bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma glutamate metabolism correlates with cognitive function and the brain‐adipose axis in a presymptomatic Alzheimer’s cohort
Authors: Fonteh Alfred N. , Arakaki Xianghong , Yu Jianquan , Castor Katherine , Harrington Michael G. 
Published: December 2020

AbstractBackgroundIn addition to the amyloid hypothesis, it is accepted that neurotransmitter and energy dyshomeostasis may underlie AD pathology. Glutamate (Glu) is one of the most common excitatory neurotransmitters and is the precursor of glutamine (Gln) and pyroglutamine (PGln). Glu signaling intersects with lipid metabolism via neuronal phospholipase A2 activation and the regulation of adiposity. Lipids are a major storage form of energy that is critical to AD pathology. We propose that disturbance in Glu metabolism may interfere with how the brain regulates lipid storage in adipose tissue and its utilization by tissues, and this process can contribute to early AD pathology. Consequently, the aim of our study is to quantify plasma Glu and its metabolites and determine their interaction with lipid metabolism in a pre‐symptomatic AD cohort.MethodsWe collected fasting blood samples from cognitively healthy (CH) study participants with normal cerebrospinal fluid amyloid/ tau ratio (CH‐NAT, n = 36) or with pathological amyloid/tau ratio (CH‐PAT, n = 34), and from AD participants (n = 26). The concentrations of Glu, Gln, and PGln were measured using liquid chromatography‐tandem mass spectrometry. Blood lipids were measured in a clinical laboratory (HMH, Pasadena) and CSF measures of Aβ42 and total tau were determined using an ELISA.ResultsBlood plasma Glu but not Gln and PGln positively correlated with CSF Aβ42/T‐tau ratio, in CH and CH‐NAT (p = 0.02) but not in CH‐PAT (p > 0.05) or AD (p = 0.99) participants. Blood plasma Glu also positively correlated with mean diastolic pressure (p = 0.02), BMI (p = 0.001), plasma triglycerides (p < 0.0001), and VLDL‐cholesterol (p < 0.0001), and negatively correlated with HDL‐cholesterol (p = 0.0003), in all CH study participants. Glu did not correlate with BMI but correlated strongly with VLDL‐cholesterol in CH‐NAT. In contrast, Glu correlated with BMI but not with VLDL‐cholesterol in CH‐PAT.ConclusionsThese data show the differential regulation of blood glutamate metabolism, CSF amyloid/tau, and plasma lipids in pre‐symptomatic AD compared with cognitively healthy participants. We propose that glutamate metabolism and the brain‐adipose interface may be involved in regulating cognitive function and improving its homeostasis may prevent the decline from cognitively healthy to pre‐symptomatic or AD pathology in elderly populations.
Dietary supplementation results in a significant incorporation of DHA into RBC phosphatidylcholine of non‐APOE ε4 allele but not for ε4 carriers
Authors: Solomon Victoria , Smirnova Yelena , Harrington Michael G. , Yassine Hussein N. , Fonteh Alfred N. 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) is commonly characterized by the accumulation of beta‐amyloid plaques in the brain causing neuroinflammation and cognitive decline. Risk for developing AD is associated with the ε4 allele of Apolipoprotein E (ApoE), a cholesterol carrier involved in lipid transport and brain injury repair. Docosahexaenoic Acid (DHA), an omega‐3 polyunsaturated fatty acid, has been shown to decrease ß‐amyloid production and prevent inflammation. The aim of our study is to determine whether DHA incorporation can account for the differences in the efficacy of DHA intervention in carriers of the ApoE ε4 allele (APOE ε4) compared with noncarriers (non‐APOE ε4).MethodWe supplied APOE ε4 (n = 15) and non‐APOE ε4 (n = 16) cognitively healthy (CDR ≤ 0.5) participants above the age of 55 with 2 g/day of daily fish oil supplements, for six months. Participants were randomized into either DHA‐treatment or placebo groups. We isolated red blood cells (RBCs) from participants at baseline (T0) and after six months (T6) and used LC/MS‐MS analyses to quantify phospholipid species. We isolated 44 phosphatidylcholine (PC) species and examined changes in DHA contents after supplementation.ResultWe found no significant differences in total PC across treatment groups nor between APOE ε4 and non‐APOE ε4 participants. Acyl DHA‐containing PC species (PC38a:6 and PC40a:6) increased significantly between T0 and T6 (p < 0.02 for all) non‐APOE ε4 participants. In contrast, no significant differences were seen between APOE ε4 carriers after DHA supplementation. No significant differences were found in plasmalogen PC‐DHA (PC40p:6) for any group. The ratio of PC‐DHA to PC‐containing arachidonic acid (C20:4n‐6), an omega‐6 fatty acid known to favor neurodegeneration, was significantly higher (p = 0.0008) for non‐carriers but not for ε4 carriers.ConclusionOur data shows that dietary supplementation gives specific incorporation of DHA into acyl‐PC species in RBCs of non‐APOE ε4 carriers but not for ε4 carriers. We propose that the increased risk of AD pathology of ε4 carriers may be due to the inefficient incorporation and transport of DHA. Alternative means are needed to enhance DHA incorporation and transport into blood cells of ε4 carriers to effectively combat cognitive decline even at its earliest stages.
The effect of heat shock protein 72 on cognitive decline and metabolic health in the 5xFAD*Tg30 Alzheimer's disease model
Authors: Marshall Jessica P.S. 
Published: December 2020

AbstractBackgroundHeat shock protein 72 (HSP72) has the potential to play a cytoprotective role in Alzheimer’s disease (AD) as previous studies have demonstrated that its elevation inhibits amyloid beta oligomerization and enhances its clearance, restores tau homeostasis and inhibits neuronal apoptosis. BGP‐15 is a compound observed to be a co‐inducer of HSP72, and therefore, we hypothesized that pharmacological activating Hsp72 with this compound or genetically up‐regulating Hsp72 may be advantageous in preventing or delaying AD progression and associated pathology.MethodWe crossed 5xFAD (overexpressing human APP and Presenilin‐1) and Tg30 (overexpressing tau) mice, to create the double transgenic 5xFAD*Tg30. We then crossed the double transgenic mice with HSP72 overexpressing transgenic mice (Hsp72Tg) to create the triple transgenic, 5xFAD*Tg30*HSP72Tg. Double transgenic mice were kept untreated or treated with BGP‐15 in their drinking water in a randomised and blinded study in both male and female mice from the ages of 2‐10months. A comprehensive battery of behavioural and metabolic tests was conducted, and results compared to littermate wildtype mice.ResultWe observed significant declines in Rotarod, Y‐Maze and Novel Object performance in the 5xFAD*Tg30 mice compared to wildtype, however neither HSP72 overexpression or BGP‐15 treatment rescued this decline. HSP72 overexpression was effective in maintaining lean mass in male mice. BGP‐15 was efficacious in significantly increasing body weight specifically in female mice. In males there was a 40% decrease in survival rates by 10months, which was improved by BGP‐15 treatment to a 15% decrease(p=0.08).ConclusionBGP‐15 may improve survival rates (male) and increased weight (females) while overexpression of Hsp72 leads to maintenance of lean mass in male5xFAD*Tg30 mice. However, both avenues used to increase Hsp72 were insufficient to protect against cognitive deficits. Further studies analysing the brain pathology of these mice are warranted.
Study of the effect of ascorbic acid on Aβ42 peptide aggregation
Authors: Sampaio Isabella , Quatroni Felipe Domingues , Zucolotto Valtencir 
Published: December 2020

AbstractBackgroundAscorbic acid (AA) is an antioxidant molecule found at high concentrations in the brain. A negative correlation was found in Alzheimer’s disease (AD) patients between the decrease in AA brain levels and the accumulation of amyloid plaques indicating that AA plays some function in amyloid aggregation, however, no studies have elucidated its mechanism of action so far, which can greatly contribute to the development of new therapeutic strategies for AD.MethodTo investigate AA as inhibitor of amyloid aggregation, amyloid‐beta 1‐42 (Aβ42) samples containing or not AA were incubated in pro‐aggregation conditions and analyzed by atomic force microscopy (AFM) and fluorescence spectroscopy using Thioflavin T. The mechanism of action presented by AA was evaluated using isothermal titration calorimetry (ITC) technique to investigate its binding to Aβ42 monomers.ResultFluorescence analyses pointed out to a decrease in fibril formation for samples incubated with AA at a concentration found in brains of healthy patients. After 72 h, these samples presented almost 80% fewer β‐sheet structures than samples without the antioxidant molecule. The fluorescence results were corroborated by AFM images, indicating that AA inhibited the amyloid aggregation in the fibrillar form. ITC measurements showed a negative cooperative binding between AA and Aβ42 monomers. In this interaction model for multiple sites, the binding of AA molecule in the first site of Aβ42 decreases the affinity constant (Kd) for the binding in the second site (Kd1>Kd2).ConclusionOur study revealed that ascorbic acid is able to inhibit the aggregation of Aβ42 peptides into fibrils through the direct binding to the monomers. Based on the thermodynamic parameters, we observed that the interaction is spontaneous and exothermic. This finding highlights ascorbic acid as a potential candidate for Alzheimer’s disease treatment and the mechanism of action provides novel insights for the inhibition of amyloid aggregation.
The role of hypusinated eIF5A in TDP‐43 cytoplasmic sequestration in AD and TDP‐43 related dementia
Authors: Smeltzer Shayna , Quadri Zainnudin , Miller Abraian , Zamudio Frank , Chaput Dale , Lee Daniel C. , Selenica Maj‐Linda B. 
Published: December 2020

AbstractBackgroundA wealth of studies have concluded that TAR DNA‐binding protein 43 (TDP‐43) pathology is associated with clinical dementia of including Frontotemporal Disorders (FTD) and Alzheimer’s Disease (AD). Interestingly, TDP‐43 pathology occurs in more than half of clinically diagnosed Alzheimer’s disease (AD) patients (1). These studies were recently complemented by the discovery of limbic‐predominant TDP‐43 encephalopathy (LATE) – underscoring the importance of age‐related TDP‐43 proteinopathy, with or without comorbid AD‐type plaques and tangles. eIF5A is the only known protein to undergo hypusination, a unique post‐translation modification at lysine (K50) (eIF5AhypK50) within the hypusine loop.MethodWe utilized a conditional TDP‐43 HeLa cellular model of sodium arsenite (SA)‐induced stress to investigate the role of hypusinated eIF5A (eIF5AHypK50) in TDP‐43 cytoplasmic mis‐localization and stress granule accumulation. We also performed LC/MS and proteomics analysis combined with Ingenuity and Enrich/GO analysis to identify relevant molecular and biological protein networks. Biochemical and immunocytochemical analysis and cellular microscopy were applied to measure TDP‐43 pathology.ResultOur proteomics analysis in M17 cellular model provided evidence for the interaction of eIF5A with TDP‐43, while functional data revealed the hypusine‐dependent manner of such interactions. SA treatment promoted co‐localization of TDP‐43 with eIF5AHypK50 both in the cytoplasm and stress granules. Importantly, pharmacological reduction of hypusination or site‐directed mutations of lysine (K) 50 residues decreased phosphorylated and insoluble TDP‐43 levels without effecting “de novo” protein synthesis. Additionally, both proteomic and biochemical analysis identified Ran‐GTP, KPNA1/2 and KPNB1 as interacting partners of eIF5AHypK50.ConclusionWe demonstrate that modifications in the hypusine loop of eukaryotic initiation factor 5A (eIF5A) reduces hallmarks of TDP‐43 proteinopathy; cytoplasmic mis‐localization, phosphorylation and sequestration. Conversely, pharmacological inhibition of hypusination reduces TDP‐43 accumulation and aggregation in cells. Additionally, we posit that eIF5AhypK50 regulates TDP‐43 cytoplasmic sequestration through interactions with nuclear pore complex (NPC) proteins, particularly importins KPNA2/B1 and Ran‐GTP. These findings elucidate novel pathways and potential therapeutic targets in AD and related dementia and require further investigations.
Higher atherosclerotic cardiovascular disease risk score and pulse pressure are associated with increased cerebrovascular pulsatility in Apolipoprotein E4 carriers
Authors: Kaufman Carolyn S. , Alwatban Mohammed R. , Ward Jaimie L. , Vidoni Eric D. , Morris Jill K. , Burns Jeffrey M. , Billinger Sandra A. 
Published: December 2020

AbstractBackgroundEvidence increasingly points to an early role for cerebrovascular dysfunction in the pathogenesis of Alzheimer’s disease (AD). Studies suggest a potential synergistic effect on dementia development between poor systemic vascular health and the strongest known genetic risk factor for AD, the Apolipoprotein E4 (ApoE4) allele. We hypothesized that atherosclerotic cardiovascular disease (ASCVD) risk score and pulse pressure (PP) would be associated with pulsatility index (PI) at rest and during moderate‐intensity exercise in ApoE4 carriers but not non‐carriers.MethodsWe conducted a secondary analysis on data from cognitively‐normal adults (65‐86 years old) who were classified as ApoE4 carriers (n = 15) or non‐carriers (n = 25). For the parent study, individuals were recruited from the University of Kansas Alzheimer’s Disease Center. We calculated the ASCVD risk score from the laboratory values and physiologic measurements obtained for each participant. We used resting brachial artery measurements to calculate pulse pressure (PP = Systolic Blood Pressure – Diastolic Blood Pressure). We recorded middle cerebral artery velocity (MCAv) using transcranial Doppler ultrasound at rest and during 8 minutes of moderate‐intensity exercise. We calculated the PI for each participant (PI = (systolic MCAv – diastolic MCAv) / MCAv mean) during rest and exercise.ResultsNo group differences between ApoE4 carriers and non‐carriers were found for age, sex, or body mass index (p > 0.05). A Spearman’s rank‐order correlation showed a significant positive correlation between ASCVD score and exercising PI for ApoE4 carriers (rs
= 0.614, p = 0.015) but not for non‐carriers (rs
= ‐0.007, p = 0.974). No association was observed between ASCVD score and resting MCAv. PP showed a positive association with resting PI in ApoE4 carriers (rs
= 0.531, p = 0.042) but not non‐carriers (rs
= 0.164, p = 0.432).ConclusionsPoor systemic cardiovascular health was associated with higher pulsatile flow in the cerebral vasculature in ApoE4 carriers but not non‐carriers. These findings provide evidence for the connection between poor systemic vascular health and poor cerebral vascular function in ApoE4 carriers. These data highlight the importance for maintaining good cardiovascular health, particularly for those at highest genetic risk of AD.
The aging rhesus macaque as a potential model for Alzheimer's disease/dementia: An in vivo study of [11C]PIB, [11C]UCB‐j, [18F]MK‐6240 and working memory performance
Authors: Fang Xiaotian T. , Williams Graham , Castner Stacy , Holden Daniel , Zheng Ming‐Qiang , Najafzadeh Soheila , Ropchan Jim R. , Arnsten Amy F.T. , Horvath Tamas , Carson Richard E. 
Published: December 2020

AbstractBackgroundNonhuman primates (NHPs) exhibit age‐related cognitive impairments, synaptic loss, and accumulation of tau and amyloid in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In a cohort of NHPs with longitudinal cognitive data, we perform SV2A ([11C]UCB‐J), amyloid ([11C]PIB), and tau ([18F]MK‐6240) PET. We aim to 1) investigate in vivo relationships and age‐related change in amyloid, tau, and synaptic density (SV2A) and 2) to relate these to cognition in NHPs.MethodMiddle‐aged (n = 5, 10.4 ± 0.5 y.o.) and old (n = 17, 19.9 ± 2.7 y.o.) NHPs were dynamically PET scanned (FOCUS 220) following i.v. injection of each of [18F]MK‐6240 (173 ± 12 MBq), [ 11C]PIB (131 ± 52 MBq), and [11C]UCB‐J (105 ± 34 MBq). Structural MR scans were acquired for registering PET to template space. Outcome measures were SUVR40‐60 for [11C]PIB, SRTM2‐derived DVR for [11C]UCB‐J, and SUVR90‐110 for [18F]MK‐6240. Cerebellum was used as reference ([11C]PIB, [11C]UCB‐J), and cerebellar gray matter for [18F]MK‐6240. A subset of the old NHPs (n = 15) were tested with the spatial‐delayed response task to assess working memory performance. Outcome measures: number‐of‐wells, time‐delay, and combined score (number‐of‐wells × time‐delay); higher score indicates better memory performance.ResultNo regional mean differences were observed in amyloid or SV2A between middle‐aged and old NHPs, though old NHPs exhibited higher variance for all tracers; mean tau was elevated in dlPFC (p = 0.0031) and hippocampus (HC, p = 0.011) in old NHP compared with middle‐aged (Figure 1). In ERC, a positive relationship was found between tau and amyloid), and in HC, a negative correlation was found between tau and SV2A (Figure 2A). Synaptic density displayed a positive relationship with combined score both in dlPFC (p = 0.0055, R2 = 0.46) and HC (p = 0.029, R2 = 0.32) (Figure 2B). Tau had a negative relationship with number‐of‐wells in dlPFC (p = 0.05, R2 = 0.40), and combined score in HC (p = 0.015, R2 = 0.40).ConclusionNHPs exhibit age‐related changes in canonical AD biomarkers as seen by PET. PET markers of SV2A, tau, and amyloid in known early‐pathology regions (dlPFC, HC) correlate appropriately with working memory performance. These studies demonstrate the potential of NHPs as a highly useful model for human AD.
Mitochondrial translocator protein (TSPO) ligand attenuates neuroinflammation and reduces complement component C1Q in a mouse model of tauopathy
Authors: Fairley Lauren H. , Sahara Naruhiko , Suhara Tetsuya , Higuchi Makoto , Barron Anna M. 
Published: December 2020

AbstractBackgroundThe mitochondrial translocator protein (TSPO) has been widely investigated as a positron emission tomography (PET) detectable biomarker of neuroinflammation, as well as a potential therapeutic target for the treatment of neurodegenerative disease. In transgenic mouse models of AD, we and others have shown that TSPO ligands attenuate inflammation and beta amyloid burden (Barron et al., 2013). However, the effect of TSPO ligands on tauopathy‐induced inflammation has not yet been investigated. Here, we analysed the effects of the prototypic TSPO ligand, Ro5‐4864, on the progression of tauopathy, gliosis and atrophy in the rTg4510 tau transgenic mouse model (TauTg).MethodTauTg and WT control mice were treated with Ro5‐4864 or vehicle for 4 months. Brain atrophy was assessed using volumetric magnetic resonance imaging, while tauopathy and neuroinflammation were assessed by PET using 11C‐PBB3 and 18F‐FEBMP tracers, respectively. To corroborate in vivo findings, immunohistochemistry was performed in sections from scanned mice to measure phosphorylated tau (AT8), inflammation (IBA1, complement component 1q, C1q) and neuronal loss (NeuN).ResultRo5‐4864 treatment reduced markers of neuroinflammation, as well as expression of the neuronal ‘eat me’ signal, C1q in rTg4510 mice. In vitro experiments using the immortalized microglial cell line, BV2, confirmed the TSPO ligands, Ro5‐4864, reduced expression of C1q in response to inflammatory stimuli.ConclusionThese findings support a protective role for TSPO ligands in reducing tauopathy‐induced neuroinflammation.
A pilot study exploring factors influencing delivery of individual cognitive stimulation therapy in the Indian context
Authors: Adhikari Dimple , Faqurudheen Hena , Dasgupta Jayashree 
Published: December 2020

AbstractBackgroundElderly with dementia in India is expected to increase to 7.6 million by 2030, however, availability of therapeutic services like Individual Cognitive Stimulation Therapy (iCST) remain limited. In order to bridge this gap, we culturally adapted the iCST modules for use with dementia patients in India and report preliminary findings from a pilot study exploring factors influencing session delivery.MethodModules were reviewed by two experienced geriatric care specialists and modified to include culturally appropriate content, images and activities such as music, cinema, games, food and festivals. To ensure appropriateness of content, inputs were taken from senior citizens. Sessions were piloted with 4 older adults who had a diagnosis of dementia by a neurologist/psychiatrist and corroborated with the Hindi Mental Status Examination (range of scores between 14 to 21 indicating initial and moderate stage of dementia). A trained care‐specialist delivered the sessions at home (3 participants) or clinic setting (1 participant). Participants were assessed on a 5‐point Likert scale for interest, mood, enjoyment, communication and anxiety for each session. Session notes were maintained to document observations and feedback was obtained from family members that was qualitatively analyzed for acceptability and feasibility.ResultParticipants were between 60‐85 years of age, with postgraduate education, retired from private or government jobs. Qualitative data from session notes and family feedback was analyzed using thematic analysis. Feedback indicated the following benefits: setting up a meaningful daily routine, improving socialization and providing respite for primary caregivers during sessions. Clients showed improvements in learning new information, self‐confidence and self‐motivation. Modules on food, faces/scenes and number games were most enjoyable. Participant interest in sessions fluctuated according to changes in medication and mood of the client, (usually impacted by day‐to‐day on goings within the family), which the specialist had to factor into session delivery. Two participants discontinued iCST, one due to development of aphasia and another due to denial of the illness by spouse and refusal to continue sessions.ConclusionAlthough iCST has several benefits, several contextual factors influence delivery of sessions, highlighting the importance of increasing public awareness for better delivery.
Sleep disturbance is associated with higher plasma Aβ: A population‐based cross‐sectional study
Authors: Gao Yao 
Published: December 2020

AbstractBackgroundGrowing evidence suggest that sleep disturbance is a risk factor for Alzheimer’s disease (AD). Amyloid‐β (Aβ) deposition in the brain is a main pathophysiology of AD. Although peripheral Aβ clearance is associated with brain Aβ deposition, but the relationship between sleep disturbance and plasma Aβ levels is unclear.MethodThis was a population‐based cross‐sectional study. A total of 1459 participants from a village in the suburbs of Xi’an, China were enrolled from January 3 to March 26, 2017. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and good sleep quality defined as PSQI score<5 points, poor sleep quality defined as PSQI score >10. Cognitive function was assessed with the mini‐mental state examination (MMSE). Fasting venous blood was taken in the morning and plasma Aβ levels were measured by ELISA. The relationships between plasma Aβ levels and sleep quality was analyzed using multiple linear regressions.ResultAmong 1459 participants, 231 had poor sleep quality (15.83%). The log‐transformed Aβ40 level had significant difference among different sleep groups (F=3.216, p=0.040). log‐transformed Aβ40 level was higher in poor sleep quality group than that in general sleep quality group [87.17 (73.42,107.34) vs. 89.69 (74.81,125.79) pg/ml, p=0.016]. In bivariate analysis, sleep quality was negatively associated with plasma log‐transformed Aβ40 level (β=‐0.025, p=0.011).ConclusionIn the cognitively normal population, the poorer sleep quality is associated with higher plasma Aβ40 level. These indicated that sleep disturbance may relate to peripheral Aβ clearance.