bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effects of Sex and APOE4 Genotype on Longitudinal Changes in White Matter Integrity Differ by Diagnostic Group Along the Spectrum of Alzheimer’s Disease
Authors: Blujus Jenna K , Oh Hwamee 
Published: December 2023

AbstractBackgroundSex and APOE ε4 (APOE4) are well‐established risk factors for Alzheimer’s disease (AD), with female ε4‐carriers at greatest risk. Uncovering the neurobiological substrates of sex and genetic effects in AD is critical to improve prevention, intervention, and treatment monitoring. While changes to white matter (WM) integrity are commonly noted in the progression of AD, it is unclear if these changes are further modulated by sex and APOE4 status. In the current study, we examined the effects of sex and APOE4 carrier status on WM integrity, both cross‐sectionally and longitudinally, across the AD continuum.MethodA total of 457 participants (233 cognitively normal (CN), 167 mild cognitive impairment (MCI), and 57 AD; 223 females; 187 APOE ε4‐carriers) was selected from the ADNI database, based on the availability two diffusion MRI (dMRI) sessions. The dMRI data were processed using FSL’s TBSS pipeline to quantify the degree of fractional anisotropy (FA). Annualized FA change maps were created to measure voxel‐wise WM change over time. The effect of sex, APOE4‐carrier status, diagnosis, and their interactions, on cross‐sectional and longitudinal WM integrity were assessed by FSL’s randomise and cluster‐level correction, controlling for age.ResultAt baseline, females exhibited greater FA than males in the fornix, right inferior fronto‐occipital fasciculus, left inferior and superior longitudinal fasciculus, while males showed greater FA in the left corticospinal tract. Additionally, there were widespread differences across the skeleton by diagnosis, with FA decreasing stepwise across the continuum (CN>MCI>AD). There were no APOE4‐related differences in baseline WM integrity. Longitudinally, a three‐way interaction between diagnosis, APOE4, and sex emerged within the corpus collasum, left anterior thalamic radiation, left corticospinal tract, left uncinate fasciculus, and left inferior and superior longitudinal fasciculus. Posthoc analyses revealed that within the AD group, but not CN or MCI groups, females underwent greater WM degeneration than males among nonε4‐carriers, while males showed greater WM degeneration than females among ε4‐carriers.ConclusionThese findings suggest that increased risk associated with sex and APOE4 genotype may change and interact with the progression of AD. Future studies are warranted to examine the contribution of cerebrovascular risk factors to AD progression in male ε4‐carriers.
Does parity and risk of dementia follow a U‐shaped relationship? Findings from the Cache County Study of Memory and Aging
Authors: Schliep Karen Cecilia , Bigler Erin Daniel , Meeks Huong , Fraser Alison , Smith Ken Robert , Ostbye Truls , Tschanz JoAnn T 
Published: December 2023

AbstractBackgroundRecent evidence from the UK Biobank of over 273,000 women indicates a U‐shaped relationship between parity and risk of dementia, with nulliparity and grand multiparity showing increased risk of dementia compared to women having 1‐3 births after adjustment for important sociodemographic and health history factors, but not Apolipoprotein E (ApoE) polymorphism. ApoE4 genotype, a known risk factor for Alzheimer’s disease and Alzheimer’s disease related dementia (AD/ADRD), has been shown to be related to higher potential female fertility due to increased concentrations of progesterone. Our objective was to determine whether a similar U‐shaped relationship is present in the population based Cache County Study of Memory in Aging (CCSMA) cohort, after controlling for important confounding factors including ApoE genotype.MethodsCCSMA was a longitudinal study that investigated risk factors contributing to AD/ADRD and other dementias. CCSMA enrolled 90% (N = 5,092, n = 2928 women) of the Cache County, Utah permanent resident population aged 65 and older as of January 1, 1995. Participants were followed for four triennial waves for AD/ADRD ascertainment. Prior number of live births for CCSMA women was assessed via self‐report and validated via linked Utah Population Database records (99% successful linkage). Adjusted risk ratios using Poisson regression with robust variance were calculated to assess whether parity was associated with later dementia risk, adjusting for important sociodemographic and health history factors (Table 1).ResultsAmong the total sample, 5.6% were nulliparous, 18.4% had 1‐2 births, 54% had 3‐5 births, and 22% had 6+ births. Over the course of the study, 12% were diagnosed with AD and 7% with ADRD. Compared to women with 3‐5 births, women with zero, 1‐2, and ≥6 live births had an aRR of 1.16 (95% CI: 0.80, 1.69), 1.00 (95% CI: 0.76, 1.32), and 1.21 (95% CI: 0.96, 1.53) (Figure 1), respectively. Results were similar for ADRD.ConclusionOur results support a U‐shaped relationship between parity and dementia risk. Whether the relationship between parity and dementia risk is being driven by social and behavioral factors involved in parenting or biological factors associated with childbearing (e.g., total endogenous estrogen exposure) warrants further investigation.
Creation of a brain homeostatic model, digital twin, and digital population for functional assessment of lipidomics
Authors: Funk Cory C , Rohrs Jennifer , Paterson Tom 
Published: December 2023

AbstractBackgroundAD is a complex, multifactorial disease, with ∼60% of variance attributed to genetics. Many studies have identified various biomarkers and lifestyle risk factors in the form of hazard ratios, relating biological mechanisms to cognitive decline. Numerous multiomic datasets (ADNI, ADSP, AMP‐AD) exist in the hopes of weaving an integrated understanding of AD pathophysiology. Traditional systems biology analyses of these datasets has demonstrated limited gains in assembling a cumulative understanding of how diverse molecular and clinical data fit together. Analyses of these proteomic, lipidomic, metabolomic datasets reveal a wealth of correlated molecular networks. Unfortunately, the functional significance of these networks is challenging to discern.MethodWe created a model of brain homeostasis and age‐driven cognitive decline, curating over 1,000 publications, and mathematically representing an array of Alzheimer’s‐related biological sub‐systems with 232 functional processes. Starting with a Digital Population of over 10 million hypotheses on the model’s foundation, we used ADNI non‐lipidomic data (APOE4 status, Abeta, Tau, MMSE, hippocampal atrophy) to create Digital Twins of 20 ADNI patients over four time points, spanning from cognitively normal to end‐stage disease. Using the ADNI lipid data from these same 20 patients, we identified 75 lipid networks, and looked for correlations between the those networks and synthetic data on the 232 functional processes from the patient’s Digital Twins.Result11 of the 75 ADNI lipidomic modules were highly correlated with 11 of the 273 functional processes in the digital twin synthetic data. These 11 functional processes were in the domains of microglia lipid droplet metabolism, reverse cholesterol transport, and neuron energy balance. Subsequent systems biology analyses of each of these lipid networks was consistent with the functional processes linked via the digital twin synthetic data. Principal component analyses of each lipidomic network yielded a quantitative assessment of the functional process that can serve as a “translator” to use those lipid data for even more accurate digital twins.ConclusionWe have created a model of brain homeostasis that can be used to create a digital population to understand the non‐linear relationships of a diversity of omics data, bridging the gap between omics, intermediate functional processes and clinical outcomes.
The structural integrity of anterior‐temporal and posterior‐medial brain regions in Alzheimer’s disease and Parkinson’s disease: Effects of APOEε4, p‐tau181 and Aβ42
Authors: Coughlan Gillian T , Zhukovsky Peter , Sanchez Erlan , McLaughlin Paula , Grady Cheryl , Black Sandra E. , Munoz Douglas , Buckley Rachel F. , Masellis Mario 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) and Parkinson’s disease (PD) are two distinct neurodegenerative brain conditions associated with varying degrees of cognitive impairment, including an overlapping amnestic phenotype. At autopsy, APOEε4 and AD proteinopathies are associated with dementia severity in both AD and PD. The extent to which in‐vivo AD biomarkers are associated with memory and underlying regional brain volume in AD and PD patients is under‐investigation. Here, we focused on plasma biomarker associations with anterior‐temporal and posterior‐medial regions that are known to accumulate tau and Aβ in AD.MethodNeuroimaging, biomarker, genetic and cognitive data were collected from 244 patients through the Ontario Neurodegenerative Disease Research Initiative (MeanAge = 68.96; 41% women; 35%APOE‐ε4‐carriers). Based on clinical diagnostic criteria, three groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 120), ii)PD with MCI or dementia(PDMCI/PDD;N = 76) and iii)PD with normal cognition(PD‐NC;N = 48). Linear regressions assessed clinical diagnosis differences in the volumetric integrity of a priori regions: anterior‐temporal(ATN; including amygdala, fusiform gyrus, and ITG) and posterior‐medial(PMN; including PCC, parahippocampal cortex and precuneus;Fig1). Differences on related item recognition memory and associative memory was examined via the FaceName Association Task. APOE(ε4‐/ε4+), p‐tau181‐UGOT and Aβ42 associations between ATN/PMN and item recognition/associative memory outcomes were estimated. Diagnostic*APOEε4*ptau181 interactions were tested. Age, sex, education and ICV were covaried.ResultBackground characteristics showed that the ADMCI/ADD group exhibited the oldest age and the highest frequency of female sex and ε4‐carriership. ADMCI/ADD and PDMCI/PDD, but not PD‐NC, exhibited elevated ptau181 and Aβ42 relative to a healthy control group. Both ADMCI/ADD and PDMCI/PDD groups exhibited PMN and ATN degradation, as well as memory impairment, relative to the PD‐NC(Fig2A‐B). Plasma p‐tau181 was associated with ATN and PMN, as well as associative memory(Fig3A). APOEε4 was associated with PMN only, as well as item recognition(Fig3B). Diagnostic*APOEε4*ptau181 interactions were not significant. Post‐hoc analysis showed significant p‐tau181xAPOEε4 interactions on item recognition and total white matter hyperintensity(WMH;Fig3C). Aβ42 was not associated with outcomes.ConclusionVolumes of the ATN and PMN are lower in cognitively impaired AD and PD patients with higher p‐tau and/or APOEε4‐carriership. P‐tau and APOEε4 may work synergistically to promote domain‐specific memory impairment and WMH burden in both AD and PD.
Drug repositioning for Alzheimer’s disease and related dementias: Network meta‐analysis using individual participant data
Authors: Liu Yu‐Lun , Kong Zifang , Tao Cui , Chen Yong 
Published: December 2023

AbstractBackgroundAlzheimer’s disease and related dementias (AD/ADRD) are chronic neurodegenerative pathology and bring a growing public health concern worldwide; particularly, treatments for AD/ADRD remain limited. Drug repositioning has alternate potential to provide an opportunity to accelerate newly identified treatments for individuals with AD/ADRD. Like, some studies have investigated effects of antihypertensive medications on dementia risk, but inconsistent results are reported. In this study, we aim to determine whether existing or approved drugs, including antihypertensive drugs and hormone replacement therapy, enable to reduce the risk of dementia or cognitive impairment.MethodWe searched PubMed, MEDLINE and EMBASE for published trials up to December 31, 2020. The primary outcome of interest was incident dementia or incident cognitive decline. We examined the following candidate repurposed drugs, including hormone replacement therapy and antihypertensive drug classes: diuretics, beta blockers (BB), angiotensin‐converting enzyme inhibitors (ACE‐I), angiotensin II receptor blockers (ARB), calcium channel blockers (CCB), alpha blockers, central agonists, vasodilators, and aldosterone blockers. We conducted a random‐effects network meta‐analysis using individual participant data to identify both direct and indirect evidence from the include trials.ResultFour trials, including 19,632 participants and 10 candidate repurposed drugs, met the eligibility criteria, as shown in Figure 1. The results of network meta‐analysis were presented as a league table in Figure 2. We found that aldosterone blockers (OR = 2.32; 95% CI: 1.41 to 3.81), ARB (OR = 1.31; 95% CI: 1.07 to 1.60) and hormone therapy (OR = 1.36; 95% CI: 1.08 to 1.71) were less effective in reducing dementia risk when compared with ACE‐I. Moreover, all the other drugs reduced dementia risk statistically significantly compared with aldosterone blockers (ORs ranging from 0.46 (95% CI: 0.27 to 0.79) for alpha blockers to 0.59 (95% CI: 0.35 to 0.99) for hormone replacement therapy).ConclusionOur findings showed some classes of antihypertensive drugs may have more potential to prevent the incidence of dementia or cognitive decline than the other classes. However, further research for validation of our results is needed.
Relation between cortical thickness and frontal lobe P50 response in neurotypical aging: MEG study
Authors: Gumenyuk Valentina , Peled Noam , Korzyukov Oleg , Murman Daniel L , Rizzo Matthew , Miller Nicholas 
Published: December 2023

AbstractBackgroundThe auditory Event Related Potential (ERP) with latency at peak at 50 ms is a potential biomarker of prodromal Alzheimer’s disease (AD). However, the relation between P50 ERP and the thickness of the gray matter over frontal brain regions in healthy individuals over 55 y.o is not well studied. We examined the relation between frontal lobe generator of auditory P50 and degree of the gray matter volume lost in healthy individuals. We hypothesized that reduced thickness in the cingulate cortex is associated with aberrant function of the frontal lobe generator of the P50 response.MethodSeven healthy subjects (ages 58‐72 years, 4 women) participated in the ongoing study. P50 response was calculated from magnetoencephalographic and electroencephalographic data during presentation of 7 tones (30 ms duration) ranging from 500 to 986 Hz. Each tone was preceded by 850 ms period of silence. Free‐surfer computed the cortical thickness for each subject as the distance between the gray/white matter boundary and the pial surface for each pair of vertices. 110 T1‐MPRAGE scans of elderly healthy controls (over 65 yo) from a Neurocognitive aging dataset were used as an average‐control group. To calculate the difference in thickness between averaged control and individual subject, the z‐value was applied. The template of 110‐averaged data was transformed into the subject’s space, and for each vertices we subtracted the mean and divide by the standard deviationResultIn this study we show, that in subjects with less thickness in the cingulate cortex the amplitude of P50 response was enhanced with respect to those subjects who had more cortical thickness (Z value >5 vs. Z value <2). The aberrant function of the frontal lobe generator of P50 response was associated with enchanted amplitude of the P50 in MEG and EEG data.ConclusionOur results suggest that age‐related deficiency in frontal lobe generators of auditory P50 in healthy aging participants is associated with a reduction of gray matter volume in cingulate cortex. Present results support the notion about age‐related changes in modulatory role of frontal lobe generator of auditory P50 that are located at the cingulate cortex.
Mobile Early Detection Memory Screening project with Older Adults in Armenia utilizing the Montreal Cognitive Assessment Test (MoCA) in cooperation with mobile eyecare hospital.
Authors: Mahakian Jane 
Published: December 2023

AbstractBackgroundThe aim of the project is to address this tremendous gap in care by developing a unique multidisciplinary in‐home mobile clinic to address the need for cognitive screening as well as provide overall healthcare for the person with Alzheimer’s and their families. The Brain Health Armenia Project is an innovative approach to addressing the need for comprehensive cognitive screening as well as the overall care of the person with dementia in Armenia. This country wide project will increase cognitive screening rates and proper diagnosis as well as visibility and awareness of Alzheimer’s disease which will help decrease myths and fears about the disease.Methodcognitive screenings by partnering with the Armenian EyeCare Project by assessing patients for cognitive screenings. The Armenian EyeCare Project is a Mobile Eye Hospital that provides care for people throughout Armenia since 2002. They also have five Regional Eye Centers. The Brain Health Armenia Project will provide cognitive screenings to people who come to the mobile Eye Hospital as well as to their Regional Eye Centers. Once screened, people who show impairment twill be offered to be part of the Brain Health Armenia Project. The Brain Health Armenia Project’s multidisciplinary team will make in home visits where they will administer assessments, provide referrals to neurologists; provide cognitive rehabilitation, care management and follow‐up; palliative and end‐of‐life care. The team will provide caregiver education and counseling about the disease as well as best practices for caring for their loved one.The target population is vulnerable adults living in Armenia’s regions outside of main city.ResultCurrently, around 14.4% of Armenia’s population is already over the age of 60 (Ryan, 2018). By 2050, 31.5% of Armenia’s population will be over the age of 60 (Ryan, 2018). The number of people in Armenia with Alzheimer’s disease is expected to grow exponentially in the coming decades.ConclusionThis Project, which the Ministry of Health endorses, will increase the importance of cognitive screening as well as care of the person with dementia and be a significant program for the country’s National Dementia Plan. This project has revealed the prevalence of dementia in Armenia.
Can exercise benefit cerebral white matter myelin? Findings from a 12‐month randomized controlled trial in older adults with vascular cognitive impairment
Authors: Silva Nárlon Cássio Boa Sorte , Dao Elizabeth , Hsu Chun Liang , Tam Roger , Lam Kevin , Alkeridy Walid Ahmed , Laule Cornelia , Vavasour Irene M , Stein Ryan G , Liu‐Ambrose Teresa 
Published: December 2023

AbstractBackgroundCerebral small vessel disease is a major underlying cause of subcortical ischemic vascular cognitive impairment (SIVCI). Myelin loss is a feature of cerebral small vessel disease, which may underly cognitive and functional decline in older adults living with SIVCI. Resistance training (RT) is a form of exercise associated with slower progression of white matter lesions, a cerebral small vessel disease marker. However, it remains to be determined whether RT can counteract myelin loss in individuals living with SIVCI. Thus, we examined the impact of a 12‐month, twice‐weekly progressive RT program on myelin content in those with SIVCI.MethodThis was a sub‐study of a 12‐month single‐blinded, randomized controlled trial. Participants (n = 91) were randomized to RT or an active control group (balance and tone exercises [BAT]). Study eligibility included: 1) age 55 years and older; 2) magnetic resonance imaging (MRI) evidence of cerebral small vessel disease; 3) mild cognitive impairment; and 4) the absence of dementia. Myelin was measured using a multi‐echo gradient and spin echo T2 relaxation MRI sequence, indexed as myelin water fraction (MWF). Differences between groups at 12 months were assessed via analysis of covariance adjusting for baseline MWF and estimated intracranial volume. MWF data from fifteen white matter tracts were analyzed. Post‐hoc regressions were conducted to determine if changes in MWF were associated with changes in mobility measured with the Short Physical Performance Battery (SPPB).ResultSeventy‐three participants (RT = 36) aged 74.1 (SD = 5.7), 64% females with high‐quality MRI data were included in the analyses. At 12 months, RT showed lower MWF levels compared with BAT in the genu of the corpus callosum (estimated mean difference [RT – BAT]: ‐0.610, 95% CI: ‐1.041 to ‐0.178, p = 0.006), fornix (‐0.883, 95% CI: ‐1.570 to ‐0.197, p = 0.012), and combined white matter tracts (‐0.326, 95% CI: ‐0.643 to ‐0.009, p = 0.044). Changes in MWF in the combined white matter tracs were positively associated with changes in SPPB (Unstandardized B = 0.124, SE = 0.061, p = 0.047).ConclusionContrary to our expectations, 12 months of balance and tone exercises, but not RT, showed positive changes in myelin. These improvements may result in better mobility in older adults with SIVCI.
Effective strategies to recruit rural family/friend caregivers of persons living with dementia in the United States into a national randomized controlled trial: preliminary results
Authors: Yank Veronica A. , Santoyo‐Olsson Jasmine , Luzanilla Maritza , Romo Elizabeth Macias , Ramirez Giselle Aguayo , Chesla Catherine , Lorig Kate , Cheng Jing , Covinsky Kenneth E , Gallagher‐Thompson Dolores , Karliner Leah 
Published: December 2023

AbstractBackgroundFamily/friend caregivers of persons living with dementia (PLWD) in rural areas of the United States (U.S.) are more isolated and under‐served than urban counterparts[1] and are under‐represented in randomized controlled trials (RCTs)[2,3]. Our objective was to identify effective strategies for recruiting rural caregivers into a national RCT and describe baseline characteristics of enrolled caregivers.MethodsWe recruited U.S. rural caregivers of PLWD into an ongoing RCT evaluating the impact of an online asynchronous 6‐week workshop (“Building Better Caregivers”) on caregiver psychological health (June 2020‐present)[4] using multiple strategies (Table, row 1). We prospectively recorded characteristics of recruitment efforts (e.g., strategy type, cost, date) and caregiver responses (tick‐box, free‐text) to the eligibility survey question “How did you hear about the Building Better Caregivers study?” We performed descriptive analyses to determine the level of recruitment success of each strategy.ResultsOf 669 eligible caregivers, 360 (54%) enrolled to date (enrollment ends April 2023). Caregivers had mean age of 62.0 years (range 23‐86); identified primarily as White (87%), female (83%), and straight/heterosexual (90%); were caring for a spouse (44%), parent (43%), other relative (7%), or friend/neighbor (6%); and lived in all U.S. Census regions (34% West, 25% Midwest, 24% South, and 18% Northeast). Recruitment efforts with advertisements on Facebook, Google, and large media outlets (e.g., daily newspapers) had low success and cost money, whereas efforts through websites of trusted community/government agencies or local media (e.g., weekly newspapers) had medium‐to‐high success and were free (Table, row 2). Efforts to recruit through national associations had limited (low‐medium) success. Efforts to recruit through community agencies and health systems achieved high success when they had robust, searchable databases of PLWD/caregivers, mailing lists, and online resources. Some frontline caregiver experts (e.g., rural caregiver support specialists) achieved high recruitment but were challenging to identify in individual states and regions.ConclusionsWe successfully recruited rural dementia caregivers into a national RCT. We found that recruitment efforts were most effective when they engaged community‐based media, organizations, and experts to reach rural caregivers who trusted them. Rural recruitment is possible and necessary to achieve equitable trial access for vulnerable rural caregivers.