bluuebunny/crossref_metadata_2025 huggingface dataset:
The need for better dementia literacy: current public understanding and awareness of dementia symptoms, risk factors and subtypes
Authors: Savage Sharon A , Ashworth Rosalie
Published: June 2023

Background

Improving public knowledge of modifiable risk factors and presenting symptoms of dementia is vital to aid early diagnosis and treatment. Unfortunately studies across the world report low levels of public awareness, even for the most common type of dementia: Alzheimer’s disease. While many people associate dementia with memory loss, little attention has been given to measuring public knowledge of key symptoms in atypical or non‐Alzheimer’s dementia subtypes. This study aimed to determine public understanding of different forms of dementia and accuracy in knowledge regarding key symptoms and risk factors.

Method

A 10‐minute face‐to‐face survey of 311 adults (58% women), aged 18 to 89 years, was conducted in Exeter, UK in 2018. The majority (93%) of participants were White/European and well‐educated. A third had some experience caring for a person with dementia. Participants were asked to define dementia, name as many subtypes as possible, indicate which of the main dementia types they had heard of, and answer knowledge questions regarding dementia symptoms, risk factors and treatment options in both Alzheimer’s and frontotemporal dementias.

Result

Although two‐thirds of participants (68%) could state at least one key fact about dementia (usually memory loss), only 11% identified dementia as a neurological or brain disease that was degenerative. Almost all participants had heard of Alzheimer’s disease (98%), although only 43% spontaneously named this type. While 57% said they had heard of Vascular dementia, less than a quarter had ever heard of Fronotemporal dementia (23%) or Dementia with Lewy Bodies (17%). Accuracy of dementia knowledge was generally low, but greater for Alzheimer’s Disease (57% accuracy across questions) than for Frontotemporal dementia (27% accuracy across questions). Knowledge was poorest regarding risk factors. Having personally known or cared for someone with dementia and having higher education levels was associated with greater knowledge in Alzheimer’s Disease (all p < .05).

Conclusion

Overall, public knowledge of dementia remains suboptimal, but particularly so for non‐Alzheimer dementias. Improving public awareness of non‐memory symptoms and how to reduce risk of dementia will be an important step for future management of dementia.
Prediction of cognitive status and 5‐year survival for elderly with diabetes by using the Neurocognitive Frailty Index (NFI)
Authors: Pakzad Sarah , Bourque Paul , Fallah Nader , Saucier Daniel
Published: June 2023

Background

Type 2 diabetes mellitus has been shown to be associated to cognitive decline and an increased risk of mild cognitive impairment and dementia in elderly persons (Biessels et al., 2014). The aim of this research was to determine whether the Neurocognitive Frailty Index (NFI, Pakzad et al., 2017) could help to predict cognitive changes in elderly people with diabetes.

Method

Participants in this study were drawn from waves 1 (1991 to 1992) and 2 (1996 to 1997) of the Canadian Study of Health and Aging (CSHA) for prediction of 5‐year cognitive changes in those who received a consensus diagnosis of no cognitive impairment (NCI) or cognitive impairment but not dementia (CIND) in wave 1 (n = 997). The CIND category was contained to individuals whose level of cognitive impairment was measured to be greater than the NCI group but less than the dementia group. NFI was defined as a combined score of 41 physical and mental components (in 8 cognitive domains) as they were available in the dataset (NFI has 42 components but we withdraw diabetes). Cognitive score (measured by 3MS) at follow‐up, and mortality were outcome.

Result

Mean NFI and standard deviation was 9.7±6.22 in people without diabetes, 11.71±5.42 in people with diabetes and 9.36±5.30 in people with diabetes but are using treatment. Multiple linear regression indicated that NFI score is significantly associated to cognitive status (3MS at follow‐up, p<0.05), however, diabetes did not show any significant association to predict this outcome. CHAID decision tree analysis stratified NFI scores into five categories, while proportional hazards analysis adjusted for age, gender and education indicated that NFI was more correlated to survival than age and had a dose‐response effect in relation to survival. Those with diabetes had a higher probability of death compared to those without (p<0.05).

Conclusion

NFI was significantly associated with cognitive changes for the elderly in those with and without diabetes. Given that the NFI is proving to be a valuable tool to assess the risk of developing dementia, further investigation is needed to clarify which modifiable risk factors may help reduce the risk of cognitive decline.
Advanced machine learning approach to increase diagnostic accuracy in atypical Alzheimer’s disease cases
Authors: Temtam Ahmed , Cruz Erica J , Okhravi Hamid , Strock Daniel , Sternick Molly , Iftekharuddin Khan M
Published: June 2023

Background

The early diagnosis of Alzheimer’s disease (AD) and other types of dementia is essential in clinical practice. Up to 50% of patients with any form of dementia may remain undiagnosed during their lifetime and the diagnosis of AD may often be inaccurate. In assessing patients, accurate diagnosis based on only clinical data and structural (MRI or CT) imaging is suboptimal in a subset of patients with atypical presentation. Although amyloid PET imaging and CSF biomarkers can provide incremental benefits, numerous obstacles preclude their wider use in clinical practice. In this work, a parametric study was performed to create a machine learning (ML) model to accurately diagnose hard‐to‐detect cases of AD, to mitigate the need for more expensive or invasive testing such as amyloid imaging or spinal tap.

Method

Data from 173 participants (MCI and mild dementia), including 105 patients (60%) with AD and 68 (40%) Non‐AD patients, were included from our memory clinic. The dataset for each participant included pertinent history, AD risk factors, scores on a neuropsychological testing battery, functional status, and MRI volumetric studies. Participants were divided into two groups: Group I (easy‐to‐detect) with a high probability of AD diagnosis based on clinical data (subjective and objective amnestic presentation) and volumetric studies (hippocampal and medial temporal lobe atrophy). Group II (hard‐to‐detect), who did not fit into the first group and the diagnosis was confirmed with either amyloid imaging or CSF analysis. The distribution of diagnosis by group: 1‐ Easy to detect (43 AD, 29 Non‐AD),2‐ Hard to detect (62 AD, 39 Non‐AD), a total of three experiments with different combinations of groups were conducted, 1‐ All Groups (Exp.1.), 2‐ Hard to detect (Exp.2.), 3‐ Easy to detect (Exp.3.). In all experiments, Leave‐One‐Out cross‐validation technique was performed.

Result

A total number of 132 features utilized, by employing feature selection approach, 13 features were selected. Our model attains the highest accuracy of 87.27% on classification of Exp.1., 83.28% on Exp.2. and 95.80% on Exp.3.

Conclusion

We investigated discrimination of AD from Non‐AD on hard‐to‐detect cases using ML. The proposed method obtains competitive performance and achieves improved accuracy results.
Regulatory T cells decrease A1‐like C3‐positive reactive astrocytes in Alzheimer‐like pathology
Authors: Stym‐Popper Grégoire , Matta Karen , Chaigneau Thomas , Rupra Roshan , Fouquet Stéphane , Dansokho Cira , Toly‐Ndour Cecile , Dorothee Guillaume
Published: June 2023

Background

Increasing evidence support a key role of peripheral immune processes in the pathophysiology of Alzheimer’s disease (AD), highlighting an intricate interplay between brain resident glial cells and both innate and adaptive peripheral immune effectors. We previously showed that regulatory T cells (Tregs) have a beneficial impact on disease progression in AD‐like pathology, notably by modulating the microglial response associated with Ab deposits in a mouse model of amyloid pathology. Besides microglia, reactive astrocytes also play a critical role in neuroinflammatory processes associated with AD. Different phenotypes of reactive astrocytes have recently been characterized, including A1 neurotoxic and A2 neuroprotective subtypes. However, the precise impact of Tregs on astrocyte reactivity and phenotypes in AD still remains poorly defined.

Methods

We assessed the impact of Treg immunomodulation on astrocyte reactivity in a mouse model of AD‐like amyloid pathology. Using 3D imaging we carried out extensive morphological analyses of astrocytes following either depletion or amplification of Tregs. We further assessed the expression of several A1‐ and A2‐like markers by immunofluorescence and RT‐qPCR.

Results

Modulation of Tregs did not significantly impact the magnitude of global astrocyte reactivity in the brain nor in the close vicinity of cortical amyloid deposits. We did not observe changes in the number, morphology, or branching complexity of astrocytes according to immunomodulation of Tregs. However, early transient depletion of Tregs modulated the balance of reactive astrocyte subtypes, resulting in increased C3‐positive A1‐like phenotypes associated with amyloid deposits. Conversely, early depletion of Tregs decreased A2‐like phenotypes of reactive astrocytes associated with larger amyloid deposits. Intriguingly, modulation of Tregs also impacted the cerebral expression of several markers of A1‐like subsets in healthy mice.

Conclusions

Our study suggests that Tregs contribute to modulate and fine tune the balance of reactive astrocyte subtypes in AD‐like amyloid pathology, by dampening A1‐like astrocytes in favor of A2‐like phenotypes. This effect of Tregs may partly relate to their capacity at modulating steady state astrocyte reactivity and homeostasis. Our data further highlight the need for refined markers of astrocytes subsets and strategy of analysis for better deciphering the complexity of astrocyte reactivity in neurodegeneration.
Head‐to‐head comparison of plasma biomarkers across the AD continuum in an Australian population
Authors: Chatterjee Pratishtha , Pedrini Steve , Doecke James D , Thota Rohith N , Villemagne Victor L , Dore Vincent , Singh Abhay K , Wang Penghao , Rainey‐Smith Stephanie , Fowler Christopher J , Taddei Kevin , Sohrabi Hamid R , Molloy Mark P , Ames David , Maruff Paul , Rowe Christopher C. , Masters Colin L. , Martins Ralph N ,   the AIBL research Group
Published: June 2023

Background

Plasma amyloid‐β (Aβ) 1‐42/Aβ1‐40 ratio, phosphorylated‐tau181 (p‐tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NFL) are putative blood‐based biomarkers for Alzheimer’s disease (AD). However, head‐to‐head comparisons of the afore‐mentioned biomarkers across the AD continuum are lacking.

Method

Plasma Aβ1‐42, Aβ1‐40, p‐tau181, GFAP and NFL were measured using the Single Molecule Array platform and compared cross‐sectionally in models with and without AD risk factors (age, sex and APOE ε4 status) across the AD continuum in Aβ PET positive confirmed participants (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) and Aβ PET negative confirmed participants (CU Aβ‐, n = 81; MCI Aβ‐, n = 26) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Area under the receiver operating characteristic curves (AUCs) for predicting Aβ PET‐/+ status were compared using DeLong test. Associations between plasma biomarker levels at baseline and prospective cognitive decline (CDR‐SOB) and brain Aβ load were also assessed.

Result

Lower plasma Aβ1‐42/Aβ1‐40 ratio and higher p‐tau181 and GFAP were observed in preclinical AD (Aβ1‐42/Aβ1‐40 ratio: ∼19%; p‐tau181: ∼70%; GFAP: ∼52%), prodromal AD (Aβ1‐42/Aβ1‐40 ratio: ∼14%; p‐tau181: ∼69%; GFAP: ∼45%) and AD (Aβ1‐42/Aβ1‐40 ratio: ∼16%; p‐tau181: ∼91%; GFAP: ∼85%), and higher plasma NFL was observed in prodromal AD (∼27%) and AD (∼45%) (Figure 1). Based on the AUCs, p‐tau181 performed equivalent to or better than (≥) other biomarkers, in predicting Aβ PET‐/+ status across the AD continuum (p‐tau AUCs for CU Aβ‐ vs CU Aβ+ ∼81%/ MCI Aβ+ ∼86%/ AD ∼92%). A biomarker panel of Aβ1‐42/Aβ1‐40 ratio, p‐tau181 and GFAP performed ≥ the biomarkers alone in predicting Aβ PET‐/+ status across the AD continuum (biomarker panel AUCs for CU Aβ‐ vs CU Aβ+ 90%/ MCI Aβ+ 89%/ AD 96%). Higher p‐tau181 (β = 0.531, p = 3.18E‐08), GFAP (β = 0.530, p = 5.07E‐08) and NFL (β = 0.487, p = 4.76E‐06) were associated with cognitive decline prospectively and lower plasma Aβ1‐42/Aβ1‐40 ratio (β = ‐6.035, p = 1.56E‐04) and higher p‐tau181 (β = 2.823, p = 4.72E‐05) and GFAP (β = 2.075, p = 0.003) were associated with increased Aβ PET load prospectively.

Conclusion

These findings suggest that plasma biomarkers are altered across the AD continuum and are associated with cognitive decline and increased brain Aβ load prospectively.
Degradation of CNTNAP2 is mediated by both macroautophagy‐lysosome pathway and ubiquitin‐proteasome pathway
Authors: Zhang Qing , Sterling Keenan , Song Weihong
Published: June 2023

Background

Recent studies suggested Contactin‐associated protein‐like 2 (CNTNAP2) as a novel risk gene for Alzheimer’s disease (AD). Reduced expression levels of CNTNAP2 were found in the brains of AD patients. However, the mechanisms underlying CNTNAP2 protein degradation remain elusive.

Method

HEK and N2a cells transfected with human CNTNAP2 plasmid were treated with cycloheximide, lysosome inhibitors, and proteasome inhibitors. Immunoprecipitation was performed to study the interaction between CNTNAP2 and ubiquitin. Immunofluorescent staining was performed to investigate colocalization.

Result

Human CNTNAP2 protein has a half‐life of approximately 4 hours. CNTNAP2 protein has a glycosylated mature form on the cell membrane and an intracellular immature form. Mature CNTNAP2 was increased by lysosome inhibitors in a dose‐ and time‐dependent manner, while immature CNTNAP2 was increased by proteasome inhibitors dose‐ and time‐dependently. In addition, CNTNAP2 was co‐immunoprecipitated with ubiquitin and was increased by macroautophagy inhibitor 3‐MA. Immunofluorescent staining further showed the co‐localization of CNTNAP2 with ubiquitin and lysosome marker LAMP1.

Conclusion

Human CNTNAP2 is degraded via both lysosome and proteasome pathways. Dysregulation of lysosome and ubiquitin‐proteasome pathways have been implicated in AD. Therefore, the present degradation study of a risk gene may deepen the current understanding of AD pathogenesis.
Melody memory project: Increasing dementia awareness through traditional gamelan music
Authors: Setiadi Tania M , Kharismayekti Manik , Utomo Amalia Fonk , Wortmann Marc
Published: June 2023

Background

Gamelan, a traditional music ensemble has become the most popular traditional music played by Balinese people for decades, both as leisure and religious activities. Musical activity can enhance cognitive function. However, there are limited activities for retired musicians.

Aim

Alzheimer Indonesia Nederland Foundation (ALZI Ned) initiated the “Melody Memory Project” which aimed to increase the quality of life and dementia awareness of the retired Balinese elderly musician through gamelan practice.

Methods

A weekly gamelan practice was conducted at the Pinda village community center, Gianyar, Bali Indonesia. Each session is preceded with dementia awareness session (e.g. sharing the 10 early signs of Alzheimer’s, brain gym) by ALZI Ned volunteers. There were health screenings once every two weeks (i.e. blood pressure/ blood sugar check, hearing problem). Cognitive assessment was conducted using Mini Mental State Examination (MMSE) before and after 6 months.

Thirty participants (age 58‐77 yo) were registered in this program. From July to October 2021, 6 practice sessions (each for 2 hrs), 2 performances and 3 health screening sessions were conducted in cooperation with the local government authorities. Due to Covid‐19 local lockdown, the program has been halted and will resume in February 2022. This activity has recently been approved as part of the village program and further continuity will be supported by the government. We expect to obtain more data by the time of the conference.
Neurofilament L dynamics description in the model of tauopathy
Authors: Pchelintseva Polina , Karelina Tatiana
Published: June 2023

Background

Neurofilament proteins are important constituents of neuronal cytoskeleton along with microtubules. Increased concentration of neurofilament light protein in cerebrospinal fluid(CSF) and plasma is considered as a potential biomarker of axonal degeneration [1]. Together with tau, neurofilaments are contained in the neurofibrillary tangles (NFT), the biomarker of Alzheimer’s disease and other tauopathies [2]. The goal of this study was to develop a quantitative systems pharmacology (QSP) model to describe neurofilament dynamics during progression of tauopathies both in human patients and in transgenic P301L Tau mice.

Method

The quantitative model correctly describes the dynamics of neurofilament proteins during neurodegeneration processes, which include cytoskeletal degradation by calpain, proteasome, autophagy and caspase, formation of pathological aggregates, release of neurofilament proteins from degenerated axons to cerebrospinal fluid and plasma. These processes are dependent on pathological processes in tauopathy models, such as changes in protein degradation, axonal transport deficits, pathological hyperphosphorylated tau accumulation. To calibrate the model, the literature data on neurofilament concentration in brain, cerebrospinal fluid and plasma, phosphorylation and degradation level were used. Description of the processes is partially based on neuron homeostasis model developed earlier [3]. The model was validated on taupathy P301L transgenic mice, amyloid APP/PS1 mice and on Alzheimer’s disease patients’ data.

Result

The described model correctly predicts the increase of neurofilament light protein concentration in CSF and plasma both in P301L transgenic mice model of tauopathy and in human patients versus controls. Pathological changes of microtubule dynamics and cytoskeleton breakdown are also described. Model predicts the reduction of NfL concentration in CSF during potential tau targeting therapy in P301L transgenic mice and humans.

Conclusion

The developed model can be helpful in simulating potential effects of therapeutics used in neurodegeneration diseases treatment.
The association among plasma p‐tau181, cognitive progression and structural brain change in early Alzheimer’s disease
Authors: Lin Yung‐Shuan
Published: June 2023

Background

Plasma levels of phosphorylated tau 181 (p‐tau181) is one of the potential blood‐based biomarkers for the diagnosis of Alzheimer’s disease (AD). However, the association among plasma p‐tau181 and cognitive progression and structural brain change still needs to be investigated.

Method

AD and mild cognitive impairment (MCI) patients diagnosed with a multidisciplinary consensus meeting were recruited. Cognitive function was assessed at baseline and at annual follow‐ups. Plasma p‐tau181 levels at baseline were measured using Quanterix SIMOA kits. The regional cortical thickness and volumes of baseline brain MRI were measured using the FreeSurfer image analysis suite. T‐tests and multiple regression were used for analyses. FDR tests were performed for multiple comparisons.

Result

A total of 162 AD and 19 MCI patients were recruited (mean age = 77.4 ± 7.3 years, 42% male, 37% APOE ɛ4 carrier, and mean MMSE = 20 ± 5.4). There were 137 patients (75.7%) having at least two annual follow‐up and the mean follow‐up time was 2.1 ± 0.4 years. The baseline plasma p‐tau181 levels were correlated with the rates of MMSE decline per year (r = 0.284, p < 0.001). After adjusting for age, gender, education, APOE ɛ4 status and baseline MMSE, the baseline plasma p‐tau181 levels were still correlated with the yearly MMSE decline (β = 0.292, p = 0.001) and was able to predict MMSE decline>3 per year (OR = 4.03, 95% CI 1.47–11.05). There were 152 patients (135 AD and 17 MCI) with valid brain MRI. The cross‐sectional analyses with adjustments of age, gender, education and APOE ɛ4 status showed significant association between plasma p‐tau181 levels and left hippocampus volume (β = ‐0.205, p = 0.010), right hippocampus volume (β = ‐0.213, p = 0.009) and right middle temporal thickness (β = ‐0.292, p < 0.001).

Conclusion

Higher plasma p‐tau181 levels were associated with the faster rate of MMSE decline in AD and MCI patients as well as the decreased volume and cortical thickness of several AD‐specific brain areas. Our study suggested that the plasma p‐tau181 could be a potential biomarker for tracking cognitive decline and reflecting structural brain changes in AD and MCI patients.
Associations between modifiable and non‐modifiable risk factors and domain‐specific cognitive decline over a 17‐year period
Authors: Glans Isabelle , Nägga Katarina , Gustavsson Anna‐Märta , Stomrud Erik , Sonestedt Emily , Nilsson Peter M , Melander Olle , Hansson Oskar , Palmqvist Sebastian
Published: June 2023

Background

Modifiable risk factors account for 40% of worldwide dementias. However, to what extent different risk factors are associated with different types of cognitive decline remains unclear. The aim of this study was to investigate how different risk factors contribute to future decline in memory and attention/executive function, respectively.

Method

Baseline examination of individuals without dementia in the prospective Swedish population‐based Malmö Diet and Cancer Study (MDCS) took place in 1991‐1996. In 2007‐2012, a randomly selected subsample was invited to a re‐examination using cognitive assessments (the Mini‐Mental State Examination [MMSE], A Quick Test of cognitive speed (AQT) and, for a sub‐population, The Montreal Cognitive Assessment (MoCA). Participants with complete data on cognitive assessments, body measurements, education and APOE genotype were included in the study (n = 2,881; n = 720 with MoCA). Linear regression models were used to examine the modifiable risk factors (hypertension, body mass index [BMI], long‐term glucose levels [HbA1c], lipid levels, physical activity and alcohol consumption) and non‐modifiable risk factor (APOE‐genotype). Follow‐up outcomes were 1) AQT‐color/form (processing speed and executive function, higher scores indicating worse function), 2) delayed recall and orientation scores from MMSE (memory function), and 3) subscores from MoCA. All models were adjusted for age, sex, education and time between baseline and cognitive assessments.

Result

Median follow‐up time was 17.3 (inter‐quartile range [IQR] 2.2) years. APOE‐e4 and higher HbA1c levels were independently associated with worse future memory function in a multivariable model (Table 1). Mean arterial blood pressure, obesity, lower HDL‐C, and higher HbA1c levels were independently associated with worse future processing speed/executive function (Table 2). Higher alcohol consumption was associated better performance in executive function (Table 2). Similar results were found using corresponding MoCA subscores (delayed recall and orientation subscores; visuospatial/executive and attention subscores).

Conclusion

In this prospective, population‐based, 17‐years follow‐up study, cardiovascular risk factors in mid‐life were associated with future decline in processing speed and executive functions, while an APOE‐e4 genotype was associated with worse memory function. Alcohol consumption in mid‐life was associated with better performance in both cognitive domains. These results suggest that targeting cardiovascular risk factors in interventions may have a greater effect on future executive function than memory.
Should oral medication dose be adjusted in Alzheimer’s disease?
Authors: Pan Yijun , Sun Jiaqi , Jin Liang , Kagawa Yoshiteru , Owada Yuji , Nicolazzo Joseph
Published: June 2023

Background

Little is known about the absorption, distribution, metabolism and excretion (ADME) of both AD and non‐AD medicines currently used in people with AD. If drug disposition processes are altered in AD, individuals with AD may be at a greater risk of additional drug‐induced adverse effects, toxicity, or lack of effectiveness. Senescence Accelerated Mouse (SAMP8) is a naturally‐occurring mouse line that displays many characteristics identified in AD patients, and it is considered as a model of sporadic AD. The current study aims to assess if ADME is affected in SAMP8 mice.

Method

We utilized a proteomics approach to assess drug transporter and metabolising enzyme expression in the small intestine, liver, and kidney in SAMP8 mice. In addition, plasma concentrations of valsartan, digoxin, quetiapine (three model drugs selected based on proteome data) following oral administration in SAMP8 mice were assessed using LC‐MS. The morphological changes of small intestine, liver and kidney was evaluated using H&E staining. The intestine permeability to these drugs was studied using Ussing chamber.

Result

Following proteomic analysis, PCA plot indicated a clear separation between SAMP8 and SAMR1 intestine, liver and kidney tissue, with global functional analysis indicated altered drug metabolism in the small intestine and liver of SAMP8 mice. The oral pharmacokinetic study revealed a significant elevation in plasma exposure (i.e. AUC) to valsartan and digoxin but reduction to quetiapine in SAMP8 mice compared to their non‐AD control mice. When interpreted together with H&E staining, ex vivo drug permeation study, and proteome data, the increase AUC to valsartan and digoxin is likely due to increased intestine leakiness. For digoxin, despite P‐glycoprotein expression was significantly increased in the small intestine, it failed to compensate the leaky gut. For quetiapine, the reduction in AUC in SAMP8 was due to increased hepatic metabolism, as increased levels of metabolites of quetiapine was detected in the plasma.

Conclusion

Consistent with our previous observation in APP/PS1 mice, drug disposition following oral administration was also noted in a mouse model of sporadic AD (SAMP8). Clinical study to evaluate altered ADME in people with AD should be considered to achieve precise medication use in people with AD.
Application of quantitative systems pharmacology model of Alzheimer’s disease for simulation of efficacy of tyrosine kinase inhibitors
Authors: Karelina Tatiana
Published: June 2023

Background

Repurposing of tyrosine kinase inhibitors (TKI), such as nilotinib, imatinib etc. for the treatment of neurodegenerative disease is considered actively. Some tyrosine kinases which are targeted by these drugs (c‐Abl, DDR) are upregulated in neurodegenerative diseases (AD and PD). Thus, discoidin domain receptors (DDRs) are important regulators of microglial state, while c‐Abl‐kinase is a key regulator of cell stress response. TKI have been shown to boost autophagy through the interaction with these targets and to allow for the clearance of toxic tau and amyloid protein aggregates. The aim of this work was to apply the quantitative systems pharmacology (QSP) model of AD amyloid and tau pathology to translate the preclinical results for prediction of potential efficacy in humans.

Method

Interaction of cell metabolism with amyloid ant tau accumulation was described earlier in QSP translational model [1]. It described dynamics of multiple biomarkers in brain, CSF and plasma. Amyloid and tau exert toxic influence on protein degradation by autophagy and proteasome and transport. In this work, c‐Abl was added as one of the drivers of AD pathology through p53 regulation, tau phosphorylation and autophagy inhibition. Data for nilotinib [2] and other TKI were used for model validation. PK data for nilotinib and other TKI were used to estimate brain concentration of the drug.

Result

Model describes boosting of autophagy by about 40% [3] after c‐Abl inhibition. This leads to the reduction of amyloid and tau pathology, in correspondence to the data observed in vitro. However, for amyloid and tau transgenic mice, efficacy of c‐Abl inhibition was significantly lower assuming brain concentrations of about 1 nM, and contribution of microglial processes due to DDR1 inhibition was added. Human data on SUVR and CSF p‐tau reduction after 1 year of nilotinib treatment were described satisfactorily.

Conclusion

The model can be applied to simulations of the efficacy of tyrosine kinase inhibitors in neurodegeneration diseases.

[1] Karelina, T. et al, (2021). CPT: PSP, 10, 545.

[2] Fowler, et al, (2019). Drugs in R and D, 19(2), 149.

[3] Lonskaya, I. et al, (2013). PLoS ONE, 8(12), e83914.
Temporal trends in the incidence of atrial fibrillation‐related strokes in Sweden, 2001‐2020
Authors: Ding Mozhu , Wennberg Alexandra MV , Ziegler Louise Dencker , Modig Karin
Published: June 2023

Background

Atrial fibrillation (AF) increases the risk of stroke, which in turn elevates the risk of dementia in old age. Thus, changes in the incidence of stroke over time could greatly affect population brain health. The prevalence of AF is increasing worldwide, but how this impacts the incidence of stroke is unclear. We aimed to provide an up‐to‐date estimate on the temporal trends in the incidence of AF‐related stroke in Sweden during the period 2001‐2020.

Method

Data from the total Swedish population aged ≥60 years during the period 2001‐2020 were used. First‐ever stroke and AF diagnoses were identified through hospital admissions and deaths in the national health registers. AF‐related stroke is defined as stroke event with documented AF diagnosis within 5 years before the event, at the time of event, or within 2 months after the event.

Result

The annual incidence rate of overall stroke declined substantially in both men and women during 2001‐2020 (incidence rate [IR] 2001 vs. 2020 = 153.0 vs. 87.7 for men; 134.7 vs. 72.1 for women). There was only a slight decline in the incidence rate of AF‐related stroke (IR 2001 vs. 2020 = 32.0 vs. 28.3 for men; 30.6 vs. 21.9 for women). The strength of the association between AF and incident stroke also decreased over time. In men, AF was associated with a hazard ratio (HR) of 1.56 (confidence interval [CI]: 1.50‐1.62) for incident stroke in 2006‐2008 as compared to a HR of 1.46 (CI: 4.41‐1.52) in 2015‐2017. In women, the HR for incident stroke associated with AF is 2.15 (CI: 2.08‐2.22) in 2006‐2008 and 1.76 (CI: 1.69‐1.82) in 2015‐2017. On the other hand, the percentage of AF‐related strokes out of all strokes increased during 2001‐2020, from 21.8% to 33.6% for men and from 23.5% to 31.6% for women.

Conclusion

The incidence of AF‐related strokes among people 60 years and over declined in Sweden during 2001‐2020, and so did the strength of the association between AF and risk of stroke. On the other hand, the percentage of AF‐related strokes out of all strokes increased over time, and one‐third of strokes were AF‐related by the end of 2020.
β‐Adrenergic receptor agonist alleviates memory interference control deficits in APPswe/PS1dE9 mice
Authors: Karunakaran Smitha
Published: June 2023

Background

Earlier studies have demonstrated that memory dysfunction during early Alzheimer’s disease (AD) is associated with an increased susceptibility to memory interference (MI). In this study, we examined whether previously stored memory representations interfered with novel similar input patterns in 2‐month‐old APPswe/PS1dE9 (APP/PS1), mice. APP/PS1 over‐expresses the Swedish mutation of amyloid precursor protein together with presenilin1 deleted in exon 9. Amyloid beta (Aβ) plaque deposition is observed at 4‐6 months of age, not at 2 months providing us with a window to study the earliest behavioural deficits that are independent of Aβ plaque deposition.

Method

(1) We introduced a proactive interference step to the well‐established novel object recognition paradigm (NOR), by exposing the mice to multiple objects of different shape, size and colour. (2) Earlier studies have demonstrated that prolonged oral administration of β‐adrenoreceptor (β‐AR) agonist (−)‐Isoproterenol hydrochloride (IPE) to mice protected them from hippocampal impairment by Aβ oligomers, and enhanced hippocampal synaptic plasticity. We provided the IPE in drinking water for three weeks from P26 till P47.

Result

Our results demonstrate that NOR is intact in APP/PS1 at 2 months of age. However, introducing a short‐term object based priming or interference prior to NOR leads to recognition memory deficits. This finding indicates that 2‐month‐old APP/PS1 is susceptible to proactive MI unlike their Wild Type counterpart who could clearly discriminate between a novel and a familiar object. Our findings indicate that, object‐based priming can activate its presence during target memory encoding, and thus negate learning in 2‐month‐old APP/PS1 mice before amyloidosis onset. β‐AR agonist treatment restored performance of APP/PS1 mice to normal levels protecting them from the effects of priming during the object recognition task.

Conclusion

These results indicate that integration or discrimination component of object memory representations relies on and can be modulated by β‐AR activation.
Influence of apolipoprotein E (apoE) on ADAM10 secretase in cerebrospinal fluid of older adults with Alzheimer’s disease
Authors: Pedroso Renata Valle , Lopez‐Font Inmaculada , García‐Ayllón María‐Salud , Zetterberg Henrik , Blennow Kaj , Cominetti Marcia Regina , Sáez‐Valero Javier
Published: June 2023

Background

The ε4 allele of APOE is the strongest genetic risk for sporadic late‐onset Alzheimer’s disease (AD), and is associated with an increase in the levels of β‐amyloid (Aβ) deposition. The main α‐secretase that inhibits the Aβ deposition is the ADAM10, which is altered in the blood and cerebrospinal fluid (CSF) of older adults with AD.

Method

To assess whether the levels of ADAM10 forms are altered in CSF of AD and non‐dementia control (NDC) individuals with different APOE genotype, we analysed a total of 13 samples from NDC (mean age = 66.3 ±9.8; T‐tau = 305 ±135 ng/L; Aβ42 = 780 ±253 ng/L) and 41 from AD (mean age 77.0 ±6.2; T‐tau = 845 ±356.1 ng/L; Aβ42 = 456 ± 66 ng/L), subdivided into NDC APOE ε3/ε3 (n = 8), NDC APOE ε3/ε4 (n = 5), AD APOE ε3/ε3 (n = 13), AD APOE ε3/ε4 (n = 14) and AD APOE ε4/ε4 (n = 14). ADAM10 was characterized in human CSF samples by western blotting.

Result

An antibody raised against to the ectodomain region of ADAM10, common to all species, recognized three bands, which might be the proADAM10 (immature form retaining the prodomain), ADAM10f (mature unprocessed full‐length form) and sADAM10 (truncated fragment). Regarding proADAM10, no differences were found among NDC with different APOE genotype. However, the AD APOE ε4/ε4 showed a reduction, which was significantly lower than AD APOE ε3/ε3 (p = 0.0011), NDC APOE ε3/ε3 (p = 0.0460) and NDC APOE ε3/ε3 (p = 0.0012), suggesting the impact of being homozygous for APOE ε4 allele on proADAM10 levels. In the ADAM10f and sADAM10, we observed similar findings. For both species of protein, AD groups carriers of APOE ε4 allele, that is, AD APOE ε3/ε4 and AD APOE ε4/ε4, presented significant lower levels of ADAM10f compared with both non‐carriers subgroups (AD APOE ε3/ε3 and NDC APOE ε3/ε3).

Conclusion

The results indicated that being a carrier of the APOE ε4 allele and having developed AD are associated with lower levels of ADAM10f and sADAM10. This study contributes to a better understanding the impact of apoE on the disease.
GENESIS OF AXONAL SWELLINGS IN TRAUMATIC INJURY
Authors: Devoto Victorio Martin Pozo , Lacovich Valentina , Feole Monica , Bhat Pratiksha , Stokin Gorazd B.
Published: June 2023

Background

Axonal swellings (AxS) are focal enlargements of axons found in a range of biological and pathological settings, including traumatic brain injury. However, the development of AxS and their early effects on axonal homeostasis are poorly understood. Here, we describe the cytoskeletal changes, transport effects and the molecular events that occur in the axon immediately after a traumatic injury.

Method

We developed an in vitro system to study in real‐time the effects of traumatic injury on the axon of mature human neurons. We also generated an algorithm which allowed us to assess the dynamics of the AxS formation in real‐time and examine the role of Ca2+ in the swellings. Through mass spectrometry analysis on isolated axons we described the axonal proteome and identified the immediate phosphorylation changes ocurring in the axon after a traumatic injury. We also used superresolution microscopy to characterize the earliest cytoskeletal changes in the axon and their impact on the movement of several axonal cargoes.

Result

As a result of the mechanical stress we observed the appereance of AxS, which were temporally correlated to Ca2+ levels increase in the axon. Interestingly, by pharmacologically blocking different sources of Ca2+ we observed that Ca2+ plays a role in sustaining the AxS and not in their formation. Proteomic and phosphoproteomic analysis revealed a significant regulation in proteins related to axon development after injury. These proteins were mainly interactors or components of the cytoskeleton, while no association to axonal degeneration or impairment in normal processes was found. We also predicted a general increase in kinases activity after injury, among them ROCK, ERK, JNK, PKC and GSK. A detailed analysis of cytoskeletal arrangement revealed modifications in the actin‐spectrin periodic structure and a mesh‐like organization of microtubules and neurofilaments in the AxS. We finally observed that the structure of swellings allows cargos to cross and that axonal transport of different cargos were not interrupted during mechanical stress.

Conclusion

These observations indicate that the mechanical stress to the axon generates segments of cytoskeletal reorganization that result from Ca2+ increase and correlate with regulation through phosphorylation of cytoskeletal and cytoskeletal interacting proteins.
Stepping towards integrated supports for family caregivers of people living with dementia: Engaging multi‐level interdisciplinary stakeholders in co‐design of competency‐based education
Authors: Parmar Jasneet K , Duggleby Wendy , Anderson Sharon Dorothy , Lobchuk Michelle , Penner Jamie , L'Hereux Tanya , Stewart Jamie D , Marion Cecelia , Huhn Arlene , Dobbs Bonnie , Sonnenberg Lyn K , Schattie‐Weiss Laura , Jowhari Sanah , McGhan Gwen , Drance Elisabeth , Lundmark Sandra , Tarnowski Glenda , Pooler Charlotte , Howatt David , Sereda Sandy
Published: June 2023

Background

Remaining home as long as possible or aging in place in their community home, particularly for those living with dementia, is highly dependent on family caregivers (FCGs) and health providers partnering with FCGs..[1] FCGs provide 90% of the care yet are marginalized within healthcare systems. Educating healthcare providers to support FCGs is a step towards addressing the inconsistent system of supports for diverse FCGs throughout variable trajectories.[2 3] Involving multilevel stakeholders in the educational co‐design process can help ensure the education is relevant for the healthcare providers who interact with FCGs.[4 5] Currently, moving best practices into healthcare is a time‐consuming process (10 to 17 years).[6 7] However, co‐design facilitates moving knowledge into practice more quickly.

Objectives

1) Detail the co‐design processes and tools used to develop competency‐based Caregiver‐Centered Care Education for the health workforce. 2) Report on the key elements associated with successful co‐design.

Method

106 multi‐level interdisciplinary stakeholders including FCGs, educators, researchers, healthcare providers and leaders, educational designers, not‐for‐profit leaders, policy influencers, and policymakers were involved in three co‐design phases: 1) Developing relationships and insights; 2) Translating insights into education design; and 3) Planning the implementation, spread, and scale‐up of the Modules. The research tools used in each of these phases included literature reviews, qualitative and survey research on specific topics, consultations (symposia, modified Delphi process, meetings), and mixed methods evaluation.

Result

Co‐design facilitated translation of best practices of Caregiver‐Centered Care into successful competency‐based training for the health workforce. Modules have been highly accessed by healthcare providers and trainees. Learners report very high satisfaction, relevance, usefulness, and significant knowledge gains upon completion. Four elements were critical to successful education co‐design: 1) an engaged co‐design team led by people knowledgeable about healthcare and FCGs; 2) co‐design team access to collaborators/staff with the appropriate theoretical, research, and facilitation skills; and 3) an expert educational design team to bring stakeholders’ ideas to life.

Conclusion

We leveraged stakeholders’ knowledge and insights to reduce the time to develop and scale an innovative population health approach in which healthcare providers are educated to support all FCGs throughout diverse care trajectories.
The neurodegeneration of the cholinergic pathways in subtypes of subjective cognitive decline
Authors: Cedres Nira , Diaz‐Galvan Patricia , Nemy Milan , Alemany Iris , Rodriguez‐Hernandez Marta A. , Barroso Jose , Westman Eric , Ferreira Daniel
Published: June 2023

Background

Neurodegeneration of cholinergic pathways may be present in individuals with subjective cognitive decline (SCD). However, variability between SCD individuals in the integrity of cholinergic pathways needs to be elucidated. Our objective was to determine characteristics of neurodegeneration of cholinergic pathways in different SCD subtypes (i.e. amnestic vs. non‐amnestic).

Method

Individuals with amnestic SCD (n = 47), non‐amnestic SCD (n = 38), and healthy controls without cognitive complaints (HC; n = 20) from the GENIC database were included (all: >60 years old; 58% females). White matter integrity was estimated by mean diffusivity (MD) on diffusion tensor imaging (DTI) for cingulum and external cholinergic pathways. Both pathways were previously modelled using tractography on DTI. Memory performance was measured based on Visual reproduction WMS‐III and TAVEC (the Spanish version of the California Verbal Learning Test, CVLT). ANOVA and bivariate Pearson correlation were used for the statistical analysis.

Result

Amnestic and non‐amnestic SCD groups were comparable to HC in the integrity of cholinergic WM pathways. Bivariate Pearson correlation analyses showed different patterns of association between the cholinergic pathways and cognition within each group. In amnestic‐SCD, worse WM integrity in both cholinergic pathways was associated with poorer immediate recall of visual information (external capsule: rxy = ‐0.42; p<0.05; cingulum: rxy = ‐0.34; p<0.05). In non‐amnestic‐SCD, worse WM integrity in both cholinergic pathways was associated with poorer delayed recall of verbal information (external capsule: rxy = ‐0.54; p<0.05; cingulum: rxy = ‐0.42; p<0.05); and worse WM integrity in the external capsule pathway was associated with poorer performance in immediate and delayed recall of visual information (rxy = ‐0.37; p<0.05 and rxy = ‐0.46; p<0.05). In HC, none of the cognitive outcomes was associated with the integrity of the cholinergic pathways.

Conclusion

The cholinergic pathways were mainly associated with immediate recall in the amnestic SCD (i.e. acquisition of new information); whereas in non‐amnestic SCD the integrity of cholinergic pathways was associated with several subcomponents of memory performance (i.e. acquisition and recall of new information). Thus, SCD subtypes show unique patterns of associations between poorer integrity of the cholinergic system and memory performance.
Quantifying AD‐related brain amyloid with linearised progression models: Model‐based vs. data‐based
Authors: Wink Alle Meije , Shekari Mahnaz , Dicks Ellen , Collij Lyduine E. , Salvadó Gemma , García David Vállez , Gispert Juan Domingo , Tijms Betty M. , Alves Isadora Lopes , Yaqub Maqsood , Barkhof Frederik
Published: June 2023

Background

Brain amyloid‐β (Aβ) is the pathological hallmark of Alzheimer’s disease (AD). In logistic disease models, Aβ accumulation is a sigmoid function of time‐since‐disease‐onset (TSDO) (figure 1). Previous positron emission tomography (PET)‐based models vary accumulation onset(t50) and duration(r) globally; capacity(K) and baseline(NS) regionally (Whittington2018). We confirm existing approaches and propose a more powerful ICA‐based approach to quantify disease severity and estimate TSDO.

Method

We used 1071 18F‐florbetapir standard uptake value ratio (SUVR) images from the ADNI‐2 study (adni.loni.usc.edu/data‐samples/data‐types/pet). Images were mapped into MNI space. Averages were extracted using the Harvard‐Oxford brain‐atlas. Whole‐brain tracer‐specific sigmoid parameters (Jack2013) obtained from the literature were used to estimate TSDO.

Of 16 models of regional Aβ accumulation (each of the 4 regional sigmoid parameters varied either regionally or globally), the optimal Bayesian information criterion was found with global t50 and r, and regional NS and K (figure 1) with global values r = 6.16y and t50 = 4.10y.

Linearised maps of NS and K were obtained by regressing the SUVR maps onto the global sigmoid. We also estimated these maps as independent components, using a 2‐component ICA on the SUVR maps. Both outcomes were used to quantify Aβ accumulation from SUVR images as weighting factors of the accumulation map.

We compared the weights from the logistic model and the ICA model in ADNI, using effect size measured with Hedges' g between cognitively normal (CN), subjective memory complaints (SMC), mild cognitive impairment (EMCI/MCI/LMCI) and AD groups. We compared 3 longitudinal visits (N = 112) in the OASIS‐3 study (see www.oasis‐brains.org) with both methods, global SUVR and Centiloid (Klunk2015) using 11C‐PiB PET SUVR images.

Result

Maps of accumulation capacity from both models had spatial correlation of 0.86 (figure 2); baseline maps had spatial correlation of 0.95. Hedges' g between ADNI groups was 2.25 for K, and 2.42 for ICA (1.46 for global SUVR). In OASIS‐3, Hedges' g between visits was 1.24 for K, 1.46 for ICA (global SUVR 0.15, Centiloid 0.4).

Conclusion

We demonstrate that linear accumulation models can be used to quantify brain Aβ with PET; maps obtained by ICA yield larger effect sizes than the logistic method for differentiating groups and measuring changes between visits.