bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physical Activity Level Moderates the Association Between Response Inhibition and Anterior Cingulate Cortex Volume in Older Adults
Authors: Stein Ryan G , Silva Narlon Cassio Boa Sorte , Brinke Lisanne F Ten , Handy Todd C , Hsiung Ging‐Yuek Robin , Liu‐Ambrose Teresa 
Published: December 2022

AbstractBackgroundAging is generally associated with a decline in executive function, a cognitive domain that is critical to functional independence. Response inhibition is an executive process that contributes to anticipation, planning, and goal setting. The anterior cingulate cortex (ACC) is a key brain structure that supports response inhibition and shows gray matter loss with age. Evidence suggests that both response inhibition performance and the Anterior Cingulate Cortex (ACC) are responsive to exercise training. Whether physical activity moderates the relationship between response inhibition and the ACC in older adults is unknown.MethodA cross‐sectional analysis of a subset of community‐dwelling older adults enrolled in a 3‐arm, 8‐week proof of concept randomized control trial of computerized cognitive training, with or without exercise, who completed T1 magnetic resonance imaging (MRI) at baseline. Of the 68 MRI participants, 11 were removed from this analysis due to poor scan quality. Response inhibition was measured using the Flanker Task from the NIH Toolbox Cognitive Battery. Participants were split into either a high or low physical activity groups determined by their median Physical Activity Scale for the Elderly (PASE) score. Caudal and rostral ACC volumes were segmented and quantified using FreeSurfer. To assess for moderation, we performed linear regressions with age‐adjusted Flanker Task score as the dependent variable, and ACC volume, high/low PASE, and the interaction of ACC volume * high/low PASE as independent variables.ResultPhysical activity level significantly moderated the association between left caudal anterior cingulate cortex (LCACC) volume and age‐adjusted Flanker Task score, (β = –6.428, t(53) = ‐2.075, p < .05). Among those with low physical activity levels (n = 30), greater LCACC volume was associated with better response inhibition (r = 0.44, p = .01) while there was no association among those with high physical activity levels (n = 27; r = ‐0.13; p = .52).ConclusionHigher physical activity may mitigate the negative effects of age‐related gray matter loss in the ACC on response inhibition performance in community‐dwelling older adults.
[18F]TRACK, a PET tracer for imaging of tropomyosin receptor kinases (Trk): efficient radiosynthesis and preliminary evaluation in the TgF344‐AD rat model of Alzheimer’s disease.
Authors: Kang Min Su , Thiel Alexander , Schirrmacher Ralf , Bernard‐Gauthier Vadim , Jaworski Carolin , Dorian Andreas , Hopewell Robert , Singleton Thomas A , Blinder Stephan , Soucy Jean‐Paul , Rosa‐Neto Pedro , Kostikov Alexey 
Published: December 2022

AbstractBackgroundA family of tropomyosin receptor kinases (TrkA/B/C) plays important roles in the regulation of neuronal differentiation, growth, and survival via their interactions with neurotrophins. A growing body of literature suggests the downregulation of Trk in many neurodegenerative conditions of the central nervous system (CNS), including Alzheimer’s disease (AD). We recently reported the development of [18F]TRACK, the PET tracers for in vivo imaging of TrkB and its first in‐human study. Here, we wish to report a fully automated GMP‐compliant radiosynthesis of [18F]TRACK at high radiochemical purity (RCP) and molar activity and its preliminary evaluation in wild‐type and a transgenic rat model of AD.MethodRadiosynthesis was performed using Scintomics GRP automated module via copper‐catalyzed 18F‐fluorination of the chiral boron pinacolate precursor. Brain imaging in wild‐type (n = 3) and TgF344‐AD rat models (n = 2) at 23 months was performed on microPET Concord R4 scanner.Result[18F]TRACK was synthesized with a 5.0±1.4 % radiochemical yield not corrected for decay (activity range 95–154 mCi) with >99% RCP and molar activities of 250 ± 75 GBq/µmol (n = 6). The synthesis was fully automated and all batches passed quality control procedures, including chemical purity, sterility and pyrogenicity. The tracer showed moderate brain uptake in wild‐type rats with the highest accumulation in the thalamus (SUVmax = 1.56 ± 0.28, 10 min post‐injection), consistent with the brain regional distribution in humans acquired in a parallel study. Preliminary data suggests lower tracer uptake in TgF344‐AD rat model of AD in thalamus, striatum and frontal cortex compared to wild‐type animals.ConclusionThis study demonstrated the feasibility of the GMP‐compliant production of [18F]TRACK in sufficient doses and molar activities for scanning multiple subjects per day or long range deliveries. Preliminary biodistribution studies showed moderate brain uptake of the tracer with preferential accumulation in the thalamus across species. These findings warrants further studies of Trk brain expression and its implication in neurodegenerative and psychiatric pathologies using [18F]TRACK.
Longitudinal medial temporal lobe gray matter volume and cognitive changes in late middle‐aged and older adults with treated and non‐treated obstructive sleep apnea
Authors: Martineau‐Dussault Marie‐Ève , André Claire , Daneault Véronique , Baril Andree‐Ann , Gagnon Katia , Legault Julie , Montplaisir Jacques , Carrier Julie , Gosselin Nadia 
Published: December 2022

AbstractBackgroundNeuroimaging studies in obstructive sleep apnea (OSA) have found both gray matter atrophy and hypertrophy in medial temporal lobe subregions, the latter probably reflecting edema. Whether and how these changes progress over time when OSA is treated or untreated remains unclear. Here, we investigated gray matter volume changes in medial temporal lobe subregions in treated OSA, untreated OSA and control participants aged > 55 years. We also explored whether the medial temporal lobe volume at baseline could predict cognitive decline.MethodTwenty‐three non‐treated OSA participants (65.8 ±5.4 years) and twenty controls (64.0 ±6.4 years) were evaluated with overnight polysomnography, MRI session and neuropsychological assessment. Twelve OSA participants then started continuous positive airway pressure (CPAP) therapy and used it at least 4 hours per night, 4 nights per week. Eleven participants refused treatment. Participants were evaluated again with MRI and neuropsychology after 18 months. We extracted the entorhinal, hippocampal and parahippocampal volumes using FreeSurfer 7.1. We performed repeated‐measure ANOVAs with Group (treated OSA, untreated OSA and controls) and Time (baseline and follow‐up) on bilateral volumes. We also performed partial correlations between bilateral medial temporal volumes at baseline and changes in cognition (Montreal Cognitive Assessment, score at follow‐up – baseline) in each group separately. Analyses were corrected for age, sex, and total intracranial volume.ResultWe found a significant Group X Time interaction for bilateral parahippocampal volumes (F = 7.2; p = 0.002) where treated OSA participants showed a decreased volume over time (p tukey<0.001), while no changes occurred in the two other groups. Regarding the predictive value of medial temporal lobe volume, in untreated participants, higher bilateral hippocampal volume at baseline was associated with more severe cognitive decline over time (r = ‐0.77; p = 0.01). In treated participants, higher bilateral entorhinal cortex volume at baseline was associated with more cognitive decline (r = ‐0.74; p = 0.035). No associations were found in controls.ConclusionThese preliminary results showed that presenting hypertrophy of the medial temporal lobe subregions at baseline is associated with worse cognitive outcome at 18‐month follow‐up in OSA participants. In the CPAP group, the decrease in parahippocampal volume might represent a reduction in hypertrophy, possibly by limiting edema.
Distinct dimensions of depression are associated with different brain‐related biomarkers
Authors: Soleimani Laili , Beeri Michal Schnaider , Heymann Anthony , Livny Abigail , Lesman‐Segev Orit H. , Lin HungMo , Ouyang Yuxia , Ravona‐Springer Ramit 
Published: December 2022

AbstractBackgroundManagement of depression, a potentially modifiable risk factor for dementia, is of great importance in older adults with Type 2 Diabetes (T2D), specifically because of their higher risk for both conditions. We previously showed in older adults (aged ≥65) with T2D in the Israel Diabetes and Cognitive Decline (IDCD) study, that different depression‐dimensions were associated with distinct patterns of cognitive outcomes. Specifically, apathy, but not other depression‐dimensions, was associated with faster decline in executive functions. Here, we investigated the cross‐sectional relationship between depression‐ dimensions with different neuropathologies, i.e., total gray matter (GM) volume, white matter hyper‐intensities (WMH) and amyloid burden.MethodAmong IDCD participants [mean age = 70.55 (SD = 4.25), 38.5% female], 209 had a brain MRI, 42 of whom also had an amyloid PET. Depression dimensions were defined based on the Geriatric Depression Scale‐ 15 item (GDS‐ 15): dysphoric mood, apathy, anxiety, hopelessness and subjective memory complaint. Gray Matter and WMH volumes were examined using a high‐resolution 3‐Tesla brain MRI. Amyloid‐β burden was defined as mean standardized uptake value ratios (SUVRs) of [18F] flutemetamol in the frontal, parietal, and temporal cortices compared to the cerebellum as reference region. We used two‐step linear regression models to study the association of GDS–domains and brain imaging markers.ResultHigher total GDS score was associated with lower GM volume (r = ‐0.14; p = 0.037) and higher volume of WMH (r = 0.20; p = 0.003), but not with brain amyloid‐β burden (r = ‐0.13; p = 0.37). Among specific depression‐ dimensions, apathy (r = 0.22; p = 0.001), and hopelessness (r = 0.15; p = 0.033) were associated with higher WMH burden, whereas the subjective memory complaints dimension was associated with lower total GM volume (r = ‐0.15; p = 0.026). Depression dimensions were not associated with amyloid burden.ConclusionIn cognitively normal older adults with T2D, higher depression scores, even below the cutoff defined as clinically significant, were associated with lower GM and higher WMH volumes. Apathy was the main driver of the association with higher WMH burden and subjective memory complaints drove the association with brain atrophy. No association was found between depression‐dimensions and amyloid‐β burden, consistent with previous findings in non‐T2D samples, on the role of vascular, rather than AD pathology, in depression.
Longitudinal change in plasma biomarkers by amyloid PET status
Authors: Bilgel Murat , An Yang , Walker Keenan A , Moghekar Abhay , Resnick Susan M. 
Published: December 2022

AbstractBackgroundIt is important to better understand the longitudinal trajectories of plasma measures of proteins implicated in Alzheimer’s disease among cognitively normal older adults.MethodWe investigated whether baseline levels and longitudinal rates of change of three Quanterix SIMOA plasma measures (amyloid‐beta 42 to 40 ratio [Aβ42/Aβ40], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]) differ by amyloid group as determined using Pittsburgh compound B (PiB) PET in the Baltimore Longitudinal Study of Aging (N=147 PiB– and 57 PiB+; 640 longitudinal measures). All participants were cognitively normal at baseline. We used linear mixed effects models with longitudinal plasma measures as the outcome. We conducted an unadjusted analysis that included binary PiB group, time from baseline, and their interaction. We also conducted an adjusted analysis that additionally included the following explanatory variables: baseline age and its interaction with time, sex, APOE ε4 carrier vs noncarrier, race, and estimated glomerular filtration rate (eGFR) from serum creatinine concurrent with plasma measurements. All variables except time were mean‐centered.ResultParticipant characteristics are presented in Table 1. Figures 1 and 2 illustrate plasma biomarkers versus age and longitudinal visit schedule per participant, respectively. PiB+ individuals had lower Aβ42/Aβ40, higher GFAP, and higher NfL at baseline (Table 2). Both PiB groups exhibited longitudinal increases in GFAP and NfL (Table 3). Aβ42/Aβ40 declined longitudinally in the PiB– group, but annual change in the PiB+ group was not statistically significant. PiB group difference in rates of change in plasma measures was statistically significant for Aβ42/Aβ40 but not for NfL. Difference in rate of change in GFAP was statistically significant in the unadjusted model only. Adjusted model fixed effect estimates are depicted in Figure 3.ConclusionSteeper decline in plasma Aβ42/Aβ40 in the PiB– group suggests that individuals may exhibit decline in this measure prior to the onset of amyloid PET positivity. Despite exhibiting baseline PiB group differences, plasma GFAP and NfL have similar rates of increase in both PiB groups. Reliable detection of such changes at the individual level, prior to the onset of cognitive impairment, may enable better personalized prediction of future outcomes.
Sex‐specific decoupling of cerebral blood flow and glucose metabolism in Alzheimer’s disease mouse model
Authors: Zhao Yifan , Jin Tao , Fitz Nicholas F , Koldamova Radosveta , Iordanova Bistra 
Published: December 2022

AbstractBackgroundCerebral blood flow (CBF) dysregulation and neurovascular impairment are central to Alzheimer’s disease (AD) etiology1. Even though two‐thirds of the AD patients are women, the sex differences in vascular and metabolic risk factors are still unclear2. Previously, we described sex‐specific CBF trajectories in mouse model of AD3. In the present study, we connect these CBF changes with cerebral glucose metabolism in the same males and females. We quantify the correlation between metabolic rate and vascular flow and identify unique points of divergence across lifespan.MethodWe used 9.4T MRI of APPswe.PSEN1dE9 mice (23 males, 24 females; young 3‐7 months, middle age 7‐15 months, and old 15‐24 months) and B6C3F1/J controls (n=20). We quantified CBF (qCBF) using T1‐weighted mapping and continuous arterial spin labeling (CASL) as previously described3.The glucose uptake rate (ΔR1ρ) was measured using chemical exchange‐sensitive spin lock (CESL) and computed as the difference between the steady state before and after intravenous injection of 2‐Deoxy‐d‐glucose (2DG)4. Region of interests were drawn manually on the cortex and subcortical areas.ResultWe found that AD females, but not AD males had lower cortical glucose metabolism than age‐matched controls, while both AD groups had lower CBF than controls. These differences were not significant in the subcortical regions. The metabolic trajectory during aging was similar between AD males and females (Fig 1A), however, the CBF trajectory of AD males showed a transient increase from young to middle age, while the female group showed an opposite trend (Fig 1B). The sex‐specific divergence between glucose consumption and CBF appeared during middle age. Male AD mice had higher positive correlation between glucose metabolism and CBF in the cortex compared to females (Fig 2A). Additionally, in both AD groups, this correlation was positive in the cortex but not in the subcortical region (Fig 2).ConclusionWhen interpreting metabolic rate of glucose and CBF as AD biomarkers, age, sex and brain region should be taken into consideration.
Cortical Microstructure Mediates CSF Amyloid and Tau Associations with Episodic Memory Performance
Authors: Nir Talia M , Salminen Lauren , Reina Julio E Villalon , Haddad Elizabeth , Zheng Hong , Thomopoulos Sophia I , Thompson Paul M , Jahanshad Neda 
Published: December 2022

AbstractBackgroundEpisodic memory impairment is common in early stages of Alzheimer’s disease (AD) and has been linked to atrophy in cortical regions that are vulnerable to AD neuropathological processes (e.g., amyloid and tau accumulation). Volumetric measures are relatively insensitive to microstructural brain changes that can occur in earlier disease stages. Microstructural properties of brain tissue can be non‐invasively assessed using advanced diffusion MRI (dMRI) models such as neurite orientation dispersion and density imaging (NODDI). While a number of studies have related white matter microstructure to AD pathology and memory, few have evaluated advanced dMRI indices in cortical gray matter where the earliest histopathological changes are thought to occur.MethodWe evaluated 66 ADNI participants (age 71.8±6.2 years; 25 Males; 46 CN/18 MCI/2 AD) with available MRI (T1‐weighted and multi‐shell diffusion) and CSF Aβ1–42, pTau181, and pTau181/Aβ1–42 data (Fig1A). Episodic memory was assessed using WMS‐R delayed logical memory scores (Del‐Mem). We estimated average NODDI ICVF, ECVF, ISOVF, and ODI (Fig1B) in an AD‐metaROI of cortical gray matter regions that are sensitive to early AD (Fig1C,D). We tested whether the effect of CSF biomarkers on Del‐Mem were mediated by metaROI measures (Fig2A), adjusting for age, sex, education, and MRI site as a grouping variable. For comparison, we re‐ran analyses with AD‐metaROI cortical thickness as the mediator.ResultLower CSF Aβ1–42 and higher pTau181/Aβ1–42 were significantly associated with lower Del‐Mem performance (FDR; q=0.05); pTau181 was not associated (Fig2B).Lower cortical ICVF, ODI, and thickness and higher ISOVF were associated both with lower Aβ1–42 and higher pTau181/Aβ1–42 (Fig2C).The effect of Aβ1–42 on Del‐Mem was fully mediated by ICVF. The effect of pTau181/Aβ1–42 on Del‐Mem was partially mediated by ISOVF. Del‐Mem was not mediated by ODI or thickness (Table1). Sensitivity analyses in the 64 non‐demented individuals revealed comparable results.ConclusionLower cortical ICVF and higher ISOVF with greater Aβ and pTau/Aβ burden, respectively, may indicate neuronal loss or edema. While both ICVF and ISOVF findings can be driven by reduced diffusion restriction, larger pTau/Aβ effects on episodic memory mediated through ISOVF may indicate that tau hyperphosphorylation and aggregation induces a greater degree of inflammation, neuronal dysfunction and death.
Presenilin1 FAD mutants and γ‐secretase inhibitors decrease VEGFR2 signaling and block angiogenic functions of brain endothelial cells
Authors: Pandey Rukmani , Robakis Nikolaos K , Georgakopoulos Anastasios 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial and progressive neurodegenerative disease where cerebrovascular abnormalities are commonly observed. Various factors, including decreased sprouting angiogenesis, can cause a reduction in capillary density observed in AD. In addition, brain vascular alterations occur before the appearance of neuropathology in animal AD models. Brain angiogenesis is a reparative function in response to toxic insults and is regulated by endothelial cells (ECs) and angiogenic factors such as the VEGF; impairment in this function would render the brain vulnerable to insults. In present study, we examine the effects of Presenilin 1 (PS1)‐Familial AD (FAD) mutants and γ‐secretase in the VEGF‐induced angiogenic signaling and functions of brain ECs.MethodPrimary cortical ECs (pCECs) from brains of wild‐type (WT) and knock‐in (KI) mice expressing either PS1 M146V or PS1 I213T FAD mutant in heterozygous state were isolated and cultured. These mice constitute a “humanized” FAD model having the same genotype as human FAD patients. We performed the in vitro angiogenesis assays using pCEC cultures. Processing of VEGFR2 was detected in HEK293 cells overexpressing VEGFR2 in the presence or absence of VEGF‐A and γ‐secretase inhibitor (RO4929097). The same processing was also analyzed by western blotting in PS1 M146V and I213T mutant pCECs treated with VEGF‐A. VEGF‐induced phosphorylation of signaling molecules downstream of VEGFR2 such as p38 kinase and PLCγ1 was also examined in WT and PS1 M146V mutant pCECs by western blotting.ResultWe found that VEGFR2 is processed by γ‐secretase and that this processing together with VEGF‐induced sprouting, tube formation, migration and angiogenic complexes between VE‐cadherin and Rok‐α kinase are decreased in the presence of γ‐secretase inhibitor or by PS1 FAD mutants. Furthermore, the VEGF‐induced phosphorylation of p38 and PLCγ1 is decreased in PS1 FAD mutant pCECs.ConclusionOur findings suggest that VEGFR2 is processed by γ‐secretase and that γ‐secretase promotes VEGF‐induced angiogenic functions of brain ECs through activation of VEGF‐VEGFR2 downstream signaling. Our data also show that a PS1 FAD mutant decreases both the VEGFR2 processing by γ‐secretase and the VEGF‐induced signaling and angiogenic functions of pCECs, providing a mechanism via which FAD mutants affect brain angiogenesis.
Triglyceride and VLDL cholesterol are lower in cognitively healthy individuals with Amyloid pathologies than those without
Authors: Arakaki Xianghong , Buennagel David P , Nolty Anne , Spezzaferri Mitchell , Rising Shant , Sin Caleb , Chui Helena C , Fonteh Alfred N. , Kloner Robert A 
Published: December 2022

AbstractBackgroundFramingham, or cardiovascular (CVD) risk score, as a composite score can accurately predict long‐term CVD risk in the general population. General lipid profiles contribute to CVD risk and Alzheimer’s disease (AD) with inconsistent reports: both high and low triglyceride or body mass index (BMI) have been linked with AD risk. However, the knowledge of their contribution to early AD is limited. To study the changes of CVD risk score and lipid in early AD, we explored the CVD risk score and lipid profile risk factors in our aging cohort.MethodWe compared estimated CVD risk score (Erisk) between cognitively healthy (CH, n=137) individuals, in participants with mild cognitive impairment (MCI, n=54), AD (n=42), and other dementia (OD) (n=23). We also compared lipid profile risk factors (BMI, triglyceride, cholesterol, high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, and very low‐density lipoprotein (VLDL) cholesterol). Furthermore, we compared those risk factors in CH participants subgroups with different status of CSF amyloid (A), phospho‐tau (T), and total‐tau (N): between those with AD risk (A+T±N±: ChA+) and those without (ChA‐T‐N‐). Bonferroni correction was used for multiple comparisons.ResultErisk and lipid profiles were not different between CH, MCI, AD, or OD. We observed lower triglyceride and VLDL cholesterol, and marginally lower BMI, in ChA+ group than in ChA‐T‐N‐ group (p<0.008, Fig 1).ConclusionThese pilot results suggest that CH participants with amyloid pathology presented with lower triglyceride and VLDL cholesterol values, and marginally lower BMI. Although these data need to be confirmed in a larger population, our study supports the concept that lower levels of triglycerides, VLDL cholesterol, or BMI may be linked to amyloid pathology in the CH stage. Further studies examining related factors and pathways that contribute to amyloid pathology such as APOE genotype and VLDL‐receptor expression are needed to fully understand the implications of our findings.