bluuebunny/crossref_metadata_2025 huggingface dataset:
Promoting Inclusion of Sexual and Gender Minority Individuals in Aging and Alzheimer’s Disease and Related Dementias Research
Authors: Flatt Jason D. , Stites Shana D. , Kittle Krystal R. , Cicero Ethan C. , Anderson Joel G , Wharton Whitney
Published: December 2022

Background

It is estimated that more than three million older adults aged 60+ in the U.S. identify as a sexual and gender minority (SGM) or lesbian, gay, bisexual and/or transgender or gender non‐binary, queer, intersex, asexual, and people with a gender identity, gender expression, or reproductive development that varies from traditional, societal, cultural, or physiological norms. SGM adults experience health disparities and many of these health disparities are risk factors for cognitive decline and Alzheimer’s disease and related dementias (ADRD). These risk factors include higher rates of subjective cognitive decline, cardiovascular disease, hypertension, diabetes, and depression compared to non‐SGM adults.

Method

We will describe community‐based participatory research approaches for engaging and recruiting SGM older adults into aging and ADRD research. We will describe best practices for collecting gender identity, sex assigned at birth, and sexual orientation. We highlight ways of reshaping healthcare practices and the broader system changes that are needed to ensure SGM people living with ADRD and their families (chosen and/or biological), receive culturally appropriate, person‐centered, and equitable care.

Result

Historical and ongoing social, structural, and institutional factors (stigma; oppression, discrimination; social exclusion; maltreatment by the healthcare system, healthcare professionals, and researchers) have created barriers for inclusion of SGM communities in health research and this may also extend to aging and ADRD research. We discuss how The RISE (Research Inclusion Supports Equity) Study is establishing a mutual commitment with SGM communities by building trust and on existing strengths, resources, and relationships within SGM communities are all necessary to promote SGM engagement and inclusion in research.

Conclusion

SGM persons living with ADRD and their care partners, as well as SGM ADRD caregivers in general are underrepresented in aging and ADRD research. These communities also experience structural, social, and financial barriers in accessing aging and healthcare services. Thus, there is a critical need for training and future research. We recommend that researchers and clinicians help advance equitable practices for SGM inclusion in research as it is necessary to improve the health and care of SGM communities affected by ADRD globally.
Quantitative amyloid‐PET measures in a memory clinic population
Authors: Collij Lyduine E. , Verweij Bart M. , Altomare Daniele , Caprioglio Camilla , de Gier Yvonne , García David Vállez , Alves Isadora Lopes , Hegde Manoj , Wolz Robin , Grootoonk Sylke , Gismondi Rossella , Stephens Andrew W , van Berckel Bart NM , Gispert Juan Domingo , Garibotto Valentina , Barkhof Frederik , Frisoni Giovanni B , Farrar Gill , Buckley Christopher ,   the AMYPAD consortium
Published: December 2022

Background

In clinical practice, visual assessment of amyloid‐PET images results in a binary classification (negative or positive) of amyloid status. While this approach has shown high clinical utility, the expected approval of disease‐modifying treatments warrants the need for objective amyloid burden quantification, to further support a high‐confidence diagnosis of Alzheimer’s disease (AD) and treatment decisions. We investigated two widely available quantification methods, i.e. Centiloid (CL) and z‐scores to optimize clinical use of amyloid‐PET.

Methods

Patients with subjective cognitive decline plus (SCD+; N=220), mild cognitive impairment (MCI; N=293) or dementia (N=216) enrolled in the AMYPAD‐DPMS that have undergone amyloid‐PET imaging and passed quality control were included in the study. Acquired static (i.e. 90‐110 min. post‐injection) [18F]flutemetamol (N=380) or [18F]florbetaben (N=349) PET images were processed using GE Healthcare’s AMYPYPE PET‐only pipeline, providing global CL, z‐scores, and z‐scores for 7 cortical ROIs. Local readers provided visual read (VR) status and regional assessments.

Results

Demographics are shown in Table 1. In total, 364 (49.9%) patients were assessed as amyloid VR‐positive and showed significantly higher CL (U=3954, p<0.001) and global z‐score (U=4197, p<0.001) values across clinical stages compared to VR‐negative patients (Figure 1A). The proportion of VR‐positive patients increased with clinical stage (SCD+: 30.0%, MCI: 48.8%, dementia: 71.8%) and global amyloid burden (CL: H=24.97, p<0.001; z‐score: H=24.43, p<0.001) was also associated with disease severity (Figure 1B). VR‐positive patients with a primary etiological diagnosis of AD showed higher overall higher amyloid burden (CL: H=6.93, p=0.008; z‐score: H=5.54, p=0.019) and specifically in the pre‐frontal cortex (H=8.18, p=0.004) compared to patients with a non‐AD primary etiological diagnosis, though percentage of frontal VR‐positivity was highly similar between groups (AD: 97.2% vs. non‐AD: 96.6%). Global CL and z‐scores were highly correlated (ρ=.987, p<0.001), by a factor of 10 (Figure 1C).

Conclusion

Our results demonstrate high agreement between CL and z‐scoring quantitative measures in a clinical population. While initial results do not indicate differences in patterns of regional positivity between AD and non‐AD subjects, differences in global amyloid burden seem to be driven by known AD‐related early accumulating regions. Additional analyses comparing other etiological groups will be presented at the conference.
Motivating Alzheimer’s Disease and Related Dementia Risk Reduction Behaviors in Older Adults: Motivational Cessation Message Development Findings
Authors: Johnson Adrienne L. , Gleason Carey E. , Cook Jessica , Mahoney Jane , Piper Megan E.
Published: December 2022

Background

Smoking, a modifiable risk factor for dementia, accounts for at least 14% of current Alzheimer’s disease cases. Older smokers are more likely to remain abstinent than younger adults when they use evidence‐based smoking treatment (EBST), thereby reducing their dementia risk. Unfortunately, older smokers are half as likely to try to quit than younger adults. Therefore, motivating older adults to quit using EBST is a vital public health priority.

Method

24 current smokers [M = 14.3 (SD = 9.5) cigarettes/day] with no dementia/MCI history, ages 50‐75 years, 83% White, 12.5% African American, 4% Mixed race, and 79% cisgender female completed a 2‐hour semi‐structured interview and survey via telephone that was analyzed using rapid content analysis.

Result

The most commonly reported health‐related concern was dementia/cognitive loss/loss of functioning, followed by cancer, heart attack/CVD, COPD/emphysema, pain/arthritis, falling, and death. Most participants believed they were at risk of their feared health‐consequence, and that quitting would help. Although all participants had seen previous advertisements for smoking cessation, the majority did not feel motivated to quit by these advertisements. Half of participants were unaware of any link between smoking and dementia, and only a quarter of participants remembered specifics about this link. The vast majority found a message about smoking raising dementia risk and quitting as a means to decrease that risk as motivating for cessation, with over half of participants stating this type of message would be more motivating than previous cessation advertisements. There were varied preferences for exact message content, but two broad categories arose: hope/change of quitting‐based messages and fear/risk of smoking‐based messages. Most participants were aware of smoking cessation pharmacotherapies from personal/relatives past use, but previous negative side effects, cessation failure, and cost were barriers to future use. Nevertheless, the majority of participants stated willingness to use some cessation pharmacotherapy. Many had not considered cessation counseling and were unaware how to access it; half were willing to use cessation counseling.

Conclusion

Hopeful/change‐ and fear‐based messages around smoking and dementia risk could motivate cessation for older smokers. Although dementia is an important health consequence of smoking, older smokers are unaware of this modifiable risk factor.
Hypertensive disorders of pregnancy and markers of vascular brain pathology after 15 years: a prospective cohort study
Authors: Hussainali Rowina Farzia , Adank Maria C , Lamballais Sander , Vernooij Meike W. , Ikram M. Arfan , Steegers Eric A.P. , Miller Eliza C. , Schalekamp‐Timmermans Sarah
Published: December 2022

Background

Substantial evidence suggests an association between hypertensive disorders of pregnancy (HDP) and long term cerebrovascular health. We aimed to determine the associations between HDP and markers of vascular brain pathology fifteen years after pregnancy

Method

This was a nested cohort study embedded in a population‐based prospective cohort followed from early pregnancy. We included 538 women, 445 (82.7%) with normotensive index pregnancies and 93 (17.2%) with HDP in the index pregnancy. Fifteen years after pregnancy (median of 14.6 years 90% range 14.0; 15.7), women had a mean age of 46.5 years (SD = 4.2). These women underwent magnetic resonance imaging to assess brain tissue volumes as well as white matter hyperintensities (WMH), lacunar infarcts, and cerebral microbleeds as markers of vascular brain pathology.

Result

Women with prior HDP had 38% (95% CI: [8% ; 75%]) higher WMH volume compared to women with previous normotensive pregnancy. This association was driven by women with gestational hypertension, who had 48% (95% CI: [11% ; 95%]) higher WMH volume compared to women with previous normotensive pregnancy. No differences were found with infarcts or cerebral microbleeds. The development of chronic hypertension after pregnancy strengthened this result, especially in women with previous gestational hypertension.

Conclusion

A history of HDP was associated with more WMH burden fifteen years after pregnancy. This effect was driven by women with previous gestational hypertension. The development of chronic hypertension after pregnancy contributed to this effect. Women with a history of HDP should be evaluated and treated early for hypertension and other cardiovascular risk factors.
Segregation of brain systems is associated with cognitive and eye movement performance in the general population
Authors: Zeng Weiyi , Coors Annabell , Ettinger Ulrich , Breteler Monique M.B.
Published: December 2022

Background

The human brain is a large‐scale network, which contains multiple segregated and functionally specialized systems. The organization of brain systems has been reported to change in a dedifferentiated way with increasing age. We investigated how age and sex are associated with brain system segregation during resting‐state in a large population‐based sample. Further, we analysed whether interindividual differences in the amount of brain system segregation are associated with cognitive and eye movement performance.

Method

The analyses were based on 3,256 participants (30‐95 years) of the Rhineland Study, a community‐based cohort study in Bonn, Germany. Functional connectivity (FC) was extracted from 200 ROIs within 7 systems (control, default, visual, somatomotor, dorsal attention, ventral attention and limbic) using resting‐state functional MRI acquired from 3T Siemens MAGNETOM Prisma MRI scanners. Segregation index was calculated using a previously established measurement taking the difference between mean within‐system FC and mean between‐system FC as a portion of mean within‐system FC. We assessed cognitive performance with tests for memory, processing speed, executive function and crystallized intelligence and an eye movement test battery. We used multivariable regression models to assess the relation between brain segregation index and cognitive and eye movement performance with adjustment for possible confounders.

Result

The global system segregation index decreased by 0.17 standard deviations (sd) per 10 years increase in age (95% confidence interval (CI): ‐0.19 – ‐0.14). Men had on average a 0.08 sd higher global system segregation index than women (95% CI: 0.02 – 0.15). Higher global system segregation was associated with higher performance in global cognition, processing speed, executive function, working memory and episodic verbal memory, and with lower crystallized intelligence. Additionally, higher global system segregation was associated with faster initiation of prosaccades and antisaccades.

Conclusion

Higher system segregation is beneficial for cognitive and eye movement tasks that place demands on processing speed, executive function and working memory, but crystallized intelligence is better when segregation is lower.
Reduced Vascular Disease Mortality Associated with Improved 5‐Year Survival in an AD Cohort Followed for 25 years
Authors: Pavlik Valory N
Published: December 2022

Background

It is important to monitor all‐cause and cause‐specific mortality in AD cohorts to assess impacts of new therapies and advances in management of co‐morbidities.

Method

We compared all‐cause and cause‐specific morality in four cohorts of Alzheimer’s disease (AD) patients ≥ 65 years old followed in an academic memory center from 1995‐2019. Patients’ clinical and neuropsychological histories were obtained from an electronic data base. Vital status and cause of death through 2019 were ascertained using the National Death Index (NDI). Cohorts were defined based on enrollment date (1995‐1999, 2000‐2004, 2005‐2009, 2010‐2014). Hazard ratios (HRs) for five‐year all‐cause and cause‐specific mortality were compared across cohorts using Cox proportional hazards and competing risks regression, adjusting for age, sex, education, duration of symptoms at baseline, history of vascular disease, and baseline MMSE score.

Result

713 patients met selection criteria, and 686 deaths occurred within five years of baseline. Mean age at baseline was 78.7 ±6.5 and mean age at death was 82.2 ± 6.4 years. AD/Dementia accounted for proportionally more deaths over time: 39%, 46%, 55%, and 58% of deaths in Cohorts 1‐4 respectively. All‐cause mortality was significantly lower in Cohort 4 than in Cohorts 1‐3 (HR Cohort 2vs1 = .99±.10, p = .97; HR Cohort 3vs1 = .95±.09, p = .62; HR Cohort 4vs1 = .63±.07; p = . <001). There was a temporal trend toward reduced CVD mortality (HR Cohort 2vs1 = .69±.14; p = .06; HR Cohort 3vs1 = .67±.13; p = .04; HR Cohort 4vs1 = .40 ±.10; p = .001).

Conclusion

The increasing proportion of AD deaths and increased survival in Cohort 4 is likely due to decreases in CVD mortality. The mortality experience of Cohort 4 can serve as a benchmark for future trends, particularly as new therapies are approved and impacts of the Sars‐CoV2 epidemic are observed.
TREM2 differentially modulates parenchymal and vascular pathology in a mouse model of cerebral amyloid angiopathy
Authors: Zhong Rui , Gram Andrea , Li Ling
Published: December 2022

Background

Cerebral amyloid angiopathy (CAA) features cerebral vascular deposition of pathological amyloid‐beta protein (Aβ) and plays an important role in the multimorbidity of aging brains including Alzheimer’s disease (AD), but it is less understood compared to parenchymal Aβ plaques. Triggering receptor expressed on myeloid cells 2 (TREM2), a key player in innate immune response, is exclusively expressed in microglia in the brain and mediates Aβ clearance and subsequently alleviates neuroinflammation. Loss‐of‐function mutations in TREM2 increase the risk of AD. Recent studies on TREM2 function using TREM2 knockout (KO) in transgenic (Tg) AD mice have shown that TREM2 modulates parenchymal Aβ deposition in the brain, although the direction of the effect depends on the specific Tg background and the stage of the disease development. However, the impact of TREM2 on CAA had not been investigated.

Methods

TREM2 KO mice were crossed with SwDI mice (C57BL/6‐Tg(Thy1‐APPSwDutIowa)BWevn/Mmjax), a model of CAA and AD, to generate SwDI/TREM2WT, SwDI/TREM2Het, and SwDI/TREM2KO mice. At the age of 16 months, the mice were euthanized for tissue collection. ELISA was utilized for the assessment of Aβ40 and Aβ42 levels in brain tissue homogenates, and histochemical and immunohistochemical or immunofluorescent assays were used to evaluate amyloid deposition, astrogliosis, and microgliosis. All results were analyzed using GraphPad Prism 9.

Results

TREM2 deficiency markedly increased overall Aβ load in SwDI/TREM2KO mice compared to SwDI/TREM2WT or SwDI/TREM2Het in the cortex, hippocampus, and thalamus. Intriguingly, TREM2 deletion led to a dramatic decrease in CAA in vasculature‐enriched regions, such as thalamus, along with reduced microglial association with CAA. Consistent with previous reports, Aβ plaque‐associated microglia were significantly reduced in SwDI/TREM2KO mice. Additional experiments are underway to explore the molecular mechanisms underlying the distinct impact of TREM2 deficiency on Aβ plaques and CAA.

Conclusion

Deletion of TREM2 increases the overall brain Aβ load whereas decreases CAA, suggesting the differential role of TREM2 in the regulation of parenchymal versus vascular deposition of Aβ in the brain.
Identifying priorities and supporting ADRD researchers through Alzheimer’s Disease Research Center Research Education Components
Authors: Spensley Sheryl B
Published: December 2022

Background

In 2018, The National Institute on Aging introduced Alzheimer’s Disease Research Center Research Education Components (RECs) to support research educational activities to complement the training of a workforce to meet the nation’s research needs in AD and related dementias, and develop the next generation of scientists to lead cross‐disciplinary, translational, team‐science projects on AD or AD‐related dementias. Identifying needs and priorities as well as determining the impact of RECs requires tracking of new initiatives, and collaboration between multiple supportive institutions.

Method

In September 2020, the ADRC REC Steering Committee was established. A major priority of the committee was to increase communication and collaboration between ADRC RECs and their trainees. To that end, the National Alzheimer’s Coordinating Center launched the ADRC REC website in 2021 (https://naccdata.org/adrc‐resources/rec‐home) to leverage existing training resources and share job and funding opportunities. To further assess needs, REC leaders were surveyed on how they defined, trained and supported their trainees. In September 2021, REC leaders met to discuss the survey results and inform the REC Steering Committee of ways that the RECs could collaborate and better support ADRD trainees.

Results

Twenty‐eight of the 32 (88%) approached ADRCs responded to the survey. The results (Figure 1) determined that 1) trainee mentoring, 2) increasing the diversity of trainees and 3) promoting and creating training opportunities were the top priorities of ADRC RECs. The REC Steering Committee has aligned its goals to support these topics. The REC Steering Committee has established a collaboration with the Alzheimer’s Association to create a core curriculum to support trainees and leverage the Association’s Professional Interest Areas to elevate trainees. Additionally, a Diversity Workgroup comprising REC leaders and ADRC affiliates has been established to develop approaches to attract, retain, mentor and support diverse trainees.

Conclusion

Bringing together and seeking input from the ADRC RECs helped identify existing opportunities as well as areas of growth for ADRC RECs. Increasing communication between RECs and supportive entities in the ADRD field, and tracking new initiatives, will facilitate greater support of ADRD researchers. Collecting metrics of need and impact will facilitate evaluation of the RECs’ success over time.
Role of insulin resistance in relationship between cardiorespiratory fitness and cognitive speed/flexibility in older adults at risk for Alzheimer’s disease
Authors: McIntyre Clayton Connor , Gaitán Julian M. , Edmunds Kyle J , Okonkwo Ozioma C.
Published: December 2022

Background

Cardiorespiratory fitness (CRF) is thought to support cognition, though underlying mechanisms of this relationship are unclear. CRF is also negatively associated with insulin resistance, which is in turn damaging to cognition. We investigated the link between CRF and cognition and whether insulin resistance mediates this relationship.

Method

We included n = 1,157 cognitively unimpaired, nondiabetic participants. CRF was estimated using a validated equation that incorporates age, sex, BMI, resting heart rate, and physical activity as inputs. The Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR) quantified insulin resistance. Standardized composite scores for global cognition (PACC3), delayed recall, immediate learning, and executive function (including factor scores for working memory and cognitive speed/flexibility) were calculated from a battery of neuropsychological tests administered by trained psychometricians. Linear regression models tested whether CRF predicted each cognitive measure. Mediation analyses determined whether HOMA‐IR was responsible for significant associations between CRF and cognition. All analyses controlled for age, sex, years of education, familial history of Alzheimer’s disease, and Apolipoprotein E4 (APOE4) carriage. Bootstrapped confidence intervals were used to estimate the effect of HOMA‐IR on the CRF‐cognition relationship.

Result

The sample was comprised of 69.8% females and 38.7% APOE4 carriers with a mean age of 64.5 ± 7.2 years and a mean of 16.3 ± 2.8 years of education. CRF was positively associated with executive function (total effect: B = .015, SE = .005, p = .003) and cognitive speed/flexibility (total effect: B = .013, SE = .006, p = .034). CRF and executive function remained positively associated when including HOMA‐IR in the regression model (direct effect: B = .012, SE = .006, p = .040) and the estimated indirect effect of HOMA‐IR on the relationship was insignificant (B = .0031, CI = [‐.0020, .0087]). The association between CRF and cognitive speed/flexibility was attenuated when HOMA‐IR was added to the regression model (direct effect: B = .006, SE = .007, p = .383) and the estimated indirect effect of HOMA‐IR on the relationship was significant (B = .007, CI = [.0007, .0147]). CRF was not associated with PACC3 (p = .258), delayed recall (p = .970), immediate learning (p = .920), or working memory (p = .236).

Conclusion

Among older adults at heightened risk for AD, insulin resistance mediates the relationship between CRF and cognitive speed/flexibility but not the relationship between CRF and executive function.
Directly Including Data with Alzheimer’s Publications Through Augmented Reality and Web Technologies – Schol‐AR
Authors: Ard Tyler , Bienkowski Michael S , Pa Judy , Contreras Joey A , Sepehrband Farshid , Yan Lirong , Toga Arthur W.
Published: December 2022

Background

Alzheimer’s disease research is multi‐disciplinary by nature and based on many forms of data, from MRI scans to microscopic image stacks. Much of this information is difficult to communicate through standard scientific articles and figures, often resulting in incomplete data reporting and suboptimal comprehension for many readers.

Method

We introduce a community‐accessible data layering approach for directly including modern digital information on top of scientific figures, enabling entire datasets to be included with scientific articles. Through this approach readers can easily view data associated with publications through mobile devices or web browsers, averting the need to simplify complex data into 2D static figures.

Result

Data layering facilitates communication and comprehension of Alzheimer’s research by enabling accessible viewing of complex information directly with scientific articles, posters, and other formats.

Conclusion

Using augmented reality and web technologies we can modernize communication of Alzheimer’s research, bridging the gap between the digital basis of modern science and the natural limitations of journal articles.
A federated framework of brain image processing using the Global Alzheimer's Association Interactive Network
Authors: Pappas Ioannis , Xiao Cally , Toga Arthur W.
Published: December 2022

Background

The Global Alzheimer's Association Interactive Network (GAAIN) is a unique federated framework that allows users to explore clinical and biomarker data from 57 Alzheimer’s disease data repositories around the world. Integrating brain image processing pipelines with GAAIN data is an important next step that will allow users to derive imaging metrics based on their own analyses.

Method

To that end, we present a federated image processing framework that expands the current capabilities of GAAIN. Within this framework, GAAIN users can initiate image processing pipelines remotely on the data partners’ imaging data prior to requesting the data. Within the same framework, GAAIN users can also explore the results derived from each imaging pipeline and perform basic analyses. Finally, results from each analysis can be imported back to GAAIN and analyzed alongside existing GAAIN variables.

Result

We present a case study by initiating a volumetric analysis directly from GAAIN.

Conclusion

This framework provides a solution for imaging data owners to house and protect their imaging data in compliance with the federated character of GAAIN, and, at the same time, for users to analyze imaging data relevant to their GAAIN cohort of interest. We believe that deploying brain image processing pipelines on existing GAAIN data repositories will be pivotal in terms of using big data to propel basic research and clinical trial design in Alzheimer’s disease.
Finding subtypes of nonlinear patterns in longitudinal cognition decline
Authors: Wang Tianhao
Published: December 2022

Background

To characterize subtypes of longitudinal cognition decline considering the possible nonlinear patterns.

Method

Older persons without dementia at study enrollment (n = 1,010) had annual cognitive testing for up to 24 years (mean = 9.9 years, SD = 5.0), died, and underwent a neuropathologic examination to quantify 9 postmortem markers of common neurodegenerative and cerebrovascular conditions. To accommodate the heterogeneity in cognitive trajectories and control for neuropathologic burden, we used a novel latent class functional mixed‐effects model which allows individuals to have different nonlinear patterns of cognitive decline under a unified model structure.

Result

In the latent class functional mixed‐effects model, postmortem markers (AD pathology, Lewy bodies, transactive response DNA‐binding protein 43 (TDP‐43) pathology, hippocampal sclerosis, atherosclerosis, gross infarcts) were associated with global cognitive decline. We found four subtypes of longitudinal cognition decline after adjustment for neuropathologic burden. The residual decline after adjustment was weakly related to age at death; it occurred in only about one third of participants, mostly proximate to death. Results were comparable after eliminating the initial cognitive assessments to minimize retest learning or controlling for frailty proximate to death. Analyses were also conducted with composite measures of episodic memory and perceptual speed. Residual decline not attributable to neuropathologic burden was confined to a subset for each outcome and was most evident proximate to death.

Conclusion

Late‐life cognitive loss involves heterogenous nonlinear patterns. It mainly reflects non‐normative pathologic and mortality‐related processes rather than normative age‐related processes.
Research‐based evaluation of a dementia support program through lived experiences
Authors: Tam Mallorie T , Jiang Yu Fei , Machado Angela , Robillard Julie M.
Published: December 2022

Background

Community support programs can improve quality of life for people living with dementia (PLWDs) and their caregivers (CGs). Important to the successful implementation of such programs is close engagement with end‐users to gain a better understanding of their needs. This study describes the perspectives of PLWDs and CGs on the First Link® dementia support program provided by the Alzheimer Society of British Columbia.

Method

Following a large‐scale survey (N = 1164), semi‐structured interviews were conducted with PLWDs and CGs who access and do not access the First Link® program to explore in greater detail the different needs and themes that emerged from the survey data. The interviews explored: 1) experiences with the program; 2) future planning; 3) meaning of independence; and 4) impact of the program on emotional and physical well‐being.

Result

A total of 38 participants were interviewed (7 PLWDs, 31 CGs). Participants who found that the First Link® dementia program was helpful pointed to their experiences being validated and feeling that they were not alone in their journey. Knowledge and education were key factors that helped participants manage the impact of dementia. Learning about what dementia is, the experiences of others, strategies on how to manage symptoms, what to plan for in the future, and how to access different services in the community, were tied to increased feelings of confidence and comfort, and decreased stress.

In terms of their future, participants expressed that it was important to have legal plans in place (e.g. power of attorney), organize personal finances, as well as prepare to manage their estate (e.g. downsizing), access home care, and transition to long‐term care facilities.

Participants provided suggestions for improvement of the First Link® dementia program such as embedding the program into the patient journey, providing more services in remote areas, providing education for HCPs, and increasing awareness of the program.

Conclusion

By emphasizing the lived experiences and needs of those living with dementia and their caregivers, this work will inform future research‐based program evaluations globally and in turn improve the existing services to support people living with and impacted by dementia.
Joint graph embedding applied to networks estimated from correlations in volumetric data reveal Alzheimers neurodegeneration patterns
Authors: He Rosemary Y , Tward Daniel J
Published: December 2022

Background

Neurodegeneration measured through volumetry in MRI is recognized as a potential Alzheimer’s Disease (AD) biomarker, but its utility is limited by lack of specificity. Quantifying spatial patterns of neurodegeneration, rather than a few structures of interest, may help address this. We turn to network based analyses developed for studying functional connectivity from signal correlations, measured through fMRI on the time scale of seconds. Our contribution applies these methods to studying volume‐change correlations, measured through structural MRI on the time scale of years.

Method

We study the ADNI1 3Yr1.5T longitudinal dataset, with scans roughly every 6 months for 3 years, and FreeSurfer volumes shared publicly by UCSF. We formed two groups using clinical dementia rating thresholded at <=1. We measured correlation between 108 structure volumes for 494 (322 vs 172) individuals, and computed adjacency matrices by thresholding at magnitude 0.8 (Figure a).

We model this dataset with the multiple random eigengraphs framework. Edge probabilities are computed from population‐specific network modes (i), and patient‐specific loadings (ii) (Figure b). We extend the method to guarantee meaningful finite‐sample results: a constant times identity is included to model the diagonal, and a sigmoid ensures probabilities are in [0,1].

The parameter sets (i) and (ii) are estimated by maximum likelihood using gradient descent, and F statistics are computed to analyze group differences. Familywise error rate is controlled at 5% using permutation testing on the maximum statistic.

Result

Using a Scree plot, we found four network modes gave accurate graph embeddings (Figure c). We found three networks gave statistically significant differences. As seen in Figure d, limbic, temporal, and ventricular structures dominate these networks.

Conclusion

The results reveal networks dominated by structures associated to AD neurodegeneration, indicating the framework has promise for studying AD. It provides an opportunity to leverage graph based tools, already well accepted in fMRI, to study neurodegeneration patterns. It has the potential to uncover networks that may increase the specificity of neurodegeneration biomarkers over those revealed from conventional mass‐univariate analysis.
Evidence for functional connectivity pattern changes in Frontotemporal dementia patients using connectome gradient mapping
Authors: Bouzigues Arabella , Russell Lucy L , Godefroy Valérie , Du Vincent Le , Saracino Dario , Ber Isabelle Le , Batrancourt Bénédicte , Levy Richard , Margulies Daniel , Rohrer Jonathan D. , Migliaccio Raffaella
Published: December 2022

Background

Frontotemporal dementia (FTD) is a neurodegenerative syndrome with a broad range of clinical manifestations making its early detection and progression monitoring difficult. As we enter the first clinical trials, useful biomarkers are needed. It is believed that functional connectivity underlies cognitive function which makes it a potential meaningful biomarker of disease progression. Studies of functional connectivity in FTD have provided a range of findings suggesting changes in resting‐state networks. However, many of the analysis methods used are either far from the biological processes or restricted to a priori defined networks. Recent work has revealed the emergence of a brain network hierarchy during neurodevelopment, separating immediate environment processing from transmodal and integrative cortices. It is assumed that this organization supports higher order cognition.

Method

We included 36 behavioural FTD patients (bvFTD) and 50 controls. We applied a novel whole‐brain analysis approach, connectome gradient mapping, to resting‐state fMRI data. This approach extracts gradients representing measures of functional similarity. Results are presented as brain parcellations within connectivity space, where the distance between parcels describes the extent of segregation between networks (Fig A).

Results

bvFTD patients showed a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. Specifically, in bvFTD patients, we observed a significant shift of cognitive/behavioural networks, such as the Limbic and Default‐mode, which are less segregated from the primary function networks, such as visual and auditory (Fig B).

Conclusion

Using this novel method, we found that the Default‐mode and Limbic networks seem particularly vulnerable in FTD whereby they lose their evolutionarily derived characteristics of segregation. These networks underlie the complex cognitive and behavioural phenotypes observed in FTD. In the near future, we will evaluate whether this model could explain the main symptoms of patients, such as cognitive disinhibition (Stroop/Hayling tests), alterations in social cognition (miniSEA) and worse general cognitive function (MMSE). Overall, this method applied to early and/or presymptomatic stages will be useful for early disease identification and predicting treatment outcomes, making it of interest in future therapeutic studies for neurodegenerative diseases.
Remotely administered computerized cognitive test battery with older adults
Authors: Chok Jas M. , Herron Tim , Schendel Krista , Lwi Sandy J. , Curran Brian , Hall Kathleen , Williams Garrett , Blank Michael , Geraci Kristin , Pebler Peter , Woods David L. , Baldo Juliana
Published: December 2022

Background

Computerized cognitive assessments are an efficient and sensitive method of identifying cognitive impairments in aging and cognitively impaired populations. The current study examines the feasibility and reliability of remote, home testing with a new tool, the California Cognitive Assessment Battery (CCAB).

Method

The CCAB runs on a remote tablet platform (Figure 1) and includes telemedical interaction with an examiner via video chat (Figure 2). Examiners administer a comprehensive set of cognitive tests, including verbal, visual, memory, and processing speed tasks, as well as psychological questionnaires (Figure 3). The tasks are scored automatically, including consensus automated speech recognition (CASR) for the transcription of responses on verbal tasks (e.g., list‐learning memory tasks, picture description, verbal fluency). For the current study, the CCAB was administered remotely to 185 healthy older military veterans (aged 60–89; 18% women) in their homes, with testing sessions under video and audio supervision and assistance. The battery was administered three times within one week to assess test‐retest reliability.

Result

Reaction times, word onset latency, response accuracy, error types, and speech samples were collected and analyzed. Participant experience was generally favorable: 98% of participants completed all three testing sessions, with 99% of all tests in those sessions completed successfully. Additionally, after a mid‐year software and examiner procedure reformulation of a small subset of CCAB tests, there was a 42% decrease in test failures and a 6% decrease in repeated tests. Individual test times were overall highly uniform across participants (Figure 4), with an entire CCAB battery having low daily test time variability. Also, compared to home noise levels, recorded speech levels were sufficient to support CASR transcript generation for scoring verbal tasks (Figure 5). Finally, in a subset of 50 participants, similar test battery characteristics were found when a CCAB session was repeated later under laboratory conditions.

Conclusion

The CCAB shows promise as an objective, reliable automated digital assessment tool to evaluate cognitive functioning in adults both at home and in the laboratory or clinic.
GWAS for CSF TREM2 levels identify new variants implicated on TREM2 biology and Alzheimer disease
Authors: Mafimoghaddam Samira , Wang Lihua , Gorijala Priyanka , Timsina Jigyasha , Nykanen Niko , Wang Fengxian , Marquié Marta , Boada Mercè , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Ruiz Agustín , Sung Yun Ju , Cruchaga Carlos
Published: December 2022

Background

It is demonstrated that the soluble TREM2 in the cerebrospinal fluid (CSF) is associated with Alzheimer disease (AD). Recent studies by our group found that it is the MS4A4A and/or MS4A6A locus that plays a role in modulating sTREM2 and is also associated with AD risk. The goal of this study is to validate and extend findings from previous studies using a larger cohort, identify functional genes, and determine the overlap of the genetic architecture of CSF TREM2 levels with other traits.

Method

We used 3,033 individuals from Knight ADRC, ADNI, DIAN, and PPMI, and 8,499,039 variants (MAF >0.01) to identify protein quantitative trait loci (pQTLs) that modify TREM2 levels via a linear regression including age, sex, first 10 genetic principal components and array/cohort as covariates. TREM2 protein measurements were obtained from SomaScan 7k platform. Colocalization analyses were conducted for AD risk as well as functional genes from eQTLGen. LDSC and GNOVA and Mendelian randomization (MR) is being used to determine the overlap of the genetic architecture of sTREM2 levels with those for AD risk, onset and progression, as well as cardiovascular and lipid traits.

Result

The pQTL analysis identified the previously discovered MS4A gene region on chr11 (rs72918674, P = 7.009e‐58) as well as a peak on chr3 (rs73823326, P = 2.227e‐09). The lead variant resides in the intron of MS4A6A gene. Conditional analysis on this variant revealed rs10897026 as an additional independent signal located in the intron of MS4A4A. Chr11 peak colocalized with AD risk (PP‐H4 = 0.97) and MS4AE and MS4A6A expression QTL in blood (PP‐H4 = 0.97 and 0.96, respectively). Four regulatory region variants are in high linkage disequilibrium (LD) with chr3 index variant. RBMS3 and TGFBR2 are two genes flanking the chr3 peak, both expressed in microglia.

Conclusion

This is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. The findings validated discoveries from previous studies and identified a novel signal on chr3 at genome‐wide significance. We propose two new genes, RBMS3 and TGFBR2 on chr3, could be involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD.
Early Validation of a Structural Magnetic Resonance Imaging Metric for Tracking Dementia‐Related Neurodegeneration
Authors: Popa Emily S. , Kress Gavin T , Thompson Paul M , Bookheimer Susan Y. , Thomopoulos Sophia I , Ching Christopher RK , Zheng Hong , Merrill David A. , Panos Stella E. , Siddarth Prabha , Bramen Jennifer E.
Published: December 2022

Background

Current research is focused on noninvasive biomarkers of neurodegeneration that can detect dementia early, benchmark disease severity, monitor disease progression, and aid in testing the efficacy of therapeutic interventions utilizing a single number1–3. The objective of this study is to create and begin to validate an intuitively meaningful biomarker called the ADNeuro‐Score.

Method

Cognitively normal (CN) individuals and patients with a mild cognitive impairment (MCI) or dementia diagnosis were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI)4. Eighty‐four cortical and subcortical regional volumes were estimated from T1‐weighted MR images using FreeSurfer5. To determine which regional volumes were associated with cognitive decline, we randomly selected 150 participants (N=50 each CN, MCI, and dementia) and performed an ANOVA with an alpha=0.05, Bonferroni corrected. A vector containing the resulting 41 regions, consistent with the existing literature6,7,8, was extracted for experimental and template cohorts (Table 1). To compute ADNeuro‐Score, a Hausdorff distance metric was used to estimate the differences between individual and average template vectors. ADNeuro‐Score was benchmarked using adjusted hippocampal volume (AHV), which is a NIA‐AA diagnostic biomarker for Alzheimer’s disease9, the most common form of dementia10. Both ADNeuro‐Score and AHV were harmonized for intracranial volume, age, sex, and scanner model11. Validation used an experimental cohort (N=929, mean age=72.67 years) and tested sensitivity to diagnosis using pairwise t‐tests and an alpha=0.001, Bonferroni corrected. Results were converted to a z‐score. We also tested association with disease severity, operationalized here as MMSE and ADASCog scores, using linear regression.

Result

Both ADNeuro‐Score and AHV differed between all three cognitive groups. ADNeuro‐Score (z=10.0) better differentiated MCI from dementia than AHV (z=8.9). AHV (z=7.3) was slightly better at distinguishing MCI from CN than ADNeuro‐Score (z=6.7). ADNeuro‐Score and AHV were similarly associated with MMSE (RADNS=0.41; RHA=0.41) and ADAS‐Cog (RADNS=0.49; RHA=0.47) scores.

Conclusion

The newly developed ADNeuro‐Score seems to be a robust and reliable way to distinguish CN, MCI and AD patients and performs equivalently to AHV in predicting MMSE and ADAS‐Cog assessment scores. We hope ADNeuro‐Score will be highly specific to AD because of its focus on AD‐effected regions. Future research will determine if ADNeuro‐Score can improve the differential diagnosis of AD.
Collection of genetic data in ethnic‐based studies across Aymaras, Quechuas and Mestizos: the challenges of the Genetics of Alzheimer’s in Peruvian Population (GAPP) study
Authors: Reyes‐Dumeyer Dolly , Montesinos Rosa , Caipa Maritza Pintado , Ore‐Gomez Maria Fernanda , RIVERA‐FERNANDEZ CLAUDIA , Soto‐Añari Marcio , Custodio Nilton , Tosto Giuseppe
Published: December 2022

Background

The Genetics of Alzheimer’s Disease in Peruvian Population (GAPP) study aims to investigate genetic and environmental risk factors for Alzheimer’s Disease (AD) in Peru. The project is led by Columbia University (CU, New York, US) and the Instituto Peruano de Neurociencias (IPN, Lima, Peru). For the past year and a half, despite the ongoing COVID‐19 pandemic, the study has collected data on cognitive function, health, diet and numerous clinical and biological risk factors for AD. In addition, we collected blood samples for DNA extraction as well as serum and plasma to look at core AD biomarkers.

Method

Recruitment prioritized populations from south Peru, the Quechuas and Aymaras, because of their high proportion of Native American ancestry (or, in other words, low admixture with European ancestry) as well as Mestizo (mixed Native‐European ancestry). Three recruitment sites were established in Lima, Puno and Arequipa. Interviewers were trained to clinically and cognitively assessed the participants and collect and ship blood samples to the main site (IPN). DNA samples were then sent to CU for processing. Serum and plasma samples were processed in Lima and stored at ‐80C for batch shipping to CU. DNA samples were sent to CD Genomics and Children’s Hospital of Philadelphia for APOE genotyping and GWAS, respectively.

Result

A database with 350 participants has been created. Blood samples from all participants were collected; 268 successfully underwent GWAS and APOE genotyping. An additional 82 samples are pending QC and genotyping. No samples were dropped at extraction, and only 0.7% failed DNA quality standards for genotyping.

Conclusion

Sample collections for genetic studies in South American indigenous populations such as Peru represent important logistic challenges. The use of blood as a main source of DNA provides an effective and reliable source for genetic data analysis. Plasma and serum biomarkers will provide additional insights into the disease manifestations and validation of the clinical diagnosis in these underrepresented populations. Ongoing recruitment will augment the analytical power of the cohort by collecting blood, serum and plasma samples from additional GAPP participants.