Cortical Brain Regions Research Articles

Neuroprotective effect of Tropisetron in Streptozotocin induced animal model of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease is a neurodegenerative pathology having genetic and non‐genetic forms. Non‐genetic forms of AD dominate over the genetic condition and is mainly sporadic. However, both forms affect cognitive functions. Although exact mechanisms are not fully understood, amyloid β deposition & tau tangle formation are considered central mechanisms to cause neurodegenerative changes in the AD brain. On the other hand, cognitive deterioration began way before the accumulation of amyloid or tau tangle formation. Cognitive functions, including learning and memory, have been majorly controlled/regulated by the cholinergic system. Here in the present study, we have explored the neuroprotective effect of tropisetron in streptozotocin‐induced animal model of Alzheimer’s disease. During the last two decades, the involvement of other neurotransmitter systems has been explored, and the serotonergic system has been demonstrated to play an essential role in memory and learning. The serotonergic system is the most extensive monoaminergic system in the brain, and alterations in serotonergic signals have been linked with Aβ and tau tangle formation. Moreover, serotonin acting through its receptor antagonist has been reported beneficial in various experimental AD models.MethodIn the present study animals were infused with STZ alternatively on 1st and 3rd day. From 15th day animals were treated with tropisteron with two subsequent doses (2.2.5mg/kg) and (5mg/kg). On 28th day animals were sacrificed. Further animals were tested for behavioral, biochemical and histopathological parameters.ResultTropisetron significantly attenuated oxidative damage and restored the reduced levels of anti‐oxidant enzymes. ICV‐STZ treatment had shown significant neuronal damage in hippocampal and cortical regions of AD brain in histopathological examination. Moreover, hippocampal neurons were observed to be irregular in morphology with dark pyknotic nuclei. This confirms the neurodegeneration in ICV‐STZ animals. Target drug tropisetron resulted in significant neuroprotection against ICV‐STZ.ConclusionThe observed outcomes of the present study suggest the neuroprotective effect of tropisteron in STZ induced animal model of Alzheimer’s disease.It would be safe to conclude that tropisetron may improve the behavioral outcomes by attenuating oxidative burden & its neuroprotective potential as seen in our histological assessment.

Alterations in the integrity of cortical and subcortical circuits in AD and MCI: Connectivity study in rs‐fMRI.

AbstractBackgroundrs‐FC has been altered in AD continuum with hyper‐hypoconnectivity patterns attributed not only to regional changes, but to disruption of functional integration or aberrant connectivity between cortical and subcortical brain regions . This study seeks to find connectivity patterns in MCI and AD with a different network extraction approach taking each network as a whole and not separated into ROIs.Methodsrs‐fMRI data from ADNI3 and OASIS3 of 64/85 AD/Control subjects, 57/59 MCI/Control subjects from both repositories were preprocessed with the CONN toolbox. Resting state networks (RSN) were extracted by cGICA using GIFT toolbox (semi‐blind INFOMAX) with 300 ROI Set template with 14 RSN. A non parametric 2‐sample t‐test was applied using the SnPM tool, all analyses in SnPM were performed using 10000 random permutations and the anatomical association of each reported cluster is extracted from the AAL atlas using the xjView tool . Regions that had statistically significant clusters with p FWE<0.001 and with k> = 100 voxels were analyzed.ResultsThere were alterations in regions of every network for each groups comparison (p < 0.001). Several ROI were repeatedly altered in analyzed RSN, temporal pole, MTG, STG, cerebellar crus, OFC, PCC, MCC, precuneus, AG, SMG, SPL, IPL, SFG, MFG, IFG, thalamus, FG and posterior cerebellar lobe. Decreased/increased activation area, changes in activation intensity and reorganization of activation areas, specially reduced activation areas in AD and greater activation areas in MCI. The RSN with more changes in connectivity patterns were DMN, DAN/VAN, MTL, SAL and FPN.ConclusionChanges in connectivity in MCI and AD show reorganization of RSN related to enlargement, reduction or displacement of activation areas, the greatest amount of change was observed in MCI with increases in activation areas and in AD a general decrease in activation areas was observed, these alterations are consistent with the inverted u‐pattern that has been described in other studies . The common ROI we found altered had been related with accumulation and aggregation of p‐Tau and βA and this could be an explanation of connectivity changes duet to the neurodegeneration and synaptic dysfunction caused by this proteins

β‐Asarone attenuates streptozotocin‐induced experimental dementia in rats: Possible role of phosphodiesterases and cyclic nucleotide signaling

AbstractBackgroundIn recent years, extract of Acorus calamus shown to inhibit phosphodiesterases (PDE) and β‐asarone has been reported to be a major active constituent. The purpose of the present study was to ascertain PDE inhibitory potential of β‐asarone and to explore its therapeutic potential in sporadic Alzheimer’s type dementia (SAD). In the current study, PDE inhibitory potential of β‐asarone was determined using in vitro assay system.MethodStreptozotocin (STZ) was infused intracerebroventrically [bilaterally (3 mg/kg) ICV] to induce SAD in rats. Spatial and non‐spatial memory was evaluated using Morris water maze and object recognition task in rats.Rats were treated with β‐asarone (12.5, 25 and 50 mg/kg) from day 10 to 21 following 1st STZ infusion. On day 22 rats were sacrificed and the cortical and hippocampal brain regions were used to identify biochemical alterationsResultSTZ infused rats showed significant learning and memory deficit which was linked with increase in oxidative stress (malondialdehyde and nitrite), compromised antioxidant defense (reduced glutathione), mitochondrial dysfunction (deficit in complex I and III activity) and pro‐inflammatory cytokine levels. Significant decrease in both cAMP and cGMP levels were also observed in STZ‐infused rats. β‐Asarone dose dependently attenuated STZ‐induced cognitive deficit, biochemical alterations and restored cyclic nucleotide levels.ConclusionThe observed results show important role of PDE inhibition and cyclic nucleotide signaling in the beneficial effects of β‐asarone and suggest therapeutic potential of β‐asarone in the management of cognitive disorders.

Spatial transcriptomics identifies disrupted circadian gene expression in a mouse model of Alzheimer’s disease

AbstractBackgroundDisruptions in circadian rhythm are a common symptom of Alzheimer’s disease (AD), which occur early in disease progression and may contribute to the neurodegenerative process. However, the mechanisms that link alterations in rhythmic transcription and disease pathology are poorly understood. Here we used brain‐wide spatial transcriptomics to elucidate progressive disruptions in diurnal transcriptional rhythms in a mouse model of AD.MethodUsing Visium spatial transcriptomic technology, we investigated transcriptional changes with spatiotemporal resolution in APP23 transgenic mice, which overexpress human APP with the Swedish mutation. Sagittal brain slices from APP23 and littermate control mice were collected at 4 Zeitgeber times (ZT). We used community detection to cluster the spatial locations according to shared patterns of gene expression, which corresponded to major anatomical brain regions. Pseudobulk profiles were computed for each cluster in each sample, and these were used in subsequent differential expression analysis using DESeq2. Rhythmic gene expression was modeled as a sinusoidal function of ZT, while controlling for covariates (sex, genotype, and age) and their interaction with time. Results were further validated using non‐parametric tests for rhythmicity implemented in Metacycle.ResultOur analysis revealed a large increase in the number of diurnally rhythmic genes in APP23 mice in several brain structures, including regions affected by neurodegeneration in AD like the hippocampus and the cortex. Additionally, many genes showed increased rhythmicity or altered circadian phase in APP23 mice in specific brain regions, when compared to controls. For example, the expression of Slc5a3, a gene involved in osmotic stress response and deregulated in human AD brains, presented strong circadian rhythms in both APP23 and controls in cortical clusters, but the amplitude of expression was significantly larger in the dentate gyrus only in APP23 mice. Importantly, this effect was observed before and after the onset of amyloid pathology.ConclusionThese data map the changes in rhythmic gene expression over the course of AD progression in the spatiotemporal context of cortical and subcortical brain regions. Our findings elucidate molecular disruptions occurring early in the development of AD, which may drive disease progression.

Visceral Abdominal Adipose Tissue and Insulin Resistance Respectively Influence Alzheimer Disease Amyloid Pathology and Neurodegeneration in Midlife

AbstractBackgroundObesity and adiposity at midlife, evidenced by high body mass index (BMI), are increasingly understood as a risk factor for Alzheimer’s disease (AD). Importantly, visceral fat is known to be associated with insulin resistance and proinflammatory state, the mechanisms involved in AD pathology. Herein, we aimed to assess the association between brain MRI volumes as well as amyloid and tau uptake with obesity, insulin resistance, and abdominal adipose tissue in cognitively normal midlife population.MethodA total of 34 middle‐aged (age: 51.27 ± 6.12 years, BMI: 32.28 ± 6.39 kg/m2), cognitively normal participants, underwent bloodwork, brain and abdominal MRI, as well as amyloid and tau PET scan. Homeostatic Model Assessment for Insulin Resistance (HOMAIR) > 1.9 was used as a measure of insulin resistance. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi‐automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer 7.1.1 was used for automatic segmentation of cortical and subcortical brain regions using a probabilistic atlas. Dynamic amyloid imaging was performed with a bolus injection of ∼15 mCi of [11C]PiB, followed by a 60‐min scan. A single intravenous bolus of between 7.2‐10.8 mCi of AV‐1451 was administered. Data from the 30‐60 minute, and 80‐100 minute post‐injection window for PiB and AV‐1451 were used for the analysis, respectively. The association of brain volumes and PiB and AV‐1451 SUVRs within the default mode network areas with BMI and VAT/SAT ratio were assessed using linear regression models.ResultWe observed lower right entorhinal white matter volumes in obese participants with insulin resistance compared to metabolically normal non‐obese group (p = 0.004), without any significant difference in PiB or AV‐1451 SUVRs. Regression models with sex, age and education as covariates showed a significant positive association between VAT/SAT ratio and left precuneus white matter PiB SUVRs (R2 = 0.31, p = 0.005), but no significant associations with AV‐1451 SUVRs.ConclusionIn our midlife obese sample with insulin resistance, there were lower right entorhinal white matter volume, which is involved in relaying information to the hippocampus. We also demonstrate higher early amyloid pathology in AD‐signature areas such as the precuneus in mid‐life persons with high VAT/SAT ratio, a marker of visceral obesity.

NEUROPROTECTIVE EFFECT OF PALIPERIDONE IN LPS INDUCED ANIMAL MODEL OF AD

AbstractBackgroundAlzheimer’s disease is a progressive neurological condition, that impairs cognition and memory. Extracellular beta‐amyloid plaques and intracellular neurofibrillary tangle formation are the two hallmarks while cognitive decline, neurotransmitter deficit, neuroinflammation, mitochondrial dysfunction, decreased cerebral glucose uptake, and oxidative stress has been known to contribute to the pathogenesis of AD. The present study was designed to investigate the neuroprotective potential of Paliperidone on intracerebroventricular (i.c.v.) Lipopolysaccharide‐induced experimental dementia of Alzheimer’s type.MethodLPS was administered by the i.c.v route on 1st day of the study in rats. Paliperidone was administered (1mg/Kg and 2mg/kg/day i.p) from the 1st to 21st day in LPS‐infused rats. Morris water maze, open‐field test, and object recognition parameters were used to assess learning, memory, behavioral changes and locomotor activity in rats. LPS infusion rapidly causes neuroinflammation and oxidative‐nitrosative stress.ResultThese markers were determined in the cortical and hippocampal brain regions of rats. While paliperidone treatment attenuates the LPS‐induced behavioral and biochemical abnormalities in rats by reducing levels of Malondialdehyde (MDA), reduced glutathione (GSH), and increasing levels of catalase. The neurodegeneration in Hippocampus and cortex regions was observed through histopathological examination. The observed cognitive improvement following paliperidone in LPStreated rats may be due to its antioxidant and anti‐inflammatory activity and restoration of cholinergic functions.ConclusionOur results suggest the therapeutic potential of paliperidone in cognitive disorders such as AD. However, more investigations are required to evaluate the potential of paliperidone in boosting memory and cognition and preventing neuronal damage.

Examining the overlap between patterns of tau deposition and cortical neurite microstructure in preclinical Alzheimer’s disease

AbstractBackgroundIncreased Amyloid‐beta (Aβ) is associated with the neuropathological features of Alzheimer’s disease (AD), and it has been suggested to amplify tau spreading in the brain that leads to neurodegeneration. However, little is known about how the pattern of tau spreading overlaps with that of cortical microstructural neurodegeneration in the preclinical stages of the disease. Here, we utilized molecular imaging and neurite orientation dispersion and density imaging (NODDI) to identify the spreading pattern of tau pathology with the disease progression in cross‐sectional data and interaction with the degradation of cortical neurite microstructures.MethodsThe study consisted of normal controls (CN) and patients with mild cognitive impairments (MCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Table 1). All participants had structural and multi‐shell diffusion magnetic resonance imaging (MRI), and positron emission tomography (PET) scans using 18F‐florbetapir (AV45) for and 18F‐flortaucipir (AV1451) for tau. The preprocessed PET images were used to generate the standardized uptake value ratio (SUVR) values in each hemisphere consisting of 180 cerebral cortical brain regions defined by the Glasser atlas. The preprocessed dMRI data were used to compute cortical NODDI coefficients (neurite density (intracellular volume fraction; ICVF), orientation dispersion index (ODI), and isotropic volume fraction (FISO)). The tau and NODDI microstructural values are then normalized compared to the Aβ− CN group by adjusting the values for age and sex. The tau spreading order was defined based on the frequencies of the normalized tau values that exceeded the given threshold and compared the patterns with the neurite microstructures.ResultsWe found a sharp increase of tau deposition in patients with Aβ+ MCI, and the medial temporal regions were identified as the earliest region to become tau positive and continue to spread to inferior temporal and inferior parietal regions. Most importantly, we found significant patterns of cortical ODI degradation with the tau spreading in the right entorhinal cortex (p = 0.004) and the right hippocampus (p = 0.02).ConclusionThe findings of this cross‐sectional study provide that regional cortical neurite imaging could provide higher sensitivity to changes in the pathological process of tau spreading in tau epicenters in AD.

Non‐invasive kinetic modeling of [18F]‐florbetaben and [18F]‐PI‐2620 with total‐body dynamic EXPLORER PET

AbstractBackgroundThis study aims to quantify amyloid and tau buildup in older individuals with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and [18F]‐PI‐2620 total‐body EXPLORER PET.MethodFifteen adults (9 CU, 2 MCI, and 3 AD) aged 66‐86 underwent dynamic total‐body 18F‐florbetaben [110min] and PI‐2620 PET [90min] (United Imaging). 3 CU adults also underwent Tau PET for this initial analysis. IDIFs were derived from descending aorta ROIs. PET volumes were motion corrected (FSL‐MCFLIRT) and linearly registered (FSL‐FLIRT) to T1W image. The DKT ATLAS was used to segment brain cortical regions that are involved in neurodegeneration for PET SUVR measurements. PET SUVR means were calculated from 10 index regions and the cerebellar gray matter as the reference. Dynamic time activity curves were fit to the two‐tissue compartment model (2TCM) using joint estimation and population metabolite‐corrected IDIFs (Li, JNM 2021). The Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).Result[18F]‐Florbetaben Aβ+/Tau‐ SUVR was the highest in each brain index region, while PI‐2620 showed elevated SUVR in brain regions associated with early Braak stages I‐III in both Aβ‐/Tau‐ and Aβ+/Tau‐ (Fig 2). In our tau‐negative cohort, PI‐2620 signal in both cortical and reference regions, as expected, had low specific distribution volume (Vs) values (1.43 ±0.56) in both HC and AD. [18F]‐Florbetaben cortical Vs values were roughly 4 times higher than cerebellum in the Aβ+/Tau‐ (AD) individual and PI‐2620 cortical Vs values were 3.5 times higher compared to the cerebellum in both HC and AD. Mean k₁ values, which reflect regional blood flow, were similar in both AD and HC in both [18F]‐florbetaben and PI‐2620 PET analyses (Table 1). SUVR and DVR from MRTM kinetic models were correlated for each tracer; with slight overestimation of SUVR compared to DVR.ConclusionAbsolute quantification of amyloid and tau binding from total‐body PET data is feasible using aorta IDIFs and enables high quality kinetic modeling for accurate measures in clinical research of aging and dementia.

Non‐invasive kinetic modeling of [18F]‐florbetaben and [18F]‐PI‐2620 with total‐body dynamic EXPLORER PET

AbstractBackgroundThis study aims to quantify amyloid and tau buildup in older individuals with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and [18F]‐PI‐2620 total‐body EXPLORER PET.MethodFifteen adults (9 CU, 2 MCI, and 3 AD) aged 66‐86 underwent dynamic total‐body 18F‐florbetaben [110min] and PI‐2620 PET [90min] (United Imaging). 3 CU adults also underwent Tau PET for this initial analysis. IDIFs were derived from descending aorta ROIs. PET volumes were motion corrected (FSL‐MCFLIRT) and linearly registered (FSL‐FLIRT) to T1W image. The DKT ATLAS was used to segment brain cortical regions that are involved in neurodegeneration for PET SUVR measurements. PET SUVR means were calculated from 10 index regions and the cerebellar gray matter as the reference. Dynamic time activity curves were fit to the two‐tissue compartment model (2TCM) using joint estimation and population metabolite‐corrected IDIFs (Li, JNM 2021). The Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).Result[18F]‐Florbetaben Aβ+/Tau‐ SUVR was the highest in each brain index region, while PI‐2620 showed elevated SUVR in brain regions associated with early Braak stages I‐III in both Aβ‐/Tau‐ and Aβ+/Tau‐ (Fig 2). In our tau‐negative cohort, PI‐2620 signal in both cortical and reference regions, as expected, had low specific distribution volume (Vs) values (1.43 ±0.56) in both HC and AD. [18F]‐Florbetaben cortical Vs values were roughly 4 times higher than cerebellum in the Aβ+/Tau‐ (AD) individual and PI‐2620 cortical Vs values were 3.5 times higher compared to the cerebellum in both HC and AD. Mean k₁ values, which reflect regional blood flow, were similar in both AD and HC in both [18F]‐florbetaben and PI‐2620 PET analyses (Table 1). SUVR and DVR from MRTM kinetic models were correlated for each tracer; with slight overestimation of SUVR compared to DVR.ConclusionAbsolute quantification of amyloid and tau binding from total‐body PET data is feasible using aorta IDIFs and enables high quality kinetic modeling for accurate measures in clinical research of aging and dementia.

Dual-systems models of the genetic architecture of impulsive personality traits: neurogenetic evidence of distinct but related factors.

Dual-systems models, positing an interaction between two distinct and competing systems (i.e. top-down self-control, and bottom-up reward- or emotion-based drive), provide a parsimonious framework for investigating the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychopathology. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted. Using IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between dual-systems factors and relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were estimated and compared. GenomicSEM dual-systems models underscored important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences (rg = 0.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g. lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). No significant associations were observed with subcortical phenotypes. Dual-systems models of the genetic architecture of IPTs tested were consistent with study hypotheses, but associations with relevant neuroimaging phenotypes were mixed (e.g. no associations with subcortical volumes). Findings demonstrate the utility of dual-systems models for studying IPT genetic influences, but also highlight potential limitations as a framework for interpreting IPTs as endophenotypes for psychopathology.

The Role of P-Selectin in Microvascular Hemodynamics and Cerebral Brain Volumes in Aging Sickle Cell Mice

Cerebral vasculopathy has been linked to the development of cognitive impairment in sickle cell disease (SCD). We have previously demonstrated that 13-month-old sickle cell mice recapitulate features of cerebral vasculopathy such as tortuous vessels, microthrombi, and hypoperfusion seen in adults with SCD. Histologically, we also showed these mice have increased cerebral microvascular deposition of P-selectin and more frequent and larger microinfarcts compared to matched controls. We further showed that these mice developed evidence of cognitive deficit compared to matched controls. Based on these observations, we hypothesized P-selectin may play a critical role in development of cerebral micro vasculopathy and downstream pathologic sequalae such as microinfarcts by enhancing leukocyte-endothelial interactions. Furthermore, abundant evidence from non-sickle mice shows that microinfarcts can exacerbate small vessel changes including gray matter volume loss. Building on our prior work, in this study, we examined the effect of P-selectin deficiency on cerebral microvascular hemodynamics and leukocyte-endothelial interaction and well as changes in cortical and subcortical gray matter volume in aged sickle mice. Male, P-selectin knockout (Psel KO) or intact (Psel WT) chimeric mice were generated by transplanting control (AA) or sickle (SS) bone marrow into P-selectin knockout (Psel -/-) or C57BL/6 (B6) recipients. To assess the impact of vasculopathy and brain gray matter volume changes longitudinally, male mice were assessed at 12-, 14- or 16-month post-transplant. Hemodynamics (mean velocity, red blood cell (RBC) flux, white blood cell stalls in capillaries as well as venules) were obtained from line-scan images acquired using in-vivo two-photon microscopy, using custom and validated MATLAB scripts. Gray matter volumes in 26 cortical and subcortical brain regions with relevance to cognitive function, were derived from parcellation of T2-weighted magnetic resonance imaging after non-linear registration to Allen brain atlas T1 anatomical space. Parcellation was accomplished by registering the Paxinos atlas to the mouse T2 now in Allen space. Brain volume analyses was accomplished using Analyze 12 software. After the completion of in-vivo studies, brains were extracted for immunohistochemistry analysis. Statistical analysis was performed using two-way ANOVA. The breakdown of the mice included in this study are; 14 B6 AA, 12 B6 SS, 12 Psel KO AA and 13 Psel KO SS. Given the high attrition rate in older mice, data from 12-, 14- and 16-month-old cohorts were combined. Mean age of B6 AA cohort was 13.1 months, 12.8 months for B6 SS, 13. 9 months for Psel KO AA and 13.6 months for Psel KO SS mice and were not statistically different. Psel KO sickle mice had a significantly lower mean capillary RBC velocity (1.733 mm/s vs 4.717 mm/s, p < 0.01) compared to Psel WT SS mice. In addition, Psel KO SS mice had relatively smaller (more normal) capillary diameter compared to Psel WT SS mice (6.248 um vs 8.613 um, p < 0.001). Interestingly, there was no statistically significant difference in RBC flux between Psel KO SS and Psel WT SS mice, however Psel KO SS mice show a lower red blood cell flux similar to that seen in Psel WT AA mice ( Figure 1). Of the 26 brain regions that were assessed, Psel KO SS mice had larger measured gray matter volume in the frontal association cortex (3.01 ± 0.77 vs 3.66± 0.33 mm 3, p= 0.0083), prelimbic cortex (1.72 ± 0.27 vs 1.95 ± 0.17 mm 3, p=0.0079), hippocampus (17.67 ± 1.56 vs 16.21± 1.97 mm 3, p=0.01)( Figure 1) including other regions such as lateral (2.12 ± 0.19 vs 1.88 ± 0.31 vs mm 3 p=0.0096) medial (1.84± 0.16 vs 1.64 ± 0.26 mm 3, p=0.01), and ventral orbital cortex( 1.95± 0.17 vs1.72 ± 0.27 mm 3, p=0.01) and dorsolateral olfactory tract (1.46 6± 0.13 vs 1.31 ± 0.20 mm 3, p=0.023 compared to the Psel WT SS mice (data not shown). In conclusion, non-hematopoetic P-selectin deficiency improves cerebral vasculopathy as demonstrated by normalization of hemodynamics in sickle mice. We also show that Psel KO SS mice had larger brain gray matter volume in regions involved in cognitive function. Additional studies are needed to identify the underlying mechanism of improvement in brain gray matter volume as well as whether P-selectin could be potential target for reducing SCD associated neurological complications.

Photoacoustic imaging of visually evoked cortical and subcortical hemodynamic activity in mouse brain: feasibility study with piezoelectric and capacitive micromachined ultrasonic transducer (CMUT) arrays.

This study investigates the feasibility of capturing visually evoked hemodynamic responses in the mouse brain using photoacoustic tomography (PAT) and ultrasound (US) dual-modality imaging. A commercial piezoelectric transducer array and a capacitive micromachined ultrasonic transducer (CMUT) array were compared using a programmable PAT-US imaging system. The system resolution was measured by imaging phantoms. We also tested the ability of the system to capture visually evoked hemodynamic responses in the superior colliculus as well as the primary visual cortex in wild-type mice. Results show that the piezoelectric transducer array and the CMUT array exhibit comparable imaging performance, and both arrays can capture visually evoked hemodynamic responses in subcortical as well as cortical regions of the mouse brain.

97 Distinct Clinical and Neuroanatomic Factors Associated with Function-based versus Patient-Reported Outcome Measures After Stroke

Objective:Patient-reported outcome measures provide valuable insights into health status after neurologic disease, but their relationships with function-based outcome measures remain incompletely understood. Here we evaluate the relationship between these two classes of measure using dimensionality-reduction techniques in patients after acute stroke and examine their associated patterns of neuroanatomical injury.Participants and Methods:Fifty-four adults with upper extremity motor deficits were serially assessed at four time points after stroke with functional outcome measures (Upper Extremity Fugl-Meyer, Barthel Index, modified Rankin Scale, Box and Blocks, 9- Hole Peg, Grip Strength) as well as patient-reported measures (PROMIS-Global Physical, Mental, and Social Health, Patient Health Questionnaire-9) of health status. At each timepoint after stroke, exploratory and confirmatory factor analysis were performed to identify and confirm the underlying factorial structure of the entire battery of outcome measures. Multivariate linear regression analysis was used to determine the amount of variance explained by clinical and demographic characteristics on extracted factors. Voxel-Based Lesion Symptom Mapping was used to examine the relationship between factors and patterns of neuroanatomical injury.Results:In the battery of stroke outcome measures, two factors were identified and retained, accounting for >78% of the overall variance across outcomes at every timepoint. Function-based measures loaded onto Factor 1 separately from patient-reported measures which loaded onto Factor 2. Results were consistent at each serial timepoint after stroke. Pre-stroke disability (p=0.03) and amount of damage to the corticospinal tract (p=0.001), explained significant variance in performance on Factor 1 (function-based outcomes), whereas education (p=0.01) and socioeconomic status (p=0.04) explained significant variance in performance on Factor 2 (PROMs). While function-based measures were related to injury to subcortical brain regions known to be important for motor function, patient-reported measures were related to injury to cortical brain regions including the insula and inferior parietal lobe, known to be important for affective processing and social cognition.Conclusions:Two distinct factors representing function-based and patient-reported measures of health status were extracted from the study battery of stroke outcome measures scored across the first year post-stroke. Each factor was associated with injury to brain regions concordant with the content of the represented assessments. These findings emphasize the distinct behavioral elements and neuroanatomical underpinnings of function-based and patient-reported outcome measures after stroke and have potential implications for precision rehabilitation.

Correlation of metal ions with specific brain region volumes in neurodegenerative diseases.

There are reports stating that deteriorations in metal homeostasis in neurodegenerative diseases promote abnormal protein accumulation. In this study, the serum metal levels in Alzheimer's disease (AD) and Parkinson's disease (PD) and its relationship with the cortical regions of the brain were investigated. The patients were divided into 3 groups consisting of the AD group, PD group, and healthy control group (n = 15 for each). The volumes of specific brain regions were measured over the participants' 3-dimensional magnetic resonance images, and they were compared across the groups. Copper, zinc, iron, and ferritin levels in the serums were determined, and their correlations with the brain region volumes were examined. The volumes of left hippocampus and right substantia nigra were lower in the AD and PD groups, while the volume of the left nucleus caudatus (CdN) and bilateral insula were lower in the AD group compared to the control group. Serum zinc levels were lower in the AD and PD groups, while the iron level was lower in the PD group in comparison to the control group. In addition, the serum ferritin level was higher in the AD group than in the control group. Serum zinc and copper levels in the AD group were positively correlated with the volumes of the right entorhinal cortex, thalamus, CdN, and insula. Serum zinc and copper levels in the PD group showed a negative correlation with the left nucleus accumbens (NAc), right putamen, and right insula volumes. While the serum ferritin level in the PD group displayed a positive correlation with the bilateral CdN, putamen, and NAc, as well as the right hippocampus and insula volumes, no area was detected that showed a correlation with the serum ferritin level in the AD group. A relationship was determined between the serum metal levels in the AD and PD groups and certain brain cortical regions that showed volumetric changes, which can be important for the early diagnosis of neurodegenerative diseases.

Transcriptional dissection of symptomatic profiles across the brain of men and women with depression

Major depressive disorder (MDD) is one of the most important causes of disability worldwide. While recent work provides insights into the molecular alterations in the brain of patients with MDD, whether these molecular signatures can be associated with the expression of specific symptom domains remains unclear. Here, we identified sex-specific gene modules associated with the expression of MDD, combining differential gene expression and co-expression network analyses in six cortical and subcortical brain regions. Our results show varying levels of network homology between males and females across brain regions, although the associations between these structures and the expression of MDD remain highly sex specific. We refined these associations to several symptom domains and identified transcriptional signatures associated with distinct functional pathways, including GABAergic and glutamatergic neurotransmission, metabolic processes and intracellular signal transduction, across brain regions associated with distinct symptomatic profiles in a sex-specific fashion. In most cases, these associations were specific to males or to females with MDD, although a subset of gene modules associated with common symptomatic features in both sexes were also identified. Together, our findings suggest that the expression of distinct MDD symptom domains associates with sex-specific transcriptional structures across brain regions.

Small volume blood-brain barrier opening in macaques with a 1 MHz ultrasound phased array

The use of focused ultrasound to open the blood-brain barrier (BBB) has the potential to deliver drugs to specific regions of the brain. The size of the BBB opening and ability to localize the opening determines the spatial extent and is a limiting factor in many applications of BBB opening where targeting a small brain region is desired. Here we evaluate the performance of a system designed for small opening volumes and highlight the unique challenges associated with pushing the spatial precision of this technique. To achieve small volume openings in cortical regions of the macaque brain, we tested a custom 1 MHz array transducer integrated into a magnetic resonance image-guided focused ultrasound system. Using real-time cavitation monitoring, we demonstrated twelve instances of single sonication, small volume BBB opening with average volumes of 59 ± 37 mm3 and 184 ± 2 mm3 in cortical and subcortical targets, respectively. We found high correlation between subject-specific acoustic simulations and observed openings when incorporating grey matter segmentation (R2 = 0.8577), and the threshold for BBB opening based on simulations was 0.53 MPa. Analysis of MRI-based safety assessment and cavitation signals indicate a safe pressure range for 1 MHz BBB opening and suggest that our system can be used to deliver drugs and gene therapy to small brain regions.

Frequency specific alterations of the degree centrality in patients with acute basal ganglia ischemic stroke: a resting-state fMRI study

This study intended to investigate the frequency specific brain oscillation activity in patients with acute basal ganglia ischemic stroke (BGIS) by using the degree centrality (DC) method. A total of 34 acute BGIS patients and 44 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. The DC values in three frequency bands (conventional band: 0.01–0.08 Hz, slow‑4 band: 0.027–0.073 Hz, slow‑5 band: 0.01–0.027 Hz) were calculated. A two-sample t-test was used to explore the between-group differences in the conventional frequency band. A two-way repeated-measures analysis of variance (ANOVA) was used to analyze the DC differences between groups (BGIS patients, HCs) and bands (slow‑4, slow‑5). Moreover, correlations between DC values and clinical indicators were performed. In conventional band, the DC value in the right middle temporal gyrus was decreased in BGIS patients compared with HCs. Significant differences of DC were observed between the two bands mainly in the bilateral cortical brain regions. Compared with the HCs, the BGIS patients showed increased DC in the right superior temporal gyrus and the left precuneus, but decreased mainly in the right inferior temporal gyrus, right inferior occipital gyrus, right precentral, and right supplementary motor area. Furthermore, the decreased DC in the right rolandic operculum in slow-4 band and the right superior temporal gyrus in slow-5 band were found by post hoc two-sample t-test of main effect of group. There was no significant correlation between DC values and clinical scales after Bonferroni correction. Our findings showed that the DC changes in BGIS patients were frequency specific. Functional abnormalities in local brain regions may help us to understand the underlying pathogenesis mechanism of brain functional reorganization of BGIS patients.

Cortical structure and the risk of amyotrophic lateral sclerosis: A bidirectional Mendelian randomization study

BackgroundCurrent observational studies indicate progressive brain atrophy is closely associated with the clinical feature of amyotrophic lateral sclerosis. However, it is unclear whether the changes in cortical structure are the cause or result of ALS. Our study aimed to investigate the causal relationship between cortical structure and ALS risk using a bidirectional two-sample MR study. MethodsWe collected publicly available genome-wide association studies' summary statistics for cortical structure from UK Biobank and ENIGMA consortium (n = 33,992) and ALS from the Project MinE (n = 138,086). We used the inverse variance weighted method (IVW) as primary analysis in order to evaluate the causal effects. In addition, the weighted median and MR Egger methods were performed to ensure the robustness and reliability of the IVW results. ResultsWe found the decreased surface of the paracentral lobule and thickness of the frontal pole and middle temporal lobe were suggestively associated with an increased risk of ALS as well as the increased surface of medial orbitofrontal and middle temporal lobe. In another aspect, the causalities between the susceptibility to ALS and the volume of the transverse temporal gyrus and superior temporal gyrus were negative. Besides, the susceptibility to ALS might also contribute to an increased thickness of the postcentral gyrus and superior parietal gyrus. ConclusionIn this two-sample MR analysis, we observed that multiple cortical brain regions are associated with a higher ALS risk. Further research into the underlying mechanisms is required to back up our findings.

Odor modality is transmitted to cortical brain regions from the olfactory bulb.

Odor perception is the impetus for important animal behaviors with two predominate modes of processing: odors pass through the front of the nose (orthonasal) while inhaling and sniffing, or through the rear (retronasal) during exhalation and while eating. Despite the importance of olfaction for an animal's well-being and that ortho and retro naturally occur, it is unknown how the modality (ortho vs. retro) is even transmitted to cortical brain regions, which could significantly affect how odors are processed and perceived. Using multielectrode array recordings in tracheotomized anesthetized rats, which decouples ortho-retro modality from breathing, we show that mitral cells in rat olfactory bulb can reliably and directly transmit orthonasal versus retronasal modality with ethyl butyrate, a common food odor. Drug manipulations affecting synaptic inhibition via GABAA lead to worse decoding of ortho versus retro, independent of whether overall inhibition increases or decreases, suggesting that the olfactory bulb circuit may naturally favor encoding this important aspect of odors. Detailed data analysis paired with a firing rate model that captures population trends in spiking statistics shows how this circuit can encode odor modality. We have not only demonstrated that ortho/retro information is encoded to downstream brain regions but also used modeling to demonstrate a plausible mechanism for this encoding; due to synaptic adaptation, it is the slower time course of the retronasal stimulation that causes retronasal responses to be stronger and less sensitive to inhibitory drug manipulations than orthonasal responses.NEW & NOTEWORTHY Whether ortho (sniffing odors) versus retro (exhalation and eating) is encoded from the olfactory bulb to other brain areas is not completely known. Using multielectrode array recordings in anesthetized rats, we show that the olfactory bulb transmits this information downstream via spikes. Altering inhibition degrades ortho/retro information on average. We use theory and computation to explain our results, which should have implications on cortical processing considering that only food odors occur retronasally.

Associations between parental depression and anxiety symptom severity and their Offspring's cortical thickness and subcortical volume

Depression and anxiety are associated with grey matter changes in subcortical regions in adults and adolescents. Parent psychopathology is associated with offspring brain structure, but it's unclear whether altered brain structure in children is associated with severity of parental depression and anxiety symptoms. We examined 123 youth (Mean age = 13.64; 62% female) with no clinically significant history of depression or anxiety and one parent diagnosed with current or past depressive or anxiety disorders. Parents completed the Mini International Neuropsychiatric Interview to assess diagnostic status and the Beck Depression Inventory-II, and the Generalized Anxiety Disorder-7 to assess current symptom severity. Youth underwent T1 weighted structural Magnetic Resonance Imaging scans. Bivariate analyses revealed higher parental depressive severity was not significantly associated with offspring grey matter. Parental anxiety severity was significantly associated with less left global surface area. When controlling for offspring age, sex and intracranial volume (ICV), offspring right surface area was negatively associated with parental depressive severity at a trend level. In previously depressed parents, greater parental depressive severity was significantly associated with offspring decreased left and right surface area. There were no significant associations between parental anxiety severity in previously depressed parents and offspring subcortical or cortical brain regions. These results highlight associations between parental depressive symptom severity and offspring brain structure and suggest that even within an already high-risk group of adolescents, there may be altered cortical surface area depending on parent symptom severity. This may help identify youth most at risk for developing a mood disorder and could help further early intervention and identification efforts.