bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reproductive experience and APOEe4 genotype interact to influence neuroplasticity and neuroinflammation in the middle‐aged brain
Authors: Lee Bonnie H , Duarte‐Guterman Paula , Lieblich Stephanie E , Ibrahim Muna , Eid Rand S , Wen Yanhua , Cevizci Mel , Galea Liisa A 
Published: December 2022

AbstractBackgroundFemales have a greater lifetime risk of Alzheimer’s disease (AD) compared to males, differences which are further exacerbated with possession of APOEe4 alleles, the greatest genetic risk factor for sporadic AD. Although studying sex and gender differences is important, so is studying sex‐linked factors such as parity (pregnancy and motherhood). Previous parity influences brain aging trajectories in both humans and rodents and may be associated with a greater risk of AD and greater neuropathology. Neuroinflammation is increased with AD, reduces hippocampal neurogenesis, and activates the tryptophan‐kynurenine pathway (TKP), and all these factors are influenced by aging and parity. We investigated whether previous parity influences neuroinflammation and neuroplasticity in middle‐aged rats, dependent on APOEe4 genotype.MethodAge‐matched wildtype (WT) and humanized (h) APOEe4e4 knock‐in female rats were nulliparous (never mothered) or primiparous (first‐time mothers). Middle‐age (13‐14 months old) rats were euthanized to examine markers of hippocampal neuroinflammation (microglia and cytokine signalling) and neurogenesis.ResultIn line with previous research, wildtype primiparous rats had greater levels of neurogenesis than nulliparous rats – however, the reverse was true in hAPOEe4 rats, as hAPOEe4 primiparous rats had lower levels of neurogenesis than hAPOEe4 nulliparous rats in the ventral hippocampus. Perhaps paradoxically, hAPOEe4 primiparous rats had fewer microglia and less proinflammatory cytokine expression (IL‐l1β, IFNγ, TNFα) than wildtype primiparous rats in the ventral hippocampus.ConclusionThese findings indicate that past reproductive experience and APOEe4 genotype need to be considered in aging and Alzheimer’s disease research.
Gonadal Hormones Contribute to Sex Differences in Autoimmunity, Pathology and Behaviour in the 3×Tg‐AD Mouse Model of Alzheimer’s Disease
Authors: Fahnestock Margaret , Song Wei , Ma Donglai , Creighton Samantha D , Mian Firoz , Michalski Bernadeta , Forsythe Paul , Sakic Boris , Zovkic Iva 
Published: December 2022

AbstractBackgroundSex‐dependent discrepancies in prevalence and autoimmune markers are characteristics of Alzheimer’s disease (AD). Using the 3xTg‐AD mouse model, we previously reported that adult males show early systemic autoimmunity along with behavioural dysfunction, altered epigenetic factors, and lack of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain AD‐like pathology and behaviour. The present study examines whether gonadal hormones play a role in the etiology of these traits in current cohorts of 3xTg‐AD mice.Method3xTg‐AD and wild‐type mice were gonadectomized or sham‐operated at 3 months of age. After behavioural phenotyping at 6 months of age, the animals were assessed for serologic markers of autoimmunity, T splenocyte distribution, molecular markers of AD pathology, and expression of genes and histone variants associated with neurodegeneration.ResultIn female transgenic (AD) mice, gonadectomy resulted in reduced levels of circulating antinuclear/nucleosome autoantibodies and poorer spatial learning performance, but did not affect the T cell population. In contrast, in transgenic male animals, gonadectomy improved spatial memory and cognitive flexibility, diminished splenic CD8+ T cells, yet had no impact on anti‐nuclear/nucleosome autoantibodies. Sex hormone‐related effects on anti‐nucleosome autoantibodies led us to focus on histones. Gonadectomized AD females exhibited enhanced expression of mouse (m) and transgenic Mapt genes, consistent with reduced binding activity of the repressive histone variant macroH2A1 at the mMapt gene body, compared to their sham counterparts. In contrast, gonadectomized AD males showed reduced expression of App and H2afy genes, reduced cortical soluble Aβ42 levels, and increased macroH2A1 binding at the mPsen1 promoter, compared to sham‐operated AD males.ConclusionFemale sex hormones enhance autoimmunity and spatial learning, whereas male sex hormones may be detrimental to spatial memory, cognitive flexibility, and autoimmunity in young adulthood. Furthermore, female sex hormones increase expression of the Mapt gene, but have no effect on App expression or Aβ42 levels. Conversely, male sex hormones increase App expression and Aβ42 levels, but have no effect on tau expression. Our work suggests that gonadal hormones contribute to sex differences in autoimmunity, AD‐like pathology, and “cognitive” function in this model. Moreover, histone variants may contribute to sex‐specific differences in AD pathology.
Dissociating the pro‐cognitive effects of donepezil and an M1 PAM
Authors: Hassani Seyed‐Alireza , Neumann Adam , Russell Jason K , Jones Carrie K , Womelsdorf Thilo 
Published: December 2022

AbstractBackgroundDonepezil, an FDA approved drug for dementia in Alzheimer’s disease, increases the extracellular concentration of acetylcholine non‐selectively stimulating cholinergic receptors indiscriminately leading to dose‐limiting side effects. Muscarinic M1 sub‐receptor specific positive allosteric modulators (PAMs) have shown promise in addressing symptoms in Alzheimer’s disease, Schizophrenia and more1. M1 PAMs have little to no agonistic properties, avoiding peripheral side effects, and are mostly centrally located allowing for the modulation of endogenous signaling of the brain2.MethodWe tested non‐human primates in two tasks measuring cognitive flexibility and attentional control3 at varying doses of donepezil and an M1 PAM (VU0453595). Attentional control was measured with a visual search task requiring animals to search for a learned target object among distractors of variable number and similarity to the target object. Cognitive flexibility was measured with a feature‐reward learning task that required animals to learn the value of objects of varying feature complexity by trial and error. Flexibility was indexed as the speed of learning, the degree of latent inhibition and the amount of target perseveration after switching the rewarded feature.ResultDonepezil enhanced attention control at a high dose (0.3 mg/kg) but enhance flexibility only moderately at a lower dose (0.06 mg/kg). In contrast, VU0453595 did not modulate attention, but at 0.1 mg/kg enhanced flexible learning, reduced target perseverations, and increased reaction time measures of decision confidence. At the dose with the most pronounced cognitive benefits donepezil resulted in gastrointestinal side effects, while VU0453595 did not cause side effects.ConclusionThese results suggest that donepezil engages the brain networks underlying cognitive flexibility and interference control at different doses4, while the M1 receptor plays a major role in facilitating flexible behavioral adaptation but with no role in controlling interference. Such receptor specific results can be used to better curate to patient‐specific needs in order to address the most debilitating symptoms with the highest efficacy.1. Melancon, B. J. et al. (2013) Drug Discovery Today https://doi.org/10.1016/j.drudis.2013.09.005.2. Ghoshal, A. et al. (2016) Neuropsychopharmacology doi:10.1038npp.2015.189
3. Womelsdorf, T. et al. (2021) Frontiers in Behavioral Neuroscience https://doi.org/10.3389/fnbeh.2021.721069
4. Hassani, S.A. et al. (2021) Biological Psychiatry Global Open Science https://doi.org/10.1016/j.bpsgos.2021.11.012.
Evaluation of the antioxidant potential of Neem (Azadirachta indica) leaf supplement in alleviating Alzheimer’s Disease like behaviour induced by Aluminum neurotoxicity
Authors: Memudu Adejoke Elizabeth Elizabeth , Jibaniya Grace Mchibuma , ANZAKU FATIMA AYINDA 
Published: December 2022

AbstractBackgroundTo evaluate the antioxidant potential of Neem (Azadirachta indica) leaf supplement in attenuating Alzheimer’s disease (AD) pathology induced by aluminum neurotoxicity (Animal model of AD). Y‐ maze test, neuro‐morphology and astrocytic proliferation will be study in the fronto‐hippocampal and cerebellar cortices to elucidates the therapeutic role of neem leaf in AD pathology.MethodsTwenty (20) adult male Wistar rats were grouped (4 groups, n = 5); Control group (A), Aluminum treated group for 7 days (B), 200mg/kg body weight Neem leaf supplement for 7 days (C), and the AD model post‐treated with 200mg/kg Neem leaf supplement for 7 days (D). Study was done for 14 days via oral administration of study materials. Neurobehavioral test for memory and learning done using Y‐maze test. Excised brain was fixed in 10% formol calcium, processed for Cresyl fast violet (CFV) stain for Nissl (chromatophilic) bodies and astrocytes immunohistochemistry using glial fibrillary acidic protein (GFAP) monoclonal primary antibodies in biotinylated secondary antibodies. Behavioural test data were analyzed using ANOVA, post hoc test and significance set at p<0.05.ResultsAluminum treated group cortical area was characterized by necrosis, chromatolysis, neuropil vacuolations and astrocytes proliferation with impaired memory demonstrated by a reduction in the number of arm entries and spontaneous alternations as compared with the control and neem treated groups. However, these pathological changes were reversed by neem leaf supplementation seen in AD model neem leaf post‐treated group (D) showing an increased number of arm entries and spontaneous alternations, regeneration of neurons and a reduced reactive astrocytes (astro‐gliosis) proliferation.ConclusionNeem leaf supplement neuroprotective and repair role in AD pathological is proposed to be via ameliorating astrocytes mediated neuroinflammatory response via the neuron‐astrocytes interaction and antioxidant role during neuroinflammation induced by aluminum in the fronto‐hippocampal and cerebellar cortices
Assessing the Biological Mechanisms linking Smoking Behavior and Alzheimer’s Disease: Mediation Analysis of Metabolomic Data
Authors: Choi Jerome , Koscik Rebecca Langhough , Jonaitis Erin M. , Johnson Sterling C. , Engelman Corinne D. , Schmitz Lauren 
Published: December 2022

AbstractBackgroundSmoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which also have both been linked to the development of Alzheimer’s disease and related dementias (ADRD). However, the molecular mechanisms between smoking and ADRD are not well established. This study characterized these mechanisms using metabolomics data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP).MethodsBased on 1,266 people who enrolled in WRAP and had the necessary data to assess whether the smoking‐cognitive function relationship is mediated by CSF or plasma metabolites, we broke down our analyses into four steps, based on the product method (Figure 1). The associations between smoking status and cognitive functions, smoking and metabolites, and metabolites and cognitive functions were assessed. All models were adjusted for age, sex, race, education level, CES‐D score, body mass index, and weekly alcohol consumption. The outcomes were Preclinical Alzheimer Cognitive Composite III (PACC3) and composite scores for Immediate Learning, Delayed Recall, and Executive Function. Mediation analyses were then implemented, and the mediation effect of metabolites was computed to explore the role of metabolites in smoking‐cognitive function pathways. False discovery rate (<0.05) were applied as criteria for each step and 95% confidence intervals were used to verify the statistical significance for the metabolites that satisfied criteria.ResultsSix plasma metabolites were associated with smoking status and cognitive composite scores. Among them, N‐acetylneuraminate was significantly associated with PACC3 [95% confidence interval (CI): 0.00051‐0.01504] and Immediate Learning [95% CI: 0.00098‐0.01846] and was a significant mediator of the association between smoking status and these cognitive composites. The proportion of the total effect that was mediated by N‐acetylneuraminate was 12% for PACC3 and 13% for Immediate Learning.ConclusionsAs a mediator, N‐acetylneuraminate contributes to the association between smoking status and cognitive function. Interestingly, N‐Acetylneuraminate is a sialic acid and sialic acids have been found to be involved in several major changes associated with AD. For example, the CD33 sialic acid‐binding domain confers protection for late‐onset Alzheimer’s disease.
Increased Serotonin Synthesis Capacity is Associated with Longitudinal Cortical Atrophy and Worsening Depressive Symptoms
Authors: Markova Teodora , Ciampa Claire J , Parent Jourdan H , Furman Daniella J , D'Esposito Mark , Jagust William J. , Berry Anne S. 
Published: December 2022

AbstractBackgroundSerotonin‐producing raphe nuclei are sites of age and Alzheimer’s disease‐related alterations in structure and function.MethodWe used [18F]Fluoro‐m‐tyrosine ([18F]FMT) positron emission tomography (PET) to measure serotonin synthesis capacity in younger (mean age = 22.08, n = 62) and older adults (mean age = 77.8, n = 49). [18F]FMT net tracer influx (Ki) was higher in older adults in both the dorsal and median raphe nuclei (both p < 0.001). To examine the functional relevance of higher raphe [18F]FMT Ki in older adults, we tested relationships with β‐amyloid status as defined by [11C]Pittburgh compound B ([11C]PiB) PET, retrospective longitudinal declines in cortical thickness, and retrospective longitudinal changes in depression symptoms measured using the geriatric depression scale (GDS).Result[11C]PiB positive (n=14) older adults showed trend‐level elevation in dorsal and median raphe [18F]FMT Ki relative to [11C]PiB negative older adults (n = 35; both p < 0.09). Higher dorsal raphe [18F]FMT Ki was associated with decreasing cortical thickness over time in the banks of the superior temporal sulcus (BanksSTS) (Monte Carlo, p < 0.05, r = ‐0.513), consistent with the interpretation that serotonin synthesis may be upregulated in response to neural losses. Decreasing cortical thickness was also associated with increasing GDS. We did not find evidence that higher dorsal raphe [18F]FMT Ki had a beneficial impact on affective function. Instead, interaction analyses revealed relationships between atrophy and increasing GDS were strongest in individuals with highest dorsal raphe [18F]FMT Ki (t = ‐2.056, p = 0.049; adjusting for age, sex, and [11C]PiB status).ConclusionTogether, these findings suggest serotonin synthesis capacity increases with age, and appears to signal poor aging trajectories. Most elevated serotonin synthesis capacity was associated with greatest cortical atrophy and drove relationships between atrophy and worsening depressive symptoms over time.
Exploration of Multidimensional Poverty and Dementia in Adults older than 50 years old in South Africa
Authors: Trani Jean‐Francois , Moodley Jacqueline , Thu May Maw Thu , Babulal Ganesh M 
Published: December 2022

AbstractBackgroundMultidimensional poverty is associated with chronic health conditions. However, limited research exists investigating the association between multidimensional poverty and dementia on a population level in low‐and middle‐income countries (LMICs).MethodThis study was conducted in Soweto between 11 November 2019 and 28 February 2020. Participants included older adults above 50 years old. Data analysis was concluded in August 2021. We calculated a measure of multidimensional poverty that includes seven dimensions and eleven indicators. Assessing Dementia 8 (AD8) and the Rowland Universal Dementia Assessment Scale (RUDAS) were used to measure dementia. Differences in level and depth of poverty between adults with no dementia and those with a score above the threshold for either AD8 or RUDAS, or for both AD8/RUDAS, and for comparing gender, age group and marital status were examined. Correlation analyses to assess overlap of dimensions of deprivation were carried out. Association between dementia and multidimensional poverty were investigated using multivariate regression model.ResultAmong 227 participants living in Soweto, South Africa, 151 adults were identified with dementia by the AD8 (66.5%), 64 by the RUDAS (28.2%) and 50 by both AD8 and RUDAS (22.0%). More men (32.1%) had no dementia compared to women (24.7%); and 20% of adults with dementia compared to 9.7% of those without dementia were found to be poor on four dimensions or more. The difference in multidimensional poverty index for k = 3 was 77.1% and 67.3% between adults with and without dementia. Education, health and employment were the main contributors of poverty. Multidimensional poverty was strongly associated with dementia as measured by AD8/RUDAS (adjusted OR 2.31, 95% CI 1.08‐4.95), with higher odds for older female (OR 2.03, 95% CI 1.00‐4.12) or those living in large households (OR 1.27, 95% CI 1.05‐1.53).ConclusionThis study found that the prevalence and depth of poverty is higher among older adults with dementia. A lack of education, poor health and unemployment are major dimensions of poverty which was associated with higher risk of dementia. These findings suggest that early improvement in social determinants of health through targeted structural policies may prevent dementia later in life.
♣Public health policies, dementia care and support in LMICs
Authors: Karanja Wambui , Mutunga Elizabeth Kasimu , Timmons Fergus 
Published: December 2022

AbstractBackgroundThe World Health Organization (WHO) recommends that low‐and‐middle‐income countries (LMICs) develop national plans to formulate public health policies in response to dementia Across Africa, no country has developed a national dementia strategy to date. Although Kenya is in the process of developing a national dementia plan, much work remains to develop care pathways that meet the diverse needs of persons with dementia across the Kenyan population. In a study on perceptions and experiences of dementia and its care in rural Kenya, family caregivers reported negative experiences of disclosure of a diagnosis of dementia. They also reported limited and insufficient provision of information on dementia. The WHO Global dementia action plan has set the target of 75% of countries providing support and training programmes for carers and families of people with dementia by 2025.MethodAlzheimer’s Society of Ireland (ASI) family caregiver training was developed to help caregivers respond to the needs of people with dementia more confidently by developing their caring skills. Though set for a population in Ireland, there are many similar challenges that caregivers in both Kenya and Ireland share. To avoid reinventing the wheel, we adopted the ASI caregiver training programme to be used in Kenya. We conducted a baseline survey to understand the needs of caregivers in Kenya before beginning course adaptation and training. . Due to COVID‐19, the training couldn’t be conducted in person and we conducted the training online with two goals:• To provide quality online education to family caregivers to provide person centred care.• To create peer support for caregivers.We adopted and piloted 6 modules of the training. We used WhatsApp and Zoom to facilitate learning for caregivers, employing micro‐learning between weekly sessions.ResultI will present the lessons learnt from culturally adapting a course for family caregivers in Kenya and providing online training for caregivers in Kenya.Conclusion
There is an urgent need for more funding in LMICs to grow programs that provide support for caregivers and people with dementia.
Programs to build capacity for more people who provide training on dementia are essential to grow awareness and understanding.
Sex differences in risk for Alzheimer’s disease with extended maternal and paternal family history and vascular risk factors. The Cache County Study.
Authors: Vernon Elizabeth K. , Gonzalez Hector Leonardo , Schwartz Sarah , Rattinger Gail B. , Drewel Mikaela , Smith Ken Robert , DeBerard Scott , Kauwe John , Buhusi Mona , Tschanz JoAnn T 
Published: December 2022

AbstractBackgroundAge, family history (FH), APOE status, and vascular factors are known risk factors for Alzheimer’s disease (AD). Sex differences in AD risk have been reported for some but not all of these factors. We examined sex differences in the association between FH and AD risk, studying the role of maternal/paternal lineage, parental longevity, and vascular factors in a population‐based cohort.Methods3677 participants (59% female) of the Cache County Memory Study [mean(SD) age = 75.75(7.11) years] were studied. FH of AD and health information were obtained from self‐report or Medicare claims and death certificates via data linkage through the Utah Population Database. AD cases were determined via clinical examination and Medicare claims and non‐cases via clinical examination or negative cognitive screenings.ResultsMultivariate logistic regression models (covarying age, education, and APOE) found that individuals with a first‐ degree relative with AD was associated with a 58% and 66% increased risk of AD in males and females, respectively. In males, APOE Ɛ4 carriers with a history of exceptional maternal longevity (survival age 87+) had 3‐times the risk of AD than males with neither risk factor (OR = 3.15, p interaction p = .020). Males with both exceptional maternal and paternal longevity (survival age 87+) had an 11%
reduced
risk of AD (OR = 0.894, interaction p = .041). A history of both maternal and paternal lineages of AD was associated with a 46%
lower
risk (OR = 0.544) at trend level significance (interaction p = .054). In females, maternal lineage of AD was associated with a 56% increased risk of AD (OR = 1.56; p = .005). Females with a history of congestive heart failure and paternal lineage of AD had twice the AD‐risk (OR = 2.26, interaction p = .013) compared to females with neither risk factor. Parental exceptional longevity was not associated with AD risk in females.ConclusionRisk for AD associated with family history varies by sex, maternal and paternal lineage of AD and exceptional parental longevity. Elucidating mechanisms and modifiable lifestyle factors underlying sex differences may facilitate developing primary AD prevention strategies.