bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel remote episodic memory assessment: An Agile development pipeline methodology for task selection
Authors: Anwyl‐Irvine Alexander L , Kaula Alexander J , Cashdollar Nathan , Taptiklis Nick , Cormack Francesca K
Published: December 2022

Background

There is a growing need to remotely monitor episodic memory decline. Recent advances in available device technology offer an opportunity to deploy novel smart phone‐based cognitive assessments. However, candidate task design options are numerous and selecting the most clinically sensitive and usable by the target population is not a trivial task. Inspired by Agile software development, we present a case‐study of a rapid iterative process for developing and selecting candidates.

Method

Design requirements: 1) Potential for early sensitivity to episodic memory changes, defined by satisfactory performance distributions; 2) Optimized for high frequency Smart Phone deployment; 3) Acceptable user feedback.

Three tasks were created: Exp 1 “Serial positioning task”, sequences of objects were memorized and recalled using a drag‐drop response (n=55). Exp 2 “Biographical association task”, AI generated faces were paired with information in a social media profile and later recalled either with questions or by clicking on probe faces (n=73). Exp 3 “Self‐generated pairing task”, where participants generated pairs of identities and later had to recall them (n=65). Each task implemented a minimum learning‐recall delay of 12 hours. Exp 4 ‐ Final versions were compared within participants and against validated CANTAB tasks using Exploratory Factor Analysis (n=155).

Result

Exp 1 “Serial positioning task”, identified a cognitive load of between 3‐4 items giving good performance‐based variability. Engaging stimuli using emoji and map‐backgrounds increased user ratings without negatively impacting variability. Exp 2 “Biographical association task”, demonstrated good distributions for recall, but only in a forced‐choice format. This was rated the least enjoyable. Exp 3 “Self‐generated pairing task”, showed ceiling effects. This task was rated equally enjoyable as Experiment 1. After comparing the Exp 4 results, the “Serial positioning task” was most predictive of age (tau‐b .256, Bf=113.7), as well as unique according to the factor analysis, and rated as most enjoyable.

Conclusion

Our agile development pipeline titrated the suitability of three candidate episodic memory tasks for future remote deployment in target clinical populations. By implementing this methodology, it was determined that the "Serial positioning task” was the best candidate for further development and testing for monitoring symptoms of memory decline.
The Cognitive Stress Test (CST): An Innovative Tool to Differentiate Cognitively Unimpaired (CU) Older Adults from those with Pre‐Mild Cognitive Impairment (Pre‐MCI) and Amnestic MCI (aMCI).
Authors: Nahmias Leeron , Beaulieu Ashleigh Nicole , Ortega Alexandra , Hincapie Diana Maria , Kitaigorodsky Marcela , Curiel Rosie E , Loewenstein David
Published: December 2022

Background

The CST is a novel assessment that was designed to measure cognitive changes during preclinical and prodromal stages of AD, that include aMCI and PreMCI, where deficits do not meet MCI. The CST employs semantically competing word lists to measure the impact of semantic interference, failure to recover from proactive semantic interference (frPSI), and its persistent effects, despite multiple trials. We hypothesized that frPSI deficits on the CST would be persistent in pre‐MCI and aMCI groups when compared to cognitively unimpaired (CU) controls.

Method

50 aMCI, 31 pre‐MCI, and 69 CU elders were administered the CST. Participants were presented with List A (18 semantically related words: occupations, household items, or transportation methods) for three initial learning trials, followed by three learning trials of List B, a categorically similar wordlist, to examine PSI and frPSI. Retroactive Semantic Interference (RSI) was assessed by using category cues to elicit recall of List A targets, followed by an additional learning trial to examine failure to recover from RSI (frRSI).

Result

Significant differences were observed between all diagnostic groups across CST Cued Recall trials that measure maximum learning, PSI, frPSI, and persistent frPSI. PreMCI and aMCI participants experienced deficits in learning List B despite two additional opportunities; a deficit that was observed even after adjusting for initial learning strength. Older adults with greater risk (preMCI and aMCI) performed similarly on indices that measures PSI, frPSI, and persistent frPSI as compared to controls. There were differences in RSI among CU and aMCI groups yet measuring frRSI did not differentiate groups. aMCI participants made more semantic intrusion errors on recall trials that cued List B words. Pre‐MCI and CU made a similar number of intrusion errors.

Conclusion

The CST extends our work by assessing persistent effects of frPSI, which have been shown to predict neurodegenerative progression and have been associated with multiple biomarkers of AD. The finding that persistent frPSI could differentiate CU from preMCI groups is a promising indicator that semantic interference deficits persist in older adults that present a heightened risk for progression to dementia and is worthy of further research.
Identifying dementia care needs of family physicians, people living with dementia, and care partners in Canada: Results of a national survey
Authors: Sivananthan Saskia , Armstrong Joshua J. , Berall Anna , Santiago Anna , Apostolides Haridos , Iroanyah Ngozi Faith , Guimond Josée , Brookes Jahnel , Ewa Vivian , Grill Allan , Aleong Rosanne , Feldman Sid
Published: December 2022

Background

There is consensus that timely detection, diagnosis and ongoing care of people with dementia is primarily the responsibility of family physicians in Canada. Yet evidence indicates low to moderate diagnosis rates and significant challenges in management of dementia. With the growing number of Canadians living with dementia, there is an increasing need to develop effective practice tools for family physicians and to understand the needs of people living with dementia and their caregivers. This nationwide study was conducted to identify the gaps in tools currently being used, and to identify the domains of care that people with lived experience of dementia and their caregivers feel are being done well, and those that require improvement by their family physician.

Method

Three nationwide surveys were distributed to target audiences: the 39‐item Dementia Care Needs Assessment Survey for family physicians, the 35‐item Dementia Journey Survey: Caregiver Experience for caregivers, and the 33‐item Dementia Journey Survey: Living with Dementia Experience for persons living with dementia. Survey questions were both multiple choice and open‐ended. Descriptive analyses were conducted on closed‐ended survey questions. Qualitative analyses of open‐ended questions were both inductive, based on observed patterns, and deductive, based on the study objectives.

Result

The surveys received 288 physician, 78 people with dementia, and 485 care partner responses. Preliminary analysis indicates consensus between physicians, people with dementia, and care partners on 15 of 22 barriers to diagnosis and care. Barriers highlighted included gaps in education and support, community resources, and access to specialists, as well as the need for improved communication around care and diagnosis. A further 4 themes were highlighted by physicians and 3 themes by people with dementia that did not overlap, indicating divergent needs. 24.7% of physicians reported using practice tools for dementia care, 10% of whom use only 1 tool for all aspects.

Conclusion

Optimal primary care is a cornerstone of a comprehensive approach to supporting people with dementia and their care partners. Identifying gaps in knowledge and tools to support practice and developing new educational programs that are aligned with the needs of people with dementia are vital to improve primary dementia care.
Late‐onset AD risk mutation PICALMH458R prevents plaque generation in 5xFAD mice
Authors: Gomez‐Arboledas Angela , Tran Kristine M , Javonillo Dominic I , Phan Jimmy , Milinkeviciute Giedre , Da Cunha Celia , Forner Stefania , Kawauchi Shimako , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N
Published: December 2022

Background

To understand the processes that drive late‐onset Alzheimer’s Disease (AD), genome‐wide association studies (GWAS) have uncovered many risk loci. One of these is within the phosphatidylinositol‐binding clathrin assembly protein (PICALM) gene, and a coding mutation has been identified (H458R) which conveys increased risk. PICALM is a cytosolic protein involved in regulating the formation of the lattice during endocytosis. The role of PICALM in AD has not fully defined, however, there are several reports indicating that PICALM affects AD risk primarily by modulating the production, transportation, and clearance of Aβ.

Method

We generated and crossed PicalmH465R
mice with the 5xFAD mouse model of AD, generating 4 groups: wild‐type (WT), PICALM
H458R homozygous (HO), 5xFAD, and 5xFAD/ PICALM
H458R HO, where we named the mice based on the human variant. They were aged to 4 months and 12 months, when plaque loads are being established and plateaued, respectively. Coronal brain sections were immunolabeled with Thioflavin‐S to visualize dense‐core plaques in the hippocampus subiculum and cortex. Plasma neurofilament light chain (NfL), a surrogate measure of brain damage, and soluble and insoluble Aβ levels were measured via meso scale discovery (MSD) technology.

Result

5xFAD/ PICALM
H458R mice exhibited significant reduction in plaque density in both brain regions compared to 5xFAD mice, as well as reductions in plaque volumes at 4‐month. However, at 12‐month, the opposite is observed with increased plaque density in 5xFAD/ PICALM
H458R compared to 5xFAD but no change in plaque volume. Similar to the observed plaque load at 4‐month, hippocampal insoluble fractions of 5xFAD/ PICALMPlasma NfL levels reflected reduced brain damage at 4‐month in 5xFAD/ PICALM
H458R and a rise to similar level as 5xFAD at 12‐month, consistent with the plaque load.

Conclusion

The results indicate PICALM
H458R variant induces age dependent effects on Ab accumulation in 5xFAD mice, with an initial suppression of plaque genesis but ultimately leading to a higher plaque burden with age
Differentially methylated CpG sites between APOE ε4 carriers and non‐carriers in blood and brain from Alzheimer disease cases and controls
Authors: Panitch Rebecca , Au Rhoda , Stein Thor D. , Farrer Lindsay A. , Jun Gyungah R
Published: December 2022

Background

The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer disease (AD). Methylation changes have been shown to occur early in AD, however, the influence of APOE genotype on methylation especially in relation to AD remains largely unknown.

Method

We evaluated differential methylation of genome‐wide CpG sites in brain between 178 APOE ε4 carriers and 511 ε4 non‐carriers in the Religious Orders Study and Memory and Aging Project (ROSMAP), in blood between 276 APOE ε4 carriers and 1118 ε4 non‐carriers in the Framingham Heart Study (FHS), and in blood between 114 APOE ε4 carriers and 187 ε4 non‐carriers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methylation patterns of the top‐ranked CpG sites were further examined in FHS participants with respect to cognitive and brain imaging traits.

Result

The most differentially methylated CpG sites among the autosomes were observed in the APOE region (chr19:45380000‐45430000) in all datasets. Significantly (P<10‐8) hypomethylated CpG sites in APOE ε4 carriers compared to non‐carriers were observed from the APOC1 gene in the FHS (cg23270113, cg05644480) and ADNI (cg07773593) datasets (P=4.6x10‐9) and from the TOMM40 gene (cg02613937, P=1.3x10‐13) in the ROSMAP dataset. Significantly (P<10‐8) hypermethylated CpG sites in APOE ε4 carriers compared to non‐carriers were observed from the APOE gene in the ROSMAP (cg14123992, cg04406254) and FHS (cg06750524) datasets. The two APOC1 CpG sites were significantly associated (P<0.05) with amyloid‐beta 42 level in plasma and several cognitive tests (Trail A, Paired Associate Learning, Verbal Fluency Test, Boston Naming Test). APOE CpG site cg06750524 was significantly associated with MRI volumetric measures of the cerebrum (P=0.01), temporal cortex (P=0.02), and frontal cortex (P=0.05).

Conclusion

We discovered novel CpG methylation differences in blood and brain between APOE ε4 carriers and non‐carriers that are associated with AD‐related traits especially involved in executive function and language. Further studies are required to link the methylation patterns to mechanisms leading to AD.
Racial and Ethnic Differences in Occupational Complexity and Late‐Life Cognition
Authors: Soh Yenee , Eng Chloe W. , Hodis Jeffrey D. , Mayeda Elizabeth Rose , Lee Catherine , Peterson Rachel L. , Whitmer Rachel A. , Glymour M. Maria , Gilsanz Paola
Published: December 2022

Background

Structural racism affects employment opportunities, resulting in occupational segregation and potential racial and ethnic health disparities. Research examining the association between occupational complexity and late‐life cognition within and across racial and ethnic groups is limited. We aim to address this research gap using the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort of Asian, Black, Latino and White community‐dwelling participants aged 65+ years.

Methods

We linked occupational complexity scores (from the Dictionary of Occupational Titles) for data (range: 0‐6), people (0‐8), and things (0‐7) to self‐reported main lifetime occupation. We assessed baseline domain‐specific cognition (executive functioning, verbal episodic memory, and semantic memory) using the Spanish and English Neuropsychological Assessment Scales. Using linear regression models, we estimated associations between each occupational complexity measure and domain‐specific z‐scores, adjusting for age, sex, race and ethnicity, and education. We also assessed effect modification by race and ethnicity.

Results

Among 1,548 participants (mean age = 76 years), 24% identified as Asian, 27% as Black, 19% as Latino, 29% as White, and 50% had a college degree or higher (Table 1). Occupational complexity with data and people varied across race and ethnicity (p‐value: >0.001 and 0.016, respectively), but not for complexity with things. Greater occupational complexity with data was associated with higher executive function (β = 0.05 SD units; 95% CI:0.02‐0.09), semantic memory (0.07 SD units; 95% CI:0.04‐0.11) and verbal episodic memory (0.06 SD units; 95% CI:0.02‐0.10) (Figure 1). Complexity with people was associated with higher executive function and semantic memory only. Complexity with things was not associated with any cognitive domain. Effect modification by race and ethnicity was significant, such that the association between greater occupational complexity with data and higher semantic memory was stronger among Latinos, compared to other racial groups.

Conclusion

Within a diverse cohort, greater occupational complexity with data and people were associated with higher late‐life cognition. Occupational complexity scores varied by race and ethnicity, as well as its associations with cognitive domains. These findings suggest that racial and ethnic differences in occupational complexity may contribute to cognitive health disparities.
Alzheimer brains: increased soluble amyloid peptides, but decreased lipid rafts
Authors: Thorwald Max A , Finch Caleb E
Published: December 2022

Background

PET imaging studies of AD patients show progressive increases of fibrillar Aβ‐ amyloid. Because current PET ligands underestimate non‐fibrillar forms, we assayed soluble Aβ in AD and controls. To identify mechanisms responsible for soluble Aβ in AD brains, we examined lipid rafts (LR), where APP is enzymatically processed. Frontal cortex was compared with cerebellum, which has minimal AD pathology.

Method

Postmortem samples (N=48) were age‐and sex matched for Braak scores. Soluble Aβ was extracted from homogenates of full thickness frontal cortex by isotonic buffer and mild detergent (RIPA; 1% NP40) and centrifuged (10,000g/1h). Supernates were assayed by dot blots with antibodies for Aβ40 and Aβ42 (Biolegend, San Diego, CA). Aβ was assayed as relative fluorescent units per gm brain. LR fractions were isolated from these same brains by kit (Invent Biotechnologies; LR‐039), validated by ultracentrifugal fractionation.

Result

Compared with cognitively normal controls (Braak 0‐1), elevations of soluble Aβ40 and Aβ42 were similar for intermediate and later stage AD (Braak 2‐3 and 4‐6). Clinical grade AD had greater increase of soluble Aβ40 (+400%) than Aβ42 (+50%) (p<0.05). LR raft yield per gram AD frontal cortex was 20% below controls (p<0.05), while cerebellar LR did not differ by Braak score. The composition of LR had a similar pattern, with 35% AD decreases of total protein and cholesterol (p<0.05); cerebellar LR again did not differ by Braak score. However, LR 4‐HNE, a marker of oxidative damage, was similarly increased in AD cortex and AD cerebellum.

Conclusion

The extensive overlap of soluble Aβ levels in controls with AD contrasts with the PET findings on fibrillar Aβ. These findings further support fibrillar Aβ as a biomarker for AD treatments and show the need for more detailed postmortem analysis of diverse soluble and insoluble Aβ aggregates in relation to PET. The decreased LR in AD frontal cortex is consistent with its extensive neuronal loss, in contrast to the cerebellum. Further studies will examine LR enzymes of APP processing as a source of the increased soluble Aβ in AD, and subcellular clearance processes, which may be impaired in association with the oxidative damage indicated by increased 4‐HNE.
Comparing ARIA‐E severity scales and effects of treatment management thresholds
Authors: Klein Gregory , Bracoud Luc , Purcell Derk , Barakos Jerome , Fiebach Jochen B. , Scelsi Marzia A. , Delmar Paul , Lyons Marco , Wojtowicz Jakub , Bullain Szofia , Barkhof Frederik , Fontoura Paulo , Baudler Monika , Doody Rachelle S.
Published: December 2022

Background

Vasogenic edema and sulcal effusions detected with Magnetic Resonance Imaging (MRI), known as Amyloid‐Related Imaging Abnormalities‐Edema (ARIA‐E), are manageable side effects of anti‐amyloid immunotherapies. Periodic MRI scans with severity assessment of ARIA‐E are used in clinical trials or to guide practice with these therapies.

Several scales with varying complexity measure radiological ARIA‐E severity to guide dosing. The ongoing GRADUATE studies use the 60‐point Barkhof Grand Total Scale (BGTS)1, continuing treatment for asymptomatic ARIA‐E ≤ 3, and temporarily suspending dosing for BGTS > 3. Other studies have used Simple ARIA‐E Severity Scales2 (SAESS‐3, SAESS‐5), continuing treatment for asymptomatic SAESS‐3 ≤ 1, but temporarily suspending dose for SAESS‐3 > 13. We previously reported good correlation between BGTS, SAESS‐3, and SAESS‐5 by a single reader. Here we report correlations among these scales scored by multiple readers and assess the impact of these various scores on ARIA management.

Methods

T2‐FLAIR MRI scans were selected from a representative set of incident ARIA‐E cases (70 with previously detected ARIA‐E, 5 without ARIA‐E from original BGTS assessment) in the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) Phase III studies. Three experienced neuroradiologists scored ARIA‐E severity using the 3 scales from pairs of baseline/follow‐up scans, blinded to prior read results. Median results of the 3 readers were computed for further analysis.

Result

Inter‐reader agreement for all 3 scales was high (ICC=0.866 [0.811, 0.908], 0.888 [0.841, 0.924], and 0.858 [0.776, 0.910] for the SAESS‐3, SAESS‐5, and BGTS scales respectively). Spearman’s rank correlation with BGTS scale was 0.88 for the SAESS‐3 scale and 0.90 for SAESS‐5. Median interquartile range (IQR) BGTS scores for the two simplified scales are shown in Figure 1. Best agreement for the SAESS‐3 > 1 treatment management threshold was achieved with BGTS > 3, with an accuracy of 93.3% (Figure 2).

Conclusions

SAESS‐3 and SAESS‐5, which may be more suitable for routine clinical practice, are well correlated to the BGTS scale. Treatment management based on the SAESS‐3 > 1 threshold shows high agreement with the BGTS > 3 threshold.

1. Barkhof et al., 2013; AJNR 34:8.

2. Bracoud et al., 2017; AAIC. P1‐047.

3. ADUHELM (aducanumab‐avwa) FDA PI.
Meta‐analysis employing the African Genome Resources panel identifies novel Alzheimer disease risk loci in African Americans
Authors: Kurup Jiji Thulaseedhara , Kunkle Brian W. , Hamilton‐Nelson Kara L. , Jean‐Francois Melissa , Schmidt Michael A. , Martin Eden R , Wang Li‐San , Beecham Gary W. , Farrer Lindsay A. , Haines Jonathan L. , Byrd Goldie S. , Schellenberg Gerard D. , Mayeux Richard , Pericak‐Vance Margaret A. , Reitz Christiane ,   Alzheimer’s Disease Genetics Consortium
Published: December 2022

Background

In the largest Alzheimer disease (AD) genome‐wide association studies to date for African‐Americans (AA; Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified in addition to APOE several novel susceptibility loci, including ABCA7, API5, RBFOX1 and IGF1R. We followed up these analyses with an increased sample size (2,913 cases, 5,802 controls) employing the African Genome Resource (AGR) panel.

Method

Single‐variant association analysis was conducted adjusting for age, sex, principal components and subsequently APOE, applying logistic regression for case‐control and general estimating equations for family‐based datasets. Within‐study results were meta‐analyzed using METAL. Gene‐based and pathway analyses were conducted via MAGMA.

Result

In addition to the previously reported AA risk loci, we identified three novel signals reaching genome‐wide significance at chromosomes 3p24 (TOP2B; P = 4.7×10−8), 3q26 (NCEH1; P = 3.7×10−8) and 9p23 (MPDZ; P = 1.7×10−8), and seventeen novel loci reaching suggestive significance at p ≤ 9×10−7. NCEH1 modulates cholesterol metabolism and is neuroprotective against α‐synuclein toxicity; MPDZ encodes a scaffolding protein involved in cytoskeleton remodeling. Top2B encodes a DNA topoisomerase involved in DNA transcription. Gene‐based analyses identified SLC39A3 (P = 2.9×10−6), involved in zinc transport, as a novel candidate gene. Pathway analyses support the notion that besides immunity, synaptic function, transcription/DNA repair, lipid processing, and intracellular trafficking, which overlap with the major AD‐associated pathways in non‐Hispanic Whites, also renal function is involved in AD etiology in African Americans.

Conclusion

We identified several novel candidate loci for AD in AA. While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non‐Hispanic White individuals, the disease‐associated loci within these pathways differ. Identification of a significant number of loci at suggestive significance indicates that future studies with further increased sample size will be valuable to identify additional disease‐associated loci in this ethnic group.
Intragenic loci within TOMM40 enhances APOE expression in human microglia
Authors: Oron Oded , Ramirez Aura Maria , Wang Liyong , Vasquez Marina Lipkin , DeRosa Brooke A , Celis Katrina , Chesi Alessandra , Grant Struan F.A. , Young Juan J , Nuytemans Karen , Vance Jeffery M. , Dykxhoorn Derek M.
Published: December 2022

Background

Previously, we demonstrated that the ancestry‐related risk for Late Onset Alzheimer’s Disease (LOAD) is driven by a local genomic region (termed Local Ancestry; LA) around APOEε4. Furthermore, we showed that in the brain of individuals bearing European LA there is higher expression of APOEε4 compared to those with African LA. In a follow‐up study, utilizing reporter assays and Capture‐C data we located two intronic regions within the European LA, both in the TOMM40 gene (named B10 and B13), that increased APOE expression in microglia and astrocytes. In this study, we sought to validate their regulatory role in APOE expression using CRISPR interference/activation (CRISPRi/a).

Method

Human Microglial Clone 3 (HMC3) CRISPRi/a lines were produced by transducing inducible dCas9‐VP64 (Activation), dCas9‐KRAB (Interference) or dCas9 (control) using lentiviral vectors. To direct the dCas9 constructs to our regions of interest, we generated multiplex vectors that encode 4 short‐guide RNAs (sgRNAs) targeting either B10 or B13. We used 4 different sgRNAs in each case to ensure full‐length coverage of the tested regions (∼850bp size). An empty multiplex vector was used as a control. We then transduced either of the multiplex vectors into the HMC3 CRISPRi/a lines. We induced expression of the dCas9 constructs for 2 or 6 days with Doxycycline (2ug/ml). RNA was extracted and the expression of APOE and TOMM40 was measured by qRT‐PCR.

Result

APOE expression significantly increased when targeting B10 or B13 (p=0.001; p=0.003 respectively) with dCas9‐VP64 after 2 days of Doxycycline treatment. Six days after treatment the significance persisted only when targeting B10 (p=0.01). No significant changes in APOE expression were observed in the cells bearing the dCas9‐KRAB presumably due to low endogenous APOE levels. Expression of TOMM40 did not vary under any treatment.

Conclusion

These preliminary results support our previous findings that regions B10 and B13 may act as regulators for APOE expression as demonstrated by the elevation of ApoE expression when targeting an activator to these regions. The expression of TOMM40 did not vary across cell lines in the evaluated time points supporting that the effect observed is specific for APOE.
Macropinocytosis of APP is controlled by a cascade of regulatory proteins
Authors: Krupa Jordan M , Tsang Adrianna R , Seah Claudia , Pasternak Stephen H
Published: December 2022

Background

The internalization of the Amyloid Precursor Protein (APP) is recognized as an important step in beta‐amyloid (Aβ) production. We have discovered that macropinocytosis of cell surface APP leads to rapid transport directly to lysosomes, bypassing early and late endosomes. This process leads to APP cleavage to Aβ and is regulated in part by Arf6.

Here, we hypothesize that the binding/cross‐linking of APP at the cell surface recruits Fe65 and results in the recruitment and activation of Arf6. Arf6 then activates downstream small GTPases that are known to regulate macropinocytosis in non‐neuronal cells (including Rac1, Cdc42 and RhoA) leading to APP internalization by macropinocytosis.

Method

Neuro2a neuronal cells are transfected with fluorescent‐tagged proteins including Fe65, Rac1, Cdc42 and RhoA. Membrane PI(4,5)P2, a marker for membrane ruffling and the initiation of macropinocytosis, is visualized using fluorescent‐tagged marker known as PLCdelta‐PH. Cells are cultured in 37°C confocal dishes on the stage of a Leica SP8 confocal microscope. Fluorescent‐labelled anti‐APP antibodies are added to bind/cross‐link APP at the plasma membrane. We then use confocal microscopy/live cell imaging to visualize the recruitment of the regulatory proteins in real time.

Result

Upon anti‐APP antibody binding, we can see APP recruited to sites on the plasma membrane enriched with PI(4,5)P2 and the plasma membrane begins to ruffle. We see Fe65 rapidly recruited to the membrane, along with active Arf6 at these sites of membrane ruffling. We also observe Rac1, Cdc42 and RhoA recruited to these regions. APP at these sites is then observed to rapidly internalize to lysosomes, demonstrated by its colocalization with the lysosomal marker LAMP1.

Conclusion

These results demonstrate the active recruitment of GTPase proteins known to regulate macropinocytosis to the membrane at sites of APP binding/cross‐linking. These regulators could be targeted to modulate APP trafficking and reduce the production of Aβ.
Perceptions of staff and leadership teams on implementation of telepresence robots in long‐term care: a qualitative descriptive study
Authors: Wong Joey , Young Erika , Hung Lillian , Mann Jim , Jackson Lynn
Published: December 2022

Background

COVID‐19’s physical distancing mandates have increased the likelihood of experiencing social isolation and loneliness for residents in long‐term care (LTC), especially those living with dementia. Social isolation correlates with health risks, including depression and cognitive decline. Telepresence robots can be remotely driven and facilitate social interactions through videoconferencing. Researchers have begun to explore opportunities of using these robots in the healthcare field; however, there is a research gap on examining factors influencing their implementation in LTC from the perspectives of key stakeholders. This qualitative descriptive study focuses on exploring LTC staff and leadership teams’ perspectives on facilitators and barriers to implementing telepresence robots.

Method

We employed purposive and snowballing methods to recruit 22 participants from two LTC homes in British Columbia, Canada: operational and unit leaders, and interdisciplinary staff including nursing staff, care aides and allied health practitioners. Consolidated Framework for Implementation Research (CFIR) guided our data collection and analysis. Semi‐structured interviews were conducted by virtual meetings. Thematic analysis was performed to identify themes.

Result

Analysis of the data produced three themes: (a) perceived needs and values for family‐resident connections, (b) engagement through conversation and partnership, and (c) confidence with training and timely support. Based on the findings and CFIR guidance, we offer a preliminary conceptual tool “START”: Share benefits and successes; Tailor policies and plans with staff partners; Acknowledge and address staff concerns; Repeated training and demonstrations; and Timely technical support.

Conclusion

This study offers pragmatic insights into staff and leadership teams’ perceptions of facilitators and barriers of implementing telepresence robots in LTC. The complexity of technology implementation will require executive and leadership teams to consider additional factors beyond the Plan‐Do‐Study‐Act (PDSA) cycle.
Effects of an Alzheimer’s and Dementia Care Co‐management Program on Quality, Clinical Outcomes, and Utilization
Authors: Reuben David , Panlilio Michelle ,   UCLA Alzheimer’s and Dementia Care Program
Published: December 2022

Background

: The quality of care provided to persons living with dementia (PLWD) and their care partners (CPs) is low, clinical outcomes are poor, and costs are high. Co‐management of dementia care by Advance Practice Providers (APPs) has the potential to improve all of these metrics.

Method

: The UCLA Alzheimer’s and Dementia Care (ADC) Program is a health system‐based co‐management model of APP Specialists (DCSs) working with primary care and specialty physicians that is designed to meet dementia care needs. DCSs approach the PLWD and CP as a dyad, providing support, including community‐based resources, to both; behavioral and medication management; and care coordination. The program has provided dementia care for over 3400 PLWD and has a current census of over 750 PLWD who are cared for by 4 nurse practitioner DCSs.

Result

Quality of care based on established dementia quality indicators assessed by medical record review was 92%. Based on an analysis of the first 1091 PLWD and their CPs, prior to entering our program, many caregivers were poorly informed about dementia caregiving and felt they were fighting this battle alone. One‐third had high stress and more than 10 percent were depressed. By the end of a year in the program, confidence in handling problems and complications of Alzheimer’s disease and dementia improved by 72 percent. CP strain (Modified Caregiver Strain Index), distress (Neuropsychological Inventory‐Distress), and depression (PHQ‐9) were reduced (all P<0.001). Moreover, the program reduced emergency department visits by 20%, days spent in the hospital by 26%, admissions to nursing homes for long‐term care by 40%, (all P<0.05) and overall Medicare costs by $2404 per person/year. The ADC Program has been disseminated to 18 sites nationwide and more than 5000 PLWD and their CPs have received ADC care.

Conclusion

Dementia co‐management with APPs can improve quality and clinical outcomes and reduce health care utilization and costs. The ADC Program can be implemented in diverse health systems indicating the potential for widespread dissemination.
The influence of cognitive status on perivascular space enlargement trajectories in a longitudinal aging cohort
Authors: Lynch Kirsten M , Toga Arthur W. , Choupan Jeiran
Published: December 2022

Background

Perivascular space (PVS) enlargement is associated with dysfunctional waste clearance and can hinder the removal of toxic metabolic substrates, such as amyloid beta (Aβ). Increased PVS visibility in white matter has been observed in cross‐sectional studies of patients with Alzheimer’s disease (AD) and mild cognitive impairment (AD). However, the utility of PVS morphology as a diagnostic biomarker for AD pathology is hindered by the lack of knowledge regarding the time course of PVS alterations across diagnostic groups. In the present study, we characterize the relationship between cognitive status and PVS morphological trajectories with age in a longitudinal cohort. Findings from this study will provide insight into the role of waste clearance processes in AD disease pathogenesis.

Method

Longitudinal neuroimaging data from 500 cognitively normal (CN) subjects, patients with stable MCI (sMCI), and patients with MCI that later convert to AD (cMCI) were obtained from ADNI3. White matter PVS morphological features were automatically defined according to the methods described in (4) using optimally thresholded vesselness maps on high resolution T1w scans. The influence of class membership on the rate of PVS alterations over time were assessed with a linear mixed effects models with REML after controlling for baseline age, gender, years of education and total white matter volume.

Result

We found a significant interaction between cognitive status and time on mean PVS cross‐sectional diameter in the white matter, where the rate of change of PVS enlargement in patients with cMCI was greater compared to CN controls (B=‐.22, t(491)=‐2.06, p=.039) and patients with sMCI (B=‐.21, t(491)=‐2.03, p=.043). No significant differences in the age‐related change to PVS count or volume were observed between groups.

Conclusion

Our findings show patients with MCI that later progress to AD show accelerated PVS enlargement compared to patients that remain in the preclinical stages of cognitive decline. Our results support the growing body of research that demonstrates a relationship between pathological PVS enlargement and neurodegenerative disorders characterized by dysfunctional waste clearance. Parenchymal PVS caliber may therefore provide an informative biomarker to aid in the early diagnosis of AD and other amyloidopathies prior to the formal onset of deleterious symptoms.
Prevalence, clinical characteristics, and association between chronic obstructive lung disease (COPD) and cognitive status in a cohort of elderly adults
Authors: Choate Radmila , Jicha Gregory A , Abner Erin L
Published: December 2022

Background

The burden of age‐related conditions, like COPD and dementia, including Alzheimer’s disease, has been increasing. COPD prevalence is highest in women aged 65‐74 (10.4%) and in men aged 75‐84 (11.2%). We hypothesized that COPD, which may lead to chronic brain hypoxia, could increase the risk for late‐life dementia. By examining the association between COPD and cognitive status, we sought to better understand potential shared risk factors associated with these highly prevalent conditions.

Method

This study examined data from the University of Kentucky Alzheimer’s Disease Research Center (UK‐ADRC) cohort, a convenience sample of community‐based older adults followed longitudinally until death and subsequent brain autopsy. Individuals with available history of COPD were included in the study. Demographics and clinical characteristics of the cohort were assessed at the last available follow‐up visit. Descriptive and comparative statistical analyses were performed for participants with and without COPD.

Result

Overall, 692 individuals were included (8.5% with COPD, mean age 77.5±7.9 years, 62.9% female, 84.3% white). The majority of those with COPD (67.8%) vs. 36.0% of those without COPD had a history of smoking (mean duration 31±15.8 vs. 21.1±14.6 years, respectively). Individuals without COPD (n = 633) did not differ demographically from those with COPD (Table 1). Hypertension and diabetes were more common in the participants with COPD compared to those without COPD (73.7% vs. 64.2%, and 20.7% vs. 15.5%, respectively). At least one APOE ε4 allele was found in 32.0% of individuals with a history of COPD and 38.7% of those without COPD. At the last available follow‐up visit, the prevalence of dementia and MCI were similar in the participants with COPD compared to those without COPD (17.0% % vs. 16.3% %, and 25.4% vs. 23.1%, respectively).

Conclusion

We found no association between the history of COPD and impaired cognitive status in this cohort. COPD may be underdiagnosed and underreported in this group of older individuals, given its lower prevalence than expected in this age group. Further research relying on more objective pulmonary function data and longitudinal studies are needed to fully understand the potential associations of COPD with risk for impaired cognitive status in this population.
Development and Validation of a clinical scale for defining RBD severity in participants of the North American Prodromal Synucleinopathy (NAPS) consortium
Authors: Choudhury Parichita , Busicescu Andrea , Lee‐Iannotti Joyce , Rangan Pooja , Shprecher David , Ju Yo‐El , Boeve Bradley F. , Postuma Ronald B ,   North American Prodromal Synucleinopathy (NAPS) Consortium
Published: December 2022

Background

REM Sleep Behavior Disorder (RBD) is a prodromal marker of α‐synucleinopathies with no standardized tool for assessing severity in clinical or research practice. RBD severity may have implications in measuring risk of phenoconversion, monitoring response to treatment and clinical trial design. This study assessed the validity of the RBD symptom severity scale (RBDSSS) and its correlation to the clinical global impression of severity (CGI‐S) in a cohort of participants enrolled in the North American Prodromal Synucleinopathy (NAPS) Consortium.

Method

Participants and their bedpartners enrolled in the NAPS cohort filled out an 8‐item questionnaire, developed by the International RBD Study Group, assessing frequency and severity of dreams, vocalizations, movements, and injuries associated with RBD, with higher scores indicating more severe symptoms. The CGI‐S is a 7‐point scale ranging from normal (1) to most severely ill (7) and was completed by a clinician based on an independent interview with the participant ± their bedpartners. Total scores for participant (RBDSSS‐PT) and bed partner (RBDSSS‐BP) questionnaires were derived by multiplying frequency and severity scores for each feature, then summing the products for possible maximum scores of 54 and 38 respectively.

Result

This cohort (n = 212) was predominantly male (82.5%) with a mean ± SE age of 65.16 ± 1.46 years. The median (interquartile range) for RBDSSS‐PT, RBDSSS‐BP and CGI‐S was 11 (4‐17), 8 (4‐14.3) and 3 (3‐4), respectively. Spearman’s rank correlation coefficients (rs) were as follows: RBDSSS‐PT vs. RBDSSS‐BP, rs = 0.579; RBDSSS‐PT vs. CGI‐S, rs = 0.642; RBDSSS‐BP vs. CGI‐S, rs = 0.487 (all P<0.0001). RBDSSS‐BP scores were significantly lower in women (6 vs. 9, Chi‐Square p = 0.009) while there were no differences in RBDSSS‐PT scores by sex. (9 vs. 11, p = 0.473).

Conclusion

A moderate correlation was observed between RBDSSS‐PT and RBDSSS‐BP suggesting good construct validity for the scale. CGI‐S correlated most with RBDSSS‐PT and had a weaker association with RBDSSS‐BP. Women had lower severity scores as reported by bed partners unlike their self‐reported scores, indicating possible sex differences in perceived RBD severity.
Mechanism of gamma‐secretase modulators
Authors: Luo Joanna E. , Wagner Steven L , Li Yueming
Published: December 2022

Background

Amyloid‐beta (Aβ) peptides are believed to be integral to Alzheimer’s disease (AD) pathogenesis through their role in the “amyloid hypothesis,” in which the accumulation of Aβ peptides initiates a cascade of pathological events leading to neurodegeneration and AD. γ‐Secretase is a transmembrane aspartyl protease which cleaves APP to generate Aβ peptides, making γ‐secretase an attractive drug target. However, inhibitors failed in clinical trials due to their unwanted side effects on other γ‐secretase substrates such as Notch. ɣ‐Secretase modulators (GSMs) selectively reduce levels of the pathogenic Aβ species without affecting Notch and overall APP processing. However, many questions on their mechanism still remain. Here we investigate the molecular mechanism of GSMs by (1) investigating the binding site of imidazole GSM E2012 using photoaffinity labeling and molecular docking and (2) investigating combination therapy with different GSMs on reducing Aβ production.

Method

Part I: We incubated clickable GSM photoaffinity probes with cell membranes in the presence or absence of competitors, followed by UV irradiation to initiate photo‐crosslinking to nearby proteins and conjugation to biotin via click chemistry. Labeled proteins were isolated with affinity chromatography by streptavidin beads, eluted, and analyzed by western blot. Probes were docked onto γ‐secretase (PDB 7D8X) using tools from Schrodinger Suite 2021‐2. Part II: We treated N2a‐APP cells with GSM‐1 (acid GSM), E2012, or BPN‐15606 (imidazole GSMs) individually or in combination for 12h. Afterwards we collected cell culture media and measured secreted Aβ38, Aβ40, and Aβ42 levels using MesoScale Discovery.

Result

We demonstrate that GSM photoprobe E2012‐BPyne labels presenilin‐1 and nicastrin in the presence of transition state analog L‐685, 458, consistent with structural observations. From molecular docking studies we observe that GSM photoprobes differentially interacted with γ‐secretase and docking scores aligned with probe labeling efficiency. Furthermore, we demonstrate that acid and imidazole GSMs synergistically inhibit cellular Aβ production.

Conclusion

Our findings have revealed insight into the binding of GSMs and the effects of two GSM classes in combination. We are currently examining the effects of combined GSMs in primary neurons and on Notch production. These studies aim to better understand the mechanisms of GSMs to target γ‐secretase in AD.
Neuroinflammation connecting amyloid‐beta and p‐tau pathology, may explain clinical heterogeneity in Alzheimer’s disease
Authors: Boon Baayla D.C. , Hoozemans Jeroen J.M. , Rozemuller Annemieke J.M. , Bouwman Femke H. , Frigerio Irene , Jonkman Laura E. , Kouri Naomi , Dickson Dennis W. , Murray Melissa E.
Published: December 2022

Background

Other than the typical (memory‐dominant) variant, Alzheimer’s disease (AD) can present as posterior cortical atrophy (PCA) and behavioral/dysexecutive AD. Tangle distribution differs amongst clinical variants. Neuroinflammation is important in AD pathogenesis and may contribute to Aβ and p‐tau distribution. The relationship between pathological hallmarks, neuroinflammation and, APOE genotype in (a)typical AD is still largely unknown.

Method

I will discuss our most recent studies on neuroinflammation in (a)typical AD from cohorts derived from the Netherlands Brain Bank and the Mayo Clinic. Atypicality is investigated from both a neuropathological perspective(N=19) and a clinical perspective (N=30, unpublished data). Additionally, the association ofAPOE ε4 with specific Aβ deposits (i.e., the ‘coarse‐grained plaque’ and the classic cored plaque) and their underlying neuroinflammatory response is investigated (N=60, unpublished data).

Result

In neuropathologically‐defined atypical AD, microglia, and complement show an atypical distribution across regions, resembling that of p‐tau. Clinical atypical AD variants show in addition to a distinct distribution for p‐tau and Aβ, a distinct distribution for activated microglia (CD68, MHC‐II), complement (C4b), and astrocytes (GFAP) (p<.05) (Fig. 1). Furthermore, when investigating Aβ in detail, we observed an atypical plaque, defined as the ‘coarse‐grained plaque’. This APOE ε4+ plaque is associated with increased neuroinflammation and p‐tau burden (ρ(58)=0.5 and 0.6;p<.05) in contrast to the classic cored plaque.

Conclusion

Our data supports that not all types of Aβ deposits are associated to p‐tau damage. Neuroinflammation, a process that is differently activated within AD variants, may be the link between Aβ aggregation and subsequent neurodegeneration and contribute to clinical variability.
Implementation of the Alzheimer’s blood‐based biomarker panel in clinical practice: the development of cutoffs for plasma Abeta1‐42/1‐40, P‐tau181, GFAP and NfL across the clinical continuum
Authors: Verberk Inge M.W. , van Harten Argonde C. , Gouda Mariam , Hussainali Zulaiga , van Engelen Marie‐Paule E. , Wilson David , Lemstra Afina W. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Teunissen Charlotte E.
Published: December 2022

Background

Several blood‐based biomarkers for Alzheimer’s disease (AD) can now be reliably measured. It is not yet clear how those markers should be interpreted in a real‐world clinical setting, where a heterogeneous group of patients presents in different syndromal stages and with different symptoms. We aim to establish a ready‐to‐implement blood‐based biomarker panel including Abeta1‐42/1‐40, P‐tau181, GFAP and NfL with cutoffs for clinical application among subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD‐dementia, frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB).

Method

We included n=1132 individuals of the Amsterdam Dementia Cohort (table 1) with known baseline amyloid‐beta (Aβ) status, who had SCD (n=237 Aβ‐, n=66 Aβ+), MCI (n=108 Aβ‐, n=151 Aβ+), AD‐dementia (n=297, all Aβ+), FTD (n=162 of whom n=121 Aβ) or DLB (n=111 of whom n=53 Aβ‐). Plasma markers were measured with Simoa (neurology 4‐plex E, P‐tau181 V2). We applied ROC analysis and subsequently LASSO regression to identify panels among the plasma markers.

Result

ROC analysis (table 2, figure 1) showed that among SCD and MCI, AUCs of the individual plasma markers to predict Aβ status were 0.738–0.799 (lowest for NfL, highest for P‐tau181). LASSO regression (table 2, figure 1) selected Abeta1‐42/1‐40, P‐tau181 and GFAP, but not NfL as the optimal panel (AUC=0.846, 95%CI: 0.812–0.880). Stratifying for SCD or MCI stage resulted in largely similar findings (not shown). When discriminating AD from FTD, AUCs of the individual plasma markers were 0.643–0.820 (lowest for Abeta1‐42/1‐40, highest for P‐tau). LASSO regression selected P‐tau181, GFAP and NfL as the optimal panel (AUC=0.889, 95%CI: 0.850–0.927). For AD versus DLB, AUCs were 0.514–0.741 (lowest for NfL, highest for P‐tau181). LASSO regression selected only P‐tau181 (AUC=0.741, 95%CI: 0.683–0.800). Plasma marker cutoffs at Youden’s indices differed depending on the diagnostic groups, with higher cutoffs for P‐tau181, GFAP and NfL in AD versus FTD or DLB analyses, compared to the SCD and MCI analyses (table 2).

Conclusion

We showed that depending on the clinical question at hand, the four biomarkers add valuable information with their own cutoffs. Decision trees might lead to ready‐to‐apply cutoffs for daily clinical practice.