bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and recognition of cognitive impairment in hospitalized older patients: a flash mob study
Authors: Visser Fleur C.W. , van Eersel Marlise E.A. , van Munster Barbara C. , Consortium Flashmob Cognition
Published: December 2023

Background

It is estimated that over one‐third of hospitalized older patients have cognitive impairment. Cognitive impairment directly impacts care during and after hospitalization. Recognition of cognitive impairment is important to provide person‐centered care, involve relatives, prevent adverse outcomes, and identify people that need support or diagnostic evaluation for dementia after discharge. Previous studies of medical records suggested under‐recognition of cognitive impairment in hospitalized older patients by healthcare professionals. The aim of this study is to investigate the prevalence of cognitive impairment in hospitalized older patients and the recognition of cognitive impairment by healthcare professionals.

Method

A cross‐sectional, observational study was conducted in three university hospitals and ten general hospitals in the Netherlands on a single day in 2022, following a flash mob design. The study was an initiative of Alzheimer Center Groningen as part of ABOARD (A Personalized Medicine Approach for Alzheimer’s Disease). Cognitive impairment, indicated by a Mini‐Cog score of <3 (out of 5), was assessed in Dutch‐speaking, hospitalized patients aged ≥ 65 years old. Patients were excluded if they were unable to perform the Mini‐Cog due to sensory impairment or severe delirium, required medical isolation, or were not willing to participate. The nurses and physicians that took care of the patient that day were asked whether they thought the patient had cognitive impairment.

Result

A total of 1,318 potentially eligible patients were available. Of these patients, 374 (28%) were excluded because they were unable to perform the Mini‐Cog or were isolated, and 187 (14%) were excluded because they were not willing to participate. Finally, a total of 757 patients (58%) were included (median age, 77 years [71‐82]; male, 386 [51%]). Of the included patients, 347 patients (46%) had cognitive impairment. Cognitive impairment was recognized by their nurse in 137 of 323 patients (42%) and by their physician in 156 patients (48%). In 135 patients (42%) cognitive impairment was not recognized by either the nurse or physician.

Conclusion

Cognitive impairment is common in older hospitalized patients, and is poorly recognized by healthcare professionals. This study highlights the need for quality improvement of cognitive impairment recognition to provide person‐centered care.
Serum biomarkers for prognosis and monitoring in asymptomatic Alzheimer’s Disease
Authors: De Meyer Steffi , Blujdea Raluca , Schaeverbeke Jolien , Reinartz Mariska , Luckett Emma S. , Adamczuk Kate , Gabel Silvy , Van Laere Koen , Dupont Patrick , Teunissen Charlotte E. , Vandenberghe Rik , Poesen Koen
Published: December 2023

Background

Prognostic and monitoring capabilities of blood‐based biomarkers for early cognitive decline, amyloid‐β (Aβ) accumulation and grey matter (GM) loss in the asymptomatic phase of Alzheimer disease require further investigation over extended time periods. This longitudinal study investigated serum glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and Aβ1‐42/Aβ1‐40 as potential prognostic and monitoring biomarkers in cognitively unimpaired (CU) elderly.

Method

We included 184 CU older adults (Table 1) who underwent baseline serum sampling and 2‐yearly neuropsychological assessment for up to 10 years (median: 6 years, Figure 1). A subset (N = 109) underwent serial blood sampling, Aβ‐PET and structural MRI at 2 (N = 73), 3 (N = 34), or 4 (N = 2) time points (time interval: 2‐10 years, median: 6 years). Cognition was evaluated in memory, language and executive functioning domains through conversion of neuropsychological tests scores to standardised z‐scores and subsequent averaging per domain. Aβ‐accumulation and GM loss were analysed in a voxelwise manner using Voxelstats with cluster‐level p
RFT<.05 and voxel‐level puncorrected<.001 significance thresholds.[1] Aβ1‐42/Aβ1‐40 was inverted to facilitate biomarker comparison. Linear‐mixed effects models were used to (i) identify the predictive value of serum biomarkers for longitudinal cognitive decline, Aβ‐accumulation and GM loss, (ii) calculate annual serum biomarker rates of change and (iii) investigate associations between longitudinal biomarker changes and longitudinal changes in cognition, Aβ‐PET and GM volume.

Result

High baseline GFAP and NfL predicted a longitudinal decline in memory (βGFAP*time = ‐0.020, pFDR
= 0.03; βNfL*time = ‐0.031, pFDR = 0.002) and language (βGFAP*time = ‐0.025, pFDR<0.001, βNfL*time = ‐0.017, pFDR = 0.04), and longitudinal GM loss within the hippocampus. Low Aβ1‐42/Aβ1‐40 predicted memory decline (βAβ1‐42/Aβ1‐40*time = ‐0.022, pFDR = 0.03) as well as Aβ accumulation within Aβ‐vulnerable regions (Figure 1). Serum GFAP (βtime = 0.022, pFDR<.001) and NfL (βtime = 0.040, pFDR<.001) increased over time. Longitudinal serum NfL increases were associated with a concomitant decline in memory (β∆NfL*time = ‐0.031, pFDR= .004), language (β∆NfL*time = ‐0.022, pFDR= .01) and GM volume (Figure 2). Serum GFAP increases were associated with precuneal Aβ accumulation. Aβ1‐42/Aβ1‐40 decreases were stronger in Aβ‐ subjects (pFDR<.001) and did not associate with Aβ accumulation, nor any other longitudinal marker.

Conclusion

Serum GFAP, NfL and Aβ1‐42/Aβ1‐40 are prognostic and/or monitoring biomarkers providing complementary information by reflecting different Aβ‐dependent or ‐independent pathophysiological processes.

REFERENCE

[1] Mathotaarachchi et al. Front Neuroinform 2016.
Consumption of coffee and tea and the risk of dementia – role of sex and vascular comorbidities
Authors: Hou Kuan‐Chu , Chen Yen‐Ching , Chen Ta‐Fu , Sun Yu , Wen Li‐Li , Yip Ping‐Keung , Chu Yi‐Min , Chiou Jeng‐Min , Chen Jen‐Hau
Published: December 2023

Background

Coffee and tea consumption has been shown to associate with the risk of dementia. However, little is known about how sex and vascular comorbidities (type 2 diabetes, hypertension, and hypercholesterolemia) modify this association.

Method

This is a multi‐center case‐control study. We recruited 278 Alzheimer’s disease (AD) and 102 small‐vessel vascular dementia (VaD) patients aged 60 or older from three teaching hospitals in Taiwan from 2007 to 2010; controls (n = 468) were recruited from the health checkup program during the same period of time. The outcomes of this study are clinically diagnosed AD and VaD. Information on coffee and tea consumption and the history of type 2 diabetes, hypertension, and hypercholesterolemia were collected based on questionnaires and medical charts. A multinomial logistic regression model was utilized to evaluate 1) the association of coffee and tea consumption with dementia risk, and 2) how sex and vascular risk factors modified these associations.

Result

Different combinations and quantities of coffee and tea consumption protected against AD and VaD. Our analyses demonstrated consumption of three or more cups of coffee or tea per day was associated with a decreased risk of AD [adjusted odds ratio (aOR) = 0.42; 95% confidence interval (CI) = 0.22‐0.78)] and VaD (aOR = 0.42; 95% CI = 0.19‐0.94). After stratification, these associations became more evident in females for AD (aOR = 0.15; 95% CI = 0.05‐0.46) and in males for VaD (aOR = 0.06; 95% CI = 0.01‐0.50). Similarly, hypertensive participants consuming higher quantities of coffee and tea had a decreased risk of AD (aOR = 0.30; 95% CI = 0.11‐0.78). Moreover, hypercholesterolemia significantly modified the association of coffee or tea consumption with the risk of dementia (Pinteraction < 0.001).

Conclusion

Coffee and tea consumption was associated with a decreased risk of AD and VaD. Sex and vascular comorbidities differentially modified the association of coffee and tea consumption with the risk of dementia.
Chronic Exposure with 5‐Alpha Reductase Inhibitor Ameliorates Anxiety and Depression‐like Behaviors By Reducing Systemic Oxidative Stress in D‐galactose‐Induced Aging Male Rats
Authors: Pintana Hiranya , Saengmearnuparp Thiraphat , Apaijai Nattayaporn , Chunchai Titikorn , Lojanapiwat Bannakij , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

The most common geriatric psychiatric disorders are anxiety and depression. The 5‐alpha reductase inhibitor (5‐ARIs), finasteride (Fin), is a standard medication used to treat benign prostatic hyperplasia (BPH), that often occurs in the elderly. However, the effects of Fin on mental health in aged population are still unclear. D‐galactose (D‐gal)‐induced aging has been recognized worldwide, as a model to mimic natural aging in rodents. Therefore, we investigated the effect of Fin on anxiety and depression‐like behaviors in D‐gal‐induced aging male rats.

Method

Twenty‐male Wistar rats (8‐week‐old) were randomly divided into two groups (n = 10/group) to receive either vehicle as control or D‐gal (150 mg/kg/day via subcutaneous injection) for 18 weeks. At week 13, rats in each group were divided into two subgroups (n = 5/subgroup) in order to receive either vehicle (drinking water) or Fin (5 mg/kg/day) via oral gavage. At the end of the treatment, elevated‐plus maze (EPM), and splash test (ST) were performed for quantifying anxiety and depression‐like behaviors, while open‐field test (OFT) to determine locomotor activity. In addition, blood in each rat was collected for determining the metabolic profiles.

Result

D‐gal‐treated rat showed no effect on metabolic disturbance, but increased systemic oxidative stress (Figure 1A‐C). Anxiety and depression‐like behavior were observed in D‐gal‐treated rats, as indicated by a decrease % preference index in the open arm of EPM and grooming time in ST (Figure 1D‐E). Fin‐treated control rats demonstrated hypercholesterolemia (Figure 1A‐B), and depression‐like behavior was observed (Figure 1E). Anxiety and depression‐like behaviors were attenuated in Fin‐treated D‐gal rats (Figure 1D‐E). Regarding the locomotor activity, no significant difference was found among all groups. (Figure 1F).

Conclusion

FIN exposure induced metabolic disturbance, and depression‐like behaviors in male rats. In contrast, Fin ameliorated anxiety and depression‐like behaviors in D‐gal‐induced aging rat, which may due to a reducing systemic oxidative stress. The findings in this study provide information for future clinical applications such as the use of Fin for therapeutic approach for anxiety/depression‐like behaviors in the elderly. However, caution is advised when using Fin in young men since it may induce depressive‐like behaviors.
Analysis of the effect of adult onset increase of neurotrophic factor GDNF expression in APP‐NL‐G‐F AD mouse model
Authors: Olfat Soophie , Andressoo Jaan‐Olle
Published: December 2023

Background

Gradual decline in cholinergic transmission and cognitive function occurs during normal aging, whereas pathological loss of cholinergic function is a hallmark of different types of dementia, including Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease dementia (PDD). Glial cell line‐derived neurotrophic factor (GDNF) is known to modulate and enhance the dopamine system. However, how endogenous GDNF influences brain cholinergic transmission has remained elusive.

Method

Recently we showed that two fold increase in endogenous GDNF expression in Gdnf hypermorphic mice, Gdnf wt/hyper, attenuated age‐associated decline in the cholinergic index and cognitive function observed in Gdnf wt/wt animals. Biochemical analysis revealed that the level of nerve growth factor (NGF), which is important for survival and function of central cholinergic neurons, was significantly increased in several brain areas of old Gdnf wt/hyper mice

Result

Our results identified endogenous GDNF as a potential enhancer of cholinergic transmission upon aging (11). Here we propose to follow up those results by analyzing the effect of adult onset increase in endogenous GDNF expression on cholinergic index, A‐beta load, NGF expression and cognition in APP‐NLGF mouse model of AD. To accelerate AD onset and to facilitate future studies we have also generated and propose characterization of APP‐NLGF conditional Hypermorph mouse model.

Conclusion

Our goal is to conclude therapeutic potential of enhanced endogenous GDNF signaling on AD associated cholinergic and cognitive decline to pave way to new dementia treatments based on GDNF mimetics currently under development by several academic and industrial laboratories.
Stress system dysfunction and changes in brain volume and functional connectivity in older adults with subclinical depressive symptoms
Authors: Touron Edelweiss , de Flores Robin , Coulbaut Laurent , Palix Cassandre , Chocat Anne , Kuhn Elizabeth , Landeau Brigitte , Mézenge Florence , Roquet Daniel , Chauveau Léa , Haudry Sacha , Vivien Denis , la Sayette Vincent De , Marchant Natalie L , Chetelat Gael , Poisnel Géraldine ,   the Medit‐Ageing Research Group
Published: December 2023

Background

Subclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD). This link could be related to stress system dysfunction, known to occur in both depression and AD, and to depend notably on the hippocampus which is particularly sensitive to AD. We aimed at investigating the links between levels of blood stress markers and changes in brain regions involved in the stress response in older adults with subclinical depressive symptoms.

Method

Cognitively unimpaired older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15‐item version of the Geriatric Depression Scale), from the baseline data of the Age‐Well trial (NCT02977819) were included. For each participant, levels of cortisol, epinephrine and norepinephrine were obtained from blood sampling. Moreover, the functional connectivity (FC) between, and the gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields were extracted from resting‐state functional, and structural T1‐weighted, MRI. Levels of blood stress markers and neuroimaging measures were compared between groups. Regression analyses were then conducted between levels of blood markers and brain measures. Analyses were corrected for age, sex, education and anxiety symptoms with statistical significance set to p<0.05.

Result

Higher blood epinephrine level (p<0.024), and FC between the hypothalamus and the CA1 hippocampal subfield (p<0.040), was found in DepS compared to NoDepS (Fig.1). This higher epinephrine level was associated with greater FC between the hypothalamus and the CA1 (p<0.007) and Subiculum (p<0.013) subfields (Fig.2). Lower GM volume in the CA1 (p<0.008) and DG/CA2‐3‐4 (p<0.013) subfields was also found in the DepS group (Fig.3), but was not associated with epinephrine level. No significant between‐group difference in blood cortisol and norepinephrine levels was observed.

Conclusion

Subclinical depressive symptoms in aging are associated with higher blood epinephrine level related to greater FC between the hypothalamus and hippocampal subfields (CA1 and Subiculum) – suggesting an increased sympathetic nervous system activity. They are also associated with GM atrophy in specific hippocampal subfields, including the CA1 that is sensitive to AD. These two distinct mechanisms at this preclinical stage of depression may at least partly explain that depression is a risk factor for AD.
Ripple effects of small group care for patients with dementia in hospital on ward nurses
Authors: Degai Yuko , Otsuka Mariko , Nakagomi Saori , Narisawa Ken , Tokunaga Shiho
Published: December 2023

Background

The average length of stay in general beds is about 16 days in Japan . Providing quality care to inpatients with dementia has been a challenge in acute hospitals. In Japan, “in‐hospital daycare”, in which patients gather in specific places in the hospital for recreation and rehabilitation, is increasing. Therefore, we aimed to clarify the current situation of “in‐hospital daycare” at hospitals in Japan and the ripple effect on dementia care in wards.

Method

A web‐based survey was conducted on 1,101 nurses working in hospitals who are certified as experts of dementia or geriatric care.

Result

Data were obtained from 272 nurses (response rate: 24.7%). 38 nurses (14%) have provided “in‐hospital daycare”, and 51 nurses (18.8%) provided it before the COVID‐19 pandemic. We analyzed data of these 89 nurses.91.0% of them recognized that “in‐hospital daycare” was effective for the patients who participated. In addition, they reported the ripple effect on ward nurses. Ripple effects are 〈ward nurses are more supportive of patient activity/diversional activity 〉〈Ward nurses are more aware of patient strengths〉〈Ward nurses noticed new aspects of patients and backgrounds, and deepened their understanding of patients〉〈Increased conversations between ward nurses and patients〉and so on.

Conclusion

Although only about 30% of facilities provide “in‐hospital day care”, it has not only an effect on participating patients, but also has a ripple effect on ward nurses. Results suggest that it contributes to improving the quality of dementia care in the ward.
DNA methylation profiling of individual neurons isolated from post‐mortem brain tissue using laser capture microdissection and adapted limiting dilution bisulfite pyrosequencing
Authors: Riemens Renzo J.M. , Kenis Gunter , Nolz Jennifer , Chaves Sonia C. Susano , Duroux Diane , Pishva Ehsan , Mastroeni Diego , Van Steen Kristel , Haaf Thomas , Hove Daniel L. A.
Published: December 2023

Background

A challenge frequently encountered in neuroepigenomic research, especially in the context of neurodegenerative diseases such as Alzheimer’s disease, is the difficulty of measuring epigenetic patterns in heterogenous bulk tissue samples, as these are known to cause noise during profiling. A viable strategy to overcome this challenge is to analyze epigenetic marks in single neurons that have been isolated using laser capture microdissection (LCM).

Method

In this study, we developed a new approach for targeted DNA methylation profiling of individual genes that combines the use of LCM and limiting dilution bisulfite pyrosequencing (LDBSP). By utilizing this method, we were able to determine the cytosine‐phosphate‐guanine (CpG) methylation rates of single alleles obtained from 50 neurons, which were isolated from unfixed post‐mortem brain tissue.

Result

We demonstrate how the methylation status of multiple genes such as RHBDF2, OXT, TNXB, DNAJB13, PGLYRP1, C3, and LMX1B, can be quantified simultaneously using the method described above. In addition, we provide an adapted data analysis pipeline for LDBSP, which accounts for and corrects methylation rates obtained from multi‐allele reactions. Furthermore, we show that the efficiency of LDBSP on DNA derived from LCM‐isolated neurons is comparable to the efficiency in previous studies using other cell types.

Conclusion

This method allows for a more precise determination of the DNA methylation status of each targeted gene in the neuronal cell samples under investigation, thereby increasing the validity of the technique.
Association of cognitive reserve with cognitive function and quality of life in the years following a diagnosis of dementia: initial findings from the IDEAL study
Authors: Gamble Laura D , Clare Linda , Martyr Anthony , Matthews Fiona E
Published: December 2023

Background

Effects of brain pathology or ageing on cognitive function are moderated by an individual’s ability to optimise or maximise the use of the brain’s resources to perform tasks, and is a concept known as cognitive reserve. In dementia, cognitive reserve may reflect the capacity to provide a buffer against effects of dementia‐related brain pathology, resulting in a delay in signs and symptoms of dementia. Studies have found that a higher level of education may not only lead to a delay in the onset of dementia, but impact on the rate of cognitive decline following a diagnosis. Here we investigate whether a latent measure of cognitive reserve at diagnosis impacts on cognitive function or quality of life in the years following a diagnosis.

Method

We used longitudinal data from 1545 individuals with mild‐to‐moderate dementia participating in the IDEAL study. Assessments took place on entry, and at 12 and 24 months. A latent measure of cognitive reserve was created based on education, social class and engagement in social and cognitive activities. Latent growth curve models were used to look for associations of cognitive reserve at diagnosis with cognitive function and quality of life in the years following diagnosis.

Result

A higher cognitive reserve was associated with higher cognitive function at the time of diagnosis, but following diagnosis individuals with a higher cognitive reserve had a faster rate of decline in cognitive function. Whilst higher cognitive reserve was associated with a higher quality of life at the time of diagnosis, there was no association between cognitive reserve and change in quality of life in the years following diagnosis.

Conclusion

Those with a higher cognitive reserve at baseline are more likely to decline in cognitive function at a greater rate following diagnosis suggesting that it may be possible to identify individuals who may decline more quickly based on their education, social class and social and cognitive activities later in life.
Distinctive modulation patterns of functional brain connectivity of the default mode network by negative social emotions are associated with Alzheimer’s disease biomarkers in community‐dwelling older adults – cross‐sectional findings from the Age‐Well trial
Authors: Klimecki Olga M , Lugo Sebastian Baez , Demnitz‐King Harriet , Gonneaud Julie , Poisnel Géraldine , Marchant Natalie L , Vuilleumier Patrik , Chetelat Gael
Published: December 2023

Background

Recent evidence in Alzheimer’s diseases suggests that early dysfunction of emotional processing may precede the onset of cognitive decline and dementia. Altered functional brain connectivity patterns also occur along with other brain changes many years before clinical AD symptoms.

Method

We combined baseline multimodal neuroimaging data from cognitively healthy older adults (N = 125) enrolled in the Age‐Well trial of the Medit‐Ageing study. The aim was to elucidate the relationship of five AD risk factors (amyloid‐beta depositions and hypoperfusion with AV45‐PET, hippocampal atrophy, cognition with PACC‐5, cardiovascular risk with CAIDE) with carry‐over effects of social emotions and related brain functions. Using k‐means clustering analysis with the AD risk factors, we first defined participants with higher or lower preclinical risk for AD. We then used functional Magnetic Resonance Imaging to probe functional brain connectivity in resting periods following negative socio‐emotional videos in the SoVT‐Rest paradigm.

Result

Participants with a higher preclinical AD risk showed reduced positivity bias in affect ratings and reduced connectivity patterns between control‐related frontal brain regions and emotion‐related limbic regions (amygdala). In particular, this fronto‐limbic connectivity was associated with higher cardiovascular risk on the CAIDE composite score.

Conclusion

We find evidence for changes in post‐emotion functional recovery patterns in fronto‐limbic brain networks in at‐risk individuals for AD. These changes might reflect impaired emotion regulation processes.
Inter‐ and intra‐individual variation in brain structural‐cognition relationships in aging
Authors: Patel Raihaan , Mackay Clare , Jansen Michelle G , Devenyi Gabriel A. , O'Donoghue M Clare , Kivimaki Mika , Singh‐Manoux Archana , Zsoldos Enikő , Ebmeier Klaus P , Chakravarty Mallar , Suri Sana
Published: December 2023

Background

The sources of inter‐ and intra‐individual variability in age‐related cognitive decline remain poorly understood. We examined the association between 20‐year trajectories of cognitive decline and multimodal brain structure and morphology in older age.

Method

We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age = 69.52 ± 4.9) and 5 repeated cognitive performance assessments between mid‐life (mean age = 53.2 ±4.9 years) and late‐life (mean age = 67.7 ± 4.9). Using non‐negative matrix factorisation, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities (Figure 1).

Result

We observed two latent variables describing distinct brain‐cognition associations. The first describes variations in 5 structural components associated with low mid‐life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid‐life performance in fluency and memory, but retention of multiple abilities (Figure 2). Expression of latent variables predicts future cognition 3.2 years later (mean age = 70.87 ± 4.9) (Figure 3).

Conclusion

Longitudinal cognitive decline and maintenance across diverse cognitive functions are both positively and negatively associated with distinct markers of cortical structure. Latent brain‐behaviour relationships predict future cognitive performance.
Evaluation of performance of genoSCORETM for predicting onset of Alzheimer’s disease in a Japanese population
Authors: Gao Qian , Daunt Paula , Kikuchi Masataka , Miyashita Akinori , Ozaki Kouichi , Niida Shumpei , Iwatsubo Takeshi , Ikeuchi Takeshi , Gibson Alex , Pither Richard
Published: December 2023

Background

The development of diagnostic tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials, cohort studies and ultimately to identify patients most likely to benefit from newly approved therapies. Cytox has developed and validated a polygenic risk scoring (PRS) algorithm, genoSCORETM, for predicting the Late Onset Alzheimer’s disease (AD) based on the work pioneered by Escott‐Price, Williams et al 1. However, both training and testing has been performed in study populations containing primarily individuals with Caucasian ethnicity. To ensure that genoSCORE can equally be applicable to all ethnic groups, we have conducted an initial evaluation to understand predictive accuracy for the onset of AD in a Japanese population.

Methods

The PRS approach used in this study is built from a sum of weighted contributions of over 100,000s SNPs associated with disease2. Due to the limited SNP coverage of existing genetic data, we only used 63,499 SNPs and utilized the core genoSCORE algorithm to calculate PRS in a cohort of 2,081 AD and 2,327 CN Japanese subjects from J‐ADNI3 and Niigata University.

Results

The preliminary result shows an AUC of 0.659 (0.643‐0.675, 95% CI) between AD and CN subjects while PRS presents a bimodal distribution, but the main distribution trend is comparable to a normal distribution of PRS of the ADNI (US) subjects. Although this is significantly less than that seen for Caucasian individuals in the ADNI study, it compares well with the results generated when the reduced number of SNPs are used only in the ADNI cohort subjects (AUC = 0.691).

Conclusions

The preliminary results show the potential use of genoSCORE in the Japanese population. However, the results are likely affected by the limited SNP coverage from the available genetic data for the Japanese population. To determine the true performance of the genoSCORE algorithm in a Japanese population, genotyping samples from this study using our proprietary variaTECTTM II array providing full SNP coverage is in progress. We will then determine the performance and make adjustments to the algorithm if required in a Japanese population of suitably characterized Alzheimer’s disease patients and age‐matched healthy controls.
Regional cortical hypoperfusion observed in elderly adults prior to development of mild cognitive impairment
Authors: Zhang Linda , Frank Darya , Alfayate Eva , del Ser Teodoro , Medina Miguel , Strange Bryan A
Published: December 2023

Background

Cardiovascular disease is associated with increased risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD), although the underlying mechanisms are not well understood. While it has been theorised that cerebral hypoperfusion caused by heart failure may directly lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of AD, it has also been suggested that decreased perfusion occurs later in disease progression. We used arterial spin labelling (ASL) MRI to compare cerebral blood flow (CBF) between cognitively unimpaired elderly individuals who would remain cognitively stable and those who would later develop MCI to determine if hypoperfusion is detectable at a preclinical stage.

Methods

647 cognitively normal elderly participants with ASL and structural T1‐weighted MRI were selected from the Vallecas Project cohort, a single‐centre longitudinal study currently in its 12th year of annual follow‐up. 586 participants remained cognitively stable (CS) while 61 participants developed MCI over the course of the study. Cortical CBF maps derived from ASL images at the visit before MCI diagnosis were analysed in a voxelwise comparison with CS individuals, with age, sex, and total intracranial volume as covariates.

Results

CBF was significantly lower in the right insular cortex in future MCI converters than CS individuals (p<0.05, family‐wise error (FWE) corrected). Hypoperfusion was also significant in the anterior corpus callosum in future converters.

Conclusion

Cerebral hypoperfusion, as measured by ASL, can already be observed in individuals before the onset of clinical symptoms.
A Scoping Review of Outdoor Activities for People Living with Dementia
Authors: Tavilsup Pattara , Abolarin Margaret , Tran Lan , Lui Allysan , Seitz Dallas
Published: December 2023

Background

Outdoor or nature‐based activities can potentially offer benefits to improve the quality of life for people living with dementia (PLWD). The aim of this scoping review is to gain a clear understanding of current studies on outdoor activities for PLWD and their caregivers, as well as to identify gaps in the literature that may require further research.

Method

We systematically searched the following electronic databases: MEDLINE (Ovid); EMBASE (Ovid); APA PsycINFO (Ovid); CINAHL; Cochrane followed the guidelines recommended by the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses Extension for scoping reviews (PRISMA‐ScR) (Tricco et al., 2018). We included primary studies that met the following criteria:1) the study population includes either PLWD or people self‐identified as caring for people with dementia; 2) study outcomes are related to outdoor activities and/or nature; 3) the study report effects of how the outdoor activities change the diagnosis of dementia either qualitatively and/or quantitatively; 4) primary studies and literature reviews, dissertations, conference presentations or discussion papers, peer reviews and non‐peer reviewed; 6) all geographical areas but published in English and year 1980 to present

Result

Our initial search resulted in 7678 potentially relevant titles and abstracts. This number was decreased to 299 articles for the full‐text review. The extracted data have been charted by the following categories: authors, year of publication, study location, aims/purpose, characteristics of included studies, methods, outcomes, and key findings. The findings were summarized using frequency counts of concepts and characteristics. Thematic analysis was undertaken which identified four themes. More specifically, we identified 1) Benefits of outdoor or nature‐based activities; 2) Interventions to improve quality of life; 3) Barriers and challenges to accessing outdoors and nature; 4) Recommendations for outdoors or nature‐based activities.

Conclusion

There is growing evidence for the benefit of outdoor activities, recommendations to improve outdoor activities and which interventions are most beneficial among people with dementia. There is limited information about factors which may act as barriers for people with dementia which will be important to ensure wider access to these activities.
The relation of loneliness and social resources with neuropathology, and cognitive resilience to neuropathology
Authors: Wagner Maude , Wilson Robert S. , Boyle Patricia A , Leurgans Sue E. , Schneider Julie A , Bennett David A. A , Grodstein Francine , Capuano Ana W.
Published: December 2023

Background

Although numerous studies report an association between loneliness and social resources with cognitive decline and dementia risk, the underlying pathways remain to be explored. Thus, we investigated two possible pathways: an association of loneliness and social resources with (i) neuropathology and (ii) with cognitive resilience to neuropathology.

Method

We examined 792 decedents from the Rush Memory and Aging Project, free of dementia at their initial report of the psychosocial risk factors of interest (loneliness, social activity, social support, social network size); all eligible participants completed ≥2 cognitive evaluations and had a postmortem neuropathology evaluation. First, we examined the associations between each psychosocial factor and nine neurodegenerative and vascular neuropathologies, using linear or logistic regression models. Second, we assessed the associations between each psychosocial factor and two cognitive resilience (CR) measures. The measures quantify how late‐life cognitive levels (CR) and cognitive decline (CRSlope) differ from what is expected, given the profile of neuropathology. All models controlled for sex, education, age at death, and medical comorbidities.

Result

We found few associations between each psychosocial factor and all nine individual neuropathologies; for example, greater loneliness was not associated with higher global AD pathology (estimated mean difference [MD] for each one‐unit increment in loneliness score = 0.002, 95%CI = ‐0.07,0.07, P = .9), while more social engagement was associated with less global AD pathology (social activity: MD = ‐0.03, 95%CI = ‐0.11,0.05, P = .5; social support: MD = 0.05, 95%CI = ‐0.02,0.11, P = .2). However, we found strong associations between higher degree of loneliness with worse CR (MD = ‐0.25, 95%CI = ‐0.37,‐0.14, P<.0001) and CRSlope (MD = ‐0.23, 95%CI = ‐0.34,‐0.11, P = .0002). In addition, greater participation in social activities was associated with better CR (MD = 0.24, 95%CI = 0.12,0.36, P = .0001) and CRSlope (MD = 0.13, 95%CI = 0.01,0.25, P = .04). There was no relationship between social support or social network and CR.

Conclusion

These findings suggest that loneliness and social activity in late life are not directly associated with the accumulation of neuropathologies but may be associated with resilience to neuropathologies.
Single cell transcriptomic heterogeneity between sporadic early and late‐onset of Alzheimer’s disease
Authors: Millon Maria Beatriz Bistue , Bruno Martin Alejandro
Published: December 2023

Background

Regulatory T‐cells (Tregs) are key modulators of immune responses, and may play a key role in the pathophysiology of various neurodegenerative disorders, including Alzheimer’s disease (AD). However, the impact of Tregs modulation of immune responses during disease progression is poorly understood and still controversial. Thus, the main objective of our ongoing study is to depict a high‐resolution transcriptomic landscape of blood immune cells during spontaneous disease progression, which will facilitate a better understanding of the protective and/or pathogenic immune responses at different stages of the disease1‐3.

Method

In 2019 a Multi‐partner consortium to expand dementia research in Latin America (ReDLat) was created. The Consortium aims to combine genomic, neuroimaging and behavioral (clinical, cognitive, socioeconomic status –SES‐) data to improve dementia characterization and identify novel inroads to treat neurodegeneration in diverse populations. ReDLat initiative supports a basic platform anchored in Argentina, Brazil, Colombia, Peru, Mexico, Chile and USA. allowing us to expand our research and combine genomic, neuroimaging and behavioral (clinical, cognitive, socioeconomic status) data to improve dementia characterization.

To investigate changes in individual T cell subsets across progressive clinical conditions we included 4 healthy controls (CTLs), 4 early‐onset sporadic AD (EOAD), 4 late onset AD (LOAD) and 4 Parkinson disease patients (PD) from ReDLat. Peripheral blood mononuclear cells (PBMCs) were isolated and a 5' single‐cell transcriptome and immune repertoire sequencing was performed.

Results

We identified transcriptionally distinct subpopulations, heterogeneity of the immune system, T cell repertoire diversity and antigen specificity among groups. Interestingly, CD4+CD25+Foxp3+ T‐regs gene expression heterogeneity was observed between sporadic EOAD and LOAD, mainly related to cytotoxicity and inflammation. Our next step is to perform multiple association studies incorporating imaging, sex, cognition and socio‐economics status (SES).

Conclusion

Although full analysis is still in progress, we identified significant changes in individual T‐cell subsets among individuals across the four proposed groups, providing a unique opportunity to identify new risk factors and therapeutics targets for AD.

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3‐Baek H (2016) Oncotarget.
Impact of White Matter Hyperintensity Changes on Cognition One Year After Mild Ischemic Stroke
Authors: Jochems Angela CC , Maniega Susana Muñoz , Clancy Una , Arteaga Carmen , Garcia Daniela Jaime , Hewins Will , Locherty Rachel , Wiseman Stewart , Hernandez Maria del C. Valdes , Chappell Francesca M , Stringer Michael S , Thrippleton Michael J , Doubal Fergus N , Wardlaw Joanna M
Published: December 2023

Background

White matter hyperintensities (WMH) are a main MRI feature of cerebral small vessel disease, and are associated with increased risk of stroke and dementia. Progression can lead to cognitive decline, but some evidence suggests that WMH can also regress. Regression might relate to better clinical outcomes, but this is not well examined yet. We explored if net WMH volume change accounts for changes in cognition 1‐year after mild ischemic stroke. We also explore tissue signatures in areas of white matter change using brain diffusion imaging.

Method

In a prospective study, we assessed vascular risk factors (VRF), structural and diffusion‐tensor brain MRI and cognition (Montreal Cognitive Assessment; MoCA) at baseline (≤3 months post‐stroke) and at 1‐year. We assessed change in cognition over 1‐year using a linear mixed model. Predictors were age, sex, stroke severity (National Institutes of Health Stroke Scale; NIHSS), combined VRFs, disability (modified Rankin Score), occurrence of incidental infarct in‐between visits and WMH volume (%intracranial volume). We studied tissue areas of stable normal‐appearing white matter (NAWM), stable WMH, regressing and progressing WMH (Figure1) and measured diffusion‐tensor fractional anisotropy (FA) and mean diffusivity (MD), to assess microstructure in each area

Result

At baseline, mean age = 67.5 (SD = 11.1), 66% male (N = 229), mean MoCA score = 25.0 (SD = 3.5). Between baseline and 1‐year post‐stroke, MoCA score decreased with older age (standardized B[95%CI]: ‐0.271[‐0.383; ‐0.159]) and increasing NIHSS (‐0.193[‐0.287; ‐0.099]). Areas of NAWM that progress to WMH already have lower FA and higher MD at baseline than NAWM that stays NAWM (N = 191; Figure2). WMH that regress to NAWM have higher FA and lower MD than stable WMH. At 1‐year, MD values seem higher and FA values seem lower in progressing WMH than at baseline.

Conclusion

Cognition deteriorates 1 year post‐stroke with older age and higher stroke severity, but not with WMH changes, when considering net WMH volume. Areas of WMH changes exist within individuals, these areas show different underlying tissue structures before becoming apparent on conventional MRI, indicating that WMH regression is real. Separate areas of WMH progression and regression might be more sensitive to cognitive changes and potentially be intervention targets.
Effects of β‐amyloid deposition, dopaminergic depletion, and perfusion on clinical features in cognitively impaired patients
Authors: Lee Young‐gun , Jeon Seun , Kang Sungwoo , Baik Kyoungwon , Ye Byoung Seok
Published: December 2023

Background

Although mixed pathologies are common in Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), effects of β‐amyloid and dopaminergic depletion on brain perfusion and clinical features have not been elucidated.

Method

In 99 patients with cognitive impairment due to AD and/or DLB and 32 control participants, 18F‐Florbetaben (FBB) PET, dual‐phase dopamine transporter (DAT) PET, and brain MRI were performed to measure β‐amyloid standardized uptake value ratio (SUVR), dopaminergic depletion in the ventral striatum, caudate, and putamen, and regional brain perfusion. Cognitive score, visual hallucination (VH), cognitive fluctuation (CF), and rapid eye movement sleep behavior disorder (RBD) were evaluated. Relationship among global FBB‐SUVR, striatal DAT uptakes, regional brain perfusion, clinical symptoms, and cognitive scores were evaluated using general linear or logistic regression models as appropriate.

Result

Global and mean lobar FBB SUVRs negatively correlated with DAT uptakes in the ventral striatum and caudate but not with putamen DAT uptake. Lower ventral striatal DAT uptake was associated with right temporo‐parietal hypoperfusion and hyper‐perfusion in the anterior cingulate cortex, vermis, motor cortex, and hippocampus, while higher FBB SUVR was associated with hypoperfusion in the left entorhinal cortex and temporo‐parietal cortex. Lower ventral striatal DAT uptake increased the risks of VH and RBD directly and indirectly through the mediation of hippocampal hyper‐perfusion, while hippocampal hyper‐perfusion fully mediated the effect of lower ventral striatal DAT uptake on the risk of CF. Higher FBB SUVR and lower DAT uptake were associated with language, memory, and executive dysfunction directly and indirectly through the mediation of regional perfusion, while regional perfusion fully mediated their effects on visuospatial dysfunction.

Conclusion

β‐amyloid deposition and striatal dopaminergic depletion reflecting AD‐ and DLB‐related neurodegenerations are inter‐correlated but differently contribute to regional perfusion changes and cognitive dysfunction.
Virtual brain model‐guided optimization of transcranial direct current stimulation in Alzheimer’s disease
Authors: Luppi Janne , Stam Cornelis J , Scheltens Philip , de Haan Willem
Published: December 2023

Background

Non‐invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) can potentially counteract disrupted local and distributed brain network activity in Alzheimer’s disease (AD) with a beneficial effect on cognition. However, results of tDCS studies in AD up till now are inconsistent, probably partly due to different methodological choices such as electrode placement. We therefore explored tDCS optimization using a virtual brain network model of AD. Our aim was to compare a large, representative set of virtual tDCS intervention setups, to identify and potentially explain the optimal theoretical tDCS electrode positions for reducing or restoring functional network disruption.

Method

We simulated 20 tDCS setups in a computational macroscopic dynamic network model of 78 neural masses, coupled according to human structural topology. AD network damage was simulated using an activity‐dependent degeneration algorithm, which produces typical gradual oscillatory slowing and loss of connectivity. Current flow modeling was used to estimate tDCS‐targeted cortical regions for different electrode positions, and excitability of the pyramidal neurons of the corresponding neural masses was modulated to simulate tDCS. Outcome measures were relative power spectral density in the lower (8‐10 Hz) and upper (8‐13 Hz) alpha bands, total spectral power, posterior alpha peak frequency, and connectivity measures phase lag index (PLI) and amplitude envelope correlation (AEC).

Result

The performance of different tDCS strategies varied considerably, with best setups temporarily improving all spectral and connectivity outcome measures, while other setups had little to no effect, or even caused network deterioration. The best performing setup involved right parietal anodal stimulation, with a contralateral supraorbital cathode. A clear correlation between the network role of a region (e.g. hub) and its involvement in successful tDCS was not observed.

Conclusion

Modeling tDCS produces specific, falsifiable predictions on how to counter disrupted brain dynamics in AD. In follow‐up studies, our general predictions will be compared to those of personalized virtual models, and then validated with tDCS‐magnetoencephalography (MEG) in a clinical AD patient cohort. This modeling‐informed approach can guide and perhaps accelerate tDCS therapy development, as well as enhance our understanding of tDCS effects.