bluuebunny/crossref_metadata_2025 huggingface dataset:
Making Community Connections for Minority Outreach in Alzheimer’s Disease
Authors: Gupta Sangeeta
Published: December 2023

Background

Recognizing the gap in communication that exists between minority populations and Alzheimer’s disease (AD)research community, education and outreach are a critical step in the effort to understand and address disparities. African‐Americans (AA) and Hispanics, are significantly more likely to have Alzheimer’s disease and related dementia (ADRD) as compared to non‐Hispanic Whites. In addition to biological risk, widespread and significant misperceptions about aging process, diagnosis and clinical management influence the way in which AD/ADRD is recognized and subsequently treated in minority populations

Method

An Alzheimer’s’ Community Engagement ‐Empower Minorities (ACE‐EM) center is proposed as an addition to existing research programs at Delaware State University (DSU). As a Historically‐Black university DSU is uniquely positioned to coordinate Alzheimer’s outreach programs in minority communities of interest. Organizations with strong ties to minority populations improve intervention effectiveness and increase impact. ACE‐EM plans to foster education and training of DSU students under the guiding framework of the Alzheimer’s disease Public Health Curriculum to develop community trusted dementia advocates – an investment for a competent future public health workforce. We recognize the importance of having conversations with family and community members about aging, AD/ADRD and how we can work together to reduce the risks of Alzheimer’s disease for future generations as outlined in the CDC Healthy Brain Initiative Road Map (2018‐2023).

Result

Center will provide a hub for scientific and community exchange for research dissemination specific to cognitive health and AD/ADRD among minorities and 2) engage community members, their families, and partners through culturally targeted and linguistically appropriate education, training, and measurements. Preliminary targeted outreach efforts and data collection in process.

Conclusion

To build empowered communities with increased awareness and understanding of cognitive health, through a range of community‐informed and community‐engaged dissemination activities.
The utility of neuropsychological process scores in verbal recall and verbal fluency in persons with or at risk for dementia: Data from COMPASS‐ND
Authors: Phillips Natalie , Sollazzo Katrina
Published: December 2023

Background

Subjective cognitive decline (SCD) is considered a risk state for decline to mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD). By definition, individuals with SCD report concerns about changes in cognitive function but perform within normal limits on formal testing. This study examined whether neuropsychology process scores on tests of auditory learning and memory (the Rey Auditory Verbal Learning Test, RAVLT) and semantic and phonemic oral fluency were able to distinguish subtle difficulties in cognition, over and above total scores.

Method

We used data from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study to examine performance in 60 cognitively normal (CN) older adults with no cognitive complaints (mean age = 69 years; mean education = 16 years), 55 participants with SCD (age = 70; education = 17), 102 with MCI (age = 72; education = 16), and 47 with AD (age = 75; education = 15). Participants were matched on age and education, except for AD participants who were older. Age and education were co‐variates in all analyses. For the RAVLT, we examined delayed recall total scores, and process measures of primacy and recency recall on the second learning trial. For fluency, we examined total scores, and process measures of clustering, switching, word frequency, and age of acquisition.

Result

RAVLT: An item position by group interaction revealed that primacy scores better distinguished all participant groups (CU>SCD>MCI>AD) than delayed recall (CU = SCD = MCI>AD). The left subiculum hippocampal subfield volume was positively associated with primacy scores in the MCI group, controlling for intracranial volume and age. Oral fluency: Both phonemic and semantic total scores discriminated CN, MCI, and AD participants in a stepwise manner; there was a non‐significant trend for SCD participants to perform more poorly than CN. Process scores did not provide additional discrimination.

Conclusion

These findings indicate that primacy scores for episodic recall are sensitive to subtle memory deficits in SCD and may reflect hippocampal atrophy, supporting the clinical use of using serial position effects in the assessment of MCI and SCD.

Learning Objective(s): Participants will learn about more detailed scoring methods for common neuropsychological tests, their sensitivity to subtle cognitive deficits in SCD, and their relationship with neuroanatomical structures.
Primacy and recency effects in verbal memory are differentially associated with post‐mortem frontal cortex p‐tau217 level in a mixed sample of community‐dwelling older adults
Authors: Gicas Kristina M , Honer William G , Petyuk Vladislav A , Wilson Robert S. , Boyle Patricia A , Leurgans Sue E. , Bennett David A. A
Published: December 2023

Background

Emerging research indicates plasma phosphorylated (p)‐tau217 levels may demonstrate sensitivity to preclinical and symptomatic Alzheimer’s disease (AD). Serial position effects (primacy and recency) in verbal memory are sensitive cognitive markers of early AD; however associations between these measures and p‐tau217 in postmortem brain samples are unclear. In a mixed sample of older adults, this study examined how primacy and recency scores measured years before death are associated with post‐mortem levels of p‐tau217, with p‐tau202 as a complementary post‐mortem measure of early tau phosphorylation.

Method

Data were used from the Rush University Religious Orders Study and the Memory and Aging Project. Participants were 1098 community‐dwelling older adults (68.9% female, M
age = 80.1) who were non‐demented at baseline and followed until death (M
follow‐up years = 9.2; status at death: 34.7% unimpaired, 26.0% mild cognitive impairment, 39.3% dementia). Baseline serial position scores were calculated as the proportion of words recalled from the beginning (primacy) and end (recency) of the CERAD Word Memory List. A neuropathological exam classified Braak stage. A middle frontal gyrus tissue sample was used to quantify p‐tau217 and p‐tau202 with selected reaction monitoring proteomics. Linear regression analyses examined associations of cognitive scores with p‐tau, adjusting for age, sex, education, APOE e4 status, Braak stage, and time to death.

Result

As expected, higher Braak scores were associated with higher levels of brain p‐tau217. In the fully adjusted model, higher baseline primacy scores (b = ‐.27, p = .026), but not recency scores (b = ‐.02, p = .901), were associated with lower levels of p‐tau217 but not p‐tau202 in middle frontal cortex. Higher delayed recall (b = ‐.08, p = .007), but not immediate recall (b = ‐.01, p = .071), was also associated with lower p‐tau217.

Conclusion

Primacy scores measured years before death were associated with the outcome of post‐mortem brain levels of p‐tau217, but not p‐tau202. The differential associations of serial position scores with p‐tau suggest they may add complementary information about early neuropathological changes when used in conjunction with routine delayed recall scores. These findings further contribute to evidence for p‐tau217 as a sensitive biomarker of AD.
Long‐term neuropathological effects of amyloid‐β immunization revealed by spatial transcriptomics
Authors: van Olst Lynn , Simonton Brooke , Ramakrishnan Abhirami , Piehl Natalie , Teregulova Victoria , Norman Jeanette , Nicoll James AR , Boche Delphine , Gate David
Published: December 2023

Background

Modern Alzheimer’s disease (AD) therapeutics include immunization against amyloid‐β (Aβ). Intriguingly, neuropathological examination of the first active Aβ vaccination trial (Elan Pharmaceuticals’ AN1792) showed some patients with evidence of Aβ clearance 15 years post‐vaccination. Yet, these patients progressed to severe dementia before death, possibly due to ongoing tau propagation. The AN1792 trial was halted when some participants developed aseptic meningoencephalitis driven by auto‐aggressive T cells. Imaging features of meningoencephalitis experienced by AN1792 subjects are pathologically reminiscent of amyloid‐related imaging abnormalities (ARIA) that currently hamper clinical trials and the therapeutic use of passive Aβ immunotherapy for AD.

Method

Here, we utilized spatial transcriptomics to sequence RNA from formalin‐fixed paraffin‐embedded (FFPE) cortical brain sections from a unique neuropathological cohort of 14 immunized AD cases and a placebo‐control from AN1792. Additional controls included 6 naïve (unimmunized) AD cases and 3 non‐neurological disease controls.

Result

We reveal a cytotoxic and migratory phenotype of infiltrating T cells in the meninges of AD patients immunized against Aβ. Specifically, brain infiltrating T cells express cytotoxic genes (e.g. GZMA), activation genes (e.g. CD74 and B2M), and migratory genes (e.g. ITGAL and VCAM1). Additionally, we discovered genetic signatures that distinguish cortical areas cleared of Aβ in immunized AN1792 subjects.

Conclusion

We show that active Aβ immunotherapy induces long‐term adaptive immune effects in the AD cortex.
TRAILBLAZER‐ALZ 3 – A Deeper Dive into Time‐to‐Event Trials
Authors: Pugh Melissa A M
Published: December 2023

Background

The pathophysiologic process of Alzheimer’s Disease (AD) is underway before cognitive decline becomes evident (i.e.; preclinical AD). Beginning treatment during this phase is believed to lead to beneficial outcomes in terms of disease progression. TRAILBLAZER‐ALZ 3 (TB3; NCT05026866) is an ongoing Phase 3 decentralized clinical trial assessing the effect of donanemab, a monoclonal antibody that removes amyloid plaques via microglial‐mediated clearance, versus placebo on clinical progression in preclinical AD. Clinical outcomes are assessed virtually by using central raters, psychometric examinations, and self‐administered tests. The primary endpoint of interest is the time to clinical progression as measured by the Clinical Dementia Rating scale global score (CDR‐GS).

Method

Two of the most frequently used methods to analyze time‐to‐event data are Kaplan‐Meier curves and Cox proportional hazards models. In TB3, the primary endpoint will be assessed via a Cox proportional hazard regression model. The key assumptions that will be made with this modeling approach are proportionality and censoring. Proportionality refers to the relative hazard being constant over time and how to treat censored observations, which refers to patients who do not reach the event during the observation period. While this approach has been used in fields such as oncology, we have adapted it for the assessment of time to clinical progression of AD cognitive decline. From this approach the hazard ratio, an estimate on the instantaneous risk, can be calculated. This measure can give insight, at a given time point, of the risk of progression of AD that a participant has.

We will also look at additional considerations of collecting data in a decentralized remote manner, such as missing data due to technology issues, and highlight the approaches that will be used to analyze additional cognitive and biomarker data.

Result

This investigation will show that we have adapted analytic techniques to determine the time to clinical progression of AD as measured by an increase in CDR‐GS from baseline at 2 consecutive visits.

Conclusion

We present an analytical method of assessing potential treatments to slow disease progression during the preclinical AD phase without requiring centralized assessment sites.
BrainChart cortical thickness centile scores: a generalizable tool to detect age‐inappropriate cortical neurodegeneration in Alzheimer’s disease
Authors: Parker Thomas D , Bethlehem Richard A.I. , Seidlitz Jakob , White Simon R , Bernstock Joshua D , Bourke Niall , David Michael CB , de Taurines Anastasia Francoise L Gailly , Giovane Martina Del , Graham Neil SN , Kolanko Magdalena A , Zimmerman Karl A , Malhotra Paresh A , Patel Maneesh , Scott Gregory PT , Alexander‐Bloch Aaron , Bullmore Edward T , Sharp David J
Published: December 2023

Background

Identifying age‐inappropriate cortical neurodegeneration on structural MRI is a key component of Alzheimer’s disease (AD) assessment. However, widely available reference standards that enable objective interpretation are lacking. BrainChart (www.BrainChart.io; https://github.com/BrainChart/Lifespan) calculates age and sex adjusted centile scores for structural MRI metrics using normative data from 101,457 participants across the lifecourse and can be applied across different datasets. We applied this approach to regional cortical thickness estimates and explored its utility in identifying patients with AD associated neurodegeneration.

Methods

Cross‐sectional BrainChart cortical thickness centile scores were calculated for 241 individuals with pathologically confirmed AD (median scan time prior to death 5.8 years), as well as 1432 cognitively normal participants (CN) from the NACC dataset. Area under the receiver operating characteristic curve (AUC) analyses were performed to identify the cortical regions that best identified patients with pathologically confirmed AD. This approach was then applied to 305 participants from the ADNI‐3 cohort, all of whom underwent clinical amyloid (florbetapir) PET and tau (flortaucipir) PET within 6 months of structural MRI (CN = 185; Mild Cognitive Impairment (MCI) = 95); AD = 26).

Results

The top ten performing regions for differentiating pathologically confirmed AD from CN in the NACC dataset were entorhinal, middle temporal, inferior parietal, isthmus cingulate, fusiform, supramarginal, inferior temporal, superior temporal, precuneus and temporal pole. AUCs ranged from 0.72 – 0.77 (figure 1 and table 1). Combining these ten regions into a single model significantly improved diagnostic separability (AUC = 0.81, figure 1). Optimal cut‐points for individual regions ranged from the 25th centile to the 35th centile, with sensitivities ranging from 57.7% to 68.9%, and specificities ranging from 72.6% to 80.9%. Using progressively lower centile scores increased specificity but decreased sensitivity (table 1).

In ADNI‐3 participants, a combined model of the same ten regions derived from the NACC dataset was able to discriminate amyloid and tau pet positive AD patients from amyloid and tau negative CN (AUC = 0.98), as well as amyloid and tau positive MCI patients from amyloid and tau negative CN (AUC = 0.85) (figure 2).

Conclusion

BrainChart age and sex adjusted cortical thickness centile scores, derived from an extensive normative dataset, represent a generalizable method for objectively identifying cortical neurodegeneration in AD.
Dysphasia after stroke and legal capacity
Authors: Voskou Panagiota
Published: December 2023

Background

Although after stroke dysphasia or aphasia is not equal to incapacity, the legal capacity of patients can be doubted. The patients’ ability to fully comprehend the given information and make decisions may be impaired. Stroke is sudden, life threatening and likely to affect capacity even in the absence of dysphasia. There are currently no published guidelines in the management of legal issues for patients and professionals.

Method

A literature review in the Pubmed database has been made, using the key‐words: stroke, legal capacity, decision‐making

Result

Brain injury after stroke may impair appreciation of decisions’ consequences and/or communicating decisions effectively, while the capacity to reason remains. Stroke may affect various brain areas, i.e. prefrontal cortex involved in decision‐making (ventromedial prefrontal cortex damage may lead to impulsive decision‐making). A right‐brain stroke may cause poor executive function, lack of initiation or neglect. Left‐hemisphere strokes may lead to aphasia and reduced capacity evaluation. The dysphasic may understand more than he can express, or vice versa.

Difficulties further compounding communication problems include: reading and writing; numeracy; inattention/concentration; fatigue; emotional control (lability); perseveration; intellectual functioning. Receptive aphasia can impair understanding medical options, while expressive aphasia may prevent communicating relative decisions.

Patients may also be susceptible to undue influence regarding testamentary and financial capacity due to communication deficits and varying levels of dependence. Depression following stroke can further impair capacity.

Conclusion

The patient may have a communication rather than a capacity deficit. Judging a patient’s ability to weigh information is often the most difficult aspect of legal capacity assessment. There is little literature or high court jurisdiction regarding whether dysphasia after stroke impairs patients’ capacity. Evaluation of the prerequisites for legal capacity requires a multi‐professional cooperation.
A machine learning examination of the utility of CSF, neuroimaging, and plasma biomarkers in late onset Alzheimer Disease
Authors: Meeker Karin L. , Luckett Patrick H. , Barthélemy Nicolas R. , Hassenstab Jason J. , Xiong Chengjie , Cruchaga Carlos , Benzinger Tammie L.S. , Schindler Suzanne E. , Bateman Randall J. , Holtzman David M. , Morris John C , Gordon Brian A. , Ances Beau
Published: December 2023

Background

Alzheimer disease (AD) biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis, and identifying target treatments. Although the number of biomarkers continues to grow, the utility and uniqueness of each is poorly understood.

Method

Data were obtained from 527 community dwelling volunteers enrolled in memory and aging studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University in St. Louis, MO. Hierarchical clustering was used to group 27 cross‐sectional imaging, cerebrospinal fluid (CSF), and plasma measures of Aβ, tau, neuronal injury, and inflammation drawn from magnetic resonance imaging, positron emission tomography (PET), mass‐spectrometry assays, and immunoassays. Neuropsychological and genetic measures were also included. Feature selection identified the strongest predictors of amyloid PET positivity across the entire cohort. Models also predicted cognitive impairment across the entire cohort and in amyloid PET positive individuals.

Result

Four main clusters emerged reflecting core AD pathology (amyloid and tau), neurodegeneration, AT8 antibody‐associated phosphorylated (p‐tau), and neuronal dysfunction and inflammation. Relative to other measures, markers from the core AD pathology cluster were the best predictors of amyloid PET status with CSF pT217/T217 (%) being the most prominent followed by CSF pT111/T111 (%) and CSF ptau181/Aβ40. In the entire cohort, Aβ and tau markers (CSF pT217/T217 (%), total‐tau/Aβ40, ptau181/Aβ40) were also the best predictors of dementia. When examining only those with positive amyloid PET, CSF total‐tau/Aβ40 was the strongest predictor of cognitive impairment followed by tau PET, CSF ptau181/Aβ40, and pT217/T217 (%). Plasma Aβ42/40 alone did not perform as well as other PET and CSF measures. CSF measures of neuronal dysfunction and inflammation were relatively poor predictors of amyloid and cognitive status.

Conclusion

Although many AD biomarkers are interrelated, relatively few have the ability to strongly predict clinical status. Relative to other markers, CSF pT217/T217 (%) is the best predictor of amyloid and impairment status across all individuals, while CSF total‐tau/Aβ40 is the best predictor of impairment in individuals already on the AD trajectory. Most non‐specific markers perform poorly in the context of AD. The current research provides insight into which biomarkers may be most useful in AD clinical practice and trials.
Explorations of Caregiver Health and Well‐Being
Authors: Anderson Maria E
Published: December 2023

Background

Recent projections have found that the global prevalence of dementia is expected to grow rapidly through 2050, rising from an estimated 57.4 million cases in 2019 to an estimated 152.8 million cases by 2050. This has alarming public health consequences, as dementia takes a toll socially, emotionally, and financially, with a global societal cost of $1.3 trillion dollars in 2019. Caregivers are at the forefront of this crisis, with more than 11 million individuals in the US providing unpaid care for individuals with dementia, estimated at 16 billion dollars worth of care/year. Studies investigating the factors that impact caregiver burden are lacking. This study aims to 1) qualitatively examine caregiver burden and quality of life (QoL) 2) identify/highlight factors that might provide support and/or improve caregiver QoL.

Method

This is a qualitative, cross‐sectional study that will use a series of interviews and questionnaires to collect data. The studies will be created on, and deployed using, Qualtrics software, a commonly used platform for survey studies.

Result

Previous research suggests that factors impacting caregiver burden and QoL will be highly individualized across demographics such as socioeconomic status and race, and that QoL will be, on average, lower among caregivers as a group compared to the general population. We hypothesize that engagement in various lifestyle factors, particularly those that are self‐focused, regardless of amount of time spent on them, will correlate with higher QoL and lower caregiver burden scores.

Conclusion

The factors that predict caregiver burden and quality of life are an important and often under‐examined part of dementia care. This study, expected to be completed in Spring 2023, will contribute to the current understanding of caregiver’s experiences, and provide practical ideas to help increase QoL and reduce burden.
Neuropsychological Characteristics of Wandering in Patients with Drug‐naïve Alzheimer’s Disease
Authors: Yang Youngsoon
Published: December 2023

Background

Wandering represents one of a major problem occurring in patients with Alzheimer’s disease (AD). To find the disproportionate neuropsychological deficit and behavioral psychological symptoms in dementia (BPSD) of AD patients with wandering compared to AD patients without wandering, this study examined the set of neuropsychological tests and caregiver‐administered neuropsychiatric inventory (CGA‐NPI).

Methods

Psychotropic‐naïve (drug‐naïve) probable AD patients with wandering (64) and without wondering (278) were assessed with the Seoul Neuropsychological Screening Battery, which included measures of memory, intelligence, and executive functioning.

Results

Patients with wandering had lower scores in the Rey‐Osterrieth Complex Figure copy, Fist‐edge‐palm, Alternating hand movement tests compared to patients without wandering. The degree of wandering in AD patients was significantly related with CGA‐NPI subdomains of aggression, disinhibition, depression, and delusions.

Conclusions

This study showed that 1) AD patients with wandering have disproportionately cognitive deficit suggesting frontal and right parietal dysfunctions, 2) wanderings are related with specific BPSD. Considering these results, AD patients with wandering may have specific neuronal anatomic substrates related with pathology of Alzheimer.
A multi‐omic approach to elucidate novel disease mechanisms and biomarkers for psychosis in Alzheimer’s disease
Authors: Pishva Ehsan , Kouhsar Morteza P , Weymouth Luke Stephen , Smith Adam R. , Wedatilake Yehani , Torkamani Ali , Sweet Robert , Ballard Clive G , Mill Jonathan , Kofler Julia , Bergh Sverre , Selbæk Geir , Lunnon Katie , Creese Byron
Published: December 2023

Background

Psychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD is associated with a distinct profile of microbiological changes, but little is known about the molecular processes driving etiology.

Method

Genome‐wide DNA methylation, small non‐coding (nc) RNAs (microRNA, transfer RNA, piwiRNA) and long coding and ncRNAs (mRNA, lincRNA, cicular RNAs) were quantified from 248 whole blood samples obtained from the Norwegian registry of persons assessed for cognitive symptoms (NorCog) cohort. Multi‐omics profiles of AD patients with psychosis (AD+P) were compared to the patients without psychosis (AD‐P).

Result

There were significant differences in DNA methylation, small ncRNAs, and long coding and ncRNAs between AD+P and AD‐P patients. Further analysis revealed specific genomic regions and molecular pathways that were differentially methylated or expressed in AD+P patients compared to AD‐P patients.

Conclusion

Our findings suggest that there may be distinct molecular signatures associated with AD psychosis, and that these differences may potentially be used as biomarkers for the early detection and diagnosis of AD psychosis.
Multi‐Modal Structural Covariance Patterns Predictive of Dementia Ratings and Geriatric Depression Severity
Authors: Nickerson Lisa D , McManus Kaitlin R. , Kumar Poornima , Frederick Blaise deB , Harper David G.
Published: December 2023

Background

More than 6 million Americans suffer from Alzheimer’s disease (AD), the most common age‐associated, neurodegenerative dementia, characterized by progressive cognitive decline and the sporadic emergence of neuropsychiatric symptoms (NPS). We applied linked independent component analysis (LICA), a unsupervised learning approach for data fusion, to identify multi‐modal gray matter patterns of covariation that were predictive of dementia ratings and depression symptoms to understand the brain circuitry underlying both.

Method

Publicly available data from 277 participants (177 healthy controls, 61 mild cognitive impairment, and 39 AD (aged 58 – 93) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset were used to conduct secondary analyses.

T1‐weighted MR images were used to compute spatial maps of cortical thickness (CT) and pial surface area (PSA) using Freesurfer and grey matter (GM) density maps using FSLVBM. CT, PSA and GM maps for each modality were concatenated across participants into 4D data files that were analyzed using FSL Linked ICA to estimate 25 multi‐modal spatial components and subject loadings quantifying the strength of each component pattern per participant. Random forest regression with 5‐fold cross validation was used to predict CDR and GDS from the resulting subject loadings (with age, sex and site).

Result

Two LICA components (Fig 1) had highest feature importance in predicting CDR (R2 = 0.41). The same two patterns (Fig1) plus two additional patterns (Fig 2) were most important in predicting GDS (R2 = 0.08).

Conclusion

Greater CDR was predicted by larger (Fig 1A) decreased GM and CT of widespread temporal lobe regions and (Fig 1B) of reduced GM of entorhinal cortex/mesial temporal lobe with nodes of the default mode network, implicated in disease progression. Greater GDS was also predicted by these two patterns as well as a pattern (Fig 2A) reflecting decreased GM in nucleus accumbens, amygdala and a cerebellar‐thalomocortical (CTC) circuit strongly implicated in cerebellar cognitive affective syndrome (CCAS) and another (Fig 2B) comprised of CT decreases in cortex and temporal regions and GM decreases in frontoparietal regions resembling areas of the frontopariatal functional connectivity network. These multi‐modal brain‐behavior mappings could be translated to better understand dementia and neuropsychiatric symptoms of AD.
The Complex CPAP and Oxygen Therapies and Quality of Life in Alzheimer Patients
Authors: Sushko Viacheslav Viktorovich , Sushko Viktor Vasilievich
Published: December 2023

Background

CPAP, as a method of artificial pulmonary ventilation by constant positive pressure, improves oxygen supply to organs and tissues, including the cells of the cerebral cortex. This effect increases when CPAP and oxygen therapy are combined.

Method

We followed 11 female patients, ages 65 to 75, with Alzheimer’s disease. They were treated for Alzheimer’s disease according to accepted standards. All of them had COVID‐19, and in the rehabilitation program, they were prescribed CPAP therapy in combination with oxygen therapy, which was performed at night when the patients were sleeping, for one month. When they went to bed at a fixed time, a helmet was put on their heads, which allowed them to perform CPAP and oxygen therapy in their sleep. One patient could not get used to sleeping in the helmet, so she was treated differently and was excluded from our study. We also changed the oxygen content of the air in the helmet every three days. The patients themselves also filled out a Quality of Life Rating Scale every two weeks.

Result

After the sessions, the patients subjectively evaluated their condition as being more rested, stronger, and able and willing to do something. Objectively, there were no improvements in patients' activity during the first two weeks of therapy. Already, after a week of therapy, a fixed bedtime led to better sleep. Also, the best effect was observed when the concentration of oxygen in the supplied air was between 35 and 40 percent. After one month of therapy, patients rated their health as good on the Quality of Life Rating Scale, whereas at the beginning of therapy, they rated their health as poor. After one month of therapy hedonic was evaluated as having joy in life, as opposed to a lack of joy in life, at the beginning of therapy. Also, all the patients themselves associated these changes with the CPAP and oxygen therapy.

Conclusion

Complex CPAP and oxygen therapy can be recommended as part of a comprehensive therapy for Alzheimer’s disease to improve their quality of life.
Serine racemase expression in the pyramidal layer of the hippocampus of rat in the hypertensive encephalopathy modeling
Authors: Mednikov Dmitry , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich
Published: December 2023

Background

Excessive influence of glutamate on NMDA receptors mediates a cascade of biochemical changes leading to the development of intracellular acidosis, accumulation of free intracellular calcium and activation of a number of enzymes with the formation of free radicals. D‐serine acts as a co‐agonist of NMDA receptors and is involved in learning and memory under normal conditions. However, it has been suggested to play a role in glutamate damage in a number of CNS diseases. The formation of D‐serine in neurons and glial cells occurs with the participation of the enzyme serine racemase (SR) from L‐serine. An increase in the content of SR and the product of its enzymatic reaction, D‐serine, is considered as a process preceding excitotoxicity.

Method

Hypertensive encephalopathy was modeled on 12‐month‐old rats by the method of exposure to negative longitudinal g‐forces in the caudocranial vector with a force of 9 G for 5 minutes with an interval of 12 hours for 28 days. The following indicators were assessed: behavioral responses, cognitive and mnestic functions, the relative number of neurons with signs of damage, and the level of expression of serine racemase.

Result

A morphometric study of the pyramidal layer of the hippocampus revealed a significant increase in the relative area of the immunopositive material in CA1 by 5.5% compared with the control (p<0.05). A feature of the expression of serine racemase in the experimental group was the translocation of immunopositive material, which was determined not only in the cytoplasm of perikaryons, but also in the dendrites of pyramidal neurons. In addition, the nature of expression changed in the experimental group to a moderately pronounced one, and in some pyramidal neurons to a pronounced one. Violation of the cytoarchitectonic of the CA1 zone was manifested in a less compact arrangement of pyramidal neurons, a pattern of spongiosis due to pericellular and perivascular edema, and the acquisition of increased tortuosity by neuronal dendrites.

Conclusion

Hypertensive encephalopathy modeling demonstrates a sharp increase in the relative number of neurons with signs of damage, a decrease in the specific
Structural changes and features of heat shock protein HSP70 and HSP90 expression in the pyramidal neurons of the hippocampus of rat in the experimental discirculatory encephalopathy modeling
Authors: Mednikov Dmitry , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich
Published: December 2023

Background

The heat shock protein (Hsp) system acts as intracellular chaperone molecules responsible for maintaining normal intracellular homeostasis by regulating the correct coagulation of newly synthesized peptides, as well as the transport and degradation of mature proteins. In addition to their role as chaperones, proteins of the Hsp family stabilize the cell membrane and inhibit the caspase‐dependent apoptosis cascade

Method

Hypertensive encephalopathy was modeled on 12‐month‐old rats by the method of exposure to negative longitudinal overloads in the caudo‐cranial vector with a 9 G force for 5 minutes with 12 hours interval for 28 days. The behavioral responses, cognitive and mnestic functions, the relative number of pyramidal neurons with hyperchromic cytoplasm and shrunken perikariya, and the level of expression of heat shock proteins 70 kDa (Hsp70) and 90 kDa (Hsp90) were assessed

Result

After 28 days of exposure to 9 G negative longitudinal overloads, the rats showed functional and morphological manifestations characteristic of hypertensive encephalopathy. There was a decrease in the basic reflexes, disorders of the cognitive sphere, as well as decrease in memory and orientation‐exploratory activity. Morphological examination of the hippocampus against the background of pronounced edema revealed a significant increase in the relative number of pyramidal neurons with hyperchromatosis and perikaryon shrinkage in all zones of the pyramidal layer (p <0.01). These signs of reversible and irreversible damage were accompanied by a significant increase in Hsp70 expression, especially pronounced in the CA3 zone (p <0.01). A significant increase in Hsp90 expression was found in the CA1 zone (p <0.05)

Conclusion

Discirculatory encephalopathy experimental modeling demonstrates signs of both reversible and irreversible alteration in all regions of the pyramidal layer of hippocampus. Differences in the ability of neurons of the pyramidal layer of different regions of the hippocampus to express Hsp70, Hsp90 were noted. In the CA1 and CA3 zones, compensatory reactions are more pronounced and are accompanied by a more pronounced expression of Hsp70, while in CA1, the expression of Hsp70 and Hsp90 is simultaneously enhanced
Age related neuropathology in a novel mouse model of Adult‐onset leukoencephalopathy
Authors: Shabestari Sepideh Kiani , Radhakrishnan Hamsi , Rothermich Winston Chang , Capocchi Joia Kai , Jullienne Amandine , Nguyen Jasmine , Tran Kayla Nhi , Pascual Jesse R. , Martini Alessandra Cadete , Head Elizabeth , Hume David A , Pridans Clare , Obenaus Andre , Stark Craig E.L. , Davtyan Hayk , Blurton‐Jones Mathew
Published: December 2023

Background

Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare human disease that is caused by mutations in CSF1R, a gene that is critical for the differentiation, proliferation, and survival of microglia. ALSP patients typically develop dementia, motor impairments, and seizures during their 30s or 40s. Upon autopsy, patients’ brains exhibit decreased numbers of microglia, white matter atrophy, astrocytosis, axonal spheroids, enlarged ventricles, and calcification. Two recent reports have further described rare cases of homozygous CSF1R mutations that lead to perinatal lethality, a complete absence of microglia, and an acceleration of ALSP pathologies. Unfortunately, there is currently no effective treatment for this devastating disease.

Method

To better understand the role of microglia in the development and progression of ALSP we utilized the ‘FIRE’ mouse model that harbors a homozygous deletion in a microglial‐specific enhancer within the CSF1R gene.

Result

Surprisingly, at 2 months of age, despite absence of microglia, FIRE mice exhibit normal brain gross anatomy, minimal white matter alterations, and little to no pathology. However, by 10‐months of age FIRE mice exhibit many of the pathologies and symptoms observed in ALSP patients, including axonal spheroids, calcification, demyelination, seizures, and behavioral deficits. Importantly, postnatal transplantation of wildtype murine microglia prevents nearly all of these pathologies, demonstrating the importance of decreased microglial numbers on the development of ALSP. Additional ongoing examinations of 2‐ and 10‐month‐old FIRE mice are exploring the sex‐related impact of microglia absence on synaptic density and utilizing MRI imaging to examine white matter integrity and calcification.

Conclusion

Taken together, these data suggest that aged FIRE mice may provide a novel and informative, albeit rapidly progressing, model of human ALSP.
Deficit accumulation in relation to dementia and survival outcomes in residential care older adults
Authors: Song Xiaowei , Greeley Brian , Low Hilary , Hoang Jenny , Kelly Ronald , McDermid Robert
Published: December 2023

Background

As people age, they are more likely to accumulate health deficits leading to an increased risk of adverse outcomes, including dementia. In community‐dwelling older adults, even combining only the deficits traditionally unrelated to dementia predicts dementia. Previously, we reported an association between deficit accumulation and dementia in residential care. Here, our objectives are to 1) understand the profiles of deficit accumulation and the relationships between traditional and non‐traditional dementia risk factors in older residents with or without dementia and 2) investigate the impact of deficit accumulation on dementia and survival outcomes in residential‐care older adults.

Method

We analyzed the first full‐assessment data of older adults in InterRAI Residential Care (RAI‐RC MDS2.0) who enrolled in facilities under the care of Fraser Health Canada between 2010 and 2019 (female = 63.8%, mean age = 84.6±8.0 years). Dementia diagnoses (n = 18169), including pure Alzheimer’s disease (AD), mixed AD, other dementia, and no dementia (n = 11,589), were recorded at annual assessments. Two indices were constructed as the mean of the coded deficits between 0 (absent) and 1 (present), employing the same descriptive levels as in the original assessment. One index contained 20 traditional dementia risk factors (e.g., cognition, hypertension, and heart disease); the other contained 20 non‐traditional ones (e.g., vision, hearing, arthritis, and continence). Participants were followed until 2021. Relationships between the indices and their impact on survival were tested. Incidental dementia outcome was examined for the non‐demented sub‐sample.

Result

Over 92% of residents had at least one daily‐living dependency. The two indices were highly correlated (R = 0.59, p<.001), and each positively related to mortality, regardless of dementia diagnoses. People with dementia accumulated more deficits and had a higher mean traditional risk index than those without dementia (F = 334.72, p<.001), while the latter group accumulated more non‐traditional risk factors on average (F = 135.39, p<.001). A higher level of the indices showed variable risks of incidental dementia at follow‐ups (p’s<.05).

Conclusion

Older residents without dementia are dominated by dependent living with a distinct deficit accumulation profile than those with dementia. Deficit accumulation has negative impact on both dementia and survival outcomes in residential care.
APPLE‐Tree remote secondary dementia prevention; opportunities for scalable public health interventions to reduce dementia risk
Authors: Cooper Claudia , Barber Julie , Aguirre Elisa M , Whitfield Elenyd M , Parnell‐Johnson Sukey M , Martin Wendy M , Higgs Paul , Minihane Anne‐Marie , Poppe Michaela , Burton Alexandra , Marchant Natalie L , Bass Nicholas , Morgan‐Trimmer Sarah , Rapaport Penny , Kales Helen C , Huntley Jonathan D , Ritchie Karen , Hunter Rachael M , Walker Zuzana , Brodaty Henry , Lang Iain A , Petersen Irene , Rio Miguel , Wenborn Jennifer , Adeleke Mariam M , Walters Kate
Published: December 2023

Background

Nearly half of people aged 60+ experience memory impairments that infer an increased risk of dementia. The UK APPLE‐Tree (Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce) trial is evaluating a secondary dementia prevention intervention for people at increased dementia risk, delivered by group video call. It is potentially the first such intervention to be scalable to whole populations.

Method

In 2020‐22, We randomized 748 people aged 60+ with subjective or objective memory impairment, without dementia, 1:1 to the APPLE‐Tree intervention or usual care. In a visual ethnography sub‐study, we recruited intervention participants, purposively for diversity of background and experiences, to participate in photo‐elicitation interviews and workshops with a professional photographer/artist; where they created and shared photographs reflecting what they valued in their daily lives, their experiences of memory concerns, and the intervention. We used qualitative thematic methods to analyse interview, observational and visual data, exploring their experiences of active dementia prevention and the intervention.

Results

We will present findings from our qualitative sub‐study. Nineteen intervention participants took part. We developed themes around: (1) connections to nature as a lifeline; (2) anchoring experiences within relationships to family; (3) reflecting on self‐growth: making active health and lifestyle changes intended to address memory concerns that were not perceived as inevitable. (4) exploring how enduring self‐identity underpinned a resilience to ageing stereotypes, and enabled adaptation and coping in response to challenges of memory concerns, ageing and the pandemic. We will describe the resulting co‐designed exhibition that was launched in London and exhibited at the Houses of Parliament.

Conclusion

We describe experiences of the first group video‐call intervention which seeks to address key risk factors for dementia, including social isolation. The shift to remote delivery of psychosocial interventions has potential gains in terms of scalability and cost‐effectiveness, but risks increasing digital exclusion in vulnerable older people, especially those with memory concerns. We will discuss what our qualitative findings tell us about the effectiveness of our strategies to develop an inclusive, useful intervention.
A cell‐autonomous role of DNAJC5 in microglial‐mediated proteostasis in Alzheimer’s disease
Authors: Rosene Matthew J , Nykanen Niko‐Petteri , Brase Logan , Harari Oscar , Benitez Bruno A.
Published: December 2023

Background

DNAJC5 encodes co‐chaperone cysteine‐string protein alpha (CSPα), a synaptic and endolysosomal protein whose mutations cause adult‐onset neuronal ceroid lipofuscinosis (ANCL). Characterized by endolysosomal dysfunction, microgliosis, synaptic loss, and protein aggregation, ANCL shares pathological features with Alzheimer’s disease (AD). The endolysosomal role of CSPα in non‐neuronal cell types has been understudied. Here, we aimed to address this gap and hypothesized that CSPα plays a yet undefined microglial role in AD.

Method

Aβ levels and plaques in human tissue were assessed through ELISA and immunohistochemistry, respectively. Bulk‐RNAseq data from two independent cohorts of AD and ANCL patients with controls (GSE5281; GSE15222) were analyzed. To assess cell‐autonomous expression, single‐nuclei RNAseq (snRNA‐seq) was mined from the parietal cortex of AD patients with APP and PSEN1 mutations (n = 16) along with sporadic AD (n = 31), non‐AD (n = 9), presymptomatic (n = 3), and control patients (n = 8). An independent cohort (GSE138852) was analyzed for rigor. Using Clue.io, candidate therapeutics projected to reverse the observed transcriptomic profile from DNAJC5 mutants in myeloid cells were identified. A cohort from iPSC‐derived microglia (GSE178317) was cross‐analyzed with the ANCL RNAseq.

Result

In tissue from ANCL patients, soluble or insoluble Aβ levels were nearly nonexistent and synaptic protein levels were reduced, but intraneuronal Aβ accumulation was increased, suggesting altered APP processing. In two independent RNAseq cohorts (GSE5281; GSE15222), DNAJC5 was reduced in AD patients versus controls. SnRNA‐seq from parietal cortex revealed higher DNAJC5 transcript levels in microglia versus neurons. RNAseq obtained from ANCL patients was cross‐referenced with dataset obtained from iPSC‐derived microglia, revealing 35 differentially expressed genes associated with proliferative microglia and 32 genes associated with the interferon/chemokine response. Analysis of ANCL transcriptomics in myeloid cell lines using Clue.io indicate HSP inhibitors (BIIB‐021, geldanamycin), an opioid receptor antagonist (BNTX), and a proteasome inhibitor (bortezomib) suggesting convergence in proteostasis in microglial cells. ANCL‐patient transcriptomics displayed reduced TSPAN14, which facilitates ADAM10 maturation, and elevated APH1B and GSAP, enzymes that promote γ‐secretase activity suggesting a shift towards amyloidogenic pathway.

Conclusion

DNAJC5 is implicated in AD pathogenesis modulating APP processing and amyloidogenesis. Furthermore, endolysosomal DNAJC5 might play a novel cell‐autonomous role in microglia under altered proteostasis.
Dihydroxytrimethoxyflavone possess memory improvement effects against scopolamine in mice via modulating multiple pathways: In‐silico and in‐vivo evidences
Authors: Singh Varinder , Singh Manjinder , Singh Thakur Gurjeet , Shri Richa
Published: December 2023

Background

Dementia is a deliberating neurodegenerative disorder which causes impairment of intellectual functions. The USFDA approved drugs has limited efficacy and numerous side effects. Thus, finding newer drugs to manage dementia and cognitive disorders is certainly required. The present study explores the potential of a natural flavone, 5,7‐dihydroxy‐3',4',5'‐trimethoxyflavone (DHF), as memory enhancer drug against scopolamine‐induced cognitive deficit in mice.

Methods

Animals were treated with DHF (5‐10 mg/kg, p.o.) for 7 days after inducing cognitive impairment by scopolamine (1mg/kg,i.p.). Memory functions (passive shock avoidance task and Morris Water Maze), brain acetylcholinesterase (AChE) activity, inflammatory markers, oxidative stress, apoptotic biomarkers and histopathological studies (H&E and congo red staining for beta amyloid) were determined to measure memory improvement effects of DHF. In‐silico (molecular docking) studies were performed to understand the interactions of DHF with key pathological enzymes related to dementia.

Results

Treatment of scopolamine administered mice with DHF improved scopolamine‐induced cognitive impairment and restore brain biochemical parameters (inhibited acetylcholinesterase activity, enhanced glutathione levels, and reduced TBARS, TNF‐α, IL‐6, IL‐1β and caspase‐3 levels). Moreover, histopathological studies showed that DHF treatment reduced the neuronal cell death and amyloid depositions in mice brain. Further, molecular docking studies revealed string interactions of DHF with crucial amino acids of AChE and caspase‐3.

Conclusion

These results suggest that DHF was effective in treating scopolamine induced cognitive deficit by improving cerebral cholinergic dysfunction and reducing brain oxidative stress, inflammation, apoptosis and beta‐amyloid depositions in mice. Thus, DHF could be developed as a potential alternative drug to treat memory disorders.