bluuebunny/crossref_metadata_2025 huggingface dataset:
Brief, Interoceptive Exposure Focused Treatment for Anxiety in Older Adults
Authors: Schubert Frederick T , Schmidt Norman B
Published: December 2023

Background

Older adults with Mild Cognitive Impairment (MCI), Alzheimer’s disease (AD) and related dementias, and their care partners often experience high levels of anxiety. This not only diminishes their quality of life but also serves as a marker for earlier onset of ADRD symptoms for individuals experiencing MCI. Moreover, there is no well‐established treatment for those with MCI/mild AD. Anxiety sensitivity (AS) is a mechanism central to the genesis and maintenance of anxiety psychopathology that exacerbates the experience of somatic and emotional sensations, leading to increased distress. Brief, computerized, mechanism‐focused interventions have been shown to effectively reduce AS. This study sought to evaluate the acceptability and efficacy of a brief AS focused intervention in older adults with probable MCI including a repeated interoceptive exposure component and the participation of a care partner.

Method

Participants (N = 16) were recruited from the community varied in age from 65 to 81 (M = 72.44; SD = 4.83). Eligible participants enrolled in an open trial consisting of a 2‐hour intervention focused on interoceptive exposure (systematic exposure to anxiety and stress symptoms to achieve habituation). All participants completed a brief cognitive assessment, AS measures pre‐ and post‐intervention, and acceptability measures post‐intervention.

Result

Average baseline Montreal Cognitive Assessment scores were 24.25 (SD = 3.24; Range = 19‐29), which is generally indicative of MCI. Paired samples t‐tests were conducted to examine changes in total ASI‐3 scores pre‐ to post‐intervention. Despite the relatively small sample, we observed statistically significant reductions in ASI‐3 total scores with a large effect size (Δ = 4.38, Hedge’s g = .80, p<.01). Additionally, the intervention was highly acceptable with 100% of participants completing the intervention and rating the quality of the intervention as good or excellent.

Conclusion

This study provides encouraging evidence that brief interventions can successfully target risk mechanisms of anxiety in older adults with probable MCI. The favorable acceptability of the intervention suggests that it would be well‐received by both those with MCI and mild AD. Future research should examine this intervention in randomized‐clinical trials and study its effects longitudinally to understand how decreases in AS persist over time and relate to cognitive outcomes.
Culturally‐informed Community‐engaged Efforts to Improve Inclusion and Engagement of Underrepresented Ethnocultural Populations in the Alzheimer’s Disease Neuroimaging Initiative 3 Study: The ADNI Diversity Task Force
Authors: Okonkwo Ozioma , Mindt Monica Rivera , Ashford Miriam T. , Conti Catherine , Strong Jospeh , Raman Rema , Miller Garrett , Donohue Michael C. , Nosheny Rachel L , Coker Godfrey , Miller Melanie Jayne , Petersen Ronald C. , Aisen Paul S. S , Weiner Michael S. W.
Published: December 2023

Background

Ethnoculturally diverse individuals from underrepresented populations (URPs), including but not limited to Black/African American and Hispanic/Latinx adults, are disproportionally affected by Alzheimer’s disease (AD) compared to non‐Hispanic/Latinx white (NLW) adults. However, URPs have historically been under‐included in AD studies. The objective of this study is to describe efforts, and the results of those efforts, to increase enrollment and engagement of ethnoculturally diverse individuals from URPs in the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3).

Methods

Efforts undertaken by ADNI to increase enrollment and engagement of URPs included (1) launching of a Diversity Taskforce (DVTF) lead by two health disparities experts in July 2020, charged with overseeing ADNI’s mission in this space. Specific DVTF activities included: (2) the establishment, funding, and instrumental support (e.g., training, consultation, resources) of diversity at 13 ADNI3 sites; (3) changing ADNI protocol to facilitate research participation of URPs (e.g., optional lumbar puncture and sharing of amyloid PET results); (4) hiring a marketing agency to launch culturally‐informed digital/social media campaigns for the 13 DVTF Sites, with local websites; (5) development of a database to capture performance metrics of inclusion efforts at the 13 DVTF Sites; and (6) formation of a six‐member External Advisory Board, comprised of leaders in health disparities research, to guide DVTF efforts.

Result

URP enrollment at these 13 DVTF sites improved from 1.1 URPs per month previously to >4 URPs per month, a 264% increase. Across all 59 ADNI sites, overall enrollment of ethnoculturally diverse individuals from URPs went from 89 (16.8%) to 126 (21.1%), representing a 25% increase in enrollment between May 2020 and September 2021. Moreover, since February 1st, 2021, ADNI enrolled 43 new participants of which 33 (77%) were from URPs.

Conclusion

It is possible to improve the enrollment and retention of URPs in AD research using a multi‐pronged community engaged approach that also provides human capital, infrastructure, and financial resources. The success of the DVTF has led to the formation of a new Engagement Core in ADNI4, tasked with implementing a scaled‐up culturally‐informed, community‐engaged research approach to URP inclusion and retention across all 59 ADNI sites.
A systematic review on the perioperative use of EEG as a predictor/diagnostic tool for postoperative delirium
Authors: Bruzzone Maria , Chapin Benjamin , Arias Franchesca , Walker Jessie , Price Catherine C.
Published: December 2023

Background

The electroencephalogram (EEG) in the perioperative setting has been increasingly used as a tool for delirium prognostication and diagnosis. Delirium in the post‐operative setting occurs in 20‐25% of the patients aged 65 and older. The has been used for a long time in the intraoperative setting, with some measures being associated with the development of POD. Recently studies have been focusing on the use of the EEG preoperatively as a prediction tool, and postoperatively as a diagnostic tool for POD.

Method

We performed a systematic review to address the role of EEG in the perioperative setting as a tool for delirium prognosis and diagnosis. Twelve randomized control trials and twenty‐eight observational studies were identified.

Result

Common preoperative findings associated with the development of POD include: higher alpha power, increased alpha band connectivity but impaired structural connectivity, increased slow wave activity involving frontal and occipitoparietal cortex with accompanying break down in functional connectivity, lower EEG‐ asymmetry, lower values of pre‐operative spectral edge frequencies, and polysomnography findings of longer non‐REM stage 2 sleep. Common intraoperative findings associated with POD include: increased magnitude and duration of EEG suppression, reduced higher frequencies, increased prevalence and duration of BSR, and low BIS values. Finally, post‐operative findings associated with POD include: greater delta power while awake, alterations in delta in wake versus sleep state, and disruptions in connectivity.

Conclusion

The use of EEG as a diagnostic and prognostic tool has promising utility in the perioperative setting. In the pre‐and intraoperative setting, certain EEG markers may be utilized to predict delirium or triage which patients are at a higher risk of developing POD. Postoperatively, EEG use can predict and help diagnose POD. More studies are needed to further systematize and validate this data.
GABAB receptor activation promotes synaptic resilience in Alzheimer’s disease
Authors: McArdle Colin J , Uneri Ayse , Niere Farr , Raab‐Graham Kimberly F
Published: December 2023

Background

Hyperexcitability and glutamate excitotoxicity are the primary contributors towards synapse loss in Alzheimer’s disease (AD). The goal of this project is to examine how other neurotransmitter systems, such as the inhibitory GABAergic system, are responding to hyperexcitability in AD. Therefore, we examined the role of metabotropic GABAB receptors (GABABRs) towards synapse loss.

Methods

Primary hippocampal neurons were cultured from both wildtype (WT) and transgenic APP/PS1 mice. In addition, treatment of non‐transgenic hippocampal neurons with Aβ oligomers (500nM) were used as another model of AD‐related pathology. Immunocytochemistry was used to determine the dendric expression of GABAB1R and GABAB2R, the two principal subunits of GABABRs. To examine changes in GABABR function, a calcium imaging protocol was utilized to quantify changes in calcium florescence following GABABR activation with baclofen (50μM). To understand whether GABABR activation is protective against synaptic loss in AD, APP/PS1 hippocampal neurons were treated with 50μM baclofen (GABABR agonist), 100μM CGP35348 (GABABR antagonist), or vehicle. This study used both colocalization of presynaptic (Synapsin‐1) and postsynaptic (PSD95) markers as well as a novel method, DetectSyn, to quantify changes in synaptic density.

Results

Dendritic GABAB1R and GABAB2R expression is upregulated in APP/PS1 hippocampal neurons as compared to WT. Non‐transgenic neurons treated with Aβ‐oligomers also show upregulations in GABAB2R, with no changes in GABAB1R. Treating WT neurons with baclofen resulted in an approximate 10% decrease in calcium florescence. The same treatment applied to APP/PS1 neurons resulted in a significantly greater decrease (∼40%) in calcium florescence. Activating GABABRs in APP/PS1 neurons increased synaptic density as compared to vehicle treated neurons. This was indicated by a greater Pearson’s coefficient between Synapsin‐1 and PSD95, as well as a greater number of DetectSyn‐PLA puncta. Antagonizing GABABRs in APP/PS1 neurons failed to rescue synaptic density (no changes in Pearson’s coefficient/DetectSyn‐PLA puncta) when compared to vehicle treated neurons.

Conclusions

Under pathological conditions, upregulation and activation of GABABRs serves as a potential mechanism to combat against hyperexcitability, therefore preventing hippocampal synaptic loss in AD.
The Look AHEAD Aging Study: design, cohort characteristics, and cognitive function
Authors: Espeland Mark A. , Wagenknecht Lynne E , Bahnson Judy , Barnes Jerry , Beckner Tara , Harris Darrin , Hayden Kathleen M. , Houston Denise K , Neiberg Rebecca H. , Pleasants Debbie , Rapp Stephen R. , Sachs Bonnie C. , Walkup Michael , Yang Mia
Published: December 2023

Background

Data on cognitive trajectories and characteristics associated with cognitive resilience among older individuals with type 2 diabetes and overweight or obesity are scant. To date, the NIA‐funded Action for Health in Diabetes (Look AHEAD) Aging Study has enrolled 1245 individuals, ages 64 to 95 years, who have been richly characterized over 18 years of prior follow‐up with factors associated with cognitive aging.

Method

Volunteers from the Look AHEAD clinical trial of a multidomain lifestyle intervention and its subsequent clinic‐based post‐trial observational phase were invited to join a 4‐year telephone‐based observational study that includes annual cognitive assessments to assess memory, attention/processing speed, executive function, and global cognitive function. A composite measure of cognitive function based on the average standardized cognitive function tests was used to capture global cognitive function. Mild cognitive impairment and probable dementia will be centrally adjudicated. Additional measures include depressive symptoms, physical function and abilities, medical events, medication use, and health related quality of life. Recruitment will be completed in early 2023.

Result

The enrolled cohort to date (N = 1590) includes 62% women, 32% individuals from traditionally under‐represented racial/ethnic minorities, 49% without college education, and 52% who had been randomly assigned to the lifestyle intervention. The mean (SD) age is 76.3 (5.6) and years of diabetes is 25.5 (5.5). When last measured, the mean BMI was 33.8 (6.3) kg/m2 and 4 m walk speed was 0.86 (0.22) m/sec. Of 1060 who were tested, 20.6% have one apoE‐e4 allele and 1.1% have two apoE‐e4 alleles. Modified Telephone Interview for Cognitive Status (TICSm) scores ranged from 12 to 48, with mean 34.7 (4.7), with no difference between intervention groups (p = 0.66). While TICSm scores tended to be lower for older participants, many still demonstrated relatively high levels of cognitive functioning, even into the 8th decade of life (attached figure).

Conclusion

The Look AHEAD Aging study holds great promise to identify factors across two decades of follow‐up that are associated with cognitive resilience in a large cohort with type 2 diabetes and overweight or obesity. Our presentation will provide data on the full cohort and cognitive battery.
Moderation effects of APOE‐ε4 on marine omega‐3 fatty acids and its relation to change in cognitive function among community‐dwelling older adults
Authors: Vyas Chirag M. , Mischoulon David , Kang Jae Hee , Cook Nancy R , III Charles F Reynolds , Chang Grace , Mora Samia , De Vivo Immaculata , Okereke Olivia I.
Published: December 2023

Background

In a recent trial, we observed no effect of omega‐3 fatty acids (omega‐3s) supplementation on cognitive decline. However, brain concentrations and metabolism of lipid molecules in response to omega‐3s may be regulated by apolipoprotein E (APOE)‐ε4 allele status. Further, while APOE‐ε4 is an established risk factor for Alzheimer disease, its association with cognitive decline is uncertain, especially in more diverse samples. The few randomized clinical trials (RCTs) addressing the moderation of effects of omega‐3s on cognitive decline by APOE‐ε4 have yielded inconsistent findings. Thus, we examined moderation by APOE‐ε4 on effects of omega‐3s vs. placebo for global and domain‐specific cognitive change over 2 years in a well‐characterized, diverse sample of older adults.

Methods

VITamin D and OmegA‐3 TriaL (VITAL) is a 2×2 factorial RCT of vitamin D3 (2000 IU/day) and/or omega‐3s (1 g/day including 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) for cardiovascular disease and cancer prevention. We included 743 VITAL in‐clinic sub‐cohort participants who completed all cognitive tests at baseline and had APOE genotype data. The primary outcome was change in global cognition (averaging z‐scores of 9 tests) over 2 years; episodic memory and executive function/attention were examined separately. We used multiplicative interaction terms in general linear models of response profiles to examine moderation by APOE‐ε4 carrier status on effects of omega‐3s vs. placebo for cognitive change outcomes over 2 years.

Results

The mean age (standard deviation) of participants was 67.1 (5.3) years; 50.6% were females; 13.5% were from racial and/or ethnic minority backgrounds; and 24.9% were APOE‐ε4 allele carriers. Over 2 years, compared with APOE‐ε4 non‐carriers, APOE‐ε4 carriers had faster declines in global cognition and episodic memory but not in executive function/attention; e.g., the mean difference in change (95% confidence interval) for episodic memory comparing APOE‐ε4 carriers vs. non‐carriers was ‐0.18 (‐0.33 to ‐0.03). There were no significant interactions between APOE‐ε4 carrier status and randomization status (omega‐3s vs. placebo) on change in global, episodic memory, or executive function/attention scores.

Conclusion

APOE‐ε4 significantly predicted cognitive decline but did not modify the effect of omega‐3s on global and domain‐specific cognitive change over 2 years.
Sporadic behavioral phenotype of Right Temporal Variant of Frontotemporal Dementia: a case report
Authors: Fernandez Paulo Eduardo Lahoz , Curti Nayara Christina de Lima , Bertolucci Paulo Henrique Ferreira
Published: December 2023

Background

There are two subtypes of the right Temporal Variant of Frontotemporal Dementia (rtv‐FTD). Semantic dementia (SMD) phenotype is defined by negative familiar history, word‐finding, anomia, comprehension difficulties, prosopagnosia, and topographagnosia. The behavioral frontotemporal dementia (bvFTD) phenotype is defined by personality changes, inappropriate behaviors, positive family history, and relatively poor performance on neurobehavioral testing with better performance on confrontational naming tests. (1) We present a rare interesting case.

Method

We describe the clinical and imaging features of a man who presented a sporadic behavioral phenotype of rtv‐FTD, showing negative genetic results.

Result

A 62‐year‐old man with 8 years of progressive behavioral impairment. He showed personality changes, and compulsive‐like / ritualistic behaviors such as excessive unpurposed accumulation of items, washing hands repeatedly every five minutes, and walking and wandering repeatedly in circles. He also had hiperorality, cravings for sweet foods, social cognition impairment, associated with loss of empathy, and inappropriate social behavior (hypersexuality, verbal aggressivity to unrelated people, and talking bad words to neighbors with no reason). After years he followed with mild to moderate apathy. The neuropsychological evaluation showed impairment of executive functioning, episodic memory impairment, and MMSE 19/30. The neurological exam was unremarkable, and the familiar history was negative. Brain MRI revealed frontotemporal atrophy with a marked asymmetry in the right temporal lobe. The genetic testing was negative, illustrating and sporadic case.

Conclusion

Theoretically, rtv‐FTD is considered a right variant of semantic phenotype, and the general assumption is that is also a sporadic disorder. Although the behavioral phenotype of rtv‐FTD normally has a genetic basis, showing positive family history, It can be presented as a sporadic disorder with non‐familial variants of FTD, as in this case. (2)

References:

1. Josephs KA, Whitwell JL, Knopman DS, Boeve BF, Vemuri P, Senjem ML, et al. Two distinct subtypes of right temporal variant frontotemporal dementia. Neurology. 2009 Nov 3;73(18):1443‐50.

2. Ulugut Erkoyun H, van der Lee SJ, Nijmeijer B, van Spaendonk R, Nelissen A, Scarioni M, et al. The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series. J Alzheimers Dis JAD. 2021;79(3):1195‐201.
Cholesterol and matrisome pathways dysregulated by APOE4 in human glia
Authors: TCW Julia , Qian Lu , Rosa Juao‐Guilherme S , Tuck Tony , Scrivo Aurora , Cuervo Ana Maria
Published: December 2023

Background

The association of Apolipoprotein E (APOE) ɛ4 risk with Alzheimer’s disease (AD) is well‐established. However, the impact of APOE ɛ4 on human brain cell function remains unclear. We hypothesized that human APOE ε4/ε4 (APOE 44) genotype contributes to disease risk through cell autonomous and non‐cell autonomous mechanisms in a human cell specific manner.

Method

Global transcriptomic analyses were performed on astrocytes, microglia, mixed cortical cultures (neurons and astrocytes) and brain microvascular endothelial cells derived from human induced pluripotent stem cells (iPSCs) and post‐mortem AD brains. Lipid pathway dysregulation identified through GSEA, WGCNA and cell type deconvolution was validated in vitro using Gas Chromatography‐Mass Spectrometry (GC‐MS), filipin staining, autophagy fluorescent reporters with immunocytochemistry and western blotting to determine the subcellular compartment that accumulates cholesterol in iPSC‐derived astrocytes, and further confirmed by immunohistochemical analysis in human APOE4 post‐mortem brain. Matrisome pathway dysregulation was validated by Luminex multiplex immunoassays and intracellular protein levels in pure astrocytes and mixed cortical cultures.

Result

Global transcriptomic analyses reveal that APOE 44 drives cholesterol metabolic dysregulation in astrocytes and microglia from human iPSCs and cell type‐deconvolved post‐mortem AD brain. APOE ε4 leads to elevated de novo cholesterol synthesis despite the intracellular accumulation of free cholesterol in lysosome and cholesterol ester in lipid droplets coupled with reduced efflux due to impaired lipophagy in iPSC‐derived astrocytes. Lysosomal cholesterol accumulation is found in astrocytes from APOE ε4 human brain. Activation of LXRs and induction of lipophagy ameliorates the lipid phenotypes in APOE ε4 astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co‐cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain.

Conclusion

Thus, human APOE ε4 causes human glia‐specific, cell autonomous and non‐cell autonomous cholesterol and matrisome pathway dysregulation that may increase AD risk.
Glia‐Selective Replacement of APOE4 with APOE2: Implications for AD‐Associated Pathologies
Authors: Johnson Lance A
Published: December 2023

Background

Compared to the ‘neutral’ E3, the E4 allele of Apolipoprotein E (APOE) confers up to a 15‐fold increase in Alzheimer’s Disease (AD) risk. Conversely, the neuroprotective E2 allele decreases AD risk by a similar degree. APOE’s strong risk profile and multitude of effects make it a promising therapeutic target. Here, we aimed to assess the therapeutic potential of allelic ‘switching’ by investigating the physiological changes associated with an inducible, in vivo APOE4 to APOE2 transition in a novel transgenic mouse model.

Methods

The APOE “switch mouse” (APOE4s2) uses the Cre‐loxP system to allow for inducible APOE allele switching from APOE4 to APOE2. These mice express a floxed human APOE4 coding region followed by the human APOE2 coding region. To study the effects of full body APOE switching, APOE4s2 mice were crossed to ubiquitous ROSA26‐CreERT1 mice. Gene expression and proteomic analyses were used to validate that the model worked as expected. Lipidomics and single‐cell RNAseq were used to measure physiological changes following the APOE4 to APOE2 allele switch.

Result

mRNA and protein analyses confirm that APOE4s2 mice synthesize full‐length human APOE4/ApoE4 pre‐switch and that the inducible switch results in successful and efficient recombination and expression of human APOE2/ApoE2. Single‐cell RNAseq shows that global, genetic replacement of APOE4 with APOE2 results in distinct alterations to glial cell transcriptomes affecting pathways involved with lipid and mitochondrial metabolism, inflammation, blood‐brain barrier integrity, and amyloid beta. Excitingly, differentially expressed genes associated with an E4 to E2 ‘switch’ included several AD GWAS, and both aging‐ and AD‐associated pathways. Additionally, untargeted lipidomics reveals changes to several lipid classes in the brain, in particular glycerophospholipids.

Conclusion

Together, these data suggest that a successful transition from APOE4 to APOE2 has broad impact on the cerebral transcriptome as well as peripheral and cerebral metabolism. Ongoing studies aim to determine whether cell‐specific replacement of APOE4 with APOE2 will rescue E4‐associated metabolic dysfunction, disease‐associated gene signatures, and AD pathology.
Attitudes toward dementia and cognitive aging among Syrian refugees resettled in Jordan: A qualitative study
Authors: Bridi Lana , Kaki Dahlia A. , Al‐Rousan Tala
Published: December 2023

Background

Mounting evidence is revealing disparities in cognitive function and heightened dementia risk among refugees, yet research in this area remains scant. Despite hosting the majority of the world’s refugee burden, limited‐resource countries like Jordan are facing challenges supporting older migrants’ needs. Syrian refugees experience high rates of dementia risk factors including cardiovascular disease, mental ill‐health, and traumatic exposures. The attitudes toward dementia amongst refugees in Jordan and what cognitive healthcare gaps this population faces remain a research gap. This study’s objectives are to identify refugees’ knowledge and attitudes toward dementia and cognitive aging, and to explore factors that facilitate or prevent access to cognitive healthcare in resource‐limited settings.

Method

32 older Syrian refugees were recruited through a local community‐based organization and interviewed in four gender‐concordant focus groups. Interviews were transcribed and translated, then coded using inductive thematic analysis.

Result

All refugees were 55 years or older and lived below the Jordanian poverty line. Results were organized using the Social Ecological Model of Health: 1) At the individual level, participants believed high levels of stress, including low socioeconomic status, poor health, and traumatic history from their refugee experience increased their dementia risk. 2) Interpersonally, there is a fear of dementia due to its possible impact and caregiving burden on loved ones, particularly with the stigma that surrounds the disease. 3) At the community level, participants noted that resettlement in Jordan – with shared language, religion, and culture – offered protective effects due to facilitated access to social connection, information, and mental health self‐care. 4) Finally, at the policy level, participants believed older refugees faced restrictive policies for economic aid, healthcare, and employment, presenting a significant barrier to healthy aging.

Conclusion

Findings from this study are the first to examine the perceptions of aging Syrian refugees in Jordan toward their cognitive aging. These results could provide essential data as the country develops its national dementia plan. Overall, participants understand their risk factors for dementia and endorse poor cognitive aging in a country that struggles to support its own population’s basic needs.
CASBA neurological assessment: Noninvasive EEG biomarkers classify amyloid‐PET, clinical diagnosis, cognitive dementia rating, and FCSRT free recall scores in patients with cognitive decline
Authors: Rauchmann Boris‐Stephan , Kleinsasser Maxwell , Hamet James , Paschall Courtnie , Perneczky Robert
Published: December 2023

Background

Alzheimer’s Disease (AD) is difficult to diagnose and stage, often relying on burdensome clinical tests for neural protein aggregation and cognitive performance. Delays and errors in the accurate diagnosis of AD reduce patient outcomes and prevent early therapeutic intervention. The CASBA electroencephalography (EEG) system leverages a custom sequence of dynamic visual stimuli to elicit and translate novel and noninvasive neural signals biomarkers into accurate estimates of amyloid burden, cognitive performance, and clinical diagnosis, to facilitate clinical decision‐making in patients with cognitive decline.

Method

In a board‐approved study, human patients with mild cognitive impairment (MCI; 71.2 ± 8.2 years old), subjective cognitive decline (SCD; 70.7 ± 6.3 years old), and AD diagnosis (71.2 ± 6.6 years old), alongside amyloid PET (Anti‐Serum Amyloid P Antibody), cognitive testing (i.e. FCSRT), and clinical dementia rating (CDR). Neural signals were collected on a 64‐channel equidistant EEG system (2048Hz, Ag/AgCl; ANT Neuro, Enschede)]. Automated preprocessing and machine learning classification pipelines were developed to extract EEG features and calculate estimates of physiological and cognitive AD metrics from these EEG biomarkers.

Result

CASBA accurately classified normal vs. subnormal FCSRT free recall score (threshold of 18, 77.3% balanced accuracy, 84.0% specificity, 70.6% sensitivity), SCD v. MCI/AD clinical diagnosis (79.4% balanced accuracy, 77.3% specificity, 81.5% sensitivity), CDR (threshold of 1, 79.2% balanced accuracy, 76.9% specificity, 81.5% sensitivity), and amyloid‐PET (composite threshold of 1.25, 83.0% balanced accuracy, 75.0% specificity, 91.9% sensitivity).

Conclusion

The CASBA neurological assessment accurately predicts important clinical data including patient diagnosis and staging, amyloid burden, and performance on key evaluations of cognition in AD. CASBA supports physician decision making and patient stratification and suggests a new method for noninvasive tracking and repeat assessment during clinical trials. As such, the CASBA neurological assessment offers a promising new tool to advance clinical care and innovation for patients with neurodegenerative disease.
Emergency department care transitions for persons living with cognitive impairment and care partners: development of a novel artificial intelligence and care coach intervention
Authors: Galske James , Gil Heidi , Dorai Chitra , Keefe Kate , Stern Edith , DeFrancesco Erica , Gettel Cameron
Published: December 2023

Background

Emergency department (ED) presentation by persons living with cognitive impairment (PLWCI) often represents a sentinel event in the care continuum, yet little data exists to date regarding effective interventions to improve ED‐to‐community care transitions for PLWCI and their care partners. Therefore, we sought to develop and refine the innovative pairing of artificial intelligence (AI)‐enabled digital advisors and an occupational therapist‐led care coach intervention to improve ED‐to‐community care transitions for PLWCI and their care partners.

Methods

We used a mixed methods, multi‐phased approach to develop the intervention, with PLWCI and care partners sampled from the LiveWell Dementia Specialists network. In the first phase, we developed and iteratively revised a codebook and conducted recorded, semi‐structured focus groups using a standardized guide. Two researchers coded the professionally transcribed data using a combined deductive and inductive approach and analyzed transcripts to identify dominant themes and representative quotations. In the second phase, we performed a 2‐day design thinking workshop using a user‐centered design approach, involving PLWCI, care partners, health care professionals, community‐based partner organizations, technologists, and AI experts. Integration of findings from the two phases provided takeaways for refinement and optimization of the intervention for eventual pilot testing.

Results

In the first phase, we performed two focus groups, involving a total of 16 participants, and generated empathy maps regarding the ED experience, the subsequent ED‐to‐community care transition, and the role of technology. PLWCI and care partners expressed: 1) concerns that their unique needs related to cognition were not addressed in the ED setting, 2) frustration with the ED discharge process and their perceived ability to follow‐up in the outpatient setting and obtain desired resources, and 3) openness to the incorporation of AI to facilitate successful ED‐to‐community care transitions. In the second phase, we identified perceived barriers and facilitators for intervention adoption during open forum discussions, depicted the current ‘As Is’ and the desired ‘To Be’ states regarding ED‐to‐community care transitions, and provided a demonstration of the AI‐enabled digital advisors and care coach intervention.

Conclusion

PLWCI and care partners were integrally engaged in the co‐creation of a two‐component novel intervention to improve ED‐to‐community care transitions.
Using the Allen Cognitive Levels to determine level of supervision needed for those with mild to moderate cognitive decline
Authors: Evans Rebecca J
Published: December 2023

Background

A comparison was made of the common screening tools for Alzheimer’s disease (AD).

Method

The Mini‐Mental State Examination (MMSE) is one of the most commonly used screening tools but has an emphasis on verbal skills and because it is so widely used, some patients with minimal cognitive decline are able to remember many of the answers from one assessment to the next. The benefits of using the Allen Cognitive Levels (ACL) became apparent as it is a functional based assessment and can be administered without the patient having to say anything.

Result

Using the Allen Cognitive Level screening tool as well as the ACL task activities to narrow a patients level to a number between 0‐6 to the nearest .2 of a point. For example, if a patient scores between 4.6‐4.8, it is recommended that the patient may live alone in the community, provided they have a safe environment with well‐established routines and rehearsed safety plans including daily and weekly supervision. Specific recommendations are available to educate family on safety equipment needs, and executive functioning strategies. For example in the 4.6‐4.8 level, verbal skills are often stronger than a patient’s ability to complete novel tasks, something that is not as easily picked up on a verbal or memory related screener.

Conclusion

The Allen Cognitive Level screener and task analysis kits are very helpful for healthcare providers including doctors or therapists to obtain specific information about a clients current cognitive level and what can be expected and how to modify the environment for the client safety and greatest level of independence. Because the levels are structured sequentially, caregivers can compare the current cognitive level to the subsequent level in order to know what to watch out for in the future and clinicians can complete the lacing screener or the task activities as the disease progresses to provide the most accurate information about a clients current cognitive level.
Systems biologic analysis of inverse etiological mechanism between Alzheimer’s disease and cancer identified key astrocytic signaling pathways in restraining Alzheimer’s disease pathogenesis
Authors: Zhao Hong , Vasquez Matthew , Ahn Ju Young , Sheng Jianting , Yin Zheng , Wong Stephen T.C.
Published: December 2023

Background

A 35% lower incidence of Alzheimer’s disease (AD) among older cancer survivors was reported versus those without cancer history(Ma, Yu et al. 2014, Zhang, Guo et al. 2015, Bowles, Walker et al. 2017, Ospina‐Romero, Abdiwahab et al. 2019, Ospina‐Romero, Glymour et al. 2020). The exclusive cellular and molecular mechanism between these two diseases may open up new vista in discovering novel mechanisms of action and effective therapeutic strategies for AD.

Method

A breast cancer‐in‐AD mouse model was established by injecting a very low number of AT3 murine breast cancer cells (1×104) into the left cardiac ventricle of 1‐month‐old female 5xFAD mice (Tg6799 on a congenic C57BL6 background, n = 5). Mice were sacrificed four weeks after tumor injection. Their brains were processed for amyloid plaque, astrocyte, microglia and oligodendrocyte immunostaining and isolation of astrocytes and microglia for generating cell‐specific RNA sequencing data, which were analyzed and then modeled by the CCCExplorer software(Choi, Sheng et al. 2015, Tsz‐Lun Yeung 2019) to identify multi‐cellular crosstalk signaling in association with plaque burden.

Result

In the breast cancer‐in‐AD mouse model, we identified a significant reduction (45%) of Aβ plaque burden in the brain of tumor‐bearing AD mice in comparing to the age‐matched cancer‐free AD mice (Fig. 1). We observed an 35% increase of the total astrocyte area and 50% increase of plaque‐associated astrocytes in the tumor‐bearing AD mice (Fig. 2). Our systems biologic analysis indicated the elevated expressions of about 50 marker genes for reactive astrocytes and positive regulators of astrocyte reactivity; suppression of Aβ production but increase of Aβ clearance in astrocytes of tumor‐bearing AD mice, and identification of 1,729 differentially expressed genes (DEGs) including 46 receptors, 45 ligands, and 12 signaling pathways of astrocytes in mediating an active astrocyte‐microglia interaction in synergistically regulating Aβ homeostasis (Fig. 3).

Conclusion

Amyloid burden is significantly reduced in AD mice bearing tumors, predominantly associated with astrocyte activation. The AD protective astrocyte signaling is being investigated for repositioning known drugs targeting early AD.
Association of mood disorder and bone health with cognitive function among healthy ageing men
Authors: Mehta Kanika , Mohebbi Mohammadreza , Pasco Julie A , Williams Lana J , Walder Ken , Ng Boon , Gupta Veer Bala
Published: December 2023

Background

High dementia prevalence and associated disability have necessitated a focus on the identification of potentially modifiable risk factors. Mental and physical health conditions such as mood disorder and bone loss have been previously linked with poor cognition although their combined effect remains largely unknown.1 We investigated whether an interaction between mood disorder and bone loss is associated with cognitive function in a population‐based sample of men.

Method

Participants free from severe cognitive impairment were drawn from the Geelong Osteoporosis Study (n = 442, mean age = 63.5 years) and cognition was assessed via the CogState Brief Battery that measured performance across four domains (psychomotor function, attention, learning and working memory).2 Mood disorder and hip bone mineral density (BMD) were evaluated using a semi‐structured clinical interview and dual‐energy x‐ray absorptiometry, respectively. Linear regression analyses adjusted for age, education, SES, mobility, smoking status, alcohol consumption and APOE ε4 status were conducted to investigate whether lifetime history of a mood disorder, hip BMD or two‐way interaction are associated with overall cognitive function and cognitive performance in individual domains.

Result

Hip BMD (Bcoeff 0.56 95% CI 0.07, 1.05) but not mood disorder (Bcoeff ‐0.50 95% CI ‐0.20, 0.10) was associated with overall cognitive function after accounting for potential confounders. Significant interaction effects were observed between the two exposures (Bcoeff ‐1.37 95% CI ‐2.49, ‐0.26) suggesting that individuals without a mood disorder displayed better overall cognitive performance with increasing BMD, whereas those with a lifetime history of mood disorder displayed poorer cognitive function with increasing BMD. Interaction effects were also observed for the individual cognitive domains (Fig. 1). Results remained virtually unchanged when mood disorder was limited to major depressive disorder.

Conclusion

This is the first‐ever study that reported an interaction between mood disorder and BMD that could be accounted for in establishing risk factors for cognitive decline.

1. Mehta K, Thandavan SP, Mohebbi M, Pasco JA, Williams LJ, Walder K, et al. Depression and bone loss as risk factors for cognitive decline: A systematic review and meta‐analysis. Ageing Res Rev 2022; 76: 101575.

2. Pasco JA, Nicholson GC, Kotowicz MA. Cohort profile: Geelong Osteoporosis Study. Int J Epidemiol 2012; 41: 1565‐75.
Effect of increasing participation in habitual intellectual activities on cognitive function in older adults without clinical dementia ‐ update on the findings of a randomized controlled trial
Authors: Lee Allen TC
Published: December 2023

Background

The preliminary findings of our randomized controlled trial, which aims to test whether doubling calligraphy practice leads to more cognitive benefits in older adults without clinical dementia, were presented in AAIC 2022. With the data collection near completion, we will present the latest findings of our study in AAIC 2023.

Method

A total of 112 community‐living older adults without clinical dementia and with prior practice of calligraphy were recruited and randomly allocated into either the control group where they continued their usual practice of calligraphy or the intervention group where they doubled their practice. Comprehensive standardized cognitive assessments were performed before and after the 6‐month intervention.

Result

Changes in global cognition and individual cognitive domains will be compared between the intervention and control groups. Compliance of intervention will also be reviewed.

Conclusion

Our findings will add insight to the effect of increasing the “dosage” of intellectual activities on cognitive function and the acceptability of cognitive intervention among community‐living older adults at risk of dementia.
MicroRNA expression based on toxic Oligomeric Amyloid Beta and Burden of Cerebrovascular Disease
Authors: Sandhu Gurveen Kaur , Zailan Fatin Zahra , Vipin Ashwati , Soo See Ann , Kumar Dilip , Leow Yi Jin , Koh Chen Ling , Chen James Xiao Yuan , Lee Faith Phemie Hui En , Ghildiyal Smriti , Kandiah Nagaendran
Published: December 2023

Background

MicroRNAs(miRNAs) form the most intensively characterised branch of non‐coding RNAs, with universal expression in a repertoire of biofluids and active regulatory roles in multiple biological pathways(Blount, Coursey, and Kocerha 2022). Therefore, any perturbance in miRNA expression produces pronounced biological effects, due to its pleiotropic nature(Blount, Coursey, and Kocerha 2022). A variety of miRNAs have been investigated in multiple dementia syndromes (Blount, Coursey, and Kocerha 2022). However, what remains to be evaluated is differential miRNA expression in dementia classified using the more toxic oligomeric amyloid beta(OAβ) as well as based on burden of cerebrovascular disease(CVD).

Method

A cross‐sectional pilot study was conducted in a cohort of 24 research participants(Table 1), stratified on the basis of their plasma OAβ levels [Multimer Detection System based plasma OAβ analysis(PeopleBio Inc, South Korea)](Dominguez et al. 2022). T3 ‐ based MRI data was evaluated for CVD status ‐ White Matter Hyperintensity load, was scored using the Fazekas scale(Table 1). Blood plasma‐based expression profiling of 376 miRNAs was conducted using the ID3EAL™ PanoramiR miRNA Knowledge Panel(MiRXES Pte Ltd, Singapore) and normalised miRNA expression was defined via the delta‐delta(d) Ct method. MiRNA target interaction analyses was conducted using miRTarBase 9.0, revealing potential reactome pathways of interest(Huang et al. 2022).

Result

Mean age and MoCA scores are 60.05 and 25.42 respectively (Table 1). 10 miRNAs(upregulated : hsa‐miR‐42, hsa‐miR‐378c, hsa‐miR‐938; downregulated: hsa‐miR‐545‐3p, hsa‐miR‐449c‐5p, hsa‐miR‐657, hsa‐miR‐23c, hsa‐miR‐888‐5p, hsa‐miR‐599, hsa‐let‐7d‐5p) were significantly differentially expressed in OAβ positivity(Table 2). 6 miRNAs(upregulated: hsa‐miR‐513c‐5p, hsa‐miR‐592; downregulated: hsa‐miR‐98‐5p, hsa‐miR‐744‐5p, hsa‐let‐7d‐5p, hsa‐miR‐517‐5p were significantly differentially expressed in CVD(Table 2). Reactome pathways demonstrating putative biological relevance are the FOXO/p53 mediated transcriptional regulation (metabolism/senescence/neuronal genes),Caspase mediated inflammatory activation, Insulin/IGF‐1/PI3K/Akt/GSK3β mediated metabolic signalling, IL‐4/IL‐13 mediated immune(inflammatory) signalling, Nervous System/Axonal Development and WNT Signalling(Table 2).

Conclusion

Findings from this cross‐sectional pilot study, have revealed 16 miRNAs to be promising biomarker candidates within the OAβ positivity and CVD burden setting. Longitudinal study with larger sample size is on‐going to confirm and validate these findings.

The authors wish to express their sincere gratitude to MiRXES Pte Ltd for their technical expertise and efforts towards the miRNA expression profiling and associated analyses.
Interleukin‐3 is associated with soluble TREM2 and mediates amyloid and tau pathology in Alzheimer’s disease
Authors: Wang Zhi‐Bo , Ma Ya‐Hui , Sun Yan , Tan Lan , Wang Hui‐Fu , Yu Jin‐Tai ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2023

Background

Dysfunction of glial cell communication is involved in Alzheimer’s disease (AD) pathogenesis. Recent studies reported that interleukin‐3 (IL‐3) participated in astrocyte‐microglia crosstalk and restricted pathological progression in AD mice. However, how IL‐3 relates to microglial activity and AD pathology in humans remains unclear.

Method

We included 311 participants with cerebrospinal fluid (CSF) IL‐3, sTREM2 (microglial biomarker), and AD biomarkers (Aβ42, p‐tau, and t‐tau) from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We compared IL‐3 levels in different stages of AD and assessed the associations between IL‐3 with sTREM2 and AD biomarkers at baseline and with longitudinal cognitive change. Mediation models were used to explore the potential mechanism of how IL‐3 affects sTREM2 and AD pathology.

Result

CSF IL‐3 levels decreased with increasing Aβ pathology and increased with increasing tau pathology, especially in cognitive impairment participants (Figure 1). CSF IL‐3 was significantly associated with CSF sTREM2 and CSF AD biomarkers (Figure 2). Mediation analysis showed that IL‐3 and sTREM2 mediated the effects of CSF Aβ on CSF tau pathology (βp‐tau = 0.053, βt‐tau = 0.055, all p < 0.001) (Figure 3).

Conclusion

Our findings suggest that IL‐3 is associated with the microglia biomarker and that they respond strongly to amyloid and tau pathologies. Hence, IL‐3 could be a key marker for clinical trial design. We encourage future studies on enhancing IL‐3 levels as a therapeutic intervention to slow the development of AD pathology.
Proteomic analysis reveal early differences in plasma exosomes of Aβ(+) vs Aβ(‐) patients with early‐onset mild cognitive impairment: from BIOFACE to BIOPEXAL study
Authors: Cano Amanda , De Antonio Ester Esteban‐ , Bernuz Mireia , Puerta Raquel , García‐González Pablo , de Rojas Itziar , Olivé Clàudia , Pérez‐Cordón Alba , Montrreal Laura , Núñez‐Llaves Raúl , Sotolongo‐Grau Oscar , Valero Sergi , Alegret Montserrat , Martín Elvira , Adami Pamela V Martino , Arriola Miren Ettcheto , Camins Antonio , Vivas Assumpta , Chiari Marta Gómez , Orellana Adelina , Tárraga Lluís , Marquié Marta , Ramirez Alfredo , Martí Mercè , Pividori Maria Isable , Boada Mercè , Ruiz Agustin
Published: December 2023

Background

in the clinical course of Alzheimer’s disease (AD) development, the dementia phase is commonly preceded by a prodromal AD phase, which is mainly characterized by reaching the highest levels of Aβ and p‐tau‐mediated neuronal injury and a mild cognitive impairment (MCI) clinical status. Because of that, most AD cases are diagnosed when neuronal damage is already established and irreversible. Therefore, a differential diagnosis of MCI causes in these prodromal stages is one of the greatest challenges for clinicians. Blood biomarkers are emerging as desirable tools for pre‐screening purposes, but the current results are still being analyzed and much more data is needed to be implemented in clinical practice. Because of that, plasma exosomes (pEXOs) are gaining popularity as a new source of biomarkers for the early stages of AD development

Method

to identify an exosome proteomics signature linked to prodromal AD, we performed a cross‐sectional study on two groups of patients with early‐onset MCI (EOMCI) (Aβ +/‐) in which 184 biomarkers were measured in pEXOs, cerebrospinal fluid (CSF), and plasma samples using multiplex PEA technology of Olink© proteomics.

Result

the obtained results showed that proteins measured in pEXOs from EOMCI patients with established amyloidosis correlated with CSF p‐tau181 levels, brain ventricle volume changes, white matter hyperintensities, and MMSE scores. In addition, the correlations of pEXOs proteins with different parameters were able to discriminate between EOMCI Aβ(+) and Aβ(‐) patients, whereas the CSF or plasma proteome did not.

Conclusion

our findings suggest that pEXOs could be able to provide information regarding the initial amyloidotic changes of AD. At this early stage, our results may indicate that pEXOs biomarker profile is associated with the AD‐specific neurodegeneration process governed by p‐tau and Aβ. Circulating exosomes may acquire a pathological protein signature of AD before raw plasma, becoming potential biomarkers for identifying subjects at the earliest stages of AD development. However, additional research is required to comprehend the molecular pathways underlying these findings and validate the obtained results in an independent cohort.