bluuebunny/crossref_metadata_2025 huggingface dataset:
Asiatic improves brain mitochondrial function, activates antioxidant response and attenuates cognitive deficits in beta amyloid overexpressing mice
Authors: Gray Nora E , Chamberlin Steven R , Bui Lillie E , Brandes Mikah S , Brumbach Barbara H , Quinn Joseph F
Published: June 2023

Background

The plant Centella asiatica can enhance mitochondrial function, promote antioxidant activity and improve cognitive deficits in mouse models of aging and Alzheimer’s disease. Asiatic acid (AA) is one of the constituent triterpene compounds present in the plant. In this study we explore the effects of increasing concentrations of AA on mitochondrial function and antioxidant response in healthy mice and investigate whether high doses of AA can elicit beneficial effects on mitochondrial function, antioxidant response and cognitive function in the 5xFAD mouse model of beta‐amyloid accumulation.

Methods

Nine month old female CF1 mice were treated with 0, 5mg, 50mg or 1000 mg of AA per 1kg of AIN‐93M diet for four weeks. Toxicity was also monitored. Hippocampal mitochondrial bioenergetics and the expression of mitochondrial and antioxidant response genes was determined. Results were compared to animals treated with 1000mg/kg of a water extract of Centella asiatica (CAW) incorporated into their diet. Additionally, six month old male and female 5xFAD mice were treated with 0 or 1000 mg/kg AA in their diet for four weeks. In the third week mice underwent cognitive testing. Hippocampal mitochondrial bioenergetics and expression of synaptic, mitochondrial and antioxidant response genes was assessed.

Results

In the healthy mice increasing concentrations of AA resulted in a dose dependent increase in basal and maximal mitochondrial respiration, mitochondrial gene expression and antioxidant gene expression. Results from the 1000mg/kg AA dose were similar to what was observed with CAW. No evidence of toxicity was observed at any concentration of AA. In the 5xFAD mice 1000mg/kg AA attenuated deficits in cognitive and mitochondrial function and induced the expression of antioxidant genes. Interestingly, there was not a consistent effect of AA on mitochondrial or synaptic gene expression.

Conclusion

These data show that high concentrations of AA can improve mitochondrial function and antioxidant response in the brains of treated animals. Consistent with the fact that mitochondrial dysfunction and oxidative stress are known to contribute to cognitive impairments this improvement was accompanied by improved cognitive function in the 5xFAD mice. Taken together these results suggest that AA is a promising cognitive enhancing therapy to develop for use in AD.
Brain regions with higher noradrenergic innervation show greater vulnerability to degeneration in preclinicial Alzheimer’s disease
Authors: Haag Lena , Lancini Elisa , Ziegler Gabriel , Yakupov Renat , Heneka Michael T. , Wagner Michael , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Fliessbach Klaus , Jessen Frank , Duzel Emrah , Betts Matthew , Hämmerer Dorothea
Published: June 2023

Background

The noradrenergic (NA) system comprises several cortical and subcortical brain areas with differential densities of NA transporters and receptors. A decline in the NA system, together with additional risk factors such as ApoE4‐status, gender, age, vascular changes and years of education may contribute to the development of Alzheimer’s disease (AD). The aim of this study was to examine whether brain areas known to be rich in NA receptors and transporters are particularly vulnerable to degeneration in preclinical AD.

Method

We examined interindividual differences in volumes of specific brain areas grouped into high and low NA density regions (NA‐high/NA‐low) for healthy controls (HC) and AD relatives (n = 122), individuals with subjective cognitive decline (SCD) (n = 152) and mild cognitive impairment (MCI) (n = 78). Structural equation modeling (SEM) was used to simultaneously examine associations between NA‐high and NA‐low regions across clinical groups. We investigated whether brain volumes in NA‐high and NA‐low areas were differentially related to known AD risk factors (ApoE4 status, CSF amyloid‐ß (Aß) 42/40 and phosphorylated tau (pTau)), and whether these links differed in HC, SCD and MCI.

Result

Estimating a two‐factor model with NA‐high and NA‐low revealed a better model fit than estimating one general factor. ApoE4‐carriers were associated with a lower ratio of Aß42/40 (‐0.472***) and a higher level of pTau (0.263***). In the whole sample, a low ratio of Aß42/40 was associated with lower brain volume in NA‐high (0.157***), but not NA‐low areas. pTau showed no significant association to NA‐high or NA‐low areas.

The group analysis revealed an increasing association between ApoE4, pTau and Aß42/40 in HC, SCD and MCI. An association between Aß42/40 and NA‐high areas was observed in all groups, whilst for an additional positive association to NA‐low in HC (0.125*), but negative association in SCD (‐0.184*). Finally, the negative association between pTau and Aß42/40 is true for SCD and MCI, but not for HC.

Conclusion

SEM can be used to separate brain regions into NA‐high and NA‐low areas. Higher risk status Aß42/40 is linked to lower brain volume in high NA density areas, suggesting a particular vulnerability of brain areas likely more affected by NA decline in AD.
Relation of modifiable lifestyle and mood factors to subjective cognitive concerns among participants and their study partners in the A4 screen data
Authors: Reynolds Gretchen , Buckley Rachel F. , Papp Kathryn V. , Schultz Stephanie A. , Rentz Dorene M. , Sperling Reisa A. , Amariglio Rebecca E.
Published: June 2023

Background

Subjective cognitive decline (SCD) is associated with future cognitive decline, elevated amyloid levels, and non‐specific variables, including mood. Participants often endorse higher cognitive concerns than their study partners (SPs), raising the possibility that participant complaints reflect multiple factors, including mood, lifestyle variables, and amyloid status. To determine the predictive value of modifiable factors, we examined the relation between SCD, lifestyle habits, amyloid, and mood among cognitively unimpaired older adults from a multi‐site secondary prevention trial (A4 screen data).

Method

Participants were 6943 individuals from A4 assessed pre‐randomization [mean(SD): age = 71.6(4.9), education = 16.4(3.0); 58% women, 95% non‐Hispanic or Latino, 90% white)]. Using descriptive analyses and linear regression models, we examined whether amyloid status (amyloid+: n = 1329/4492) and self‐reported mood (Geriatric Depression Scale [GDS]) or lifestyle habits (exercise, sleep) predicted subjective cognitive concerns (CFI; participant‐ and SP‐reported).

Result

Participants endorsed healthy lifestyle habits (mean hours of aerobic exercise/week = 2.9; mean hours of sleep/night = 7.1), minimal mood symptoms (mean GDS = 1.1), and higher cognitive concerns than SPs (t(5996) = ‐25.08, p<.001). Lower mood (t = 29.49, p<.001), older age (t = 5.75, p<.001), and lower education (t = ‐3.92, p<.001) predicted participant concerns on the CFI, with additive predictive value of lower self‐reported exercise (t = ‐2.90, p = .004) and sleep duration (t = ‐2.12, p = .035); however, only lower participant‐reported mood (t = 12.90, p<.001) and older participant age (t = 6.54, p<.001) predicted SP concerns. Adding amyloid to the model in a subset, all predictors for participant concerns remained except sleep, while only amyloid status (t = 4.59, p<.001), lower mood (t = 11.53, p<.001), and older age (t = 4.72, p<.001) predicted SP concerns.

Conclusion

Cognitively unimpaired participants endorsed higher cognitive concerns on the CFI compared to their SPs. Participant concerns were associated with multiple predictors (age, education, mood, amyloid status, exercise, sleep), while SP concerns were only associated with age, mood, and amyloid status. Participants may be more aware of early changes and endorse concerns reflecting various factors, including personal lifestyle habits, while SP report may be more specific to cognitive changes due to age and amyloid burden. These findings expand understanding of how various factors (e.g., biomarkers, mood, lifestyle habits) may contribute differently to participant and SP cognitive concerns, which may inform research recruitment and clinical care.
Identification of novel genetic variants and biomarkers for cognitive decline in Alzheimer’s disease
Authors: Ali Muhammad , Wang Fengxian , Mafimoghaddam Samira , Euesden Jack , Robins Chloe , Pulford David J. , Cruchaga Carlos
Published: June 2023

Background

Alzheimer’s disease (AD) is a complex, multifactorial disease that is incurable in the aging population. The success of genome‐wide association studies (GWAS), as a cross sectional design, to identify novel genetic risk factors for AD in recent years is well known; however, case‐control studies are less likely to uncover genetic factors that influence other aspects of the disease, such as progression and onset.

Method

In order to identify common and rare genetic variants associated with rates of cognitive decline in AD, we aim at systematically analyzing the largest collection of longitudinal and GWAS data (N = 7,241), across non‐Hispanic white individuals from multicenter cohorts (Knight‐ADRC, ADNI, NACC, and GSK) with at least 1.5 years of follow up after being diagnosed with AD. We also aim at exploring if genetic risk factors, alone or interacting with other genetic factors, are associated rate of cognitive decline in patients with AD when aggregated together into a single Polygenic Risk Score (PRS). Furthermore, external proteomics data will be combined with the genetics data for Mendelian Randomization (MR) analyses in order to discover causal biomarkers for cognitive decline and AD risk.

Result

Preliminary results found a suggestive signal in chr21 (min P = 8.7e‐8) approaching close to the genome‐wide significance threshold. Moreover, some other suggestive signals were detected in chr2 (min P = 3.8e‐06) and chr1 (min P = 3.7e‐06) that warrant further investigation. Further results and key findings of the post‐GWAS analyses will be presented during the AAIC meeting.

Conclusion

We have leveraged these datasets to generate prediction models for rate of cognitive decline in AD. The identification of AD‐specific genetic variants and biomarkers will enable the characterization of appropriate therapeutic targets for slowing or halting the AD progression.
E2511, a novel small compound TrkA biased positive allosteric modulator, reinnervates cholinergic neuron and activates cholinergic functions in non‐clinical studies
Authors: Tomioka Takeyasu , Hiramatsu Naoki , Moriyama Yoshiyuki , Kosasa Takashi
Published: June 2023

Background

Cholinergic innervation is particularly vulnerable in many neurodegenerative diseases associated with cognitive dysfunction, and loss of cholinergic neurons in Alzheimer’s disease (AD) is pathogenic event observed from early stage correlated with cognitive impairment. Nerve growth factor (NGF) plays a major role in the maintenance and function of cholinergic neurons, and a decrease in trophic signalling by NGF‐Tropomyosin receptor kinase A (TrkA) contributes to cholinergic neurodegeneration and cognitive decline during the course of AD. The activation of NGF‐induced trophic signal could be a promising therapy for the neurodegenerative diseases including AD, reinnervating and maintaining cholinergic neurons to functional status. E2511 was identified as a novel small compound TrkA biased positive allosteric modulator that can enhance specific trophic signal of NGF signal without induction of NGF‐like adverse effect via direct binding to TrkA in primary neuron culture and animal model. We present evidence that E2511 induced functional restoration of cholinergic neuron in animal model and rats.

Method

The trophic effect of E2511 on cholinergic neurons was assessed by biochemical studies such as western blotting and immunohistochemistry in human Tau P301S transgenic mice (Tau tg mice) following once‐daily oral administrations of E2511 for 3 months. E2511 TrkA downstream trophic effects on acetylcholine (ACh) were evaluated in cerebrospinal fluid (CSF) collected from cisterna magna in normal SD rats treated with once‐daily oral E2511 for 14 days, using an original LCMS method.

Result

Chronic administration of E2511 demonstrated reinnervative effects on cholinergic presynapses as well as a correlation with improvement of the number of cholinergic neurons in Tau tg mice. In SD rats, CSF ACh increased in a dose‐dependent manner at exposures associated with cholinergic reinnervation, with changes also correlating with increases in choline acetyltransferase mRNA level. These results suggest that CSF ACh may be a useful marker to establish the E2511 effective dose in humans.

Conclusion

E2511 functionally reinnervates cholinergic neuronal network in the Tau tg mice. CSF ACh increased in a dose‐related manner in SD rats. CSF ACh may be used as a pharmacodynamic marker to establish the dose showing the reinnervative effect of E2511 in clinical studies.
Donanemab exposure‐efficacy relationship in patients with early symptomatic Alzheimer’s disease
Authors: Gueorguieva Ivelina , Chua Laiyi , Chow Kay Hoong , Ernest C Steven , Willis Brian A. , Shcherbinin Sergey , Sims John R. , Chigutsa Emmanuel
Published: June 2023

Background

Donanemab is an IgG1 antibody targeting N3pG (a modified beta amyloid present solely in brain plaques). A population pharmacokinetic/amyloid positron emission tomography (PET) imaging model described donanemab’s effect on amyloid plaque measurements and associated treatment‐effect with maintaining median (95%CI) threshold concentration of 4.43 (0.96 to 10.4 mg/mL). The extent to which exposure exceeded this threshold did not influence degree of amyloid removal. The current analysis aimed to quantify treatment effect on change in clinical decline (integrated AD Rating Scale, iADRS); evaluate the relationship of donanemab‐mediated changes in amyloid plaque on iADRS; and evaluate patient factors potentially affecting response to donanemab treatment.

Method

Analyses included patients with early symptomatic Alzheimer’s disease (AD, including prodromal AD and mild AD dementia) randomized to donanemab monotherapy versus placebo in a phase 2 study (TRAILBLAZER‐ALZ; N = 256; NCT03367403). Exposure‐response modeling employed a non‐linear mixed effects modeling approach. The treatment‐efficacy model utilized a Richard’s logistic function to fit the time course of all available iADRS data and characterize clinical decline. The impact of absolute or relative change from baseline in amyloid PET measurements (centiloids) was evaluated as a predictor of clinical decline.

Result

Disease progression model‐based analyses showed donanemab significantly reduced rate of clinical decline by 28% in the overall population and 42% in APOE ε4 carriers (iADRS, p<.001 for both). No clear treatment‐effect was identified in the smaller APOE ε4 noncarrier population (27% of study participants). Overall, serum concentrations of donanemab were not correlated with clinical decline. Antidrug antibody titer did not affect donanemab’s efficacy. Model simulations showed patients would benefit from donanemab treatment regardless of baseline disease severity, and patients with worse iADRS score at baseline had a greater absolute drug effect (difference between donanemab and placebo at 76 weeks). APOE ε4 carriers who had a 100% decrease in amyloid level from baseline with donanemab treatment are predicted to achieve, on average, a 43.5% slowing of clinical decline rate versus placebo‐treated patients (Figure).

Conclusion

Findings show donanemab treatment would benefit patients regardless of baseline disease severity. Both exposure‐efficacy and amyloid plaque biomarker models showed donanemab reduces rate of clinical decline and produces better patient outcomes than placebo.
Linguistic markers of Alzheimer’s in Spanish speakers: Automated metrics for free speech and verbal fluency tasks
Authors: Garcia Adolfo M
Published: June 2023

Background

Automated speech analysis can reveal objective, scalable markers of Alzheimer’s disease (AD). Yet, few studies have targeted Spanish, the most spoken language in Latin America, where AD is quickly escalating. Also, most research presents low interpretability, targeting linguistic features unrelated to the disorder’s core neuropsychological profile. Working with Hispanics, we have validated novel automated metrics capturing critical lexico‐semantic targets for AD: semantic granularity (coarseness of concepts) and ongoing semantic variability (conceptual closeness of successive words) –Figure 1A. I aim to describe and illustrate these metrics via two experiments comparing AD patients and healthy controls (HCs) on free speech and verbal fluency tasks. To test for specificity, replications were conducted in Parkinson’s disease (PD) and behavioral variant frontotemporal dementia cohorts.

Method

In Experiment‐1, 21 AD patients, 16 HCs, and 18 PD patients performed spontaneous and semi‐spontaneous speech tasks. In Experiment‐2, 32 AD patients, 27 HCs, 19 PD patients, and 32 bvFTD patients performed phonological and semantic fluency tasks. In both studies, responses were transcribed and lemmatized. Semantic granularity scores were computed on Python’s NLTK library to access WordNet, a lexical taxonomy leading from hypernyms (top node: ‘entity’) to hyponyms (e.g., ‘dog’). Each word’s granularity is defined as the distance between its node and ‘entity’ (Figure 1B). Ongoing semantic variability was analyzed with a FastText model pre‐trained with Spanish corpora. Each unique word in the vocabulary was assigned a vector, and the distance between words was quantified with the cosine of the angle between their assigned vectors (Figure 1C). Extracted features from both dimensions were analyzed through ANOVAs and XGBoost classifiers.

Results

In Experiment‐1, relative to HCs, AD (but not PD) patients used more unspecific and fewer specific concepts, alongside more discontinuous conceptual choices. These features robustly classified between AD patients and HCs, but not between PD patients and HCs. In Experiment‐2, only AD patients exhibited reduced semantic granularity, which contributed to robust subject‐level classification. Ongoing semantic variability failed to distinguish among groups.

Conclusion

These novel digital metrics can reveal objective, interpretable, and specific markers of AD in Spanish speakers, providing culture‐specific data for a vast but understudied linguistic community.
AT(N) Biomarker profiles and Alzheimer’s Disease clinical status and memory in adults with down syndrome
Authors: Hartley Sigan L , Tudorascu Dana L. , Lee Laise , Petersen Melissa , Cohen Ann D. , Klunk William E , Laymon Charles M , Zaman Shahid , Christian Bradley T. , Handen Benjamin L.
Published: June 2023

Background

Down syndrome (DS) is seen as a genetic form of Alzheimer’s disease (AD). The National Institute on Aging and the Alzheimer’s Association proposed the AT(N) model for classifying AD biomarkers of amyloid (A), tau (T), and neurodegeneration or neuronal injury ([N]) in non‐DS populations. It is not yet known how the AT(N) classification system maps onto AD pathology and symptomology in DS. The goals of the present study were to: 1) examine AT(N) profiles in DS based on PET amyloid‐beta (Aβ) (A), tau PET (T), and hippocampal volume ([N]); and 2) evaluate potential differences in clinical AD status and memory performance by AT(N) profile in DS.

Method

Analyses included 138 adults with DS (age: M = 39.1, SD = 8.0) enrolled in the Alzheimer’s Biomarker Consortium‐ Down Syndrome study. PET Aβ and tau were assessed using [11C]PiB and [18F]AV‐1451. Structural MRI data was used to index hippocampal volume and adjusted for intracranial volume. Thresholds for elevated (+ vs. ‐) A (Aβ CL >19), T (tau composite SUVr >1.21) and (N) (hippocampal volume < 1 SD from sample mean) were based on prior studies. Clinical AD status (cognitively stable, mild cognitive impairment [MCI‐DS], dementia, and unable to determine) were based on direct measures and caregiver‐report but blind to imaging and biofluid data. The Cued Recall Test was used to assess episodic memory.

Result

Overall, 66% of participants were A‐/T‐/(N)‐, 14% were A+/T‐/(N)‐, 9% were A+/T+/(N)‐, and 5% were A+/T+/(N)+. The remaining 6% had an alternative profile (e.g. A‐/T‐/(N)+). One‐way analyses of variance indicated a significant difference in age and clinical AD status by A/T/N profile. General linear models controlling for age and premorbid intellectual disability level indicated differences in memory by A/T/(N) profile.

Conclusion

This study adds to the understanding of AT(N) biomarker profiles in DS and their association with AD symptomology. Clinical AD status of MCI‐DS and dementia and worse memory performance were associated with elevated T and (N), in line with non‐DS populations. The unable to determine status paralleled the MCI and dementia status groups. Findings inform models that predict the transition to AD in DS.

aging after age 90.
Development and validation of a dementia risk index for use with administrative healthcare data in Canada
Authors: Chowdhury Mohammad Z I , Seitz Dallas , Jafari Behnaz
Published: June 2023

Background

Identification of individuals at high risk for dementia is important for planning health services and targeting prevention strategies. While dementia risk indices are available with clinical data, few have been created for use with population‐based administrative data in Canada. The purpose of this study was to establish a dementia risk index for people aged 50 years and older in Alberta, Canada, utilizing routinely gathered administrative healthcare databases. Using population‐based data, we can better understand the risk of dementia to identify individuals and populations at greatest risk.

Method

The study population included all individuals in Alberta, Canada, aged 50 years or older and free of diagnosed dementia on April 1, 2013. Participants were followed for up to 5 years to assess new diagnoses of dementia using a validated algorithm. A total of 59 known measurable dementia risk factors were assessed as potential predictors of dementia. At a 3:2 ratio, the sample was randomly divided into derivation and validation sets. The risk prediction model was created using a Cox proportional hazard model from a list of candidate variables in the derivation sample, and its performance to predict dementia was evaluated in the validation sample.

Result

One million participants aged 50 years and older without dementia were included in the study sample (mean age 62.95 years, 50.52% female), and 41,834 (3.86%) individuals developed dementia during follow‐up (mean duration 4.78 years). Out of 59 candidate variables, 17 variables were identified as independent risk factors for dementia, including advanced age, female gender, increased overall medical comorbidity, neighborhood measures of socioeconomic deprivation, specific medical conditions, mental health diagnoses, and measures of health service utilization. The final multivariate Cox proportional hazards model demonstrated good discriminative ability (Harrel’s C‐statistic = 0.87).

Conclusion

This risk prediction index, derived using population‐based data, can reliably identify Canadian adults at increased risk of dementia. This risk index may assist clinicians, and the general public in assessing their risks for dementia and facilitate discussions on the most effective ways to reduce this risk. Understanding individual or population‐based dementia risk differences can help design dementia prevention and health promotion programs.
Mild behavioral impairment as an indicator of early dementia neurodegeneration: Evidence from structural neuroimaging
Authors: Guan Dylan X. , Rehman Tanaeem , Nathan Santhosh , Durrani Romella , Smith Eric E. , Ismail Zahinoor
Published: June 2023

Background

Mild behavioral impairment (MBI) refers to the de novo emergence of persistent neuropsychiatric symptoms in older adults and has been associated with cognitive decline and incident dementia. The purpose of this study was to identify the structural neural correlates of MBI using a hypothesis‐driven region‐of‐interest (ROI) approach.

Method

The study cohort consisted of 744 participants (60.3% female; mean and SD of age = 71.0 ± 9.7 years; mean and SD of education: 15.8 ± 5.3 years) without dementia from the National Alzheimer’s Coordinating Centre dataset. Structural T1‐weighted images for each participant were processed and segmented using FreeSurfer and then normalized by age, sex, intracranial volume, scanner characteristics, and image quality to generate adjusted measures of grey matter volume (GMV) for each ROI. Our primary ROIs included five regions, each representing one Braak stage: entorhinal cortex (stage I), hippocampus (stage II), fusiform gyrus (stage III), inferior temporal cortex (stage IV), and frontal pole (stage V). We also included three hippocampal subfields (CA1, CA3, CA4) and four ROIs commonly associated with various psychiatric disorders (amygdala, insula, anterior cingulate, prefrontal cortex) as a secondary analysis. All ROIs are anatomically highlighted in Figure 1. Participants were classified as MBI+ if they presented with MBI symptoms derived from the Neuropsychiatric Inventory Questionnaire for two consecutive visits one year apart. Logistic regressions adjusting for cognitive diagnosis (cognitively normal, n = 568; mild cognitive impairment, n = 176) were used to model the relationship between ROI GMV (predictor) and MBI status (outcome).

Result

As shown in Table 1, lower GMV in early Braak stage ROIs (entorhinal cortex and hippocampus) was associated with MBI+ status. This trend was maintained for all hippocampal subfield ROIs. However, mid‐late Braak stage ROI (fusiform gyrus, inferior temporal cortex, frontal pole) GMVs were not associated with MBI status. For psychiatric disorder ROIs, lower GMV in only the amygdala was associated with MBI+ status.

Conclusion

Our findings demonstrate that the presence of MBI may implicate neurodegeneration in regions linked to early‐stage dementia. Furthermore, this explicitly identifies MBI as a neurodegenerative marker sharing few neuroanatomical correlates with psychiatric disorders, despite their clinical manifestations.

aging after age 90.
Alzheimer’s disease and other dementias in China: Secular trend in disease burden from 1990 to 2019 and projections to 2030
Authors: Geng Jiawei , Hesketh Therese
Published: June 2023

Background

Alzheimer’s disease and other dementias (ADOD) inflict substantial burden on the individual, family and society. China has the world’s highest number of people living with dementia, but the national‐level secular trends have not been well‐characterized.

Method

Drawing on data from the Global Burden of Disease Study 2019, we explored the burden of ADOD in China from 1990 to 2019, including its prevalence, incidence, mortality, years of lost (YLLs), years of life lived with disability (YLDs), disability adjusted life years (DALYs), and attributable specific risk factors. Temporal trends in disease burden were calculated by average annual percentage changes (AAPCs) using log‐linear regression in age‐standardized rates. We utilized Bayesian age‐period‐cohort models with integrated nested Laplace approximations to predict the age‐sex‐specific number of new cases and deaths from 2020 to 2030.

Result

The age‐standardized prevalence, incidence, deaths, YLLs, YLDs and DALYs for ADOD were 788.28, 103.83, 23.32, 254.42, 114.07 and 368.49 per 100,000 population in 2019 respectively, with increasing trends observed (AAPC [95% Confidence Interval]: 0.66% [0.57 to 0.75], 0.33% [0.27 to 0.40], 0.15% [0.07 to 0.23], 0.10% [0.01 to 0.20], 0.65% [0.56 to 0.75], and 0.26% [0.21 to 0.31]) during the past three decades. Although ADOD is more prevalent in females, AAPCs in all indicators were more pronounced in males. More dementia cases were attributable to smoking in males than in females. Proportions of DALYs attributable to high BMI increased over time in both sexes, and the cases attributable to high fasting glucose were comparable in both sexes. Incidence and mortality from ADOD are projected to be 2,967,059 and 527,960 cases in 2030, representing a 1.65‐fold increase.

Conclusion

Increasing incidence and mortality due to ADOD will continue in coming years due to population aging, although age‐standardized mortality rates showed a slight decrease. Further research on modifiable risk factors and targeted prevention strategies are warranted.
Investigating the Regulatory Role of PKR in Systemic Inflammation Triggered Neuroinflammation and its Role in Cholinergic Neurons in Modulating Cognitive Functions
Authors: Cheng Wai‐Yin , Ho Yuen‐Shan , Chang Raymond Chuen‐Chung
Published: June 2023

Background

Double‐stranded RNA‐dependent protein kinase (PKR) is a key signaling molecule that regulates immune responses by regulating macrophage activation, various inflammatory pathways, and the formation of inflammasomes. Meanwhile, PKR in neurons helps mediate stress responses of Aß to trigger apoptosis and affects cognitive functions. This study aims at investigating whether PKR can be a pharmacological target to prevent systemic inflammation‐triggered neuroinflammation and cognitive dysfunctions.

Method

The experimental model of laparotomy is adopted to address the systemic inflammation initiated by surgery. Male C57BL/6J and PKR‐KO mice were divided into two groups: control group under sevoflurane anesthesia and laparotomy group under sevoflurane anesthesia. Cytokine mRNA expression in tissues was examined by quantitative RT‐PCR. Behavioral tests were performed to examine the effects of laparotomy on cognitive functions. Furthermore, to examine the role of PKR in cholinergic neurons, stereotaxic injection of dominant negative AAV‐DIO‐PKR‐K296R into the right lateral ventricle of the Rosa‐ChAT‐IRES‐Cre mice was performed to inhibit PKR in cholinergic neurons.

Result

Our preliminary study showed that laparotomy induced systemic and neural inflammation in male C57BL/6J mice. At 4 h and one day after laparotomy, genetic knockout of PKR in mice potently downregulated the elevated IL‐1ß expression generated by laparotomy in both the liver and frontal brain. Additonally, cognitive impairment was observed in wild type mice following laparotomy in terms of the decline in problem‐solving abilities, impaired short‐term and long term memory in the puzzle box test; reduced recognition memory in the novel object recognition test; and impaired spatial working memory in the spontaneous Y‐maze; while for PKR‐KO mice, cognitive flexibility, short‐term and long term memory recognition memory remained intact after laparotomy. Furthermore, at 4 weeks after stereotaxic injection of AAV‐DIO‐PKR‐K296R, a significant reduction of p‐PKR level was observed in cholinergic neurons. It implies that the AAVcan inhibit the phosphorylation of PKR in cholinergic neurons.

Conclusion

This study reveals that genetic knockout of PKR in mice could attenuate laparotomy induced systemic inflammation, neuroinflammation, and cognitive impairment.Further studies will be performed to examine the effect of knockout of PKR in cholinergic neurons on cognitive functions.

Acknowledgement:The study is supported by General Research Fund (17123217) to RCCC.
Plasma Aβ42/Aβ40 and p‐tau181 are associated with clinical progression in amnestic mild cognitive impairment: An 8‐year longitudinal study
Authors: Xiao Zhenxu , Wu Wanqing , Ma Xiaoxi , Liang Xiaoniu , Zheng Li , Ding Saineng , Lei Qiqi , Chen Ke‐Liang , Zhao Qianhua , Ding Ding
Published: June 2023

Background

Previous studies indicated that blood‐based biomarkers could predict cognitive decline in Alzheimer’s disease (AD) continuum.

Method

Two hundred and fifty‐one participants with amnestic mild cognitive impairment (aMCI) from the Shanghai Memory Study were followed up for a maximum of 8 years. Baseline blood biomarkers were measured with the single‐molecule array (Simoa) platform. Multipoint clinical diagnosis and domain‐specific cognitive functions were assessed to investigate the longitudinal relationship between blood biomarkers and clinical AD progression.

Result

Participants with high‐risk plasma Aβ42/Aβ40 (A) and p‐tau181 (T) level demonstrated the highest probability of incident AD (HR 5.54, 95% CI 2.99‐10.27), and the most dramatic decline in global cognition, attention, executive function, visuospatial function, and language. Comparing to young‐old participants, the old‐old ones with low‐ and moderate‐risk AT showed higher AD risks (HR 3.70, 95% CI 1.16‐11.81; HR 3.15, 95% CI 1.37‐7.26), and faster cognitive deterioration.

Conclusion

The results supported the use of plasma Aβ42/Aβ40 and p‐tau181 as accessible and feasible indicators of AD progression and the long‐term cognitive deterioration, especially in patients with older age.
Codesign methods when developing a decision guide for eating and drinking problems among hospital patients with severe dementia
Authors: Anantapong Kanthee , Bruun Andrea , Walford Anne , Smith Christina , Manthorpe Jill , Sampson Elizabeth , Davies Nathan
Published: June 2023

Background

Decisions about eating and drinking for people with severe dementia in acute hospitals are often difficult. Using a codesign process, we developed a decision guide for family carers and hospital professionals to help everyone making these decisions.

Method

We conducted a systematic review and qualitative interviews with people with mild dementia, family carers and hospital professionals in the UK. We ran four online workshops with family carers and hospital professionals to codesign the decision guide. In parallel with the codesign workshops, a matrix approach was used to synthesise data from all studies, including the workshop data, and to develop a prototype of the decision guide. We refined the prototype through workshops and discussions among the research team and lay people. User testing evaluated the prototype, which finalised the decision guide.

Result

Most participants were aware of the limited benefits of artificial nutrition and hydration for people with severe dementia. However, participants often found conversations and decision‐making processes confusing and fragmented in hospitals. The codesign process highlighted the importance of meeting individuals’ needs and preferences. The decision guide aimed not only to help people reach evidence‐based decisions but also to support conversations and decision‐making processes. It was designed to clarify the decision‐making process, provide necessary information about eating and drinking interventions, and elicit the values/preferences of everyone involved. It emphasises person‐centred care, best‐interests decision‐making, and multidisciplinary team approaches. From the user‐testing, family carers and hospital professionals perceived the decision guide to be useful in starting conversations and helping with the decision‐making processes. The final version of the decision guide was widely disseminated and is being used in clinical practice.

Conclusion

The codesigned decision guide may facilitate conversations between family carers and hospital professionals and help them reach shared decisions that meet the needs and preferences of people with severe dementia. Further evaluation research of the decision guide is required to test its real‐world impacts.
Sex‐specific associations of dietary iron intake with incident dementia: A prospective cohort study
Authors: Pan Wenfei , Chen Hui , Ni Chunxiao , Zhu Jiayi , Zong Geng , Yuan Changzheng , Yang Min
Published: June 2023

Background

Iron has been associated with age‐related cognitive decline and dementia in middle aged and older adults. Nevertheless, as the major source of iron in the body, whether dietary iron intake is related to incident dementia remains poorly understood.

Method

A total of 191,694 dementia‐free participants (55.0% female; mean±SD age, 56.2 ± 7.9 years) from the UK Biobank who completed at least one 24h dietary recall at study baseline (2009‐2012) were followed to 2021 (mean = 9.5 years). Dietary iron intake was calculated using the 24h dietary recalls. Incident dementia was identified through hospital admissions and death registries. Cox proportional hazard models were used to assess the overall and sex‐specific associations of dietary iron intake with incident dementia. Participants with iron intake between the 20th and 80th percentiles were considered as reference group.

Result

During a total of 1,813,480 person‐years, a total of 918 (650 women and 268 men) participants developed dementia. When adjusted for sociodemographic, lifestyle, and other dietary factors, participants in the lowest quintile of iron intake were at significantly higher dementia risk (hazard ratios [HR], 1.40, 95% confidence interval [CI], 1.10‐1.78), while the highest quintile was not significantly related to incident dementia (HR, 1.22, 95% CI, 0.97‐1.55). We detected a significant sex difference in the relations of dietary iron intake to dementia (P‐interaction < 0.001). We observed a U‐shaped association between dietary iron intake and incident dementia in male participants (HRlow, 1.50, 95% CI, 1.09‐2.07; HRhigh, 1.40, 95% CI, 1.03‐1.91; P‐nonlinearity<0.001). Nevertheless, no significant correlation was seen in women, regardless of their menopause status.

Conclusion

Our study findings suggested a U‐curve relationship between dietary iron intake and risk of dementia among males, which may be related to the differences in direct iron metabolism between the sexes. Further research is warranted to confirm the findings and to investigate the underlying mechanisms of the observed gender differences.
Association of loss of occlusal support with 15‐year risk of dementia
Authors: Asher Sam , Suominen Anna Liisa , Stephen Ruth , Ngandu Tiia , Koskinen Seppo , Solomon Alina
Published: June 2023

Background

Recent studies link tooth loss with dementia, however, the mechanism that underlies this association is not known. One hypothesis attributes this association to loss of sensory stimulation from the masticatory apparatus. Since establishment of occlusal contacts between the opposing teeth enables functionality (e.g., mastication, etc.) as well as supports the facial structure by maintaining static occlusal contacts, hence, this study examines the effect of loss of occlusal support (number of occlusal pairs) on dementia risk.

Method

This study included 4013 dementia‐free participants (1880 males, 2133 females), aged 30‐93 years (mean 47.23 years) from Finnish Health 2000 survey. Tooth count and number of occlusal pairs (maximum 10 pairs) were recorded in oral clinical examination. Dementia diagnosis up till 2015 was retrieved from hospital discharge and causes of death registers. Cox regression models were generated to assess 15‐year dementia risk against loss of occlusal pairs. Association was adjusted for age, gender, years of education, cardiovascular risk, socioeconomic status, dietary index, depression, and overall tooth count. Analysis was further expanded by stratifying number of occlusal pairs into having ≥8 pairs, 4‐7 pairs, and ≤3 pairs. Sensitivity analysis was conducted for participants aged ≥55 years.

Result

137 participants developed dementia over 15 years. Fully adjusted model indicated 13% higher risk of dementia for each occlusal pair lost (Model 3). Further adjustment for overall tooth count increased dementia risk to 21% (Model 4). In stratified analysis, having ≤7 occlusal pairs carried significantly higher risk of dementia. This association appeared to be dose‐dependent, with having 4‐7 pairs carrying twice the dementia risk while having ≤3 pairs carrying almost three times the dementia risk in comparison to having ≥8 pairs. The findings were corroborated by sensitivity analysis for each occlusal pair lost. In stratified sensitivity analysis having ≤3 pairs was associated with higher risk of dementia but hazards ratio for having 4‐7 pairs failed to achieve statistical significance.

Conclusion

Preliminary results indicate that loss of occlusal support/number of occlusal pairs independently increases dementia risk. Further in‐depth studies assessing the impact of particular tooth types lost and the possible mechanisms are warranted.
Transferable structural, static and dynamic functional MRI features for predicting conversion from mild cognitive impairment to Alzheimer’s disease in Shanghai Memory Study and ADNI cohorts
Authors: Chen Zhihan , Chen Ke‐Liang , Li Yuxin , Geng Daoying , Li Xiantao , Liang Xiaoniu , Lu Huimeng , Ding Saineng , Xiao Zhenxu , Ma Xiaoxi , Zheng Li , Ding Ding , Zhao Qianhua , Yang Liqin
Published: June 2023

Background

Mild cognitive impairment (MCI) is a critical prodromal stage of Alzheimer’s disease (AD) with high risk of conversion. It is of great challenge to construct reliable biomarkers for predicting conversion from MCI to AD, while the underlying mechanism is still not fully explored. Inter‐dataset generalizability is a prerequisite for clinical use of biomarkers and always a shortage of neuroimaging‐based studies.

Method

In this study, we propose a novel framework by integrating structural MRI (sMRI) and both static and dynamic resting‐state functional MRI (fMRI) measurements to investigate the differences between MCI converters (MCI_C) and non‐converters (MCI_NC), and then utilized support vector machine (SVM) to construct the prediction models based on selected features. A total of 186 MCI patients with both MRI and three‐year outcome data were selected from two independent cohorts: Shanghai Memory Study (SMS) cohort for selection of MRI predictors and internal cross‐validation, and ADNI cohort for external validation on the generalizability of these MRI predictors.

Result

In comparison with MCI_NC, the MRI converters were mainly characterized by alterations of medial temporal lobe (MTL) with atrophy extending to lateral temporal and regional hyperactivity and instability, posterior parietal cortex (PPC) with atrophy and inter‐regional hypo‐connectivity and connectional instability, and occipital cortex with functional instability. All of the imaging‐based prediction models achieved an AUC above 0.7 and ACC above 70% in both SMS and ADNI cohorts. The combination of static and dynamic fMRI features resulted in overall good performance as relative to static or dynamic fMRI solely, supporting the contribution of dynamic features into the fMRI model. In both cohorts, the best imaging model was the multi‐modality MRI model which provided excellent performance with AUC above 0.85 and average ACC/sensitivity/specificity around 80%.

Conclusion

This inter‐cohort validation study provides a new insight into the mechanisms of MCI conversion and paves a way for eventual clinical use of MRI biomarkers.
Prevalence and progression of subjective cognitive decline among rural Chinese older adults: A Population‐based follow‐up study
Authors: Xu Shan , Ren Yifei , Liu Rui , Li Yuanjing , Hou Tingting , Wang Yongxiang , Wang Lidan , Cong Lin , Du Yifeng , Qiu Chengxuan
Published: June 2023

Background

Few studies have examined occurrence and progression of subjective cognitive decline (SCD) in rural China. We aimed to investigate the prevalence of SCD and explore factors associated with progression from SCD to cognitive impairment, no dementia (CIND) and Alzheimer’s disease (AD).

Method

This community‐based study included 2488 cognitively unimpaired participants (age ≥65 years; 55.18% women; and 39.87% illiterate) in the Shandong Yanggu Study of Aging and Dementia who were examined at baseline (2014‐2015), of these, 1843 were followed in 2018. Demographic, epidemiological, clinical, and neuropsychological data were collected following a structured questionnaire. SCD was defined based on the Chinese version of the self‐rated Ascertain Dementia 8‐item Questionnaire (AD8) score. CIND and AD were diagnosed following the international criteria. Data were analyzed with the multivariate logistic regression models.

Result

At baseline, 997 of the 2488 participants were defined to have SCD. The prevalence of SCD was 40.07%, and the prevalence was increased with age. Of the 1843 participants in the follow‐up examination in 2018, 189 were diagnosed with CIND and 58 with AD. Having SCD at baseline was significantly associated with the multi‐adjusted odds ratio (OR) of 1.55 (95% confidence interval = 1.14‐2.12) for incident CIND and 2.91 (1.56‐5.42) for incident AD. Of 745 participants with SCD at baseline, 97 progressed to CIND and 43 to AD during the average 3.79 years of follow‐up. Multivariable logistic regressions showed that the multi‐adjusted OR of incident CIND was 0.51 (0.26‐0.98) for high social support, whereas the multi‐adjusted OR of incident AD was 1.22 (1.14‐1.31) for older age (per 1‐year increment), 0.31 (0.11‐0.85) for high education, 2.77 (1.17‐6.57) for carrying the apolipoprotein E (APOE) ε4 allele, 0.29 (0.11‐0.75) for high social support, and 3.98 (1.37‐11.52) for mild depressive symptoms.

Conclusion

SCD affects over 40% of rural‐dwelling older adults in China who are free of cognitive impairment. Older people with SCD are more likely to develop CIND and AD. Older age, illiteracy, APOE ε4 allele, low social support, and depressive symptoms are associated with accelerated progression from SCD to CIND or AD.
Injurious falls before, during, and after dementia diagnosis: A population‐based study
Authors: Zhang Lulu , Wang Jiao , Dove Abigail , Yang Wenzhe , Li Xuerui , Qi Xiuying , Xu Weili
Published: June 2023

Background

Falls are common among older adults with dementia, but the timing of incident injurious falls at different stages of dementia diagnosis is unclear. We aimed to examine injurious falls before, during, and after dementia diagnosis to detect when the occurrence of falls starts to increase prior to dementia onset, when people with dementia are at highest risk of falls, and which factors are associated with falls among people with dementia.

Method

This study included 4874 participants aged ≥55, consisting of 2437 incident dementia cases detected in a dementia‐free cohort from the Swedish Twin Registry and 2437 1:1 matched (i.e., same birth year and sex) non‐demented controls from the cohort. Dementia diagnosis and date of onset were identified from the National Patient Registry (NPR) and the Swedish Cause of Death Register. Information on injurious falls, including date of occurrence and history of chronic disease, was obtained from the NPR. Data on demographics, lifestyle, and anthropometrics were collected through a self‐reported questionnaire. Data were analyzed using conditional Poisson regression and generalized estimating equation (GEE) models.

Result

In Poisson regression analysis, the adjusted incidence rates of injurious falls among dementia cases and controls were similar (around 3.65‐9.08 per 1,000 person‐years) in the 6‐10 years preceding dementia diagnosis. Compared to controls, the incidence of falls in dementia cases started to increase beginning 5 years prior to dementia diagnosis (incidence rate ratio [IRR] 1.50, 95% confidence interval [CI] 1.11‐2.03), reaching a peak (IRR 3.37, 95% CI 2.85–3.97) in the year of dementia diagnosis, and declining rapidly 3 years after dementia diagnosis (IRR 1.38, 95% CI 1.05–1.79). In multi‐adjusted GEE models, alcohol consumption, living alone, and stroke were significantly associated with incident falls among people with dementia.

Conclusion

Compared to dementia‐free people, those with dementia have a greater incidence of injurious falls that increases in the 5 years leading up to dementia diagnosis and peaks during the year of dementia diagnosis. Alcohol consumption, living alone, and stroke may predict falls among people with dementia. Our findings highlight the importance of a tailored preventive strategy against falls among people with dementia, especially in the diagnosis stage.