bluuebunny/crossref_metadata_2025 huggingface dataset:
Persistent financial adversity across adulthood and cognitive ageing: A lifecourse investigation.
Authors: Liu Yiwen , Wels Jacques , James Sarah‐Naomi , Keuss Sarah E , Maddock Jane , Parker Thomas D , Stafford Jean , Schott Jonathan M , Richards Marcus , Patalay Praveetha
Published: December 2023

Background

Cognitive decline in older age has significant health, economic and social consequences and there is evidence that financial adversity might play a role. Financial adversity, for many, is not an acute but a chronic stressor. However, little is known about the effect of persistence exposure to financial adversity across the lifecourse on cognitive ageing.

Method

Using data from the 1946 British birth cohort (N = 2,759) with an embedded neuroimaging study (Insight46; N = 356‐468), we examined the prospective association between financial adversity (low household income, financial hardships; 26‐53 years) and cognitive performance (69 years) and decline (53‐69 years), as well as volumetric measures of brain health (69‐71 years) in older adulthood. Cognitive decline was modelled using latent growth curves, with derived intercepts and slopes used in subsequent regression analyses, adjusted for sex, childhood socioeconomic circumstances (SEC), baseline cognition and internalising symptoms, and educational attainment. Sex, childhood SEC and APOE‐ɛ4 genetic risk were further tested as moderators in regression models using interaction terms. This study has been pre‐registered (https://doi.org/10.17605/OSF.IO/6Y9NV).

Result

Increased exposure to financial adversity showed dose‐response associations with slower verbal memory decline and lower processing speed and verbal memory at 69 years (Table 1). Each increased period of exposure to low household income or financial hardships was associated with a 0.11 and 0.08 standard deviation (SD) decrease in processing speed, and a 0.32 and 0.22 SD decrease in verbal memory at 69 years, respectively. Males persistently exposed to financial hardships showed slower processing speed decline but increased brain atrophy compared to females. Those whose fathers were in unskilled profession or unemployed in childhood, and who also persistently experienced low income themselves showed greater brain atrophy (Fig. 1). APOE‐ɛ4 carriers who persistently experienced financial adversity were also at greater risk for brain atrophy (Fig. 2).

Conclusion

Persistent financial adversity is directly associated with cognitive performance and may be differentially associated with brain atrophy depending on demographic and genetic factors. Reducing the frequency of financial adversity over the lifecourse may improve cognitive performance and protect against genetic susceptibility to brain atrophy and subsequent dementia risk in the ageing population.
3D Reconstruction of human brain post‐mortem photography and integration of dementia histopathology
Authors: Ortega‐Cruz Diana , Bress Kimberly S. , Gazula Harshvardhan , Rabano Alberto , Iglesias Juan Eugenio , Strange Bryan A
Published: December 2023

Background

In Alzheimer’s Disease (AD) and other types of dementia, neuropathological assessment serves as ground truth for diagnosis and validation of novel biomarkers. Such assessment commonly implies inspection of a single histological slide per region of interest. Pathology burden quantification, as well as investigation of its spatial distribution, is thus biased by the variability of tissue sampling in routinary neuropathological practice. Numerous efforts have sought to overcome this lack of generalizability using 3D reconstruction of histology, but available approaches rely on dense sectioning and an MRI scan, which may not be attainable by many brain banks.

Method

We present a histology mapping pipeline that uses blockface images of brain hemisphere slices for 3D spatial localization. The slices are first geometrically stacked and coarsely aligned using a probabilistic atlas. Next, deep learning contrast synthesis is employed to obtain a high‐resolution 3D image of the hemisphere with MRI‐like contrast, which is subsequently registered nonlinearly to a standard atlas (MNI). Histological slides are then registered to the corresponding coronal slice within the subject‐specific reconstructed hemisphere. Finally, the registrations are concatenated to deform the histology to the standard space. We show the applicability of this pipeline by analyzing the distribution of tau AD pathology along the longitudinal axis of the hippocampus in 26 patients with no significant co‐pathologies aside from AD.

Result

We took advantage of the inter‐subject spatial variability observed after 3D slide mapping to achieve extensive sampling along the hippocampal long axis. Our results show an anterior‐posterior gradient of tau burden in the hippocampus that is consistent with previous work using ex vivo MRI and dense histological sampling, further supporting the reliability of the pipeline.

Conclusion

Our pipeline enables studying pathology in 3D using sparse sampling and in absence of a subject‐specific MRI reference. Moreover, given that dissection photography is standard practice in brain banks, our method is widely applicable to any prospective or retrospective human histology dataset.
Prevalence, incidence, and prognostic indicators of Dementia in patients with TIA and Stroke: the Population‐based Rotterdam Study
Authors: Claus Jacqueline Josephine , Box Camiel , Vinke Elisabeth J. , Rosbergen Mathijs T. , Vernooij Meike W , Ikram M. Kamran , Ikram M. Arfan , Wolters Frank J.
Published: December 2023

Background

Risk of dementia is high after major stroke, but reliable estimates of dementia by stroke severity, accounting for competing risk of mortality, in a population‐based setting are scarce. In this study, we aimed to determine risk and prognostic indicators of dementia before and after TIA and stroke.

Method

We included all individuals with first‐ever TIA or stroke from the population‐based Rotterdam Study, between 2002‐2018, and matched those on age (+/‐3 years) and sex, using an incidence density sampling approach. We determined prevalence of pre‐event dementia by event severity (TIA vs. minor stroke [NIHSS≤3] vs. major stroke [NIHSS>3]). Similarly, we determined risk of dementia at 1‐,5‐ and 10‐year post‐event using the subdistribution hazards (SDH) cumulative incidence function (CIF), and explored prognostic indicators of dementia.

Result

Among 1352 participants with first‐ever TIA or stroke (mean age: 79.4 (9.5) years, 59.7% women), 466 had TIA, 392 minor stroke, 494 major stroke. Prevalence of pre‐event dementia was higher among patients with major stroke (90/494; 18.2%) than among those with minor stroke (29/392; 7.3%), TIA (37/466; 7.9%). During 10‐year follow‐up, dementia occurred in 784 of 4703 participants without pre‐event dementia or reference participants. Compared to TIA patients, dementia risk was higher after major stroke (HR 2.17; 95% CI 1.53–3.07) and minor stroke (HR 1.63; 95% CI 1.17–2.26). Dementia risk was associated with male sex (SDH‐ratio 1.23; 95% CI 1.04–1.45), age (per 1‐year increase: 1.07; 1.06–1.08), higher education (0.61; 0.44–0.86), diabetes mellitus (1.29; 1.06–1.56), atrial fibrillation (1.40; 1.14–.71), and premorbid cognition (MMSE≤24, 2.39; 1.87–3.05). Among 417 patients with available pre‐event brain MRI, white matter hyperintensity burden (per 1‐% increase of proportion of total brain volume: 1.24; 95% CI 1.07–1.45) and presence of microbleeds (2.14; 1.18–3.86) were indicators of post‐stroke dementia.

Conclusion

Dementia incidence after TIA and stroke is increased in patients with major stroke and to a lesser extent minor stroke, but not TIA. Event severity in combination with clinical and imaging indicators may hold potential for the prediction of cognitive decline after stroke.
Early Cognitive Screening is recommended for the Population with Higher Blood Pressure Variation: A Cross‐sectional Study from a Blood Pressure Management Cohort in Hong Kong
Authors: Jia Pingping , Chan Aaron TC , Yiu Karen KL , Yu Ruby , Tsoi Kelvin KF
Published: December 2023

Background

Cognitive impairment was shown to be associated with blood pressure (BP) and blood pressure variability (BPV), but the association with BPV is still uncertain in Chinese. This study explored whether BPV is associated with cognitive impairment among the elderly in Hong Kong.

Method

Participants in a community‐based cohort for regular BP measurements with health surveys were randomly invited to have a cognitive assessment with a shortened validated version of MoCA. Different thresholds of mild cognitive impairment (MCI) were used with reference to the age group and educational background. BPV was defined as standard deviation. K‐means clustering methods were applied to group the standard deviation of BPV into high, medium, and low variations. Logistic and quantile regression models were conducted to explore the association of MCI with systolic or diastolic BPV and a combined BPV classification. Odds ratios (OR) were adjusted for age, gender, educational background social economic status, and other medical histories, including hypertension, hyperlipidemia, diabetes, and stroke.

Result

A total of 573 participants with a mean age of 72 years were included. Most participants were females (86%). The median follow‐up times were eight months with a median number of nineteen BP records. Systolic BPV was shown to be associated with a higher risk of MCI (adjusted OR: 1.16; 95% CI: 1.03 to 1.31); whereas diastolic BPV was not significantly associated with MCI (adjusted OR: 1.05; 95% CI: 0.85 to 1.24) (Table 1). In the combined groupings for BPV classifications, participants with high BPV were shown to have around 5 times higher risk of MCI than those with low BPV.

Conclusion

Early stage of cognitive impairment was shown to be associated with systolic blood pressure variability in the Hong Kong population. Early cognitive screening for those with high blood pressure variability levels is recommended.
Metabolic Syndrome Score is Associated with Lower Myelin in Cognitively Healthy Adults
Authors: Burzynska Agnieszka Z , Lee Jongho , Colmenares Andrea Mendez , Hiner Grace Z , Thomas Michael L , Choi Joon Yul
Published: December 2023

Background

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors, including abdominal obesity, glucose intolerance, elevated blood pressure (BP), and dyslipidemia. MetS is a known risk factor for cognitive dysfunction and dementia (Yaffe et al., 2004. YAMA), and has been linked to brain atrophy and altered WM microstructure measured with diffusion tensor MR (Alfaro et al., 2018, Metabolism). The metabolic cost of myelin maintenance makes WM particularly vulnerable to metabolic dysfunction. Here, we aim to explore the relationships between MetS and myelin, as well as test whether WC‐myelin association (Bouhrara et al., 2021, Int J Obes) is independent from systolic BP.

Method

Sample included 90 cognitively and neurologically healthy adults (Bookheimer et al., 2019, Neuroimage), aged 20 to 79 (M = 53, SD = 17) with 76% women. Additional exclusion criteria included systolic blood pressure >140, BMI>33, and >2 on modified Hachinski Ischemic Scale. Myelin water imaging was collected using a 3T Siemens Skyra with a 32‐channel coil and 3D‐gradient and spin‐echo (GRASE) sequence (1.9×1.9×4mm, TR = 1000ms, echoes = 32, first echo = 10ms, echo spacing = 10ms). Myelin Water Fraction maps were nonlinearly aligned to FMRIB58_FA using TBSS in FSL. MetS score was calculated as a sum of z‐scored waist circumference (WC), systolic BP, BMI, and self‐reports history of elevated cholesterol and glucose.

Result

A linear regression analysis with MWF as the dependent variable, adjusting for sex, race, ethnicity, age, and age2, income and education, indicated that greater MetS score was associated with lower MWF in several regions including the genu corpus callosum, anterior corona radiata, and external capsule. WC was negatively associated with whole WM MWF (B = ‐.265, t(79,9) = ‐2.150, p = 0.035) after controlling for the above covariates and systolic BP.

Conclusion

Associations between MetS with myelin content were detected especially in the late‐myelinating regions. This aligns with the development‐to‐degeneration hypothesis of WM aging, with lower oligodendrocyte‐to‐axon ratio as a possible factor contributing to metabolic vulnerability of late‐myelinating tracts. We also replicated the WC‐myelin association, although in fewer regions and with smaller effects sizes. Together, our results suggest that different metabolic syndrome components may exert both additive/synergistic, and independent effects on myelin integrity across adulthood.
“Don’t you recognize me…?”: Insights From Social Media Posts On The Impact of Alzheimer’s Disease On Care Partners
Authors: Frederiksen Kristian Steen , Crawford Rebecca , Hahn‐Pedersen Julie Hviid , Morrison Ross , Jeppesen Rose , Doward Lynda C , Weidner Wendy S
Published: December 2023

Background

Caring for someone with Alzheimer’s disease (AD) can have a profound impact on care partners’ wellbeing and daily life. We conducted a social media (SM) review to gain insights into how the impact of AD on care partners is described by persons‐living‐with‐AD (PwADs)/care partners/family members.

Method

Web‐based searches identified SM data from 4 sources: YouTube, Alzheimer’s Association, Alzheimer Society of Canada, and Dementia UK. English‐language SM posts uploaded between May 2011‐May 2021 shared by PwADs/care partners/family members were included in the review if posts discussed the impact of AD on care partners. SM data were analyzed thematically.

Result

Of 279 SM posts identified, 55 met the review criteria (21 blog posts, 21 videos, 13 comments). The 55 posts were shared by 70 contributors (4 PwADs and 66 PwAD care partners/family members) who discussed self‐reported/observed impacts of AD on care partners and family members. Notable areas affected included psychological and emotional well‐being (n = 53, 75.7%); a profound theme raised was the emotional distress and sadness (n = 24; 34.3%) associated with the care partners’ experience of ‘living bereavement’; i.e., the gradual psychological receding of a loved one prior to their passing. Care partner emotional distress was also exacerbated by the PwAD’s AD‐related symptoms such as altered behaviour and memory loss. Contributors also reported impacts on care partner, overall health‐related‐quality‐of‐life (n = 27, 38.6%), daily life (n = 9, 12.9%), work and employment (n = 8, 11.4%) and physical health (n = 5, 7.1%). Prioritisation of patient care had long‐term consequences for care partners such as diminished personal wellbeing, family and personal sacrifices including loss of employment and unanticipated financial burden.

Conclusion

SM research provides a unique approach to explore the experiences and challenges associated with caring for someone with AD potentially not captured through traditional research methods. Insights from SM data emphasized the burden of ‘living bereavement’ for care partners and the subsequent need for improved coping strategies/interventions to enable care partners to better manage this phenomenon. The care partners’ candid posts provided valuable insights on the psychological, social, and financial impairments associated with becoming a care partner, which require further investigation.
A multi‐omics approach to investigate the synapse dysfunction in Alzheimer’s disease
Authors: Kumar Subodh
Published: December 2023

Background

Synapse dysfunction is an early event for Alzheimer’s disease (AD) progression. Synapse dysfunctions are caused by multiple cellular and pathologic factors such as Amyloid beta, p‐tau, inflammation and aging. However, exact molecular mechanism of synapse dysfunction is largely unknown in AD. Therefore, to understand the molecular basis of synapse dysfunction in AD, we conducted a high throughput multi‐omics analysis of synaptosome fraction in AD and cognitively normal postmortem brain samples.

Method

Synaptosomes were extracted from healthy control (HC) postmortem brain (n = 14) and AD postmortem brains (n = 27). Next, we performed miRNAs and mRNAs HiSeq analysis on synaptosomal RNAs. We also used HC (n = 10) and AD (n = 10) synaptosome samples for mass spectroscopy proteomic analysis. We conducted the synaptosomal miRNAs and mRNA sequencing and mass spec analysis on the same groups of samples. Further, we conducted a high throughput multi‐comics analysis to understand the molecular interaction of deregulated synapse miRNAs, mRNAs and proteins at AD synapse.

Result

MiRNA HiSeq analysis showed the significant deregulation of several miRNAs in synaptosome fraction in AD vs HC. Our study also identified the several novel potential candidate miRNAs those were deregulated in AD vs HC synaptosomes. Similarly, several protein coding genes and novel transcript were also found to be deregulated in AD vs HC synaptosomes. Further, mass spec analysis showed significant deregulation of several synaptic proteins in AD vs HC synaptosomes. Further, to understand the molecular interaction of synapse miRNAs‐mRNA‐proteins and their deregulation in AD, we conducted high throughput multi‐Omics analysis. Study revealed the involvement of omics targets in several biological process and molecular function such as signal transduction, protein binding, GABAergic synapse and synaptic vesicle cycle etc.

Conclusion

Our study unveiled the synapse centered novel omics candidates those could be potential therapeutic targets for synapse dysfunction in AD.
Mclena‐1: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Lenalidomide in Patients with Mild Cognitive Impairment Due to Alzheimer’s Disease; Interim progress
Authors: Decourt Boris , Wilson Jeffrey , Dumitrescu Liliana , Ritter Aaron , Sabbagh Marwan
Published: December 2023

Background

Accumulating evidence indicates that inflammation mediated by tumor necrosis factor alpha (TNF alpha), interleukins (e.g. IL‐1 beta, IL‐2, and IL‐6), and chemokines (e.g. IL‐8), is prominent in Alzheimer’s disease (AD) patients. These data suggest that systemic inflammation plays a crucial role in the cause and effects of AD neuropathology. Thus, we propose that modulating systemic inflammation via a pleiotropic immunomodulator is a putative therapeutic intervention if administered at a proper time window during the course of the disease.

Method

This is a Phase II, proof‐of mechanism, placebo‐controlled clinical study on amnestic mild cognitive impairment (aMCI) male and female subjects administered 10 mg/day the immunomodulator, anti‐cancer agent lenalidomide for 12 months on a 1:1 ratio (15 placebo + 15 drug‐treated subjects total) followed by a 6 months washout period. Amyloid loads is measured by FBP PET. The primary endpoints are cognition measured via a large battery cognitive tests every 3 months, and comparison of brain amyloid loads (Florbetapir PET imaging) and neurodegeneration (volumetric MRI) pre‐ and post‐drug treatment. The secondary endpoints are safety, which is evaluated through reported adverse events (AEs), clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital signs, physical and neurological examinations, and electrocardiograms. The tertiary and exploratory objectives will assess blood inflammatory markers after lenalidomide vs. placebo administration.

Results

To date, 15 participants have signed consent, 7 screen failed, 2 withdrew consent and 6 have completed treatment after 12 months. Adverse events occurred as expected in cancer cohorts. No severe AEs have occurred so far. Importantly, assuming a 1:1 randomization in the blinded phase, several participants have received lenalidomide continuously for 12 months without interruption. Though blinded, the completers appeared to be stable.

Conclusion

In the current project we aim to investigate lenalidomide as a possible AD therapy. Our study should allow determining whether or not lenalidomide is safe in subjects suffering neurological disorders, and whether it can alter the clinical course of AD. To date, AEs are as expected and the safety and tolerability are manageable. A second trial coined MCLENA 2 will start soon. It will focus on biomarker endpoints (rather than cognition) following treatment for 6 months
Association of MIND Diet with Cognitive Decline among African Americans and non‐Hispanic White Older Adults
Authors: Agarwal Puja
Published: December 2023

Background

Cognitive impairment is a significant public health problem. The Mediterranean‐DAH intervention for Neurogenerative Delay (MIND) diet is associated with slower cognitive decline and reduced Alzheimer’s dementia risk. However, most findings have been reported among predominantly White populations. In this study, we examined the association of the MIND diet with cognitive decline in the Chicago Health and Aging Project (CHAP), a population‐based study that is predominantly African American.

Methods

The study sample consisted of 5,259 participants (mean ± SD age = 73.5 ± 6.0 years, education = 12.6 ± 3.5 years, 62% African American, 62% female) who completed a food frequency questionnaire and at least two cognitive assessments (a composite of 4 cognitive tests) over an average follow‐up of 7.85 ± 4.57 years. The MIND diet score was analyzed by tertile. We used linear mixed models adjusted for age, sex, socioeconomic status (composite of education, income, and occupation), and total calories. Additional sensitivity analysis adjusted for lifestyle (physical and cognitive activities) and vascular risk factors (diabetes, hypertension, stroke, and myocardial infarction).

Results

The average MIND diet score was lower for African Americans than non‐Hispanic Whites (6.97 vs.7.12, p = 0.0035). Among non‐Hispanic Whites, the second (β(SE) = 0.0121 (0.0059), p = 0.0396) and third (β(SE) = 0.0146 (0.0058), p = 0.0115) tertiles of the MIND diet score were associated with slower cognitive decline compared to the lowest tertile. Among African Americans, only the highest tertile of the MIND score was associated with slower cognitive decline (T3 vs. T1: β(SE) = 0.0088 (0.0043), p = 0.0415). Among African Americans, the association was no longer significant after adjusting for lifestyle and vascular risk factors. However, among non‐Hispanic Whites, the association between the MIND diet and cognitive decline remained significant.

Conclusion

The MIND diet association with cognitive decline varied by race. Whether our findings are due to lifestyle, vascular health or other correlated risk factors that impact cognitive decline differently by race warrants further investigation.
Dissociable influences of maternal vs paternal Alzheimer’s risk on neurocognitive and cardiovascular health in men and women
Authors: Savignac Chloé , St‐Onge Frederic , Villeneuve Sylvia , Badhwar AmanPreet , Taliun Sarah A Gagliano , Farhan Sali , Geddes Maiya R. , Medina Yasser Iturria , Poirier Judes , Spreng R. Nathan , Bzdok Danilo
Published: December 2023

Background

Parental history of sporadic Alzheimer’s disease (AD) is considered a prime risk factor since at least the late 1980s. Routinely used clinical samples of at‐risk individuals (8‐16 subjects) may conceal weaker population‐based effects, especially those of paternal inheritance. We performed a phenome‐wide examination of the dissociable influences of maternal vs. paternal AD risk on male vs. female probands in the largest single‐site family‐based at‐risk AD cohort: PREVENT‐AD.

Method

We built sex‐specific PLS‐regression models in which the APOE genotypes (e.g., ɛ3/3, ɛ3/4, ɛ3/2) were estimated based on ∼1,000 patient visits, each covering ∼260 risk indicators, to derive three APOE‐driven intermediate phenotypes (IPs). We examined how much the three IPs vary with regard to sex and maternal vs. paternal AD lineage across the phenome. We assessed the sex‐specific and lineage‐specific variation of the IPs over a 4‐year follow‐up period. Lastly, we examined how matri‐ vs. patrilinear AD risk captured by the IPs were expressed in AD‐vulnerable brain structures.

Result

Across IPs, we linked patrilinear AD risk to verbal‐numerical cognition and cardiovascular health in males. In contrast, we linked matrilinear AD risk to memory performance in both sexes. Over time, the mean difference in cognitive performance decreases with regard to sex but increases with regard to AD lineage. Cis‐ and trans‐generational sex effects in neocortex subregions (e.g., mPFC, PCu) were captured by the first and second IPs, respectively. The third IP mainly captured trans‐generational sex effects in hippocampus subregions (e.g., CA1, CA4).

Conclusion

We uncovered IPs of AD susceptibility differently expressed in male and female probands and affected by the diagnosed parent’s sex. Maternal inheritance highlighted memory performance in both sexes, whereas paternal inheritance was particularly linked to cardiovascular health in males. The inheritance of the IPs was reflected in the brain structure at both superficial and deeper layers of the cortex. As the first study of its kind, our cross‐generational analysis of matri‐ vs. patrilinear AD risk bridges the epidemiological and clinical literature by leveraging the power of ∼1,000 patient visits. Our completely data‐driven framework ultimately dissociated phenotypes of maternal and paternal AD risk single‐handedly expressed in male and female probands.
Brain and Body Group Fitness program for those with dementia and their caregivers through community partnership
Authors: Creapeau Lindsey J. G. , Wells Lisa , Pettis Laurie , Fasching Pete , Airth‐Kindree Norah
Published: December 2023

Background and Objectives

The growing prevalence of Alzheimer’s Disease and related dementias (ADRD) calls for nonpharmacological interventions to reduce the negative impact on quality of life to those affected with the impairment and their caregivers. Brain and Body Fitness (BBF) is a group program combining physical, cognitive, and socialization strategies to engage people living with dementia to maximize benefits for sustained function while slowing cognitive decline.

Research Design and Methods

The purpose of this study was to determine if BBF participants (N = 49 affected partners; N = 38 caregivers) were impacted in four quality of life indicators: anxiety, sleep, fatigue, and depression. Ex post facto data was utilized and demographic information was not collected.

Results

Data reveals significant reductions in depression symptoms and significant improvements in sleep quality for affected participants though no statistically significant improvements for caregivers. Anecdotally, the program demonstrates trends of overall mood improvement in both partners.

Discussion and Implications

Communities may consider adopting a similar model in other areas to provide additional support for residents with dementia and their caregivers.

Session Plan

This collaborative session will provide the following:

• Short background and demographics of Eau Claire County and prevalence of dementia

• Overview of the Brain and Body Fitness Program and wellness promotion

• Share results & recommendations of the UW‐Eau Claire research study

• Demonstrate a shortened Brain and Body Group Fitness Program class (including body weight exercises, stretching and language activities) with volunteers that choose to participate (optional). Learn ways to start a Brain & Body Group Fitness Program in your community

Learning objectives

• Develop and understanding of the innovative Brain and Body Group Fitness program model

• Identify strategies to adopt a similar program in your community

• Learn how the benefits the BBF program can provide enhanced quality of life to those living with dementia in the community and their caregivers
Association between cardiovascular health and brain age: a large population‐based study in the UK Biobank
Authors: Huang Huijie , Wang Jiao , Ma Jun , Xu Weili
Published: December 2023

Background

Cardiovascular health (CVH) has been associated with cognitive decline and dementia, but the extent to which CVH impact brain age remains unclear. We aimed to investigate the association of CVH assessed by Life’s Essential 8 (LE8) score with neuroimaging‐based brain age and brain predicted age difference (PAD).

Method

The study included a total of 34098 participants (mean age 54.82±7.50 years; 53.21% female) from the UK Biobank, who underwent brain magnetic resonance imaging (MRI) scans 9 years after baseline. A brain age prediction model with the best prediction performance was trained from 9 candidate models (Lasso, support vector regression, and XGBoost, with or without the addition of 2 variable selection methods, respectively) based on T1‐weighted MRI, T2‐FLAIR, T2∗, diffusion‐MRI, task fMRI, and resting‐state fMRI in 4355 healthy participants. Using the model, we calculated brain age and brain PAD (predicted age‐chronological age). Baseline LE8 score was calculated by the mean score of 8 metrics (diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure) and tertiled as low, moderate, and high CVH. Data were analyzed using linear regression models.

Result

At baseline, LE8 score was ranged from 15.00 to 100.00. In linear regression adjusted for age, sex and education, better CVH was associated with younger brain age (β [95% CI]: ‐0.029 [‐0.032, ‐0.026]) and smaller brain PAD (β [95% CI]: ‐0.033 [‐0.035, ‐0.030]). Compared to moderate CVH, low CVH was associated with older brain age (β [95% CI]: 0.444 [0.345, 0.543]) and bigger brain PAD (β [95% CI]: 0.513 [0.422, 0.604]), whereas high CVH was associated with younger brain age (β [95% CI]: ‐0.360 [‐0.459, ‐0.261]) and smaller brain PAD (β [95% CI]: ‐0.398 [‐0.489, ‐0.307]). The additional adjustment did not alter the relationships observed. After stratification by age, cardiovascular disease (CVD), or APOE ε4, the association remained significant among adults aged 40‐60 years and 60+ years, among CVD and non‐CVD, as well as among APOE ε4 carriers and non‐ carriers.

Conclusion

Better cardiovascular health is associated with younger brain age and reduced brain PAD. This association is significant even in middle‐aged, non‐CVD and non‐carriers adults.
Fluid Biomarkers of Neurodegeneration in Mild Cognitive Impairment: A Meta‐Analysis
Authors: Gaur Amish , Rivet Luc , Mah Ethan , Bawa Kritleen Kaur , Gallagher Damien , Herrmann Nathan , Lanctôt Krista L.
Published: December 2023

Background

Mild cognitive impairment (MCI) is a well‐established prodromal stage of Alzheimer’s disease and is often accompanied by early signs of neurodegeneration (e.g., neuronal loss) that may influence subsequent prognosis. To facilitate a better characterization of the underlying neuropathology, a thorough investigation of proteins associated with neurodegenerative processes in MCI is needed. Thus, the present study systematically assessed the available literature to quantitatively evaluate cerebrospinal fluid (CSF) and peripheral blood concentrations of biomarkers related to neurodegeneration in individuals with MCI compared to healthy controls (HCs).

Method

Original peer‐reviewed articles that assessed the following CSF and/or peripheral biomarkers: neurofilament light chain (NFL), total‐tau (T‐tau), glial fibrillary acidic protein (GFAP), heart‐type fatty acid binding protein (HFABP), neuron‐specific enolase (NSE), and S100 calcium‐binding protein B (S100B) in both MCI and HCs were included for meta‐analysis. Standardized mean differences (SMDs) and 95% confidence intervals were calculated using a random‐effects model. Heterogeneity was assessed using the I2 statistic.

Result

A total of 109 study cohorts were included in the meta‐analysis. In CSF, concentrations of NFL (MCI n = 2771, HC n = 4263, SMD [95% CI] = 0.69 [0.56, 0.83], p < 0.001), GFAP (MCI n = 513, HC n = 1620, SMD [95% CI] = 0.41 [0.08, 0.74], p = 0.02), and HFABP (MCI n = 363, HC n = 245, SMD [95% CI] = 0.57 [0.23, 0.55], p < 0.001) were elevated in MCI. In peripheral blood, concentrations of NFL (MCI n = 6520, HC n = 9439, SMD [95% CI] = 0.41 [0.32, 0.49], p < 0.001), T‐tau (MCI n = 4463, HC n = 5921, SMD [95% CI] = 0.19 [0.09, 0.29], p < 0.001), and GFAP (MCI n = 1758, HC n = 3179, SMD [95% CI] = 0.39 [0.23, 0.55], p < 0.001) were increased in MCI. Significant heterogeneity was identified for all comparisons and was explored through meta regression and subgroup analysis.

Conclusion

The present study identified several fluid biomarkers of neurodegeneration in MCI. Importantly, elevated biomarker levels can be detected in both CSF and less‐invasively through peripheral blood. Future studies should focus on assessing the clinical utility of monitoring these biomarkers as they may provide further insight into neuronal and astroglial pathology occurring in the early stages of cognitive decline.
Pharmacologically targeted mitochondrial fission/fusion performs neuroprotection against trastuzumab‐induced cognitive deficits in rats via suppressing mitochondrial dysfunction and oxidative stress
Authors: Maneechote Chayadom , Ongnok Benjamin , Khuanjing Thawatchai , Arinno Apiwan , Prathumsap Nanthip , Chunchai Titikorn , Arunsak Busarin , Nawara Wichwara , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

Trastuzumab (TRZ) has been utilized primarily as a chemotherapeutic treatment for advanced human epidermal growth factor receptor type 2‐expressing malignant tumors. Regardless, TRZ‐associated neurotoxicity has emerged as an adverse clinical complication of oncologic therapy by increasing oxidative stress and damaging mitochondrial function. As the neuroprotective effects of mitochondrial fission inhibitor (MDV) and fusion promoter (M1) have been illustrated for a variety of neurological pathologies, the anti‐neurotoxic mechanisms of MDV and M1 against TRZ are unknown.

Method

Twenty male Wistar rats were randomly divided into either the TRZ group (4 mg/kg/day for 7 days, I.P., n = 15) or the control group (CON, n = 5). In the TRZ group, rats also received one of the following co‐treatments: 1) vehicle (VEH, n = 5), 2) MDV (1.2 mg/kg/day, n = 5), or 3) M1 (2 mg/kg/day, n = 5) via I.P. injection for 7 days. Subsequently, novel object location (NOL) and novel object recognition (NOR) tests for long‐term learning and memory were performed. Then, the brain tissue was used for determining mitochondrial functions, and the blood serum was also used to measure the oxidative stress levels.

Result

TRZ (the VEH group) increased brain mitochondrial dysfunction and systemic oxidative stress via increasing reactive oxygen species (ROS) production, mitochondrial depolarization, mitochondrial swelling, and serum malondialdehyde levels, respectively, when compared to the CON group (p<0.05, Figure 1). TRZ (the VEH group) impaired long‐term learning and memory, as indicated by the attenuated percentage preference index of NOL and NOR tests, compared to the CON group (p<0.05, Figure 1). MDV and M1 co‐therapies exerted neuroprotection by rescuing brain mitochondrial function and systemic oxidative stress, resulting in the restoration of long‐term cognitive parameters (p<0.05, Figure 1).

Conclusion

Targeting brain mitochondrial dynamics could be an effective remedy against TRZ‐induced cognitive impairment in rats via suppressing mitochondrial dysfunction and oxidative stress. Therefore, pharmacological inhibition of mitochondrial fission and promotion of mitochondrial fusion could be a novel anti‐neurotoxicity‐induced by TRZ.
Artificial Intelligence Model‐based Alzheimer’s Disease Dementia Classification Using Electroencephalogram‐acquired Brain Functional Network
Authors: Hong Yuseong , Jeong Taegyun , Park Ukeob , Youn Young Chul , Kang Seung Wan
Published: December 2023

Background

Alzheimer’s disease dementia (ADD) is a predominant neurodegenerative disorder that results severe abnormalities in cognitive functions. However, most diagnoses rely on assessments made by individual clinical experts.

Hence, we aim to establish a novel biomarker which can provide both accuracy and objectivity. Electroencephalogram (EEG) data were utilized for the training of artificial intelligence (AI) models, making use of its cost‐advantage and simple utility.

Method

19‐channel EEG data were recorded at Chung‐Ang University hospital in accordance with international 10‐20 system at resting state with eyes being closed. We first converted 19 channels into 68 regions of interest (ROIs) using standardized low resolution brain electromagnetic tomography (sLORETA). Henceforth, imaginary part of coherence (iCoh) between each ROI were calculated, reflecting functional connectivity between the ROIs. The iCoh values were then utilized in the calculation of the brain’s functional brain network.

The subjects were divided into non‐ADD and ADD group. The resulting training dataset consisted of 118 non‐ADD and 110 ADD subjects, where the number of non‐ADD training data were adjusted in order to account for data imbalance. The test dataset included 476 non‐ADD and 27 ADD subjects.

The classification model was trained using 68 ROI source powers and functional brain network features. Only statistically significant features were selected for feature reduction purposes. Through primary classification via light gradient boosting method (LGBM), top 30 features with high importance values were selected and were employed in the training of our final LGBM classification model.

Result

Through appropriate hyperparameter tuning, the LGBM classification model resulted in 87.67% accuracy, 88.89% sensitivity and 87.61% specificity. From the receiver operating characteristic (ROC) curve, 0.9506 area under ROC curve (AUC) was achieved.

Conclusion

The LGBM model resulted in promising classification performance, solely through EEG features. In addition, functional brain network features had higher importance in comparison with source power features, indicating high potential of EEG brain network features in distinguishment of neurodegenerative diseases.
A Cognitive Screening Test for detecting Alzheimer’s Disease Dementia in the Deaf older adults in Austria, and Greece: the De‐Sign Erasmus+ project
Authors: Tsatali Marianna , Cernek Sabrina , Dimou Athanasia‐Lida , Dolza Enrico , Hoffmann‐Lamplmair Doris , Maggiora Nicola Della , Martinetz Patrick , Ntova Tarsitsa , Plachoura Evanthia , Seifert Romeo , Ströbele Thomas , Tsolaki Magdalini , Teichmann Birgit
Published: December 2023

Background

Until now there is a lack of cognitive screening tests for Deaf older adults to detect Alzheimer’s Disease Dementia (ADD) across Europe, as well as limited access to the therapeutic methods imposed. Therefore, the Deaf population has little access to dementia services.

Method

To fill this gap, the current Erasmus+ project aims to adapt the first dementia screening test for Deaf people in Austria and Greece being initially available for the British Deaf older adults and therefore, provide a valid and reliable tool to detect cognitive deficits by means of ADD in this population.

Result

For the project’s purposes, a group of experts will translate and adapt the CST in Austrian (ÖGS) and Greek sign languages (GSL), and after piloting the new CST versions, they will be administered in approximately 100 Deaf older adults in each country. Additionally, the following tests will be also administered: the Montreal Cognitive Assessment (MoCA), the Verbal Learning and Memory Test, and the Digit Span (forwards and backwards). To assess the psychometric properties of the new versions of CST, internal reliability, test retest reliability, as well as concurrent validity will be calculated. Finally, a digital web‐based platform including tests’ administration guidelines along with the test per se will be developed. To disseminate the project’s results, detailed seminars on the test administration as well as the use of the platform will be implemented to experts from the fields of dementia and sign languages.

Conclusion

To introduce dementia screening as well as ADD detection in the Deaf in Austria and Greece.
Comparison of white matter hyperintensities between Latin American and American individuals with Alzheimer’s disease and cognitively normal older adults
Authors: Altschuler Florencia , Fraile‐Vazquez Matias , Canziani Verónica , Vigilante Sofia Paz , Ibanez Agustin , Campo Cecilia Gonzalez
Published: December 2023

Background

White matter hyperintensities (WMH) are Flair signal abnormalities frequently seen in periventricular and subcortical brain regions in the elderly. They are presumed to be, at least in part, a sign of cardiovascular disease (CVD). WMHs are associated with stroke, cognitive decline, and dementia. Given that most of the literature on dementia comes from high‐income countries, little is known about dementia in Latin American countries (LAC), which have an increased risk of dementia and CVD due to unique demographic, socioeconomic, cultural and ethnic factors. Our study aims to characterize the effects of white matter hyperintensities (WMH) in patients with AD within LAC and to compare these findings with a sample from the USA.

Method

A total of 491 latin american subjects (235 cognitively normal (CN), 256 AD) and 271 american subjects (165 CN, 106 AD), underwent a brain MRI. WMH were extracted from T2‐FLAIR images using the Lesion Segmentation Toolbox and were divided into periventricular (pWMH) or deep (dWMH) depending on their distance from the ventricles. Linear mixed‐effects were used to model the volumes of WMH as a function of age, gender, years of education, intracranial volume, average cortical thickness, and region (LAC or USA).

Result

AD groups from both regions showed larger total, dWMH and pWMH volumes compared to HC. Higher pWMH from AD and HC was associated with age, female sex and inversely associated with years of education. On the other hand, the increase in dWMH was found to be associated with female sex for the HC group and with age for AD. Cortical thinning was associated with an increase in total, subcortical and periventricular WMH for both groups. No statistically significant association was found between the region (USA or LAC) and WMH.

Conclusion

AD showed higher WMH compared to HC. Our findings suggest that pWMH and dWMH have different clinical correlates. No associations between region and WMH load or distribution were found. Future studies need to elucidate if there is an increase in other signs of CVD (such as cerebral microbleeds, brain lacunae, enlarged perivascular spaces) in Latin America and if they are linked to cognition and social determinants of health.
The Effect of APOE Genotype on Endolysosomal Dynamics in Neurons
Authors: Nyberg Emma MC , Konings Sabine C , Lindblom Nils JN , Klementieva Oxana , Martinsson Isak , Gouras Gunnar K
Published: December 2023

Background

APOE genotype is known as the most important genetic risk factor for developing AD. Understanding the cellular differences between the ApoE isoforms will be crucial for understanding the fundamental pathways that are disrupted in AD and potential pathways that can be therapeutically targeted. Accumulating evidence is suggesting that ApoE isoforms influence the endosomal system, one of the earliest sites affected in AD. However, our understanding of how the isoforms affect the endolysosomal pathway is still limited. We aim to understand how ApoE isoforms affect the endosomal pathway, but also understand the dynamics of the system in the context of ageing and activity.

Method

To study cellular changes in neurons we are using primary hippocampal/cortical brain cultures, harvested from ApoE KO mice and targeted replacement mice, expressing human ApoE3 or ApoE4. Neurons in culture have accelerated maturation and with time in culture gradually show signs of age‐like stress. To study ApoE in the context of ageing, mature cultures at 18 days in vitro (DIV18) and more aged cultures at DIV25 were used. To explore how ApoE isoforms adapt to elevated activity DIV18 primary cultures were treated for 48 H with the GABA receptor antagonist bicuculline.

Result

Our preliminary data suggests that especially early endosomes are affected in ApoE4 neurons. Interestingly, the appearance of the early endosomes seems to differ depending on both the intracellular localization and time in culture. However, the protein level of the early endosomal marker EEA1 remained unaltered in ApoE4. In addition, preliminary data indicate that ApoE4 has reduced capacity to adjust the endosomal system following 48 hours bicuculline treatment. When studying the trafficking of fluorescently tagged EGF (which has an established endolysosomal route), preliminary results show potential differences between both DIV18 and DIV25 but also between ApoE‐isoforms, suggesting that both time in culture and ApoE isoforms influence endolysosomal trafficking.

Conclusion

The endolysosomal pathway is a highly dynamic and important system for all cells, including neurons and is increasingly linked to AD. Our preliminary findings point toward an ApoE isoform effect on endosomal trafficking and that its dynamics might be disrupted by ApoE4.
Resting‐state network connectivity changes in prodromal stage of Alzheimer’s disease
Authors: Mateu Karen Aguilar , Laguardia Ana María Castro , Guerra Jorge Llibre
Published: December 2023

Background

Alzheimer Disease (AD), the most common type of dementia, is accompanied by a generalized loss of neurons and cause severe changes in brain’s structure and function. Mild Cognitive Impairment is associated with a higher risk of developing dementia. This clinical classification is particularly relevant because each subtype is linked to a presumed etiology, with the amnestic subtypes (aMCI) considered as a prodromal form of AD (Petersen et al., 2009, 2014). Resting state fMRI functional connectivity (FCrs‐fMRI) analysis is broadly used to detect brain network differences in neurodegenerative diseases such as AD.

Method

Forty‐five participants were evaluated: patients with aMCI (n = 17), patients with dementia due to AD (n = 14) and healthy controls (HC) (n = 14). All participants received an extensive neuropsychological battery and brain MRI scanning. Resting state functional scans consisted of 240 T2*‐weighted echo planar imaging volumes (repetition time 3000 ms; echo time 60 ms; ip angle 90°; 32 axial slices; matrix 64×64; voxel size 3.3×3.4×4 mm). Additionally, a high‐resolution T1‐weighted magnetization prepared rapid acquisition gradient echo image was acquired. Data analyses were performed using the Functional Connectivity Toolbox (CONN) for Matlab (https://www.nitrc.org/frs/) to identify large‐scale patterns of temporal signal‐intensity coherence, interpreted as functional connectivity (Beckmann et al., 2005). Regions of interests (ROIs) analysis was performed for each participants and among group. Spatial maps of the group independent component analysis were used in a linear model t against each individual fMRI data set.

Result

The Default Mode Network (DMN) showed two regions of lower functional connectivity (FC) in AD when comparing with HC within the precuneus (p<0.001 uncorrected). No regions of FC changes were found in the DMN when comparing aMCI with HC or AD.

Conclusion

The changes in FC rsfMRI in adults with AD are specifically related to regions of the DMN.