bluuebunny/crossref_metadata_2025 huggingface dataset:
What does it take to get a diagnosis? Dementia recognition and diagnosis pathways among Indigenous peoples
Authors: Jacklin Kristen , Ketcher Dana , Blind Melissa J , Lambrou Nickolas H. , Pederson Collette , Johnson January , Hill Annamarie , Dertinger Melinda , Koski Jessica , Trudeau Rhonda , Pitawanakwat Karen , Strong Lois , Summers Marlene , Martin Wesley , Warry Wayne , Lewis Jordan P , Zuelsdorff Megan , Gleason Carey E.
Published: December 2022

Background

Patients, caregivers, and providers face an oftentimes‐confusing healthcare terrain around dementia diagnostics and care given the lack of standardization for screening and evaluation of neurocognitive disorders. This can be further compounded by systemic healthcare inequalities and historical and present‐day marginalization faced by Indigenous populations.

Method

We present a segment of a pilot study (NIH R56 AG 62307) which sought to explore the impact of Alzheimer’s disease and related dementias (ADRDs) in Indigenous populations across four diverse settings, three in the United States and one in Canada. Community‐based researchers conducted key informant interviews with healthcare providers (n = 20) and sequential focus groups (SFGs) with local health care staff and formal caregivers (14 sessions, n = 17). Data were coded based on research questions and objectives in consultation with project leaders, coders, and community‐based researchers.

Result

In recognizing a cognitive change, all participants identified the importance of family members who often brought their concerns to the attention of a healthcare provider. Additionally, participants in the US and Canada identified events like hospital admissions as a “catastrophic event” (e.g., injury, missed medication, physical decline) as another route for diagnosis. A unique pathway that Canadian participants identified was the role of personal support workers (PSWs) and community nurses in noticing cognitive changes among individuals they served. Finally, providers mentioned various pathways for receiving a dementia diagnosis. While all providers mentioned taking steps to rule out other reasons for cognitive decline, the specific next step for the diagnosis varied widely. The possible professionals to see for a diagnosis included social workers, family doctors, tribal dementia care specialists, behavioral health specialists, psychiatrists, and neurologists.

Conclusion

Family members are crucial in recognizing the changes associated with ADRDs. A strength of the Canadian healthcare system is that PSWs and community nurses can also help identify changes, potentially before hazardous “catastrophic events” bring people to the hospital. Once a cognitive change has been identified, the diagnostic pathway is complicated, non‐standardized, and irregular – in other words difficult to navigate. Policies and procedures need to be put in place, delineating standardized protocols to better help family caregivers and patients dealing with ADRDs.
Aligning PCPS and Patients with Alzheimer’s Research Efforts: MyAlliance for Cognitive Health
Authors: Burns Jeffrey M. , Niedens Michelle , Perales Jaime , Moore W. Todd , Peltzer Jill , Barton Kelli , Berkley‐Patton Jannette , Vidoni Eric D
Published: December 2022

Background

Failure to engage and enroll participants from diverse backgrounds is among the biggest challenges slowing generalizable research efforts to treat and prevent Alzheimer’s disease and related dementias. Pivoting to a ‘service first’ approach for engaging all communities may increase research participation by improving the value proposition.

Method

The University of Kansas Alzheimer’s Disease Research Center is taking a programmatic approach to accelerate participation in research and emphasize reaching under‐represented groups (URG: predominantly African Americans, Latinos, and rural residents in the region). The program is a community and service‐oriented strategy for engaging a diverse population through 1) a PCP Network to improve dementia care through a financially‐sustainable Chronic Care Management program, 2) a Patient Network (MyAlliance Research Registry, derived from patients in the PCP network), and 3) a Community Network of diverse stakeholders delivering robust outreach and education. We hypothesized that the sustaining value of this approach would increase enrollee diversity.

Result

To date, MyAlliance has provided social work support to 71 practices and 1169 unique individuals with dementia and their families. Over 2100 individuals receive our weekly communications, and 4 community organizations have trained more than 80 staff members in dementia‐capable engagement with the community. The result has been that since implementation of MyAlliance, 29% of enrollments (255 of 868) identify as URG, double the URG enrollment prior to implementation (14.5%, 658 of 4551).

Conclusion

Service‐based approaches that emphasize community needs and community access points may increase enrollment and enrich the diversity of the participants.
A novel whole‐brain imaging pipeline for high resolution spatial and temporal measurements of amyloid‐beta plaque dynamics in pre‐clinical Alzheimer’s Disease animal models
Authors: Ragan Tim , Ferron Gianna , Linehan Stefan T , Sasner Michael , Garceau Dylan , Elk Kevin J
Published: December 2022

Background

Alzheimer’s Disease (AD) has a strong spatial‐temporal component to its progression, where different brain regions are affected by amyloid‐beta (Aβ) plaque deposition at varying time points. Standard imaging and analysis platforms can neglect these details, as they lack the ability to pair high‐yield whole‐brain imaging with region‐specific quantitation. Furthermore, many Aβ analyses require homogenization of tissue, prohibiting secondary analysis. To address this gap, we have developed a novel high‐throughput whole‐brain imaging pipeline for pre‐clinical AD models to quantitatively track plaque progression as a function of brain region across time while producing indexed tissue sections for secondary staining and analysis.

Method

Aβ plaques in the well characterized 5XFAD mouse model of AD were labeled with Methoxy‐X04, an Aβ plaque‐specific compound, prior to transcardial perfusion and whole‐brain excision. The brains were processed on the TissueCyte Serial Two‐Photon Plus (STP2) imaging platform to produce fully aligned multi‐channel volumetric datasets, yielding high resolution 3D models of each brain. Registration to the Allen Mouse Brain Common Coordinate Framework (CCFv3) and region‐specific plaque analysis were conducted to determine plaque size, density, and total number per animal brain. The regional density of dystrophic neurites (Lamp1) and microglia (Iba1) were segmented and quantified through secondary analysis to evaluate the signal in high and low Aβ growth rate regions for select sections and remapped to the original 3D whole‐brain dataset.

Result

The analysis of whole‐brain plaque distribution in the 5XFAD mouse model revealed distinct spatial‐temporal changes across the brains (Figure 1, Figure 2). STP2 imaging, combined with CCFv3 mapping and secondary analysis of Lamp1 and Iba1 allowed for targeted evaluation of Aβ plaques, and a comparison of regional molecular changes between models.

Conclusion

Our novel technology has great promise for quantifying the spatial‐temporal Aβ plaque efficacy of AD animal models, and the production of translatable pre‐clinical AD drug discovery data. The high sensitivity and precision of the STP2 platform can benefit region‐specific disease progression compared to standard laboratory approaches.
Tailoring Recruitment Communication using Virtual Human Technology to Increase Participation of Older Minority Adults in Clinical Trials
Authors: Krieger Janice , Anton Stephen
Published: December 2022

Background

Older adult minorities are an underserved population, who are at a particularly high risk for developing chronic health conditions and are significantly underrepresented in clinical research. Well‐known barriers, including research‐related mistrust (e.g., belief that participants lack choice, mistrust of white researchers), complicated messaging, lack of cultural diversity/sensitivity among clinical trials staff, and the exclusion of decisional support providers in decision‐ making could impede older adult minority participation in clinal trials.

Tailoring content and source preferences to be patient‐ centered, culturally sensitive (i.e., promote feelings of comfort, trust, respect), simple to understand, and personally relevant to the receivers (patients and caregivers) has been linked to positive health behaviors among older adult minorities. Additionally, tailoring is critical to improving comprehension, clear and complete understanding of the messaging. However, tailoring has not been systematically studied as a strategy to increase clinical trial participation rates of older adult minorities, including those with cognitive challenges. Our long‐term goal is to increase clinical trial participation among older adult minorities (Black/African American, Hispanic/Latinx, and/or rural adults over the age of 50) using virtual human technology (VHT). Specifically, we are using community‐based participatory research principles to develop virtual humans that can interact with receivers to deliver tailored intervention content.

Method

In Aim 1, we will conduct focus groups with older adult minorities to redesign ALEX to develop culturally sensitive messages designed specifically for older adults, including those with subjective cognitive difficulties. In Aim 2, we will disseminate the intervention and track engagement of older adult minority participants into active, NIH‐funded clinical trials across different modalities for remotely delivering ALEX. In Aim 3, we will compare whether using ALEX to deliver interactive and tailored clinical trial content is more effective than standard (e.g., static) recruitment materials for enrolling older minorities into NIH‐funded clinical trials.

Result

We will describe patient and caregiver preferences for intervention modality and content.

Conclusion

Achievement of these project aims is expected to result in an adaptable, minimally tailored VHT recruitment intervention for increasing older adult minority participation rates in active NIH‐funded clinical trials.
Polygenic risk score for Alzheimer’s disease and APOE ε4 status in relation to cognitive decline: a population‐based study of individuals followed over 16 years.
Authors: Najar Jenna , Thorvaldsson Valgeir , Skoog Johan , Kern Silke , Waern Margda , Zetterberg Henrik , Blennow Kaj , Skoog Ingmar , Zettergren Anna
Published: December 2022

Background

Polygenic risk scores for Alzheimer’s disease (AD‐PRS) have been associated with incident AD and dementia. However, few long‐term studies have examined the effect of AD‐PRSs, and the interaction with APOE ε4 status, on cognitive performance over time in the general population.

Method

A population‐based sample of 855 participants born 1930 were examined at age 70, 75, 79, and 85 years. AD‐PRSs that surpassed four P value thresholds (P<5e‐8, P<1e‐5, P<1e‐3, P<1e‐1) were generated based on information from recent genome‐wide association studies. Cognitive performance was measured at all examinations using a composite global cognitive score based on five psychometric tests (Thurstone’s Picture Memory, immediate recall of 10 words, Block Design, PSIF [perceptual speed], and Mini‐Mental State Examination score). Linear mixed effect models with random intercepts and slopes were used to analyze the effect of AD‐PRSs and APOE ε4 status on cognitive performance. The models included sex*age, AD‐PRS*age, APOE ε4 status*age, and 10 principal components to correct for population stratification. Analyses were repeated in samples without prevalent and incident dementia.

Result

The interaction‐term 5e‐8 AD‐PRS*age (β=‐0.2, P=.03) and APOE ε4 status*age (β=‐0.2, P=.02) were associated with cognitive decline. The results remained in those without prevalent and incident dementia (the 5e‐8 AD‐PRS*age: β=‐0.2, P=.02, APOE ε4 status*age: β=‐0.2, P=.007). No association was observed between AD‐PRSs that surpassed P value thresholds >5e‐8 and cognitive performance over time (1e‐5 AD‐PRS*age: β=‐0.06, P=.08, 1e‐3 AD‐PRS*age: β=‐0.03, P=.3, and 1e‐1AD‐PRS*age: β=‐0.02, P=.6). Further, neither APOE ε4 status nor AD‐PRSs were associated with cognitive performance at baseline (APOE ε4 status: β=‐0.9, P=.3, the 5e‐8 AD‐PRS: β=0.6, P=.5, 1e‐5AD‐PRS: β=0.5, P=.2, 1e‐3 AD‐PRS: β=0.5, P=.1, and 1e‐1 AD‐PRS: β=0.2, P=.6).

Conclusion

We found an effect of a 5e‐8 AD‐PRS and APOE ε4 status on cognitive decline in individuals from the general population followed over 16 years, regardless of dementia diagnosis. These results contribute with additional knowledge to identify individuals at increased risk of cognitive decline, which may be important to implement personalized prevention as early as possible.
Elucidating the molecular basis of altered Presenilin 2 expression on Alzheimer’s disease pathology
Authors: Perdok Anika , Sannerud Ragna , Vegh Zsuzsanna , Serneels Lutgarde , Annaert Wim
Published: December 2022

Background

γ‐Secretase is an intramembrane protease which plays a pivotal role in the onset and progression of Alzheimer’s disease (AD). Presenilin provides the catalytic activity of which two homologues exist, Presenilin‐1 and Presenilin‐2 (Psen1/2). Psen2/γ‐secretase complexes are restricted in their localization to the late endosomes and lysosomes, as opposed to the broader distribution of PSEN1/ γ‐secretase, making it the main generator of intracellular abeta (Aβ). Although the focus has been on the extracellular pool, this toxic intracellular pool has been shown to precede plaque and tangle formation and correlates well with synaptic dysfunction highlighting its importance. This project aims to unravel the effects of altered Psen2 expression and this intracellular pool on AD pathogenesis.

Methods

We generated novel mouse models by crossing the well characterized APP NL‐G‐F model with a Psen2 knock out (KO) mouse and an in‐house generated Psen2 knock in (KI) model carrying the familial AD‐linked N141I mutation (FAD‐Psen2).

Results

Curiously, opposed to expectations, we found an identical accelerated plaque pathology coinciding with the presence of dystrophic neurites and amyloid precursor protein c‐terminal fragment (APP‐CTF) accumulation in both genotypes. These alterations in pathology equally translated to an earlier deficit in working memory for both APPxPsen2KO and APPxFADPsen2. In contrast, gliosis was markedly different with increased and earlier microglia recruitment in the case of APPxPsen2KO whereas APPxFAD‐Psen2 displayed a delayed recruitment.

Conclusion

These surprising differential effects on distinct pathological features suggest both a protective role for Psen2 as well as specific, yet unexplored, roles in neurons as well as glial cells. We are currently examining primary neurons and microglia from the different genotypes to explore underlying molecular mechanisms.
Tau accumulation and degeneration differ across functional networks in atypical Alzheimer's disease phenotypes
Authors: Phillips Jeffrey S , Burke Sarah E , Cousins Katheryn A Q , Arezoumandan Sanaz , Ohm Daniel T , Chen Min , Cook Philip , Dubroff Jacob G. , Nasrallah Ilya M. , McMillan Corey T , Grossman Murray , Wolk David A. , Irwin David J.
Published: December 2022

Background

Recent models of Alzheimer's disease (AD) posit that pathogenic tau propagates through interconnected structural networks, suggesting amnestic and non‐amnestic AD (aAD & naAD) phenotypes could reflect differential involvement of functional networks. We tested this hypothesis by contrasting longitudinal grey matter (GM) atrophy and tau accumulation across AD clinical phenotypes in 7 canonical functional networks.

Methods

We analyzed longitudinal 3‐Tesla T1‐weighted MRI from 122 patients [aAD=49; logopenic primary progressive aphasia (lvPPA)=31; posterior cortical atrophy (PCA)=23; behavioral/dysexecutive AD (bvAD)=6; corticobasal syndrome (CBS)=6; mixed naAD=4] with autopsy or CSF evidence of AD pathology and 91 cognitively normal controls (Table 1). Thirty‐one patients (aAD=9; lvPPA=7; PCA=9; bvAD=2; CBS=3; naAD=1) had longitudinal flortaucipir PET (FTP‐PET) data. We computed baseline values and annualized change for GM volume and FTP‐PET standardized uptake value ratios (SUVRs) in the 100‐label, 7‐network parcellation of Schaefer et al. (2018). Linear mixed effects models (α=0.05, corrected) adjusting for MMSE assessed group differences in atrophy and tau accumulation.

Results

All groups exhibited significant baseline and longitudinal atrophy vs. controls in multiple networks (Figs. 1‐2). Differences in longitudinal atrophy rate (Fig. 2) were observed in the dorsal attention network [PCA>lvPPA, t(371)=3.1, p<0.04], salience network [PCA>aAD, t(371)=3.1, p<0.04], and limbic network [CBS>aAD, t(371)=3.3, p<0.02; CBS>bvAD, t(371)=3.7, p<0.006]. PCA patients exhibited FTP‐PET SUVR increases in all networks (all p<0.02), while aAD patients displayed increases in all networks except visual and limbic (all others p<0.0001). LvPPA patients exhibited net SUVR increases only in the somatomotor network [t(97)=3.5, p<0.001]. At baseline, lvPPA patients had left > right atrophy in all networks [all t>3.7, p<0.0002]; right > left atrophy was observed in the visual network for PCA and CBS; the salience network for PCA and bvAD; and in the dorsal attention, frontoparietal control, and default mode networks for bvAD [all t>3.0, p<0.03]. In longitudinal analyses, no hemispheric differences were found in rates of GM volume loss or FTP‐PET change.

Conclusion

AD clinical variants exhibited GM atrophy and tau accumulation in partially overlapping networks. Investigating early‐stage disease will be crucial for assessing whether disease spread through canonical functional networks can explain anatomic differences in aAD and naAD phenotypes.
The PIONEER Study: A Multi‐center, Randomized, Double‐blind, Placebo‐controlled Phase 2 Trial of the Effects of T3D‐959 on Safety, Cognition, Function and Plasma Biomarkers in Mild to Moderate Alzheimer’s Disease Subjects: Study Update.
Authors: Stanek Jessica , Swearingen Blake , Gabriel Hoda , Strittmatter Warren , Chamberlain Stan , Didsbury John
Published: December 2022

Background

T3D‐959 is a novel (non‐amyloid/non‐tau‐directed) new chemical entity aimed at improving dysfunctional brain glucose energy and lipid metabolism in Alzheimer’s disease (AD). Dysfunctional brain metabolism in AD results from increasing resistance to insulin. Insulin resistance contributes to amyloid plaque formation, tau tangle formation and inflammation. T3D‐959, a brain‐penetrant, small molecule dual nuclear receptor agonist, acts as an insulin sensitizer to overcome insulin resistance to restore and maintain metabolic homeostasis.

Method

PIONEER is a randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients (MMSE = 14‐26) dosed orally once‐a‐day for 24‐weeks in 4 parallel arms (T3D‐959 15mg, 30mg, 45mg and placebo QD in a 1:1:1:1 ratio). Co‐primary outcome measures include the ADAS‐cog11 cognition and global function ADCS‐CGIC measures. Secondary outcome measures include DSCT and plasma Aβ 42/40 ratio. Exploratory outcome measures include plasma NfL tau, ptau217 and ptau181, apathy as measured by the NPI, expressive language function as measured by CFT, physical activity as measured by RAPA, plasma metabolomic and proteomic biomarkers and change in absolute regional, and whole brain, cerebral metabolic rate for glucose (CMRgl) as assayed by FDG‐PET.

Result

PIONEER commenced in March 2021. The study is two‐thirds enrolled and ongoing [See ClinicalTrials.gov identifier NCT04251182]. Blinded, grouped, summary cognitive and functional endpoint data, as well safety data will be presented and discussed.

Conclusion

PIONEER is designed to evaluate the efficacy and safety of multiple dose strengths of T3D‐959 in patients with mild to moderate severity AD. Topline results are expected in 2023.
Identification and Treatment of Agitation in Nursing Home Settings: Applying the IPA Algorithm
Authors: Lanctôt Krista L. , Wang Janet Hui Jue
Published: December 2022

Background

With an estimated prevalence of 55%, agitation is particularly common among nursing home residents. The recent International Psychogeriatric Association (IPA) agitation treatment algorithm describes steps for the identification and treatment of agitation across multiple care settings.

Method

This abstract describes the application of the IPA algorithm to the long‐term care (LTC) setting.

Result

In the IPA algorithm, nonpharmacologic care is considered first and continued for both treatment and prevention. In LTC residents, nonpharmacologic interventions are a key first step. For agitation in nursing home residents with dementia, the current evidence suggests that group activity based interventions (e.g., recreation therapy), resident interventions (e.g., massage and touch therapy, and music therapy) and multidisciplinary training and care (e.g., person‐centred care) are the most consistently effective nonpharmacologic treatments. There are several caveats that may impact efficacy of interventions. Feasibility and scalability considerations may impact implementation of nonpharmacologic interventions in long‐term care settings. Most interventions require training, implementation, or supervision by external specialized staff. Feasibility of interventions may also be limited by the capabilities of individuals with dementia; sensory impairments and physical disabilities may preclude some residents from participating in interventions such as music therapy or exercise. As such, interventions must be personalized. Data also show that nonpharmacologic interventions that modify the environment or stimulate the senses may be effective for different aspects of agitation in LTC residents with dementia. Pharmacologic care is personalized and guided by the major features of the agitation including when it occurs, severity and whether it represents a danger to self or others. Importantly, recent efforts have evaluated multi‐modal interventions in LTC. Taken in toto, literature to date provides evidence for use of the above mentioned nonpharmacological interventions for mild agitation in long‐term care facilities. Implementing these interventions requires assessment of medical and environmental causes for agitation, ongoing nonpharmacologic intervention and then pharmacologic interventions as necessary.

Conclusion

Future studies should continue to investigate the long‐term effects of multi‐modal nonpharmacological interventions, alone and in combination with pharmacologic interventions in participants with severe agitation.
Aggregation‐prone human tau accelerates lifespan and motility decline in a Caenorhabditis elegans model of tau polymerization
Authors: Nunez Wendy C Aquino , Ackley Brian D
Published: December 2022

Background

Tau aggregates is a key molecular hallmark of Alzheimer’s disease and other Alzheimer’s Disease‐Related Disorders. In these neurodegenerative disorders tau is aggregated in areas of the brain that exhibit high levels of synaptic and neuronal degeneration. Most animal models focus on neuronal death as is an apparent phenotype; however, we lack an in vivo model to observe the events that occur early in pathology compared to the endpoint (neuronal death). Thus, we want to build a model using C. elegans to understand the factors that initiate tau polymerization and toxicity.

Method

To this end, we have generated a transgenic C. elegans model expressing different variants of the longest human tau isoform (hTau40) tagged to GFP. We used a pan‐neuronal promoter to express wild‐type hTau40 and several aggregation‐prone hTau40 variants. We also used mutated alleles to test the conditions under which wild‐type tau is induced to aggregate or can exacerbate the phenotype observed under the aggregation‐prone tau variants. We used confocal microscopy to assess the accumulation of tau‐GFP within neurons in an age‐dependent manner. In addition, we used a combination of lifespan, behavior and biochemical assays to evaluate the role of tau‐GFP intensity/location with the overall healthspan of the nematode.

Result

We observed differences in the accumulation and presentation of tau variants can be measured in vivo using GFP. Wild‐type tau‐GFP appears smooth and filamentous and localized to axons and cell bodies. On the contrary, the aggregation‐prone 3PO‐tau is punctate in axons with extensive inclusions of GFP in cell bodies which increases in an age‐dependent manner. The expression of aggregation‐prone tau variants appears to correlate with the decreased lifespan and decreased motility, which is an indication that tau aggregation within the cell bodies is toxic.

Conclusion

These results suggests that we can use our model to identify factors that can regulate tau aggregation in vivo. Additionally, the further development of this C. elegans model can be use to question early physiological changes that occur early vs. late in the disease while identifying or validating possible risks factors.
Reference Intervals for Plasma Biomarkers of Alzheimer’s Disease
Authors: Cooper Jennifer G , Stukas Sophie K , Ghodsi Mohammad , Ahmed Nyra , Holmes Daniel , Wellington Cheryl L
Published: December 2022

Background

Several blood‐based biomarkers are emerging as potential screening, diagnostic, and prognostic tools for Alzheimer’s disease (AD), including: the ratio of amyloid beta 42 over 40 (Aβ42/40), reflecting the pathology of amyloid plaques; phosphorylated tau‐181 (p‐tau‐181), reflecting the formation of neurofibrillary tangles; neurofilament light (NF‐L), reflecting axonal damage observed in neurodegeneration; and glial fibrillary acidic protein (GFAP), reflecting neuroinflammation through astrocyte activation. A critical step in the translation of these biomarkers from research to clinical implementation is establishment of reference intervals derived from an appropriate population.

Methods

900 plasma samples from male and female participants aged 3‐79 years old were analyzed for Aβ42/40, p‐tau‐181, NF‐L and GFAP to create reference intervals (RI). Samples are obtained from the Canadian Health Measures Survey (CHMS), a national study that collects demographics, health questionnaires, clinical data and biospecimens from participants. Analysis was preformed on the Quanterix Simoa HD‐X analyzer using the Neurology 4‐plex E and p‐tau‐181 assay. Discrete and continuous RIs were produced for each biomarker. Discrete RIs are produced according to the Clinical Laboratory Standards Institute guidelines (EP20‐A3c). Continuous RIs are created using quantile regression.

Results

Participant samples were selected from the following age bins designated by the CHMS biobank: 3 to 5 years (N=56), 6 to 11 years (N=58), 12 to 19 years (N=58), 20 to 39 years (102), 40 to 59 years (N= 102), 60 to 79 years (N=140). After analysis, age partitions for discrete RI were created, resulting in two to five age‐bins per biomarker which reference intervals were generated for. Continuous RIs produced smooth centile curves across all ages, from which point estimates for any age can be calculated.

Conclusions

Both discrete and continuous RIs for plasma Aβ42/40, p‐tau‐181, NF‐L and GFAP may help refine normative cut offs for each biomarker across the lifespan.
Understanding comorbid metabolic dysfunctions in Alzheimer’s disease using the AD‐BXDs
Authors: Dai Miko , Dunn Amy R , Hadad Niran , Cousineau Cody , Bridges Dave , Kaczorowski Catherine C. , O'Connell Kristen MS
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurogenerative disease characterized by cognitive deficits. Cognitive decline in AD is often accompanied and preceded by non‐cognitive comorbidities, including metabolic dysfunctions such as weight loss. Therefore, understanding how comorbid metabolic dysfunctions contribute to AD disease progression can provide useful insights into early disease risk detection and intervention.

Method

We investigated how genetics, diet, and sex interact to modify metabolic symptoms of AD using 39 mouse strains from the AD‐BXD panel (Neuner et al., 2019, Neuron) at 4, 6 and 14 months of age. Mice were fed normal chow diet, or 45% high‐fat diet (HFD) starting at ∼2.5 months of age. We monitored food/water intake as well as the activity of mice over a period of five days, and measured metabolic phenotypes via indirect calorimetry, nuclear magnetic resonance, and glucose tolerance test. Plasma samples were collected and assayed for lipid panel, cytokines, and metabolism‐related hormones to investigate molecular changes in the periphery. Heritability of metabolic traits were calculated, and heritable traits were mapped using GEMMA with appropriate covariates (Zhou and Stephens, 2012, Nature Genetics) to identify associated genetic variants.

Result

We observed a wide range of variations across the AD‐BXD population in metabolic and cognitive responses to aging and diet. Overall, the presence of the 5XFAD transgene reduced lean and fat mass across the population. Aging exacerbated the loss of lean mass due to the 5XFAD transgene but does not have such interactive effect on percent fat mass. Genetic background significantly modifies the effect of the transgene on multiple phenotypes including body weight, sleep, and glucose tolerance. Responses to a HFD also differed by sex and AD genotype and are substantially modulated by gene‐by‐environment interactions across phenotypic domains. Both cognitive and metabolic phenotypes have moderate to high heritability, allowing us to identify genetic loci associated with these traits.

Conclusion

Our data characterizing metabolic and cognitive phenotypes from the genetically diverse AD‐BXDs are important resources to study the role and origin of comorbidities in AD. Future studies on mechanism of the observed metabolic disruptions may lead to discovery of therapeutic targets to delay, prevent, or treat AD.
Worse Performance of Complex Daily Activities is associated with Plasma Neurofilament Light
Authors: Keleman Audrey A. , Wisch Julie K. , Bollinger Rebecca M. , Schindler Suzanne E. , Morris John C. , Ances Beau M , Stark Susan L.
Published: December 2022

Background

The preclinical stage of Alzheimer disease (AD) is a clinically silent period that is detectable through neuroimaging and biofluid biomarkers of amyloid, tau, and neurodegeneration. We evaluated whether performance of cognitively‐focused complex daily activities is associated with plasma biomarkers of brain amyloidosis or neuroaxonal injury in cognitively normal (CN) older adults.

Method

In this cross‐sectional analysis of an ongoing longitudinal cohort study, CN older adults performed three cognitively‐focused complex daily activtites (shopping, checkbook balancing, and medication management) from the Performance Assessment of Self‐Care Skills (PASS) in their home. PASS tasks were scored for independence of performance, with more assistance required indicating worse performance. Participants also had a plasma sample obtained within two years of completing the PASS. Plasma amyloid (Aβ42 and Aβ40) were evaluated by high precision immunoprecipitation mass spectrometry assays and neurofilament light (NfL), a marker of neuroaxonal injury, was measured with single molecule array (Simoa) assays. Amyloid Probability Score (APS) was calculated from a combination of plasma Aβ42/Aβ40, APOE status, and age and reflects the likelihood that an individual will be amyloid positive on an amyloid positron emission tomography (PET) scan. Nonparametric partial correlations were used to examine the associations between PASS performance and biomarkers of AD (plasma Aβ42/Aβ40, APS, and plasma NfL), controlling for age and sex.

Result

105 CN participants (mean age 74.7 years, 55% female, 88% white) were included. After controlling for age and sex, worse performance of complex daily tasks (more assistance required) was associated with increased plasma NfL (Spearman’s ρ: 0.234, p = 0.04) but not plasma Aβ42/Aβ40 or APS.

Conclusion

This study suggests that worse performance of complex daily activities in CN older adults may be associated with increased plasma NfL, a marker of neuroaxonal injury, but not with other plasma biomarkers of brain amyloidosis (plasma Aβ42/Aβ40 or APS). These findings could lead to a better understanding of functional changes that may associate with neuroaxonal injury prior to the onset of noticeable memory symptoms in AD or related dementias.
Cognitive outcome measures used for assessing urban and rural disparities in dementia and cognition: A scoping review
Authors: Valdivieso‐Mora Esmeralda
Published: December 2022

Background

Evidence of disparities in dementia and cognition by gender, race/ethnicity, and income‐level of countries has long been available. A growing body of literature examining urban/rural disparities has been recently accumulating. Most of the studies comparing within‐country regions indicate that rural older adults have a greater cognitive disadvantage and higher risk for dementia than their urban counterparts. These findings are not consistent across all studies. The purpose of this study was to examine the literature on rural/urban disparities in dementia and cognitive aging.

Method

A scoping review of 16 studies examining differences in dementia and cognitive functioning of urban and rural older adults was conducted. Studies were categorized by country. Relevant information from their methods was systematized, based on their populations/samples, outcome measures and main finding of cognitive advantage (ruralrural, rural = urban).

Result

Most of the studies addressing rural and urban disparities have been conducted in large, industrialized countries. The main focus of the studies reviewed has been on comparing dementia rates, not healthy aging. Most studies have administered cognitive screening questionnaires to identify dementia cases (MMSE, Modified MMSE, Telephone Interview for Cognitive Status, CSI‐D, etc.). The criteria used to define rurality and urbanity varied from study to study.

Conclusion

Regions of the world with larger rural areas are underrepresented in the study of rural and urban disparities of dementia and cognitive aging. From the group of studies reviewed, important conceptual and methodological lessons were identified. The variability in the operational definition of rurality between studies is a major challenge for consolidating the literature on urban and rural disparities in dementia and cognitive aging. A culturally appropriate neuropsychological battery could be used to identify true urban and rural disparities in cognitive functioning. None of the studies examined whether the assessment tools and cognitive factors were comparable for both rural and urban older adults, assuming the tests are equivalent across regions. Research focusing on the measurement equivalence of neuropsychological batteries between rural and urban regions are warranted.
Effect of increasing participation in habitual intellectual activities on cognitive function in older adults without clinical dementia ‐ preliminary findings from a randomized controlled trial
Authors: Lee Allen TC
Published: December 2022

Background

Based on our longitudinal observational study of >15,000 community‐living older adults, we previously reported that those with regular participation in intellectual activities in late life are at a lower risk of developing clinical symptoms of dementia in six years. Nevertheless, the dose‐response relationship between intellectual activities and cognitive benefits remains unclear. To address this knowledge gap, we have designed a two‐arm, parallel‐design, single‐blind randomized controlled trial, with the aim to test whether doubling calligraphy practice results in more cognitive benefits in older adults without clinical dementia.

Method

Community‐living older adults without clinical dementia and with prior practice of calligraphy as defined by one hour of calligraphy per week were randomly allocated into either the control group where they continued their usual practice of calligraphy or the intervention group where they doubled their practice. Cognitive outcomes were assessed before and after the six‐month intervention.

Result

The preliminary data of the fourteen subjects who completed our study showed that a decreasing trend in the ADAS‐Cog score (pre = 7.1±3.2, post = 5.3±4.8, p = 0.23), an increasing trend in the delayed recall test score (pre = 8.8±0.5, post = 9.3±1.0, p = 0.48), less errors in word recognition (pre = 3.1±0.8, post = 1.7±1.2, p = 0.005), and an increasing trend in the category fluency test score (pre = 17.1±4.7, post = 18.3±2.9, p = 0.52) were found in the intervention group. Repeated measures analysis of variance showed that the improvement in word recognition was greater in the intervention group than in the control group (p = 0.01).

Conclusion

Our study, which is currently still ongoing, will shed light on whether increasing the “dosage” of intellectual activities could provide additional cognitive benefits to older adults and help them achieve cognitive maintenance.
Validation of a modified MOCA translation for use among Arabic‐speaking immigrants in the U.S.
Authors: Ajrouch Kristine J , Tarraf Wassim , Brauer Simon , Zahodne Laura B. , Antonucci Toni C
Published: December 2022

Background

The only validated, widely‐used dementia screen that has Arabic language norms/cutoffs is the Montreal Cognitive Assessment (MoCA). Yet, Arabic translations of the MoCA vary across countries. This study considers various Arabic translations of the MoCA, and presents a modified translation for use among Arabic‐speaking immigrants in the U.S.

Method

The modified translated version of the MoCA was administered to 32 Arabic‐speaking adults age 65+ living in metro‐Detroit. Eight (25%) had an ADRD diagnosis. To assess the reliability of the MoCA, each item was standardized and Cronbach’s alpha was calculated. To assess the similarity of ADRD and non‐ADRD respondents with regards to each MoCA item as well as with regards to demographics we used Fisher’s exact test for binary variables and t‐test for continuous variables. Ordinary least squares models were used to examine how an ADRD diagnosis predicts the MoCA score, adjusting for demographics.

Result

The mean age of the sample is 73 years old. Sixty‐two percent (62%) are female and 28% have a high school education or more. The alpha was acceptably high at .87. The MoCA item‐level scores for respondents with and without ADRD diagnoses showed that all respondents correctly identified the picture of a camel. There are also five items for which none of the ADRD respondents gave correct responses: trail‐making, verbal fluency F, both abstraction questions, and the cube‐copy test. Bivariate analyses further indicate that ADRD respondents are older than non‐ADRD respondents (p<.001). There is no significant difference in gender or education level. Those with ADRD diagnosis scored lower overall on the MoCA ( = ‐.35; se = .37), with 58% of the variation explained by the diagnosis and demographics. We interpret the result as a small effect size as indicated by the Cohen’s heuristic for the difference between means (0.2‐0.49).

Conclusion

The Arabic language MoCA is able to distinguish respondents with an ADRD diagnosis. Decision points about translations should consider national contexts to maximize equivalencies across samples.
Assessing Cognitive Impairment in People with Dementia Associated Disorders: Self‐Reported Recognitive Impairment Contrasted with Computerized Multi‐Domain Cognitive Testing – Truth be Told
Authors: Kaczmarek Olivia , Baek Steven , Peraza‐Bonilla Sophia , Sethi Avtej , Bumstead Barbara , Zarif Myassar , Gudesblatt Mark
Published: December 2022

Background

Dementia associated diseases (DAD) are characterized by progressive impairment of cognition that interferes with an individual’s ability to function independently. Clinically, cognitive impairment (CI) can vary in degree and combination across multiple cognitive domains (CD). Clinician and patient with DAD (PwDAD) recognition of such varied types/degrees of CI might not only be sub‐optimal, but also unable to recognize subtle change and progression. Patient self‐reported outcome measures (PRO) are used to gauge CI or disability progression. Traditional measures (MOCA, MMSE) include a dichotomous outcome measure and routine neuropsychological screening might not be practical. Quantitative and objective screening across multiple CD can be accomplished in routine care with validated, examiner independent, computerized multi‐domain cognitive assessment battery (CAB‐NT, NeuroTrax). NeuroQOL Cognitive Function Short‐Form (CF‐SF) is one validated disease agnostic PRO that can be incorporated to evaluate patient perception of disease impact and change on CI. The relationship of CF‐SF to multi‐domain quantitative CAB has not been explored in PwDAD.

Method

Retrospective review of consecutive PwDaD who completed both CF‐SF and CAB‐NT on the same day in the course of routine care. CAB‐NT included 7 cognitive domains: memory (Mem), executive function (Exe), attention (Att), information processing speed (Inf), visual spatial (Vis), verbal function (Ver), motor skills (Mot) as well as a global cognitive summary score (GCS).

Results

Linear regression analysis of relationship was explored with significance (p<0.05). 196 PwDAD, (65% female, average age 73+/‐ 9 years). “Significant” relationships (p<0.05) were identified through regression analysis for the following CD scores: GCS (r2 = 0.03), Exe (r2 = 0.04), Att (r2 = 0.06), and Mot (r2 = 0.04).

Conclusion

PwDAD self‐perception of their cognitive abilities do not accurately reflect objective CAB performance measures of cognitive function. CF‐SF PRO scores do not reflect cognitive performance across multiple cognitive domains and should not be considered appropriate screening tools to incorporate into routine care to determine when to consider the need for examiner independent measures to accurately monitor disease impact or change. Objective computerized testing measures across multiple cognitive domains provides useful insight and value based information for clinicians to gauge the presence of or change in cognitive impairment.
The Relationship of Self‐Reported Depression and Self‐Perceived Cognitive Function in People with Dementia Associated Disorders: A Complex Relationship That Requires More Than Perception and Self‐Report
Authors: Kaczmarek Olivia , Baek Steven , Peraza‐Bonilla Sophia , Sethi Avtej , Bumstead Barbara , Zarif Myassar , Gudesblatt Mark
Published: December 2022

Background

Dementia associated diseases (DAD) refers to multiple clinical conditions all characterized by progressive impairment of cognition that interferes with an individual’s ability to function independently due to such cognitive impairment (CI). Clinically, CI can vary in degree and combination across multiple important individual cognitive domains (CD). Depression is also reported to be an early sign of or as a potential risk factor of Alzheimer’s or another DAD. Enhanced awareness of the presence of depression in people with DAD (PwDAD) and the relationship of self‐reported depression to self‐perception of cognitive function may provide insight into current screening methods incorporated in routine care and treatment options prescribed as well as the need to include further information as treatment options become more complex and time available to holistically evaluate patient needs evolves.

Method

Retrospective cross‐sectional analysis of PwDAD who completed both the patient reported outcomes (PRO) Neuro QOL Cognition Function‐ Short Form (CF‐SF) and Neuro QOL Depression‐Short Form (SFD‐SF) in routine care. Linear regression analysis of relationship was explored with significance (p<0.05).

Results

213 PwDAD, 65% female, average age 70 +/‐ 15 years. A statistically significant negative relationship was identified between self‐reported depression identified by Neuro‐QOL PRO SFD‐SF and self‐perceived cognition abilities (CF‐SF) (r2 = 0.25).

Conclusion

There is an inverse relationship between PRO self‐reported depression and self‐reported/self‐perceived cognitive ability in PwDAD. Incorporating PRO Cognitive Function‐Short Form as the sole measure of cognitive function or simply as a screening tool to determine when to objectively measure cognitive function in PwDAD without simultaneously screening for depression and not incorporating other objective value‐added cognitive measurement tools should not be recommended.
Proteomic profiling of cognitive function in middle‐aged and elderly adults
Authors: Tin Adrienne , Fohner Alison E , Yang Qiong , Seshadri Sudha , Brody Jennifer A. , Fornage Myriam , Group The NeuroCHARGE Working
Published: December 2022

Background

Dementia is a pressing public health issue that affects 55 million adults worldwide. Some risk factors for cognitive decline and poor brain health appear to affect the blood brain barrier or cerebrovasculature. Therefore, it is plausible that circulating proteins may reflect causes and consequences of poor brain health. Identifying associated circulating proteins could help uncover important biological pathways in cognitive decline and dementia.

Methods

We conducted a cross‐sectional study of circulating proteins and cognitive function among participants without prevalent dementia or stroke in three cohorts: Atherosclerosis Risk in Communities (ARIC) study (n = 4,286), Cardiovascular Health Study (CHS, n = 2,297), and Framingham Heart Study (FHS, n = 706). Circulating proteins were quantified using a modified aptamer technology (SomaScan). Cognitive function was assessed by the first principal component (PC1) of measured cognitive scores from three different domains. We used linear regression to evaluate the association between each protein and PC1 controlling for age, sex, race, education level, and APOE Ɛ4 carrier status. We used fixed effect meta‐analysis to combine the cohort results from all age groups and two cohorts aged≥ 65. Statistical significance levels were Bonferroni corrected.

Results

The mean (SD) age in years was 74 (5) in ARIC, 75 (5) in CHS, and 46 (8) in FHS. Females comprised 58% of ARIC, 62% of CHS, and 55% of FHS. The number of proteins in common was 1,019 for all three cohorts and 4,672 for ≥65 years only. Meta‐analysis identified 76 significant proteins overall (p<4.9E‐5 = 0.05/1,019) and 211 significant proteins among age ≥65 (p<1.1E‐5 = 0.05/4,672). Among the significant associations, heterogeneity was moderate (median I2 of 78% in the overall meta‐analysis and 66% in the older age group). Some significant proteins are known biomarkers of dementia, such as GDF15 and SVEP1.

Conclusions

Large‐scale proteomic profiling identified plasma proteins significantly associated with cognitive function across 3 cohorts. Further replication and characterization, such as enrichment analysis, are underway to further elucidate the relationship between these associated circulating proteins and brain health.