bluuebunny/crossref_metadata_2025 huggingface dataset:
Alzheimer’s disease perturbs gene‐gene correlation networks across brain regions
Authors: Mitra Sanga , B P Kailash , Srivatsan C R , Saikumar Naga Venkata , Philip Philge , Narayanan Manikandan
Published: June 2023

Background

Functional imaging has revealed how Alzheimer’s disease (AD) disrupts functional connectivity between brain regions, but the molecular basis of such changes has been less explored1. Genomic studies can reveal molecular/gene biomarkers in AD, but they have mostly been confined to within‐region analyses2. Here, we perform inter‐region analysis to explore how synchronized activities across brain regions are disrupted by gene‐pair rewiring in AD.

Method

We retrieved data on 264 AD and 372 control human post‐mortem RNA‐seq samples from Mount Sinai Brain Bank dataset for four brain regions: frontal pole (FP), superior temporal gyrus (STG), parahippocampal gyrus (PHG), and inferior frontal gyrus (IFG)3. Considering two brain regions at a time, we identified all pairs of genes across the two regions whose correlation strength is significantly altered in the AD group relative to the Control group4 (Fig. 1). The network of such differentially correlated (DC) genes provides information complementary to known differentially expressed genes in AD, and probably reflects cell‐intrinsic changes5 since we adjust for cell compositional effects.

Result

We found extensive DC gene pair rewiring in AD between pairs of brain regions, the most prominent being the coupling of PHG with other brain regions. Our analyses revealed that each brain region mostly uses a unique set of genes while interacting with other brain regions. Decomposing the bipartite DC network into gene modules revealed that certain gene modules affected in AD were enriched for synaptic signaling and ion transport pathways, whereas several others were enriched for AD GWAS (Genome‐wide Association Studies) signals. A module enriched for AD GWAS signal is also enriched for NF‐κβ signaling pathway, a key mediator of brain inflammation in AD. Beyond modules, we also identified individual genes such as ZKSCAN1 (Zinc Finger with KRAB And SCAN Domains) acting as a hub gene for most of the inter‐region comparisons and were enriched for AD GWAS signal.

Conclusion

These findings provide novel insights into the network of pairwise gene relations underlying the functional connectivity between brain regions and highlights how disruption of different factors rewires this network in AD patients.

1. Science, 1241‐4,2015.

2. Genome Med., 104,2016.

3. Sci Data., 180185,2018.

4. BMC Res Notes., 54,2017.

5. Bioinformatics, 1584‐91,2015.
Perplexity and its structural cerebral correlates: A promising marker for cognitive decline?
Authors: Herold Christina Josefa , Frankenberg Claudia , Abulimiti Ayimunishagu , Schultz Tanja , Kong Li , Schröder Johannes
Published: June 2023

Background

Recent studies identified linguistic changes as a promising marker of early Alzheimer´s disease (AD) and mild cognitive impairment (MCI). Perplexity – i.e. a measure of content complexity and therefore predictability of speech – is considered as a predictive marker of AD and MCI in otherwise healthy elderly (Frankenberg et al., 2019). A higher score indicates a reduced predictability, i.e. for persons with high variability in their speech, the perplexity feature will have a very high value. However, the underlying brain structures are still unknown.

Method

Perplexity was automatically examined in voice recordings of extensive autobiographical interviews obtained in 38 participants in their mid‐70ties (N = 26 cognitively healthy, N = 12 with MCI) from the Interdisciplinary Longitudinal Study on Adult Development and Aging (ILSE). Perplexities of 1‐gram and 2‐gram language models are investigated: The 1‐gram language model considers one word at a time, the 2‐gram language model considers each word in the context of its predecessor. Whole‐brain correlations between gray matter and perplexity were controlled for total intracranial volume, sex and education.

Results

Analyses yielded significant positive correlations between measures of perplexity and right parahippocampal gyrus, right middle occipital gyrus, left middle temporal gyrus and right superior temporal gyrus (1 gram) as well as left precuneus and left anterior cingulate (2 gram).

Conclusion

The correlation of perplexity with parahippocampal gyrus is paralleled by associations between this structure and autobiographical memory (Frankenberg et al., submitted). The superior temporal gyrus points to planum temporale, while the precuneus is involved in motor coordination and is connected to the anterior cingulate, which is associated with functions such as error detection and attention. The middle temporal gyrus is also considered to be language‐relevant in particular for lexical‐semantic and conceptual semantic aspects and the middle occipital gyrus is discussed as the Occipital Word Form Sensitive Area.
Genetic mapping of APP and amyloid‐β biology modulation by trisomy 21
Authors: Mumford Paige , Tosh Justin , Anderle Silvia , Gkanatsiou Eleni , Lau Gloria , Noy Sue , Cleverley Karen , Saito Takashi , Saido Takaomi C. , Yu Eugene Y. , Brinkmalm Gunnar , Portelius Erik , Blennow Kaj , Zetterberg Henrik , Tybulewicz Victor , Fisher Elizabeth , Wiseman Frances K
Published: June 2023

Background

Individuals who have Down syndrome frequently develop early onset Alzheimer’s disease, a neurodegenerative condition caused by the build‐up of aggregated amyloid‐β and tau proteins in the brain. Amyloid‐β is produced by APP, a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimer’s disease in these individuals.

Methods

Here we use a combination of next‐generation mouse models of Down syndrome (Tc1, Dp3Tyb Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid‐β accumulation (AppNL‐F) to determine how chromosome 21 genes other than APP modulate APP/amyloid‐β in the brain when in three copies.

Results

We demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid‐β accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid‐β accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2.

Conclusion

Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid‐β in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD‐DS compared to those who have familial AD caused by triplication of APP.
Improving Asian Americans’ awareness and interest in clinical research: Examining the role of culturally tailored messaging
Authors: McGowan Melissa , Jarvis‐Gibson Jeanne , Bui Elise , Rehberg Kathryn , Mitchell Alexandra , Manohar Rhea , Simoneau Elizabeth , Miscally Memi , Massett Holly A
Published: June 2023

Background

Asian Americans and Pacific Islanders (AAPI) are one of the fastest‐growing populations in the United States, yet these communities comprise less than one percent of participants in NIH’s Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) clinical research. This underrepresentation is due to numerous barriers well‐documented in the literature, with a key deterrent being a lack of culturally and linguistically appropriate outreach materials. This abstract presents findings from focus groups conducted by the National Institute on Aging (NIA) to identify culturally and linguistically appropriate message concepts that raise awareness, address barriers and motivate Asian American and Pacific Islanders to consider participation in AD/ADRD research studies.

Method

Eighteen virtual focus groups (N = 103 individuals) were conducted with Chinese Americans, Filipino Americans, and Indian Americans who are at‐risk for AD/ADRD or are caregivers to people living with dementia. Focus groups were conducted in Chinese, Hindi, Tagalog and English. The sessions tested multiple audience‐tailored message concepts designed to increase interest and encourage participation in AD/ADRD clinical research. These discussions also examined participants’ preferred language, terminology and communication approaches.

Result

Overall, message concepts that 1) emphasized the value of caring for family members; 2) offered a sense of hope; 3) communicated a clear call to action; and 4) provided opportunities to learn more information about clinical research resonated across all groups. Between participant audiences, there were some important differences, including around terminology preferences. For example, Chinese‐American participants expressed concern about the term “caregiver” as it implied that taking care of a loved one was a burden or a professional job, rather than a familial responsibility. Concept visuals will be presented.

Conclusion

This research conducted by NIA improves our understanding of messaging concepts that do and do not resonate with AAPI, providing valuable insight into themes that should be leveraged to effectively promote awareness about AD/ADRD clinical research with these communities. The finding from this study were used to develop, finalize and make available to the research community a suite of culturally and linguistically appropriate materials to increase awareness and interest in AD/ADRD clinical research among AAPI communities.
Understanding counseling challenges of dementia risk prediction through discourse‐linguistic approaches – the media perspective of the PreTAD study
Authors: Schwegler Carolin , Werken Katrin , Snijders Katharina Elisabeth , Stümpel Johanne , Rostamzadeh Ayda , Ribaldi Federica , Marquié Marta , Schmitz‐Luhn Björn , Boada Mercè , Frisoni Giovanni B , Jessen Frank , Woopen Christiane
Published: June 2023

Background

Diagnostics for early detection of Alzheimer’s disease (AD), using biomarkers, and dementia risk prediction are constantly evolving which will eventually lead to an extended availability even for symptom‐free individuals. These developments of predictive medicine are changing medical procedures and ways of thinking as well as opportunities for patients. Furthermore, they are slowly exerting influence on public attitudes towards medicine. The PreTAD project aims at providing insights on people’s perspectives towards prediction as well as the effect of predictive medicine on individuals and society from a clinical, ethical, legal and linguistic point of view.

Method

In the linguistic part of the PreTAD study, we address the fact that patients and their relatives bring common knowledge, discursive arguments and attitudes – and thereby certain expectations – into the doctor‐patient‐interaction, for example into a counseling visit for predictive interventions. Among personal sources, the origin and distribution of that knowledge can be the public media discourse (online and offline). On the basis of an empirical linguistic media analysis (German, English), we seek to determine public knowledge about AD and dementia risk prediction before we aim to elaborate communicative patterns and influential arguments of the public discourse on this topic.

Result

The findings of the linguistic approach of the PreTAD study contribute to the understanding of people’s perspectives, preconceptions, stereotypes, expectations and hopes regarding dementia risk prediction. To ensure good clinical practice regarding predictive interventions, especially in pre‐symptomatic at‐risk stages, the latter have to be acknowledged and carefully negotiated in doctor‐patient‐interaction.

Conclusion

A closer look at public knowledge, influential communicative patterns and attitudes towards AD, early detection diagnostics, and dementia risk prediction can shed light on the broader context of present counseling challenges.
Extended insight into selective vulnerability of neurons in AD using machine learning approach
Authors: Srivastava Gyan P
Published: June 2023

Background

Alzheimer’s disease is characterized by the spread of tau pathology and loss of neurons with a specific spatio‐temporal pattern. Recent publications have attempted to uncover the identity of the selectively vulnerable neurons using single‐nucleus transcriptomic data derived from affected brain regions from patients with Alzheimer’s disease. Correlating advancing tau pathology as measured by Braak staging with neuronal loss, one of the major markers reported for the susceptible excitatory neurons was RORB, which was also validated using quantitative neuropathological methods. However, the heterogeneity of RORB expression in the highlighted clusters suggested that not all RORB expressing neurons may be susceptible. Besides, further classifying neuronal population into sub‐populations shows population specific RORB expression.

Method

Therefore, we further extended our insight into selective vulnerability of neuronal sub‐populations using a machine learning (ML) approach. We identified a transcriptionally homogeneous population using ML‐based classifiers with high accuracy and AUC > 0.90.

Result

Our analysis shows that fine mapping of transcriptionally similar neurons is key to pinpoint sub‐populations that are selectively lost during later Braak stages. For instance, refined sub‐population analysis revealed that neuronal populations with moderate RORB expression were lost while those with higher RORB expression do not show significant change with advancing Braak stage.

Conclusion

Our analysis provides a reference of neuronal sub‐populations and associated markers that could be further interrogated to uncover potential mechanisms that underlie selective degeneration in Alzheimer’s Disease.
G protein‐biased GPR3 signaling induces glial activation and ameliorates amyloid pathology in a preclinical Alzheimer’s disease mouse model
Authors: Thathiah Amantha , Huang Yunhong , Huang Yunhong , Guimaraes Thais Rafael , Todd Nicholas , Ferguson Carolyn , Weiss Kathryn , Stauffer Fiona , McDermott Breanne , Hurtle Bryan T. , Saito Takashi , Saido Takaomi , MacDonald Matthew L , Farris Sean P. , Homanics Gregg E.
Published: June 2023

Background

Biased G protein‐coupled receptor (GPCR) ligands preferentially activate G protein‐ or β‐arrestin signaling pathways and are leading to the development of drugs with superior efficacy and reduced side‐effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer’s disease (AD), biased GPCR signaling is an unexplored area of investigation in AD. Previous work demonstrated that Gpr3 deficiency ameliorates amyloid‐β (Aβ) pathology. However, Gpr3‐deficient mice display several adverse phenotypes, including elevated anxiety‐like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein‐signaling. We hypothesized that generation of a G protein‐biased GPR3 mouse model, which maintains G protein‐signaling while eliminating β‐arrestin signaling, would attenuate AD‐associated phenotypes while preserving the beneficial effects of GPR3‐mediated G protein‐signaling.

Methods

We used a CRISPR/Cas9 genome‐editing strategy to develop two novel G protein‐biased GPR3 mouse models. We utilized a broad range of molecular, cellular, and biochemical methodologies, including mass spectrometry, immunoblot and immunohistochemical analyses, RNA profiling, and behavioral testing to determine the physiological relevance of G protein‐biased GPR3 signaling in naïve mice and in the preclinical AppNL‐G‐F AD mouse model.

Results

We determine that, in contrast to Gpr3‐deficient mice, G protein‐biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We then established that GPR3 is expressed in neurons, microglia, and astrocytes and is associated with cell‐type‐specific effects on AD pathogenesis. Accordingly, we determine that G protein‐biased signaling leads to a reduction in Aβ generation in neurons, the activation and hypertrophy of disease‐associated‐microglia (DAM) and pan‐reactive astrocytes, and to an increase in amyloid plaque compaction in AppNL‐G‐F mice.

Conclusions

These studies provide the first demonstration of G protein‐biased signaling in neuronal regulation of Aβ generation and microglial and astrocytic regulation of neuroinflammation in a preclinical AD mouse model and open an exciting area of investigation on biased agonism as a therapeutic intervention strategy for AD.
Care management needs of family caregivers at different stages of dementia
Authors: Huang Huei‐Ling , Shyu Yea‐Ing L , Hsu Wen Chuin
Published: June 2023

Background

In Taiwan, more than 90% of persons with dementia who live at home are cared for by family caregivers. According to previous researches, family caregivers of dementia have a higher level of burden than almost all other diseases of old age. In addition, due to the different courses of dementia in each stage, coupled with the complexity of its problems, persons with different stages of dementia have different care demands. Therefore, this study aimed to explore the care management needs of family caregivers caring for persons with dementia at different stages.

Method

A cross‐sectional study was conducted. Of the 250 family caregivers of persons with dementia were included. The Care Management Needs Scale (CMNS) was used to measure the care management needs of family caregivers, which is divided into six dimensions of needs (care service, psychological support, immediate information, anticipated information, referral and tracking of long‐term care resources, and individual case management service). The severity of dementia was determined by a neurologist using the Clinical Dementia Rating (CDR) scale.

Result

From very mild dementia to severe dementia, the dimension with the highest needs at each stage are individual case management service, immediate information, referral and tracking of long‐term care resources, and care service, respectively. The overall needs, care service and psychological support in moderate dementia are significantly higher than very mild dementia. According to the needs of each item, the three highest needs are related to the dimension of immediate information and individual case management service in very mild dementia and mild dementia; in the case of moderate to severe dementia, care service began to appear in the three highest needs.

Conclusion

The study concluded that different stages of dementia have different care management needs. When moderate dementia (CDR = 2.0), the need for care services will begin to increase. The findings suggest that care management should be provided for different stages of dementia. This study’s results provide a knowledge base for designing dementia stage‐specific care management in clinical practice and developing community‐based, long‐term care systems for family caregivers of persons with dementia.
Dietary pattern and brain structure among young adults
Authors: Thomas Aline , Labache Loïc , Tsuchida Ami , Arsandaux Julie , Zago Laure , Tzourio Christophe , Crivello Fabrice , Samieri Cécilia
Published: June 2023

Background

Environmental factors, such as nutrition, influence brain physiology and health throughout the life course. While research has focused on the extremes of the age spectrum, less is known about early adulthood, yet a critical period for the consolidation of brain maturation and the building of adult behaviors. Nutrition may impact late maturational changes in the post‐adolescent brain and contribute to the degree of brain reserve that minimizes the risk to develop dementia. We took advantage of a large sample of young adults to evaluate the association of dietary behavior with brain structure characteristics.

Method

This cross‐sectional study included 1721 university students (18‐35 years‐old) from the French i‐Share cohort, who underwent brain MRI. A 12‐item online Food Frequency Questionnaire was used to evaluate consumption in major food groups and to determine dietary patterns from Principal Component Analysis (PCA). Multivariable‐adjusted linear regressions were used to estimate the association of PCA scores with brain structure (cortical thickness and surface area, grey matter and white matter volumes, diffusion parameters).

Result

The first PCA component (explained variance, 17%) contrasted a healthy diet (higher fruit and vegetable intakes) to a poor diet (higher fast food, sugary drink and snack consumptions). In models adjusted for total intracranial volume, age, sex, physical activity, body mass index, alcohol and tobacco consumptions, a higher PCA score (reflecting healthier diet) was associated with lower total gray matter volume (β for 1 point score = –0.17 [95%CI, –0.31; –0.03] cm3), in various brain areas (Figure). Healthy diet was also associated with lower global white matter volume (β = –0.18 [–0.32; –0.03] cm3). No association was found with diffusion tensor imaging, and neurite orientation dispersion and density imaging metrics in the white matter.

Conclusion

In this large sample of young adults, healthier diet was associated with lower brain volumes, independent of multiple potential confounders. Gray matter volume loss during post‐adolescence is a marker of brain maturation; thus, environmental factors emphasizing this loss may benefit maturation. Our results raise the hypothesis that a healthy diet may favor and a poor diet may hamper brain maturation; an assumption which deserves further investigation in other populations.
Alpha‐secretase ADAM10 as a blood‐based biomarker in Alzheimer’s disease and type 2 diabetes mellitus
Authors: de Oliveira Danielle dos Santos Maia Salheb , Grigoli Marina Mantellatto , Cominetti Marcia Regina
Published: June 2023

Background

AD (Alzheimer’s disease) is a progressive neurodegenerative disease characterized by extensive neuronal losses and deposits of neurofibrillary tangles and senile plaques. Patients with T2DM (type 2 diabetes mellitus) have structural brain changes and cognitive impairment, with a high risk of developing AD. These data suggest that insulin may play a key role in brain activity and memory formation. Based on these findings, AD has been called by some researchers T3DM (type 3 diabetes mellitus) or cerebral diabetes. Our group has been studying peripheral biomarkers for AD since 2010. Among them, our focus is the study of ADAM10 (A Disintegrin And Metalloprotease), an α‐secretase that inhibits the formation of senile plaques and, therefore, is protective against AD. We observed that this protein is decreased in platelets and increased in plasma of elderly people with this dementia compared to cognitively healthy elderly people.

Method

The participants of this research were people aged 60 or over, divided into 4 groups: participants with AD, participants with T2DM, participants with AD and concomitant presence of T2DM and cognitively unimpaired (CU) controls with regular plasma glucose levels. In this work, due to the COVID‐19 pandemic, we are presenting the results of a pilot trial carried out with data collected from 9 participants in each group. Patients’ blood was collected and plasma was used in assays to determine ADAM10 levels using an ADAM10‐specific Enzyme‐Linked Immunosorbent Assay (ELISA) kit (Life Sciences, catalog number LS‐F23768). Results were confirmed using SDS‐PAGE followed by western blotting analyses with the primary antibody anti‐ADAM10 (Ab39180 rabbit, Abcam). A “young control” performed with plasma samples from a young donnor and soroalbumin bands were used as endogen controls to avoid interassay biases in the densitometry analyses.

Result

Plasma ADAM10 was elevated in persons with AD and T2DM and these levels were even higher when plasma from patients with both diseases was analysed.

Conclusion

This study shows a clinical impact related to a new approach that could be used in the treatment of AD, also observing the metabolic and inflammatory states of the patients. Study also contributes to a better understanding of the biology of the disease itself.
Dementia increases medical costs and length of hospital stay of motorcycle crash‐related hospitalizations: A nationwide population‐based cohort study in Taiwan
Authors: Liu Chih‐Ching
Published: June 2023

Background

Prior studies showed dementia had a higher risk of hospitalization for a motor vehicle accident injury than the general population. However, the effect of dementia on the medical cost and length of inpatient days of motorcycle crash‐related hospitalizations still unknown. This study describes the total amount of medial cost and length of inpatient days for motorcycle crash‐related hospitalizations among patients with and without dementia and assesses whether dementia is related to a higher medical cost and length of inpatient days for motorcycle crash‐related hospitalizations.

Method

This was a population‐based, retrospective cohort study. Dementia aged 40‐64 and its age‐ and sex‐ matched participants without dementia were identified when they had the first hospitalization for MVAI. Data were obtained from the Taiwan National Health Insurance Research Database entries and Taiwan Police‐reported Traffic Accident Registry between 2006 and 2015. Linear regression with generalized estimating equations were applied to compare the medical cost and length of inpatient days of people with and without dementia.

Result

Over the 10‐year follow‐up periods, the mean medical expenses related to the first hospitalization for MVAI among patient with and without dementia was NTD $ 81207±136647 and NTD $ 58947±135543, respectively, with a difference in log10 average inpatient costs of NTD $ 0.082 (95%CI 0.054‐0.110). Additionally, compared to patients without dementia, patients with dementia were significantly related to a longer inpatient stay due to the first hospitalization for MVAI (11.6±15.9 vs. 9.0±32.3 days), with a difference in log10 average inpatient days of 0.054 days (95%CI 0.029‐0.078).

Conclusion

In motorcycle crash‐related hospitalizations, dementia was associated with higher medical cost and longer length of inpatient stay than those for patients without dementia.
Combining data and mathematical models for the design of personalised light interventions to improve sleep timing in aging
Authors: Rodriguez Thalia , Cleator Sean F , Monica Ciro Della , Revell Victoria Louise , Dijk Derk‐Jan , Skeldon Anne C
Published: June 2023

Background

More than 70% of people living with dementia (PLWD) experience sleep disturbances (e.g., early bedtime, long time in bed) even in the early stages of cognitive decline. Light interventions have been proposed as a promising non‐pharmacological approach to improve sleep timing, but current implementations are burdensome and not personalised. Quantitative tools for designing pragmatic light interventions for the home‐setting could benefit PLWD and their carers.

Here, we report on a quantitative computational tool which combines readily collectable data with a new mathematical model to provide personalised advice on light interventions. Our focus is on designing low‐burden interventions requiring minimal changes to lifestyle or sleep‐wake routines.

Method

Eighteen older adults (65‐80 y) monitored their light exposure and sleep for a period of 7‐10 days at home using a wristworn monitor (Actiwatch Spectrum) and a sleep diary from which we calculated daily sleep timing and duration.

We constructed a new mechanistic mathematical model for sleep timing that incorporates sleep homeostasis, circadian rhythmicity and light data (HCL). For each participant, we fitted the model to their sleep timing and duration data. We then used simulations to predict the effect of different light interventions on sleep timing and used optimisation to determine light exposure patterns that promote a target sleep onset time.

Result

Individuals varied in their sleep duration (07:18 ± 0:56 hh:mm; mean ± SD) and mid‐sleep timing (03:22 ± 01:00 hh:mm). We successfully retrieved ‘personal’ model parameters that accurately captured sleep duration and timing for 17 of the 18 participants. Our simulations indicated that the effect of a given light exposure pattern on sleep timing depends on the personalised model parameters, suggesting that an intervention that works for one person may not work for someone else. We were able to propose light exposure patterns requiring minimal behavioural change, facilitating adherence.

Conclusion

It is possible to extract individual physiological parameters for sleep‐wake regulation from data collected in the field. These individual parameters can be used to design personalised light interventions. Our fully‐documented code could be combined with passive sleep monitors and environmental light sensors to unobtrusively recommend personalised light exposure patterns in close‐to real time.
Air pollution and the risk of dementia: The rotterdam study
Authors: de Crom Tosca O.E. , Oudin Anna , Ginos Bigina N.R. , Ikram M. Kamran , Voortman Trudy , Ikram M. Arfan
Published: June 2023

Background

Air pollution has been suggested to increase the risk of dementia, by triggering neuro‐inflammation, oxidative stress, and cerebrovascular damage. However, studies on the association between exposure to air pollution and the risk of dementia yielded inconsistent results. We therefore determined exposure to air pollution in association with the risk of dementia and cognitive decline in the population‐based Rotterdam Study.

Method

Between 2009 and 2010, we determined air pollutant levels at participants residential addresses using land use regression models. Determined air pollutant levels included particulate matter with an aerodynamic diameter of less than 10 µm (PM10) and 2.5 µm (PM2.5), a proxy of elemental carbon (PM2.5 absorbance), nitrogen oxide (NOx), and nitrogen dioxide (NO2). As the individual air pollutant levels were highly correlated with each other (r = 0.71‐0.98), we obtained the first unrotated component of a principal component analyses (PCA) for all air pollutants. We followed participants up for dementia until 2018 and determined cognitive performance during two subsequent examination rounds. Using Cox proportional hazard models and linear mixed models, we determined the association of exposure to air pollution with the risk of dementia and cognitive decline.

Result

Of the 7511 non‐demented participants at baseline (median age 68 years, 58.6% women), 545 developed dementia during a median follow‐up of 7 years. Mean ± standard deviation (SD) levels per µg/m3 were 26.1 ± 1.0 for PM10, 16.8 ± 0.4 for PM2.5, 1.5 ± 0.1 for PM2.5 absorbance, 46.1 ± 12.2 for NOx, and 32.6 ± 3.4 for NO2. The individual air pollutant levels were not significantly associated with the risk of dementia, neither was the first unrotated component of a PCA for all air pollutants (hazard ratio [95% confidence interval] per SD increase: 1.04 [0.95‐1.15], Figure 1). Air pollutant levels were also not associated with decline in cognitive function.

Conclusion

Exposure to air pollution was not statistically significantly associated with the risk of dementia or cognitive decline. Yet, observed effect estimates were in the hypothesized direction and variability in pollutant levels may have been to limited to identify meaningful associations.
The differential contribution of immediate memory and executive functions in age‐related neurocognitive disorders
Authors: Abbatantuono Chiara , Taurisano Paolo , Pepe Ilaria , Clemente Livio , Alfeo Federica , Paparella Giulia , Calia Clara , Lancioni Giulio , De Caro Maria Fara
Published: June 2023

Background

Comprehensive neuropsychological assessment (NPA) has proven to be a diagnostic and monitoring procedure that contributes to the understanding of neurocognitive disorders (NCDs). Despite memory deficits being considered as hallmarks of age‐related cognitive decline, executive impairment has emerged as the strongest correlate of functional dependence that characterizes major NCD. Hence, the present study aims to: (1) examine the neuropsychological predictors of major NCD; (2) compare between indices of immediate memory and executive functions involved in cognitive decline.

Method

Out of a dataset of 179 (Mage = 75±5.43; women = 96) elderly outpatients, 97 individuals (Mage = 76±5.72; women = 51) met the DSM‐5 criteria for NCD as they presented impairment in at least one cognitive domain and, in the case of major NCD, impact on activities of daily living. The sample underwent NPA consisting of a two‐screening procedure; ten domain‐specific tests; psychodiagnostic‐functional evaluation. Analyses relied on multivariate and non‐parametric tests to examine differential clinical profiles and NPA tools, respectively.

Result

A prior analysis using the Hosmer‐Lemeshow test confirmed the goodness of the model (χ2 = ‐4,771; p = .782) (diagnostic labels: major vs. mild NCDs). The final model obtained could correctly predict 71% of cases. Logistic regression through backward elimination revealed that the lower the scores at Frontal Assessment Battery (FAB), the greater the chances of fitting major NCD (vs. mild NCD) (B = ‐.284; p = .006). Friedman test enabled multiple comparisons within the whole sample, and by considering mild and major groups separately, with respect to immediate memory (FCSRT‐ISC and Babcock Story‐IR) and executive indices (Clock Drawing Test and Digit Span Backwards). The analyses showed a significant difference between the ranks of test scores only within the major NCD group through Bonferroni correction (χ2 = 8.813, p = .032), revealing a greater drop in Clock Drawing Test than in Babcock Story‐IR (χ2 = ‐.906, p = .030).

Conclusion

These preliminary findings point to the importance of considering, besides memory indices, executive performances in elderly patients affected by severe cognitive‐functional impairment, consistent with potential implications of planning difficulties in the progressive loss of everyday life autonomy. Screening for executive functioning may also enhance the understanding about the clinical course from mild to severe disease, thus orienting clinicians in the differential diagnosis, secondary prevention, and treatment of NCDs.
Eye movement dysfunction for screening mild cognitive impairment
Authors: Song Jiaqi , Wang Lisong , Lü Yang
Published: June 2023

Background

Early screening of cognitive impairment is crucial to delay cognitive deterioration and daily living disability in the elderly. However, the complexity and high cost of existing strategies appear to be great limits to the early screening on a large scale. Eye movement test shows a huge advantage in the early identification of mild cognitive impairment (MCI) because of quick, non‐invasive and cost‐effective features.

Method

The study involved a total of 151 participants: 90 MCI patients and 50 cognitive normal controls (CN) . All participants underwent eye movement signals under four visual tasks, including direct gaze towards target, smooth pursuit tasks, saccading toward a jumping target and looking away a jumping target. Five features were extracted from eye movement signals by linear and nonlinear analysis, including saccade number in resting state, saccade number in smooth persuit tasks, saccade lantency, antisaccade lantency, antisaccade error rate. Discriminant features selection was performed using the logistic regression (LR) analysis. Receiver operator characteristic (ROC) analyses and the area under the curve (AUC) were employed to investigate classification ability.

Result

After the penalization of LR analysis, there were two top features that exhibited significant differences between MCI and CN, which included saccade number in smooth pursuit tasks and antisaccade error rate (p<0.05). ROC curves showed a favorable diagnostic accuracy of the two features in the discrimination between controls and MCI (AUC: 0.823, P<0.01).

Conclusion

These results suggest that eye movement test has the potential to screen patients with MCI from the elderly with cognitive normality. Therefore, eye movement test is a powerful tool for broad screening in community‐dwelling older adults.
Identification of genetic regulators of human metabolites in CSF
Authors: Wang Ciyang , Mafimoghaddam Samira , Novotny Brenna C , Sung Yun Ju , Farias Fabiana H.G. , Yang Chengran , Wang Fengxian , Marquié Marta , Boada Mercè , de Rojas Itziar , Alvarez Ignacio , Aguilar Miquel , Fernandez Victoria , Harari Oscar , Cruchaga Carlos
Published: June 2023

Background

Brain metabolism perturbation in dementia is not well understood. Metabolite levels are quantitative traits that have been linked to genetic loci. Existing metabolite quantitative trait loci (MQTL) were found mostly using tissues other than cerebrospinal fluid (CSF) and brain, which being less than ideal for studying neurodegenerative diseases. The first CSF MQTL study was published last year, but with limited power. Therefore, we hope to expand our knowledge on MQTL in the central nervous system to better understand neurological disorders.

Method

We performed metabolome‐wide genome‐wide association study (M‐GWAS). More than 400 metabolites passed QC in CSF from 2329 participants recruited from five cohorts (CASTLE project). We performed a three‐stage study design: discovery (1224 CASTLE participants), replication (meta‐analysis of results from 1087 CASTLE participants and 291 CSF participants (Panyard, D.J. et. al 2021)) and meta‐analyses. Linear regression model includes age, sex, genetics principal components, genotyping array, and cohort information as covariates. We defined an association region to be 1 Mb interval centered on the index SNP (lowest study‐wide P value) by performing clumping of signals using plink1.9. We merged association regions if they share overlapping chromosome location to identify genetic locus associated with metabolite level traits. Future plan includes association study including rare variants, functional annotation of each locus, conditional analysis to identify independent signals, replication of identified signals, M‐GWAS for Brain metabolomics datasets (1169 samples in total), comparing features of identified associations amongst multi‐tissue (CSF, brain and blood) using mashr in R. In addition, colocalization and Mendelian randomization analysis will be performed to discover metabolites contributing to neurological disorders.

Result

The preliminary CSF M‐GWAS study jointing five cohorts identified 165 associations in 125 metabolites from 90 loci. Meta‐analysis on the discovery and replication results will be utilized for the downstream functional annotation, tissue comparison, and disease mechanistic exploration.

Conclusion

We present the largest CSF M‐GWAS study so far and showed a substantial number of genetic association findings for metabolites. We not only expect to replicate a number of our findings using studies with blood and CSF tissues, but also expect to discover novel signals that has potential for being unique to CSF.
Feasibility of a remote dance intervention for institutionalized older people with cognitive impairment
Authors: Drumond Gabrielle Oliveira , Menezes Ana Clara Nogueira , Lamha Anna Carolina Ferreira , Mara Fernanda , Almada Nascimento , Bastos Mayara Oliveira , Shigaeff Nadia
Published: June 2023

Background

Dance therapy has recently been proposed as a non‐pharmaceutical strategy to improve cognitive decline in people with Dementia or MCI, as well as to improve certain psychosocial aspects such as quality of life, mood and functionality. Due to the COVID‐19 pandemic, most older people living in long‐term care institutions have had their activities of daily living – such as physical therapy and other activity groups – interrupted to preserve social distancing rules. Therefore, the aim of this study was to create a dance therapy program that could be implemented as a remote intervention for older people living in a long‐term institution who had Mild Cognitive Decline (MCI) or Dementia.

Method

A selection of older people, living in a long‐term institution in the city of Juiz de Fora, Brazil, diagnosed with MCI and Dementia, was made. To achieve this objective, the medical records of the residents were analyzed and screening tests such as the Mini‐Mental State Examination (MMSE) and, as a secondary measure, the Geriatric Depression Scale (GDS) were applied.

Result

After the screening process, the program was planned with the help of a certified Senior Dance instructor, in order to arrange choreographies that were safe for all participants and could be performed remotely. In total, the program had 29 sessions, which spanned a period of 15 weeks, twice a week. There was an intervention group consisting of five participants with MCI or Dementia. A social worker of the institution helped with the choreography, in person, and a group of seven undergraduate students from different backgrounds (psychology, medicine and music) took turns conducting the remote sessions.

Conclusion

The remote program was extremely well received by its participants and by the caregivers of the institution: they reported that the participants were waiting for the sessions and that their disposition and mood improved significantly since the beginning of the intervention. This allowed us to conclude that the creation of a remote dance program was not only feasible, but that it can promote mental and cognitive health in institutionalized older people with cognitive impairment. Thus, this strategy should be better explored by these institutions.
Experience of dementia care burden: An exploratory study from India
Authors: Thaploo Geenaa , Navya N , Dasgupta Jayashree
Published: June 2023

Background

In India, dementia care is typically provided by family caregivers. Traditionally caregiving is undertaken by women family members, however, changing societal and family structures may mean more men become involved in caregiving roles. This study explores gender differences in experience of care burden for older adults.

Method

A retrospective analysis was conducted to examine contextual factors contributing to care burden using case records of individuals visiting a non‐hospital based elder care organization in India. All had been administered Zarit Burden Interview – 22 (ZBI), Lawton Independent Activities of Daily Living Scale (IADL) and Katz Activity of Daily Living Scale (ADL). Mixed methods analysis was used to examine overall care burden across genders and factors contributing towards subjective experience of care burden.

Result

Data was examined from 60 family caregivers of older adults (M = 22; F = 38). Majority were carers for dementia and reported feeling the care recipient was dependent on them which was corroborated by findings of dependency on IADL (44%) and ADL (26%). Overall, caregivers experienced mild to moderate burden and ZBI scores did not differ significantly across genders t (48) = .70, p = .48<0.05, however, they did not feel comfortable handing care to anyone else. Only 31% caregivers had support from paid attendants with families preferring to manage care themselves. Item analysis revealed subjective experience of care burden differed across genders. Women (42%) experienced feeling strained quite frequently / nearly always compared to men (18%). Although men reported that they experienced stress due to caregiving, item analysis revealed that majority of men in regard to their health (M = 50%, F = 0%) or social life (M = 41%, F = 29%) reported never being greatly impacted due to caregiving activities as compared to women.

Conclusion

Findings indicate although men and women family carers of dementia experience similar levels of care burden, women experience greater strain as compared to men. Findings from this study has implications for development of gender sensitive caregiver support modules.
Higher systolic and diastolic blood pressures in recently postmenopausal women are associated with higher white matter hyperintensity volume more than a decade later in the keeps continuation study
Authors: Kara Firat , Tosakulwong Nirubol , Lesnick Timothy G. , Schwarz Christopher G. , Senjem Matthew L. , Fields Julie A. , Min Paul H , Lowe Val J. , Jack Clifford R. , Bailey Kent R. , James Taryn T. , Lobo Rogerio A. , Manson JoAnn E. , Pal Lubna , Hammers Dustin B , Malek‐Ahmadi Michael H. , Cedars Marcelle I. , Naftolin Frederick , Miller Virginia M. , Harman Sherman M. , Dowling N. Maritza , Gleason Carey E. , Kantarci Kejal
Published: June 2023

Background

Women have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later.

Method

Women (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio.

Result

The median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/<120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2).

Conclusion

Higher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life.