Hippocampal Volume Reduction Research Articles

Identifying Morphological Patterns of Hippocampal Atrophy in Patients With Mesial Temporal Lobe Epilepsy and Alzheimer Disease.

Purpose: Mesial temporal lobe epilepsy (MTLE) and Alzheimer's disease (AD) are two distinct neurological disorders associated with hippocampal atrophy. Our goal is to analyze the morphologic patterns of hippocampal atrophy to better understand the underlying pathological and clinical characteristics of the two conditions.Methods: Twenty-five patients with AD and 20 healthy controls with matched age and gender were recruited into the AD group. Twenty-three MTLE patients and 28 healthy controls with matched age and gender were recruited into the MTLE group. All subjects were scanned on 3T-MRI scanner. Automated volumetric analysis was applied to measure and compare the hippocampal volume of the two respective groups. Vertex-based morphologic analysis was applied to characterize the morphologic patterns of hippocampal atrophy within and between groups, and a correlation analysis was performed.Results: Volumetric analysis revealed significantly decreased hippocampal volume in both AD and MTLE patients compared to the controls. In the patients with AD, the mean total hippocampal volume was 32.70% smaller than that of healthy controls, without a significant difference between the left and the right hippocampus (p < 0.05). In patients with MTLE, a significant reduction in unilateral hippocampal volume was observed, with a mean volume reduction of 28.38% as compared with healthy controls (p < 0.05). Vertex-based morphologic analysis revealed a generalized shrinkage of the hippocampi in AD patients, especially in bilateral medial and lateral regions. In MTLE group, atrophy was seen in the ipsilateral head, ipsilateral lateral body and slightly contralateral tail of the hippocampus (FWE-corrected, p < 0.05).Conclusions: MTLE and AD have distinctive morphologic patterns of hippocampal atrophy, which provide new insight into the radiology-pathology correlation in these diseases.

Handgrip Strength Is Associated With Hippocampal Volume and White Matter Hyperintensities in Major Depression and Healthy Controls: A UK Biobank Study.

Emerging evidence suggests that handgrip strength (a proxy for muscular fitness) is associated with better cognitive performance in people with major depressive disorder (MDD). The underlying processes are unclear, although hippocampal volume (HCV) reductions and white matter hyperintensities (WMHs) have been implicated. Therefore, we investigated the associations between handgrip strength and various brain region volumes and WMHs in MDD and healthy controls (HCs). This study is a cross-sectional analysis of handgrip strength and neuroimaging data from the UK Biobank. Generalized linear models were used to assess the relationship between grip strength and gray matter, white matter, total brain volume, left and right hippocampus volume, and WMHs in MDD and HCs, adjusting for age, sex, education, and body weight. The sample included 527 people with MDD (54.3 ± 7.3 years, 37.2% male) and 1764 HCs (56.6 ± 7.2 years, 53% male). In MDD, stronger handgrip was significantly associated with increased left (coefficient ± SE = 108.1 ± 27.6, t = 3.92) and right (76.8 ± 30.4, t = 2.53) HCV. In HCs, only right HCV related to handgrip strength (44.8 ± 18.1, t = 2.47). Interaction analyses found stronger associations between grip strength and HCV in MDD compared with HCs, for both hippocampal regions. Stronger handgrip was associated with reduced WMHs in people with MDD (-0.24 ± 0.07, t = -3.24) and HCs (-0.11 ± 0.04, t = -2.47). Maximal handgrip strength was not associated with gray matter, white matter, or total brain volumes in either group. Stronger grip strength is associated with greater left and right HCV and reduced WMHs in MDD. Future research should investigate directionality and consider if interventions targeting strength/muscular fitness can improve brain health and reduce the neurocognitive abnormalities associated with MDD.

Mesial temporal lobe epilepsy: Revisiting the relation of hippocampal volumetry with memory deficits

ObjectiveNeuropsychological tests can infer the lateralization of the epileptogenic focus, associating verbal memory to mesial structures in the left temporal lobe and visual or nonverbal memory to the right side. High-field magnetic resonance imaging (MRI) with high-resolution protocols allows acquisitions suitable for advanced postprocessing with precise volumetry of brain structures, and functional MRI demonstrates evidence that epilepsy should be seen as a network pathology, involving several structures in the brain. Since the literature showing associations between the volumetry of brain structures in left and right mesial temporal lobe epilepsy (MTLE) and verbal and visual memory performance on neuropsychological tests is conflicting, we revisited these relationships, considering the hippocampal volumetry of patients with unilateral MTLE. MethodsAutomatized hippocampal volumes were obtained using FreeSurfer software from MRI exams of 35 patients with unilateral MTLE and hippocampal atrophy and homolateral ictal onset zone defined by video electroencephalography concordant to the side of hippocampal volume reduction (15 on the left side). Verbal memory was assessed using the Rey Auditory-Verbal Learning Test (RAVLT), and visual memory tests employed the Rey–Osterrieth Complex Figure Test (ROCFT). The statistical analysis explored relationships between hippocampal volumetry, lateralization, and performance on memory tests. ResultsIn general, we observed deficits in both verbal and visual memory for patients with left and right hippocampal volume reduction. Patients with left hippocampal volume reduction had poorer performance on verbal memory tests compared with those with right hippocampal atrophy (t = −3.813, p < 0.001). Visual memory deficits were seen on both left and right MTLE without a statistically significant difference (t = 0.074, p = 0.942). The correlation between the Hippocampal Asymmetry Index (HAI) and visual and verbal Z-scores was significant only for visual Z-score in right MTLE (R = −0.45, p = 0.048). ConclusionsVerbal memory deficit seems to be more consistent in patients with left hippocampal volume reduction. Although it had only a moderate correlation to HAI, visual memory deficit is suggested as a poorer indicator for right MTLE. Considering that verbal and visual memory deficits are seen on both right and left MTLE, MTLE should not be regarded as a unilateral, focal, or local insult but as a multifactorial and network pathology, possibly involving several brain structures.

Transient Hypoxemia Disrupts Anatomical and Functional Maturation of Preterm Fetal Ovine CA1 Pyramidal Neurons.

Children who survive premature birth often exhibit reductions in hippocampal volumes and deficits in working memory. However, it is unclear whether synaptic plasticity and cellular mechanisms of learning and memory can be elicited or disrupted in the preterm fetal hippocampus. CA1 hippocampal neurons were exposed to two common insults to preterm brain: transient hypoxia-ischemia (HI) and hypoxia (Hx). We used a preterm fetal sheep model using both sexes in twin 0.65 gestation fetuses that reproduces the spectrum of injury and abnormal growth in preterm infants. Using Cavalieri measurements, hippocampal volumes were reduced in both Hx and HI fetuses compared with controls. This volume loss was not the result of neuronal cell death. Instead, morphometrics revealed alterations in both basal and apical dendritic arborization that were significantly associated with the level of systemic hypoxemia and metabolic stress regardless of etiology. Anatomical alterations of CA1 neurons were accompanied by reductions in probability of presynaptic glutamate release, long-term synaptic plasticity and intrinsic excitability. The reduction in intrinsic excitability was in part due to increased activity of the channels underlying the fast and slow component of the afterhyperpolarization in Hx and HI. Our studies suggest that even a single brief episode of hypoxemia can markedly disrupt hippocampal maturation. Hypoxemia may contribute to long-term working memory disturbances in preterm survivors by disrupting neuronal maturation with resultant functional disturbances in hippocampal action potential throughput. Strategies directed at limiting the duration or severity of hypoxemia during brain development may mitigate disturbances in hippocampal maturation.SIGNIFICANCE STATEMENT Premature infants commonly sustain hypoxia-ischemia, which results in reduced hippocampal growth and life-long disturbances in learning and memory. We demonstrate that the circuitry related to synaptic plasticity and cellular mechanisms of learning and memory (LTP) are already functional in the fetal hippocampus. Unlike adults, the fetal hippocampus is surprisingly resistant to cell death from hypoxia-ischemia. However, the hippocampus sustains robust structural and functional disturbances in the dendritic maturation of CA1 neurons that are significantly associated with the magnitude of a brief hypoxic stress. Since transient hypoxic episodes occur commonly in preterm survivors, our findings suggest that the learning problems that ensue may be related to the unique susceptibility of the hippocampus to brief episodes of hypoxemia.

Mesenchymal Stem Cells Therapy Improved the Streptozotocin-Induced Behavioral and Hippocampal Impairment in Rats.

Sporadic Alzheimer's disease (sAD) is the most prevalent neurodegenerative pathology with no effective therapy until date. This disease promotes hippocampal degeneration, which in turn affects multiple cognitive domains and daily life activities. In this study, we hypothesized that long-lasting therapy with mesenchymal stem cells (MSC) would have a restorative effect on the behavioral alterations and cognitive decline typical of sAD, as they have shown neurogenic and immunomodulatory activities. To test this, we chronically injected intravenous human MSC in a sAD rat model induced by the intracerebroventricular injection of streptozotocin (STZ). During the last 2weeks, we performed open field, Barnes maze, and marble burying tests. STZ-treated rats displayed a poor performance in all behavioral tests. Cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble burying behavior, the latter being representative of daily life activities. On the hippocampus, we found that STZ promotes neuronal loss in the Cornus Ammoni (CA1) field and decreased neurogenesis in the dentate gyrus. Also, STZ induced a reduction in hippocampal volume and presynaptic protein levels and an exacerbated microgliosis, relevant AD features. The therapy rescued CA1 neurodegeneration but did not reverse the decrease of immature neurons, suggesting that the therapy effect varied among hippocampal neuronal populations. Importantly, cell therapy ameliorated microgliosis and restored hippocampal atrophy and some presynaptic protein levels in the sAD model. These findings, by showing that intravenous injection of human MSC restores behavioral and hippocampal alterations in experimental sAD, support the potential use of MSC therapy for the treatment of neurodegenerative diseases.

Abnormal hippocampal structure and function in juvenile myoclonic epilepsy and unaffected siblings.

Juvenile myoclonic epilepsy is the most common genetic generalized epilepsy syndrome, characterized by a complex polygenetic aetiology. Structural and functional MRI studies demonstrated mesial or lateral frontal cortical derangements and impaired fronto-cortico-subcortical connectivity in patients and their unaffected siblings. The presence of hippocampal abnormalities and associated memory deficits is controversial, and functional MRI studies in juvenile myoclonic epilepsy have not tested hippocampal activation. In this observational study, we implemented multi-modal MRI and neuropsychological data to investigate hippocampal structure and function in 37 patients with juvenile myoclonic epilepsy, 16 unaffected siblings and 20 healthy controls, comparable for age, gender, handedness and hemispheric dominance as assessed with language laterality indices. Automated hippocampal volumetry was complemented by validated qualitative and quantitative morphological criteria to detect hippocampal malrotation, assumed to represent a neurodevelopmental marker. Neuropsychological measures of verbal and visuo-spatial learning and an event-related verbal and visual memory functional MRI paradigm addressed mesiotemporal function. We detected a reduction of mean left hippocampal volume in patients and their siblings compared with controls (P < 0.01). Unilateral or bilateral hippocampal malrotation was identified in 51% of patients and 50% of siblings, against 15% of controls (P < 0.05). For bilateral hippocampi, quantitative markers of verticalization had significantly larger values in patients and siblings compared with controls (P < 0.05). In the patient subgroup, there was no relationship between structural measures and age at disease onset or degree of seizure control. No overt impairment of verbal and visual memory was identified with neuropsychological tests. Functional mapping highlighted atypical patterns of hippocampal activation, pointing to abnormal recruitment during verbal encoding in patients and their siblings [P < 0.05, familywise error (FWE)-corrected]. Subgroup analyses indicated distinct profiles of hypoactivation along the hippocampal long axis in juvenile myoclonic epilepsy patients with and without malrotation; patients with malrotation also exhibited reduced frontal recruitment for verbal memory, and more pronounced left posterior hippocampal involvement for visual memory. Linear models across the entire study cohort indicated significant associations between morphological markers of hippocampal positioning and hippocampal activation for verbal items (all P < 0.05, FWE-corrected). We demonstrate abnormalities of hippocampal volume, shape and positioning in patients with juvenile myoclonic epilepsy and their siblings, which are associated with reorganization of function and imply an underlying neurodevelopmental mechanism with expression during the prenatal stage. Co-segregation of abnormal hippocampal morphology in patients and their siblings is suggestive of a genetic imaging phenotype, independent of disease activity, and can be construed as a novel endophenotype of juvenile myoclonic epilepsy.

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease

Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures. ClinicalTrials.gov identifier: NCT02167256.

Evaluation of hippocampal volume and serum brain-derived neurotrophic factor as potential diagnostic markers of conversion from amnestic mild cognitive impairment to Alzheimer disease: A STROBE-compliant article.

Amnestic mild cognitive impairment (aMCI) is a transitional stage between normal aging and Alzheimer disease (AD), and is associated with an increased risk of AD. Many studies have shown that apolipoprotein E epsilon 4 (APOE ε4) genotype is a major genetic predictor of AD progression, especially in patients with aMCI. However, the application of APOE genotyping in the diagnosis of MCI progressing to AD is limited by its low sensitivity and specificity, which often leads to high false-positive rate. The aim of this study was to evaluate serum brain-derived neurotrophic factor (BDNF) and hippocampal volume as predictors of aMCI to AD transition in APOE ε4 genotype patients.A total of 178 subjects were diagnosed with aMCI. The patients with aMCI that progressed to AD within 2 years were included in the MCI-AD group (n = 86), those maintaining an aMCI diagnosis after 2 years were placed in the MCI-MCI group (n = 92), and neurologically healthy age-matched individuals were set as controls (n = 90). APOE genotypes were determined. Blood samples from all subjects were drawn at baseline, 12 months, and 24 months for serum BNDF assessments. Hippocampal delineations were monitored by magnetic resonance imaging.Compared to control group, aMCI-AD patients (the patients with aMCI that progressed to AD within 2 years) exhibited worse performance on cognitive and neuropsychological batteries. Meanwhile, we found that aMCI-AD patients were associated with abnormally low serum BDNF level and greater hippocampal volume loss than MCI-MCI patients (patients maintaining an aMCI diagnosis after 2 years). Moreover, patients with aMCI who were carriers of APOE ε4 showed a notable decrease in serum BDNF and a significant reduction in hippocampal volume, especially in those who progressed to AD.The present study demonstrates that aMCI that evolves into AD in patients with the APOE ε4 genotype may be predicted by hippocampal volume and serum BDNF.

Individuals in the prediabetes stage exhibit reduced hippocampal tail volume and executive dysfunction

IntroductionHigh glucose levels are associated with cognitive impairment and total hippocampal volume reductions. However, the effects of the blood glucose level on hippocampal subfield volumes remain unclear, especially in the prediabetes stage.MethodsSixty participants were enrolled in this cross‐sectional study and were divided into the nondiabetes, prediabetes, and diabetes groups according to their medical history and A1c level. A full battery of neuropsychological tests was used to assess the global cognition, executive function, attention, verbal fluency, working memory, immediate memory, and delayed memory. FreeSurfer 6.0 was used for the hippocampus parcellation. Hippocampal subfield volumes were adjusted by intracranial volume. Analyses of covariance, multiple linear regression, and partial correlation analysis were used to explore the relationship between A1c level, cognitive function, and hippocampal subfields volume, in which age, sex, education years, body mass index, history of hypertension, level of cholesterol, and the presence of ApoE4‐positive status were adjusted.ResultsSignificant differences in the total left hippocampal volume (p = 0.046) and left hippocampal tail volume (p = 0.014) were noted among three groups. Significant correlation was identified between the A1c level and the volume of left hippocampal tail (r = −0.334, p = 0.009) after adjusting all the covariants. Increased A1c level was significantly associated with executive dysfunction, as assessed by trail making test B (R = 0.503, p = 0.0016) and Stroop test C (R = 0.506, p = 0.001).ConclusionsOur results support that the left hippocampal tail volume may be served as an early marker of diabetes‐related brain damage, associated with executive dysfunction. Clinicians should pay closer attention to adults in the prediabetes stage to prevent later cognitive impairment.

Hippocampal Volume, Cognitive Functions, Depression, Anxiety, and Quality of Life in Patients With Cushing Syndrome.

Cushing syndrome (CS) is associated with hippocampal atrophy and psychopathology. The primary objective of this systematic review was to assess hippocampal volume (HV) in patients with CS. The secondary objectives were to assess patients' cognitive functioning, depressive and anxiety symptoms, and quality of life. PubMed, Embase, Cochrane, LILACs, and Scopus databases were searched for relevant studies until 1 May 2019. Case-control studies comparing patients with CS with healthy control subjects, or studies assessing patients with CS before and after surgery were included. The initial search resulted in 18 studies fulfilling the inclusion criteria. Data extraction regarding all outcomes was performed independently by two reviewers. Quality assessment was assessed with the Newcastle-Ottawa Scale for case-control studies. Meta-analysis was performed using a random effect model. The right-side HV in patients with CS was reduced by a standard mean difference of 0.68 (95% CI, -1.12 to -0.24; P = 0.002; I2 = 0%) compared with healthy control subjects, but with no increase in HV after surgery. Patients had more depressive symptoms, impaired cognitive functions, and reduced health-related QoL (HRQoL), which all responded favorably to surgery. The data did not support the presence of anxiety in patients with CS. An overall reduction of HV in patients with CS was not suggested by the study findings. However, most cognitive domains were significantly affected and responded favorably to surgery. Depressive symptoms and reduced HRQoL were present in patients with CS and improved after surgery.

Potential Value of Plasma Amyloid-β, Total Tau, and Neurofilament Light for Identification of Early Alzheimer's Disease.

The objective of the study was to explore the potential value of plasma indicators for identifying amnesic mild cognitive impairment (aMCI) and determine whether levels of plasma indicators are related to the performance of cognitive function and brain tissue volumes. In total, 155 participants (68 aMCI patients and 87 health controls) were recruited in the present cross-sectional study. The levels of plasma amyloid-β (Aβ) 40, Aβ42, total tau (t-tau), and neurofilament light (NFL) were measured using an ultrasensitive quantitative method. Machine learning algorithms were performed for establishing an optimal model of identifying aMCI. Compared with healthy controls, Aβ40 and Aβ42 levels were lower and NFL levels were higher in plasma of aMCI patients with an exception of t-tau levels. In aMCI patients, the higher plasma Aβ40 levels were correlated with the impaired episodic memory and negative correlations were observed between plasma t-tau levels and global cognitive function and gray matter (GM) volume. In addition, the higher plasma NFL levels were correlated with reduced hippocampus volume and total GM volume of the left inferior and middle temporal gyrus. An integrated model included clinical features, hippocampus volume, and plasma Aβ42 and NFL and had the highest accuracy for detecting aMCI patients (accuracy, 74.2%). We demonstrated that plasma Aβ40, Aβ42, t-tau, and NFL may be useful to identify aMCI and correlate with cognitive decline and brain atrophy. Among these plasma indicators, Aβ42 and NFL are more valuable as key members of a peripheral biomarker panel to detect aMCI.

Ketaminaren eragin antidepresiboak. Ekintza mekanismo berriak farmako antidepresiboen bilaketarako

Beste Medikuntza-arloetan ez bezala, Psikiatrian gaixotasun psikiatrikoei buruzko hipotesi etiologikoak ebidentzia farmakologikoetan oinarritzen dira. Horrela, 1950eko hamarkadan depresioaren kontrako farmakoak garatzen hasi ziren, behin ikusita zer-nolako eraginak zituzten tuberkulosiaren kontrako farmako batzuek. Lehenengo antidepresiboek neuro-transmisio monoaminergikoa bultzatzen zutenez, hipotesi monoaminergikoa sortu zen, eta depresioari buruzko ikerkuntzak serotoninaren, noradrenalinaren eta dopaminaren (monoaminen) gutxiagotzea hartu zuen oinarri. Orduz geroztik hipotesi monoaminergikoak, eta bere bariazioek, farmako antidepresiboen garapena baldintzatu dute. Hala ere, azkeneko urteetan egindako ikerketek erakutsi dute estresak eta depresioak neuronen atrofia eta galera eragiten dutela, eta horrekin batera kortex eta sistema linbikoaren bolumena murrizten dela. Ebidentzia berri hauen arabera, depresioa ez litzateke izango garuneko gune zehatz bateko asaldura hutsa, baizik eta gogo aldartea, kognizioa eta oroimenak kontrolatzen dituzten zirkuitu neuronalen asaldura. Depresioari buruzko azkeneko ikerketa preklinikoek eta klinikoek agerian jarri dute ketaminak (anestesiko disoziatiboa) eragin antidepresibo harrigarriak dituela, azkarrak eta iraunkorrak. Oinarrizko ikerketek ketaminak sinapsi konexioak oso azkar handitzen dituela frogatu dute, depresioan antzemandako neurona-atrofia leheneratzen dutela. Ebidentzia hauek farmako antidepresibo berrien bilaketa berpiztu dute, eta hainbat mekanismo berri proposatu dira helburu horretarako.

Hippocampal volume and depression among young children

Clinical depression can occur in young children as early as age three. This very early onset variant of depression shows the same clinical features with developmental adjustments as depression that onsets later in life. One robust neural feature of adult depression is reduced hippocampal volume. We measured hippocampal volume in a sample of 35 children aged 4–7 who were either in a clinical trial for preschool onset depression or were recruited from the community. We used T1 MPRAGE acquisitions on a Siemen's Scanner, with Freesurfer 5.3 used to segment the hippocampus. Depression was measured using the K-SADS early childhood (K-SADS-EC) to create a dimensional depression severity score and the Child Behavior Checklist (CBCL) Depression T-Score. Multilevel models indicated that greater depression severity as measured by either the CBCL Depression Score or the K-SADS-EC was associated with lower hippocampal volume, even controlling for total gray matter, maternal depression, income-to-needs ratio, and stressful life events. These data indicate evidence for reduced hippocampal volume among children with PO-MDD who were more severely depressed. Findings are consistent with the idea that hippocampal volume reductions are an early occurring associated neural marker of MDD, particularly for more severe depression.

Polygenic risk for circulating reproductive hormone levels and their influence on hippocampal volume and depression susceptibility

Altered reproductive hormone levels have been associated with the pathophysiology of depressive disorders and this risk may be imparted by their modulatory effect upon hippocampal structure and function. Currently it is unclear whether altered levels of reproductive hormones are causally associated with hippocampal volume reductions and the risk of depressive disorders. Here, we utilize genome-wide association study (GWAS) summary statistics from a GWAS focusing on reproductive hormones, consisting of 2913 individuals. Using this data, we generated polygenic risk scores (PRS) for estradiol, progesterone, prolactin and testosterone in the European RADIANT cohort consisting of 176 postpartum depression (PPD) cases (100% female, mean age: 41.6 years old), 2772 major depressive disorder (MDD) cases (68.6% female, mean age: 46.9 years old) and 1588 control participants (62.5% female, mean age: 42.4 years old), for which there was also a neuroimaging subset of 111 individuals (60.4% female, mean age: 50.0 years old). Only the best-fit PRS for estradiol showed a significant negative association with hippocampal volume, as well as many of its individual subfields; including the molecular layer and granule cell layer of the dentate gyrus, subiculum, CA1, CA2/3 and CA4 regions. Interestingly, several of these subfields are implicated in adult hippocampal neurogenesis. When we tested the same estradiol PRS for association with case-control status for PPD or MDD there was no significant relationship observed. Here, we provide evidence that genetic risk for higher plasma estradiol is negatively associated with hippocampal volume, but this does not translate into an increased risk of MDD or PPD. This work suggests that the relationship between reproductive hormones, the hippocampus, and depression is complex, and that there may not be a clear-cut pathway for etiology or risk moderation.

Social Network Position Moderates the Relationship between Late-life Depressive Symptoms and Memory Differently in Men and Women

Late-life depression has been considered to be associated with memory deficits and hippocampal volume reduction. Considering that not all depression patients undergo the same amount of cognitive impairment or regional brain volume loss, moderating factors such as complex mental activity and social activity have been examined to assess whether these factors attenuate the detrimental impact of depressive symptoms on cognitive function and regional brain volume. However, the premise that a cognitively stimulating experience may modify the association between depressive symptoms and memory or hippocampal volume has not been investigated using social network data, which would reflect individuals’ concrete characteristic of everyday social activity. In a social network, a brokerage position which connects two otherwise unconnected others demands mental and physical efforts. Using complete social network data in an entire village in South Korea, we examined whether opportunities for brokerage in social networks alter the negative association between depressive symptoms and episodic memory function or hippocampal volume in older adults. Initially, 125 participants were included in the analysis involving episodic memory function. Then, of which 65 participants completed the MRI scan, and were included in the subsequent analysis containing the hippocampal volume. Furthermore, we investigated the gender-specific effect of brokerage based on the previously reported gender difference in the effect of social networks. We found a gender-specific moderating effect of brokerage. For men, a large opportunity for brokerage weakened the negative association between depressive symptoms and memory performance and left hippocampal volume. In contrast, women showed that a large opportunity for brokerage was not beneficial for assuaging the impact of depressive symptoms on memory performance and hippocampal volume. In women, the opportunity for brokerage was positively associated with the detrimental impact of depressive symptoms on memory performance and hippocampal volume. Our findings suggest that occupying a bridging position in a social network may minimize the impact of depressive symptoms on memory function and hippocampal volume among older men, whereas the opposite holds true for older women.

COGNITIVE AND NEURAL MECHANISMS OF THE ACCELERATED AGING PHENOTYPE IN PTSD

Introduction Posttraumatic Stress Disorder (PTSD) affects 6.8% of adults in the United States and is associated with high rates of disability, comorbid medical and psychiatric disorders, and suicide. Older adults make up an increasingly large proportion of PTSD patients as the population skews older and Veterans from recent conflicts age. PTSD in older adults is often chronic, leads to increased mortality from cardiovascular disease and other medical conditions, and promotes adverse aging associated syndromes such as frailty. Moreover, older PTSD patients exhibit faster cognitive decline and have twice the risk of dementia compared to individuals without PTSD. Accelerated biological aging may explain these findings, as PTSD is associated with similar brain changes to those occurring with cognitive aging, including bilateral hippocampal volume reductions specifically in the cornu ammonis 3 (CA3) and dentate gyrus (DG) sub-regions and increased microvascular lesions (white matter hyperintensities). The goal of this presentation is to describe ongoing work from our laboratories characterizing the mechanisms by which PTSD accelerates aging cognitively and physically. We will present data linking cognitive dysfunction in PTSD with indicators of brain health such as DG CBV and increased white matter hyperintensities and physical decline with increased levels of inflammation and oxidative stress. Methods To date. N=17 adults 50 years and older with PTSD and N=9 trauma exposed healthy controls (TEHCs) have undergone testing to assess cognitive function and physical performance. Neuropsychological testing and magnetic resonance imaging (MRI) including cerebral blood volume (CBV)-fMRI were used to assess cognitive function and brain health. Neuropsychology testing included a modified form of the Benton Visual Retention Task (ModBent), a task that has been validated as a measure of DG function relative to age. Tasks such as gait speed and tests of strength, including grip strength and the short physical performance battery, were used to assess physical decline. Inflammatory markers IL-6, CRP, and telomere length, and urinary isoprostanes, a measure of oxidative stress, were also used to examine physical decline. Measures were compared between the PTSD patients and trauma exposed healthy controls. We expect to substantially increase the sample size available for presentation by the time of the Annual Meeting. Results Enrolled PTSD subjects to date show deficits in every cognitive domain when compared to the TEHC, particularly on measures of processing speed and executive function, where their performance is > 1 SD below that of age-matched TEHCs. CBV fMRI (N=15) analyzed to date shows PTSD patients to have diminished DG CBV compared to TEHC, and lower DG CBV is associated with increasing symptom severity as measured by the Clinician Administered PTSD Scale (r=-0.49). Reaction time on ModBent increased (worsened) with increasing symptom severity (r=0.50). Overall hippocampus volume is smaller in PTSD patients than TEHC (d=-.23), although PTSD patients have on average greater ICV (d=0.30). PTSD patients also display deficits in every physical performance task compared to the TEHC patients and report reduced physical activity and worse physical conditions. PTSD patients have higher levels of inflammatory markers IL-6 (d=0.18) and CRP (d=0.25) as well as urinary isoprostanes (d=0.05), a marker of oxidative stress. Conclusions These data indicate that PTSD, particularly chronic PTSD, is associated with unhealthy aging trajectories. These findings are consistent with the hypothesis that older adults with PTSD have marked neurocognitive and physiologic performance decrements compared to age-matched TEHC. This research was funded by NIMH. PDF: http://submissions.mirasmart.com/Verify/AAGP2019/Original/AAGP2019-000325/AAGP2019-000325_Fig1.pdf

A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss.

The understanding of the natural history of Alzheimer’s disease (AD) and temporal trajectories of in vivo molecular mechanisms requires longitudinal approaches. A behavioral and multimodal imaging study was performed at 4/8/12 and 16 months of age in a triple transgenic mouse model of AD (3xTg-AD). Behavioral assessment included the open field and novel object recognition tests. Molecular characterization evaluated hippocampal levels of amyloid β (Aβ) and hyperphosphorylated tau. Magnetic resonance imaging (MRI) included assessment of hippocampal structural integrity, blood–brain barrier (BBB) permeability and neurospectroscopy to determine levels of the endogenous neuroprotector taurine. Longitudinal brain amyloid accumulation was assessed using 11C Pittsburgh compound B positron emission tomography (PET), and neuroinflammation/microglia activation was investigated using 11C-PK1195. We found altered locomotor activity at months 4/8 and 16 months and recognition memory impairment at all time points. Substantial early reduction of hippocampal volume started at month 4 and progressed over 8/12 and 16 months. Hippocampal taurine levels were significantly decreased in the hippocampus at months 4/8 and 16. No differences were found for amyloid and neuroinflammation with PET, and BBB was disrupted only at month 16. In summary, 3xTg-AD mice showed exploratory and recognition memory impairments, early hippocampal structural loss, increased Aβ and hyperphosphorylated tau and decreased levels of taurine. In sum, the 3xTg-AD animal model mimics pathological and neurobehavioral features of AD, with early-onset recognition memory loss and MRI-documented hippocampal damage. The early-onset profile suggests temporal windows and opportunities for therapeutic intervention, targeting endogenous neuroprotectors such as taurine.

Blood pressure variability and brain morphology in elderly women without cardiovascular disease.

To examine the relationship between blood pressure (BP) variability (BPV), brain volumes, and cognitive functioning in postmenopausal women with few modifiable cardiovascular risk factors. Study participants consisted of postmenopausal women enrolled in the Women's Health Initiative Memory MRI study (WHIMS-MRI) without cardiovascular disease, diabetes mellitus, hypertension, or current smoking at baseline (1996-1999). BP readings were taken at baseline and each annual follow-up visit. BPV was defined as the SD associated with a participant's mean BP across visits and the SD associated with the participant's regression line with BP regressed across visits. Brain MRI scans were performed between 2004 and 2006. Cognitive functioning was assessed at baseline and annually thereafter with the Modified Mini-Mental State Examination (3MSE) scoring until 2008. The final sample consisted of 558 women (mean age 69 years, median follow-up time [interquartile range] 8 [0.8] years). In adjusted models including mean systolic BP, women in the highest tertile of systolic BPV had lower hippocampal volumes and higher lesion volumes compared to women in the lowest tertile. No relationship between BPV and 3MSE scoring was detected. In postmenopausal women with few modifiable cardiovascular risk factors, greater visit-to-visit systolic BPV was associated with reductions in hippocampal volume and increases in lesion volumes at later life. These data add evidence to the emerging importance of BPV as a prognostic indicator even in the absence of documented cardiovascular risk factors.

Effect of stress gene-by-environment interactions on hippocampal volumes and cortisol secretion in adolescent girls.

Adolescence is a time of increased susceptibility to environmental stress and mood disorders, and girls are particularly at risk. Genes interacting with the environment (G × E) are implicated in hypothalamic-pituitary-adrenal axis dysregulation, hippocampal volume changes and risk or resilience to mood disorders. In this study, we assessed the effects of stress system G × E interactions on hippocampal volumes and cortisol secretion in adolescent girls. We recruited 229 girls aged 12-18 years, and scans were obtained from 202 girls. Of these, 76 had been exposed to higher emotional trauma (abuse or neglect). Hippocampal volumes were measured using Freesurfer and high-resolution structural magnetic resonance imaging scans. Saliva samples were collected for measurement of cortisol levels and genotyping of stress system genes: FKBP5, NR3C1 (both N = 194) and NR3C2 ( N = 193). Among girls with the 'G' allelic variant of the NR3C1 gene, those who had been exposed to higher emotional trauma had significantly smaller left hippocampal volumes ( N = 44; mean = 4069.58 mm3, standard deviation = 376.99) than girls who had been exposed to minimal emotional trauma with the same allelic variant ( N = 69; mean = 4222.34 mm3, standard deviation = 366.74). In healthy adolescents, interactions between emotional trauma and the 'protective' NR3C1 'GG' variant seem to induce reductions in left hippocampal volumes. These G × E interactions suggest that vulnerability to mood disorders is perhaps driven by reduced 'protection' that may be specific to emotional trauma. This novel but preliminary evidence has implications for targeted prevention of mood disorders and prospective multimodal neuroimaging and longitudinal studies are now needed to investigate this possibility.

Hippocampal subfield volumes in major depressive disorder and bipolar disorder

BackgroundThe hippocampus is not a uniform structure, but rather consists of multiple, functionally specialized subfields. Few studies have explored hippocampal subfield volume difference in the same sample of major depressive disorder (MDD) and bipolar disorder (BD) cases. We aimed to investigate the difference of hippocampal subfield volume between patents with MDD and BD and healthy controls (HCs). MethodsA total of 102 MDD and 55 BD patients and 135 HCs were recruited and underwent T1-weighted image. Hippocampal subfield volume was calculated by automated segmentation and volumetric procedures developed by Iglesias et al. and implemented in FreeSurfer. Volume differences between the groups were analyzed using the analysis of covariance and controlling for age, sex, and total intracranial cavity volume. ResultsPatients with MDD had significantly reduced volumes in the bilateral cornu ammonis 1 (CA1), CA4, the granule cell layer (GCL), molecular layer (ML), whole hippocampus, the left CA2/3, and right presubiclum and subiculum. Patients with BD had significantly reduced volumes in the right CA1, GCL, and the whole hippocampus as compared to HCs. No significant volume differences were observed between the MDD and BD groups. Illness duration was negatively correlated with volumes of the left CA1, CA4, ML, presubiculum, subiculum, and the whole hippocampus in patients with BD. ConclusionWe observed hippocampal subfield volume reductions in both MDD and BD, a finding which more prominent in MDD. The inverse correlation between BD illness duration and hippocampal subfield volume may evidence the neuroprogressive nature of BD.