Effects of multiple anesthetic exposures on rhesus macaque brain development: a longitudinal structural MRI analysis.

Concerns about the potential neurotoxic effects of anesthetics on developing brain exist. When making clinical decisions, the timing and dosage of anesthetic exposure are critical factors to consider due to their associated risks. In our study, we investigated the impact of repeated anesthetic exposures on the brain development trajectory of a cohort of rhesus monkeys (n = 26) over their first 2 yr of life, utilizing longitudinal magnetic resonance imaging data. We hypothesized that early or high-dose anesthesia exposure could negatively influence structural brain development. By employing the generalized additive mixed model, we traced the longitudinal trajectories of brain volume, cortical thickness, and white matter integrity. The interaction analysis revealed that age and cumulative anesthetic dose were variably linked to white matter integrity but not to morphometric measures. Early high-dose exposure was associated with increased mean, axial, and radial diffusivities across all white matter regions, compared to late-low-dose exposure. Our findings indicate that early or high-dose anesthesia exposure during infancy disrupts structural brain development in rhesus monkeys. Consequently, the timing of elective surgeries and procedures that require anesthesia for children and pregnant women should be strategically planned to account for the cumulative dose of volatile anesthetics, aiming to minimize the potential risks to brain development.

Assessing cerebrovascular reactivity (CVR) in rhesus macaques (Macaca mulatta) using a hypercapnic challenge and pseudo-continuous arterial spin labeling (pCASL).

Cerebrovascular reactivity (CVR) is a measure of cerebral small vessels' ability to respond to changes in metabolic demand and can be quantified using magnetic resonance imaging (MRI) coupled with a vasoactive stimulus. Reduced CVR occurs with neurodegeneration and is associated with cognitive decline. While commonly measured in humans, few studies have evaluated CVR in animal models. Herein, we describe methods to induce hypercapnia in rhesus macaques (Macaca mulatta) under gas anesthesia to measure cerebral blood flow (CBF) and CVR using pseudo-continuous arterial spin labeling (pCASL). Fifteen (13 M, 2 F) adult rhesus macaques underwent pCASL imaging that included a baseline segment (100% O2) followed by a hypercapnic challenge (isoflurane anesthesia with 5% CO2, 95% O2 mixed gas). Relative hypercapnia was defined as an end-tidal CO2 (ETCO2) ≥5 mmHg above baseline ETCO2. The mean ETCO2 during the baseline segment of the pCASL sequence was 34 mmHg (range: 23-48 mmHg). During this segment, mean whole-brain CBF was 51.48 ml/100g/min (range: 21.47-77.23 ml/100g/min). Significant increases (p<0.0001) in ETCO2 were seen upon inspiration of the mixed gas (5% CO2, 95% O2). The mean increase in ETCO2 was 8.5 mmHg and corresponded with a mean increase in CBF of 37.1% (p<0.0001). The mean CVR measured was 4.3%/mmHg. No anesthetic complications occurred as a result of the CO2 challenge. Our methods were effective at inducing a state of relative hypercapnia that corresponds with a detectable increase in whole brain CBF using pCASL MRI. Using these methods, a CO2 challenge can be performed in conjunction with pCASL imaging to evaluate CBF and CVR in rhesus macaques. The measured CVR in rhesus macaques is comparable to human CVR highlighting the translational utility of rhesus macaques in neuroscience research. These methods present a feasible means to measure CVR in comparative models of neurodegeneration and cerebrovascular dysfunction.

Epigenetic MLH1 silencing concurs with mismatch repair deficiency in sporadic, naturally occurring colorectal cancer in rhesus macaques.

BACKGROUND: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers. METHODS: We conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation. RESULTS: Similar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273*), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs. CONCLUSIONS: These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.

Mediterranean diet protects against a neuroinflammatory cortical transcriptome: Associations with brain volumetrics, peripheral inflammation, social isolation, and anxiety in nonhuman primates (Macaca fascicularis).

Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets; however, the underlying biology is poorly understood. We assessed the effects of Western versus Mediterranean-like diets on RNAseq-generated transcriptional profiles in lateral temporal cortex and their relationships with longitudinal changes in neuroanatomy, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques (Macaca fascicularis). Diet resulted in differential expression of seven transcripts (FDR < 0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., "lunatic fringe" (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14, LFNG, MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with peripheral monocyte transcript levels, neuroanatomical changes determined by MRI, and with social isolation and anxiety. These results provide important insights into the potential mechanistic processes linking diet, peripheral and central inflammation, and behavior. Collectively, our results provide evidence that, relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and socioemotional behavior. Ultimately, such protective effects may confer resilience to the development of neuropathology and associated disease.

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

INTRODUCTION: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. METHODS: We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aß] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aß-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N = 299), mild cognitive impairment (MCI; N = 192), or dementia (DEM; N = 65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). RESULTS: Plasma biomarkers differed across diagnostic groups (DEM > MCI > CU), were altered in Aß-PET-positive individuals, and were associated with poorer brain health and kidney function. DISCUSSION: eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. HIGHLIGHTS: Plasma biomarkers differ across diagnostic groups (DEM > MCI > CU) and are altered in Aß-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

Association of fractal dimension and other retinal vascular network parameters with cognitive performance and neuroimaging biomarkers: The Multi-Ethnic Study of Atherosclerosis (MESA).

INTRODUCTION: Retinal vascular network changes may reflect the integrity of the cerebral microcirculation, and may be associated with cognitive impairment. METHODS: Associations of retinal vascular measures with cognitive function and MRI biomarkers were examined amongst Multi-Ethnic Study of Atherosclerosis (MESA) participants in North Carolina who had gradable retinal photographs at Exams 2 (2002 to 2004, n = 313) and 5 (2010 to 2012, n = 306), and detailed cognitive testing and MRI at Exam 6 (2016 to 2018). RESULTS: After adjustment for covariates and multiple comparisons, greater arteriolar fractal dimension (FD) at Exam 2 was associated with less isotropic free water of gray matter regions (ß = -0.0005, SE = 0.0024, p = 0.01) at Exam 6, while greater arteriolar FD at Exam 5 was associated with greater gray matter cortical volume (in mm3 , ß = 5458, SE = 20.17, p = 0.04) at Exam 6. CONCLUSION: Greater arteriolar FD, reflecting greater complexity of the branching pattern of the retinal arteries, is associated with MRI biomarkers indicative of less neuroinflammation and neurodegeneration.

Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [11C]MPC-6827 PET imaging in rodent models of Alzheimer's-related pathology.

INTRODUCTION: Microtubule (MT) stability is crucial for proper neuronal function. Understanding MT dysregulation is critical for connecting amyloid beta (Aß) and tau-based degenerative events and early changes in presymptomatic Alzheimer's disease (AD). Herein we present positron emission tomography (PET) imaging properties of our MT-PET radiotracer, [11C]MPC-6827, in multiple established AD mouse models. METHODS: Longitudinal PET, biodistribution, autoradiography, immunohistochemistry, and behavioral studies were conducted at multiple time points in APPswe/PSEN1dE9 (APP/PS1), P301S-PS19 (P301S), 5xFAD, and age-matched control mice. RESULTS: Longitudinal [11C]MPC-6827 brain imaging showed significant increases in APP/PS1, P301S, and 5xFAD mice compared to controls. Longitudinal MT-PET correlated positively with biodistribution, autoradiography, and immunohistochemistry results and negatively with behavior data. DISCUSSION: Our study demonstrated significant longitudinal [11C]MPC-6827 PET increases in multiple AD mouse models for the first time. Strong correlations between PET and biomarker data underscored the interplay of MT destabilization, amyloid, and tau pathology in AD. These results suggest [11C]MPC-6827 PET as a promising tool for monitoring MT dysregulation early in AD progression. HIGHLIGHTS: Longitudinal positron emission tomography (PET) imaging studies using [11C]MPC-6827 in multiple established Alzheimer's disease (AD) mouse models revealed an early onset of microtubule dysregulation, with significant changes in brain radiotracer uptake evident from 2 to 4 months of age. Intra-group analysis showed a progressive increase in microtubule dysregulation with increasing AD burden, supported by significant correlations between PET imaging data and biodistribution, autoradiography, and molecular pathological markers. [11C]MPC-6827 PET imaging demonstrated its efficacy in detecting early microtubule alterations preceding observable behavioral changes in AD mouse models, suggesting its potential for early AD imaging. The inclusion of the 5xFAD mouse model further elucidated the impact of amyloid beta (Aß) toxicity on inducing tau hyperphosphorylation-mediated microtubule dysregulation, highlighting the versatility of [11C]MPC-6827 in delineating various aspects of AD pathology. Our study provides immediate clarity on high uptake of the microtubule-based radiotracer in AD brains in a longitudinal setting, which directly informs clinical utility in Aß/tau-based studies.

Parametric cerebral blood flow and arterial transit time mapping using a 3D convolutional neural network.

PURPOSE: To reduce the total scan time of multiple postlabeling delay (multi-PLD) pseudo-continuous arterial spin labeling (pCASL) by developing a hierarchically structured 3D convolutional neural network (H-CNN) that estimates the arterial transit time (ATT) and cerebral blow flow (CBF) maps from the reduced number of PLDs as well as averages. METHODS: A total of 48 subjects (38 females and 10 males), aged 56-80 years, compromising a training group (n = 45) and a validation group (n = 3) underwent MRI including multi-PLD pCASL. We proposed an H-CNN to estimate the ATT and CBF maps using a reduced number of PLDs and a separately reduced number of averages. The proposed method was compared with a conventional nonlinear model fitting method using the mean absolute error (MAE). RESULTS: The H-CNN provided the MAEs of 32.69 ms for ATT and 3.32 mL/100 g/min for CBF estimations using a full data set that contains six PLDs and six averages in the 3 test subjects. The H-CNN also showed that the smaller number of PLDs can be used to estimate both ATT and CBF without significant discrepancy from the reference (MAEs of 231.45 ms for ATT and 9.80 mL/100 g/min for CBF using three of six PLDs). CONCLUSION: The proposed machine learning-based ATT and CBF mapping offers substantially reduced scan time of multi-PLD pCASL.

MicroRNA expression in extracellular vesicles as a novel blood-based biomarker for Alzheimer's disease.

INTRODUCTION: Brain cell-derived small extracellular vesicles (sEVs) in blood offer unique cellular and molecular information related to the onset and progression of Alzheimer's disease (AD). We simultaneously enriched six specific sEV subtypes from the plasma and analyzed a selected panel of microRNAs (miRNAs) in older adults with/without cognitive impairment. METHODS: Total sEVs were isolated from the plasma of participants with normal cognition (CN; n = 11), mild cognitive impairment (MCI; n = 11), MCI conversion to AD dementia (MCI-AD; n = 6), and AD dementia (n = 11). Various brain cell-derived sEVs (from neurons, astrocytes, microglia, oligodendrocytes, pericytes, and endothelial cells) were enriched and analyzed for specific miRNAs. RESULTS: miRNAs in sEV subtypes differentially expressed in MCI, MCI-AD, and AD dementia compared to the CN group clearly distinguished dementia status, with an area under the curve (AUC) > 0.90 and correlated with the temporal cortical region thickness on magnetic resonance imaging (MRI). DISCUSSION: miRNA analyses in specific sEVs could serve as a novel blood-based molecular biomarker for AD. HIGHLIGHTS: Multiple brain cell-derived small extracellular vesicles (sEVs) could be isolated simultaneously from blood. MicroRNA (miRNA) expression in sEVs could detect Alzheimer's disease (AD) with high specificity and sensitivity. miRNA expression in sEVs correlated with cortical region thickness on magnetic resonance imaging (MRI). Altered expression of miRNAs in sEVCD31 and sEVPDGFRß suggested vascular dysfunction. miRNA expression in sEVs could predict the activation state of specific brain cell types.

Long term survivors of stereotactic radiosurgery for brain metastases: do distant brain failures reach a plateau and what factors are associated with a brain metastasis velocity of zero?

PURPOSE: Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS). The present study sought to retrospectively analyze brain metastasis patients who have survived 2 years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of zero. METHODS: This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases who survived greater than 2 years after first SRS. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least 2 years of imaging follow-up without distant brain failure (DBF). RESULTS: Median age at first SRS is 61 (IQR: 53, 70). Kaplan-Meier estimated median overall survival is 4.9 years and time to DBF is 1.5 years (95% CI 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3 years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures reach a plateau at 4 years where the cumulative incidence of DBF is 82%. 70% of first time DBFs have occurred by 2 years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03). CONCLUSION: Approximately one third of brain metastasis patients who live beyond 2 years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at 4 years. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS.

Comparing data-driven and hypothesis-driven MRI-based predictors of cognitive impairment in individuals from the Atherosclerosis Risk in Communities (ARIC) study.

INTRODUCTION: A data-driven index of dementia risk based on magnetic resonance imaging (MRI), the Alzheimer's Disease Pattern Similarity (AD-PS) score, was estimated for participants in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: AD-PS scores were generated for 839 cognitively non-impaired individuals with a mean follow-up of 4.86 years. The scores and a hypothesis-driven volumetric measure based on several brain regions susceptible to AD were compared as predictors of incident cognitive impairment in different settings. RESULTS: Logistic regression analyses suggest the data-driven AD-PS scores to be more predictive of incident cognitive impairment than its counterpart. Both biomarkers were more predictive of incident cognitive impairment in participants who were White, female, and apolipoprotein E gene (APOE) ε4 carriers. Random forest analyses including predictors from different domains ranked the AD-PS scores as the most relevant MRI predictor of cognitive impairment. CONCLUSIONS: Overall, the AD-PS scores were the stronger MRI-derived predictors of incident cognitive impairment in cognitively non-impaired individuals.

Mediterranean and Western diet effects on Alzheimer's disease biomarkers, cerebral perfusion, and cognition in mid-life: A randomized trial.

INTRODUCTION: Mid-life dietary patterns are associated with Alzheimer's disease (AD) risk, although few controlled trials have been conducted. METHODS: Eighty-seven participants (age range: 45 to 65) with normal cognition (NC, n = 56) or mild cognitive impairment (MCI, n = 31) received isocaloric diets high or low in saturated fat, glycemic index, and sodium (Western-like/West-diet vs. Mediterranean-like/Med-diet) for 4 weeks. Diet effects on cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral perfusion were assessed to determine whether responses differed by cognitive status. RESULTS: CSF amyloid beta (Aß)42/40 ratios increased following the Med-diet, and decreased after West-diet for NC adults, whereas the MCI group showed the reverse pattern. For the MCI group, the West-diet reduced and the Med-diet increased total tau (t-tau), whereas CSF Aß42 /t-tau ratios increased following the West-diet and decreased following the Med-diet. For NC participants, the Med-diet increased and the West-diet decreased cerebral perfusion. DISCUSSION: Diet response during middle age may highlight early pathophysiological processes that increase AD risk.

Associations among vascular risk factors, neuroimaging biomarkers, and cognition: Preliminary analyses from the Multi-Ethnic Study of Atherosclerosis (MESA).

INTRODUCTION: Little is known about how antecedent vascular risk factor (VRF) profiles impact late-life brain health. METHODS: We examined baseline VRFs, and cognitive testing and neuroimaging measures (ß-amyloid [Aß] PET, MRI) in a diverse longitudinal cohort (N = 159; 50% African-American, 50% White) from Wake Forest's Multi-Ethnic Study of Atherosclerosis Core. RESULTS: African-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aß positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aß. Aß was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline. DISCUSSION: Results suggest the convergence of multiple vascular and Alzheimer's processes underlying neurodegeneration and cognitive decline.

MEGnet: Automatic ICA-based artifact removal for MEG using spatiotemporal convolutional neural networks.

Magnetoencephalography (MEG) is a functional neuroimaging tool that records the magnetic fields induced by neuronal activity; however, signal from non-neuronal sources can corrupt the data. Eye-blinks, saccades, and cardiac activity are three of the most common sources of non-neuronal artifacts. They can be measured by affixing eye proximal electrodes, as in electrooculography (EOG), and chest electrodes, as in electrocardiography (ECG), however this complicates imaging setup, decreases patient comfort, and can induce further artifacts from movement. This work proposes an EOG- and ECG-free approach to identify eye-blinks, saccades, and cardiac activity signals for automated artifact suppression. The contribution of this work is three-fold. First, using a data driven, multivariate decomposition approach based on Independent Component Analysis (ICA), a highly accurate artifact classifier is constructed as an amalgam of deep 1-D and 2-D Convolutional Neural Networks (CNNs) to automate the identification and removal of ubiquitous whole brain artifacts including eye-blink, saccade, and cardiac artifacts. The specific architecture of this network is optimized through an unbiased, computer-based hyperparameter random search. Second, visualization methods are applied to the learned abstraction to reveal what features the model uses and to bolster user confidence in the model's training and potential for generalization. Finally, the model is trained and tested on both resting-state and task MEG data from 217 subjects, and achieves a new state-of-the-art in artifact detection accuracy of 98.95% including 96.74% sensitivity and 99.34% specificity on the held out test-set. This work automates MEG processing for both clinical and research use, adapts to the acquired acquisition time, and can obviate the need for EOG or ECG electrodes for artifact detection.

Mapping default mode connectivity alterations following a single season of subconcussive impact exposure in youth football.

Repetitive head impact (RHI) exposure in collision sports may contribute to adverse neurological outcomes in former players. In contrast to a concussion, or mild traumatic brain injury, "subconcussive" RHIs represent a more frequent and asymptomatic form of exposure. The neural network-level signatures characterizing subconcussive RHIs in youth collision-sport cohorts such as American Football are not known. Here, we used resting-state functional MRI to examine default mode network (DMN) functional connectivity (FC) following a single football season in youth players (n = 50, ages 8-14) without concussion. Football players demonstrated reduced FC across widespread DMN regions compared with non-collision sport controls at postseason but not preseason. In a subsample from the original cohort (n = 17), players revealed a negative change in FC between preseason and postseason and a positive and compensatory change in FC during the offseason across the majority of DMN regions. Lastly, significant FC changes, including between preseason and postseason and between in- and off-season, were specific to players at the upper end of the head impact frequency distribution. These findings represent initial evidence of network-level FC abnormalities following repetitive, non-concussive RHIs in youth football. Furthermore, the number of subconcussive RHIs proved to be a key factor influencing DMN FC.

Rhesus Macaque Brain Developmental Trajectory: A Longitudinal Analysis Using Tensor-Based Structural Morphometry and Diffusion Tensor Imaging.

The typical developmental trajectory of brain structure among nonhuman primates (NHPs) remains poorly understood. In this study, we characterized the normative trajectory of developmental change among a cohort of rhesus monkeys (n = 28), ranging in age from 2 to 22 months, using structural MRI datasets that were longitudinally acquired every 3-4 months. We hypothesized that NHP-specific transient intracranial volume decreases reported during late infancy would be part of the typical developmental process, which is driven by volumetric contraction of gray matter in primary functional areas. To this end, we performed multiscale analyses from the whole brain to voxel level, characterizing regional heterogeneity, hemispheric asymmetry, and sexual dimorphism in developmental patterns. The longitudinal trajectory of brain development was explained by three different regional volumetric growth patterns (exponentially decreasing, undulating, and linearly increasing), which resulted in developmental brain volume curves with transient brain volumetric decreases. White matter (WM) fractional anisotropy increased with age, corresponding to WM volume increases, while mean diffusivity (MD) showed biphasic patterns. The longitudinal trajectory of brain development in young rhesus monkeys follows typical maturation patterns seen in humans, but regional volumetric and MD changes are more dynamic in rhesus monkeys compared with humans, with marked decreases followed by "rebound-like" increases.

Diet, psychosocial stress, and Alzheimer's disease-related neuroanatomy in female nonhuman primates.

INTRODUCTION: Associations between diet, psychosocial stress, and neurodegenerative disease, including Alzheimer's disease (AD), have been reported, but causal relationships are difficult to determine in human studies. METHODS: We used structural magnetic resonance imaging in a well-validated non-human primate model of AD-like neuropathology to examine the longitudinal effects of diet (Mediterranean vs Western) and social subordination stress on brain anatomy, including global volumes, cortical thicknesses and volumes, and 20 individual regions of interest (ROIs). RESULTS: Western diet resulted in greater cortical thicknesses, total brain volumes, and gray matter, and diminished cerebrospinal fluid and white matter volumes. Socially stressed subordinates had smaller whole brain volumes but larger ROIs relevant to AD than dominants. DISCUSSION: The observation of increased size of AD-related brain areas is consistent with similar reports of mid-life volume increases predicting increased AD risk later in life. While the biological mechanisms underlying the findings require future investigation, these observations suggest that Western diet and psychosocial stress instigate pathologic changes that increase risk of AD-associated neuropathology, whereas the Mediterranean diet may protect the brain.

Impact of brain metastasis velocity on neurologic death for brain metastasis patients experiencing distant brain failure after initial stereotactic radiosurgery.

PURPOSE: Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS). METHODS: From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment. RESULTS: Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p < 0.01), and 31% vs 48% (p < 0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01). CONCLUSION: Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.

Hippocampal CA1 and CA3 neural recording in the human brain: validation of depth electrode placement through high-resolution imaging and electrophysiology.

OBJECTIVE: Intracranial human brain recordings typically utilize recording systems that do not distinguish individual neuron action potentials. In such cases, individual neurons are not identified by location within functional circuits. In this paper, verified localization of singly recorded hippocampal neurons within the CA3 and CA1 cell fields is demonstrated. METHODS: Macro-micro depth electrodes were implanted in 23 human patients undergoing invasive monitoring for identification of epileptic seizure foci. Individual neurons were isolated and identified via extracellular action potential waveforms recorded via macro-micro depth electrodes localized within the hippocampus. A morphometric survey was performed using 3T MRI scans of hippocampi from the 23 implanted patients, as well as 46 normal (i.e., nonepileptic) patients and 26 patients with a history of epilepsy but no history of depth electrode placement, which provided average dimensions of the hippocampus along typical implantation tracks. Localization within CA3 and CA1 cell fields was tentatively assigned on the basis of recording electrode site, stereotactic positioning of the depth electrode in comparison with the morphometric survey, and postsurgical MRI. Cells were selected as candidate CA3 and CA1 principal neurons on the basis of waveform and firing rate characteristics and confirmed within the CA3-to-CA1 neural projection pathways via measures of functional connectivity. RESULTS: Cross-correlation analysis confirmed that nearly 80% of putative CA3-to-CA1 cell pairs exhibited positive correlations compatible with feed-forward connection between the cells, while only 2.6% exhibited feedback (inverse) connectivity. Even though synchronous and long-latency correlations were excluded, feed-forward correlation between CA3-CA1 pairs was identified in 1071 (26%) of 4070 total pairs, which favorably compares to reports of 20%-25% feed-forward CA3-CA1 correlation noted in published animal studies. CONCLUSIONS: This study demonstrates the ability to record neurons in vivo from specified regions and subfields of the human brain. As brain-machine interface and neural prosthetic research continues to expand, it is necessary to be able to identify recording and stimulation sites within neural circuits of interest.

PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains.

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer's disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0-120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the "test" and "retest" data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.