bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long‐term deprivation of ovarian hormones via ovariectomy alters functional connectivity, brain neurochemistry and white matter integrity in a mouse model of Alzheimer's disease
Authors: Kara Firat , Belloy Michael E , Voncken Rick , Sarwari Zahra , Yadav Garima , Anckaerts Cynthia , Langbeen An , Leysen Valérie , Shah Disha , Jacobs Jules , Hamaide Julie , Bols Peter , Van Audekerke Johan , Daans Jasmijn , Guglielmetti Caroline , Kantarci Kejal , Prevot Vincent , Rossner Steffen , Ponsaerts Peter , Van Der Linden Annemie , Verhoye Marleen 
Published: December 2020

AbstractBackgroundThe abrupt loss of ovarian hormones before menopause, induced by oophorectomy, has been associated with accelerated aging, multimorbidity, and Alzheimer’s disease (AD). We investigated the impact of prolonged loss of ovarian hormones on AD progression in a transgenic mouse model of amyloid pathology using in vivo diffusion tensor MRI, resting‐state functional MRI (rsfMRI) and spectroscopy (MRS).MethodFemale 3.5‐month‐old TG2576 (TG) (N=27) and wild‐type (WT) (N=27) mice were ovariectomized (TGOVX) or sham‐operated (TGSHAM). When they became 18‐month‐old, 1‐H MRS (ROIs: hypothalamus, hippocampus, and cerebral cortex), DTI and rsfMRI was performed. ROI based analysis was performed on rsfMRI and DTI (Fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity, and radial diffusivity). The brain samples were then evaluated by histology and ELISA to assess Aβ load and activated glial cells. The loss of ovarian hormones via OVX was validated with elevated plasma luteinizing hormone level: OVX>SHAM (p<0.05). Two‐way ANOVA and post‐hoc (Student’s‐t) tests were used for statistical analysis. P values were adjusted for multiple comparisons (FDR‐p).ResultThe multimodel imaging data showed that there was a significant increase in taurine and total creatine (markers for inflammation and energy metabolism) in the hypothalamus, decrease in FA and AxD (markers for white matter integrity) in the white matter regions, and decrease in the functional connectivity between the prefrontal cortex and the hippocampus and dorsal and ventral hippocampus regions (a neural marker of network activity and integrity) (FDR‐p <0.05 (Figure 1)) in TGOVX mice compared to TGSHAM mice (post‐hoc t‐test). rsFMRI showed a significant increase in rsfMRI connectivity in WTOVX mice compared to WTSHAM mice. Complementary histological (and ELISA) analysis revealed no differences in Aβ load (plaque and soluble) and activated glial cells between the TG groups.ConclusionThe MRI results suggest that inflammatory response was elevated, energy metabolism was disrupted and white matter and network integrity decreased after prolonged ovarian hormone loss. These MRI results support other data from human and animal studies suggesting that abrupt hormonal changes associated with premenopausal removal of ovaries may increase the risk factors of AD, and accelerate the disease progression by causing abnormalities in brain structure, function and metabolism.
PS1 FAD mutants inactivate ephrinB1 and BDNF‐dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of NMDA receptor
Authors: Rahim Md A. 
Published: December 2020

AbstractBackgroundExcitotoxicity is thought to play a key role in brain neurodegeneration and stroke. Here, we show that neuroprotection against excitotoxicity by trophic factors ephrinB1 (efnB1) and BDNF (called here Factors) involves de novo formation of “survival complexes” which are Factor‐stimulated complexes of NMDA receptor (NMDAR) with Factor receptor (FR) and PS1.MethodPrimary cortical neuronal cultures from wild type or from PS1 hemizygous (PS1+/‐) or homozygous (PS1‐/‐) knockout (KO) mouse embryos were used to examine the role of PS1 on NMDAR‐FR complex formation. We also used two independently constructed PS1 FAD mutant knock‐in (KI) mice, one expressing human FAD mutant allele PS1 M146V and the other expressing FAD allele I213T, to test the effects of PS1 FAD mutants on Factors‐dependent neuroprotection, NMDAR complexes with FR and PS1, and NMDAR EPSCs. In addition, postmortem human brains carrying PS1 FAD mutants were used to test the relevance of our study in human disease mechanism.ResultAbsence of PS1 reduces the formation of survival complexes and abolishes neuroprotection. EphB2‐ and NMDAR‐derived peptides designed to disrupt formation of survival complexes also decrease the Factor‐stimulated neuroprotection. Strikingly, the neuroprotective effect of Factors and the levels of de novo Factor‐stimulated survival complexes decrease dramatically in neurons expressing PS1 Familial Alzheimer disease (FAD) mutants. Mouse neurons and brains expressing PS1 FAD mutants contain increased amounts of constitutive PS1‐NMDAR complexes. Additional evidence indicate that constitutive PS1‐NMDAR complexes formed in PS1 FAD mutant‐expressing neurons may differ from those formed in WT neurons and that neurons of PS1 FAD mutant‐expressing brains are more vulnerable to cerebral ischemia than neurons of WT brains. Furthermore, NMDAR‐mediated EPSCs at CA1 synapses are altered by PS1 FAD mutants. Importantly, high levels of PS1‐NMDAR complexes were also found in postmortem brains of AD patients expressing PS1 FAD mutants.ConclusionTogether, our data identify a novel PS1‐dependent neuroprotective mechanism against excitotoxicity and indicate a pathway by which PS1 FAD mutants may decrease Factor‐depended neuroprotection against toxic insults. These findings have implications for the pathogenic effects of FAD mutants and therapeutic strategies.
Brain‐age predicts subsequent dementia in memory clinic patients
Authors: Biondo Francesca , Jewell Amelia , Pritchard Megan , Mueller Christoph , Steves Claire J , Cole James 
Published: December 2020

AbstractBackgroundThe lack of disease‐modifying therapies in the current dementia epidemic emphasises the importance of targeting earlier disease stages. Cognitive measures alone do not confer sufficient sensitivity and specificity for this, motivating research into neuroimaging biomarkers that might detect more subtle early changes. One promising measure, so‐called ‘brain age’, has previously been associated with neurological and psychiatric disorders, and predictive of future health outcomes. This includes the development of dementia in observational research cohorts (Gaser et al., 2013; Wang et al., 2019). Here we present results from a community sample of people referred to memory clinics (the Brain Ageing and Risk of Cognitive Decline [BARCODE] project), determining whether baseline brain‐age in people with subject or mild cognitive impairment predicted subsequent dementia diagnosis.MethodWe used T1‐weighted MRI n=318 memory clinic patients with subjective or mild cognitive impairment (192 female and mean [SD] age of 76.3 [0.5] years). Using in‐house software (https://github.com/james‐cole/brainageR) we calculated brain‐predicted age difference (brain‐PAD) for each patients. We determined which participants went on to develop dementia via linkage to electronic health records. Logistic regression analysis tested whether brain‐PAD at time of scan predicted a subsequent dementia diagnosis, controlling for age and sex.ResultOut of 318 participants, n=248 subsequently received a dementia diagnosis. Logistic regression (McFadden’s R
2=0.19) indicated that brain‐PAD scores at time of scan were significantly higher in patients who subsequently received a dementia diagnosis, B(SE)=0.04(0.02), p<0.05, OR 1.04 (95%CI 1.00‐1.08).ConclusionStructural brain ageing is detectable in older adults with memory impairments. Critically, memory clinic patients with older‐looking brains are more likely to receive a subsequent dementia diagnosis. This illustrates the value of using brain age as a sensitive biomarker that has the potential to be used early‐on in memory clinics to detect patients at high‐risk of developing dementia.
Developing breath volatiles fingerprinting for Alzheimer's and Parkinson's diseases
Authors: Bayer Charlene W 
Published: December 2020

AbstractBackgroundWe tested the feasibility that an AD‐breath volatiles (BVOC) fingerprint will be useable to predict, track disease progression in combination with more traditional modalities, and therapeutic interventions responsiveness for AD resulting in an inexpensive, non‐invasive point‐of‐care tool. Additionally, we also hypothesized that the AD BVOC fingerprint will be functional for early differentiation of AD from other neurodegenerative diseases.MethodAlveolar breath was collected by breathing into a sampling device and mass spectrometric analysis. Discriminatory statistical modeling was applied to the identified BVOCs, classifying MCI versus controls and identifying BVOCs with greatest discriminatory impact. Differentiation between AD and PD was examined by mixing our MCI and previously collected PD data.ResultMCI from controls were classified with 97.8% accuracy with an ROC Curve AUC of 0.998. PD or MCI samples were differentiated with 92.5% correctly controls versus MCI or PD and 100% as either MCI or PD. Investigation of probable mechanistic BVOC formation pathways in MCI/AD resulted in two primary pathways: neuroinflammation and e stress and dysregulated glucose metabolism with differences between inflammatory BVOCs in AD versus PD.ConclusionWe demonstrated feasibility of MCI/AD BVOC fingerprinting for early stage identification of disease via a 97.8% correct classification and the ability to differentiate between AD and PD as example of two neurodegenerative diseases. We showed the probable dysregulated glucose metabolism and inflammatory pathways via BVOCs.
Increases in plasma neurotensin levels and brain neurotensin receptors were associated with brain pathology in obese, insulin‐resistant rats
Authors: Saiyasit Napatsorn , Chunchai Titikorn , Apaijai Nattayaporn , Pratchayasakul Wasana , Sripetchwandee Jirapas , Chattipakorn Nipon , Chattipakorn Siriporn C. 
Published: December 2020

AbstractBackgroundOur previous studies reported that long‐term high‐fat diet (HFD) consumption caused not only obese‐insulin resistance, and peripheral oxidative stress, but also brain pathologies, including increased brain oxidative stress, neuronal death, and dendritic spine loss. Neurotensin (NT) is an endogenous tridecapeptide, in which has been expressed in peripheral and central nervous system. Alterations of NT levels have been associated with several neuropathological conditions such as Alzheimer's disease, and obesity associated eating disorders. However, the association between the level of plasma NT, brain NT receptor (NTR), and peripheral/brain pathologies under HFD‐induced obese‐insulin resistance is still unclear. The present study hypothesizes that an increase in peripheral/brain NT are associated with the peripheral/brain pathologies in time‐dependent manner of HFD consumption.MethodsMale Wistar rats were received either a normal diet (ND) or HFD for 12 and 40 weeks (n=4‐6 per diet/each time point). At the end of each time point, plasma NT levels and metabolic parameters were determined. Brains were collected to measure the levels of hippocampal reactive oxygen species (ROS), the dendritic spine densities, the levels of brain NT, the expression of NTR, and apoptotic‐related proteins after being sacrificed.ResultsAn increase in plasma NT level and gut NTR1 expression (Figure 1A‐B), the metabolic disturbances, peripheral oxidative stress, as indicated by increasing the level of serum malondialdehyde, and systemic inflammation as indicated by increasing the level of serum lipopolysaccharide of 12‐ and 40‐week HFD‐fed rats were observed, when compared to ND‐fed rats at the same time point. Additionally, increased hippocampal ROS production, and decreased dendritic spine density (Figure 1C) were found in 12‐ and 40‐week HFD‐fed rats. However, the expression of brain NTR1 (Figure 1D) and brain apoptotic‐related proteins were significantly increased in only 40‐week HFD‐fed rats.ConclusionThese findings suggest that the alterations of peripheral NT level and brain NTR are associated with peripheral/brain pathologies after chronic HFD consumption. Therefore, an increase in plasma NT level would be one of the early biomarker prior to the development of brain pathologies in obese condition.
Development of a method of low‐intensity transcranial magnetic stimulation based on the resonance of neurotransmitters
Authors: Novikov Vadim V , Bobkova Natalia V , Fesenko Evgeny E 
Published: December 2020

AbstractBackgroundIn this work the effect of the weak combined magnetic fields (MFs) was studied in vivo in heritable animal model of AD: well characterized mice transgenic for mutant APPswe and mutant presenilin 1 (PS1dE9) that cause early onset familial Alzheimer’s disease (AD).MethodTransgenic mice (Tg) and control C3H mice were exposed to the same MF at age of 8 months. Mice were also exposed by MF in two groups at the same time (Tg+MF and C3H+MF). Setups for generating a magnetic field inside the head were equipped with portable inductors that were mounted on the body. A direct current was supplied to generate a constant component of MFs with induction of 42 mcT. An alternating current signal produced by a programmable sinusoidal current generator was fed to create a variable component of MFs with induction of the amplitude of 80 nT. The current signal was the sum of frequencies in the range 4.0 ‐ 5.0 Hz. These frequencies correspond to the cyclotron frequencies of glutamic and aspartic acids as well as acetylcholine. After exposure to the MFs, the mice were trained in a Morris water maze for 18 days (four trials per day). Spatial memory was tested on the following day after completion of training with the hidden platform removed. During the test period (60 s), occupancy time spent in each sector was recorded.ResultThe MFs improved the memory in Tg animals. The results of the factor analysis demonstrate that factors of the sector preference became statistically significant for Tg groups after MFs exposure.ConclusionThus, the data suggest that MFs can be applied for preventive purposes in a group of risk of AD.
Understanding trisomy 21–associated alterations in APP/Amyloid‐β biology using mouse models
Authors: Wiseman Frances K. 
Published: December 2020

AbstractBackgroundPeople who have Down syndrome (DS) are at significantly increased risk of developing Alzheimer’s disease (AD). An additional copy of the chromosome 21 encoded gene, APP, in the absence of DS causes the early development of AD, and triplication of APP is likely to have a key role in early AD development in people who have DS. We have previously shown in a mouse model that an additional copy of genes on chromosome 21 other than APP, exacerbates Aβ accumulation and worsens APP‐transgene associated mortality; suggesting gene(s) on chromosome 21 in addition to APP modulate AD development in people who have DS.MethodsWe crossed mouse models of DS (Dp2Tyb, Dp3Tyb, Dp10Yey and Dp17Yey) that have segmental duplications of subregions of chromosome 21 with a conventional mouse model of amyloid deposition (J20 APP transgenic), to determine which groups of genes on chromosome 21 are sufficient to alter APP/Aβ biology.ResultsWe determined that a causal gene(s) for altered Aβ aggregation lies between Mir802 and Zbtb21 (within the ‘Dp3Tyb’ mouse duplication). We also found that a dosage sensitive gene(s) that enhances APP transgene‐associated mortality is located between Mis18a and Runx1 (within the ‘Dp2Tyb’ mouse duplication) and that dosage‐sensitive genes that protect against APP transgene‐associated mortality are located between Mir802 and Zbtb21 (Dp3Tyb duplication), Prmt2 and Pdxk (Dp10Yey duplication) and also between Abcg1 and Rrp1b (Dp17Yey duplication). We go on to show that the rescue of mortality by the Dp10Yey duplication occurs independently of changes to the frequency or duration of APP transgene‐associated seizures. These data show an extra copy of multiple chromosome 21 gene orthologous modulate multiple AD‐related phenotypes in mouse models. Similar mechanisms may also occur in people who have DS when they develop AD‐dementia and may contribute the AD‐clinical differences that occur in this patient population.ConclusionsThese data suggest that Alzheimer’s disease in people who have Down syndrome is modulated by the additional copy of chromosome 21 genes other than APP. We now aim to identify these genes, to provide further novel mechanistic insight into the development of Alzheimer’s disease in people who have Down syndrome.
Illness perceptions and affective symptoms: Predictors of self‐management behaviors in mild cognitive impairment
Authors: Kim Hyejin , Sereika Susan M , Bender Catherine , Albert Steven , Lingler Jennifer 
Published: December 2020

AbstractBackgroundAlthough a recent guideline on mild cognitive impairment (MCI) recommends non‐pharmacological interventions (i.e., self‐management behaviors such as exercise and cognitive training) for the management of MCI, predictors of such behaviors have not been identified in this population. We explored predictors of four categories of self‐management behaviors (i.e., physical activity, cognitive‐enhancing medication, mental activity, and vitamin/herbal supplements) in persons with MCI (PwMCI).MethodsUsing a cross‐sectional design, we conducted a secondary analysis pooling two existing datasets. We examined the predictive role of perceptual factors (i.e., individuals’ perceived understanding of MCI and its cause), affective symptoms (i.e., anxiety and depression), and clinical/sociodemographic factors. We also measured the total number of (range: 0‐4), and performance of each (‘yes’ or ‘no’) of the four categories of self‐management behaviors. We performed hierarchical linear (for the total number of self‐management behaviors) and binary logistic (for each self‐management behavior) regression analyses, controlling for age, sex, years of education, and the number of comorbid conditions as potential covariates.ResultsParticipants (N=137) were on average 71.5 years old with 16.1 years of education. Most were Caucasian (92.0%) and diagnosed with amnestic MCI (82.5%). Although we did not find any main effects of predictors, some interactions were significant through further model expansion. Better performance of self‐management behaviors was associated with 1) lower levels of perceived understanding of MCI in men (b= ‐0.090, =.037), and 2) lower levels of anxiety symptoms in Caucasian participants (b= ‐0.206, p=.049). In hierarchical logistic regression analyses, higher levels of perceived understanding of MCI were associated with the better performance of physical (OR=0.942, 95%CI=[0.898, 0.980]) and mental (OR=0.959, 95% CI=[0.922,0.998]) activities among participants with lower levels of education. Among participants with more years of education, higher levels of perceived understanding of MCI were associated with better adherence to cognitive‐enhancing medication (OR=1.043, 95% CI=[1.002, 1.085]), and more anxiety symptoms were associated with better performance of mental activity (OR=1.048, 95% CI=[1.003,1.095]).ConclusionOur findings suggest that perceived understanding of MCI, levels of anxiety, and demographic factors should be considered together when evaluating the performance of self‐management behaviors to prevent or delay further cognitive changes among PwMCI.
Tracking the origin of tau spread in the brain
Authors: Jacobs Heidi I.L. , Becker Alex , Kwong Kenneth , d’Oleire Uquillas Federico , Papp Kathryn V. , Properzi Michael J , Rentz Dorene M. , Fakhri Georges El , Sperling Reisa A. , Johnson Keith A. 
Published: December 2020

AbstractBackgroundAutopsy studies report that the locus coeruleus (LC) is the first site to accumulate tau, after which it spreads topographically to the entorhinal cortex (EC) and limbic regions. Once tau has reached the cortex, its spread is assumed to occur via connectivity and to be facilitated by Aβ. We aimed to examine whether lower LC integrity is related to tau accumulation in the EC, followed by spreading of tau to cingulate regions. In addition, we examined whether Aβ facilitates tau accumulation beyond these initial regions.MethodOne‐hundred‐and‐five individuals (Figure 1) from the Harvard Aging Brain Study underwent 3T‐MRI (including LC imaging),Aβ and tau‐PET imaging and neuropsychological assessments. Assessments up to 8 years prior to LC‐imaging were included (median:5.02 years). LC intensity (normalized to pontine tegmentum) was regressed onto each vertex of the cortical mantle of the PET data. Robust regressions and mediation analyses related LC intensity to tau, Aβ and cognition (composites and subtests). LME models examined interactions between LC intensity and Aβ on cognitive changes. Covariates were age, sex and education. Results were compared to LME models of tau spread via connectivity in a previously examined extended sample (n=252).ResultLC intensity was associated with medial and lateral temporal tau (peak:EC (t=4.69)). These associations became more widespread with increasing Aβ (Figure 2). This is consistent with results in the extended sample showing that spread from the EC to the posterior cingulate cortex via structural connections was greater in individuals with elevated Aβ (Figure 3). LC intensity was specifically positively associated with cross‐sectional memory (p=0.024) (Figure 4A‐B) and this was mediated by entorhinal tau (mediation: p=0.007, Figure 4C‐D). Finally, lower LC intensity predicted Aβ‐associated retrospective memory decline (Figure 5, p=0.0009). In the extended sample, lower connectivity and higher downstream‐connected tau accrual was associated with greater prospective memory decline in elevated Aβ persons (Figure 3).ConclusionLC intensity measures are associated with initial cortical Alzheimer’s disease (AD) pathology. Elevated Aβ facilitates tau spread to regions outside the medial temporal lobe and accelerates AD‐related cognitive decline. These results mimic autopsy findings of the anatomy of tau spreading and can advance early detection.