bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of lifecourse socioeconomic status and midlife brain health in Black adults
Authors: Turney Indira C , Lao Patrick J. , Rivera Andres M. , Berroa Joncarlos , Brickman Adam M. , Manly Jennifer J. 
Published: December 2023

AbstractBackgroundA recent study showed that middle‐aged Black participants exhibited the magnitude of brain aging observed during late life, suggesting accelerated brain aging. Lifecourse socioeconomic status (SES) is an important predictor of health status, like cognition and Alzheimer’s disease (AD), and may help us understand some of the underlying mechanisms that contribute to accelerated brain aging in middle‐aged Black adults. SES predicts health outcomes throughout the lifespan, and there may be a period of susceptibility where SES is most impactful (e.g., SES in childhood vs adulthood). This study assessed whether childhood or midlife SES better predicts midlife brain health in Black adults.MethodParticipants were 140 middle‐aged Black adults from the Offspring study of Racial/Ethnic Disparities in AD with MRI (mean age = 54.9 (SD = 9.2) years; 63% women). We used general linear models to examine the relationship of childhood SES (e.g., composite of parent’s income, education, occupation) and Midlife SES (e.g., midlife income) with MRI‐based cerebrovascular disease (e.g., white matter hyperintensity volume; WMH) and neurodegeneration (e.g., AD signature cortical thickness), controlling for sex/gender and age, and additionally household size in midlife SES models only. We also assessed whether health factors (e.g., hypertension, diabetes) attenuated the effects of lifecourse SES on MRI markers.ResultChildhood SES was not associated with midlife cortical thickness or WMH volume. For midlife SES, participants making less than $35k/year (New York City median income) had lower cortical thickness (B = ‐0.39, CI = ‐0.075,‐0.002) and greater WMH volume (B = 0.192, CI = 0.048,0.336). Estimated marginal means predicted that if these participants made $35k+/year, they would instead show a 1.5% increase in cortical thickness and 32.8% reduction in WMH volume. History of hypertension (47%) and diabetes (22%) was unrelated to MRI markers and did not attenuate the relationship between midlife SES and MRI markers.ConclusionMidlife SES, but not childhood SES, was associated with midlife brain health in people racialized as Black. Results did not show a direct association between vascular risk and brain health or suggest that vascular risk was in the pathway from SES to brain health. Rather, higher income may maintain vascular and structural brain health in midlife.
Combined effect of persistent cytomegalovirus infection and Tumor Necrosis Factor‐α Polymorphism on age‐related cognitive decline
Authors: Vacher Michael , Lee Silvia , Ha Phuongnhi , Waters Shelley , Laws Simon , Price Patricia 
Published: December 2023

AbstractBackgroundHuman cytomegalovirus (HCMV) is a ubiquitous infectious agent, widely distributed in human populations. Its infection has been correlated with a number of age‐related disorders but associations with neurocognitive decline are not seen consistently. The Tumor Necrosis Factor‐α (TNF) is a cytokinine playing a key role in inflammation and TNF polymorphisms have been associated with various autoimmune diseases. In this study, we investigated the impact of TNF genotype and HCMV on age‐related cognitive decline.MethodThe study cohort consisted of 200 Caucasian Australians (aged 59‐89 years) drawn from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. We used linear regression models to assess the effect of TNF genotype, HCMV and their interaction on a series of domain‐specific composite scores (Preclinical Alzheimer Cognitive Composite; PACC, Recognition, Attention Processing, Language). The models accounted for the potential effect of age, education level and Apolipoprotein E genotype.ResultThe interaction between HCMV and TNF genotype significantly predicted PACC (b = 5.3; SE = 2.56; p = 0.04) and Recognition scores (b = 1.9; SE = 0.78; p = 0.01). Interactions were not significant in the other domains investigated (attention processing & language).ConclusionThe results suggest that the presence of TNF polymorphism, combined with HCMV infection have a protective effect against cognitive loss. Further research is needed to understand the underpinning mechanisms.
Alzheimer’s disease plasma markers and depressive symptoms: an IPD meta‐analysis
Authors: Twait Emma L. , Kamarioti Maria , Verberk Inge M.W. , Teunissen Charlotte E. , Nooyens Astrid C.J. , Verschuren Monique WM , Visser Pieter Jelle , Huisman Martijn , Kok Almar A.L. , Slagboom P. Eline , Beekman Marian , Ikram M. Arfan , Schuurmans Isabel K , Wolters Frank J. , Moonen Justine E. , Gerritsen Lotte , van der Flier Wiesje M. , Geerlings Mirjam I. 
Published: December 2023

AbstractBackgroundDepression has been associated with an increased risk of Alzheimer’s disease (AD), but the biological mechanisms are still not fully understood. Plasma biomarkers, such as amyloid‐beta, tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL), have been associated with AD pathophysiology. However, the relationship with depression is unclear. Assessing these biomarkers in the blood allows for the opportunity to assess if AD pathology is related to depressive symptoms on a large‐scale. We hypothesized if depression is part of the AD process, then these markers will be associated with depressive symptoms.MethodA two‐stage IPD meta‐analysis was performed based on eight cohorts of individuals without dementia as part of the Netherlands Consortium of Dementia Cohorts (NCDC). We examined the cross‐sectional association between each plasma marker for AD (amyloid‐beta42/40 ratio, p‐tau181, NfL, and GFAP) with depressive symptoms (the GDS‐15, PHQ‐9, CES‐D, and SF‐36). Plasma markers were assessed using Single Molecular Array (Simoa; Quanterix) assays. Both plasma markers and depressive symptoms were standardized. We estimated the effect per plasma marker with depressive symptoms using linear regressions, correcting for age, sex, education, and APOE e4 allele presence, in each cohort. The effect estimates were entered into a random‐effects meta‐analysis. We also performed subgroup analyses assessing sex differences and between those with and without an APOE e4 allele.ResultThis study involved 7210 participants with an age range of 38 to 102 years. Based on clinical cut‐offs per questionnaire, high depressive symptomology ranged from one to 22% per cohort. None of the plasma markers were associated with depressive symptoms in the meta‐analysis. However, subgroup analyses found an association with NfL and depressive symptoms in women (beta 0.07; 95% CI: 0.03‐0.10, p < 0.001) and in those with an APOE e4 allele (beta 0.11; 95% CI: 0.05‐0.17, p = 0.001).ConclusionAD pathology did not show an overall relationship with depressive symptoms. However, in women and in those with a genetic risk for AD, NfL showed an association. As NfL is a marker of overall neurodegeneration, this pathology in plasma may be specific to depressive symptoms in certain subgroups.
Effects of Physical Activity, Vascular Burden and Clinical Diagnosis on White Matter Integrity
Authors: Konwar Srijan 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia. Both degenerative and vascular pathology tend to contribute to dementia as AD coexists with single or multiple cardiovascular risk factors (vascular burden). Modifiable lifestyle factor such as physical activity has been associated with lower vascular burden (VB) and a lower risk of dementia. To test whether physical activity characterised as being inactive or active helped preserve white matter microstructure in a sample consisting of healthy controls and patients from the clinical AD continuum (mild cognitive impairment to dementia) with either low or high VB.Method213 participants were recruited from three memory clinics and were classified as being either physically active (n = 113) or inactive (n = 100) based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) questionnaire. Voxel‐wise tract‐based spatial statistics (TBSS) was carried out using a set of 5000 permutations and threshold‐free cluster enhancement (TFCE) to find significant clusters for fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity (MD) and radial diffusivity (RD).ResultParticipants who were physically active had higher FA and lower AxD, MD and RD values relative to the inactive participants. Changes in indices of WM integrity were widespread across the brain covering mainly association and projection tracts but a few commissural tracts. A three‐way interaction effect between Group × Physical Activity × VB was found for FA that was present in mainly projection tracts with a rightward asymmetry along with some association and commissural tracts. Post hocs revealed greater FA in physically active patients with high VB compared with inactive patients with high VB in projection and association/limbic tracts with a rightward asymmetry. Furthermore, the patients with high VB showed higher FA in bilateral projection fibers and cerebellar regions compared with inactive controls with high VB.ConclusionTBSS analysis revealed that high risk patients such as those with high VB achieved the maximum benefit by being physically active as it led to a much greater preservation of white microstructure relative to controls with high VB. This preservation of white matter microstructure was only observed in patients but not in controls.
Clinical Phenotypes of Alzheimer’s Disease: Pathological Correlates of Regional Cortical Volume
Authors: Reijner Niels , Frigerio Irene , Bouwman Maud M.A. , Guizard Nicolas , Jubault Thomas , Lin Chen‐Pei , Hoozemans Jeroen , Rozemuller Annemieke J.M. , Bouwman Femke H. , Barkhof Frederik , Gordon Elizabeth , Berg Wilma D.J. , Jonkman Laura E. 
Published: December 2023

AbstractBackgroundRecent studies highlight distinct patterns of cortical atrophy in amnestic (typical) and non‐amnestic (atypical – behavioural, dysexecutive and visuospatial) clinical phenotypes of Alzheimer’s disease (AD). The current study aimed to assess regional phenotypic MRI patterns of cortical atrophy, and their association with Amyloid‐beta (Aβ), phosphorylated Tau (pTau), and axonal degeneration (NfL).MethodPostmortem In‐situ 3DT1 3T‐MRI data were collected for 28 AD (14 typical, 14 atypical) and 10 control brain donors. Images were segmented using QyScore® and regional volumes according to the AAL3 atlas were obtained. At subsequent autopsy, Eight brain regions from the right hemisphere were selected and immunostained for Aβ (4G8), pTau (AT8), and Neurofilament light (NfL), and quantified for area% load. Group comparisons and MRI volume‐pathology associations were analyzed using linear models with covariates age, gender, postmortem delay, and intracranial volume when applicable.ResultsWhen assessing regional cortical volumes, compared to controls, typical AD showed a more parietal‐temporal, while atypical AD showed a more a frontal‐temporal atrophy pattern (fig1).Typical and atypical phenotypes showed different pathological load across all selected regions in both Aβ and NFL (p = 0.032,p = 0.0007, respectively). Subsequent explorative assessment indicates a difference in regional pTau distribution between behavioural, dysexecutive and visuospatial subtypes, specifically in the occipital region (fig2).Addressing MRI‐pathology associations across all selected regions, we observed a positive association between cortical volume and Aβ in typical AD (β = 1.98,p = 0.026), while both pTau and NFL showed a negative association (β = ‐0.26,p = 0.004; β = ‐2.00,p = 0.001, respectively). In atypical AD, only NFL showed a significant negative association (β = ‐2.27,p<0.001) with cortical volume. Regionally (fig3), only NfL associated with MRI volume; with the precuneus in both typical and atypical AD (β = ‐2.81,p = 0.044; β = ‐3.81,p = 0.011, respectively), and with posterior cingulate cortex volume in atypical AD (β = ‐3.24,p = 0.045).ConclusionThis study found varying atrophy patterns in AD phenotypes when compared to controls. Across all selected regions, typical AD showed volume‐pathology associations with Aβ, pTau and axonal damage, while atypical AD only showed associations with axonal damage, indicating a possible difference in volume‐pathology associations between phenotypes. Regionally, cortical volume was predominantly associated with axonal damage, rather than Aβ or pTau protein accumulation, in parietal regions.
Trajectory of MRI and FDG‐PET biomarkers in Alzheimer’s disease
Authors: Heeman Fiona , Moscoso Alexis , Dunås Tora , Schöll Michael 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) has a long preclinical phase, which is hypothesised to start with the accumulation of β‐amyloid (Aβ) plaques, followed by tau neurofibrillary tangles and neurodegeneration. Despite presenting quite different types of information, MRI‐derived volumetric measures and FDG‐PET‐derived metabolism are both commonly used as proxy of neurodegeneration in AD. The aim of this work is to assess the trajectory of both of these biomarkers in AD, relative to time to amyloid‐positivity.Method3289 MRI scans (682 participants) and 2472 FDG‐PET scans (1296 participants) were included from the ADNIGO, 1,2 and 3 cohorts. For MRI scans, total volume was calculated for a meta‐ROI consisting of entorhinal, inferior, middle temporal and fusiform gyri. For FDG‐PET, standardized uptake value ratios (SUVR) were calculated from 30‐60 min post injection for a meta‐ROI consisting of the angular, posterior cingulate and inferior temporal gyri, normalised to the pons. All metrices were transformed into z‐scores using the references values of the Aβ‐negative subjects. Age of amyloid‐positivity was determined by fitting a nonlinear mixed effects model to 3607 Centloid values corresponding to 1690 participants. Next, time to amyloid‐positivity was calculated for each scan. The relationship between time to amyloid‐positivity and (z‐scored) SUVR or cortical volume values was modelled using a non‐linear mixed effects model with spline function and trajectories from both modalities were compared.ResultsBaseline demographics can be found in Table 1. Figure 1 shows the trajectory of amyloid deposition that was used to determine age of amyloid‐positivity. Cortical volume and SUVR showed similar trajectories over time, with steeper decline in both measures after the event of amyloid‐positivity (Figure 2). The overlay of both biomarker trajectories shows that for the meta‐ROI, there is no difference in when these biomarkers become abnormal.ConclusionsThe present results suggest that measures of neurodegeneration from MRI and FDG‐PET scans corresponding to a meta‐ROI, follow very similar trajectories. Future work will investigate if this also holds true for smaller regions of interest.
Investigating drug repurposing for the prevention of Alzheimer’s disease and related dementias using electronic health records in the University of Pennsylvania Health System
Authors: Li Lu , Wu Qiong , Lundin Sori Kim , Naj Adam C. , Gur Ruben C , Rascovsky Katya , Wolk David A. , Tao Cui , Chen Yong 
Published: December 2023

AbstractBackgroundAlzheimer’s disease and related dementias (ADRDs) are a group of complex neurodegenerative diseases and disorders that pose a growing global public health burden. Developing new treatments for ADRDs has been difficult and there is a pressing need for new therapeutic options. Drug repurposing, which involves finding new uses for existing drugs, has gained increasing attention as a potential strategy for ADRD prevention. Here we aimed to identify drugs that may be repurposed for Alzheimer’s disease (AD) or ADRD prevention using a data‐driven approach from a large multi‐site electronic health record (EHR) database.MethodUsing structured EHR data from the University of Pennsylvania Health System (UPHS) between January 2012 and March 2022, we constructed a cohort of 13,091 individuals with mild cognitive impairment (MCI) and hypertension. We conducted multivariate Cox proportional hazard analyses to investigate the effect of exposure to medications on time to AD/ADRD adjusting for potential risk factors, including age at MCI diagnosis, sex, race, and several comorbidities. We identified and investigated five classes for the treatment of hypertension, including beta‐blockers (BBs), Renin‐angiotensin‐system (RAS), calcium channel blockers (CCBs), Diuretics, and antihypertensives (AHM). To ensure adequate statistical power, generic drugs with more than 500 users were identified and examined.ResultMultivariate analyses revealed that two drug classes (Table 1) had significantly reduced hazard ratios (HR) for developing dementia including Diuretics (HR = 0.885, P = 0.038) and BBs (HR = 0.881, P = 0.027). Additionally, furosemide in the Diuretics category (HR = 0.723, P < 0.001) and propranolol in the BBs category (HR = 0.529, P = 0.045) demonstrated protective effects on developing dementia. On‐going secondary analyses stratified by gender, age groupConclusionThis study identifies 2 drug categories and 2 generic drugs that may confer protection against the onset of AD/ADRDs. Further follow‐up, such as a randomized trial, is needed to confirm these associations and explore potential therapeutic applications. This study’s approach to harmonizing and analyzing records from a large multi‐site EHR database approach represents a promising data‐driven strategy for identifying drug repurposing opportunities for AD/ADRD prevention.
Mitophagy biomarkers are changed in the continuum of Alzheimer’s disease
Authors: Veverova Katerina , Katonova Alzbeta , Horakova Hana , Angelucci Francesco , Laczó Jan , Hort Jakub , Shi Liu , Fang Evandro Fei , Vyhnalek Martin 
Published: December 2023

AbstractBackgroundAutophagy is a cellular self “garbage clearance ”system through which cells eliminate and recycle dysfunctional cytoplasmatic components, such as defective organelles and misfolded protein aggregates. Mitophagy is the sub‐type of autophagy that recognizes and degrades damaged or superfluous mitochondria to maintain cellular homeostasis. Emerging evidence demonstrates that autophagy and mitophagy are impaired in Alzheimer’s disease (AD); its upregulation ameliorates Aß pathology and slows down the cognitive decline in animal models of AD, thus representing a potentially treatable target. The change in the mitophagy biomarkers in individuals with AD needs to be clarified. We aimed to explore the changes of mitophagy biomarkers in biomarkers‐defined individuals in various stages of AD and compare them to cognitively unimpaired individuals (CU).MethodWe included 228 biomarker‐defined individuals from the Czech Brain Aging Study:98 AD dementia (ADD), 88 mild cognitive impairment due to AD (MCI‐AD), and 42 CU individuals. They underwent clinical examination, complex neuropsychological assessment, and brain MRI. Commercial ELISA kits were used to measure standard AD biomarkers in CSF (Aß42, Aß40, pTau, tTau), a biomarker of neurodegeneration (neurofilament light chain – NfL), synaptic dysfunction (neurogranin, Ng), and mitophagy biomarkers in CSF (PINK1‐ mitochondrial kinase crucial for mitophagy) and in serum (BNIP3L‐ mitophagy receptor, TFEB‐ transcription factor critical for lysosomal degradation).ResultWe found a significant increase in PINK1 CSF and BNIP3L serum levels in ADD compared to MCI‐AD and CU (ps<.001). TFEB serum levels were decreased in ADD compared to MCI‐AD and CU (ps<.05). Additionally, in ADD, PINK1 correlated with NfL (r = 0.27) and Ng (r = 0.47). In MCI‐AD, there was a correlation between PINK1 and Ng (r = 0.51), but not with NfL. There was no correlation in CU individuals with NfL or Ng.ConclusionWe identified candidate proteins of mitophagy that are changed in various cognitive stages of AD. In the ADD stage, there is an upregulation of the mitophagy inducers, PINK1 and BNIP3L, together with decreased levels of TFEB, a master regulator of lysosomal biogenesis. One of the possible explanations is that these findings reflect impairment in the final stage of autophagy–lysosomal degradation. Further research is needed to clarify its pathophysiological importance in the AD cascade.
The diurnal variation of Alzheimer’s disease plasma biomarkers: a 25h study with hourly sampling
Authors: Brum Wagner S. , van Doorn William , Zimmer Eduardo R. , Zetterberg Henrik , Ashton Nicholas J. , Meex Steven JR , Blennow Kaj 
Published: December 2023

AbstractBackgroundNovel plasma biomarkers can accurately reflect key pathological features of Alzheimer’s disease (AD). To ensure their safe clinical implementation in the near future, determining whether they present a diurnal rhythm is a key pending task in the field. This would help to elucidate whether the time of day in which blood samples are collected could influence blood biomarker results in clinical trials, research studies and clinical practice. Thus, we aimed to determine the diurnal rhythm of novel AD plasma biomarkers.MethodIn this study, we included n = 24 cognitively unimpaired older adults (median age [IQR]: 73 [64‐83] years). After overnight fasting and refraining from exhaustive physical activities for 2 days, volunteers were restricted to a standardized experimental environment from 8:30AM to 9:30AM on the following day (NCT02091427). Plasma‐EDTA samples were collected hourly (n = 26 time points), and we quantified biomarkers of tau pathology (p‐tau181), amyloid‐β (Aβ42, Aβ40, Aβ42/Aβ40), glial activation (glial fibrillary acidic protein, GFAP) and neurodegeneration (neurofilament light, NfL) with Simoa HD‐X instruments (UGOT assay: p‐tau181; Quanterix Neurology‐4‐Plex‐E for others). For visualization, biomarker concentrations were CV‐transformed, a standard procedure in which each measurement corresponds to the percent variation from each individual’s mean value over a day.ResultBiomarkers generally demonstrated stable values during a day’s period (Figure 1). When evaluating CV‐transformed concentrations, the observed 5th and 95th quantiles of within‐individual variation over a day were: Aβ42, ‐18.4% to 15.4%; Aβ40, ‐13.7% to 14.4%; Aβ42/Aβ40, ‐9.4% to 8.7%; P‐tau181, ‐15.7% to 21.5%; GFAP, ‐24.0% to 26.8%; NfL, ‐16.2% to 19.9%. Plasma Aβ42 and Aβ40 increased during the day, reaching a peak during sleep (2:00AM), with a similar pattern but much smaller in magnitude for Aβ42/Aβ40 (Figure 2A‐C). P‐tau181 presented a peak in the morning, while GFAP and NfL also presented a peak during sleep (Figure 2D‐F).ConclusionNovel AD plasma biomarkers seem to present a diurnal rhythm. A night‐time biomarker peak, such as observed for plasma Aβ42 and Aβ40, could be explained by sleep‐related clearance of certain proteins from the brain. Nevertheless, the clinical impact of our findings will depend on the analyte of interest and clinical context of their application.