bluuebunny/crossref_metadata_2025 huggingface dataset:
TML‐6 is a novel anti‐aging and Aβ‐lowering drug candidate with potential for anti‐Aβ antibody drug combination therapy
Authors: Yu Hsu Chia‐ , Wang Hui‐Chen , Shie Feng‐Shiun , Hsueh Jung‐Tsung , Wu Chiu‐Chu , Hou Ting‐Yi , Lin Tzu‐Han , Su Ih‐Jen
Published: December 2023

Background

These suggest that TML‐6’s ability to enter the brain parenchyma and possibly interact with and reduce Aβ, while possessing anti‐aging and anti‐inflammatory properties contributes to its effects on alleviating AD‐like pathology and behavioral deficit in APP/PS1 mice. Importantly, TML‐6 is safe and has promising drug bioavailability and exposure in pre‐clinical development. Taken together, TML‐6 exhibits promising druggability and meets the current strategy to develop as a first‐in‐class oral therapeutic drug for AD.

Method

TML‐6 was applied to investigate the binding with Aβ peptide (1‐40 or 1‐42), hERG, and safety panel screening assay in vitro. Further, the effects of TML‐6 treatment on reducing AD‐like pathology, TML‐6 concentration in plasma‐to‐brain ratio, and inflammaging biomarkers in APP/PS1 mice were evaluated. Lastly, pharmacokinetic and toxicology studies in rats and dogs were performed.

Result

Data from pre‐clinical development showed that TML‐6 bound Aβ1‐40 and Aβ1‐42 in vitro and improved behavioral deficits with reduced inflammaging in AD model mice (e.g., TNF‐α, IL‐1β, & IL‐6). The TML‐6 levels in the plasm and brain tended to dose‐dependently increase in AD mice, which inversely correlated with behavioral deficits and AD‐like pathologies. TML‐6 was well tolerated in toxicology in rats and dogs and had no off‐target safety pharmacology issue by hERG & safety panel screening. Most importantly, formulation optimization of TML‐6 exerted satisfactory drug bioavailability and exposure.

Conclusion

These suggest that TML‐6’s ability to enter the brain parenchyma and possibly interact with and reduce Aβ, while possessing anti‐aging and anti‐inflammatory properties contributes to its effects on alleviating AD‐like pathology and behavioral deficit in APP/PS1 mice. Importantly, TML‐6 is safe and has promising drug bioavailability and exposure in pre‐clinical development. Taken together, TML‐6 exhibits promising druggability and meets the current strategy to develop as a first‐in‐class oral therapeutic drug for AD.
SNX19 in human autopsy brains and cerebral organoids
Authors: Ma Liang , Wang Jinghui , Chen Qiang , Estevez Vanesa , Sargurupremraj Muralidharan , Kleinman Joel , Weinberger Daniel , De Jager Philip L , Hsieh Jenny , Seshadri Sudha
Published: December 2023

Background

The gene encoding sorting nexin SNX19 is highly expressed in neurons. SNX19 modulates synaptic functions that have been implicated in Aβ formation and tau phosphorylation. In our recent postmortem brain transcriptomic study (n = 409), we found an association of SNX19 gene expression with increased schizophrenia risk. To date, this gene has not been studied in AD. In this project, we will define AD risk single nucleotide variants (SNVs) at this locus, linking the SNVs to SNX19 gene expression and DNA methylation sites in human postmortem brains. we will test the hypothesis that SNX19 induces neuronal dysfunction and Alzheimer’s disease (AD)‐related pathologies in hiPSCs derived cerebral organoids.

Method

We collected human postmortem bulk brain dorsolateral prefrontal cortex (DLPFC) RNA‐seq data from Religious Orders Study/Memory and Aging Project (ROSMAP N = 656). We obtained two human induced pluripotent stem cells (hiPSCs) from HipSci.

Result

We performed a multi‐trait analysis and identified single nucleotide variants (SNVs) in SNX19 that were associated with AD and DSST. To uncover the regulatory mechanism linked to the SNX19‐AD risk SNVs, we examined the possible association of these SNVs with SNX19 abundance. As expected, the SNVs are significantly associated with SNX19 gene expression in DLPFC from 656 aging brains generated by ROSMAP (p‐value < 1e‐20).

Given the role of DNA methylation in influencing local gene expression and splicing in the human brain, we evaluated the association between SNV genotype and DNA methylation levels from 401 autopsy brains in our schizophrenia study. We identified cg14779329 as the top hit with schizophrenia functional SNV rs10791098. Interestingly, this CpG site was replicated to be associated with DSST‐risk SNVs in 692 ROSMAP brains.

To determine whether SNX19 protein influences aspects of neurodegeneration, we have performed CRISPR gene editing in hiPSCs. We are generating cerebral organoids to assess the SNX19 impact on neuronal morphology, AD‐related pathologies and synaptic function.

Conclusion

Our study identified novel AD factors at SNX19 in human postmortem brains and will define its role in AD using human‐derived tissue cultures.
Influence of lung function on macro‐ and micro‐structural brain changes in mid‐ and late‐ life: a large population‐based cohort study in the UK Biobank
Authors: Wang Jiao , Dove Abigail , Yang Wenzhe , Bennett David A. A , Xu Weili
Published: December 2023

Background

Lung function has been associated with cognitive decline and dementia, but the extent to which lung function impacts brain structural changes remains unclear. We aimed to investigate the association of lung function with structural macro‐ and micro‐ brain changes across mid‐ and late‐ life in a large population‐based cohort study.

Method

The study included a total of 37,590 neurologic disorder‐free participants aged 40‐70 years from the UK Biobank, who underwent brain magnetic resonance imaging (MRI) scans 9 years after baseline. After 2.5 years, a subsample (n = 3,941) underwent a second MRI scan. Lung function was assessed using a composite score based on forced expiratory volume in 1 second, forced vital capacity, and peak expiratory flow, and divided into tertiles (i.e., low, moderate, and high). Regional brain volumes (including total brain, gray matter, white matter, hippocampus, and white matter hyperintensities) and diffusion markers (fractional anisotropy [FA] and mean diffusivity [MD]) were assessed. Data were analyzed using linear regression and mixed‐effects models.

Result

At baseline, lung function ranged from ‐3.43 to 22.91 among all participants. In multi‐adjusted linear regression, low lung function was dose‐dependently related to smaller brain volumes and lower white matter integrity. Compared to high lung function, low lung function was associated with smaller total brain (β [95% CI]: ‐0.083 [‐0.097, ‐0.070], gray matter ‐0.145 [‐0.161, ‐0.130], white matter ‐0.017 [‐0.031, ‐0.004], and hippocampal ‐0.102 [‐0.128, ‐0.075]) volume, as well as poor white matter health (FA ‐0.165 [‐0.195, ‐0.135] for lower, WMH 0.269 [0.242, 0.295] and MD 0.168 [0.140, 0.196] for higher). Over the 2.5 years follow‐up, low PF was associated with reduced white matter (‐0.021 [‐0.041, ‐0.002]) and hippocampal (‐0.078 [‐0.110, ‐0.046]) volume, reduced FA (‐0.063 [‐0.091, ‐0.035]), and increased WMH volume (0.065 [0.016, 0.114]) and MD (0.121 [0.089, 0.154]). After stratification by age, the associations remained significant among adults aged 40‐60 years and 60+ years.

Conclusion

Low lung function is associated with macro‐ and micro‐ structural brain changes involving both neurodegenerative and vascular pathologies. This association is significant in both mid‐ and late‐ life.
Determinants underlying COVID‐19 vaccination behaviour in people with young‐onset dementia and their carers in the United Kingdom: A mixed‐methods study
Authors: KAFADAR Aysegul Humeyra , Jones Katy A , Stephan Blossom CM , Dening Tom
Published: December 2023

Background

Vaccine hesitancy is a risk to global health and has become particularly salient considering the COVID‐19 pandemic. To date, no studies have investigated COVID‐19 vaccination behaviour in people with young‐onset dementia (YOD) and their carers. This study aimed to fill this gap.

Method

26 participants with YOD and 24 carers for a person with YOD (i.e., aged <65 years) from the UK were enrolled. Participants filled out a self‐administered online questionnaire including demographic data, history of COVID‐19, and adulthood vaccination. Following this, participants attended a one‐to‐one semi‐structured interview focused on their experiences and thoughts on COVID‐19 vaccines and the vaccination process.

Result

The mean age of participants with YOD was 42.2 (range 26‐60), 88.5% were male, and 96.2% self‐identified as Black. The mean age of carers was 31.7 (range 19‐54 years), 70.8% were male, and 79.2% self‐identified as Black. In total, more than 30 reasons for acceptance and hesitation were identified. Willing to protect themselves, loved ones, and the community were identified as important reason to accept the vaccination by both groups. Recommendations from family members or healthcare professionals and wanting to go back to normal life were two of the most commonly repeated acceptance reason for people with YOD. Meanwhile, two of the most frequently mentioned acceptance reasons in carer groups were believing vaccination is the right thing to do and knowing the severity of COVID‐19.

Several causes of vaccine hesitancy were mentioned by both groups, including fear of vaccine side effects and hearing negative news about the vaccination. In addition, people with YOD, but not carers, also identified fear of needles and suspicion that vaccination would exacerbate dementia as important causes of vaccine hesitancy. Important difficulties experienced in the vaccination process included long queues for vaccination, remote vaccine centre locations, and needing to be accompanied to the hospital for each dose.

Conclusion

Participants delayed or refused COVID‐19 vaccination largely due to resolvable reasons such as a lack of time, issues around queuing, inaccurate information about vaccines, or previous negative experiences. Future research should explore the factors of COVID‐19 vaccination behaviour in women and in other ethnic groups.
Towards inclusive trial design for vascular cognitive impairment in the diverse context of India
Authors: Alladi Survana
Published: December 2023

Background

The burden of vascular contribution to cognitive impairment and dementia is substantially higher in low and middle‐income countries like India compared to the high‐income countries (HIC). Nearly 40% of 5.3 million people with dementia are estimated to be due to vascular aetiology. This high burden of vascular cognitive impairment (VCI) is due to a greater prevalence of vascular risk factors such as diabetes, hypertension and stroke as well as low awareness and a wide treatment gap. Lack of validated diagnostic instruments in various regional languages and availability brain imaging pose challenges to diagnosis of VCI. These factors pose unique challenges to reducing the burden of VCI in India. Novel clinical trials are being implemented to risk of progression of VCI, but these efforts are mainly restricted to HIC. The limited availability of evidence for effective treatment and preventive strategies in the context of diverse countries like India are major impediments to effective public health interventions to reduce burden.

Method

We present results from a large cohort of 2000 individuals from multiple centres across the country including individuals at high risk of developing VCI, patients with vascular mild cognitive impairment and vascular dementia. Languages spoken by patients included Kannada, Telugu, Hindi, Malayalam, Urdu, Bengali and English among others. A were illiterate and around 60% were bilingual.

Results

Harmonised cognitive and functional measures adapted to multiple Indian languages and educational variability were used to detect VCI in the diverse population. MRI imaging to detect vascular imaging biomarkers was performed to detect infarcts, cortical atrophy, microbleeds and white matter lesions, for accurate identification of vascular damage and neurodegeneration. Collaborations between multiple centres in a systematic manner are ongoing. Novel public health initiatives with support of policy makers are also being implemented to improve brain health by increasing awareness and reducing risk of stroke and dementia in the community.

Conclusions

These large‐scale efforts towards developing clinical‐trial readiness of VCI cohorts in the community across India will be crucial to fill research evidence gaps and implement clinical trials in India in concurrence with ongoing global efforts.
Attenuating DNA hypermethylation enhances insulin signaling and reduces apoptosis in an in vitro model of DLB
Authors: Lin Chih‐Li , Tsou Sing‐Hua , Huang Chien‐Ning , Chang Ching‐Chi , Ho Ying‐Jui
Published: December 2023

Background

Dementia with Lewy bodies (DLB) is the second most prevalent degenerative dementia after Alzheimer’s disease (AD). The cause of DLB is known to be associated with abnormal protein aggregations called Lewy bodies within affected neurons. Studies have shown that Lewy bodies are mainly composed of α‐synuclein. Normal α‐synuclein is a water‐soluble monomer. However, when triggered by certain factors, the folding of the protein changes, causing it to aggregate and accumulate inside neurons. Previously, we have demonstrated that amyloid β (Aβ) can promote α‐synuclein aggregation and neurotoxicity, which provides a molecular mechanism that reasonably explained the pathogenesis of DLB. A major risk factor for DLB is known to be aging, but its role in disease progression, especially with regard to epigenetic regulation, is still unclear.

Method

In this study, we investigated whether DNA hypermethylation, a common phenomenon in cellular aging, might be a factor in the progression of DLB. Through the in vitro experimental mode of DLB, we analyzed the content of α‐synuclein aggregations, the difference in cell viability and the activity changes of methylation‐related pathways in mouse HT‐22 neuronal cells.

Result

We found that the DLB neuronal cells display a significant tendency to undergo DNA hypermethylation, which inhibits stemness and reduces the content of neurotrophic factors. This makes it more difficult for neuronal cells to survive under stress. In addition, DLB neuronal cells also showed significant insulin resistance, which interferes with autophagic clearance, upregulates the senescence‐related pathways, and exacerbates the aggregation and accumulation of α‐synuclein.

Conclusion

DLB cells significantly increase the hypermethylation and thus inhibit insulin signaling, making the affected cells more vulnerable to neurotoxicity. Accordingly, the administration of epigenetic regulators by targeting neuronal DNA hypermethylation may lead to develop novel therapeutic strategies against DLB.
Increasing Cognitive Evaluations in Primary Care: Implementing the GSA KAER Model at a Large Healthcare System
Authors: Gaster Barak
Published: December 2023

There is widespread recognition that patients with Alzheimer’s disease and related dementias (ADRD) receive better care if they receive an earlier diagnosis. In 2022, the Alzheimer’s Association published a survey of primary care providers (PCPs) indicating that a large majority agree that making an early diagnosis of ADRD is important. However, more than half of PCPs said that they lack the knowledge and confidence to assist in making such a diagnosis.

Starting in 2021, the University of Washington launched the Cognition in Primary Care Program to meet that need. Developed with funding from the Centers for Disease Control and Prevention, as an adaptation of the Gerontological Society of America’s KAER Toolkit, the primary goals of the Cognition in Primary Care Program are to increase cognitive evaluations by PCPs and to increase the number of patients diagnosed with ADRD and mild cognitive impairment (MCI).

Using practical training modules for PCPs with concise, evidence‐based checklists embedded in the electronic health record (EHR), the program has now been widely adopted by PCPs in a wide variety of clinics serving diverse populations of patients. Evaluations by PCPs describe the program as being of high quality and relevant to their practice. Results on the General Practitioners’ Attitude and Confidence Scale for Dementia (GPACS‐D) six months after the intervention show confidence in evaluating cognition. In addition, the number of MoCA tests uploaded to the EHR increased from 2.7 per month to 5.8 per month, and there was high utilization of the EHR checklist tools. Preliminary data also show that the number of visits in which PCPs have billed a diagnosis of MCI increased from 7.5 per month to 14.4 per month.

The strengths of the Cognition in Primary Care Program include its emphasis on actions that PCPs can take to promote brain health and the implementation of innovative EHR tools which PCPs can use in their clinical practice. The Cognition in Primary Care Program is an effective model, shown to be acceptable to PCPs, easy to integrate into a large health system, and successful at increasing cognitive evaluations in the primary care setting.
Feasibility Testing of a Brief Memory Care Plan Tool
Authors: Gholizadeh Shadi , Harris Amy , Buell Kathryn M. , Popolizio Elizabeth M. , Muskat Jennifer Johnson , Smith Erica C. , Feldman Andrew J. , Citron Ken
Published: December 2023

Background

As interest shifts from a biomedical, task‐based approach to dementia care to a more person‐centered approach, understanding and adoption of behavioral, non‐pharmacological approaches to supporting people living with Alzheimer’s disease and other dementias (PwD) is increasing. Previous research has identified that the quality of the assessment and care plan is associated with the quality of care delivery and likelihood of a person‐centered approach. Home care agencies are an important but understudied source of nonmedical care for PwD. Having dementia‐specific tools to aid in the design and delivery of care can help support person‐centered care delivered by home care teams.

Method

A brief web‐based memory care plan tool targeting care goals, care challenges, and techniques was piloted in two offices in the United States with a sample of people living with dementia (N = 34) receiving professional home care services. Nine individuals in care management‐type positions overseeing the nonmedical home care completed the memory care supplements for existing clients over two weeks. The care managers also completed a survey about their experience with the tool.

Results

The tool was identified as acceptable and useful by the care managers. The three most common care goals identified were the following: providing cognitive engagement and stimulation, preventing challenging behavioral expressions, and reducing social isolation. The three most common challenges were the following: anosognosia, resistance to accepting care in the home or resistance toward the personal care approach, and communication challenges. An important functional aspect of the tool that was identified was the necessity of fillable free text options alongside structured responses to allow care managers to personalize goals, challenges, and techniques.

Conclusion

These findings support the feasibility of a brief web‐based tool that can be completed in under 10 minutes developed to identify key care goals, challenges, and associated techniques for people living with dementia. Given the feasibility and acceptability of incorporating this tool into the broader home care assessment, a methodologically robust trial should be considered to further explore the effectiveness and value of the tool on outcomes relevant to the PwD and care partner.
Vascular dysfunction as a potential link between infection and Alzheimer’s disease
Authors: Li Pengfei , Wu Yan , Halushka Perry , Liu Meng , Fan Hongkuan
Published: December 2023

Background

Microbial infections are a risk factor for Alzheimer’s disease (AD). Herpesvirus and Gram‐negative bacteria have been detected in brain tissue samples of AD patients, indicating an infectious etiology of AD (Lotz et al., Front. Cell. Neurosci., 2021; 15:691136). Multiple mechanisms that contribute to brain injury after infections including disruption of the blood‐brain barrier (BBB), neuro‐inflammation, brain hypoperfusion, and accumulation of amyloid‐β (Aβ) in the brain are also observed in AD patients. However, the host and pathogen factors contributing to breakdown of the BBB and mechanisms leading to neuro‐invasion of pathogens in AD remain to be investigated.

Method

The cecal ligation and puncture (CLP) model, which is a murine polymicrobial infection model, and 5xFAD transgenic mice were used to evaluate vascular dysfunction in infection and AD. Brain pericyte markers, pericyte/endothelial cell (EC) coverage, vascular leakage, and Aβ accumulation were determined in infection and AD models. In addition, brain pericytes were isolated from infection and AD models, and pericyte Fli‐1 levels were determined by Western blot. The effects of Fli‐1 on Aβ‐induced pericyte loss were assessed.

Result

We demonstrated that pericyte markers CD13 and PDGFRβ and Pericyte/EC coverage were significantly decreased in brain tissue at 24 hours post CLP. Similarly, greater pericyte loss was also observed in 5xFAD mice compared to WT mice. Pericyte loss is associated with vascular leakage, as evidenced by IgG infiltration into the brain tissue 24 hours after CLP. Soluble Aβ 40 levels in the hippocampus were increased at 30 days after CLP. IgG infiltration into the brain tissue and increases of Aβ 40 levels were also observed in 5xFAD mice at 6 months of age. To elucidate the underlying mechanism of pericyte loss in infection and AD, brain pericytes were isolated from CLP mice and 5xFAD mice. Our data demonstrated that pericyte Fli‐1 levels were significantly increased in CLP mice and 5xFAD mice, and suppression of Fli‐1 decreased Aβ‐induced pericyte loss.

Conclusion

These composite results indicate that Fli‐1 contributes to pericyte loss, vascular dysfunction, and Aβ deposition, and they suggest that upregulation of pericyte Fli‐1 may represent a potential link between infection and AD.
Association of microglial activation with Alzheimer’s pathologies, presynaptic loss, hippocampal atrophy, and cognitive decline
Authors: Lan Guoyu , Sun Pan , Cai Yue , Li Anqi , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Loss of function of triggering receptor expressed on myeloid cells 2 (TREM2) and progranulin (PGRN), predominantly expressed by microglia in the brain, contribute to the development of Alzheimer’s disease (AD). Although animal studies suggest that the expressions of TREM2 and PGRN increase in activated microglia, their associations with AD‐related pathologies and subsequent outcomes are not well characterized. This study aimed to explore how cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) and PGRN relate to β‐amyloid (Aβ), tau, synaptic loss, neurodegeneration, and cognitive decline.

Method

We identified 610 ADNI participants with Aβ PET and CSF biomarkers measurements at baseline and 250 individuals with longitudinal CSF biomarkers measurements. All participants had concurrent longitudinal structure MRI and Preclinical Alzheimer’s Cognitive Composite (PACC) assessments. Using generalized linear models, we investigated the associations of CSF microglial biomarkers with Aβ PET, CSF p‐Tau181, CSF presynaptic biomarker growth‐associated protein‐43 (GAP‐43), hippocampal atrophy, and cognitive decline.

Result

CSF p‐Tau181 levels rather than Aβ PET were positively associated with CSF microglial biomarkers, whereas higher Aβ PET SUVRs were related to attenuated effects of CSF p‐Tau181 on changes in CSF sTREM2 and CSF PGRN (Figure. 1). Mediation analyses further showed that Aβ PET and CSF p‐Tau181 had opposing effects on CSF microglial biomarkers (Figure. 2). In addition, CSF sTREM2 rather than CSF PGRN were positively associated with CSF GAP‐43 cross‐sectionally and longitudinally, independent of Aβ PET and CSF p‐Tau181 (Figure. 3). Furthermore, augmented microglial activation was associated with slower rates of hippocampal atrophy (sTREM2: standard β (βstd) = 0.11, p = 0.007; PGRN: βstd = 0.11, p = 0.003), but only CSF sTREM2 was related to reduced rates of cognitive decline (βstd = 0.11, p = 0.003).

Conclusion

This study provides novel insights into the opposing microglial immune response to Aβ and tau pathologies, where elevated CSF p‐Tau181 rather than Aβ plaque is associated with microglial activation. TREM2‐dependent signaling may contribute to the microglia‐related presynaptic loss beyond Aβ and tau pathologies, and microglial activation is protective against hippocampal atrophy and cognitive decline. These findings are critical for understanding the roles of neuroinflammation in AD or other neurodegenerative diseases.
Immune modulatory therapeutics in AD ‐ can we find the Goldilocks zone?
Authors: Golde Todd E
Published: December 2023

Background

Immunoproteostasis is a term describing the relationship between the immune system, proteinopathies present in many neurodegenerative disorders, and brain cell dysfunction. The relevance of immunoproteostasis to Alzheimer’s disease (AD) is supported by genetic, pathological, and modeling studies. Long‐standing dogma argues that immune suppression might be beneficial disease modification in AD, has now been challenged by more recent empirical data. More generally, manipulation of the immune activation states regardless of “direction”, has potential for harm as well as benefit; thus, caution is warranted before testing novel immune therapies in humans.

Methods

I will present summary data from our own laboratory and collaborators and the broader published data to highlight the challenges of finding the Goldilocks zone for immune therapies in AD. I will also present new analysis arising from multi‐omic data generated in the accelerating medicine partnership consortium relating to immune activation states in mouse models of AD relevant pathologies and in humans as they develop AD.

Results

Empirical preclinical data demonstrate that the balance of positive (e.g., amyloid reduction, synaptic integrity) and negative effects (e.g., excessive synaptic pruning, overt toxicities) of any immune manipulation may limit therapeutic benefit. Too often though preclinical studies are limited to a single time point and look at a very limited set of outcomes. Transcriptomic and proteomic studies demonstrate that innate immune responses during the development of pathology in mouse models may be quite disparate than what may occur in humans.

Conclusions

As a field we must grapple with whether we can identify immune manipulations that fall within a “Goldilocks zone”‐ where disease modification with minimal or no damage is achieved. We need both more stringent, less myopic, preclinical paradigms to evaluate potential immune therapies, and we also need better theragnostic tools to evaluate target engagement and disease modification by immune modulatory strategies in humans. Given the gaps in our knowledge regarding immune manipulations and broader impacts of these on brain function as well as the potential for any immune manipulation to have impacts that fall out of the Goldilocks zone and do more harm than good, a cautious more rigorous, data driven approach is warranted.
Conducting clinical research and embedding person‐centred care into the hospital setting during a global pandemic: Challenges and solutions
Authors: Burley Claire V , Williams Anna M , Chenoweth Lynnette
Published: December 2023

Conducting scientific research in the healthcare context is an ongoing challenge. Immediate clinical care and related tasks take priority out of necessity, often in difficult circumstances including unplanned staff absenteeism and turnover, and resource limitations. These challenges are further exacerbated in times of crisis, such as the current worldwide pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The pandemic disproportionately affects vulnerable populations, such as people living with dementia who rely on aged and healthcare services. Concurrently research studies aiming to improve health and aged care for these people are also being negatively impacted by the pandemic. There is a need for the development of guidelines that will support researchers to implement and maintain quality studies during pandemics, to prevent unnecessary delay in the dissemination of research findings, that have the potential to improve healthcare delivery quality and outcomes.

This presentation first highlights the main challenges and solutions that have emerged in a study aiming to improve healthcare for people living with dementia in hospital settings, using evidence‐based person‐centred care. In addition to evaluating health outcomes for people living with dementia and cost‐effectiveness, we are using a knowledge translation framework (Goodenough et al., 2017; Damschroder et al., 2009) to evaluate the implementation of the intervention (process and outcomes) and determine nationwide scalability for hospital ward and care services. Evidence on how to adapt research processes to enable research programs to continue throughout the pandemic will be presented, followed by a set of guidelines to support researchers to engage successfully in clinical research during a pandemic. The guidelines aim to be generalisable to all clinical research projects that have been impacted by the current SARS‐CoV‐2 pandemic, as well as projects that may face future similar crises.

References

Damschroder LJ, Aron DC, Keith RE, et al. 2009. Fostering implementation of health research findings into practice: A consolidated framework for advancing implementation science. Implement Sci. 4(50):15 ‐20.

Goodenough B, Young M. (2017). Innovation to Implementation for Dementia (i2i4dementia): A Practical Guide to Knowledge Translation in Health Care (with examples from aged care and dementia). Dementia Collaborative Research Centres, Australia. Access: DementiaKT.com.au
Modifiable Factors Associated with Mortality among the Oldest Old with Cognitive Impairment: A Longitudinal Study in China
Authors: Li Bingyu
Published: December 2023

Background

The oldest old (aged above 80 years) have the highest death rate, and CI (Cognitive Impairment) significantly increases risk of mortality. Studies investigating mortality associated with dementia mostly identified non‐modifiable factors, providing limited practical implications. This study aims to investigating factors associated with mortality among the oldest old with dementia, with particular focus on modifiable factors.

Method

Our study included 6,997 older adults aged 80 years above who were diagnosed with CI. Data were from the Chinese Longitudinal Healthy Longevity Study (CLHLS). CI was measured by the Mini‐mental State Examination (MMSE). Cox proportional hazard regression combined with Least Absolute Shrinkage and Selection Operator (LASSO) was applied to select factors and evaluate their association with mortality of the oldest adults with CI.

Result

Of the 6,997 participants, 6,451 died with median survival time of 2.2 years. 21 out of the 56 variables were selected from the LASSO‐penalized Cox regression model. Consistent with previous studies, the hazard of mortality increases by 19% with every incremental 10 years of age (95% CI: 12‐27%). The hazard of morality among women was 23% lower than that of men (95% CI: 18%‐29%). History of diabetes also increases the hazard of mortality. In terms of modifiable factors, daily outdoor activities, daily watching TV or listening to the radio, being married, good chewing ability are associated with lower mortality, while smoking and high systolic blood pressure increases the risk of mortality in a dose‐response manner.

Conclusion

Several modifiable factors are associated with mortality among the oldest adults with CI. Analysis suggests that healthy diet, cognitive stimulating leisure activities, marriage, and good chewing ability may contribute to lowering the risk of mortality among this population.
Association between regular laxative use and incident dementia in UK Biobank participants
Authors: Sha Feng
Published: December 2023

Background

Use of OTC laxatives is common in the general population. The microbiome‐gut‐brain axis hypothesis suggests use of laxatives be associated with dementia. We aim to examine the association between regular use of laxatives and incidence of dementia.

Method

This prospective cohort study is based on 476,219 participants aged 40 to 69 years with no history of dementia. Regular use of laxatives is defined as self‐reported use in most days of the week for the last 4 weeks at baseline (2006‐2010). The outcomes are all‐cause dementia, Alzheimer’s disease and vascular dementia, identified from linked hospital admissions or death register (up to 2020).

Result

18,235 (3.6%) reported regular use of laxatives. Over a mean follow‐up of 9.8 years, 218 (1.3%) participants with regular use of laxatives and 1,969 (0.4%) with no regular use developed all‐cause dementia. Multivariable Cox regression models adjusting for sociodemographics, lifestyle factors, medical conditions and regular medication use showed that regular use of laxatives was associated with increased risk of all‐cause dementia (hazard ratio [HR] 1.51; 95% confidence interval 1.30‐1.75) and vascular dementia (HR 1.65; 1.21‐2.27), with no significant association observed for Alzheimer’s disease (HR 1.05; 0.79‐1.40). The risk of both all‐cause dementia and vascular dementia increased with the number of regularly used laxative types (P‐trend 0.001 and 0.04, respectively). Among the participants who clearly reported that they were using just one type of laxative (n = 5800), only those using osmotic laxatives showed a statistically significantly higher risk of all‐cause dementia (HR 1.64 [1.20‐2.24]) and vascular dementia (HR 1.97 [1.04‐3.75]). These results remained robust in various subgroup and sensitivity analyses.

Conclusion

Regular use of laxatives was associated with a higher risk of all‐cause dementia and vascular dementia, particularly in those who used multiple laxative types or osmotic laxative.
The effect of short Aβ(1‐38) peptides on cognitive decline and conversion to AD dementia: longitudinal data using the DELCODE cohort
Authors: Schneider Luisa Sophie , Freiesleben Silka Dawn , Wagner Michael , Priller Josef , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Jessen Frank , Duzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Schmid Matthias , Peters Oliver
Published: December 2023

Background

The current research consensus is that long Aβ(1‐42) peptides are neurotoxic pathological hallmarks of AD. Interestingly, short Aβ peptides, such as Aβ(1‐38), appear to be less neurotoxic and may counteract AD neuropathology. However, research on Aβ(1‐38) is scarce and their effect on AD pathophysiology in humans in vivo remains unclear. Here, we investigate whether higher relative concentrations of Aβ(1‐38) levels in the cerebrospinal fluid (CSF), compared to Aβ(1‐42) alone, with phospho Tau (pTau) or with both, protect against cognitive decline and risk of conversion to AD dementia.

Method

Participants with subjective cognitive decline (n = 56), mild cognitive impairment (n = 60) and AD dementia (n = 61) from the DELCODE study with a likely pathological Aβ42/P‐tau ratio of > 9.68 at baseline were included. Cognitive performance was assessed annually for five years with the Mini‐Mental State Examination (MMSE) and the Preclinical Alzheimer Cognitive Composite (i.e., PACC5), which was derived from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Conversion to AD dementia was assessed with the Clinical Dementia Rating (CDR) and NINCDS‐ARDA criteria. CSF was collected at baseline. Data was analysed using statistical model fitting procedures for linear mixed models, i.e., Likelihood Ratio (LR) testing. Additionally, we controlled for baseline diagnostic status and the relative effect of Aβ(1‐42) and pTau.

Result

Higher Aβ(1‐38) baseline levels were associated with better follow‐up performance on the PACC5 in all three groups across the AD continuum (p < .001). For the MMSE, only the MCI group showed significantly better follow‐up performance (p = .003), and a trend was found in the other groups (SCD: p = .090, AD p = .099). Furthermore, higher Aβ(1‐38) baseline levels decreased risk of conversion to AD dementia within three years by 88% (p = .003) in the SCD and MCI groups.

Conclusion

Across the AD spectrum, higher Aβ(1‐38) levels protect against cognitive decline and reduce the risk of conversion to AD dementia. This could inform individual risk prediction in memory clinic patients.
Kidney function and risk of incident dementia in 202,702 UK Biobank participants
Authors: Yeh Tian‐Shin , Clifton Lei , Collister Jennifer , Liu Xiaonan , Hunter David J , Littlejohns Thomas J
Published: December 2023

Background

Poorer kidney function could represent a novel modifiable risk factor for dementia, however previous findings are inconclusive. In the current study, we utilized a large population‐based cohort with long follow‐up to investigate whether glomerular filtration rate (GFR), an indicator of kidney function, and albuminuria, an indicator of kidney damage, were associated with an increased risk of all‐cause dementia.

Method

The sample consisted of 202,702 UK Biobank participants aged ≥60 years and free from dementia and end‐stage kidney disease at baseline between 2006‐2010. Estimated GFR was derived from serum creatinine and cystatin C (eGFRcr‐cys) and categorized as ≥90 (normal/high function), 60‐89 (mildly decreased function) and <60 ml/min/1.73m2 (moderately/severely decreased function). Albuminuria was defined using the urinary albumin to creatinine ratio (ACR). ACR was categorized into <3 (normal/mildly increased), 3‐30 (moderately increased), and >300 (severely increased) mg/mmol. Incident dementia was determined through cohort‐wide linkage to hospital and death records. The associations were assessed using Cox proportional‐hazard models adjusted for age, sex, ethnicity, socioeconomic status, education, household income, country, smoking status, alcohol intake, body mass index, hypertension, diabetes, and APOE‐ε4 allele status.

Result

Over 15 years of follow‐up, 6,042 participants developed incident dementia. The fully‐adjusted Hazard Ratios (HR) were 1.00 (95% Confidence Interval [CI] 0.94‐1.06) and 1.42 (95% CI 1.28‐1.58) for eGFRcr‐cys 60‐89 and <60 respectively, compared to ≥90 ml/min/1.73m2. Moderately/severely decreased eGFRcr‐cys remained associated with incident dementia after restricting to participants with more than 10 years of follow‐up (HR = 1.33, 95% CI 1.13‐1.56). The HRs for moderate and severely increased ACR were 1.16 (95% CI 1.07‐1.26) and 2.24 (95% CI 1.79‐2.80), respectively, compared to normal/mildly increased ACR (<3mg/mmol). Dose‐response associations were observed when combining eGFRcr‐cys and ACR, with those in the severest eGFRcr‐cys and ACR group having the greatest risk of dementia (HR = 4.70, 95% CI 2.34‐9.43).

Conclusion

Kidney dysfunction and albuminuria were associated with a higher risk of incident all‐cause dementia. These findings provide additional evidence that kidney dysfunction could be a potential modifiable risk factor for dementia or target for identifying those at high risk of the condition.
Neurofunctional Correlates of Activities of Daily Living in Patients with Posterior Cortical Atrophy
Authors: Chu Min , Lv Xuedan , Yang Caishui , Wu Liyong
Published: December 2023

Background

Research on posterior cortical atrophy (PCA) has concentrated on cognitive decline, especially visual processing deficits. However, few studies have focused on the activities of daily living (ADL), and no study has investigated the neurometabolic basis of ADL impairments. We aimed to identify regions of hypometabolism associated with ADL in PCA patients.

Method

Twenty‐nine PCA patients, 35 typical Alzheimer’s disease (tAD) patients, and 26 healthy volunteers were recruited. Each subject completed a scale for total ADL [TADL, including basic ADL (BADL) and instrumental ADL (IADL) subscales] and 18F fluorodeoxyglucose positron emission tomography. Voxel‐wise multivariable regression analysis was conducted at the level of the whole‐brain, PCA‐related hypometabolism patterns, and PCA‐specific hypometabolism patterns.

Result

The general cognitive status of PCA patients was similar to tAD patients; however, they performed worse in TADL, BADL, and IADL. In all analysis levels, TADL was associated with the bilateral parietal lobe, including the right superior parietal lobe, right inferior parietal cortex, right angular gyrus, and left superior parietal lobe. BADL was associated with the bilateral parietal lobe located in the right superior parietal lobe, right inferior parietal cortex, and left superior parietal lobe. IADL was associated with the bilateral superior parietal lobe. Bilateral superior parietal lobe hypometabolism was associated with TADL, BADL, and IADL.

Conclusion

Hypo‐metabolism in the bilateral superior parietal lobes contributes to the decline of ADL in PCA, which is a promising target for future non‐invasive neuromodulation interventions.
Altered anterior insular metabolic connectivity in asymptomatic MAPT P301L carriers
Authors: Chu Min , Nie Binbin , Jiang Deming , Wu Liyong
Published: December 2023

Background

The insula is the predominant brain region impaired in behavior variant frontotemporal dementia (bvFTD). However, structural and functional changes in the sub‐insula in the asymptomatic stage of bvFTD are unknown. The aim of this study is to describe structural and functional changes in insular subregions in asymptomatic carriers of the P301L mutation of the microtubule‐associated protein tau (MAPT) gene and patients with bvFTD.

Method

Six asymptomatic MAPT P301L mutation carriers and 12 MAPT negative control subjects of the same pedigree were enrolled, along with 30 patients with a clinical diagnosis of bvFTD and 30 matched controls. All subjects underwent hybrid positron emission tomography/magnetic resonance imaging. Atlas‐based parcellation using a fine‐grained Brainnetome Atlas was conducted to assess gray matter (GM) volume, metabolism, and metabolic connectivity in the sub‐insula (region of interest).

Result

There was no significant GM atrophy or hypometabolism in insula subregions in asymptomatic MAPT P301L carriers, although decreased metabolic connectivity between vIa‐middle temporal gyrus, vIa‐temporal poles, dIa‐middle temporal gyrus and dIa‐temporal poles; and increased connectivity between vIa‐orbitofrontal, vIa‐dorsal lateral superior frontal gyrus, and dIa‐orbitofrontal and dIa‐dorsal lateral superior frontal gyrus were observed. Patients with bvFTD had significant atrophy and hypometabolism in all insula subregions and decreased metabolic connectivity in the whole brain, including vIa/dIa‐middle temporal and vIa/dIa‐temporal poles. The standardized uptake value ratios of vIa and dIa were negatively associated with behavioral disinhibition scale scores.

Conclusion

Metabolic connectivity is altered in vIa and dIa subregions of the sub‐insula in MAPT P301L mutation carriers before the occurrence of atrophy, hypometabolism, and clinical symptoms.
Increase in Matrix Metaloproteinase‐10 is associated with tau, neurodegeneration and reduced brain perfusion in the right temporal lobe
Authors: Michopoulou Sofia , Prosser Angus , Dickson John , Guy Matt J , Teeling Jessica , Kipps Christopher
Published: December 2023

Background

Blood brain barrier dysfunction amplifies neuroinflammation, which may drive Alzheimer’s Dementia (AD) pathology. Regional cerebral blood flow (RCBF), measured by HMPAO SPECT, is an established biomarker for AD diagnosis. Matrix Metalloproteinase‐10 (MMP‐10), an enzyme involved in blood brain barrier function through regulating the breakdown of extracellular matrix, was recently proposed as a biomarker of progression to AD. In this study, we examine the relationship between RCBF and levels of MMP‐10 in the cerebrospinal fluid (CSF).

Materials and Methods

Datasets of 91 participants from a heterogenous clinical cohort, investigated for dementia due to cognitive complaints were analysed. CSF levels of MMP‐10 were measured using the OLINK proximity extension array platform. HMPAO SPECT scans were analysed using Statistical Parametric Mapping (SPM). A univariate linear regression model was used in SPM to quantify the impact of MMP‐10 changes on brain perfusion.

Results

SPM results showed that higher levels of MMP‐10 in CSF are associated with significant reduction in RCBF (family‐wise error corrected p<0.05). The neuroimaging signature of changes in RCBF with increasing MMP‐10 is outlined in Figure 1. The main cluster of reduction in perfusion is on the right temporal lobe with an additional cluster on the right medial frontal lobe.

Conclusion

Increased levels of MMP‐10 in CSF have been associated with blood brain barrier vulnerability and faster cognitive decline in AD. Here we identified a right sided neuroimaging signature in RCBF with increasing levels MMP‐10. This may indicate that by the time of symptoms onset the right side is the fastest progressing as it is catching up with the left side. Right sided changes have been previously associated with delusions, disinhibition and irritability in AD and linked with increased carer burden. The significant reduction in RCBF of the right temporal lobe identified in our study, further reinforces a role for MMP‐10 as a marker of progression to AD.

Acknowledgement: Dr Sofia Michopoulou, is funded through an Integrated Clinical Academic Lectureship by Health Education England (HEE) / NIHR for this research project (NIHR301287). The views expressed in this publication are those of the authors.