bluuebunny/crossref_metadata_2025 huggingface dataset:
Through the Bloodstream: A Novel Biomarker Search for Early Blood‐Based Alzheimer’s Diagnosis Using an Adversarial Autoencoder
Authors: Ko Grace , Hwang Paul , Dae ko kyung
Published: June 2023

Background

Alzheimer’s Disease (AD) is a neurodegenerative disease marked by loss of memory and cognitive functions. As there is no Alzheimer’s cure, an essential early diagnosis can lead to earlier treatment access and time to prepare financially. Current diagnosis methods are expensive and hard to access, which is why there has been a shift to use blood tests. The problem with blood‐based diagnosis is their use of biomarkers as there are only a few known biomarkers of Alzheimer’s. We used an Adversarial Autoencoder (AAE) to increase sensitivity in identifying potential biomarkers in blood samples.

Method

We applied the AAE to identify potential biomarkers through a single cell RNA sequencing dataset from peripheral blood cells (PBC). We synthesized single cell matrices from the trained AAE using randomly sampled sets from the original dataset, and found common genes among them. Afterwards, we determined the molecular mechanisms of these common genes using a gene ontology (GO) enrichment analysis to validate their genomic functions.

Result

From the experiment, we succeeded in identifying 157 potential biomarkers for Alzheimer’s using the AAE. Not only are these biomarkers related to the immune response system, the molecular mechanisms of these genes are enriched in Alzheimer’s. This enrichment further indicates the potential of these genes to be useful biomarkers in early diagnosis.

Conclusion

Our approach using the AAE and the single cell RNA sequence dataset could be a new method for biomarker search in Alzheimer’s early diagnosis.
LEADing Advance care conversations: Development of an intervention platform
Authors: Dassel Kara B , Nachtweih Emily , Supiano Katherine P , Utz Rebecca , Iacob Eli
Published: June 2023

Background

The LEAD Guide (
Life‐Planning in Early Alzheimer’s Disease; Dassel et al., 2019) addresses changes in cognition and goals of care along the Alzheimer’s disease and related dementias (ADRD) continuum and anticipates the need for surrogate decision‐makers upon loss of the care recipient’s decisional abilities.

Method

We developed a preliminary interactive version of the LEAD Guide, which serves as the foundation of a self‐administered intervention designed to promote and guide community‐based ADRD dyads through a dementia‐focused ACP process. The intervention model includes the LEAD Guide, along with education/information about ACP in the context of ADRD, and interactive instructions. We developed the LEAD Intervention using an iterative design process, which relied on feedback from a 11‐member community advisory board comprised of a clinical dementia specialist, the Director and Program Manager from the State Chapter of the Alzheimer’s Association, and community‐based ADRD dyads. We used Qualtrics, a web‐based survey platform, to simulate the basic functionality and flow of the interactive web‐delivered intervention we envisioned. We then conducted extensive beta‐testing with our community advisory board through written surveys and focus groups.

Result

In general, users were enthusiastic about the LEAD Intervention and appreciated the opportunity to engage in meaningful guided ACP with their family member. Recommended revisions fell into two categories: technological (adding a progress bar, reducing the number of items per page, adding back arrows, reducing text and using more graphics/figures, closed‐captioning, video‐facilitated instructions) and personalization (using piped text that integrates participants’ names into survey items to increase a personal feel, and creating downloadable copies of participants’ LEAD Guide responses).

Conclusion

The process of creating a feasible, acceptable, and efficacious intervention requires input from ADRD experts as well as community‐based caregivers and persons with mild ADRD. The iterative process that our research team engaged in with our community advisory board members provided invaluable information on how to create and revise a web‐based ACP intervention platform for community‐based ADRD dyads. We are currently enrolling 60 ADRD dyads in the revised web‐based intervention, with the goal of exploring the impact on relationship quality, decision‐making self‐efficacy, and ACP congruence within participant dyads.
Altered transposable elements expression and gene networks remodeling precede disruptions in sleep/wake cycles in a tauopathy mouse model of AD
Authors: de Evsikova Caralina Marin , Evsikov Alexei
Published: June 2023

Background

Alzheimer’s Disease (AD) is an widespread neurodegenerative disorder, common in elder and Veterans communities, culminating in dementia with non‐cognitive behavioral and metabolic symptoms, such as hyperactivity and altered sleep/wake patterns. In demented patients, sleep/wake cycle disruptions facilitate weight loss, which is associated with adverse outcomes like accelerated AD progression and higher institutionalization. Tg4510 mice, which express a P301L mutant variant of human tau, develop both cognitive and non‐cognitive symptoms. Several mouse models of tau deposition, including Tg4510 mice, also have negative energy balance. To identify early factors affecting AD, we measured locomotor, sleep/wake patterns in vivo, and analyzed RNA‐seq data from Tg4510 mice to identify gene and transposable elements (TE) expression changes involved in behavioral derangements in AD.

Method

Locomotor activity, sleep and wake intervals and patterns were measured using in vivo metabolic cages for two weeks over 24 hr and day and night cycles from Tg4510 mice (n = 5‐7) vs. controls (n = 7‐10) before and after the onset of tauopathy (at 2 and 7 months of age respectively). In additional experiments, we analyzed RNA‐seq from hippocampi of Tg4510 mice (n = 5) vs. controls (n = 6). Using our established TTESA bioinformatics pipeline, reads were aligned to reference genome and expression of genes or TEs was measured with featureCounts. Pathway enrichment analysis using Visual Annotation Display was used to discover common functional and disease pathways using Gene Ontology, Protein Ontology, and Mammalian Phenotype Ontology.

Result

We observed altered locomotor and sleep patterns during the night phase starting in young Tg4510 vs. controls. TTESA results detected the majority of significantly differentially expressed TEs were retrotransposons (70%), which consisted mainly of long terminal repeats (LTRs; 70%) and some LINE retroelements (30%) and SINEs (<8%) in transgenic mice. VLaD pathway analysis revealed several biological processes upregulated in transgenic mice, including non‐cognitive behavioral pathways were downregulated, such as the regulation of circadian sleep/wake cycle with changes in the expression levels of Per2, Per3 (p<0.0001).

Conclusion

Early dysregulation of TEs may be involved in rewiring gene expression networks underlying behavioral changes in wake and sleep cycles and other circadian patterns of behavior in this humanized mouse model of AD.
The effects of different knee osteoarthritis criteria on trail‐making test times in an elderly Malaysian cohort
Authors: Tan Guo Jeng G , Tan Maw Pin
Published: June 2023

Background

Knee osteoarthritis (KOA) is a common cause of morbidity among older people with its prevalence expected to increase with population ageing. The relationship between KOA and cognitive performance, however, is not well understood despite both conditions sharing common risk factors including age and metabolic syndrome. We evaluated the cognitive performance of individuals with and without KOA to evaluate this relationship.

Method

Data is from the Promoting Independence in our Seniors with Arthritis (PISA) study, which is comprised older adults with and without KOA recruited from an urban tertiary hospital and its catchment population. Basic demographics, physical and psychosocial characteristics were recorded. Cognitive performance was determined using the Trail‐Making Test (TMT). KOA was defined using the American College of Rheumatology (ACR) criteria, presence of knee pain, self‐reported physician diagnosis (SRPD), and the Kellgren‐Lawrence’s (KL) radiographic criteria. Multiple linear regression models were created and bootstrapping was used for Kellgren‐Lawrence in view of the smaller sample who had radiographic investigations.

Result

Two‐hundred and thirty participants, mean (SD) age of 66.93 (7.12) years, were recruited. KOA was present in 120 (58.0%), 94 (40.9%), 85 (39.9%), and 33 (57.9%) according to ACR, knee pain, SRPD and KL criteria respectively. TMT‐A scores were variably influenced by age, gender, years of education, grip strength, functional reach and presence of metabolic syndrome using the four KOA criteria. TMT‐B scores were influenced by age, gender, years of education, grip strength and depression scores differentially using the four KOA criteria. No significant associated was observed between KOA and TMT‐A or TMT‐B scores after adjustment for the potential confounders above.

Conclusion

Knee OA was not associated with differences in cognitive performance evaluated with TMT which is a cognitive screening tool which mainly evaluates attention, working memory and executive function. The presence of KOA did not influence TMT performance in this study, which suggests that KOA does not affect the above cognitive domains regardless of criteria for diagnosis. This suggests that cognitive impairment and KOA do not share common pathological processes despite the presence of common risk factors.
Nanoparticle based intranasal drug delivery system of some herbal medicinal plants for Alzheimer’s disease
Authors: Singh Manisha
Published: June 2023

Background

Diseases of the Central Nervous System (CNS) such as epilepsy, schizophrenia, meningitis, migraine, Parkinson’s disease and Alzheimer’s disease require delivery of the drug to the brain for effective treatment but it remains problematic area to deal with, as the central nervous system (CNS) is isolated from the whole body by the blood–brain barrier (BBB). This tight physiological barrier limits the drug diffusion towards the brain parenchyma and is considered as the bottleneck in brain drug development. Now this can be circumvented by intraventricular or intracerebral administration. Intra Nasal delivery thus attributes to non‐invasive, essentially painless, high vascularity and the permeability of the nasal mucosa, which aids the drug in bypassing the aforementioned processes of degradation. Now the increasing realization of the side effects of allopathic medicines, coupled with the growing awareness about the medicinal benefits as well as therapeutic effect of herbal products is pushing up the demand for herbal extracts and herbal‐based supplements worldwide.

Method

In this study we designed a natural compound based Nanoformulations for drug delivery via nasal route to treat Alzheimer’s condition

Result

After various preliminary studies we prepared standard extract loaded Nanoformulations with their particle size between the range 80 – 290nm and sustained release kinetics profile. Further, the toxicity analysis (morphological, cell viability, cytotoxicity assays) of these nanoformulations was performed on RPMI2650 (Human nasal septum) and NB41A3 (Mouse hippocampus) cell lines based on the route and site of drug delivery. Lastly, in vivo experiments were performed with AD (cognitive impairment) induced mice model. There was seemingly, a significant decrease in anti ß amyloid antibody positive neurons in case of optimised nanoformulations in comparison to the galantamine. It was also found to have reduced lesions caused due to the amyloid aggregation reflecting a noted improvement in dispersing and reducing the lesions in the hippocampal tissues.

Conclusion

In conclusion, the present study demonstrates that the developed nanoformulations have potential therapeutic effects on improving the pathological state of AD, and might be taken further as a promising candidate for clinical research to evaluate its efficacy in humans.
Carotid pulse wave velocity measured using a fast single‐slice oblique‐sagittal phase‐contrast MRI is associated with cognitive impairment
Authors: Tang Jianing , Pahlavian Soroush Heidari , Joe Elizabeth B , Chui Helena C , Yan Lirong
Published: June 2023

Background

Arterial stiffness is one of the earliest markers of vascular dysfunction1. Elevated arterial stiffness leads to the transmission of excessive pulsations into the downstream microvasculature, which may be linked to cognitive impairment in aged individuals. Pulse wave velocity (PWV) is an established surrogate of arterial stiffness. To date, PWV measurement at carotid arteries or above has been still limited. Previous work has introduced a fast MRI method to measure carotid PWV (cPWV) using single‐slice oblique‐sagittal phase‐contrast MRI (OS PC‐MRI)3. In this study, we evaluated the association between cPWV and cognitive impairment in an aged group.

Method

The MRI experiments were conducted on Siemens Prisma 3T MRI scanner. A 2min TOF MRI was performed to localize carotid arteries including CCA and ICA. The 3D MR angiogram was reformatted to determine an oblique slice to maximally cover both CCA and ICA (Figure 1a). A single‐slice retrospectively gated 2D OS PC‐MRI with a single in‐plane velocity encoding (CCA to ICA) (Venc = 80cm/s, temporal resolution = 14.22ms) was performed to simultaneously acquire blood velocity waveforms at each location along the CCA‐ICA segment. cPWV was calculated as the inverse slope of the line fitted to the transit time versus distance along the vessel (Figure 1b). 15 elderly participants (age: 71.4 ± 8.5 years) were enrolled in this study. Each participant underwent cognitive assessments including CDR and 13 out of 15 were conducted the MoCA.

Result

There was a significant difference (p = 0.0496) in cPWV between the participants with normal cognition (CDR = 0) and cognition impairment (CDR> = 0.5). Figure 3 shows the scatter plot of cPWV vs. MoCA. Overall, cPWV increased with lower MoCA. However, there was no significance (r = ‐0.5294, p = 0.0767) obtained between cPWV and MoCA given a small sample size and the presence of a suspicious data point indicated by a green circle in Figure 3. After excluding this potential outlier, a significant negative correlation between cPWV and MoCA was obtained (r = ‐0.8113, p = 0.0014).

Conclusion

The pilot study demonstrates that increased cPWV is associated with cognitive impairment, suggesting cPWV measured using 2D OS PC‐MRI could be an imaging marker for cognitive impairment.
Association between different dementia diagnosis and kidney function decline: A Swedish registry study
Authors: Xu Hong , Garcia‐Ptacek Sara , Lindholm Bengt , Eriksdotter Maria , Carrero Juan Jesus
Published: June 2023

Background

Population studies have shown that chronic kidney disease(CKD) and CKD progression are associated with dementia, particularly Alzheimer’s dementia(AD) and vascular dementia(VD). However, the impact of different brain pathogenesis on these associations is not known.

Method

Observational study of patients with recently diagnosed dementia disorders from the Swedish Dementia Registry(SveDem) 2007‐2018 linked with complete information of kidney function tests [estimated glomerular filtration rate(eGFR)] over time from the Stockholm CREAtinine Measurements(SCREAM) registry. The study exposure were different dementia diagnosis [AD, VD, mixed dementia, dementia with Lewy Bodies(DLB) and Parkinson’s disease dementia(PDD), frontotemporal dementia(FTD), unspecified dementia(UNS) and other dementia types]. The study outcome was CKD progression, defined as the composite of a sustained eGFR decline of>30% from baseline, initiation of kidney replacement therapy or death attributed to kidney disease. We performed competing risk analyses where death from non‐renal causes was considered as competing events for CKD progression. Confounders included demographics, comorbidities, and baseline kidney function.

Result

We included 20,618 patients, of whom, 6,452(31%) had AD, 7,012(34%) had mixed dementia, 3,987(19%) had VD, 764(4%) had DLB or PDD, 312(2%) had FTD, and 2,091(10%) patients were diagnosed with unspecified or other dementia diagnoses. The mean age was 80 years (60%female). During median follow‐up time of 2.5 (IQR1.0‐4.5) years, 2,225(11%) events of CKD progression occurred, along with 8,684(42%) non‐renal deaths. After adjusting for confounders and accounting for competing risks, a higher risk of CKD progression compared to patients with AD was observed for patients with VD [sub‐HR, 95%CI 1.19;1.05‐1.34], mixed (1.13;1.02‐1.26), UNS or other dementia types (1.13;0.96‐1.32), while patients with DLB or PDD dementia had 46% lower risk of CKD progression (0.54;0.39‐0.76), and those with FTD showed no difference compared to AD (0.99;0.64‐1.51).

Conclusion

VD and mixed dementia (vs AD diagnosis) were associated with a higher risk of CKD progression, whereas DLB or PDD dementia were associated with lower risk of CKD progression. Since DLB and PDD dementia involve less and VD and mixed dementia more vascular pathology, this suggests that vascular mechanisms may play an important role in the brain‐kidney axis. Future studies are needed to explore this hypothesis.
Protocol for investigating brain health risk and protective factors in 18‐40 year olds: The PREVENT Next Generation study
Authors: Booi Laura , Farina Francesca R , Wells Katie , Dounavi Maria‐Eleni , Gregory Sarah , Jenkins Natalie D , Low Audrey , Mak Elijah , Newton Coco , Saunders Stina , Lawlor Brian , Ritchie Craig W.
Published: June 2023

Background

Evidence suggests that the early detection and management of modifiable risk factors can reduce, or partially prevent, incidence of neurodegenerative diseases. While there is consensus that risk factors should be addressed as early as possible, research has largely focused on childhood or mid‐ and later‐life. As a result, there is a significant gap in our understanding of risk (and protective) factors in younger adulthood, as well as attitudes towards brain health in this group. The PREVENT Next Generation (PNG) study builds on the PREVENT Dementia project to investigate risk and protective factors in 18‐40 year olds.

Method

The first phase of the PNG study will establish a foundational understanding of knowledge and attitudes towards brain health and risk reduction among adults aged 18‐40 years. We will conduct focus groups with adults aged 18‐40 years with and without a family history of neurodegenerative disease (n = 10 per group). Participants will be recruited via links with volunteer and community centre enterprises in the UK. To ensure inclusion of equitable perspectives, we will emphasise recruitment of diverse populations, including racialized and neurodiverse communities, and those with lower socioeconomic status. Focus groups will be recorded and transcribed. Data will be analysed using thematic analyses.

Result

Themes identified will be used to inform the next phase of the PNG study, which is to develop and distribute an online survey about brain health to an international sample of adults aged 18‐40 years.

Conclusion

Survey findings will inform the development of a large cohort study aimed at identifying biological, psychological and lifestyle factors that influence brain health in adults up to mid‐life.
Interdisciplinary antipsychotic stewardship between operator and neurobehavioral consultant
Authors: Posar Steven Laurence , Reid Anita , Heiser Daniel , Kinzie Janean , Pinon Jose D
Published: June 2023

Background

Antipsychotic utilization in skilled nursing facilities (SNFs) is a major focus of regulatory compliance and a key theme in resident care. At first, improvements via national rate lowering initiatives were effective, but as of late, reductions have slowed. Due to a slowing of industry‐wide advancements in the care of behavioral and psychological symptoms of dementia (BPSD), the Federally mandated patient centered care initiative has not widely incorporated “best practices” for BPSD care. This has opened an opportunity for innovations in clinical care of BPSD. In a shared initiative with this operator, we have implemented a joint program focused on rigorous clinical diagnosis and “best practices” in pharmacology support, specifically aimed at assessing and reducing antipsychotic use whenever appropriate.

Methods

In three targeted buildings, all patients identified as receiving antipsychotic medication were enrolled in a specific assessment and treatment protocol designed to mitigate antipsychotic use where possible. Diagnoses were reviewed by Clinical Psychology, Psychiatry, Consultative Gerontology (where indicated), and building Social Service. Additionally, behavioral documentation for each resident was reviewed, and a team approach to polypharmacy, all psychotropic medications, and antipsychotic reductions were implemented. Data was verified by facility pharmacy records, and reports detailing the proportion of residents taking antipsychotic medications were generated in January, March, and July of 2021.

Results

Prior to full implementation of the protocol (January 2021), antipsychotic rates were 32%, 14% and 18% in the three buildings. Immediately following initial review, rates were noted to be similar to baseline (Table 1). After implementation of clinical protocols, we found that the proportion of residents using antipsychotic medications declined to 9.6%, 4.2% and 6.3% respectively (Table 1, Figure 1). In addition, there were no noted harms, nor deteriorations related to the discontinuation of these medications.

Conclusion

Implementation of a shared cooperative clinical protocol between the SNF facility staff and clinical treatment team resulted in a reduction of antipsychotic use of more than 65% with no noted harms nor clinical decline.
DNA Methylation in Risk for Cognitive Impairment and Type 2 Diabetes in a Mexican American Cohort
Authors: Daniel Ann Abraham , Silzer Talisa , Hall Courtney , Sun Jie , Zhou Zhengyang , Phillips Nicole , Barber Robert
Published: June 2023

Background

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are among the leading causes of mortality among the growing aging Mexican American population (≥ 65 years old) in the US (Vega et al. 2017). In comparison to their non‐Hispanic white counterparts who most likely develop inflammation associated AD, aging Mexican Americans have an earlier onset of AD and metabolism related predisposition for AD (O'Bryant et al. 2010). Mild cognitive impairment (MCI) is a phenotype that often leads to AD and is also prevalent in this cohort (O'Bryant et al. 2013). The risks for AD, MCI and T2D are multifactorial, involving a form of epigenetic regulation called methylation where a methyl group is added to the cytosine base in DNA (Shao et al. 2017; Juvinao‐Quintero et al. 2019). We aim to elucidate an epigenetic association between cognitive impairment (identified here as AD and MCI), and T2D that is unique to the Mexican American population.

Method

A total of 551 aging participants from the Texas Alzheimer’s Research and Care Consortium (TARCC) consisting of 252 non‐Hispanic white individuals and 299 Mexican Americans were selected, after quality control. First, participants were stratified into groups of individuals diagnosed with cognitive impairment (CI) alone and controls without CI within each ethnic group. Secondly, this cohort was stratified into individuals with T2D alone and controls without T2D. Thirdly, participants were stratified into those with both CI and T2D versus normal healthy controls. Lastly, any differential methylation associated with each ethnic group will be compared and contrasted. Peripheral blood drawn from participants was used to obtain individual methylation profiles using the Illumina Infinium MethylationEPIC chip array. Differential methylation was assessed using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R. The Beta MIxture Quantile dilation (BMIQ) method was used for data normalization.

Result

Results will be analyzed using gene set enrichment and pathway analysis tools.

Conclusion

Identifying possible methylation sites associated with CI and T2D could contribute towards developing ethnicity‐specific biomarkers for Mexican Americans.
Associations between memory strategies performance and CSF biomarkers: A new approach for the early intervention in MCI
Authors: Chino Brenda N , Torres Lucia , Żelwetro Agnieszka , Rojo Inmaculada Concepción Rodríguez , Carnes Anna , Piñol‐Ripoll Gerard , Yubero Raquel , Paul Nuria , Maestú Fernando
Published: June 2023

Background

Diagnostic research criteria for Alzheimer’s Disease (AD) recommend the cerebrospinal fluid (CSF) as a sensible and validated biomarker to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI). Also, it has been established that episodic memory failure is a proxy for AD, while executive functions impairment could be leading to other types of dementia. One of the tests designed to simultaneously evaluate these cognitive functions with high sensitivity and specificity to discriminate between neurocognitive disorders is the Test of Memory Strategies (TMS). The main goals of the present study were 1) to assess the correlations between TMS and CSF markers (i.e., Aβ42, t‐tau, and p‐tau) in a sample of MCI patients, and 2) to provide additional validation for TMS as a clinical tool for Alzheimer’s Disease (AD) early detection.

Method

135 participants were recruited from a multicenter international study in Poland and Spain, but only 47 were selected (Mean age: 68.58 ± 10.03). The sample was split according to the Erlangen Score Diagnostic Algorithm (ESA) into: CSF ‐ (n = 11) and CSF + (n = 36). Correlations analyses between the five TMS word‐list conditions and CSF biomarkers were conducted, and analysis of covariance (ANCOVA) was performed to define the effect on ESA classification in the sample, using the site of origin of the participants as covariable.

Results

Significant associations between the TMS‐3 condition and Aβ42, t‐tau, and p‐tau were observed for the whole sample. Also, the CSF‐ obtained a higher cognitive performance in the TMS‐3 than the possible AD group (CSF+).

Conclusions

Our results revealed that combining CSF biomarker measures and TMS scores could contribute to a better characterization and a more precise approach to AD. Furthermore, considering that the TMS‐3 condition is mostly associated with executive functions, future interventions should focus on this cognitive construct and how it could affect the patient’s ability to encode and organize the information in memory.
The role of anemia and haemoglobin concentration on cognitive function in the Longitudinal Ageing Study of India‐Diagnostic Assessment of Dementia (LASI‐DAD)
Authors: Winchester Laura M , Newby Danielle , Bauermeister Sarah , Ranson Janice M , Chien Sandy , Hu Peifeng , Llewellyn David J , Lee Jinkook , Nevado‐Holgado Alejo J
Published: June 2023

Background

Anemia is a condition characterised by low haemoglobin concentration, which is common in elderly populations. In India, anemia is widely researched in childhood development and women of reproductive age, although studies in older populations are lacking. The Longitudinal Ageing Study India ‐ Diagnosis of Dementia (LASI‐DAD) dataset is an ideal cohort to better understand the potential impact of anaemia and changes in blood haemoglobin and cognition in an elderly dataset.

Method

2,758 respondents from the LASI‐DAD cohort, aged 60 or older, had venous blood samples taken for complete blood count and harmonised cognitive function tests. Haemoglobin concentration was used as the exposure in the linear regression models. Cognition data from in‐depth cognitive tests and informant interviews used the Harmonized Cognitive Assessment Protocol (HCAP). A summary value for each of the 11 tests was used as the outcome. We corrected for age and gender in the basic model with the full model also containing adjustments for rural location, smoking and BMI.

Result

Cases of anemia are more common in older and rural participants in the Indian population. We found a positive association between haemoglobin concentration and all the harmonised cognitive test measures except the visuospatial measures (b = 0.038 ‐ 0.072 p < 0.05). The strongest association was identified for memory‐based measures (immediate episodic, delayed episodic and recognition, b = 0.045 ‐ 0.072 p < 0.05). This was supported by an association between the general cognitive score and the other red blood count tests including the derived measure mean corpuscular haemoglobin concentration (b = 0.06 p = 0.0001) and Red Cell Distribution Width (b = ‐0.11 p < 0.0001).

Conclusion

We have established for the first time in a large South Asian population that anaemia may be an important potentially modifiable risk factor for low cognitive function. As the LASI‐DAD cohort expands to include new timepoints it will be possible to run longitudinal analysis to examine the causal relationship between these measures.
The gut microbe‐derived methylamine TMAO protects against neuroinflammation through restraint of pro‐inflammatory glial behaviour
Authors: McArthur Simon
Published: June 2023

Background

While the ultimate cause(s) for Alzheimer’s disease (AD) are unknown, factors that can modify the risk of its development are clearer. Consumption of a seafood‐rich diet has repeatedly been shown to protect against AD. What is less clear however, is why. Much attention has focussed on omega‐3 fatty acids given their anti‐inflammatory effects in vitro, but translation to human studies have been disappointing. Omega‐3 fatty acids are not the only bioactive components in seafood however. In particular, we have recently shown the dietary methylamine trimethylamine N‐oxide (TMAO), produced by gut microbial metabolism of seafood‐enriched choline, to enhance blood‐brain barrier integrity, prevents glial activation and protect cognitive function following peripheral inflammatory challenge.

Methods

We investigated whether protective effects of TMAO treatment could be extended to neuroinflammatory challenge. Male C57Bl/6 (n = 6) were pre‐treated for 4 weeks with or without TMAO through the drinking water (0.5g/l) prior to unilateral i.c.v. injection of 4 mg/kg streptozotocin (STZ) or saline vehicle. Two weeks post‐lesioning (continuing TMAO treatment as appropriate) animals were killed and assessment was made of hippocampal inflammation. In parallel, the molecular mechanism of action of TMAO was investigated in vitro using immortalised and primary murine microglia, challenged with oligomeric β‐amyloid (100nM).

Results

Animals treated with STZ showed significant increases in both microglial and astrocytic density in both the CA1 and dentate gyrus regions of the hippocampus, two weeks post‐lesioning, effects that were almost completely attenuated by TMAO pre‐treatment. Study of oxidative and inflammatory markers is ongoing. In vitro analyses of immortalised and primary microglia showed TMAO pre‐treatment (20 µM, 24 h) to prevent lipopolysaccharide (10 ng/ml) or oligomeric β‐amyloid (100nM)‐induced secretion of TNFα, nitric oxide and reactive oxygen species.

Conclusion

Together, these data further highlight the importance of TMAO in the gut‐brain axis, and emphasise gut microbial metabolism as a conduit for dietary effects upon the brain. Given that TMAO is ultimately derived from dietary choline, these changes may help explain the well‐known beneficial effects of consumption of a seafood‐rich diet upon dementia risk.
Analysis of amyloid deposits in the retina and implications for use as a biomarker of Alzheimer’s Disease
Authors: Campbell Melanie CW , Mason Erik L , Emptage Laura , Wang Jiyuan , Hamel Michael T , Redekop Rachel , Kitor Monika , Strazzeri Jennifer , Brooks Melissa , Araujo Joseph A , Ran Chongzhao , Hsiung Ging‐Yuek Robin , Mackenzie Ian R , Hirsch‐Reinshagen Veronica , Hunter Jennifer J
Published: June 2023

Background

In humans and the naturally occurring canine model of Alzheimer’s disease (AD), we and others observe amyloid deposits in the retina en face. We have previously shown that detecting the number of amyloid deposits with polarised light, using wide field, dye free retinal imaging, can predict the degree of severity of AD pathology in the brain. But some who take thin, transverse retinal sections find amyloid while others do not. Here, we report the surface area of retinal amyloid deposits in human and the canine model of AD.

Method

Formalin‐fixed retinas from 29 individuals with a moderate to high likelihood of AD (with some comorbidities excluded) and 20 canines were flat‐mounted and imaged in florescence and polarized light (Fig 1). The full retina was imaged for 24 human and 16 canine retinas. For 4 canines, in‐vivo blue light fluorescent retinal images were collected before and after injection of an amyloid dye, CRANAD‐28. Deposits visible only after injection were counted. Fluorescence and polarization images were compared post‐mortem in a canine after an injection of CRANAD‐28. Amyloid deposits were segmented using custom methods. The total area of segmented deposits was then divided by the total retinal area imaged.

Result

In retinas from individuals with AD brain pathology, the area of the retinal covered by amyloid deposits was on average 0.01% and correlated with the number of deposits (Fig 2). In vivo (Fig 3), the area of the canine retina covered by amyloid deposits was on average 0.29% (Fig 4). In one ex vivo retina, fluorescent and polarization positive deposits had a concurrence of 93% and the average area of fluorescent deposits (0.14%) was larger than the same deposits imaged in polarimetry (0.08%) (Fig. 5).

Conclusion

These findings and our previous report of an almost constant density of amyloid deposits across the retina, should guide in vivo imaging of amyloid in the retina as a biomarker of AD. Across all human and canine retinas, amyloid deposits covered less than 0.6% of the retinal surface. Careful, extensive sampling is needed. The surface area of amyloid deposits is an additional potential biomarker of disease severity.
Association of psychological stress and memory decline in US adults
Authors: Reddy Ananya , Zhang Yutong , Alonso Alvaro , Kulshreshtha Ambar
Published: June 2023

Background

Psychological stress can have long‐term health consequences and has been linked to many chronic conditions. Recent evidence suggests that psychological stress and poor mental health may have long‐term effects on cognition. We aimed to assess the association between psychological stress and memory decline in a nationally representative sample.

Method

We assessed data on participants aged 45 years from the 2020 wave of the Behavioral Risk Factor Surveillance System (BRFSS). BRFSS is a survey of health behaviors and conditions that is administered by telephone across the US. Participants self‐reported memory decline over the past year and days of psychological stress in the past month (categorized as <15 – low, or ≥15 – high), in addition to several sociodemographic factors. The association between memory decline and psychological stress was assessed by multivariate logistic regression, adjusting for age, sex, income, lifestyle and cardiovascular risk factors. Education and race were assessed as effect modifiers.

Result

Of 48,460 participants (53.9% female, 82.7% White), 4,132 (8.5%) reported memory decline over the past year. Among those with high psychological stress, 1,248 (25.1%) reported memory decline, compared to 2,884 (6.6%) among participants with low stress (p<0.001). In our crude model, high psychological stress was significantly associated with memory decline (OR = 4.72, 95% CI: 4.39, 5.09). This association persisted after adjusting for demographic, lifestyle and cardiovascular risk factors (OR = 4.18, 95% CI: 3.87, 4.52). There was significant interaction by education and race such that the association between psychological stress and memory decline was stronger in non‐whites with less education (OR = 6.56, 95% CI: 5.39, 7.99) and weaker in more educated whites (OR = 3.62, 95% CI: 3.23, 4.01).

Conclusion

In this analysis of a nationally representative sample, psychological stress was significantly associated with memory decline. This association was modified by education level and race, with larger effect sizes among those who were non‐white or had less education. Since psychological stress is a modifiable risk factor, these findings suggest that access to mental health resources and stress reduction efforts may be instrumental in preventing cognitive decline. Further studies are needed to elucidate the role of psychological stress in cognitive decline.
Updated APOE and TOMM40 rs2075650 genotype effects on cognition: a UK Biobank study
Authors: Pollpeter Amy , Klinedinst Brandon S , Larsen Brittany A , Li Tianqi , Wang Qian , Barnett Neil , Moody Shannin , Pappas Colleen , Willette Sara A , Parvin Mohammadiarvejeh , Jonathan Mochel , Allenspach‐Jorn Karin , Willette Auriel A
Published: June 2023

Background

58‐79% of late‐onset Alzheimer’s disease (AD) is due to genetic heritability. The epsilon 4 (ε4) variant of Apolipoprotein E (APOE) is the strongest genetic risk factor for AD, yet only accounts for 20% of AD heritability. In addition, the APOE ε2 or ε3 variants appear to have either a protective or neutral effect on AD risk respectively. Translocase of Outer Mitochondrial Membrane 40 (TOMM40) is next to APOE and may modulate different APOE variant effects, such as with the Single Nucleotide Polymorphism (SNP) at rs2075650. Thus, we explored main and interaction effects of TOMM40 and APOE on longitudinal measures of executive function and memory.

Method

10,347 adults (40‐70y) in the UK Biobank were genotyped for APOE and TOMM40 ‘650. Executive function and memory were tested at baseline and twice over a period of 6‐10 years. Main effects within APOE haplotypes and TOMM40 SNP genotypes (A,G) were analyzed, as well as interactions between these genetic markers.

Result

Having the TOMM40 ‘650 G risk variant was related to better baseline cognitive scores regardless of APOE haplotype (ps <.05), but a greater decline over time in APOE4 carriers (ps <.05) The effects of the APOE haplotype were strongly modulated by sex. Men vs. women had less protective or more detrimental effects based on APOE2 or APOE4 haplotype respectively.

Conclusion

The data suggests that TOMM40 modulates APOE, regardless of its haplotype. Future studies should stratify APOE by haplotype to re‐test our findings. In addition, more research needs to be done on the effect of having what we term a “mixed” APOE haplotype (carrying a copy of both the protective and risk gene variants).
Enlarged perivascular spaces are associated with white matter injury and cognition in an autosomal dominant vascular neurodegenerative disease (CADASIL)
Authors: Oh Bradley C , Wang Earnest Y , Tsuei Torie , Cobigo Yann , Baida Maria , Tabdili Yasmine , Park Ryan , Kramer Joel H. , Miller Bruce L , Rosen Howard J. , Elahi Fanny M
Published: June 2023

Background

Enlarged perivascular spaces (EPVS), quantified on brain imaging, can reflect structural changes of blood vessels or of the surrounding fluid filled spaces. EPVS measures are emerging as promising biomarkers of cerebral small vessel disease, especially in dementia research. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a vascular neurodegenerative disease (VNDD) caused by mutations in the NOTCH3 gene. CADASIL involves disease of small vessels and presents with headaches, early onset strokes, and progressive neuropsychiatric dysfunction. We asked whether “burden” of EPVS is associated with clinical outcomes in CADASIL.

Method

Brain MRIs were obtained in a CADASIL cohort (n = 27) and age/sex matched controls (n = 27). EPVS and WMH (white matter hyperintensity, measure of injury) were quantified with a semi‐ automated pipeline, using T1/T2 and FLAIR images, respectively. Participants underwent clinical and neuropsychological tests measuring executive function. Linear regression models were built to test associations between EPVS with WMH (a classical biomarker in CADASIL) and executive function. All models were adjusted for age and sex.

Result

We found no group differences in total EPVS volumes between CADASIL and the control group (β = 0.04, p = 0.73). Age was significantly associated with EPVS only in the control group (β = 0.018, p < 0.05). We found a significant inverse association of EPVS with executive function in CADASIL (β = ‐0.11, p < 0.05) and a positive association of EPVS with WMH (β = 0.28, p = 0.05).

Conclusion

CADASIL, a vasculo‐centric neurodegenerative disease includes prominent SVD pathology that may be driving total EPVS volumes. This may represent an accelerated vascular aging phenotype. Associations with cognition and MRI measure of white matter injury (WMH) in CADASIL confirm that EPVS may be a relevant biomarker to track in CADASIL. Longitudinal studies will be of great value in determining the utility of EPVS as a disease‐relevant biomarker in future therapeutic trials in CADASIL.
Late life onset of persistent psychosis and incident dementia: risk stratification by baseline cognitive status
Authors: Munir Amlish , Ghahremani Maryam , Smith Eric E. , Creese Byron , Fischer Corinne E. , Ismail Zahinoor
Published: June 2023

Background

Mild Behavioral Impairment (MBI) is a validated neurobehavioral syndrome characterized by later life emergent and persistent neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. Psychosis is one of the five domains of MBI, although dementia risk with MBI‐psychosis is not well quantified. Here, we assessed the longitudinal association of MBI‐psychosis with incident dementia in dementia‐free participants.

Method

Data were obtained from the National Alzheimer Coordinating Centre (NACC). Participants with neurodevelopmental, neurological and/or psychiatric disorders were excluded. Participants with normal cognition (NC) or mild cognitive impairment (MCI) at baseline were included. MBI‐psychosis status was defined based on persistence of Neuropsychiatric Inventory Questionnaire delusions and hallucinations symtoms across two consecutive visits. Kaplan‐Meier curves of ten‐year dementia‐free survival probability were generated for MBI‐psychosis versus those with no NPS prior to dementia diagnosis. Cox proportional hazard models were implemented to assess the risk of dementia, adjusted for age, sex, education, race, APOE e4 status, and clinical cognitive diagnosis. Interaction terms were included for relevant demographic variables. Secondary analyses were implemented to compare the risk associated with MBI‐psychosis to MBI without psychosis.

Result

The final sample consisted of 3,446 participants with no NPS (age = 73.1±9.6; 63% female; 13.2% MCI), and 58 with MBI‐psychosis (age = 74.9±9.9; 55.2% female; 69% MCI). MBI‐psychosis was associated with lower chance of dementia‐free survival over ten years and 3.36 times greater risk for dementia compared to no NPS (CI:2.19‐5.15, p<0.001). Moderation analysis revealed that in NC, those with MBI‐psychosis were at 8.15 times greater risk of dementia than those with no NPS (CI:2.57‐25.88, p<0.001). In MCI, the MBI‐psychosis‐associated dementia risk was 3.08 times greater (CI:1.95‐4.85, p<0.001). In the secondary analysis comparing MBI‐psychosis to MBI without psychosis (n = 2068), MBI‐psychosis was associated with 2.29 times greater risk of dementia (CI: 1.52‐3.4, p<0.001).

Conclusion

Although psychosis is an infrequently endorsed MBI domain, when present, it is associated with substantial risk for dementia. This risk differs between cognitive strata and is significantly greater when MBI‐psychosis emerges in NC versus MCI. The emergence of persistent psychotic symptoms in later life should be flagged for clinical attention, and a dementia assessment considered.
Electrophysiological signatures of memory depletion in mild cognitive impairment
Authors: Chino Brenda N , Cuesta Pablo , Pacios Javier , Torres Lucia , Doval Sandra , Dolado Alberto Marcos , Fuertes Miguel Yus , Fernández Ricardo Bruña , Maestú Fernando
Published: June 2023

Background

MCI diagnosis does not necessarily imply the development of dementia. For this reason, characterizing the MCI profile is fundamental to the early identification of electrophysiological markers associated with a higher risk of developing Alzheimer’s Disease (AD). Longitudinal studies demonstrated that the delay recall measure is a good predictor of conversion and is one of the most common manifestations of the preclinical stage. This study has for purpose compared the power spectrum in the resting‐state of MCI and their relationship with neuropsychological and structural measures.

Method

We compared the power spectrum in resting‐state eyes‐closed magnetoencephalographic of 93 MCI participants (aged from 64 to 87) recruited from the Hospital Universitario San Carlos (Madrid, Spain). According to their memory performance in delay recall, the sample was split into (i) ‘moderate’ MCI (n = 52) group and (ii) ‘severe’ MCI (n = 41) group. The groups did not differ in age or years of education.

Results

The severe MCI patients showed higher theta power than patients with moderate MCI were significant differences between both. Also, moderate MCI correlated significantly with years of education (rho = ‐0.31, p < 0.02) and TMT A time (rho = 0.40, p < 0.004). In the Severe MCI group, the theta power showed significant correlation with MMSE (rho = ‐0.43, p < 0.001) and total hippocampus (rho = 0.41, p < 0.001).

Conclusion

Loss of delay recall performance seems to be associated with electrophysiological alterations that can be used as non‐invasive markers of AD progression.
Non‐verbal communication of nursing home residents and care staff
Authors: Khan Zunera , Da Silva Miguel Vasconcelos , Testad Ingelin , Ballard Clive G
Published: June 2023

Introduction

People living with dementia (PlwD) in nursing homes (NH) have complex needs with impairments in cognition, communication, and daily function. Complex needs may arise with impairments in communication and difficulty in expressing needs. PlwD often experience neuropsychiatric symptoms (NPS) with poor quality of life (QoL), which can be impacted by impairments in non‐verbal communication (NVC). NVC plays a key role in improving communication and engagement with PlwD. This study examines current NVC practices in NH between PlwD and care staff.

Methods

225 NH from the Care Home Research Network, King’s College London were invited to take part on an online anonymous questionnaire. The questionnaire included 13 questions on NVC and NH demographics. Care staff provided information on communication cues used between residents and staff during instrumental care and social activities. The use of NVC was rated on a Likert scale.

Results

Thirty‐two NH completed the questionnaire, with 56% having 40‐90 beds. 9% of staff reported the use of verbal communication, 25% reported using combined verbal and NVC, whilst majority reported using NVC to communicate with residents (66%). The most observed NVC in residents was facial expressions (71.9%), followed by eye expression (53.1%) and touch (50%). Other NVC included the use of pitch, hand gestures and head nods (37%). Staff NVC cues included facial expressions (81.3%), eye contact (81.3%), hand gestures (75%), pitch of voice and head nods, (both, 66%). Furthermore, 34% of the staff used body language to assist residents with NPS, whilst 28% used touch. During social activities, facial expressions were used very often (78.1%) by residents, followed by head nods, touch and hand gestures (46%). Whilst receiving care, facial expressions were reported very often (68.8%). Other common cues involved touch (50%) and eye contact (41%).

Conclusion

NH residents and staff use a broad range of NVC channels to interact with one another and was the most reportedly used strategy. Developing interventions to improve communication between staff and PlwD should prioritize NVC, given its extensive use. Improving NVC would facilitate care staff to address needs better, reduce NPS and improve QoL.