Hippocampal Volume Research Articles

The association between childhood adversity and hippocampal volumes is moderated by romantic relationship experiences

AbstractReduced hippocampal volumes are a feature of many mental disorders. Childhood maltreatment is a known risk factor for the development of psychopathology and has consistently been linked to hippocampal volume reductions in adults, but not in children and adolescents. We propose that maltreatment‐related difficulties in coping with developmental tasks in adolescence and young adulthood might underlie the delayed emergence of hippocampal volume reductions in maltreated individuals. In a study with 196 healthy young adults (mean age [years]: 24.0 ± 3.2, 50% female, 20.6% living with a partner (missings: n = 2)), we investigated the interaction between childhood maltreatment (Childhood Trauma Screener) and the breakup of a steady romantic relationship (List of Threatening Experiences Questionnaire) on hippocampal magnetic resonance imaging grey matter volumes. The experience of a romantic relationship breakup moderated the association between childhood maltreatment and bilateral hippocampal volumes, revealing more negative associations with hippocampal volumes in participants with at least one breakup compared to those with no breakup experience (right hippocampus: β = − 0.05 ± 0.02, p = 0.031, p (FDR) = 0.031; left hippocampus: β = −0.06 ± 0.02, p = 0.005, p (FDR) = 0.009). Moreover, our findings provide some evidence that childhood maltreatment is related to smaller bilateral hippocampal volumes only in those adults who suffered from a relationship breakup (right hippocampus: β = −0.23 ± 0.10, p = 0.018, p (FDR) = 0.018; left hippocampus: β = −0.24 ± 0.10, p = 0.016, p (FDR) = 0.018;). Our study highlights the interaction of adult social bonds with early adversity on vulnerability to psychopathology.

Dysregulated Neurofluid Coupling as a New Noninvasive Biomarker for Primary Progressive Aphasia.

Accumulation of pathological tau is one of the primary causes of Primary Progressive Aphasia (PPA). The glymphatic system is crucial for removing metabolite waste from the brain whereas impairments in glymphatic clearance in PPA are poorly understood. Thus, this study aims to investigate the role of dysregulated macroscopic cerebrospinal fluid (CSF) movement in PPA. Fifty-six PPA individuals and ninety-four healthy controls were included in our analysis after excluding those with excessive head motions during the scan. The coupling strength between blood-oxygen-level-dependent (BOLD) signals in the gray matter and CSF flow was calculated using Pearson correlation and compared between the groups. Its associations with clinical characteristics including scores from Clinical Dementia Rating (CDR), Mini-Mental State Exam, Geriatric Depression Scale and with morphological measures in the hippocampus and entorhinal cortex were examined. PPA subjects exhibited weaker global BOLD-CSF coupling compared to HCs, indicating impairments in glymphatic function in the patients (p = 0.01). In the PPA but not HC group, global BOLD-CSF coupling correlated with the CDR scores (p = 0.04) and hippocampal volume (p = 0.009). The observed decoupling between global brain activity and CSF flow and its association with symptomatology and brain structural changes in PPA converges with previous reports on the same measure in other neurodegenerative diseases. These findings support the potential role of global BOLD-CSF coupling as a noninvasive marker for glymphatic dysregulation in PPA.

Neuroinflammation modifies the relationship between stress and perivascular spaces in an elderly population with different levels of cognitive impairment

BackgroundPerivascular spaces (PVS) are fluid-filled spaces surrounding the brain parenchymal vasculature. Literature suggests that PVS may play a significant role in aging and neurological disorders, including Alzheimer’s disease (AD). The aim of this study is to investigate whether the relationship between MRI-visible PVS and stress is influenced by neuroinflammation in an elderly population with different levels of cognitive impairment.MethodsUsing brain MRI scans acquired at 1.5 T, PVS were quantified in a cohort of 461 individuals, consisting of cognitively healthy controls (n = 48), people with mild cognitive impairment (MCI, n = 322) and Alzheimer’s disease (AD, n = 91). PVS volume fraction was calculated in the basal ganglia and centrum semiovale using a semi-automated segmentation approach. Stress was quantified with levels of salivary cortisol. Inflammatory biomarkers measured from plasma included cytokines, matrix metalloproteinases and C-reactive protein. General linear models were used to test the relationship between PVS and cortisol, when interacting with inflammatory markers. This was done on the whole cohort and within each clinical cognitive group.ResultsIn the centrum semiovale, higher inflammation levels reduced the relationship of cortisol with PVS. In basal ganglia, higher levels of C-reactive protein reduced the negative relationship of cortisol with PVS. All analyses were accounted for age, sex, body mass index (BMI) and total hippocampal volume. There was a significant interaction effect between cortisol and C-reactive protein on PVS volume fraction in the MCI group.DiscussionThese findings suggest an influence of neuroinflammation on the PVS structure in Alzheimer’s disease spectrum, and offer insight for better understanding physiological processes of cognitive impairment onset.

Associations of Amyloid Burden, White Matter Hyperintensities, and Hippocampal Volume With Cognitive Trajectories in the 90+ Study.

Associations of Amyloid Burden, White Matter Hyperintensities, and Hippocampal Volume With Cognitive Trajectories in the 90+ Study.

Role of Cardiovascular Risk in Associations of Brain-Derived Neurotrophic Factor with Longitudinal Brain and Cognitive Trajectories in Older Adults

ABSTRACT Background Higher levels of brain-derived neurotrophic factor (BDNF) have been associated with better neurocognitive outcomes. BDNF is present in cardiovascular tissue, and some evidence suggests it may benefit cardiovascular function. The current study assessed whether there is a mediating and/or moderating role of cardiovascular health in the relationship between BDNF and brain and cognitive outcomes. Method We examined longitudinal data from 397 older adults (aged 54–89;164 females, 233 males) enrolled in the Alzheimer’s Disease Neuroimaging Initiative with available plasma BDNF, medical, neuroimaging, and cognitive assessments. We used path analysis and linear regression to estimate the mediating and moderating roles of two measures of cardiovascular health, the Framingham Risk Score (FRS) and pulse pressure, in the relationships between BDNF and longitudinal changes in brain structure (white matter hyperintensity volume, hippocampal volume, and primary visual cortex volume) and cognitive function (executive function, episodic memory, and language). Results There was no significant association of plasma BDNF with FRS or pulse pressure (ps > 0.31), precluding mediation. There were no robust associations between BDNF and longitudinal change in any brain structural or cognitive measures (ps > .12). Higher FRS was significantly associated with greater increases in WMH volume (ps < .01). FRS and pulse pressure were not associated with any other brain structural or cognitive outcomes (ps > .07). Conclusion These results suggest that cardiovascular health may not play an important role in the influence of BDNF on neurocognitive health in older adults.

Exposure to Sunset Yellow FCF since post-weaning causes hippocampal structural changes and memory impairment in the adult rat: The neuroprotective effects of Coenzyme Q10.

This study aimed to investigate whether exposure to Sunset Yellow FCF (SY) since post-weaning can lead to hippocampal structural changes and memory impairment in adult rat and whether the Coenzyme Q10 (CoQ10) can protect against these adverse effects. The weanling rats were randomly divided into six groups and were treated daily by oral gavage for 6 weeks, as follows: (I) control group, administered distilled water (0.3mL/100 g/day); (II) CoQ10 group, received 10mg/kg/day CoQ10; (III) low SY group, received 2.5mg/kg/day SY; (IV) high SY group, received 70 mg/kg/day SY; (V) low SY + CoQ10 group; and (VI) high SY + CoQ10 group. At the end of the sixth week, the novel object recognition (NOR) test was conducted to evaluate memory. Then, after sacrificing animals, the cerebral hemispheres were removed for stereological study and evaluation of MDA levels. The low and high doses of SY led to significant neuronal loss and a decrease in the volume of the hippocampus (CA1 and DG subregions), as well as increased the MDA level, which was associated with short- and long-term memory impairment. Although, administration of CoQ10 prevented the hippocampal neural loss and volume, and caused a reduction in MDA and improved memory in the low and high SY groups. It seems that CoQ10 could prevent the neuronal loss and hippocampal atrophy caused by post-weaning exposure to SY through preventing oxidative stress, ultimately improving memory impairment in rats.

Elevated serum sodium is linked to increased amyloid-dependent tau pathology, neurodegeneration, and cognitive impairment in Alzheimer's disease.

Vascular dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). While sodium is essential for maintaining vascular function, its role in AD pathology remains unclear. We included 353 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), assessing serum sodium levels, cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, magnetic resonance imaging (MRI), and cognitive function. An independent sample (N = 471) with available CSF sodium-related proteins and AD biomarkers was also included. Associations between serum sodium levels and AD pathology, neurodegeneration, and cognition were evaluated using linear regression models. Spearman's correlation analyses assessed the relationships between CSF sodium-related proteins and AD biomarkers. Higher serum sodium levels were associated with increased AD pathology, reduced hippocampal volume, and greater cognitive decline (all p < 0.05). The relationship between serum sodium and amyloid PET was evident in several AD-susceptible brain regions, including the neocortex and limbic system. Individuals with high serum sodium exhibited higher tau pathology, lower hippocampal volume, and more severe cognitive decline per unit increase in amyloid PET compared to those with low serum sodium (all p < 0.05). Among the 14 CSF sodium-related proteins, which were inter-correlated, six were significantly correlated with CSF AD pathology and amyloid PET, while two were correlated with hippocampal volume and cognitive function, with sodium channel subunit beta-2 (SCN2B) and sodium channel subunit beta-3 (SCN3B) showing the strongest correlations. These findings underscore the crucial role of serum sodium in AD progression, highlighting a potential network of sodium dysregulation involved in AD pathology. Targeting sodium may offer a novel therapeutic approach to slowing AD progression, particularly by impeding the progression of amyloid-related downstream events.

Enlarged choroid plexus related to atrophy of hippocampal subfield volumes and glymphatic dysfunction in benzodiazepine use disorder.

The aim of this study was to explore the relationship of choroid plexus (CP) volume with hippocampal subregion volume and glymphatic system in patients with benzodiazepine use disorders (BUD). Eighty-four participants were recruited including 23 patients with BUD, 29 patients with chronic insomnia (CI) and 32 healthy controls (HC). The morphological alterations in CP, hippocampal subfield volumes and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index were compared between the three groups and the relationships between CP volume and hippocampal subfield volumes and the glymphatic system were further investigated. Compared with the HC individuals, the CP volumes augmented and hippocampal subfield volumes reduced in patients with BUD (P < .05) but not in patients with CI (P > .05). In patients with BUD, there were extensive relationships between augmented CP volume and decreased hippocampal subfield volumes (P < .05, r = -0.421--0.513). CP volume was negatively related with the DTI-ALPS index (r = -0.582, P = .004) within the BUD group. In patients with BUD, the volume of bilateral cornu ammonis (CA)1 body, molecular layer (ML) body, hippocampal tail, left CA1 head volumes, right dentate gyrus body volumes, and right CA4 body volumes were positively related with the Montreal Cognitive Assessment scores (P < .05, r = 0.422-0.683). Right CA1 and ML body volumes positively related with the Mini-Mental State Examination scores (P < .05, r = 0.503-0.575). The enlarged CP related to atrophy of hippocampal subfield volumes and the glymphatic system dysfunction were shown in BUD patients.

Deferiprone in Alzheimer Disease

Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target. To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD. This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff. Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months. The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis). Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%). These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD. ClinicalTrials.gov Identifier: NCT03234686.

Do total hippocampus and hippocampal subfield volumes relate to navigation ability? A call towards methodological consistency

Despite the need for successful navigation, humans vary greatly in their ability to navigate, and these individual differences may relate to variation in brain structure. While prior research provides support for a correlation between hippocampal volume and navigation ability in both navigation experts and in older individuals, this relationship is under scrutiny for healthy, young adults. We assessed 99 healthy young adults’ ability to navigate in a virtual, desktop maze and correlated their performance with total hippocampal gray matter volume. For a subset of these individuals, we further segmented the medial temporal lobe – including regions of the hippocampus – into anatomically-distinct subregions to uniquely examine the association between volumes of hippocampal subfields and navigation. Given the need to distinguish between similar-looking maze hallways and partially overlapping routes, young adults with stronger pattern separation ability may perform better in this task. Thus, we theorized that successful navigation would positively correlate with hippocampal CA3 and dentate gyrus (DG) subfield volumes due to these regions’ role in pattern separation. CA1 and entorhinal cortex (ERC) are both associated with rodent spatial memory, too, suggesting a possible relationship between their volumes and navigation performance. Consistent with our hypotheses, we observed a positive relationship between volumes of hippocampal subfields and wayfinding accuracy, while ERC and parahippocampal cortex volumes correlated with navigation efficiency. However, when analyzing total hippocampal volume, a nuanced interpretation is warranted. We found evidence of Simpson’s Paradox, where total hippocampal volume and navigation accuracy displayed no correlation in males, a negative correlation in females, yet a positive correlation when considering the full sample of males and females combined. Furthermore, no significant relationship was observed between total hippocampal volume and path efficiency. Given these findings, we urge caution in interpreting the results because these associations differ by analysis techniques (including voxel-based morphometry), after sex stratification, and with anterior and posterior hippocampal subdivisions. Overall, this study enhances our understanding of the relationship between brain volume and navigation ability for young adults but also emphasizes the need for methodological consistency across studies with respect to boundary definitions, neuroimaging techniques, statistical methods, and factors that give rise to individual differences.

Association of lamina cribrosa thickness and hippocampal volume in Alzheimer's disease patients.

Alzheimer's disease (AD) is the most common cause of dementia and affects a large portion of the elderly population worldwide. To analyze the relationship between lamina cribrosa thickness (LCT) and hippocampal volume in patients with AD and mild cognitive impairment (MCI). The sample in the present study consisted of 20 recently diagnosed MCI patients, 20 recently diagnosed AD patients, and 20 matched healthy volunteers. Every patient underwent magnetic resonance imaging (MRI) scans. The VolBrain software (open-access platform for MRI brain analysis) was used to calculate the hippocampal volume. Optical coherence tomography was performed to measure the LCT. Analysis of variance and Pearson chi-squared tests were employed to assess the results. The lowest total hippocampal volume (p < 0.05) was in the AD group, which was 6.14 ± 0.66 mm3, while in the control group, it was 7.7 ± 9.65 mm3, and 6.69 ± 0.46 mm3 in the MCI group. In comparison to the rest of the groups, in the AD group, the LCT was the thinnest (202.17 ± 16.35 µm). As per the results of the study population as a whole, low hippocampal volume causes low LCT, which shows an important relationship (r: 0.41; p < 0.05). The current findings present evidence of the relationship between hippocampal volume and LCT in patients with AD and MCI.

Effects of aerobic training on brain architecture, hippocampal volume, cardiorespiratory parameters, and health-related quality of life among patients with schizophrenia: A systematic review

Background: Schizophrenia is considered to be a condition that usually manifests at any age but commonly seen in young people and is associated with a genetic propensity in brain development. Aim: The study explores the impact of aerobic training on brain architecture, hippocampal volume, cardiorespiratory parameters, and quality of life in young individuals with schizophrenia. The investigation focuses on the correlation between genetic predisposition, hippocampal atrophy, and diminished cardiorespiratory fitness, aiming to discern potential benefits of aerobic exercise on both physical and mental health outcomes. Methods: A systematic search was conducted in major online databases, such as Cochrane, Embase, PEDro, Web of science and PubMed (Medline). Two authors independently evaluated possibilities of bias, retrieved data and decided which trials should be included in the analysis. Total of 13 published articles (randomized clinical and controlled trials) with 656 patients was included from January 2010 to December 2020. Results: Following aerobic exercise training, people with schizophrenia presented with an increased hippocampus volume and enhanced cardiorespiratory endurance (P ˂0.05). Due to a lack of information, we rated the majority of the studies’ risk of bias in relation to random sequence creation, allocation concealment, and selective reporting as uncertain. Conclusion: Findings from the present review propose aerobic exercise program as a meaningful therapeutic intervention for schizophrenia patients in terms of maintaining appropriate brain architecture, increasing the hippocampal volume, improving cardiorespiratory parameters and health related quality of life.

Structural and functional alterations of the hippocampal subfields in T2DM with mild cognitive impairment and insulin resistance: A prospective study.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and is often accompanied by mild cognitive impairment (MCI). The detrimental effects of T2DM and IR on the hippocampus have been extensively demonstrated. Few studies have examined the effects of IR on structure and function of hippocampal subfields in T2DM-MCI patients. A total of 104 T2DM patients were recruited in this prospective study and divided into four groups (T2DM-MCI-higherIR, n = 17; T2DM-MCI-lowerIR, n = 32; T2DM-nonMCI-higherIR, n = 19; T2DM-nonMCI-lowerIR, n = 36). Structure and function MRI data were captured. Clinical variables and neuropsychological scores were determined for all participants. Hippocampal subfield volume and functional connectivity were compared among four groups. Partial correlation analysis was performed between imaging indicators, clinical variables, and neuropsychological scores in all patients. T2DM-MCI-higher IR group had the smallest volumes of bilateral hippocampal tail, right subiculum-body, right GC-ML-DG-body, and right CA4-body. IR in right hippocampal tail, right subiculum-body, and right GC-ML-DG-body exerted main effect. Furthermore, elevated functional connectivity was found between right subiculum-body and bilateral dorsolateral prefrontal cortex and right anterior cingulate-medial prefrontal cortex. Hippocampal subfield volume positively correlates with total cholesterol and triglycerides and negatively correlates with fasting insulin. The present study found that T2DM-MCI patients have structural and functional alterations in hippocampal subfields, and IR is a negative factor influencing the alteration of hippocampal subfields volume. These findings support the importance of IR in T2DM-MCI patients and might be potential neuroimaging biomarkers of cerebral impairment in T2DM-MCI patients.

Behavioral and psychological symptoms and brain volumes in community-dwelling older persons from the Nakayama Study

The frequency of behavioral and psychological symptoms of dementia (BPSD) is high, and it is a challenge to elucidate its neural substrates underlying their development. In recent years, many findings have been reported on the relationship between BPSD and brain volume in dementia patients. However, the results are not fully conclusive. Furthermore, there have been few population-based studies. Therefore, the relationship between BPSD and brain volume was investigated as an exploratory study. Of the 927 older persons who participated in the fifth Nakayama study, 90 were included in this analysis, consisting of 52 patients with mild cognitive impairment and 38 patients with dementia, with head MRI and the Neuropsychiatric Inventory (NPI) data. Multiple regression analysis was used to examine the association between the total score of each BPSD score on the NPI and brain volume estimated by FreeSurfer. On multivariate adjustment, even after false discovery rate correction, insular cortical volumes decreased significantly as total scores for apathy/indifference increased (p value = 0.002, q-value = 0.01). Similarly, total brain volume decreased significantly as total scores for appetite and eating disturbance increased (p value = 0.03), and parietal, temporal, and hippocampal cortical volumes also decreased significantly as total scores for appetite and eating disturbance increased (all p and q values < 0.05). This study’s results suggest that apathy is negatively correlated with insular cortical volume, and that appetite and eating disturbance are also correlated with brain regions, including parietal, temporal, and hippocampal volume in a community-dwelling older population.

Contribution of automated hippocampal volume measurements to radiological diagnosis in cases of mesial temporal sclerosis

Aims: Epilepsy, particularly drug-resistant epilepsy in adults, is often caused by Mesial Temporal Sclerosis (MTS), which can develop after brain injury from febrile illnesses or trauma. Magnetic Resonance Imaging (MRI) is crucial for diagnosing MTS, although challenges such as patient movement and mild or bilateral hippocampal atrophy can complicate the diagnosis. T1-weighted hippocampal volume measurements are effective in detecting MTS, with recent software advancements enabling automatic hippocampal segmentation. This study compared the hippocampal volumes and indices between adults with MTS and a control group of similar age and sex in the Turkish population. This study aimed to highlight structural differences in the hippocampus associated with MTS. Methods: This study involved a retrospective review of cranial MRIs scans from patients with MTS, confirmed through histopathological examination after epilepsy surgery. To ensure unbiased comparisons, a control group was selected using propensity score matching by age and gender. Two experienced neuroradiologists independently assessed the MRIs findings for MTS without knowledge of hippocampal volumetric data. Hippocampal volumes were measured using FreeSurfer software and standardized using the hippocampal volume index (HVI) and hippocampal asymmetry index (HAI). Results: In our study of 38 patients, MTS was found in 55.2% of patients on the right side and in 44.8% of patients on the left side, with no bilateral cases. Visual MRI analysis identified MTS in 84.2% of patients, with an area under of curve (AUC) of 0.921. Automatic volumetry detected MTS in 23 patients with an AUC of 0.791. Combining both methods, MTS was diagnosed in 33 patients, with an AUC of 0.922. Conclusion: Automated volumetric analyses have been shown to enhance the detection of hippocampal volume loss in patients with MTS.

Circulating medium- and long-chain acylcarnitines are associated with plasma P-tau181 in cognitively normal older adults.

Alzheimer's disease (AD) pathogenesis involves dysregulation in diverse biochemical processes. Nevertheless, plasma tau phosphorylated at threonine 181 (P-tau181), a recognised AD biomarker, has been described to reflect early-stage cortical amyloid-β (Aβ) deposition in cognitively normal (CN) adults. Therefore, identifying changes in plasma metabolites associated with plasma P-tau181 at the pre-clinical stage may provide insights into underlying biochemical mechanisms to better understand initial AD pathogenesis. In the current study, plasma P-tau181, quantified via single molecule array (Simoa) technology, and plasma metabolites, quantified via targeted-mass spectrometry, were investigated for associations in CN older adults and upon stratification by positron emission tomography (PET)-Aβ load. In addition, the P-tau181-linked metabolites were evaluated for cognitive performance and neuroimaging markers of AD and the potential to distinguish between CN Aβ- and CN Aβ+ individuals. Significant positive associations of medium- and long-chain acylcarnitines (ACs) were observed with P-tau181 in the entire cohort, CN Aβ- and CN Aβ+, suggesting a link between initial Aβ pathology and fatty acid oxidation-mediated energy metabolism pathways. However, in CN Aβ-, additional linear associations of P-tau181 were observed with muscle metabolism and nitric oxide homeostasis-associated metabolites. Upon investigating the P-tau181-linked metabolites for cognitive performance, significant inverse correlations of the verbal and visual episodic memory and the global composite score were noted in CN Aβ+ with medium- and long-chain ACs, suggesting prognostic value of ACs accompanying weaker cognitive performance. While investigating neuroimaging markers, ACs had positive associations with PET-Aβ load and inverse associations with hippocampal volume in CN Aβ+, indicating connections of ACs with initial AD pathogenesis. Furthermore, based on receiver operating characteristics analysis, the associated ACs potentially classified PET-Aβ status in older adults. Therefore, plasma P-tau181-linked circulating ACs may serve as potential prognostic markers for initial AD pathogenesis in CN older adults. However, further cross-sectional and longitudinal research in highly characterised AD cohorts is needed to validate current findings.

SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes.

We investigated hippocampal synaptic density using synaptic vesicle 2A positron emission tomography (PET), and its association with amyloid beta (Aβ) and cognitive performance in healthy apolipoprotein E (APOE) ε4 carriers. Synaptic density was assessed in 46 individuals (APOE ε4/ε4 n=14; APOE ε3/ε4 n=16; APOE ε3/ε3 n=16) with [11C]UCB-J-PET standardized uptake value ratios (SUVRs), by using the centrum semiovale as a reference region. Differences in hippocampal [11C]UCB-J SUVRs were analyzed with analysis of variance (ANOVA) and linear models. Associations among [11C]UCB-J SUVR, Aβ, hippocampal volume, and cognitive variables were analyzed with Spearman correlation. Hippocampal synaptic density was different among the APOE groups (PANOVA=0.016): APOE ε4/ε4 carriers had lower [11C]UCB-J SUVRs compared to APOE ε3/ε3 (p=0.013). Hippocampal synaptic density did not correlate with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score (rho=-0.052, p=0.74), Alzheimer's Prevention Initiative Preclinical Cognitive Composite (APCC) score (rho=0.17, p=0.28), or [11C]PiB uptake (rho=-0.10, p=0.50). Hippocampal synaptic loss emerges early in the AD continuum and is measurable in vivo in cognitively unimpaired high-risk individuals. Synaptic density was studied in vivo in healthy older adults using [11C]UCB-J positron emission tomography. Apolipoprotein E (APOE) ε4/ε4 carriers had lower hippocampal synaptic density compared to APOE ε3/ε3. Synaptic density was not associated with cognitive performance in this population. Hippocampal synaptic alterations occur before clinical symptoms in APOE ε4/ε4 carriers.

It takes three: Parental hostility, brain morphology and child externalizing problems in a parent-offspring neuroimaging trio design.

Hostility often co-occurs in parents and associates with increased aggression and inattention problems in children. In this population-based cohort of 484 mother-father-child neuroimaging trios, we investigated the degree to which associations of prenatal and childhood parental hostility would be associated with maternal, paternal and child brain structural differences. Also, we examined whether hippocampal volumes of the parents or child mediate the association of prenatal parental hostility with child externalizing behaviors. Maternal and paternal hostility was assessed with the hostility subscale of the Brief-Symptom-Inventory at three time points: prenatally at 30 weeks gestation, and when the child was 3 and 10 years old. During adolescence assessment wave (age 14), maternal, paternal, and offspring assessment included a magnetic-resonance-imaging (MRI). Child externalizing problems were assessed with Youth-Self-Report-Child-Behavior-Checklist.Our findings suggest that maternal and paternal hostility were each associated with smaller gray matter, white matter, and hippocampal volumes of their own and their partner's brain. Prenatal maternal but not paternal hostility was associated with smaller total gray matter, white matter, and hippocampal volumes in the offspring. The child's hippocampal volumes partially mediated the associations of prenatal parental hostility (latent-construct) with adolescent externalizing behavior, even after adjusting for prior child externalizing problems. Moreover, parental psychopathology may have long-lasting neurodevelopmental correlates in children that underlie the intergenerational transmission of behavioral problems. The behavior of family members results from a system of interdependent dyadic relationships over time that associate with specific brain structural differences.Significance statement Parental hostility often co-occurs in the parents. Research suggests that what transpires in one family subsystem, e.g. hostility among parents, is related to what transpires in other subsystems, e.g. mother-child or father-child, and can negatively impact child development. To understand the neurobiological effects of parental hostility on the families, these can best be studied with trio analysis as parents and children may all be affected. Overall, the findings elucidate how hostility of a parent negatively relates to different family subsystems and associated brain characteristic, such as the hippocampal volume. Our findings suggest that the behavior of family members results from a system of interdependent dyadic relationships over time that associate with specific brain structural differences.

Elevated circulating levels of GFAP associated with reduced volumes in hippocampal subregions linked to mild cognitive impairment among community-dwelling elderly individuals.

Cerebrospinal fluid biomarkers are challenging to use for diagnosing mild cognitive impairment (MCI) in large populations, and there is an urgent need for new blood biomarkers. The aim of this study is to investigate whether astrocyte activation is correlated with hippocampal atrophy, and to assess the potential of glial fibrillary acidic protein (GFAP) as a biomarker for diagnosing MCI among community-dwelling older individuals. This cross-sectional study included 107 older adults. The levels of GFAP in serum were measured, and the volumetric assessment of gray matter within hippocampal subregions was conducted using Voxel-Based Morphometry (VBM). The relationship between hippocampal subregion volume and blood biomarkers were analyzed using partial correlation. The effectiveness of blood biomarkers in differentiating MCI was assessed using a receiver operating characteristic (ROC) curve. We found that serum GFAP levels were significantly elevated in the MCI group compared to the cognitively normal (CN) group. Additionally, individuals with MCI exhibited a reduction gray matter volume in specific hippocampal subregions. Notably, the right dentate gyrus (DG) and right cornu ammonis (CA) subregions were found to be effective for distinguishing MCI patients from CN individuals. Serum levels of GFAP demonstrate a sensitivity of 65.9% and a specificity of 75.6% in differentiating patients with MCI from CN individuals. Specific atrophy within hippocampal subregions has been observed in the brains of community-dwelling elderly individuals. Elevated levels of circulating GFAP may serve as a sensitive peripheral biomarker indicative of hippocampal-specific cognitive alterations in patients with MCI.

Red-cell omega-3 fatty acids associate with increased hippocampal volume and superior longitudinal cognition in atrial fibrillation

Abstract Background Atrial fibrillation (AF) is associated with cognitive impairment and dementia. Omega-3 Fatty Acids (n-3 FAs) have anti-thrombotic, anti-inflammatory and anti-oxidative properties; however, their neuroprotective effects remain controversial. Here, we report the association of n-3 FAs with both structural (hippocampal volume) and functional (cognition) readouts in a large cohort of AF pts. Purpose a) To determine the association of n-3 FAs and left and right hippocampal volume at baseline in AF pts. b) To assess the predictive value of HV and n-3 FAs for the risk of cognitive impairment after a 7-year follow-up period. Methods This prospective ongoing multicenter Swiss Atrial Fibrillation study (Swiss-AF) included 2,359 pts with documented AF and baseline red-cell n-3 FAs levels, measured by gas chromatography and mass spectrometry. Hippocampal volume (HV) and segmentation based intracranial volume (ICV) were analyzed by FreeSurfer's (v 7.4.0) subregion segmentation module and Sequence Adaptive Multimodal SEGmentation from brain MRI in 1,736 pts. Detailed neurocognitive assessments in pts at baseline and follow up periods were performed. We used mixed-effect linear regression models to determine the association of n-3 FAs and HV. For conversion to cognitive impairment (defined as MoCA score &amp;lt; 26), we performed cox-proportional hazards regression model. Two adjustment models were applied as described in the figures. Results Patients with AF (mean age, 73 years old [±8.5 SD]; 157 women [27%]) with 9569 cognitive evaluations (mean follow-up, 3.6 years [±2.3 SD]) were assessed. At baseline, we observed statistically significant associations between total n-3 FAs levels (EPA + DHA + ALA + DPA) and individual n-3 FAs (EPA, DHA, DPA) with increased HV after adjustment for ICV and other covariates (Fig1A, 1B). After all adjustments, EPA remained associated with both bilateral HV and right HV. Furthermore, we observed a significant association between HV and neurocognitive assessments, as measured both in global (MoCA, CoCo) and specific tests (TMT-A, TMT-B, DSST, SF) (Fig1C). Over time, quartile 4 (Q4, highest n-3) compared to quartile 1 (Q1, lowest), had a 16% lower risk of cognitive impairment (HR, 0.84 [CI 0.75-0.93]; P=0.001) for total n-3 FAs and even 30% lower specifically for EPA (HR, 0.7 [CI 0.63-0.78]; P&amp;lt;0.001). The risk of cognitive impairment was 47% lower (HR, 0.53 [CI 0.45-0.63]; P&amp;lt;0.001) when the highest HV Q4 was compared to lowest HV Q1 (Fig2A). In combination, the highest quartile of bilateral HV and EPA demonstrated an increased probability of being cognitive impairment-free and they had a 72% lower (HR, 0.28 [0.18-0.43]; P&amp;lt;0.001) risk of cognitive impairment (Fig2B). Conclusions 1. Red cell n-3 FAs levels are associated with higher HV in AF pts. 2. Higher baseline levels of n-3 FAs, particularly of EPA, are associated with both an increased HV and a decreased risk of cognitive impairment after 7 years follow up.