements available. Amyloid abnormality on PET was based on visual read or cohort‐specific cutoffs, and for CSF on cohort‐specific or data‐driven cutoffs. Global cognition was assessed by Mini‐Mental State Examination (MMSE), functional performance by Clinical Dementia Rating global scale (CDR), and memory immediate and delayed recall by verbal learning tests. We examined baseline amyloid abnormality associations with cognitive performance over time and potential modification by APOE‐e (up to 3‐way interactions) using random‐slope/random‐intercept linear mixed‐models corrected for age, sex, education with random cohort effects.

Result

Mean follow‐up duration was 2.1 (range 0.5‐8) years. Baseline MMSE was worse in persons with abnormal‐amyloid compared with normal‐amyloid (NC mean difference = 0.2, p = 0.04, MCI mean difference = 2.4, p<0.001). In NC, amyloid abnormality was not associated with decline in any domain (Table 1), nor was the association influenced by APOE‐e4. In MCI, amyloid abnormality was associated with lower baseline performance and steeper decline on all domains (Table 1). In APOE‐e4‐carriers with MCI, MMSE decline was steeper than in non‐carriers (p<0.001, 1.5x steeper in amyloid‐abnormal, 3x steeper in amyloid‐normal). The rate of decline on immediate/delayed recall in MCI was higher in APOE‐e4‐carriers than non‐carriers, independent of amyloid status (p<0.001). For both NC and MCI, decline was steepest in persons with e4e4, followed by e3e4, e3e3, e2e4, and e2e3 (p = 0.001, Figure 1), independent of amyloid status.

Conclusion

Amyloid abnormality was not associated with cognitive decline in persons with NC after a short‐term follow‐up. In MCI, amyloid abnormality was closely associated with cognitive decline in several domains, with an additive effect of APOE‐e on decline. These results may be relevant for future trial recruitment strategies. Future studies should examine long‐term outcomes in NC.
Individual movement patterns in real‐world navigation as a digital marker of cognitive health in the elderly
Authors: Marquardt Jonas , Mohan Priyanka , Spiliopoulou Myra , Glanz Wenzel , Butryn Michaela , Kuehn Esther , Schreiber Stefanie , Maass Anne , Diersch Nadine
Published: December 2022

Background

During normal aging and, particularly, during pathological aging, people often show problems in spatial navigation (SN), rendering it a promising marker of cognitive health in the elderly. However, SN is rarely investigated in people experiencing subjective cognitive decline (SCD), which is considered a very early stage of Alzheimer’s disease. Impaired performance of SCD patients was observed in a computerized navigation task. However, it remains unclear, how this translates to their everyday navigation behavior. Capitalizing on recent advancements in digital technologies, we measured the performance of healthy younger (HYA), healthy older adults (HOA), and SCD patients, when they solve a smartphone‐based navigation task in the real‐world.

Method

We developed a novel smartphone‐based application “Explore” to track GPS data in 67 individuals (HYA, n = 24, HOA, n = 25, SCD, n = 18, still in progress), while they were asked to find five points of interest on the medical campus in Magdeburg. Dynamic time warping was applied to investigate similarities between the raw trajectories. Also, aggregated measures of navigation performance were extracted (e.g., wayfinding distance, wayfinding duration, orientation stops, help usage). Mixed effect models were used to evaluate the effect of group membership on these summary measures. In addition, within‐group heterogeneity in navigation performance was investigated using clustering algorithms.

Result

Mixed effect models (Figure 1) show that HYA outperform HOA and SCD on all aggregated measures (all p ≤ .018). Between HOA and SCD, no significant differences were found for wayfinding distance and duration (p ≥ .102). However, a trend was detected for amount of help usage (p = .071) and number of orientation stops (p = .057), indicating that SCDs perform slightly worse compared to HOA. The cluster analysis of the movement trajectories revealed that our sample is best described by four navigation patterns (Figure 2).

Conclusion

We provide first evidence that movement trajectories from a real‐world navigation task can be clustered into different groups, that could be indicative of age and cognitive health in the elderly. Our preliminary data indicate that certain measures of real‐world navigation behavior might differ between SCD and HOA, which needs to be confirmed in the full sample when data acquisition is complete.
Using technology to assist creative arts activities in dementia care
Authors: Christensen Justin , MacRitchie Jennifer , Floridou Georgia , Timmers Renee , De Witte Luc
Published: December 2022

Background

Alongside a growing use of creative arts within community and residential settings to support the health and wellbeing of older adults living with dementia, is an increasing availability of technology, although development for this context has up till now been limited. To examine how technology might be used to meet the leisure, health, and wellbeing needs of people living with dementia, we conducted a scoping review to assess the current state of development of creative assistive technologies across various art‐forms.

Method

Our research questions asked i) what are the arts‐based activities being delivered through technology for older adults living with dementia or mild cognitive impairment, and ii) what are the characteristics of technologies being used to enhance these arts‐based activities? A comprehensive search was conducted using PubMed, PsychINFO, Web of Science, Scopus and ACM Digital Library databases. Two raters independently screened titles and abstracts, rating whether articles fit our inclusion criteria. A total of 3762 records were retrieved, of which 51 articles were included after full‐text screening.

Result

Music (29), visual art (7), storytelling (6) and film‐making (2) were delivered through technology to older adults living with dementia. Other activities included dance (1), interactive light and sound (1), and incorporating arts activities into multi‐sensory objects (3). Two applications specifically allowed a choice between multiple creative arts (2). Single papers focused on Technologies were mainly custom‐made devices rather than applications using everyday devices such as smartphones or computers. Devices were often oriented towards individual use, supported by carers rather than groups of individuals at once, with fewer flexible in use alternate between solo/group. Outcomes measured were predominantly in terms of validating feasibility of the device and/or arts activity reported.

Conclusion

Current research concerning technology‐assisted creative arts activities for people living with dementia mainly demonstrates feasibility of new devices, indicating that the field in general is predominantly in the prototyping stage. Future research should consider device development past prototyping, and consider comparing devices across different art‐forms i.e, applications having a varied range of artforms which allow for individual needs and interests to be accommodated.
Sex differences in CSF biomarkers profile of accelerated biological aging individuals at risk of Alzheimer’s disease
Authors: Rodríguez‐Fernández Blanca , Suárez‐Calvet Marc , Arenaza‐Urquijo Eider M , Milà‐Alomà Marta , Minguillón Carolina , Molinuevo Jose Luis , Suridjan Ivonne , Kollmorgen Gwendlyn , Wild Norbert , Navarro Arcadi , Fauria Karine , DeVivo Immaculata , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Sala‐Vila Aleix , Vilor‐Tejedor Natalia , Crous‐Bou Marta ,   for the ALFA study
Published: December 2022

Background

Prevalence of Alzheimer’s disease (AD) is higher in women than in men; however, underlying biological mechanisms remain unknown. Being aging the major risk factor for AD, sex dimorphism in biological aging could explain sex‐specific patterns of disease manifestation across the Alzheimer’s continuum. This study aimed to explore whether there are sex‐specific differences in specific biological pathways among individuals at accelerated or decelerated biological aging.

Methods

This study included 370 middle‐aged cognitively unimpaired participants at risk of AD from the Alzheimer’s and Families (ALFA) cohort (61.9% women). Telomere length (TL) was determined by qPCR from DNA extracted from peripheral blood leukocytes [Figure 1A]. TL values were normalized by computing z‐scores. Delta‐age was calculated as the residuals from regressing TL z‐scores on chronological age separately in women and men. Accelerated and decelerated aging groups were defined as those individuals in the 10th and 90th percentiles of delta‐age, respectively [Figure 1B]. Aβ42, Aβ40, CCL2, p‐tau, t‐tau, NfL, neurogranin, SNAP25, GAP43, synaptotagmin1, sTREM2, YKL40, GFAP, S100B, IL6, sVCAM1, sICAM1, and α‐synuclein were measured in CSF. Biomarker measurements were performed using immunoassays (colorimetric ELISA, MSD, Elecsys®, Simoa and the exploratory Roche NeuroToolKit robust prototype assays) and mass spectrometry. Differences on CSF biomarkers levels were assessed using non‐parametric tests for equality of means. P‐values <0.05 were considered significant. Multiple comparisons corrections were performed.

Results

Levels of CSF t‐tau, p‐tau, GAP43 and α‐synuclein were significantly higher in accelerated aging females compared to males (q‐values = 0.030, 0.031, 0.022, 0.041, respectively) [Figure 1C]. These differences were not observed when comparing the whole sample of women and men. Intra sex‐specific differences showed that the cytokine CCL2 was significantly higher in men at accelerated aging compared to men at decelerated aging (p‐value = 0.028) [Figure 1D].

Conclusions

Accelerated aging women present higher levels of CSF biomarkers for tau‐pathology and synaptic dysfunction compared to their male counterparts. Accelerated biological aging could be associated with neuroinflammatory processes in cognitively unimpaired men at risk of AD. Biological aging based on TL determination could provide useful insights in tracking sex‐specific patterns of disease progression across the AD continuum.
Design and implementation of the participatory German network for translational dementia care research (TaNDem) – A Qualitative Study on the Perspectives of Stakeholders and Healthcare Providers in Dementia Care Research
Authors: Scharf Annelie , Raedke Anika , Köhler Stefanie , Heppner Marie Marleen , Purwins Daniel , Roes Martina , Teipel Stefan , Hoffmann Wolfgang , Michalowsky Bernhard
Published: December 2022

Background

Currently, there is a lack of sustainable, translational structures in dementia care research that enable a nationally guided participatory interaction between research, care practice, and those affected by dementia. A close cooperation between research and care practice with a simultaneous inclusion of those affected by dementia is essential to translate scientific evidence into practice and address routine care needs in healthcare research. Within the project TaNDem we aim to close the gap between research and practice by establishing a translational dementia care research network with participatory elements. We interviewed healthcare providers to identify their expectations for the design and implementation of this network.

Methods

We interviewed n = 87 stakeholders in healthcare practice and healthcare research within focus group interviews. We followed a structured interview guide including, questions about (i) the main objectives and areas of such network, (ii) the preferred way of coordination, collaboration, and interaction, (iii) and barriers and facilitators of implementation. The recorded interviews were transcribed and analyzed using qualitative content analysis according to Mayring.

Results

Interviewees expressed the desire for an understandable translation of research results for practitioners, for a strengthening of networking, and for interaction between research and practice. Stakeholders would like to see evaluations of healthcare situations in specific geographic regions and the involvement of people affected by dementia in research. Furthermore, they preferred better communication between researchers and practitioners, support in identifying suitable cooperation partners, and a unified approach towards health policy. According to collaboration, regional and national meetings as well as communication channels could be implemented via online platforms, databases, or local advisory hubs. Obstacles mentioned include limitations in terms of staff, budget and time of stakeholders, as well as regional differences and duplicate structures. To successfully implement the TaNDem network, there should be local contact persons. Furthermore, the cooperation should be based on trust and jointly defined objectives that add value to the individual’s work of each member of the research network.

Conclusion

The results show that stakeholders in healthcare practice and healthcare research have similar expectations related to a participatory collaboration that provides an added value to all participants.
Underlying cerebrovascular pathology in Subjective Cognitive Decline: A systematic review and meta‐analysis
Authors: Gonzalez‐Burgos Lissett , Pitti Helda , Diaz‐Galvan Patricia , Barroso Jose , Badji Atef , Westman Eric , Ferreira Daniel , Cedres Nira
Published: December 2022

Background

Subjective cognitive decline (SCD) implies self‐reported cognitive complaints in absence of objective cognitive impairment. SCD has been postulated as an early marker of Alzheimer’s Disease (AD). However, longitudinal studies have linked SCD to future vascular dementia. Thus, we conducted a systematic review and meta‐analysis aiming to synthesise and analyse the available data on the association between SCD and the presence of underlying cerebrovascular pathology measured by MRI.

Method

Our study was performed following the PRISMA statement. The search strategy included terms for “subjective cognitive decline” and “white matter signal abnormalities”. It was conducted in 3 databases (PubMed, Scopus and Web of Science) from origin by December 8th, 2021. Two authors screened the studies in a 2‐stepwise approach. Primary studies including cognitively unimpaired adults with subjective cognitive complaints meeting the SCD‐I criteria for SCD that evaluated cerebrovascular pathology based on white matter signal abnormalities (WMSA) on MR images were selected. Study quality was assessed using the FLC 3.0 tool. Meta‐analysis comparing case‐control mean difference of WMSA was performed.

Result

Of 240 articles identified, 16 research articles were selected. Of those, 8 case‐control studies were selected for the meta‐analysis. The sample size of the SCD group across the studies ranged from 8 to 906 participants, with age ranged from 40 to 84 years. All eight studies comprised a total of 2.637 SCD individuals. Study quality was deemed moderate (n=6) to high (n=10). The meta‐analysis showed a significant overall effect‐size between the mean WMSA burden of SCD and the controls, that was not significantly heterogeneous (Q(gl=7)=14.20; p=0,04; I2=42,5%). SCD was significantly associated with higher CVP burden based on neuroimaging measures.

Conclusion

This is the first study to synthesise and analyse the current evidence on the association between SCD and WMSA. Our findings show the usefulness of SCD as a marker of underlying cerebrovascular pathology. Thus, the potential role of SCD as a preclinical stage of vascular cognitive impairment needs further investigation. Changes in lifestyle (e.g. exercise, diet, smoking cessation), cognitive stimulation or pharmacotherapy may be key to avoid an evolution towards cognitive deterioration in SCD.
Odor identification and discrimination as markers of early Alzheimer’s disease
Authors: Audronytė Eglė , Kaubrys Gintaras
Published: December 2022

Background

Reliable markers are essential in order to achieve accurate diagnosis in the early stages of Alzheimer’s disease (AD). Olfactory impairment has been identified as a possible non‐invasive biomarker of AD. Odor identification tasks are most commonly used for measuring olfactory abilities. However, odor identification is associated to verbal abilities and cultural context. The aim of this study was to determine whether odor discrimination could be a valid marker of early AD.

Method

65 participants were enrolled in the study. 26 patients with mild cognitive impairment due to AD (MCI‐AD), 26 patients with mild dementia due to AD (MD‐AD) and 13 cognitively normal elderly subjects (CN). All participants underwent cognitive examination (MMSE, CDR, ADAS‐Cog 13, fluency tests) and olfactory function assessment (Burghart Sniffin’ Sticks odor identification and odor discrimination tests).

Result

MD‐AD and MCI‐AD subjects performed significantly worse than CN subjects in both odor identification (mean correct responses ± SD was 6.77±1.91; 9.08±2.30; 13.31±1.55 respectively; p<0.001) and odor discrimination (mean correct responses ± SD was 6.27±1.66; 8.19±1.65; 12.92±1.71 respectively; p<0.001) tests. MD‐AD subjects performed significantly worse than MCI‐AD subjects in both odor identification (p<0.05) and odor discrimination (p<0.001) tests.

Both odor identification and odor discrimination tests had AUC>0.9 on ROC analysis for differentiating MCI‐AD subjects from CN subjects (AUC 0.938 and 0.982) and for differentiating MD‐AD subjects from CN subjects (AUC 0.99 for both). Neither odor identification, nor odor discrimination test reached AUC>0.8 on ROC analysis for differentiating MCI‐AD from MD‐AD subjects (AUC 0.777 and 0.793).

Odor identification differentiated MCI‐AD from CN subjects with sensitivity of 69% and specificity of 100% at cut‐off score of ≤10 correct responses. Odor discrimination differentiated MCI‐AD from CN subjects with sensitivity of 77% and specificity of 100% at cut‐off score of ≤9 correct responses.

Conclusion

The study confirmed that tests for olfactory dysfunction can reliably differentiate patients with mild cognitive impairment due to AD from cognitively normal subjects. Both odor identification and discrimination are reliable markers for identification of patients with early Alzheimer’s disease.
Testing causality in the association between amyloid‐β and tau in genetically identical twins
Authors: Coomans Emma M , Tomassen Jori , Ossenkoppele Rik , Konijnenberg Elles , Rikken Roos M. , Collij Lyduine E. , Golla Sandeep SV , Windhorst Albert D. , Tijms Betty M. , Barkhof Frederik , Scheltens Philip , de Geus Eco J.C. , Visser Pieter Jelle , van Berckel Bart NM , den Braber Anouk
Published: December 2022

Background

The amyloid‐cascade hypothesis of Alzheimer’s disease posits that there is a causal relationship between amyloid‐β (Aβ) and tau pathology. However, the mechanism through which Aβ would cause tau remains unclear. We cannot exclude the possibility of an additional underlying factor influencing Aβ at one time‐point and tau at a later time‐point. One such potential underlying factor can be genetic variation among individuals. This study aimed to examine the relationship between Aβ and tau, taking potential genetic confounding into account using a genetically identical twin design.

Methods

We included 70 identical twins (35 pairs) from the EMIF‐AD PreclinAD study with normal baseline cognition. We extracted baseline global [18F]flutemetamol (Aβ)‐PET binding potential (BPND) and 4‐year follow‐up [18F]flortaucipir (tau)‐PET BPND in a temporal meta‐region‐of‐interest. If Aβ is causally related to tau, the twin with more Aβ should also have more tau compared to the co‐twin. We tested this using regional and voxel‐wise within‐pair difference models, in which the within‐pair difference in Aβ is regressed on the within‐pair difference in tau. The resulting effect represents an association that is free of confounding due to factors that are shared between twins of the same pair, which includes genetic factors (twins are genetically identical), but also shared demographic (e.g. sex, age) and shared environmental (e.g. raised in the same family) factors.

Results

Participant characteristics are shown in Table 1. Total group analysis showed that global Aβ‐PET BPND was associated with temporal tau‐PET BPND (β=0.49, p<0.001) (Fig‐1A). The twin‐difference model replicated this. We observed a highly comparable effect size for the association between within‐pair differences in global Aβ‐PET and within‐pair differences in temporal tau‐PET (β=0.56, p<0.001) (Fig‐1B). Compared to the total group voxel‐wise analysis, we observed an overlapping (and more widespread) pattern when regressing within‐pair differences in global Aβ‐PET on within‐pair differences in voxel‐wise tau‐PET, except for effects on tau in the medial temporal lobe (Fig‐2).

Conclusion

Our within‐pair difference results show that the association between Aβ and tau is minimally affected by confounding by genetic variation. Our voxel‐wise results support a causal association between global Aβ and tau outside of the medial temporal lobe.
Concordance of CSF AD biomarkers between intraventricular and lumbar CSF in iNPH
Authors: Lukkarinen Heikki , Vanninen Aleksi , Tesseur Ina , Pemberton Darrel , Van Der Ark Peter , Herukka Sanna‐Kaisa , Rauramaa Tuomas , Hiltunen Mikko , Zetterberg Henrik , Leinonen Ville
Published: December 2022

Background

The core Alzheimer’s Disease cerebrospinal fluid (CSF) biomarkers, amyloid β 1‐42 (Aβ42), total tau (T‐tau) and phosphorylated tau 181 (P‐tau181), have presented added value for differential diagnostics in the field of neurodegenerative diseases. Moreover, the concentration gradient of these biomarkers between intraventricular (V‐CSF) and lumbar region CSF (L‐CSF) has been partly established for idiopathic normal pressure hydrocephalus (iNPH) patients. In this study, we aim to provide conversion factors between V‐CSF and L‐CSF.

Method

Altogether 138 patients were diagnosed for possible iNPH and received ventriculoperitoneal shunt. Lumbar CSF samples were obtained 3‐months prior shunt surgery. Additional intraoperative interventricular CSF samples were obtained from 97 patients. Furthermore, follow‐up samples of 41 patients were obtained 0‐, 3‐, 6‐ and 18‐months (0M, 3M, 6M, 18M) postoperatively by shunt valve and lumbar punctures. Aβ42, T‐tau and P‐tau181 CSF concentrations of samples collected were analyzed using Elecsys (Cohort of 97 patients) and Innotest (Cohort of 41 patients) assays.

Result

Preoperative L‐CSF Aβ42, T‐tau and P‐tau181 associated to intraoperative V‐CSF (Sprearman ρ=0.54 Aβ42, r=0.34 T‐tau, r=0.55 P‐tau, all p<0.001). Strong associations were seen between postoperative L‐ and V‐CSF for all biomarkers in the every follow‐up sampling point (Spearman ρ Aβ42: 0M=.77, 3M=.88, 6M=.83, 18M=.84) (T‐tau: 0M=.92, 3M=.91, 6M=.92, 18M=.94) (P‐tau181: 0M=.96, 3M=.95, 6M=.94, 18M=.94) (all p<0.0001). Regression equations were determined for intraoperative V‐CSF and preoperative L‐CSF (Aβ42: V‐CSF=185+0.34*L‐CSF, T‐tau: Ln(V‐CSF)=3.11+0.49*Ln(L‐CSF) and P‐tau181: V‐CSF=8.2+0.51*L‐CSF, all p<0.01), and for postoperative V‐CSF and L‐CSF (Aβ42: V‐CSF=86.7+0.75*L‐CSF, T‐tau: V‐CSF=86.9+0.62*L‐CSF and P‐tau181: V‐CSF=1.9+0.75*L‐CSF all p<0.0001).

Conclusion

The Aβ42, T‐tau and P‐tau181 showed linear dependency between ventricular and lumbar CSF for preoperative L‐CSF and intraoperative V‐CSF as well as for postoperatively collected L‐CSF and V‐CSF. The regression equations based on these findings provide a novel tool to use V‐CSF for diagnostics and prognostics entities that rely on the lumbar CSF concentrations.
Health‐Related Quality of Life Among Sexual and Gender Minority Older Adults Living With Cognitive Impairment
Authors: Kim Hyun‐Jun , Fredriksen‐Goldsen Karen , Jung Hailey H.
Published: December 2022

Background

While sexual and gender minority (SGM) older adults are found to be at heightened risks of cognitive impairment, they may face unique challenges in health‐related quality of life (HRQOL) due to bias, social isolation, and other SGM‐related risks. This study examined risk and protective factors predicting HRQOL among SGM older adults living with cognitive impairment.

Method

A subset of longitudinal survey data collected over three time points (2014, 2016, 2018) was drawn from the Aging with Pride: National Health, Aging, and Sexuality/Gender Study. Participants were 855 people who were born in 1964 or earlier and self‐reported having cognitive impairment at Wave 1 (2014). We employed multilevel modeling to investigate the effects of risk and protective factors on the overall levels of physical and psychological HRQOL and their longitudinal changes.

Result

Lifetime SGM‐related discrimination and victimization (b = ‐0.17, p < .001; b = ‐0.22, p < .001, respectively), identity stigma (b = ‐0.91, p < .05; b = ‐2.97, p < .001), and insufficient food intake (b = ‐2.70, p < .001; b = ‐3.69, p < .001) were associated with lower physical and psychological HRQOL. Having more chronic conditions (b = ‐1.52, p < .001) was associated with lower physical HRQOL. Factors positively associated with physical and psychological HRQOL were physical activity (b = 0.12, p < .01; b = 0.19, p < .001), outdoor leisure activity (b = 3.57, p < .001; b = 5.40, p < .001), optimal sleep (b = 3.47, p < .001; b = 2.32, p < .001), and social network size (b = 0.19, p < .01; b = 0.66, p < .001).

Conclusion

The results of this study have important implications for further research. Most research on cognitive impairment has previously adopted a disease and deficit‐focused model rather than investigating the resilience and quality of life of people living with cognitive impairment. It is critical to further identify ways to help SGM older adults with cognitive impairment adhere to health‐promoting behaviors and to foster and maintain social resources as we develop targeted and culturally responsive interventions that support their optimal aging.
Identifying Latent Patterns and Predictors of Health Behaviors and Healthcare Barriers among LGBT Older Adults
Authors: Jung Hailey H. , Kim Hyun‐Jun , Fredriksen‐Goldsen Karen
Published: December 2022

Background

Health behaviors are multi‐dimensional and associated with various barriers to healthcare. With no previous research having investigated patterns of health behaviors in conjunction with healthcare barriers among lesbian, gay, bisexual, and transgender (LGBT) older adults, we aim to identify latent classes of the behavior and barrier patterns, to examine differences in physical and psychological health‐related quality of life (HRQOL) by the specified latent classes, and to explore predictors of the class membership.

Method

Three‐step latent class analysis with survey weights was conducted using baseline data of the Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS, N = 2,450). Health behavior and healthcare barrier indicators were analyzed in four dimensions: risk‐taking behavior, health‐promoting behavior, preventive care, and healthcare barriers.

Result

The best empirical and substantive fit was determined with four classes consisting of (1) healthy behaviors and minimal barriers (C1, 39%), (2) unhealthy behaviors and high barriers (C2, 31%), (3) healthy behaviors and healthcare system barriers (C3, 19%), (4) Very healthy self‐care behaviors, low preventive care use, and moderate barriers (C4, 11%). Compared to C1, C3 had lower physical HRQOL and C2 had lower physical and psychological HRQOL. C4 did not differ in HRQOL from C1. Modifiable predictors of C2 include more day‐to‐day discrimination and lower mastery and social support.

Conclusion

Efforts to lower healthcare barriers are warranted in addition to interventions to strengthen social support and to reduce marginalization. Positive relationships between LGBT older adults and healthcare need to be established via trust‐building and cultural competency.
White matter health in the context of Alzheimer’s disease pathophysiology
Authors: Raghavan Sheelakumari , Przybelski Scott A. , Reid Robert I. , Lesnick Timothy G. , Ramanan Vijay K , Botha Hugo , Matchett Billie J , Murray Melissa E. , Reichard Ross R. , Knopman David S. , Radford Jonathan Graff , Jones David T. , Lowe Val J. , Mielke Michelle M. , Machulda Mary M. , Petersen Ronald C. , Kantarci Kejal , Whitwell Jennifer L , Josephs Keith A , Jack Clifford R. , Vemuri Prashanthi
Published: December 2022

Background

Multi‐compartment modelling of white matter (WM) microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on WM health through the neurite (axons and dendrites) density index and free water measures. We hypothesized that cerebrovascular disease (CVD), Alzheimer’s disease (AD), and an FDG pattern suggestive of TDP‐43 proteinopathy would be associated with distinct NODDI readouts of WM damage which would be informative for identifying the substrate for cognitive impairment.

Method

We identified two independent cohorts with multi‐shell diffusion MRI, amyloid and tau PET, and cognitive assessments. One, were participants from the Mayo Clinic Study of Aging, a population‐based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota. The second were 61 amyloid positive AD participants from the Mayo AD Research Center.

Result

We observed an increase in free water and decrease in neurite density in the genu of the corpus callosum associated with vascular risk factors, which we refer to as vascular WM component (Figure 1). Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal WM where we measured parahippocampal cingulum and inferior temporal WM bundles. Worsening temporal neurite density was associated with (antemortem confirmed) FDG TDP‐43 signature. Post‐mortem neuropathologic data on a small subset (n=9) of this sample lend support to our findings. In the population‐based cohort where vascular disease was more prevalent, the vascular WM component explained variability in global cognition (partial R2 of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory) (Table 1). In the AD dementia clinic‐based cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non‐trivial contribution of the temporal WM component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition.

Conclusion

White matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether CVD versus neurodegenerative disease caused by tau deposition or TDP‐43 pathology) for cognitive impairment in older individuals.