bluuebunny/crossref_metadata_2025 huggingface dataset:
A global functional network biomarker across aging and dysexecutive Alzheimer’s disease
Authors: Corriveau‐Lecavalier Nick , Gunter Jeffrey L. , Kamykowski Michael G. , Radford Jonathan Graff , Botha Hugo , Wiepert Daniela A , Schwarz Christopher G. , Yacoub Essa , Knopman David S. , Boeve Bradley F. , Ugurbil Kamil , Petersen Ronald C. , Jack Clifford R. , Terpstra Melissa , Jones David T.
Published: December 2022

Background

Disruption of the default mode network (DMN) is thought to be a common feature of aging and across Alzheimer’s disease (AD) clinical phenotypes, while syndromic variability could be reflected in selective degeneration of macro‐scale networks optimally supporting specific mental abilities (Fig 1). As part of a collaborative effort between Mayo Clinic and the Human Connectome Project‐Aging (HCP‐A), we aimed to delineate a biomarker of global network failure across aging and the dysexecutive (dAD) and amnestic phenotypes of AD, and biomarkers of focal degeneration specific to each AD phenotype.

Method

We used a regression framework to assess the relationships between a marker of DMN dysfunction, the network failure quotient (NFQ), and factors relevant to AD such as age, cortical thickness (global cortical thickness, inferior parietal lobe), hippocampal volume, and cognition (episodic memory, cognitive flexibility) in the HCP‐A cohort, which consists of 725 non‐demented older adults. We then fit centile curves to the HCP‐A cohort to assess whether the NFQ and focal degeneration markers could distinguish dAD (n=10) and amnestic AD (n=8) patients from the HCP‐A cohort at the group‐ and individual‐level. Participants were scanned using the HCP‐A protocol, allowing for the acquisition of high‐resolution multi‐echo structural images and longer resting‐state connectivity acquisition time compared to traditional protocols.

Result

The NFQ related to age, cortical thickness, hippocampal volume, and cognition in the HCP‐A cohort. It also strongly discriminated dAD and amnestic AD from the HCP‐A cohort but did not discriminate between AD phenotypes. In contrast, markers of focal degeneration were phenotype‐specific; parieto‐frontal areas yielded largest effect sizes for dAD patients, and hippocampal and temporal areas best discriminated patients with amnestic AD (Fig 2).

Conclusion

The NFQ may reflect shared system‐level pathophysiological mechanisms across aging and the dysexecutive and amnestic phenotypes of AD whereas focal degeneration markers highlight distinct pathognomonic processes across AD phenotypes. These findings suggest that inter‐individual variability in cognitive impairment in AD would be closely tied to modular, phenotype‐specific network degeneration combined with a common global functional disruption of the DMN. Such information has crucial implications for clinical biomarkers and to provide a deeper understanding of heterogeneity in AD.
Pulse pressure trajectories predict brain microstructure in an APOE‐dependent manner among cognitively normal older adults
Authors: Parada Humberto , Bergstrom Jaclyn , Reas Emilie T.
Published: December 2022

Background

Arterial stiffness is associated with increased risk of cognitive decline and dementia in older adults; however, the mechanisms by which arterial stiffness impacts brain health remain unclear. We examined whether trajectories of pulse pressure (PP), a surrogate marker of arterial stiffness, beginning in midlife predicted brain microstructure at older age, using the multicompartment diffusion MRI technique restriction spectrum imaging (RSI). We assessed whether effects of PP on executive function were mediated by brain microstructure, and whether APOE genotype modified associations between PP and microstructure.

Method

We included 146 cognitively normal adults (mean age=76.6, SD=6.8 years) who underwent RSI and cognitive testing in 2014‐2016 and measurements of PP up to eight times before MRI, from 1984‐2016. Participants were classified according to PP trajectory using latent class growth modeling. Restricted isotropic diffusion (RI), neurite density, isotropic free water (IFW), and hindered isotropic diffusion (HI) were computed in five subcortical regions and 15 white matter tracts. Multiple linear regression examined associations between PP trajectories and microstructure, and between microstructure and Trails B performance. Mediation analyses, adjusted for covariates, evaluated whether microstructure mediated effects of PP trajectories on executive function. Age‐and‐sex‐adjusted partial correlations tested associations between continuous PP and RSI metrics by APOE genotype (ε4 carriers versus non‐carriers).

Result

Participants with high PP trajectories (n=50) had lower RI and higher HI and IFW in multiple subcortical regions and fiber tracts compared to those with low PP trajectories (n=96), and of these, eight were also associated with Trails B performance. Associations between high PP trajectories and worse executive function were mediated by lower RI in the amygdala (βa*βb=4.13, 95%CI=0.91‐11.01) and in several fiber tracts including the parachippocampal cingulum (βa*βb=3.77, 95%CI=0.95‐9.93) and fornix (βa*βb=3.71, 95%CI=0.59‐10.19). High PP more strongly correlated with lower RI in the hippocampus, uncinate fasciculus, and inferior fronto‐occipital fasciculus (IFO); with high IFW in the IFO and superior corticostriatal fasciculus, and with high amygdala HI, among APOE4 ε4 carriers than non‐carriers (Figure).

Conclusion

Prolonged elevated PP predicts subcortical and white mater microstructural abnormalities, particularly for those at greater risk for dementia, and may contribute to impaired executive function via microstructural injury.
Reproductive health data and its relationship to baseline brain imaging and cognitive measurements in cognitively unimpaired female PSEN1 E280A mutation carriers and non‐carriers from the API ADAD Trial
Authors: Ghisays Valentina , Vila‐Castelar Clara , Giraldo‐Chica Margarita , Acosta‐Baena Natalia , Protas Hillary D. , Malek‐Ahmadi Michael H. , Chen Yinghua , Luo Ji , Lee Wendy , Bocanegra Yamile , Muñoz Claudia , Herrera Karina , Hu Nan , Sink Kaycee M. , Clayton David , Alvarez Sergio , Langbaum Jessica B. , Chen Kewei , Su Yi , Tariot Pierre N. , Quiroz Yakeel T. , Lopera Francisco , Reiman Eric M. , Ríos‐Romenets Silvia , Group API ADAD Colombia Trial
Published: December 2022

Background

The impact of sex steroid hormones on Alzheimer’s disease (AD) remains to be further clarified. Research suggests that shorter reproductive span, late menarcheal age, early menopause, oophorectomies and hysterectomies, are associated with increased dementia risk. We examined reproductive health and its associations with brain imaging and cognitive measurements in unimpaired female Presenilin 1 (PSEN1) E280A mutation carriers and non‐carriers from the Alzheimer’s Prevention Initiative Autosomal Dominant AD (API ADAD) Trial (NCT01998841).

Method

A total of 151 cognitively unimpaired 30‐53 year‐old females (101 PSEN1 mutation carriers and 50 non‐carriers) were included. Reproductive health data (i.e., menarcheal age, number of pregnancies, deliveries, miscarriages, and living children) from all participants were examined, as well as the extent to which menarcheal age was related to age‐adjusted baseline 1) cortical amyloid plaque burden (florbetapir PET), 2) Precuneus cerebral glucose metabolism (fluorodeoxyglucose PET), 3) hippocampal volume (3TMRI), and 4) the API ADAD preclinical cognitive composite score, which includes the MMSE Orientation score, CERAD Word List Delayed Recall and Constructional Praxis, Multilingual Naming Test and Raven’s Progressive Matrices subset. We examined associations with the cognitive and brain imaging measures corrected for multiple comparisons (Bonferroni).

Result

Carrier and non‐carrier females did not differ on number of pregnancies, deliveries, miscarriages, or living children. Female carriers had a significantly younger menarcheal age than non‐carriers (12.8 ±1.5 versus 13.7±1.6 years, p = 0.007, Bonferroni). Among carrier females, older menarcheal age was associated with lower scores on the Raven’s test (Bonferroni: r = ‒0.28,p =0.035). Menarcheal age was not associated with scores on the cognitive composite or other individual subtests, or with brain imaging measures.

Conclusion

Our findings suggest reproductive health data did not differ between carrier and non‐carrier females, except for a slightly younger menarcheal age compared to non‐carriers, and that menarcheal age may have a very limited impact on brain pathology and function at preclinical stages of ADAD. Longitudinal studies with larger samples are needed to clarify the extent to which earlier menarcheal age may be related to changes in cognitive function in mutation carrier females transitioning from preclinical to clinical stages.
Prediction of Aβ State from Brain Amyloid PET Images Using Machine Learning Algorithm
Authors: Simfukwe Chanda , Youn Young Chul
Published: December 2022

Background

Analyzing brain amyloid positron emission tomography (PET) images to access the occurrence of β‐Amyloid (Aβ) deposition in Alzheimer’s patients requires a lot of time and effort from physicians and also the variation of each interpreter may differ. For this reason, a machine learning model was developed using a convolutional neural network (CNN) as an objective decision to predict the Aβ‐positive and Aβ‐negative status from brain amyloid PET images.

Method

A total of 154 cognitively impaired subjects were used in this study. The 18F‐florbetaben (18F‐FBB) PET was administered on all participants and the criteria for differentiating Aβ‐positive and Aβ‐negative state was based on brain amyloid plaque load score (BAPL) that depended on the visual assessment of PET images by the physicians. We applied the CNN algorithm trained in batches of 52 augmented 18F‐FBB PET images per subject from two classes: Aβ‐positive and Aβ‐negative states that were determined based on the BAPL scores.

Result

The binary prediction of the model average performance matrices was evaluated after 40 epochs of 5 trial‐based on test datasets. The model accuracy for predicting Aβ‐positivity and Aβ‐negativity was 82.00±0.03 in the test dataset. The sensitivity and specificity were 97.00±0.02 and 97.00±0.02 with an area under the curve (AUC) of 90.00±0.03.

Conclusion

Based on this study, the designed CNN model has the potential to be used clinically for screening amyloid PET images.
Racial differences in white matter hyperintensity load in aging, MCI, and AD
Authors: Morrison Cassandra , Dadar Mahsa , Collins Louis D
Published: December 2022

Background

Cerebral small vessel disease (CSVD), often measured using white matter hyperintensities (WMHs) is a pathological change to the brain that increases ones’ risk for both age‐related cognitive decline and dementia. Several studies have noted that there is greater risk of CSVD in African Americans than in Caucasians. However, limited research has examined WMHs as a proxy of CSVD in an ethnically diverse sample. The goal of this research was to determine whether WMH load differs between African Americans and Caucasians.

Methods

Participants for this study were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI1, GO, 2, and 3). They were included if they had baseline WMH measurements and a baseline diagnosis. WMHs were segmented using a previously validated automatic technique (Dadar et al., 2018). A total of 91 African Americans and 1846 Caucasians were included in this analysis. To compare samples, 91 Caucasian participants were randomly matched to African Americans based on age, sex, education, and diagnosis. This random selection was completed 1000 times using bootstrap resampling. A linear mixed effects was completed to examine the influence of race on WMH load: WMH ∼ Race + Age + Sex + Education + Diagnosis. The 95% confidence limits of the t‐statistics distributions for the 1000 samples were examined to determine whether the differences were statistically significant.

Results

The following figure shows the t‐statistic, 95% confidence intervals, and p‐value distributions of the 1000 bootstrapped samples. The 95% confidence intervals are between t=‐3.06 and t=‐0.89 for total WMH load, indicating significance, as the limits do not include 0.

Conclusions

Accounting for age, sex, education, and diagnostic status, racial differences were observed for total WMH load. That is, African Americans had higher total WMH load than Caucasians. Future research should examine whether these findings are observed longitudinally and if they influence cognition in an ethnically diverse sample.
Spousal caregiver burden among patient with cognitive impairment: effects on nutrition and other lifestyle factors
Authors: Jeon So Yeon , Kim Jeong Lan
Published: December 2022

Background

Among old adults, caring for a spouse with cognitive decline is well‐known to be associated with significant risk to the caregiver`s health such as cardiovascular disease, depression and, especially, cognitive impairment. It is important to understand the caregiving‐related risk factors for caregiver`s cognitive decline. Therefore, in this study, we examined the impact of caregiver`s burden on the lifestyle factors (malnutrition, sleep, depression, and physical activity) influencing cognitive decline among SCGs, focusing on nutritional status which contribute to SCG’s cognitive decline.

Method

From May 2020 to May 2021, clinical evaluation and blood tests were conducted for patients who visited Chungnam National University Hospital Geriatric Neuropsychiatric Clinic with their spouse. A total of 51 subjects were included in the analysis. As clinical assessment, we evaluated the care burden (Zait burden interview), depression(Geriatric‐Depression‐Scale), sleep quality (Pittsburgh‐Sleep‐Quality‐Index), cognitive function(Mini‐Mental‐state‐exmination) physical activity(International‐Physical‐Activity‐Questionnaire), and dietary habits (Mini‐Nutrional‐Assessment).

Result

As the care‐recipient’s cognitive function declined, the caregiver`s burden were increased (β = ‐0.66, p < 0.001). In linear regression analysis adjusted for age and sex, the SCG`s burden was significantly associated with the worse dietary habits (β = ‐3.194, p = 0.003) and increased level of depressed mood (β = 0.525, p < 0.001). The SCG`s burden showed a trend level association with sleep quality (β = 0.292, p = 0.050) but no significant relationship with physical activity (β = ‐0.053, p = 0.742). The results were unchanged after excluding care‐recipients with normal cognition (n = 7).

Conclusion

This study provides substantial evidence that SCGs are at risk for depression and malnutrition, which can further affect cognitive decline. As such, these factors should be well assessed and monitored among SCGs for patient with cognitive impairment.
Effective Connectivity Is A More Promising Biomarker for Brain Health in Middle‐Aged Adults Than Functional Connectivity: Bogalusa Heart Study
Authors: Chuang Kai‐Cheng , Pillai Sreekrishna R. , Bazzano Lydia , Carmichael Owen T.
Published: December 2022

Background

Effective connectivity, the causal influence that functional activity in a source brain location exerts over functional activity in a target brain location, has the potential to provide richer information about brain networks than functional connectivity, which only quantifies activity synchrony between regions. However, head‐to‐head comparisons of effective and functional connectivity from functional MRI data are rare, especially among diverse cognitively healthy middle aged and older adults.

Method

100 Bogalusa Heart Study participants performed a Stroop task during functional MRI (Table 1). Effective connectivity and functional connectivity among 24 regions of interest (ROIs) previously identified as activated by this task [1] were calculated using deep stacking networks [2] and Pearson correlation, respectively. Graph metrics were then calculated from directed graphs resulting from effective connectivity and undirected graphs resulting from functional connectivity. Linear regression models related graph metrics to demographic, cardiometabolic, and cognitive measures.

Result

Figure 1 shows the group‐consensus effective and functional connectivity graphs. Systolic blood pressure (SBP) was associated with effective connectivity based characteristic path length (Pearson’s r = 0.22, p‐value = 0.038) and modularity (r = 0.25, p‐value = 0.02) (Figure 2). Diastolic blood pressure (DBP) was associated with effective connectivity based degree, density, clustering coefficient, modularity, transitivity, characteristic path length, and global efficiency (|r| = 0.26 ‐ 0.35, maximum p‐value = 0.013) (Figure 2). Word reading and vocabulary scores from the Wide Range Achievement Test (WRAT) were associated with effective connectivity based degree, density, clustering coefficient, transitivity, characteristic path length, modularity, and global efficiency (|r| = 0.21 ‐ 0.27, maximum p‐value = 0.049). Logical Memory II Recognition scores associated with effective connectivity based assortativity (r = 0.24, p‐value = 0.025). Associations between functional connectivity based graph metrics and demographic, cardiometabolic, and cognitive measures were not significant.

Conclusion

In a diverse, cognitively healthy, middle‐aged community sample, graph metrics derived from effective connectivity based directed graphs tracked more closely with recognized indicators of brain health than traditional functional connectivity based undirected graph metrics. References: [1] Sheu, L. K. et al. (2012). Psychophysiology. [2] Chuang, K.‐C. et al. (2021). Machine Learning in Clinical Neuroimaging.
Gut microbiota regulates neuroinflammation and progression of neurodegeneration in a mouse model of tauopathy
Authors: Seo Dong‐oh , O'Donnell David , Jain Nimansha , Ulrich Jason D , Herz Jasmin , Lemieux Mackenzie , Stanley Jack G. , Franke Emily , Serrano Javier R. , Bao Xin , Karlsson Maria , Meier Marty , Desai Chandani , Lelwala‐Guruge Janaki , Li Yuhao , Shi Yang , Wang Chao , Cheng Jiye , de Lima Kalil Alves , Dodiya Hemraj B. , Hibberd Matthew , Griffin Nicholas , Handley Scott , Kipnis Jonathan , Sisodia Sangram S. , Gordon Jeffrey I. , Holtzman David M.
Published: December 2022

Background

Although mounting evidence supports that an unbalanced gut microbiota (GM) is linked to amyloid‐β deposition, the contribution of the GM to tau‐mediated neurodegeneration (TN) is poorly characterized. Our preliminary data have shown that the GM manipulations, using either treatment with a combination of antibiotics (ABX) or raising animals in germ‐free (GF) conditions, regulate TN (Seo, et al., AAIC 2021). However, further investigation is needed to sort out the underlying mechanisms that are involved in the interaction between GM and TN. Here, we explore neuroinflammation as a potential mediator in the interaction between GM and TN.

Method

P301S tau transgenic mice were crossed with human ApoE knock‐in mice (ApoE3 or ApoE4) or ApoE knockout mice (EKO) to generate P301S::ApoE3/E3, ApoE4/E4, or P301S/EKO mice, termed TE3F, TE4F, and TEKO, respectively. Each group was gavaged with either ABX or H2O from postnatal day 16‐22, housed in a specific pathogen‐free facility, and euthanized at 9.5 months of age. A separate group of TE4F mice was housed under GF conditions. Collected brains were sectioned and used for immunohistochemistry analysis.

Results

In agreement with brain atrophy measurements that we previously reported, TE3F mice treated with a short‐term ABX showed significantly lower phosphorylated tau (p‐tau) staining compared to the H2O‐treated group (p < 0.01), but not TE4F and TEKO mice treated with ABX. GF‐TE4F mice also showed a marked decrease in p‐tau staining compared to conventionally‐raised animals (p < 0.01). Further quantification of gliosis, as measured by GFAP and Iba1 immunostaining, did not reveal any ABX treatment effects. However, when we assessed the expression of clec7a+ microglia, which marks reactive microglia, ABX treated animals showed significantly lower clec7a+ staining across the different APOE isoform groups (p < 0.01). Furthermore, microglial morphology analysis revealed that ABX treatment drive microglia to a more homeostatic‐like state in TE3F mice, but not in TE4F nor TEKO mice. Remarkably, GF‐TE4F mice showed a marked decrease in both GFAP and Iba1 expression compared to the control TE4F mice (p < 0.05).

Conclusion

Our results support the hypothesis that GM manipulation modulates tau‐mediated neurodegeneration via influencing a neuroinflammatory mechanism.
PDE5 inhibitors against synaptic and cognitive impairment in Alzheimer’s disease and related dementia
Authors: Arancio Ottavio , Zuccarello Elisa , Fiorito Jole , Acquarone Erica , Argyrousi Elentina , Staniszewski Agnieszka , Calcagno Elisa , Puzzo Daniela , Deng Shi‐Xian , Landry Donald
Published: December 2022

Background

Gene transcription mechanisms leading to synaptic plasticity and memory formation, including phosphorylation of the transcription factor CREB, are perturbed in Alzheimer’s disease (AD). In this regard, cyclic guanosine monophosphate (cGMP), which activates cGMP‐dependent protein kinases that, in turn, phosphorylate CREB, has been implicated in the memory and synaptic plasticity impairment occurring in the disease. Sildenafil (Viagra®), the well‐known FDA approved inhibitor of phosphodiesterase 5 (PDE5I), the enzyme that degrades cGMP, has shown efficacy in AD animal models (Zuccarello et al, Biochem Pharmacol. 2020) and was recently significantly associated with a reduced risk of AD in an unbiased study including 7.23 million individuals (Fang et al, Nat. Aging 2020).

Method

Following the development of a library of small molecules inhibiting phosphodiesterase 5 (PDE5), compound efficacy was tested in different animal models of Aβ and tau elevation. Specifically, these animals were tested using a combination of biochemical (western blotting of proteins involved with gene transcription machinery), electrophysiological [analysis of long‐term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation], and behavioral (assessment of spatial and associative memory through radial arm water maze and fear conditioning) techniques.

Result

Structure activity relationship (SAR) analysis of existing PDEI scaffolds led to the design and synthesis of compound 7a, a quinoline customized for AD with improved physiochemical properties compared to existing inhibitors. The molecule has outstanding inhibitory activity against PDE5 (IC50 = 0.27nM) and selectivity against all other PDE isoforms (PDE5/PDEs > 1000). It also crosses the blood brain barrier (AUC0‐tratio = 0.41) and has similar Tmax values in the brain and plasma, indicating that its distribution to the brain is fast. Moreover, similar to other PDE5Is, 7a re‐established normal LTP and both spatial and associative memory after Aβ and tau elevation. Finally, the compound re‐established normal increase of CREB phosphorylation and cGMP levels after memory induction in the presence of Aβ and tau.

Conclusion

Up‐regulation of CREB activation through PDE5 inhibitors might be beneficial against Aβ and tau‐induced synaptic and memory dysfunctions.
Does tadalafil increase brain blood flow? The PASTIS trial
Authors: Hainsworth Atticus H , Pauls Mathilde , Binnie Lauren , Benjamin Philip , Betteridge Shai , Clarke Brian , Dhillon Mohani‐Preet , Ghatala Rita , Hainsworth Fearghal , Howe Franklyn , Khan Usman , Kruuse Christina , Madigan Jeremy , Moynihan Barry , Patel Bhavini , Pereira Anthony , Rostrup Egill , Shtaya Anan , Spilling Catherine A , Trippier Sarah , Williams Rebecca , Young Robin , Barrick Thomas R , Isaacs Jeremy D
Published: December 2022

Background

This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely‐used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of vascular cognitive impairment.

Method

In a double‐blinded, placebo‐controlled, cross‐over trial, female and male participants received tadalafil (20mg) and placebo on two visits at least 7 days apart (randomized to order of treatment). The primary endpoint was change in subcortical CBF, with secondary outcome measures including change in cortical CBF and a panel of neuropsychological assays of cognition. The Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease (PASTIS) trial was funded by the ADDF and the UK Alzheimer’s Society (Clinical trial registration: clinicaltrials.gov/ct2/show/NCT02450253; eudract.ema.europa.eu/2015‐001235‐20).

Result

Tadalafil increased CBF non‐significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = 0.0960). There were incidental treatment effects on systolic and diastolic blood pressure (‐7.8, ‐4.9 mmHg respectively; P<0.001). No serious adverse events were observed.

Conclusion

The PASTIS trial did not identify a significant treatment effect of single‐administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens.
Automating the verbal paired associates test to assess memory remotely and at scale
Authors: Cormack Francesca K , Kaula Alexander J , Taptiklis Nick
Published: December 2022

Background

Verbal neuropsychological tests are sensitive to the early signs of neurodegeneration in older adults. However, their dependence on in‐person testing and manual scoring make them unsuitable for large‐scale screening and home‐based monitoring. To address this, we have developed a fully automated verbal paired associate learning (VPA) test. Here we describe the program of work to refine and validate this task, and ensure suitability of the test for remote, repeat administration.

Methods

Two phases of data collection were carried out. In the first, data was collected from 3,264 participants aged 17–86 years (M = 34.5, SD = 12.32) at home and on their own devices. The automated VPA task comprises eight word‐pairs, learned over three attempts. Automatic speech recognition (ASR) scores responses in real‐time, using the Neurovocalix platform. Following this phase, the task was refined to better enable repeat testing. This included producing a large corpus of algorithmically generated pairs, controlling for important linguistic features (e.g. frequency and concreteness), and adding brief familiarisation to the first visit to increase reliability and stability. We assessed: 1) the accuracy of automated scoring 2) the impact of participant characteristics and task design on performance and consistency 3) participant feedback.

Results

Data from the first phase showed excellent correspondence between human and automated scoring of VPA, with a correlation .93 (p < 0.001), and the expected sensitivity to ageing number of task performance. Participant demographics and technology choice did not impact correspondence between ASR scoring and manual scoring. In the second phase data collection, we compared VPA performance in participants with (N = 190) and without (N = 186) prior familiarisation. Familiarisation dramatically improved consistency of participant performance, eliminating the significant effect of task order on performance (F > 100, p < 0.001). Participants reported that they found the task engaging and easy to understand, and repeated testing over five sessions in older adults was well tolerated.

Conclusions

Together, these results demonstrate that remote, automated, voice‐based, cognitive assessments are feasible and acceptable. These methods may therefore be useful in the context of home‐based screening or monitoring in remote clinical trials, enabling longitudinal assessment of memory in AD.
Generative Adversarial Network‐Enhanced Ultra‐low‐dose [18F]‐PI‐2620 Tau PET/MR Imaging
Authors: Chen Kevin , Tesfay Robel , Koran Mary Ellen , Ouyang Jiahong , Shams Sara , Liang Tie , Khalighi Mehdi , Mormino Elizabeth C. , Zaharchuk Greg
Published: December 2022

Background

In neurodegenerative diseases such as Alzheimer’s disease, simultaneous PET/MRI provides a “one‐stop shop” to acquire biomarkers as outlined by the AT(N) criteria. However, to enable large‐scale imaging studies of dementia with frequent follow‐ups, a reduction of injected radiotracer dose and the enhancement of the degraded image quality after reconstruction needs to be addressed.

With deep learning‐based methods, we have previously demonstrated the use of U‐Net‐based methods that incorporate spatially correlated PET/MRI information to produce high quality 18F‐florbetaben amyloid PET images from scan protocols with markedly reduced injected radiotracer dose (as low as ∼1% dose). However, for tau radiotracers, where the uptake is focal, has greater image noise, and the signal is weaker than that of amyloid, we also aim to investigate whether a generative adversarial network (GAN) can enhance ultra‐low‐dose tau PET images and whether the generated images are of diagnostic quality.

Method

44 participants (18 female, 70.2±7.5 years) were recruited to train the ultra‐low‐dose tau GAN; 221±61 MBq of the tau radiotracer 18F‐PI‐2620 was injected. T1‐weighted and T2‐FLAIR MRI were acquired simultaneously. A subset of the list mode consisting of 1/20 of the events (simulating 5% dose) was reconstructed to produce an ultra‐low‐dose PET image and used as inputs along with the MR images to train the GAN.

The image quality of the enhanced PET and the ultra‐low‐dose PET images were compared to the original full‐dose image using three image‐based metrics ; the mean and standard deviation of uptake in the medial temporal lobe and inferior temporal cortex as well as SUVRs were also calculated. Three clinicians were recruited to evaluate tracer uptake on various regions of interest.

Result

The enhanced images showed significant noise reduction compared to the low‐dose image (Figure); uptake patterns in the low‐dose and enhanced images were read accurately (Gwet’s AC1>0.84 for all relevant regions) compared to their full‐dose counterparts.

Conclusion

The deep learning‐enhanced images had marked noise reduction and were able to be read clinically for regional uptake patterns of tau accumulation similarly as the full‐dose images. This technique can potentially increase the utility of hybrid PET/MR imaging in clinical diagnoses and longitudinal studies.
Dementia Analytics Research User Group (DARUG) ‐ A Model for meaningful stakeholder engagement in dementia research
Authors: Carlin Paul , Wallace Jonathan , Moore Adrian , Hughes Catherine , Black Michaela , Rankin Deborah , Hoey Leane , McNulty Helene
Published: December 2022

Background

The importance of involving stakeholders in research is widely recognised but few studies provide details to implementation in practice. The use of real‐time technology involving patients, carers and professionals in project design, monitoring, delivery and reporting could maximise contribution. Stakeholder engagement was included as part of a Dementia Analytics Research User Group project which applied machine learning to the Trinity‐Ulster‐Department of Agriculture (TUDA) data set, identifying clinical and lifestyle factors associated with cognitive health in 5000 community‐dwelling older Irish adults.

Method

An innovative model for engagement (ENGAGE) was used1 ‐ a methodological and technology platform, that gains insight into group thinking and consensus. Developed by Ulster University, this produces a report in real time for sharing to all stakeholders, thus ensuring active involvement in defining the research question. Using a Personal and Public Involvement (PPI) approach, representatives from patient and carer groups (including TUDA participants ), charities (e.g., Alzheimer’s UK), as well as professionals, were invited to attend one of three scoping events. Each event commenced with an overview by the project team of the value of data analytics and initial data analysis. The PPI groups were then invited to answer specific questions relating to risk factors for dementia and were asked to articulate their expectations on the potential outcomes from the project. These responses were analysed using ENGAGE and word clouds generated for discussion to help refine the project going forward.

Results

Participants (n=87) Lifestyle, Genetics, Stress and were the dominant emerging themes for risk factors of dementia. Prevention, Help and Information/ Research emerged as strong themes, with the mind maps showing stimulus, understanding and awareness as key outputs of this project. The outcomes of this engagement model were utilised to successfully inform the subsequent data analytics portion of the study2.

Conclusion

The model performed well, capturing discussions in real time. Feedback was positive and helped to focus and inform the research team’s thinking. What was not so successful was the longer‐term inclusion in the project, with engagement through remote channels tending to drift over time, somewhat exacerbated by COVID 19 restrictions. The team aim to follow up on this aspect.
Racial and Ethnic Differences in Hospice Use and End‐of‐life Hospitalizations among Medicare Beneficiaries with Dementia
Authors: Lin Pei‐Jung , Zhu Yingying , Olchanski Natalia , Cohen Joshua T , Neumann Peter J , Faul Jessica D , Fillit Howard M , Freund Karen M
Published: December 2022

Background

The pool of studies examining ethnoracial differences in hospice use and end‐of‐life hospitalizations among patients with dementia is limited and results are conflicting. This study examined how dementia end‐of‐life care utilization and patient treatment preferences differ by race and ethnicity.

Methods

Using U.S. national survey data from the Health and Retirement Study linked with Medicare and Medicaid claims, our sample included 5,058 beneficiaries aged ≥65 years diagnosed with dementia who died in 2000‐2016. We examined the frequency and costs of hospice care, emergency department (ED) visits, and hospitalizations during the last 180 days of life among Medicare decedents with dementia. We analyzed the proportion of dementia decedents with advance care planning and their end‐of‐life care preferences.

Results

Less than half of beneficiaries with dementia in our sample (48%) used hospice in the last 180 days of life; of these, one in three hospice users received the service for seven days or less. In adjusted analysis, non‐Hispanic (NH) Blacks, nursing home residents, and survey respondents represented by a proxy were less likely to use hospice, whereas older age, females, higher education, more severe cognitive impairment, and more IADL limitations were associated with higher hospice enrollment. Among dementia decedents, NH Blacks and Hispanics used more ED and inpatient services and incurred >50% higher inpatient expenditures at the end of life, compared with NH whites. More NH Black and Hispanic beneficiaries with dementia enrolled in hospice were subsequently admitted to the ED or hospital before death. The proportion of dementia beneficiaries completing advance care planning was significantly lower among NH Blacks and Hispanics compared with NH whites (21% and 21% vs. 57%, p<0.01). More NH Black and Hispanic decedents with dementia had written instructions choosing all care possible to prolong life, whereas more NH whites preferred to limit care in certain situations, withhold treatments, and forgo extensive life‐prolonging measures.

Conclusion

Our results highlighted substantial unmet end‐of‐life care needs among older adults with dementia, especially among NH Blacks and Hispanics. Medicare should consider alternative payment models to promote culturally competent end‐of‐life care and reduce low‐value interventions and costs among the population with dementia.
INSPIRATION: results of a cross‐sectional AD risk‐profiling study
Authors: Zeyen Philip , Sannemann Lena , Escher Claus , Müller Theresa , Bohr Lara , Snijders Katharina Elisabeth , Rostamzadeh Ayda , Jessen Frank
Published: December 2022

Background

Previous studies indicate that 30% to 40% of all Alzheimer’s disease (AD) cases are attributable to modifiable risk factors. In addition to cardiovascular risk factors also stress and sleep disturbances have been identified as risk factors (Escher et al. 2019; Sindi et al. 2018). Here, we report results from the cross‐sectional Individual risk profiling for Alzheimer’s disease and dementia prevention (INSPIRATION) study and provide a detailed overview on the frequency and distribution of AD risk factors.

Method

The cross‐sectional assessment of healthy study participants (aged 50 or older) included established and self‐developed questionnaires and physical examination. We inquired about demographics, medical history, family history, physical activity, diet, BMI, hearing loss, presence of depression, anxiety, stress, resilience, and loneliness. In addition, we performed neuropsychological testing (CERAD+) and blood sampling for genetic testing.

Result

Results in 162 participants showed a mean age of 64.6 years (50‐86 years), mean education years of 16.3 (10‐20) and a mean MMST score of 29.5 (26‐30). Moreover, 63% were female, 49% were retired, 51% were part‐ or full‐time employed and 70% had at least one relative with dementia.

The four most frequent lifestyle risk factors were non‐adherence to Mediterranean diet in 69% of subjects, obesity in 49% with a mean BMI of 25.8 kg/m2 (16.1‐41.6kg/m2sleep disturbances in 52% and reduced resilience in 23% of the subjects. Concerning pre‐existing diagnoses known to increase AD risk, the four most frequent were hypercholesterinemia (50%), a thyroid disease (36%), hypertension (34%) and vitamin deficiency (33%).

A preliminary analysis of ApoE ε4 status for n = 123 participants revealed that 32.5% were heterozygotes; the remaining 67.5% were non‐carriers. The full set of assessed risk factors will be presented.

Conclusion

The results of the INSPIRATION study aid to understand the prevalence and distribution of a large number of modifiable AD risk factors in a community‐dwelling sample. The data will be used to develop a tool box of interventions for personalized strategies to prevent AD in a population which is particularly interested in dementia prevention.
Estimating the association between parity and mid‐ to later‐life cognitive function in rural South Africa: Evidence from “Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa” (HAALSI)
Authors: Phillips Meredith L , Kobayashi Lindsay C , Chakraborty Rishika , Kabudula Chodziwadziwa , Harezlak Jaroslaw , Ludema Christina , Rosenberg Molly
Published: December 2022

Background

The burden of cognitive decline is projected to rise over the next decades, particularly in low‐ and middle‐income countries, contributing to economic hardship, morbidity, and mortality. Reproductive life‐history, including parity, may be associated with later‐life cognitive ability. Using data from the population‐representative “Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa” (HAALSI) cohort, we estimated the association between parity and mid‐ to later‐life global cognitive function.

Method

Data were from in‐person interviews with 2242 men and 2604 women aged ≥40 in the rural Agincourt sub‐district, Mpumalanga province, South Africa in 2014/15. Cognitive function was assessed as time orientation and immediate and delayed recall of a 10‐word list. Number of living children was self‐reported. We used multivariable linear regression with parity (number of children: 0, 1‐2, 3‐4, 5‐9, 10+) as the categorical predictor and z‐standardized cognitive function as the outcome. Analyses were stratified by sex/gender, controlling for age, education, and literacy.

Result

Among men, there was a U‐shaped relationship between parity and cognitive function (p<0.001), whereby men with 3‐4 children had the highest mean z‐standardized cognitive scores (mean: 0.244, SD: 0.984, Table 1, Figure 1). Women also had a U‐shaped relationship between parity and cognitive function (p = 0.0254), whereby women with 5‐9 children had the highest mean z‐standardized cognitive scores (mean: ‐0.017, SD: 0.935, Table 2, Figure 1). Among men, adjusted regression models showed that parity was associated with higher cognitive function, across all categories compared to no children (Estimates [95% CI]: 1‐2: 0.32 [0.17‐0.48], 3‐4: 0.50 [0.35‐0.65], 5‐9: 0.50 [0.36‐0.74], 10+: 0.55 [0.36‐0.74]; Table 3). Among women, only the 5‐9 children group (Estimate [95% CI]: 0.16 [0.00‐0.31]) had cognitive scores that were significantly different from having no children (Table 3).

Conclusion

Data from this representative sample in rural South Africa indicate that the relationship between parity and later life cognition varies by sex/gender, with having children being associated with greater cognitive performance in men, compared to women. This sex/gender difference may be due to sex and gender differences in biological and social roles involved in childbearing and rearing.
A Methodological Framework for Investigating Diversity in Clinical Research
Authors: Jackson Jonathan D.
Published: December 2022

Background

Many reports and reviews have been published on best practices in research recruitment, engagement, and retention (RER), yet clinical research broadly lacks identifiable mechanisms to translate these qualitative reports into quantifiable, testable hypotheses on the science of RER. A science of diversity requires precise mechanisms for true efficacy, but before this is possible, we must develop key methodological and ontological frameworks. Thus, we are in dire need a basic sciences approach to identify mechanisms that underpin RER research, and disparities in Alzheimer’s disease and related dementias (ADRD) clinical research more broadly.

Method

A science of diversity in clinical trials must ensure research conducted under the umbrella of this discipline is not methodologically confounded. Although researchers studying health inequities have begun to parse health disparitiesfrom health inequities, recruitment into research may still conflate foundational causal concepts, obscuring researchers’ ability to truly determine the nature of group differences. An ordered methodological framework was proposed, formalizing key biases that may confound efforts to diversity clinical research samples, and to determine the nature of health inequities and disparities among marginalized and minoritized populations.

Result

In addition to aspects of biological differences and structural inequities that may inform group differences in both RER and ADRD clinical research, three additional sources of bias were identified: biases of selection and inclusion into research, error and biases of measurement, and biases of implementation of research protocols. Notably, existing tools to measure and mitigate these sources of noise are available, ensuring that detected group differences are not confounded by shortcomings in scientific design.

Conclusion

I present this novel framework to support a rigorous methodological approach to the study of diversity in ADRD clinical trials, anchoring a formalized science of RER and ensuring that estimates of health disparities and inequities in ADRD research are free of biases introduced by well‐intentioned research teams. Implementing this methodological approach is expected to improve accrual of diverse and representative populations into ADRD research, and to improve the quality and generalizability of ADRD clinical research itself.
Caregiving Experiences and Health of LGBTQ+ Caregivers: Results from the Equality in Caregiving Study
Authors: Kittle Krystal R. , Flatt Jason D. , Anderson Joel G , Verble Danielle D , Likos Kelly D. S. , Wharton Whitney
Published: December 2022

Background

Between 27% and 45+% of LGBTQ+ adults care for someone with a chronic illness, with 11% caring for someone living with Alzheimer’s disease and related dementias (ADRD). LGBTQ+ caregivers may experience greater strain than non‐LGBTQ+ caregivers, but differences in characteristics and experiences between LGBTQ+ ADRD and non‐ADRD caregivers are less understood.

Methods

An online survey of demographic characteristics, caregiving experiences, and health‐related questions was administered to LGBTQ+ ADRD (n = 25) and non‐ADRD (n = 24) caregivers recruited from across the U.S. as a part of a larger clinical trial. Descriptive statistics were used to characterize the sample. Non‐parametric tests were used to assess differences between LGBTQ+ ADRD and non‐ADRD caregivers.

Results

Caregivers identified as lesbian (31%), gay (29%), bisexual (18%), queer (8%), heterosexual (6%), and additional identities (8%). Most identified as cisgender female (34%) or male (24%), followed by transgender (16%) and genderqueer, non‐binary, or gender fluid (10%). Respondents were aged 18‐81 (48.42 ± 16.46 years). The majority identified as White (71.4%), had an average of 16.65 years of education (SD = 2.48), and were a child/grandchild (55.1%) or other relative (28.6%) of the person with ADRD. Most had been providing care for 3 to 4 years (37.5%) or 5 to 10 years (25%). ADRD caregivers provided help with slightly more IADLs (7.2 vs. 7.0) and ADLs (6 vs. 5.3) than non‐ADRD caregivers (non‐significant, n.s.). ADRD caregivers reported slightly higher levels of perceived stress (mean: 17.9 vs. 17.6, n.s.) than non‐ADRD caregivers. ADRD caregivers reported a slightly higher score for positive aspects of caregiving (mean: 27.5 vs. 27.0) than non‐ADRD caregivers. ADRD caregivers were more likely to report being asked by a health care provider about needing help with caring for their care recipient than non‐ADRD caregivers (18.0% vs. 10.0%; p = .02).

Conclusion

LGBTQ+ ADRD and non‐ADRD caregivers were similar across experiences of positive aspects of caregiving and perceived stress. ADRD caregivers were more frequently asked by a health care provider about needing help in providing care compared with non‐ADRD caregivers. More research is needed to understand the experiences and needs of LGBTQ+ ADRD caregivers, particularly in more racially and ethnically diverse communities.