CA1 Volumes Research Articles

Hypoxemia during rapid eye movement sleep mediates memory impairment in older adults at risk for dementia via CA1 hippocampal volume loss

AbstractBackground and PurposeObstructive sleep apnea is associated with increased dementia risk. Nocturnal hypoxemia, which can be more severe during rapid eye movement (REM) sleep, may be a key mechanism. This study examines how REM hypoxemia affects memory and explores whether hippocampal vulnerability to hypoxemia mediates this effect in older adults at risk for dementia.MethodsOlder adults aged ≥50 years (N = 338) with subjective or mild cognitive impairment (i.e., objective impairment) underwent neuropsychological, mood, and medical assessment, magnetic resonance imaging scanning (n = 135), and overnight polysomnography. Verbal learning and memory were assessed with the Rey Auditory Verbal Learning Test. REM sleep hypoxemia was measured using the Oxygen Desaturation Index‐3% (REM‐ODI). Hippocampal subfield (CA1, CA3, subiculum, and dentate gyrus) volumes were derived from T1 and high‐resolution hippocampus T2 scans. We determined whether the relationship between REM‐ODI and learning and memory was mediated by hippocampal subfield volume. Analyses were repeated in non‐REM sleep to determine whether the effects were REM‐specific.ResultsAlthough there was not a direct effect of REM‐ODI on verbal learning (p > 0.05) or memory (p > 0.05), mediation analyses showed a significant indirect effect of high REM‐ODI on poorer verbal learning (β = −0.09, 95% confidence interval [CI] = −0.238 to −0.005) and memory (β = −0.100, 95% CI = −0.255 to −0.005), which was mediated by CA1 volume. These associations were absent in non‐REM sleep (p > 0.05).ConclusionsHypoxemia during REM sleep may impair memory in people at risk for dementia by reducing CA1 hippocampal volume. Research is needed to explore whether interventions targeting REM sleep hypoxemia are protective against memory decline.

Exploring the cognitive assessment potential of MRI-based volumetric hippocampal segmentation in Parkinson's disease.

To investigate the potential of magnetic resonance imaging (MRI)-based total and segmental hippocampus volume analysis in the assessment of cognitive status in Parkinson's disease (PD). We divided participants into three groups Group A-Parkinson patients (Pp) with normal cognitive status (n=25), Group B-Pp with dementia (n=17), and Group C-healthy controls (n=37). Three-dimensional T1W Fast Spoiled Gradient Recalled Echo images were used for Volbrain hippocampus subfield segmentation. We used the "Winterburn" protocol, which divides the hippocampus into five segments, Cornu Ammonis (CA),CA2/CA3, CA4/dentate gyrus, stratum radiatum, lacunosum, and moleculare, and subiculum. A total of 79 participants were included in the study, consisting of 42 individuals with PD (64.2% male) and 37 healthy controls (54.1% male). The mean age of PD was 60.9±10.7 years and the mean age of control group was 59.27±12.3 years. Significant differences were found in total hippocampal volumes between Group A and B (p=.047. Statistically significant group differences were found in total, right, and left CA1 volumes (analysis of variance [ANOVA]: F(2,76)=8.098, p=.001; F(2,76)=7.628, p=.001; F(2,76)=5.084, p=.008, respectively), as well as in total subiculum volumes (ANOVA: F(2,76)=4.368, p=.016). Post hoc tests showed that total subiculum volume was significantly lower in individuals with normal cognitive status (0.474±0.116cm3) compared to healthy controls (0.578±0.151cm3, p=.013). Volumetric hippocampal MRI can be used to assess the cognitive status of Pp. Longitudinal studies that evaluate Pp who progress from normal cognition to dementia are required to establish a causal relationship.

Differential Vulnerability of Hippocampal Subfields to Amyloid and Tau Deposition in the Lewy Body Diseases.

Alzheimer disease (AD) copathologies of β-amyloid and tau are common in the Lewy body diseases (LBD), dementia with Lewy bodies (DLB) and Parkinson disease (PD), and target distinct hippocampal subfields compared with Lewy pathology, including subiculum and CA1. We investigated the hypothesis that AD copathologies impact the pattern of hippocampal subregion volume loss and cognitive function in LBD. This was a cross-sectional and longitudinal, single-center, observational cohort study. Participants underwent neuropsychological testing and 3T-MRI with hippocampal segmentation using FreeSurferV7. PiB-PET and flortaucipir-PET imaging of comorbid β-amyloid (A) and tau (T) were acquired. The association of functional cognition, β-amyloid, and tau loads with hippocampal subregion volume was assessed. The contribution of subregion volumes to the relationship of AD-related deposits on functional cognition was examined with mediation analysis. The effects of AD-related deposits on the rate of subregion atrophy were evaluated with mixed-effects models. Of 103 participants (mean age: 70.3 years; 37.3% female), 52 had LBD with impaired cognition (LBD-I), 26 had normal cognition (LBD-N), and 25 were A- healthy controls (HCs). Volumes of hippocampal subregions prone to AD copathologies, including subiculum (F = 6.9, p = 0.002), presubiculum (F = 7.3, p = 0.001), and parasubiculum (F = 5.9, p = 0.004), were reduced in LBD-I compared with LBD-N and HC. Volume was preserved in CA2/3, Lewy pathology susceptible subregions. In LBD-I, reduced CA1, subiculum, and presubiculum volumes were associated with greater functional cognitive impairment (all p < 0.05). Compared with HC, subiculum volume was reduced in A+T+ but not A-T- participants (F = 2.62, p = 0.043). Reduced subiculum volume mediated the effect of amyloid on functional cognition (0.12, 95% CI: 0.005 to 0.26, p = 0.040). In 26 longitudinally-evaluated participants, baseline tau deposition was associated with faster CA1 (p = 0.021) and subiculum (p = 0.002) atrophy. In LBD, volume loss in hippocampal output subregions-particularly the subiculum-is associated with functional cognition and AD-related deposits. Tau deposition appears to accelerate subiculum and CA1 atrophy, whereas Aβ does not. Subiculum volume may have value as a biomarker of AD copathology-mediated neurodegeneration and disease progression.

Hippocampal subfield volume in older adults with and without mild cognitive impairment: Effects of worry and cognitive reappraisal

Studies have confirmed that anxiety, especially worry and rumination, are associated with increased risk for cognitive decline, including Alzheimer’s disease and related dementias (ADRD). Hippocampal atrophy is a hallmark of ADRD. We investigated the association between hippocampus and its subfield volumes and late-life global anxiety, worry, and rumination, and emotion regulation strategies. We recruited 110 participants with varying worry severity who underwent magnetic resonance imaging and clinical interviews. We conducted cross-sectional regression analysis between each subfield and anxiety, worry, rumination, reappraisal, and suppression while adjusting for age, sex, race, education, cumulative illness burden, stress, neuroticism, and intracranial volume. We imputed missing data and corrected for multiple comparisons across regions. Greater worry was associated with smaller subiculum volume, whereas greater use of reappraisal was associated with larger subiculum and CA1 volume. Greater worry may be detrimental to the hippocampus and to subfields involved in early ADRD pathology. Use of reappraisal appears protective of hippocampal structure. Worry and reappraisal may be modifiable targets for ADRD prevention.

Memory impairment in Amyloidβ-status Alzheimer's disease is associated with a reduction in CA1 and dentate gyrus volume: In vivo MRI at 7T

IntroductionIn Alzheimer's disease (AD), early diagnosis facilitates treatment options and leads to beneficial outcomes for patients, their carers and the healthcare system. The neuropsychological battery of the Uniform Data Set (UDSNB3.0) assesses cognition in ageing and dementia, by measuring scores across different cognitive domains such as attention, memory, processing speed, executive function and language. However, its neuroanatomical correlates have not been investigated using 7 Tesla MRI (7T MRI). MethodsWe used 7T MRI to investigate the correlations between hippocampal subfield volumes and the UDSNB3.0 in 24 individuals with Amyloidβ-status AD and 18 age-matched controls, with respective age ranges of 60 (42–76) and 62 (52–79) years. AD participants with a Medial Temporal Atrophy scale of higher than 2 on 3T MRI were excluded from the study. ResultsA significant difference in the entire hippocampal volume was observed in the AD group compared to healthy controls (HC), primarily influenced by CA1, the largest hippocampal subfield. Notably, no significant difference in whole brain volume between the groups implied that hippocampal volume loss was not merely reflective of overall brain atrophy. UDSNB3.0 cognitive scores showed significant differences between AD and HC, particularly in Memory, Language, and Visuospatial domains. The volume of the Dentate Gyrus (DG) showed a significant association with the Memory and Executive domain scores in AD patients as assessed by the UDSNB3.0.. The data also suggested a non-significant trend for CA1 volume associated with UDSNB3.0 Memory, Executive, and Language domain scores in AD. In a reassessment focusing on hippocampal subfields and MoCA memory subdomains in AD, associations were observed between the DG and Cued, Uncued, and Recognition Memory subscores, whereas CA1 and Tail showed associations only with Cued memory. DiscussionThis study reveals differences in the hippocampal volumes measured using 7T MRI, between individuals with early symptomatic AD compared with healthy controls. This highlights the potential of 7T MRI as a valuable tool for early AD diagnosis and the real-time monitoring of AD progression and treatment efficacy. ClinicalTrials.govID NCT04992975 (Clinicaltrial.gov 2023)

The combination treatment of hypothermia and intranasal insulin ameliorates the structural and functional changes in a rat model of traumatic brain injury.

The present study aimed to investigate the combination effects of hypothermia (HT) and intranasal insulin (INS) on structural changes of the hippocampus and cognitive impairments in the traumatic brain injury (TBI) rat model. The rats were divided randomly into the following five groups (n = 10): Sham, TBI, TBI with HT treatment for 3h (TBI + HT), TBI with INS (ten microliters of insulin) treatment daily for 7days (TBI + INS), and TBI with combining HT and INS (TBI + HT + INS). At the end of the 7th day, the open field and the Morris water maze tests were done for evaluation of anxiety-like behavior and memory performance. Then, after sacrificing, the brain was removed for stereological study. TBI led to an increase in the total volume of hippocampal subfields CA1 and DG and a decrease in the total number of neurons and non-neuronal cells in both sub-regions, which was associated with anxiety-like behavior and memory impairment. Although, the combination of HT and INS prevented the increased hippocampal volume and cell loss and improved behavioral performances in the TBI group. Our study suggests that the combined treatment of HT and INS could prevent increased hippocampal volume and cell loss in CA1 and DG sub-regions and consequently improve anxiety-like behaviors and memory impairment following TBI.

Hippocampal capillary pericytes in post-stroke and vascular dementias and Alzheimer’s disease and experimental chronic cerebral hypoperfusion

Neurovascular unit mural cells called ‘pericytes’ maintain the blood-brain barrier and local cerebral blood flow. Pathological changes in the hippocampus predispose to cognitive impairment and dementia. The role of hippocampal pericytes in dementia is largely unknown. We investigated hippocampal pericytes in 90 post-mortem brains from post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer’s disease (AD), and AD-VaD (Mixed) subjects, and post-stroke non-demented survivors as well as similar age controls. We used collagen IV immunohistochemistry to determine pericyte densities and a mouse model of VaD to validate the effects of chronic cerebral hypoperfusion. Despite increased trends in hippocampal microvascular densities across all dementias, mean pericyte densities were reduced by ~25–40% in PSD, VaD and AD subjects compared to those in controls, which calculated to 14.1 ± 0.7 per mm capillary length, specifically in the cornu ammonis (CA) 1 region (P = 0.01). In mice with chronic bilateral carotid artery occlusion, hippocampal pericyte loss was ~60% relative to controls (P < 0.001). Pericyte densities were correlated with CA1 volumes (r = 0.54, P = 0.006) but not in any other sub-region. However, mice subjected to the full-time environmental enrichment (EE) paradigm showed remarkable attenuation of hippocampal CA1 pericyte loss in tandem with CA1 atrophy. Our results suggest loss of hippocampal microvascular pericytes across common dementias is explained by a vascular aetiology, whilst the EE paradigm offers significant protection.

Unraveling the link: white matter damage, gray matter atrophy and memory impairment in patients with subcortical ischemic vascular disease.

Prior MRI studies have shown that patients with subcortical ischemic vascular disease (SIVD) exhibited white matter damage, gray matter atrophy and memory impairment, but the specific characteristics and interrelationships of these abnormal changes have not been fully elucidated. We collected the MRI data and memory scores from 29 SIVD patients with cognitive impairment (SIVD-CI), 29 SIVD patients with cognitive unimpaired (SIVD-CU) and 32 normal controls (NC). Subsequently, the thicknesses and volumes of the gray matter regions that are closely related to memory function were automatically assessed using FreeSurfer software. Then, the volume, fractional anisotropy (FA), mean diffusivity (MD), amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values of white matter hyperintensity (WMH) region and normal-appearing white matter (NAWM) were obtained using SPM, DPARSF, and FSL software. Finally, the analysis of covariance, spearman correlation and mediation analysis were used to analyze data. Compared with NC group, patients in SIVD-CI and SIVD-CU groups showed significantly abnormal volume, FA, MD, ALFF, and ReHo values of WMH region and NAWM, as well as significantly decreased volume and thickness values of gray matter regions, mainly including thalamus, middle temporal gyrus and hippocampal subfields such as cornu ammonis (CA) 1. These abnormal changes were significantly correlated with decreased visual, auditory and working memory scores. Compared with the SIVD-CU group, the significant reductions of the left CA2/3, right amygdala, right parasubiculum and NAWM volumes and the significant increases of the MD values in the WMH region and NAWM were found in the SIVD-CI group. And the increased MD values were significantly related to working memory scores. Moreover, the decreased CA1 and thalamus volumes mediated the correlations between the abnormal microstructure indicators in WMH region and the decreased memory scores in the SIVD-CI group. Patients with SIVD had structural and functional damages in both WMH and NAWM, along with specific gray matter atrophy, which were closely related to memory impairment, especially CA1 atrophy and thalamic atrophy. More importantly, the volumes of some temporomesial regions and the MD values of WMH regions and NAWM may be potentially helpful neuroimaging indicators for distinguishing between SIVD-CI and SIVD-CU patients.

Smaller anterior hippocampal subfields in the early stage of psychosis

Hippocampal volume is smaller in schizophrenia, but it is unclear when in the illness the changes appear and whether specific regions (anterior, posterior) and subfields (CA1, CA2/3, dentate gyrus, subiculum) are affected. Here, we used a high-resolution T2-weighted sequence specialized for imaging hippocampal subfields to test the hypothesis that anterior CA1 volume is lower in early psychosis. We measured subfield volumes across hippocampal regions in a group of 90 individuals in the early stage of a non-affective psychotic disorder and 70 demographically similar healthy individuals. We observed smaller volume in the anterior CA1 and dentate gyrus subfields in the early psychosis group. Our findings support models that implicate anterior CA1 and dentate gyrus subfield deficits in the mechanism of psychosis.

Naringin Reduced the Density and Total Number of Aβ Plaques and Restored Memory Function and Volume of Hippocampal CA1 Area in Alzheimer's Disease Model Rats: A Stereological Study

Background: Alzheimer's disease (AD), the most prevalent form of dementia worldwide, is characterized by memory impairment and the accumulation of tau and beta-amyloid (Aβ) plaques. Naringin, a flavonoid, has exhibited strong anti-inflammatory, anti-oxidant, and anti-apoptotic properties. Objectives: In this study, we aimed to demonstrate the neuroprotective effects of naringin on memory function, the total number and density of Aβ plaques, and the volume of the hippocampal CA1 region in a scopolamine (SCO)-induced AD model in rats. Methods: Forty male Wistar rats were randomly divided into the following groups: A control group, a saline + SCO (3 mg/kg) group (pretreated with 200 µL saline), and 3 treatment groups receiving naringin at doses of 50 mg/kg/day + SCO, 100 mg/kg/day + SCO, and 200 mg/kg/day + SCO (pretreated with 50, 100, or 200 mg/kg of naringin) for 14 consecutive days via intraperitoneal (IP) injection. After the 14-day pretreatment period, the saline + SCO and 3 naringin treatment groups received SCO (3 mg/kg) to induce an AD-like condition. Memory function was assessed using the inhibitory passive avoidance test. Following brain harvesting, paraffin-embedded coronal brain slices were stained with Congo red, and the density and the total number of Aβ plaques and the volume of the hippocampal CA1 area were estimated using unbiased stereological techniques. Results: The results indicated that naringin significantly improved memory function, with the most pronounced effect observed in the naringin 200 mg/kg + SCO group. Stereological analysis revealed that SCO reduced the volume of the hippocampal CA1 area and increased the total number and density of Aβ plaques. Pretreatment with naringin significantly restored the hippocampal CA1 volume in the 200 mg/kg + SCO group compared to the saline + SCO group. Additionally, naringin reduced the total number and density of Aβ plaques, with the most significant decrease observed in the 200 mg/kg + SCO group. Conclusions: Naringin restored memory function and the volume of the hippocampal CA1 region while reducing the total number and density of Aβ plaques in a SCO-induced AD model in rats. This stereological study complements previous molecular research on naringin's neuroprotective effects in AD-like pathogenesis.

Statistical learning in epilepsy: Behavioral and anatomical mechanisms in the human brain.

Statistical learning, the fundamental cognitive ability of humans to extract regularities across experiences over time, engages the medial temporal lobe (MTL) in the healthy brain. This leads to the hypothesis that statistical learning (SL) may be impaired in patients with epilepsy (PWE) involving the temporal lobe, and that this impairment could contribute to their varied memory deficits. In turn, studies done in collaboration with PWE, that evaluate the necessity of MTL circuitry through disease and causal perturbations, provide an opportunity to advance basic understanding of SL. We implemented behavioral testing, volumetric analysis of the MTL substructures, and direct electrical brain stimulation to examine SL across a cohort of 61 PWE and 28 healthy controls. We found that behavioral performance in an SL task was negatively associated with seizure frequency irrespective of seizure origin. The volume of hippocampal subfields CA1 and CA2/3 correlated with SL performance, suggesting a more specific role of the hippocampus. Transient direct electrical stimulation of the hippocampus disrupted SL. Furthermore, the relationship between SL and seizure frequency was selective, as behavioral performance in an episodic memory task was not impacted by seizure frequency. Overall, these results suggest that SL may be hippocampally dependent and that the SL task could serve as a clinically useful behavioral assay of seizure frequency that may complement existing approaches such as seizure diaries. Simple and short SL tasks may thus provide patient-centered endpoints for evaluating the efficacy of novel treatments in epilepsy.

Depression and Hippocampal Subfield Volume in Older Adults

AbstractBackgroundMajor Depressive Disorder (MDD) is associated with higher risk for developing Alzheimer’s Disease (AD), (Bennett &amp; Thomas, 2014). Both conditions are associated with smaller hippocampal subfield volumes, and both preferentially affect females (Shi et al., 2021). We examined the relationship between depression diagnosis and hippocampal subfield volume, by carrier status for AD genetic risk variant APOE4 and sex. We hypothesized that the association between depression and subfield volume would be stronger in females due to the higher rate of depression.MethodWe examined 1726 cognitively intact older adults from the Health and Aging Brain Study ‐ Health Disparities (HABS‐HD) cohort (Table1) who had available hippocampal high resolution MRI scans (Siemens Skyra or Vida‐3T). Scans were segmented into CA1, CA23DG, and subiculum using Automatic Segmentation of Hippocampal Subfields (ASHS) software and subfield volume was averaged bilaterally. We used separate multiple linear regressions to assess the association between depression and each hippocampal subfield volume, covarying for age, sex, years of education, number of MRI slices segmented, intracranial volume, and scanner. We corrected for multiple comparisons across regions using FDR correction. We also evaluated CA1 and CA23DG volume to depression diagnosis, stratifying by APOE4 positivity and sex and testing for formal interactions.ResultSee Table 2 for results. Depression was associated with smaller CA1 and CA23DG volume across all participants. Depression was associated with smaller CA1 and CA23DG in the APOE4 negative group, but not the APOE4 positive group. The depression by APOE4 interaction was significant for CA23DG volume (𝛽 = 0.25, p = 0.049). Depression was associated with smaller CA1 and CA23DG volumes in males, but not in females, with trend level interaction effects in the CA1 (𝛽 = 0.13, p = 0.095) and CA23DG (𝛽 = 0.17, p = 0.067).ConclusionDepression was associated with smaller CA1 and CA23DG volumes in older adults consistent with past literature. In contrast to our hypotheses, depression was associated with lower hippocampal subregional volumes more in those with lower risk for Alzheimer’s disease (male and APOE4‐ adults).Variability induced by other AD risk factors may mask the relationship between depression and hippocampal subregion volume when AD risk is higher.

The Alzheimer multifactorial therapeutic agent E2F4DN prevents long‐term potentiation and cognitive loss and improves neuronal survival in homozygous 5xFAD mice

AbstractBackgroundDespite many decades of work, we still lack effective therapies against Alzheimer’s disease (AD), likely due to its complex etiology, which requires a multifactorial therapeutic approach. Among the variety of proposed etiological factors, synaptic failure has proof to be an early hallmarks of AD (Nat. Neurosci. 2016;19:443‐453), which precedes neuronal‐death (J. Neurosci. 2006;26:10129‐10140). We have recently shown, using both transgenic mice and gene therapy, that E2F4 is a multifactorial therapeutic target against AD (Neurotherapeutics 2021;18:2484‐2503, Mol. Neurobiol. 2022;59:3016‐3039), likely due to its homeostatic function (Int. J. Mol. Sci. 2022;23:12093). The phosphorylation of two conserved Thr residues of E2F4 is necessary to induce cognitive loss in AD (Neurotherapeutics 2021;18:2484‐2503). Therefore, we have developed a novel therapy consisting in neuronal expression of a dominant negative form of E2F4 (E2F4DN), which cannot be phosphorylated in the conserved Thr residues (Neurotherapeutics 2021;18:2484‐2503, Mol. Neurobiol. 2022;59:3016‐3039). In this work we wanted to verify whether the expression of E2F4DN could correct AD‐associated synaptic dysfunction and neuronal loss in 5xFAD mice, a known mouse model of AD.MethodWe expressed E2F4DN (intravenous administration of AAV‐E2F4DN) in 6 weeks old control and homozygous 5xFAD mice, and stereological, electrophysiological and behavioral studies were performed at 6 months. Cell counting was achieved by unbiased stereology in the CA1 hippocampal region. Cognition was analyzed through novel‐object location and contextual fear conditioning test. Synaptic function (basal synaptic transmission, presynaptic function and long‐term potentiation (LTP)) were measured by electrophysiological recordings of field excitatory postsynaptic potentials in hippocampal CA3‐CA1 synapses. Afterwards, the mechanism underlying memory recovery was evaluated analyzing protein levels of different subunits of the synaptic receptors AMPA and NMDA.ResultE2F4DN expression in neurons prevents neuronal death in the hippocampus (CA1) of homozygous 5xFAD mice, reaching similar values of cell number and CA1 volume to those observed in control mice. Moreover, E2F4DN prevents LTP loss leading to cognitive improvement, as 5xFAD mice treated with our therapy present a noticeable improvement hippocampal‐dependent memory. This effect correlates with the increase of key LTP regulators.ConclusionE2F4‐Based Gene Therapy improves neuronal survival, LTP and cognition, being a safe multifactorial approach for AD treatment.

Developing Topics.

Hippocampal formation atrophy is a well-established imaging biomarker of several neurological diseases, including Alzheimer's disease, temporal lobe epilepsy, and schizophrenia. The hippocampus is divided into subfields that have different functions and vary in sensitivity to different diseases. This study investigates the potential interaction between COVID-19 and the various hippocampus subfields, which may shed light on the long-term neurological consequences of the virus. We obtained high-resolution T1-weighted (T1w) and T2-weighted (T2w) MRI images using 7T scanners located at three sites in two countries: Pittsburgh (n = 14) and Texas (San Antonio and Houston) (n = 40) in the USA, and Nottingham, UK (n = 33). We evaluated the hippocampus subfields using the ASHS package [1-3]. Imaging sets of 51 subjects with minimal or no manual segmentation corrections (Figures 1 and 2) were included in the analysis. We conducted T-tests with Bonferroni correction, adjusting for age and intracranial volume to identify the differences in hippocampus subfield volumes across groups. Participants who needed admission into the ICU due to Covid-19 showed a significantly lower (p-value = 0.0034) left CA1 volume compared to participants who did not require ICU (Figure 3). In addition, several other non-significant trends were observed. Our preliminary findings suggest that Covid-19 may impact the hippocampus, particularly in patients who required intensive care. However, the study - as of to date - has a small sample size and lacks a comparison group with patients who were admitted into ICU for acute illnesses other than Covid-19. Additionally, longitudinal data is needed to track the long-term effects of the disease on the hippocampal subfields. NIH R56AG074467, R01MH111265 and R01AG063525

Piecing it together: atrophy profiles of hippocampal subfields relate to cognitive impairment along the Alzheimer's disease spectrum.

People with Alzheimer's disease (AD) experience more rapid declines in their ability to form hippocampal-dependent memories than cognitively normal healthy adults. Degeneration of the whole hippocampal formation has previously been found to covary with declines in learning and memory, but the associations between subfield-specific hippocampal neurodegeneration and cognitive impairments are not well characterized in AD. To improve prognostic procedures, it is critical to establish in which hippocampal subfields atrophy relates to domain-specific cognitive declines among people along the AD spectrum. In this study, we examine high-resolution structural magnetic resonance imaging (MRI) of the medial temporal lobe and extensive neuropsychological data from 29 amyloid-positive people on the AD spectrum and 17 demographically-matched amyloid-negative healthy controls. Participants completed a battery of neuropsychological exams including select tests of immediate recollection, delayed recollection, and general cognitive status (i.e., performance on the Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]). Hippocampal subfield volumes (CA1, CA2, CA3, dentate gyrus, and subiculum) were measured using a dedicated MRI slab sequence targeting the medial temporal lobe and used to compute distance metrics to quantify AD spectrum-specific atrophic patterns and their impact on cognitive outcomes. Our results replicate prior studies showing that CA1, dentate gyrus, and subiculum hippocampal subfield volumes were significantly reduced in AD spectrum participants compared to amyloid-negative controls, whereas CA2 and CA3 did not exhibit such patterns of atrophy. Moreover, degeneration of the subiculum along the AD spectrum was linked to a significant decline in general cognitive status measured by the MMSE, while degeneration scores of the CA1 and dentate gyrus were more widely associated with declines on the MMSE and tests of learning and memory. These findings provide evidence that subfield-specific patterns of hippocampal degeneration, in combination with cognitive assessments, may constitute a sensitive prognostic approach and could be used to better track disease trajectories among individuals on the AD spectrum.

Age-related differences in hippocampal subfield volumes across the human lifespan: A meta-analysis.

The human hippocampus (Hc) is critical for memory function across the lifespan. It is comprised of cytoarchitectonically distinct subfields: dentate gyrus (DG), cornu ammonis sectors (CA) 1-4, and subiculum, each of which may be differentially susceptible to neurodevelopmental and neurodegenerative mechanisms. Identifying age-related differences in Hc subfield volumes can provide insights into neural mechanisms of memory function across the lifespan. Limited evidence suggests that DG and CA3 volumes differ across development while other regions remain relatively stable, and studies of adulthood implicate a downward trend in all subfield volumes with prominent age effects on CA1. Due to differences in methods and limited sampling for any single study, the magnitude of age effects on Hc subfield volumes and their probable lifespan trajectories remain unclear. Here, we conducted a meta-analysis on cross-sectional studies (n = 48,278 participants, ages = 4-94 years) to examine the association between age and Hc subfield volumes in development (n = 11 studies), adulthood (n = 30 studies), and a combined lifespan sample (n = 41 studies) while adjusting estimates for sample sizes. In development, age was positively associated with DG and CA3-4 volumes, whereas in adulthood a negative association was observed with all subfield volumes. Notably, the observed age effects were not different across subfield volumes within each age group. All subfield volumes showed a nonlinear age pattern across the lifespan with DG and CA3-4 volumes showing a more distinct age trajectory as compared to the other subfields. Lastly, among all the study-level variables, only female percentage of the study sample moderated the age effect on CA1 volume: a higher female-to-male ratio in the study sample was linked to thegreater negative association between age and CA1 volume. These results document that Hc subfield volumes differ as a function of age offering broader implications for constructing theoretical models of lifespan memory development.

Ultra-high-field 7T MRI reveals changes in human medial temporal lobe volume in female adults during menstrual cycle

Ovarian hormones have substantial effects on the brain, and early menopause has been associated with increased risk of accelerated brain aging and dementia later in life. However, the impact of ovarian hormone fluctuations on brain structure earlier in life is less understood. Here we show that ovarian hormone fluctuations shape structural brain plasticity during the reproductive years. We use longitudinal ultra-high field neuroimaging across the menstrual cycle to map the morphology of medial temporal lobe subregions in 27 participants. Controlling for water content and blood flow, our findings reveal positive associations between estradiol and parahippocampal cortex volume, progesterone and subiculum and perirhinal area 35 volumes, and an estradiol*progesterone interaction with CA1 volume. This research offers a blueprint for future studies on the shared dynamics of the brain and ovarian function and a fundamental stepping stone towards developing sex-specific strategies to improve brain health and mental health.

Hippocampal sclerosis of aging at post-mortem is evident on MRI more than a decade prior.

Hippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically-defined features is unknown. We investigated pre-mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia-associated pathologies. We analyzed hippocampal volumes from magnetic resonance imaging (MRI) segmentations in 64 dementia patients with longitudinal MRI follow-up and post-mortem neuropathological evaluation, including HS assessment in the hippocampal head and body. Significant HS-associated hippocampal volume changes were observed throughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer's disease (AD) neuropathology and were driven specifically by CA1 and subiculum atrophy. AD pathology, but not HS, was associated significantly with the rate of hippocampal atrophy. HS-associated volume changes are detectable on MRI earlier than 10 years before death. Based on these findings, volumetric cutoffs could be derived for in vivo differentiation between HS and AD. Hippocampal atrophy was found in HS+ patients earlier than 10 years before death. These early pre-mortem changes were driven by reduced CA1 and subiculum volumes. Rates of hippocampus and subfield volume decline were independent of HS. In contrast, steeper atrophy rates were associated with AD pathology burden. Differentiation between AD and HS could be facilitated based on these MRI findings.

Association of Sleep-Disordered Breathing and Medial Temporal Lobe Atrophy in Cognitively Unimpaired Amyloid-Positive Older Adults.

Sleep disordered breathing (SDB) has been related to amyloid deposition and an increased dementia risk. However, how SDB relates to medial temporal lobe neurodegeneration and subsequent episodic memory impairment is unclear. Our objective was to investigate the impact of amyloid positivity on the associations between SDB severity, medial temporal lobe subregions, and episodic memory performance in cognitively unimpaired older adults. Data were acquired between 2016 and 2020 in the context of the Age-Well randomized controlled trial of the Medit-Aging European project. Participants older than 65 years who were free of neurologic, psychiatric, or chronic medical diseases were recruited from the community. They completed a neuropsychological evaluation, in-home polysomnography, a Florbetapir PET, and an MRI, including a specific high-resolution assessment of the medial temporal lobe and hippocampal subfields. Multiple linear regressions were conducted to test interactions between amyloid status and SDB severity on the volume of MTL subregions, controlling for age, sex, education, and the ApoE4 status. Secondary analyses aimed at investigating the links between SDB, MTL subregional atrophy, and episodic memory performance at baseline and at a mean follow-up of 20.66 months in the whole cohort and in subgroups stratified according to amyloid status. We included 122 cognitively intact community-dwelling older adults (mean age ± SD: 69.40 ± 3.85 years, 77 women, 26 Aβ+ individuals) in baseline analyses and 111 at follow-up. The apnea-hypopnea index interacted with entorhinal (β = -0.81, p < 0.001, pη2 = 0.19), whole hippocampal (β = -0.61, p < 0.001, pη2 = 0.10), subiculum (β = -0.56, p = 0.002, pη2 = 0.08), CA1 (β = -0.55, p = 0.002, pη2 = 0.08), and DG (β = -0.53, p = 0.003, pη2 = 0.08) volumes such that a higher sleep apnea severity was related to lower MTL subregion volumes in amyloid-positive individuals, but not in those who were amyloid negative. In the whole cohort, lower whole hippocampal (r = 0.27, p = 0.005) and CA1 (r = 0.28, p = 0.003) volumes at baseline were associated with worse episodic memory performance at follow-up. Overall, we showed that SDB was associated with MTL atrophy in cognitively asymptomatic older adults engaged in the Alzheimer continuum, which may increase the risk of developing memory impairment over time. ClinicalTrials.gov Identifier: NCT02977819.

Smaller cornu ammonis (CA3) as a potential risk factor for suicidal behavior in mood disorders

Mood disorders and suicidal behavior have moderate heritability and familial transmission, and are associated with smaller hippocampal volumes. However, it is unclear whether hippocampal alterations reflect heritable risk or epigenetic effects of childhood adversity, compensatory mechanisms, illness-related changes, or treatment effects. We sought to separate the relationships of hippocampal substructure volumes to mood disorder, suicidal behavior, and risk and resilience to both by examining high familial risk individuals (HR) who have passed the age of greatest risk for psychopathology onset. Structural brain imaging and hippocampal substructure segmentation quantified Cornu Ammonis (CA1-4), dentate gyrus, and subiculum gray matter volumes in healthy volunteers (HV, N = 25) and three groups with one or more relatives reporting early-onset mood disorder and suicide attempt: 1. Unaffected HR (N = 20); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 25); and 3. HR with lifetime mood disorder and a previous suicide attempt (HR-MOOD + SA, N = 18). Findings were tested in an independent cohort not selected for family history (HV, N = 47; MOOD, N = 44; and MOOD + SA, N = 21). Lower CA3 volume was found in HR (vs. HV), consistent with the direction of previously published findings in MOOD+SA (vs. HV and MOOD), suggesting the finding reflects a familial biological risk marker, not illness or treatment-related sequelae, of suicidal behavior and mood disorder. Familial suicide risk may be mediated in part by smaller CA3 volume. The structure may serve as a risk indicator and therapeutic target for suicide prevention strategies in high-risk families.