Brain Markers Research Articles

Examination of Cognitive Function, Neurotrophin Concentrations, and both Brain and Systemic Inflammatory Markers Following a Simulated Game of American Football.

Hoffman, JR, Ostfeld, I, Zamir, A, Amedi, R, Fonville, TR, Horstemeyer, MF, and Gepner, Y. Examination of cognitive function, neurotrophin concentrations, and both brain and systemic inflammatory markers following a simulated game of American football. J Strength Cond Res 36(3): 686-694, 2022-This investigation examined the effect of a simulated American football game on cognitive function, neurotrophin concentrations, and markers of both systemic and brain inflammation. Members of the Israel national team (6 linemen and 9 skill position players) were examined 1 week before (PRE), immediately post (IP) and 24-hour post (24P) game. Blood was obtained, and cognitive function was measured at each assessment. No head injuries to any of the players participating in the study occurred. Significant (p < 0.001) decreases in acute memory, and a trend (p = 0.066) toward a decrease in delayed memory was noted at IP. Significant negative correlations were observed between playing time (number of plays) and concentration changes from PRE to IP (r = -0.801; p = 0.001) and from PRE to 24P (r = -0.549; p = 0.034). All cognitive function measures returned to PRE levels by 24P. Increases from PRE were noted in tumor necrosis factor-alpha (TNF-α) (p = 0.041) at IP and in brain-derived neurotrophic factor (p = 0.009) and C-reactive protein (CRP) (p = 0.019) concentrations at 24P. Circulating CRP concentrations and the cytokine markers, interleukin (IL)-4, IL-6, IL-10, and TNF-α, were significantly elevated in linemen compared with skill players. Brain inflammatory markers (S100B and glial fibrillary acidic protein) and total tau protein (a marker of brain injury) were not elevated from PRE. No change from PRE was noted in either myoglobin or creatine kinase-MM concentrations. In conclusion, muscle damage and inflammatory marker responses observed from the scrimmage game were consistent with muscle desensitization associated with football participation. In addition, the systemic inflammatory marker results observed in linemen were suggestive of chronic low-grade inflammation.

Combined fMRI Region- and Network-Analysis Reveal New Insights of Top-Down Modulation of Bottom-Up Processes in Auditory Laterality.

Dichotic listening along with the right-ear advantage (REA) has been a standard method of investigating auditory laterality ever since it was first introduced into neuropsychology in the early 1960s. Beginning in the 1980s, authors reported that it was possible to modulate the bottom-up driven perceptual REA by instructing subjects to selectively attend to and report only from the right or left ear. In the present study, we investigated neuronal correlates of both the bottom-up and top-down modulation of the REA through two fMRI analysis approaches: a traditional region approach and a network connectivity approach. Blood-Oxygenation-Level-Dependent (BOLD) fMRI data were acquired while subjects performed the standard forced-attention paradigm. We asked two questions, could the behavioral REA be replicated in unique brain markers, and second if the profound instruction-induced modulation of the REA found in behavioral data would correspond to a similar modulation of brain activation, both region- and network-specific modulations. The subjects were 70 healthy adult right-handers, about half men and half women. fMRI data were acquired in a 3T MR scanner, and the behavioral results replicated previous findings with a REA in the non-forced (NF) and forced-right (FR) conditions, and a tendency for a left-ear advantage (LEA) in the FL-condition. The fMRI data showed unique activations in the speech perception areas of the left temporal lobe when directly contrasted with activations in the homologous right side. However, there were no remaining unique activations when the FR- and FL-conditions were contrasted against each other, and with the NF-condition, using a conservative significance thresholding. The fMRI results are conceptualized within a network connectivity frame of reference, especially with reference to the extrinsic mode network (EMN). The EMN is a generalized task-positive network that is upregulated whenever the task demands exceed a certain threshold irrespective of the specifics and demands of the task. This could explain the similarity of activations for the FR- and FL-conditions, despite the clear differences in behavior.

Causal Structure Discovery Identifies Risk Factors and Early Brain Markers Related to Evolution of White Matter Hyperintensities

Causal Structure Discovery Identifies Risk Factors and Early Brain Markers Related to Evolution of White Matter Hyperintensities

Causal structure discovery identifies risk factors and early brain markers related to evolution of white matter hyperintensities

Our goal was to understand the complex relationship between age, sex, midlife risk factors, and early white matter changes measured by diffusion tensor imaging (DTI) and their role in the evolution of longitudinal white matter hyperintensities (WMH). We identified 1564 participants (1396 cognitively unimpaired, 151 mild cognitive impairment and 17 dementia participants) with age ranges of 30–90 years from the population-based sample of Mayo Clinic Study of Aging. We used computational causal structure discovery and regression analyses to evaluate the predictors of WMH and DTI, and to ascertain the mediating effect of DTI on WMH. We further derived causal graphs to understand the complex interrelationships between midlife protective factors, vascular risk factors, diffusion changes, and WMH. Older age, female sex, and hypertension were associated with higher baseline and progression of WMH as well as DTI measures (P ≤ 0.003). The effects of hypertension and sex on WMH were partially mediated by microstructural changes measured on DTI. Higher midlife physical activity was predictive of lower WMH through a direct impact on better white matter tract integrity as well as an indirect effect through reducing the risk of hypertension by lowering BMI. This study identified key risks factors, early brain changes, and pathways that may lead to the evolution of WMH.

Apolipoprotein E loss of function: Influence on murine brain markers of physiology and pathology.

The canonical role of Apolipoprotein E (ApoE) is related to lipid and cholesterol metabolism, however, additional functions of this protein have not been fully described. Given the association of ApoE with diseases such as Alzheimer's Disease (AD), it is clear that further characterisation of its roles, especially within the brain, is needed. Therefore, using protein and gene expression analyses of neonatal and 6-month old brain tissues from an ApoE knockout mouse model, we examined ApoE's contribution to several CNS pathways, with an emphasis on those linked to AD. Early neonatal changes associated with ApoE-/- were observed, with decreased soluble phosphorylated tau (p-tau, -40 %), increased synaptophysin (+36 %) and microglial Iba1 protein levels (+25 %) vs controls. Progression of the phenotype was evident upon analysis of 6-month-old tissue, where decreased p-tau was also confirmed in the insoluble fraction, alongside reduced synaptic and increased amyloid precursor protein (APP) protein levels. An age comparison further underlined deviations from WT animals and thus the impact of ApoE loss on neuronal maturation. Taken together, our data implicate ApoE modulation of multiple CNS roles. Loss of function is associated with alterations from birth, and include synaptic deficits, neuroinflammation, and changes to key AD pathologies, amyloid-β and tau.

Brain oxidative stress and cognitive function in older adults with diabetes and pre-diabetes who are at risk for dementia

AimsDiabetes is an established risk factor for dementia. This study aimed to examine the relationship between various cognitive domains, brain oxidative stress and markers of diabetes in older adults at risk for dementia. MethodsOlder adults at risk for dementia underwent comprehensive neuropsychological and medical assessment. At risk was defined as those with subjective and/or objective cognitive impairment. Pre-diabetes and type 2 diabetes were defined using American Diabetes Association definitions for fasting blood glucose and HbA1c. Brain oxidative stress as indicated by glutathione (GSH) was assessed via magnetic resonance spectroscopy in the anterior cingulate cortex. ResultsOne-hundred and forty-seven older adults completed a neuropsychological assessment and fasting blood sample with 63 also undergoing magnetic resonance spectroscopy. Those with pre-diabetes/diabetes according to FBG had impaired memory retention, set-shifting and response inhibition, compared to those with normal blood glucose. In contrast, there were no significant differences in any cognitive outcome using the HbA1c definition. Increasing glucose and HbA1c levels were associated with reduced GSH concentration in the anterior cingulate. ConclusionsThis study demonstrates that in older adults at risk for dementia, having pre-diabetes or diabetes is associated with impaired memory and executive dysfunction. It also highlights the potential role of oxidative stress as a pathophysiological mechanism that may underpin the link between diabetes and cognitive dysfunction.

Neural markers of proactive and reactive cognitive control are altered during walking: A Mobile Brain-Body Imaging (MoBI) study

The processing of sensory information and the generation of motor commands needed to produce coordinated actions can interfere with ongoing cognitive tasks. Even simple motor behaviors like walking can alter cognitive task performance. This cognitive-motor interference (CMI) could arise from disruption of planning in anticipation of carrying out the task (proactive control) and/or from disruption of the execution of the task (reactive control). In young healthy adults, walking-induced interference with behavioral performance may not be readily observable because flexibility in neural circuits can compensate for the added demands of simultaneous loads. In this study, cognitive-motor loads were systematically increased during cued task-switching while underlying neurophysiologic changes in proactive and reactive mechanisms were measured. Brain activity was recorded from 22 healthy young adults using 64-channel electroencephalography (EEG) based Mobile Brain/Body Imaging (MoBI) as they alternately sat or walked during performance of cued task-switching. Walking altered neurophysiological indices of both proactive and reactive control. Walking amplified cue-evoked late fontal slow waves, and reduced the amplitude of target-evoked fronto-central N2 and parietal P3. The effects of walking on evoked neural responses systematically increased as the task became increasingly difficult. This may provide an objective brain marker of increasing cognitive load, and may prove to be useful in identifying seemingly healthy individuals who are currently able to disguise ongoing degenerative processes through active compensation. If, however, degeneration continues unabated these people may reach a compensatory limit at which point both cognitive performance and control of coordinated actions may decline rapidly.

Heterogeneity in the links between sleep arousals, amyloid-β, and cognition.

BACKGROUNDTight relationships between sleep quality, cognition, and amyloid-β (Aβ) accumulation, a hallmark of Alzheimer’s disease (AD) neuropathology, have been shown. Sleep arousals become more prevalent with aging and are considered to reflect poorer sleep quality. However, heterogeneity in arousals has been suggested while their associations with Aβ and cognition are not established.METHODSWe recorded undisturbed night-time sleep with EEG in 101 healthy individuals aged 50–70 years, devoid of cognitive and sleep disorders. We classified spontaneous arousals according to their association with muscular tone increase (M+/M–) and sleep stage transition (T+/T–). We assessed cortical Aβ burden over earliest affected regions via PET imaging and assessed cognition via neuropsychological testing.RESULTSArousal types differed in their oscillatory composition in θ (4–8 Hz) and β (16–30 Hz) EEG bands. Furthermore, T+M– arousals, interrupting sleep continuity, were positively linked to Aβ burden (P = 0.0053, R²β* = 0.08). By contrast, more prevalent T–M+ arousals, upholding sleep continuity, were associated with lower Aβ burden (P = 0.0003, R²β* = 0.13), and better cognition, particularly over the attentional domain (P < 0.05, R²β* ≥ 0.04).CONCLUSIONContrasting with what is commonly accepted, we provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. This suggests that sleep arousals, and their coalescence with other brain oscillations during sleep, may actively contribute to the beneficial functions of sleep and constitute markers of favorable brain and cognitive health trajectories.TRIAL REGISTRATIONEudraCT 2016-001436-35.FUNDINGFRS-FNRS Belgium (FRSM 3.4516.11), Actions de Recherche Concertées Fédération Wallonie-Bruxelles (SLEEPDEM 17/27-09), ULiège, and European Regional Development Fund (Radiomed Project).

Associations of Adverse Childhood Experiences with Executive Function and Brain-Derived Neurotrophic Factor

Adverse childhood experiences (ACEs) may predict markers of neurocognitive performance (i.e., executive function; EF) and brain health/plasticity (i.e., brain-derived neurotropic factor; BDNF). This pilot examined the magnitude of effects between: 1) ACES and EF performance, 2) ACEs and BDNF levels, and 3) EF performance and BDNF levels. We hypothesize that higher ACEs will be associated with poorer EF scores and lower BNDF levels and that lower EF scores will be associated with lower BDNF levels. Given the pilot nature of the study, an emphasis is placed on effect size vs. significance. Participants were 36 middle-aged women enrolled in the NICE SPACES trial (age=31.4 years, BMI=34.2, racially minoritized=37.9%). ACES were quantified using the 10-item Adverse Childhood Experiences Scale. EF was measured using the fluid cognition composite from the NIH Toolbox – Cognition Battery. BDNF was estimated using proBDNF levels estimated from serum collected via venipuncture. Higher ACEs levels were not directly associated with EF scores (b = 0.03, p = .854); but did show a meaningful negative beta coefficient with BDNF levels (b = -0.34, p = .053). EF scores and BDNF showed a positive coefficient that did not reach significance (b = .26, p = .122). In a modest pilot of middle-age women, higher ACEs were associated with lower BDNF, indicating greater adversity in childhood is linked to lower neurotrophins levels in adulthood. The lower BDNF levels may help explain poorer performance on cognitive tasks. Larger follow-up studies in more powered samples are warranted given the size of detected coefficients.

Cross-lagged Relationships Between Depressive Symptoms and Altered Default Mode Network Connectivity Over the Course of Adolescence

BackgroundAlthough the peak onset of depressive symptoms occurs during adolescence, very few studies have directly examined depression-related changes in resting-state (RS) default mode network activity during adolescence, controlling for potential neural markers of risk. MethodsThis study used data from a longitudinal adolescent cohort to investigate age-specific, persistent (i.e., lagged), and dynamic associations between RS functional connectivity within the default mode network and depressive symptoms during adolescence using a random intercept cross-lagged panel framework. The Neuroventure sample consisted of 151 adolescents ages 12–14 at study entry without any neurological illness who were assessed three times during a 5-year follow-up with 97% follow-up across the three assessments. Depressive symptoms were measured using the depression subscale of the Brief Symptoms Inventory. RS functional magnetic resonance imaging data were collected using a 3T Siemens Magnetom Trio scanner in a single 6-minute sequence. ResultsAfter controlling for relationships between random intercepts, future depression risk was predicted by RS couplings in the perigenual anterior cingulate cortex and anterior dorsomedial prefrontal cortex (β = −0.69, p = .014) and in the left inferior parietal lobule and anterior superior frontal gyrus (β = −0.43, p = .035). Increases in depressive symptoms at previous time points significantly predicted changes in functional connectivity between the posterior cingulate cortex and the precuneus and posterior middle temporal gyrus (β = 0.37, p = .039) and between the dorsal precuneus and posterior middle temporal gyrus (β = 0.47, p = .036). ConclusionsThis study was able to disassociate the RS brain markers of depression from those that appear to follow early-onset depression.

Higher Angiotensin II Type 1 Receptor Levels and Activity in the Postmortem Brains of Older Persons with Alzheimer's Dementia.

Aging is a key risk factor in Alzheimer's dementia (AD) development and progression. The primary dementia-protective benefits of angiotensin II subtype 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, a brain-specific renin-angiotensin system (b-RAS) exists, which can be altered by AT1R blockers. Brain RAS acts mainly through 3 angiotensin receptors: AT1R, AT2R, and AT4R. Changes in these brain angiotensin receptors may accelerate the progression of AD. Using postmortem frontal cortex brain samples of age- and sex-matched cognitively normal individuals (n = 30) and AD patients (n = 30), we sought to dissect the b-RAS changes associated with AD and assess how these changes correlate with brain markers of oxidative stress, inflammation, and mitochondrial dysfunction as well as amyloid-β and paired helical filament tau pathologies. Our results show higher protein levels of the pro-inflammatory AT1R and phospho-ERK (pERK) in the brains of AD participants. Brain AT1R levels and pERK correlated with higher oxidative stress, lower cognitive performance, and higher tangle and amyloid-β scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology.

Characterization of SLC34A2 as a Potential Prognostic Marker of Oncological Diseases.

The main goal of this study is to consider SLC34A2 as a potential prognostic marker of oncological diseases using the mutational, expression, and survival data of cancer studies which are publicly available online. We collected data from four databases (cBioPortal, The Cancer Genome Atlas; cBioPortal, Genie; International Cancer Genome Consortium; ArrayExpress). In total, 111,283 samples were categorized according to 27 tumor locations. Ninety-nine functionally significant missense mutations and twelve functionally significant indel mutations in SLC34A2 were found. The most frequent mutations were SLC34A2-ROS1, p.T154A, p.P506S/R/L, p.G257A/E/R, p.S318W, p.A396T, p.P410L/S/H, p.S461C, p.A473T/V, and p.Y503H/C/F. The upregulation of SLC34A2 was found in samples of myeloid, bowel, ovarian, and uterine tumors; downregulation was found in tumor samples of breast, liver, lung, and skin cancer tumors. It was found that the life expectancy of breast and thymus cancer patients with an SLC34A2 mutation is lower, and it was revealed that SLC34A2 overexpression reduced the life span of patients with brain, ovarian, and pancreatic tumors. Thereby, for these types of oncological diseases, the mutational profile of SLC34A2 can be a potential prognostic marker for breast and thymus cancers, and the upregulation of SLC34A2 can be a potential prognostic marker for brain, ovarian, and pancreatic cancers.

Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan

The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer’s disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20–81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37–72 years of age), the developmental ABCD study (N = 10 283; 9–11 years of age), and a middle-aged sample (N = 339; 40–65 years of age). Hippocampal volume, brain amyloid-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aβ plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF Aβ42 (FDR-corrected p = 6.9x10-2), and lower ratios of Aβ42 to Aβ40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF Aβ42 to Aβ40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers. ConclusionThe inverse correlation between APOEε 4 and blood CRP levels existed before any pathological AD biomarker was observed, and only in the low CRP level range. Thus, we suggest to investigate whether APOEε 4 can confer risk by being associated with a lower inflammatory response to daily exposures, possibly leading to greater accumulation of low-grade inflammatory stress throughout life. A lifespan perspective is needed to understand this relationship concerning risk of developing AD.

Self‐rated daily language use, more than self‐rated bilingual language competency, moderates the effects of brain on cognition in a Hispanic cohort

AbstractBackgroundSome studies suggest that bilingualism may be associated with better cognition but the impact of bilingualism versus language practice on cognition and brain integrity is not well understood. Here, bilingualism encodes the knowledge of one language or two while language use encodes daily language practice (predominantly English or Spanish, or daily use of both). In a Hispanic cohort, we the assess effects of language variables on cognitive outcomes of baseline and longitudinal executive function and episodic memory, incorporating brain measures, age, gender, and education, and also whether they moderate the relationships between cognition and the MRI markers of brain integrity.MethodA baseline Hispanic cohort (N = 100) with a single MRI scan and a longitudinal subset (N = 73) with serial scans were sampled from the UC Davis Aging and Diversity cohort (Table 1). Linguistic measures were based on self‐reports. They were bilingualism, and among bilingual participants, daily language use. Baseline and longitudinal executive and memory were modeled by regressions incorporating age, education level, brain signature regions, and language variable ‐ first for bilingualism in the entire cohort and then for language use restricted to the bilinguals.ResultBilingualism was not a significant predictor of baseline outcomes and there were no moderations with brain variables (Table 2). Among bilinguals, English‐only speakers showed significantly increased association of gray matter (Table 3) to memory compared to those who daily spoke Spanish or both languages. Longitudinally, bilingualism had no direct or moderating effects on cognitive change (Table 4). Bilinguals speaking primarily English had significantly increased association of atrophy signatures with both cognitive changes compared to Spanish or speakers of both languages (Table 5).ConclusionResults suggest a complex pattern of moderation of brain atrophy effects on cognitive decline in self‐reported bilinguals depending on whether daily language use is predominantly English, Spanish, or both. Bilinguals who spoke predominantly English were more susceptible to brain atrophy effects in comparison with those who used both languages or predominantly Spanish. These results have important implications for understanding how bilingualism relates to cognitive reserve but require replication in larger and different samples.

The association between physical activity and brain integrity is partly mediated by cardiovascular mechanisms

AbstractBackgroundPhysical activity (PA) has been associated with decreased risk of dementia, but the mechanisms underlying this association remain to be determined. One hypothesis is that PA might reduce cardiovascular risk factors (CVRFs), which in turn would benefit brain health. Our objective was to assess the role of CVRFs in the association between PA and neuroimaging markers of brain integrity.MethodBaseline data of 134 cognitively unimpaired older adults (mean age: 69) from the Age‐Well cohort were analyzed. They underwent a PA questionnaire, CVRFs collection (systolic blood pressure, body mass index [BMI], current smoker status, HDL‐cholesterol, total cholesterol, and insulin), and multimodal neuroimaging (structural and diffusion MRI, FDG‐ ]and Florbetapir‐PET). A global measure of brain integrity was obtained for each neuroimaging modality by extracting the averaged signal across the whole gray matter (GM), or white matter for diffusion. Correlations were first conducted to assess the association between PA, CVRFs, and each neuroimaging modality. Multiple regression and mediation analyses were then performed to test whether the associations found between PA and neuroimaging were mediated by CVRFs.ResultHigher PA was associated with higher global GM volume and FDG metabolism, but not with amyloid deposition or white matter integrity. Higher PA was also associated with lower insulin levels and BMI, but not with the other CVRFs. Lower insulin and BMI were related to higher GM volume, but not to FDG metabolism. Adjusting for insulin and BMI (separately), the association between PA and FDG metabolism remained unchanged while the association with GM volume did not. When adding insulin and BMI in the same model, BMI was the only significant predictor of GM volume. This was confirmed by a mediation analysis.ConclusionPA is specifically associated with greater brain volume and FDG metabolism in older adults. While the association between PA and FDG metabolism appears to be independent from CVRFs, the link with GM volume is mediated by changes in BMI and insulin, with BMI driving the effects. Our results suggest that maintenance of a healthy BMI through PA could help preventing disturbed insulin metabolism usually observed in aging, thus promoting brain health.

TMS‐induced EEG perturbation as a marker of psychological resilience to deleterious mental health effects during the COVID‐19 pandemic

BackgroundSocial, economic and psychological hardships associated with the COVID‐19 pandemic are expected to result in a global burden on mental health outcomes. However, while some individuals suffer from increasing distress and reduced quality of life, others will show no negative effects. A better understanding of brain mechanisms subtending resilience would be helpful in informing future recommendations to individuals and societies facing the present pandemic and future similar events. Here, we compared neurophysiological brain markers between individuals who exhibited resilience or vulnerability to pandemic associated psychological stress.Method23 participants from the longitudinal study cohort of the Barcelona Brain Health Initiative (Cattaneo et al., Front. Aging Neurosci. 2018;10:321) who underwent concurrent transcranial magnetic stimulation with electroencephalography (TMS‐EEG), were classified as either resilient (n=16) or non‐resilient (n=7), based on their scoring in the PHQ‐4 questionnaire (Kroenke et al., Psychosomatics 2009;50(6):613–21) along four timepoints; one before COVID‐19 outbreak and three spanning 2.5 months during the pandemic. Individuals maintaining a score below 3 across all timepoints were deemed resilient, while those scoring below 3 before pandemic but higher than 2 at any pandemic timepoint were considered non‐resilient. TMS‐EEG data was collected by delivering 120 single TMS pulses to the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobule (IPL). TMS evoked global mean field amplitude and local response at the stimulation site were computed.ResultFigure 1 depicts time‐series for DLPFC and IPL responses for both groups of subjects. Overall, non‐resilient individuals exhibited a larger global response to TMS perturbation during DLPFC stimulation, as well as larger local current density estimates during IPL stimulation.ConclusionThese preliminary results revealed that non‐resilient individuals were more susceptible to TMS perturbation, shown by global DLPFC and local IPL reactivity. Notably, these targets are nodes of the default mode and cognitive control networks affected by stress (van Oort et al., Neurosci. Biobehav. Rev. 2017;83:281–97), and the left frontal cortex has been proposed as a cognitive resilience hub (Franzmeier et al., J. Alzheimer’s Dis. 2017;59(4):1381–92.). Future studies should investigate and confirm the possibility that these nodes constitute a shared neurophysiological substrate for psychological and cognitive resilience.

P.0282 Evidence for steroid hormone associations with key brain markers of information filtering in healthy women

P.0282 Evidence for steroid hormone associations with key brain markers of information filtering in healthy women

TAMI-24. INHIBITION OF GBM INVASION BY THE Α-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID (AMPA) GLUTAMATE RECEPTOR ANTAGONIST PERAMPANEL

Abstract BACKGROUND Extensive tumor cell invasion within the brain represents a major problem for effective treatment of glioblastomas (GBMs). The invasive processes can be divided into three types: Collective cell invasion, perivascular infiltration, and single-cell invasion into the brain parenchyma. GBM cells can form synapses with neural cells pointing at an extensive communication network between brain and GBM cells which can be mediated via the metabolites Glutamine and Glutamate both needed for GBM cell proliferation. In this context, it has been shown in preclinical models that Perampanel, an antiepileptic agent, functioning as non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, has an inhibitory effect on GBM growth. To delineate how Perampanel affects GBM invasion, we utilised a highly characterized 3D GBM-brain organoid invasion model where single-cell invasion was studied in real-time following Perampanel treatment. METHODS A brain coculture model, consisting of rat brain organoids expressing various markers of the human adult brain, where confronted with GFP-labelled tumor cells. By using time-lapse confocal microscopy, we quantified single-cell invasion patterns and speed of invasion using two glioma stem cell models (BG5 and BG7). RESULTS Perampanel treatment significantly reduces tumor cell invasion into the brain organoids with the strongest effect seen in the most invasive GBM (BG5). The single-tumor cell invasion ratio was reduced by 72 % compared to the control (p= 0.0033). In contrast, collective cell invasion was reduced by 19 % (p= 0.028). Statistical analysis was performed using an unpaired sample t-test. CONCLUSION The AMPA glutamate receptor antagonist Perampanel significantly inhibits GBM invasion, suggesting an important role of the glutamate-glutamine cycle between the GBM cells and neurons in the invasion process. Moreover, this communication and exchange of metabolites seem to be more prominent where single GBM cells invade into the brain parenchyma compared to areas where collective invasion take place.

γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer's Disease-like Pathology and Neurodegeneration in a Mouse Model.

Oxidative stress in Alzheimer’s disease (AD) is mediated, in part, by the loss of glutathione (GSH). Previous studies show that γ-glutamyl transpeptidase (GGT)-resistant GSH analog, Ψ-GSH, improves brain GSH levels, reduces oxidative stress markers in brains of APP/PS1 transgenic mice, a mouse model of AD, and attenuates early memory deficits in the APP/PS1 model. Herein, we examined whether Ψ-GSH can attenuate the disease progression when administered following the onset of AD-like pathology in vivo. Cohorts of APP/PS1 mice were administered Ψ-GSH for 2 months starting at 8 month or 12 months of age. We show that Ψ-GSH treatment reduces indices of oxidative stress in older mice by restoration of enzyme glyoxalase-1 (Glo-1) activity and reduces levels of insoluble Aβ. Quantitative neuropathological analyses show that Ψ-GSH treatment significantly reduces Aβ deposition and brain inflammation in APP/PS1 mice compared to vehicle-treated mice. More importantly, Ψ-GSH treatment attenuated the progressive loss of cortical TH+ afferents and the loss of TH+ neurons in the locus coeruleus (LC). Collectively, the results show that Ψ-GSH exhibits significant antioxidant activity in aged APP/PS1 mice and chronic Ψ-GSH treatment administered after the onset of AD pathology can reverse/slow further progression of AD-like pathology and neurodegeneration in vivo.

Factors affecting brain structure in smoking-related diseases: Chronic Obstructive Pulmonary Disease (COPD) and coronary artery disease.

BackgroundChanges in brain structure and cognitive decline occur in Chronic Obstructive Pulmonary Disease (COPD). They also occur with smoking and coronary artery disease (CAD), but it is unclear whether a common mechanism is responsible.MethodsBrain MRI markers of brain structure were tested for association with disease markers in other organs. Where possible, principal component analysis (PCA) was used to group markers within organ systems into composite markers. Univariate relationships between brain structure and the disease markers were explored using hierarchical regression and then entered into multivariable regression models.Results100 participants were studied (53 COPD, 47 CAD). PCA identified two brain components: brain tissue volumes and white matter microstructure, and six components from other organ systems: respiratory function, plasma lipids, blood pressure, glucose dysregulation, retinal vessel calibre and retinal vessel tortuosity. Several markers could not be grouped into components and were analysed as single variables, these included brain white matter hyperintense lesion (WMH) volume. Multivariable regression models showed that less well organised white matter microstructure was associated with lower respiratory function (p = 0.028); WMH volume was associated with higher blood pressure (p = 0.036) and higher C-Reactive Protein (p = 0.011) and lower brain tissue volume was associated with lower cerebral blood flow (p<0.001) and higher blood pressure (p = 0.001). Smoking history was not an independent correlate of any brain marker.ConclusionsMeasures of brain structure were associated with a range of markers of disease, some of which appeared to be common to both COPD and CAD. No single common pathway was identified, but the findings suggest that brain changes associated with smoking-related diseases may be due to vascular, respiratory, and inflammatory changes.