Left Hippocampal Volume Research Articles

UK Biobank imaging in a memory clinic population: associations between imaging‐derived phenotypes and cognition in the Oxford Brain Health Clinic

AbstractBackgroundSince August 2020, the Oxford Brain Health Clinic (BHC) has seen over 200 NHS memory clinic patients (O’Donoghue et al., 2022). In addition to high‐quality cognitive and lifestyle assessments and opportunities for research participation, patients receive a clinical MRI scan (T1‐weighted, T2‐FLAIR, and SWI) and can consent to additional research scans (diffusion MRI – dMRI, resting‐state functional MRI – rfMRI, and arterial spin labelling ‐ ASL) aligned to the UK Biobank (Griffanti et al., 2022). In this project, we aimed to automatically extract imaging‐derived phenotypes (IDPs) from the different imaging modalities acquired at the BHC and perform unimodal group‐level analyses to explore associations with cognition and diagnoses in this real‐world memory clinic population.MethodAs of January 2023, scans were analysed from 176 BHC patients, 101 of whom completed the additional research MRI scans. Cognitive scores (ACE‐III total score, N = 166) were available from the BHC appointment, and subsequent diagnoses (N = 118) were extracted from electronic healthcare records. Scans were processed using the UK Biobank pipeline (Alfaro‐Almagro et al., 2018), adapted to include previously described modifications (Griffanti et al., 2022). All IDPs were deconfounded for age, sex, and head size. We calculated Spearman correlations with ACE‐III cognitive scores and group comparisons (Kruskal‐Wallis tests) between 3 diagnostic groups: dementia, MCI, and no dementia‐related diagnosis. Results were corrected for multiple comparisons (false discovery rate with Benjamini‐Hochberg procedure; FDR‐adjusted p = 0.000016).Result11 IDPs significantly correlated with ACE‐III (Figure 1). Four voxel‐based morphometry temporal lobe measures, 3 FreeSurfer temporal lobe measures, FIRST left hippocampal volume, and SIENAX peripheral grey matter volume positively correlated with ACE‐III, in line with known dementia‐related atrophy patterns (Figure 2). dMRI mean diffusivity in the bilateral parahippocampal part of the cingulum negatively correlated with ACE‐III, highlighting white matter disruption (Figure 3). No FDR‐corrected differences were found between diagnostic groups.ConclusionUsing an unselected patient population, all of whom have a degree of memory problems, this work provides real‐world validation of associations that are well‐established in the research context. This represents a key step towards integrating research‐quality imaging in the memory clinic. Imaging and clinical variables are planned to be available through DPUK.

The utility of neuropsychological process scores in verbal recall and verbal fluency in persons with or at risk for dementia: Data from COMPASS‐ND

AbstractBackgroundSubjective cognitive decline (SCD) is considered a risk state for decline to mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD). By definition, individuals with SCD report concerns about changes in cognitive function but perform within normal limits on formal testing. This study examined whether neuropsychology process scores on tests of auditory learning and memory (the Rey Auditory Verbal Learning Test, RAVLT) and semantic and phonemic oral fluency were able to distinguish subtle difficulties in cognition, over and above total scores.MethodWe used data from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study to examine performance in 60 cognitively normal (CN) older adults with no cognitive complaints (mean age = 69 years; mean education = 16 years), 55 participants with SCD (age = 70; education = 17), 102 with MCI (age = 72; education = 16), and 47 with AD (age = 75; education = 15). Participants were matched on age and education, except for AD participants who were older. Age and education were co‐variates in all analyses. For the RAVLT, we examined delayed recall total scores, and process measures of primacy and recency recall on the second learning trial. For fluency, we examined total scores, and process measures of clustering, switching, word frequency, and age of acquisition.ResultRAVLT: An item position by group interaction revealed that primacy scores better distinguished all participant groups (CU>SCD>MCI>AD) than delayed recall (CU = SCD = MCI>AD). The left subiculum hippocampal subfield volume was positively associated with primacy scores in the MCI group, controlling for intracranial volume and age. Oral fluency: Both phonemic and semantic total scores discriminated CN, MCI, and AD participants in a stepwise manner; there was a non‐significant trend for SCD participants to perform more poorly than CN. Process scores did not provide additional discrimination.ConclusionThese findings indicate that primacy scores for episodic recall are sensitive to subtle memory deficits in SCD and may reflect hippocampal atrophy, supporting the clinical use of using serial position effects in the assessment of MCI and SCD.Learning Objective(s): Participants will learn about more detailed scoring methods for common neuropsychological tests, their sensitivity to subtle cognitive deficits in SCD, and their relationship with neuroanatomical structures.

Feasibility of comprehensive heart‐brain MRI for investigating hemodynamic coupling in aging

AbstractBackgroundCardiovascular risk factors have been linked with dementia risk in aging adults. However, mechanisms underlying heart‐brain hemodynamic coupling and effects on the brain remain unclear. 4D flow MRI is uniquely poised to systematically evaluate complex hemodynamics along the heart‐brain pathway. Owing to advancements yielding shorter scan times, 4D flow MRI can be acquired in approximately 7 minutes (heart) and 10 minutes (brain). This supports practical add‐on of 4D flow MRI to neuroimaging scans for comprehensive heart‐brain MRI evaluation in under an hour. We aimed to build a heart‐brain MRI acquisition and analysis framework to study relationships between hemodynamics and brain structure with age.Method17 healthy participants (age = 53.5±16.3[24‐76] years) underwent heart‐brain MRI at 3T (MAGNETOM Prisma, Siemens, Erlangen, Germany), including a free‐breathing whole‐chest 4D flow MRI research sequence, intracranial dual‐venc 4D flow MRI research sequence, and T1‐ and T2‐weighted structural neuroimaging. Participants were cognitively healthy and screened for history of cardiovascular and cerebrovascular problems that may influence blood flow. 4D flow MRI was used to evaluate blood flow velocities in the aorta and Circle of Willis (Figure 1: left). Mean velocity was determined on a voxel‐wise basis over the entire cardiac cycle. Volumetric and cortical thickness analysis was performed with FreeSurfer (v7.3; Figure 1: right). Left and right hippocampal and amygdala volumes were averaged and corrected for intracranial head size. We examined relationships between hemodynamics, volume and thickness measures, and age using Pearson correlations and multiple regression.ResultMean aortic velocity was associated with age (r = ‐0.59, p = 0.012), hippocampal volume (r = 0.68, p = 0.003), amygdala volume (r = 0.59, p = 0.012), and inferior temporal thickness (r = 0.49, p = 0.044). Figure 2. Mean velocity in the Circle of Willis (r = ‐0.49, p = 0.048), amygdala volume (r = ‐0.66, p = 0.004) and inferior temporal thickness (r = ‐0.60, p = 0.010) were also associated with age. Using multiple regression, mean aortic velocity was associated with hippocampal volume (p = 0.018) adjusting for age.ConclusionThis study demonstrates capture of comprehensive heart and brain data in a single imaging exam for assessment of age‐related relationships in hemodynamics and brain structure. Heart‐brain MRI is a promising tool for evaluation of hemodynamic coupling along the entire heart‐brain pathway. Grant support: NIH NIA P30AG059988, P30AG072977, K01AG080070; NINDS R21NS122511:

The Pattern of Hippocampus and Entorhinal Cortex Subregion Atrophy in Early Alzheimer’s Disease

AbstractBackgroundAtrophy of the hippocampus and entorhinal cortex (EC) develops early in Alzheimer’s disease (AD). The nature of atrophy along the anterior‐posterior longitudinal axis of the hippocampus and EC in individuals with amnestic mild cognitive impairment (aMCI) with positive AD biomarkers (AD aMCI) has been less researched. We aimed to reveal a possible different pattern of atrophy in longitudinal axis of the hippocampus and EC between AD aMCI individuals and those with AD biomarker negative aMCI (non‐AD aMCI).MethodIn total, 100 older adults with AD aMCI (n = 26), non‐AD aMCI (n = 23), mild AD dementia (n = 22) and cognitively normal (CN; n = 29) from the Czech Brain Aging Study (CBAS) underwent clinical and cognitive testing, and brain MRI with the 3‐dimensional T1‐weighted high‐resolution magnetization‐prepared rapid gradient echo sequences. An automated processing pipeline using the Advanced Normalization Tools based on the CBAS population template and a manual segmentation protocol were used to measure left and right subregional hippocampus and EC volumes including hippocampus head (HH), body (HB) and tail (HT), and anterolateral (alEC) and posteromedial (pmEC) entorhinal cortex volumes, respectively. Volumes were normalized to estimated total intracranial volume.ResultCompared to the CN group, the AD aMCI group had lower subregional hippocampus and EC volumes (p<0.05) except for right and left HH volumes. Compared to the non‐AD aMCI group, the AD aMCI group had lower right HB (p<0.05), right and left HT (p<0.01), right alEC (p<0.05), and right (p<0.01) and left (p<0.05) pmEC volumes. The mild AD dementia group had lower all subregional hippocampus and EC volumes compared to the CN group (p<0.05).ConclusionThese results are in line with previous research that demonstrated atrophy of the hippocampus and EC in early AD and indicate that atrophy of the posterior hippocampus and EC subregions may reflect AD pathology in aMCI individuals. Volumetric differences along the anterior‐posterior axis of the hippocampus and EC could serve as a potential biomarker to identify the underlying pathology in different neurodegenerative diseases.

Cross‐Sectional Associations Among Sleep Quality, Hippocampal Volume, and Memory Complaints in the Offspring Study

AbstractBackgroundPoor sleep quality, a modifiable risk factor for dementia, that is prevalent in non‐Hispanic Black and Hispanic adults, is associated with greater memory complaints and smaller hippocampal volumes in predominantly non‐Hispanic White samples. These associations among sleep quality, memory complaints, and hippocampal volumes are understudied in non‐Hispanic Black and Hispanic adults—populations disproportionately affected by poor sleep quality and cognitive performance. The objective of the current study was to examine associations among sleep quality, memory complaints, and hippocampal volumes in a racially and ethnically diverse, community‐based sample. Given sociocultural and environmental differences that affect sleep, brain measures, and cognitive performance, we hypothesize that poorer sleep quality is associated with more memory complaints and smaller hippocampal volumes, especially in Black and Hispanic adults.MethodParticipants included Black, Hispanic, and White adults from the Northern Manhattan community (n = 1175; 56±11 years; 67% women; 14±3 years of education; 17% Non‐Hispanic White; 20% Non‐Hispanic Black; 63% Hispanic). Participants self‐reported their sleep quality with the 9‐item Pittsburgh Sleep Quality Index, which measures average sleep disturbance over the past month. Participants self‐reported experiences with forgetting (e.g., names, faces, directions) with an abbreviated version of the Memory Functioning Questionnaire. In a subsample of participants, hippocampal volumes were measured on T1‐weighted MRI scans with FreeSurfer software. Sleep quality, hippocampal volume, and memory complaints were treated as continuous variables. We ran multivariable regression analyses adjusted for age, education, gender identity, depression severity, and intracranial volume for analyses with hippocampal volume.ResultAcross racial and ethnic groups, poorer sleep quality was associated with more memory complaints (n = 1175, B = ‐0.31, CI: [‐41,‐.22]). These associations were similar when analyses were stratified by racial and ethnic group. Among Hispanic adults, there was a trending association between poorer sleep quality and smaller left hippocampal volumes (n = 246, B = ‐8.94, CI: [‐18.75,0.88]).ConclusionPoorer sleep quality was associated with more memory complaints across racial and ethnic groups and showed a trending association with smaller hippocampal volumes in Hispanic adults. Future studies with larger samples should replicate these findings with longitudinal data to quantify the temporal relationship of sleep quality with memory complaints and structural brain changes.

Plasma neurofilament light and brain volumetric outcomes among middle‐aged urban adults

AbstractBackgroundElevated plasma neurofilament light chain (NfL) is associated with dementia, but the specific underlying mechanisms are largely unknown. We examined cross‐sectional and longitudinal relationships of plasma NfL with selected brain structural magnetic resonance imaging (sMRI) prognostic markers of dementia, namely global and cortical brain, hippocampal and white matter lesion volumes (WMLV).MethodData were extracted from three prospective visits within the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study, selecting participants with complete v1 (2004‐2009) and v2 (2009‐2013) plasma NfL exposure and ancillary sMRI data at vscan (2011‐2015, n = 179, mean v1 to vscan time: 5.4y). Multivariable‐adjusted linear regression models were conducted, overall, by sex, and by race, correcting for multiple testing with q‐values.ResultNfL(v1) (Loge transformed) had a moderately strong association with larger WMLV at follow‐up vscan visit, after a period of 5‐6 years of follow‐up, overall (β = +2.131±0.660, b = +0.29, p = 0.001, q = 0.0029). Moreover, a 1 unit increase in NfLv2 was linked to a left hippocampal volume that was lower by 125 mm3 (p = 0.004, q = 0.015), using minimally adjusted models and mainly among males. Associations were largely unaltered by further adjustment for downstream health‐related factors.ConclusionIn summary, plasma NfL may be an independent medium‐term (within 5 years) marker for increase in WMLV, and a short term (within 1 year) marker for smaller hippocampal volumes normalized to the intracranial volume, independently of other confounding factors. Therefore, plasma NfL holds promise as a blood‐based marker to predict future subclinical brain pathologies in middle‐aged adults.

Moderate-Severe TBI as a Progressive Disorder: Patterns and Predictors of Cognitive Declines in the Chronic Stages of Injury

Background Moderate-severe traumatic brain injury (TBI) has been associated with progressive cognitive decline in the chronic injury stages in a small number of studies. Objective This study aimed to (i) replicate our previous findings of decline from 1 to 3+ years post-injury in a larger, non-overlapping sample and (ii) extend these findings by examining the proportion of decliners in 2 earlier time windows, and by investigating novel predictors of decline. Methods N = 48 patients with moderate-severe TBI underwent neuropsychological assessment at 2, 5, 12 months, and 30+ months post-injury. We employed the Reliable Change Index (RCI) to evaluate decline, stability and improvement across time and logistic regression to identify predictors of decline (demographic/cognitive reserve; injury-related). Results The proportions of patients showing decline were: 12.5% (2-5 months post-injury), 17% (5-12 months post-injury), and 27% (12-30+ months post-injury). Measures of verbal retrieval were most sensitive to decline. Of the predictors, only left progressive hippocampal volume loss from 5 to 12 months post-injury significantly predicted cognitive decline from 12 to 30+ months post-injury. Conclusions Identical to our previous study, 27% of patients declined from 12 to 30+ months post-injury. Additionally, we found that the further from injury, the greater the proportion of patients declining. Importantly, earlier progressive hippocampal volume loss predicted later cognitive decline. Taken together, the findings highlight the need for ongoing research and treatment that target these deleterious mechanisms affecting patients in the chronic stages of moderate-severe TBI.

Early emotional caregiving environment and associations with memory performance and hippocampal volume in adolescents with prenatal drug exposure

Early adversities, including prenatal drug exposure (PDE) and a negative postnatal emotional caregiving environment, impact children’s long-term development. The protracted developmental course of memory and its underlying neural systems offer a valuable framework for understanding the longitudinal associations of pre- and postnatal factors on children with PDE. This study longitudinally examines memory and hippocampal development in 69 parent–child dyads to investigate how the early caregiving emotional environment affects children with PDE’s neural and cognitive systems. Measures of physical health, drug exposure, caregiver stress, depression, and distress were collected between 0 and 24 months At age 14 years, adolescents completed multiple measures of episodic memory, and at ages 14 and 18 years, adolescents underwent magnetic resonance imaging (MRI) scans. Latent constructs of episodic memory and the caregiving environment were created using Confirmatory Factor Analysis. Multiple regressions revealed a negative emotional caregiving environment during infancy was associated with poor memory performance and smaller left hippocampal volumes at 14 years. Better memory performance at 14 years predicted larger right hippocampal volume at 18 years. At 18 years, the association between the emotional caregiving environment and hippocampal volume was moderated by sex, such that a negative emotional caregiving environment was associated with larger left hippocampal volumes in males but not females. Findings suggest that the postnatal caregiving environment may modulate the effects of PDE across development, influencing neurocognitive development.

Abnormalities of Hippocampal Subfield and Amygdalar Nuclei Volumes and Clinical Correlates in Behavioral Variant Frontotemporal Dementia with Obsessive-Compulsive Behavior-A Pilot Study.

(1) Background: The hippocampus (HP) and amygdala are essential structures in obsessive-compulsive behavior (OCB); however, the specific role of the HP in patients with behavioral variant frontotemporal dementia (bvFTD) and OCB remains unclear. (2) Objective: We investigated the alterations of hippocampal and amygdalar volumes in patients with bvFTD and OCB and assessed the correlations of clinical severity with hippocampal subfield and amygdalar nuclei volumes in bvFTD patients with OCB. (3) Materials and methods: Eight bvFTD patients with OCB were recruited and compared with eight age- and sex-matched healthy controls (HCs). Hippocampal subfield and amygdalar nuclei volumes were analyzed automatically using a 3T magnetic resonance image and FreeSurfer v7.1.1. All participants completed the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Neuropsychiatric Inventory (NPI), and Frontal Behavioral Inventory (FBI). (4) Results: We observed remarkable reductions in bilateral total hippocampal volumes. Compared with the HCs, reductions in the left hippocampal subfield volume over the cornu ammonis (CA)1 body, CA2/3 body, CA4 body, granule cell layer, and molecular layer of the dentate gyrus (GC-ML-DG) body, molecular layer of the HP body, and hippocampal tail were more obvious in patients with bvFTD and OCB. Right subfield volumes over the CA1 body and molecular layer of the HP body were more significantly reduced in bvFTD patients with OCB than in those in HCs. We observed no significant difference in amygdalar nuclei volume between the groups. Among patients with bvFTD and OCB, Y-BOCS score was negatively correlated with left CA2/3 body volume (τb = -0.729, p < 0.001); total NPI score was negatively correlated with left GC-ML-DG body (τb = -0.648, p = 0.001) and total bilateral hippocampal volumes (left, τb = -0.629, p = 0.002; right, τb = -0.455, p = 0.023); and FBI score was negatively correlated with the left molecular layer of the HP body (τb = -0.668, p = 0.001), CA4 body (τb = -0.610, p = 0.002), and hippocampal tail volumes (τb = -0.552, p < 0.006). Mediation analysis confirmed these subfield volumes as direct biomarkers for clinical severity, independent of medial and lateral orbitofrontal volumes. (5) Conclusions: Alterations in hippocampal subfield volumes appear to be crucial in the pathophysiology of OCB development in patients with bvFTD.

Abstract 16099: Life’s Essential 8 and Genetic Predisposition Predict Brain Volume Change, Mild Cognitive Impairment and Dementia Risk

Introduction: Life’s Essential 8 (LE8) are the key measures for improving and maintaining cardiovascular health, as defined by the American Heart Association in 2022. The associations of LE8 with future brain volume change, mild cognitive decline (MCI), and dementia have been unclear. Hypothesis: We hypothesized that LE8 status might be related to future brain volume change, and predict risk of MCI and all-cause dementia. Apolipoprotein E (APOE) gene and polygenic risk score (PRS) may modify the association between them. Methods: We used cohort data from UK Biobank. LE8 was categorized into low (&lt;50 score), moderate (50-79 score), and high (≥80 score) levels. Genetic predisposition was measured by APOE e4 carrier status and a polygenic risk score (PRS) calculated based on 39 non-APOE genetic variants. Linear regression models were used to analyze LE8 every 10-score increase and change of brain volume (total and hippocampus etc.). Cox regression models were used to estimate the hazard ratio (HR) and 95%CI on the association between LE8 and MCI and dementia. Results: We included 126,785 participants with a mean (SD) age of 56.0 (8.0) years and 53.5% were female. After a median of 13.0 years follow-up, we recorded 1797 (1.4%) people with MCI, and 1055 (0.8%) with dementia. Every 10-score increase of LE8 was related to 2826.11mm 3 increase in total brain volume, 8.41 and 12.04 mm 3 increase in left and right hippocampus volume respectively, while 393.41mm 3 decrease in ventricular cerebrospinal fluid volume (p values all &lt;0.001). Compared to people with a low LE8, those with a high LE8 were associated with decreased risk of MCI (HR 0.54, 95% CI 0.44-0.68) and dementia (0.63, 0.47-0.85). Compared to people with high LE8 and no APOE e4 allele, those with low LE8 and one or two APOE e4 alleles were associated with increased risk of MCI (2.36, 1.69-3.29) and dementia (4.37, 2.86-6.68). The joint effects of LE8 and PRS showed that people with high LE8 and low PRS had lower risk of dementia. Conclusions: High LE8 was associated with increased total brain volume, hippocampus volume and decreased ventricular cerebrospinal fluid volume. Higher LE8 was also linked to reduced risk of MCI and dementia. There were joint effects between LE8 and APOE, PRS on MCI and dementia risk.

Automatic MRI volumetry in asymptomatic cases at risk for normal pressure hydrocephalus.

The occurrence of significant Alzheimer's disease (AD) pathology was described in approximately 30% of normal pressure hydrocephalus (NPH) cases, leading to the distinction between neurodegenerative and idiopathic forms of this disorder. Whether or not there is a specific MRI signature of NPH remains a matter of debate. The present study focuses on asymptomatic cases at risk for NPH as defined with automatic machine learning tools and combines automatic MRI assessment of cortical and white matter volumetry, risk of AD (AD-RAI), and brain age gap estimation (BrainAge). Our hypothesis was that brain aging and AD process-independent volumetric changes occur in asymptomatic NPH-positive cases. We explored the volumetric changes in normal aging-sensitive (entorhinal cortex and parahippocampal gyrus/PHG) and AD-signature areas (hippocampus), four control cortical areas (frontal, parietal, occipital, and temporal), and cerebral and cerebellar white matter in 30 asymptomatic cases at risk for NPH (NPH probability >30) compared to 30 NPH-negative cases (NPH probability <5) with preserved cognition. In univariate regression models, NPH positivity was associated with decreased volumes in the hippocampus, parahippocampal gyrus (PHG), and entorhinal cortex bilaterally. The strongest negative association was found in the left hippocampus that persisted when adjusting for AD-RAI and Brain Age values. A combined model including the three parameters explained 36.5% of the variance, left hippocampal volumes, and BrainAge values, which remained independent predictors of the NPH status. Bilateral PHG and entorhinal cortex volumes were negatively associated with NPH-positive status in univariate models but this relationship did not persist when adjusting for BrainAge, the latter remaining the only predictor of the NPH status. We also found a negative association between bilateral cerebral and cerebellar white matter volumes and NPH status that persisted after controlling for AD-RAI or Brain Age values, explaining between 50 and 65% of its variance. These observations support the idea that in cases at risk for NPH, as defined by support vector machine assessment of NPH-related MRI markers, brain aging-related and brain aging and AD-independent volumetric changes coexist. The latter concerns volume loss in restricted hippocampal and white matter areas that could be considered as the MRI signature of idiopathic forms of NPH.

43 Laterality of Hippocampal Volume Differentially Predicts Verbal Versus Nonverbal Memory Performance

Objective:Epilepsy is a chronic neurological disease, and surgery is a common treatment option for persons who do not respond to medication. Neuropsychology plays an important role in the epilepsy presurgical workup, characterizing the cognitive functioning of patients with epilepsy as well as assisting in the determination of which hemisphere seizures originate in the brain through testing of different cognitive functions. NeuroQuant is a relatively newer software that analyzes clinical neuroimaging to quantify brain volume. The objective of this study was to determine if changes in left versus right total hippocampal volume predicted changes in verbal versus nonverbal memory performance.Participants and Methods:Cognitive performance and NeuroQuant bilateral hippocampal volume were examined in a cross-sectional sample of 37 patients with epilepsy. All patients had undergone a comprehensive presurgical neuropsychological evaluation as well as magnetic resonance imaging (MRI) and these results were analyzed using a series of linear regression analyses.Results:Total left hippocampal volume was a significant predictor of delayed verbal free recall (RAVLT F(1, 31) = 4.79, p&lt; .036, RA2 = 0.13, and ß=.37, p&lt;.036). Even when controlling for the effects of biological sex, education, and depression, left hippocampal volume remained a significant predictor (ß=.42, p&lt;.025). Total left hippocampal volume did not predict other verbal memory scores. Total right hippocampal volume was a significant predictor of delayed nonverbal figure recall (RCFT F(1, 31)= 6.46, p&lt;.016), RA2 = .17 and ß=.42) p&lt;.016). When controlling for the effects of biological sex, education, and depression, right hippocampal volume remained a significant predictor (ß=.404, p&lt;.026). Total right hippocampal volume did not predict other nonverbal memory scores.Conclusions:These findings validate prior research demonstrating the importance of the left hippocampus in verbal memory and right hippocampus in nonverbal memory. Findings also demonstrate the clinical utility of neuropsychological evaluation in determining laterality in the epilepsy presurgical workup process, as well as support NeuroQuants’ inclusion as an additional consideration in that process.

30 Hippocampal Internal Architecture Subfield Volumes Associated with Systematic Inflammatory Biomarkers in Multiple Sclerosis

Objective:Multiple Sclerosis (MS) affects up to 500,000 adults in the United States, with cognitive impairment present in 45%-65% of people. Studies showed hippocampal atrophy in MS, but the underlying mechanisms remain unknown. Inflammation has been proposed to play a significant role, and associations between systemic inflammatory biomarkers and hippocampal atrophy have been shown in other neurological conditions. However, research exploring serum biomarker and volumetric associations in MS are lacking. Given that conventional imaging methods lack resolution for hippocampal internal architecture (HIA), new protocols were developed. We used the High-Resolution Multiple Image Co-Registration and Averaging (HR-MICRA) method to visualize the HIA subfields. We investigated the relationship between subfield volumes generated from HR-MICRA scans and systemic serum biomarkers in MS.Participants and Methods:Patients with MS were recruited (N= 34, mean age= 54.6, 35.3% Black) underwent Magnetic Resonance Imaging (MRI), and serum biomarkers were obtained, specifically chosen for their potential role in MS. Inflammatory biomarkers included; granulocyte colony stimulating factor (G-CSF), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor- a (TNF- a), and growth factors; vascular endothelial growth factor (VEGF); insulin-like growth factor-1 (IGF-1), and brain derived growth factor (BDNF). Imaging was performed in a Siemens Prisma 3T scanner with a 64-channel head coil using the HR-MICRA method. Hippocampal subfields were calculated using the Automated Segmentation of Hippocampal Subfields (ASHS) package. We used the Magdeburg Young Adult 7T Atlas for sub-hippocampal structures and Penn Temporal Lobe Epilepsy T1-MRI Whole Hippocampus ASHS Atlas for general hippocampal structure and segmentation. Pearson's product-moment analyses provided correlations between biomarkers and hippocampal subfield volumes for each cerebral hemisphere. A statistical significance level of p &lt; 0.05 was used for all analyses.Results:Correlations emerged between left hemisphere Cornu Ammonis (CA) 2 and G-CSF (r = -.384; p = .025); IL-10 (r = -.342; p = .048); VEGF (r = -.371; p= .031); and CA3 with IL-10 (r = -.488, p = .003); G-CSF (r = -.386; p= .024); VEGF (r = -.352; p= .041). Dentate gyrus correlated with MMP-9 (r =.416; p=.014); IL-10 (r = -.365; p =.034). BDNF was correlated with right hemisphere CA1 (r = -.417, p = .014), CA2 (r = -.497; p= .003) and CA3 (r = -.451; p=.007).Conclusions:In our sample of persons with MS, left hemisphere hippocampal subfield volumes were negatively correlated with inflammatory biomarkers, supporting previous reports linking inflammation to reduced brain volumes in other neurological conditions. In the right hemisphere, we found negative correlations between HIA and BDNF, suggesting a neuroprotective function for BDNF in this neurodegenerative disease. These findings in a representative sample of patients with MS highlight the need for further research exploring the relationship between HIA and systemic serum biomarkers in MS.

3 Olfactory Dysfunction as a Preclinical Biomarker of AD: Psychophysical Olfactory Performance Reflects Hippocampal Integrity in Non-Demented Older Adults

Objective:One of the greatest challenges of the Alzheimer’s disease (AD) epidemic is identifying the disease prior to substantial neurological compromise. The established biomarkers of AD, such as measures of cognitive impairment, hippocampal atrophy, and CSF measures of beta amyloid and tau, used in research and drug trials are less indicative of AD pathology in preclinical, non-demented, populations. Olfactory dysfunction, a well-established sensory impairment of AD found to correlate strongly with tau burden and hippocampal volume measures, has shown to be a promising preclinical biomarker for AD progression. Several studies have found either impaired odor identification or odor memory at baseline to predict 5-year follow-up cognitive decline and conversion from MCI to AD, but less is known about how olfactory performance reflects the integrity of associated brain regions such as the hippocampus. The present analysis aims to explore the value of psychophysical olfactory assessment as biomarker measure in preclinical AD studies and drug trials by investigating its relationships with structural measures of the hippocampus.Participants and Methods:A sample consisted of non-demented older adults (age &gt;75), recruited from the UCSD Alzheimer’s Disease Research Center as part of a ongoing olfactory biomarker study. Participants completed the AD Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13), San Diego Odor Identification Test (SDOIT), tests of odor recognition memory (ORMem) and odor associative memory (OAM), and MRI derived hippocampal volumes and average hippocampal occupancy (Avg HOC). Left and right hippocampal volumes were adjusted for each participant’s estimated intracranial volume. Bivariate correlations were calculated for ADAS-Cog-13 and SDOIT total scores, performance scores for odor recognition and odor associative memory tests, and the three hippocampal measures (bilateral volumes and average occupancy).Results:ADAS-Cog-13 score did not show significant correlations with either hippocampal measure at the .05 level. SDOIT scores were significantly correlated with the measure of Avg HOC (p&lt;.05). ORMem false positive responses were significantly correlated with Avg HOC (p&lt;.01) and right hippocampal volume (p&lt;.05). ORMem miss responses and OAM errors were both correlated with left (p&lt;.05) and right (p&lt;.01) hippocampal volumes.Conclusions:These results demonstrate that psychophysical assessments of odor identification and odor memory can better reflect the integrity of the hippocampus in nondemented older adults, compared to the neuropsychological ADAS-Cog-13. This is congruent with olfactory dysfunction preceding cognitive-memory decline in AD cases and provides support for the utility of psychophysical olfactory assessment along with other established AD biomarkers in research and drug trials in preclinical populations.Acknowledgements:Supported by NIH grant # R01AG062006-04 from the National Institute on Aging to CM. Special thank you to the staff and participants of the UCSD ADRC, especially Christina Gigliotti, and Aaron Jacobson at the UCSD Center for fMRI.

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

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

Effects of brain atrophy and altered functional connectivity on poststroke cognitive impairment

Background and PurposeBrain atrophy and disrupted functional connectivity are often present in patients with poststroke cognitive impairment (PSCI). This study aimed to explore the relationship between remote brain atrophy, connectional diaschisis and cognitive impairment in ischemic stroke patients to provide valuable information about the mechanisms underlying cognitive function recovery. MethodsForty first-time stroke patients with basal ganglia infarcts and twenty-nine age-matched healthy people were enrolled. All participants underwent T1-weighted and functional MRI scans, comprehensive cognitive function assessments at baseline, and 3-month follow-up. Brain volumes were calculated, and the atrophic regions were regarded as regions of interest in seed-based functional connectivity analyses. Pearson correlation analysis was used to explore the relationships among cognitive performance, brain atrophy, and functional connectivity alterations. ResultsCompared with healthy participants, stroke patients had worse cognitive performance at baseline and the 3-month follow-up. Worse cognitive performance was associated with smaller bilateral thalamus, left hippocampus, and left amygdala volumes, as well as lower functional connectivity between the left thalamus and the left medial superior frontal gyrus, between the right thalamus and the left median cingulate and paracingulate gyri, between the right hippocampus and the left medial superior frontal gyrus, and between the left amygdala and the right dorsolateral superior frontal gyrus. ConclusionsIn patients with basal ganglia infarction, connectional diaschisis between remote brain atrophy and the prefrontal lobe plays a significant role in PSCI. This finding provides new scientific evidence for understanding the mechanisms of PSCI and indicates that the prefrontal lobe may be a target to improve cognitive function after stroke.

Verbal memory depends on structural hippocampal subfield volume.

To investigate correlates in hippocampal subfield volume and verbal and visual memory function in patients with temporal lobe epilepsy (TLE), mild amnestic cognitive impairment (MCI) and heathy participants (HP). 50 right-handed participants were included in this study; 11 patients with temporal lobe epilepsy (TLE), 18 patients with mild amnestic cognitive impairment (MCI) and 21 healthy participants (HP). Verbal memory performance was evaluated via the verbal memory test (VLMT) and visual memory performance via the diagnosticum for cerebral damage (DCM). Hippocampal subfield volumes of T1-weighted Magnetic Resonance Imaging (MRI) scans were computed with FreeSurfer version 7.1. Stepwise correlation analyses were performed between the left hippocampal subfield volumes and learning, free recall, consolidation and recognition performance scores of the VLMT as well as between right hippocampal subfield volumes and visual memory performance. The volume of the left subicular complex was highly correlated to learning performance (β = 0.284; p = 0.042) and free recall performance in the VLMT (β = 0.434; p = 0.001). The volume of the left CA3 subfield showed a significant correlation to the consolidation performance in the VLMT (β = 0.378; p = 0.006) and recognition performance in the VLMT (β = 0.290; p = 0.037). There was no significant correlation identified between the right hippocampal subfields and the visual memory performance. The results of this study show verbal memory correlates with hippocampal subfields and support the role of left subiculum and left CA2/CA3 in verbal memory performance.

Comparison of Hippocampal Volume Change after Whole-Brain Radiotherapy with and without Hippocampal Avoidance: A Post-Hoc Analysis of a Phase II Randomized Trial

Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) preserves verbal memory compared to conformal WBRT in the previously reported randomized phase II clinical trial. In the present study, we analyzed the changes in hippocampus volume between groups at longitudinal follow-up time points. We hypothesize better preservation of hippocampus volumes with time in the HA-WBRT group. In this post-hoc analysis of a single institution, single-blind, randomized phase II trial, patients with brain metastases were randomized to receive either HA-WBRT or conformal WBRT with 30 Gy in 10 fractions. Patients received gadolinium contrast-enhanced MRI every three months or when clinically indicated after WBRT until progression. Only patients with at least one follow-up MRI were included. The MRI was used to assess baseline intracranial volume, hippocampal volume, the ratio of the total hippocampus to total intracranial volume (HT%), and the ratio of the left (HL%) or right (HR%) hippocampus to total intracranial volume. The volumes were automatically calculated by volBrain, an online MRI brain volumetry system. We used linear mixed models with fixed and random effects to compare the changes of repeated measures of the hippocampus volumes over time between the two groups. Among 70 randomized patients, 51 (25 in the HA-WBRT group and 26 in the WBRT group) were included in the present analysis. There were no significant differences between the two groups in the baseline demographics, HT%, HR%, and HL%. The median follow-up time was 13.9 months (range 2.1-31.8 months), and more than 60% of patients had at least one year of follow-up. Linear mixed model analyses showed a more significant decrease of HT% over time in the WBRT arm (regression coefficient β = -0.002, p = 0.001) compared to the HA-WBRT arm (regression coefficient, β = -0.001, p = 0.254), with a significant group by time interaction (F-value = 4.27, p = 0.050). The HL% was stable over time in the HA-WBRT arm (β = 0.0001, p = 0.769) while it decreased in the WBRT arm (β = -0.001, p = 0.003), with a significant group by time interaction (F-value = 6.51, p = 0.015). In contrast, the HR% decreased over time in both groups (HA-WBRT: regression coefficient β = -0.001, p = 0.006; WBRT: regression coefficient β = -0.001, p < 0.001) without significant group by time interaction (F-value = 0.20, p = 0.662). HA-WBRT better preserves total hippocampus volume with time compared to WBRT, with the main effect contributed by preserving the left hippocampus volume. Further research is warranted to establish the relationship between hippocampus volume perpetuation and cognitive function preservation. The future goal is to investigate whether left-side unilateral HA-WBRT provides similar neurocognitive function preservation compared to standard bilateral HA-WBRT.

Cognitive function and the longitudinal hippocampal axis in mesial temporal sclerosis

ObjectiveThe relationship of preoperative memory deficits in patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS) to the distribution of neuronal loss is uncertain. Building on the material specificity theory, we tested the hypothesis that visual memory deficits are associated with posterior hippocampal atrophy, whereas verbal memory deficits are associated with anterior hippocampal atrophy. MethodsWe studied 22 adults with mTLE and HS, calculating hippocampal head, body, and tail volumes, correcting for estimated total intracranial volume, using automated segmentation. Preoperative memory ability was evaluated with the Wechsler Memory Scale (WMS-II: logical memory, verbal paired associates, family pictures, and faces subtests). We correlated memory ability with hippocampal division volumes using SPSS 26.1 (repeated measures ANOVAs, one-way ANOVAs, Pearson r correlations) for statistical analysis. ResultsWe found a significant main effect of hippocampal subdivision, reporting volumetric differences between the head, body, and tail. Pairwise comparisons reported that the hippocampal head had significantly greater volume than both the body and tail (p < 0.001). For both left and right focus groups, the ipsilateral hippocampi were significantly smaller than the contralateral.Linear regression reported a left hippocampal model (head, body, and tail volumes) predicted performance on logical memory with the left hippocampal tail volume being the strongest predictor. A right hippocampal model (head, body, and tail volumes) predicted memory ability for family pictures and verbal paired associates at a trend level. ConclusionsIpsilateral hippocampal head and tail seem more vulnerable to injury than the body in both the left and right mTLE. Our study suggests there may be functional differences along the hippocampal longitudinal axis, particularly for the left hippocampal tail with verbal memory. Our findings are consistent with material-specific right-left differences in memory processing.

Pathway-specific polygenic scores for Alzheimer's disease are associated with changes in brain structure in younger and older adults.

Genome-wide association studies have identified multiple Alzheimer's disease risk loci with small effect sizes. Polygenic risk scores, which aggregate these variants, are associated with grey matter structural changes. However, genome-wide scores do not allow mechanistic interpretations. The present study explored associations between disease pathway-specific scores and grey matter structure in younger and older adults. Data from two separate population cohorts were used as follows: the Avon Longitudinal Study of Parents and Children, mean age 19.8, and UK Biobank, mean age 64.4 (combined n = 18 689). Alzheimer's polygenic risk scores were computed using the largest genome-wide association study of clinically assessed Alzheimer's to date. Relationships between subcortical volumes and cortical thickness, pathway-specific scores and genome-wide scores were examined. Increased pathway-specific scores were associated with reduced cortical thickness in both the younger and older cohorts. For example, the reverse cholesterol transport pathway score showed evidence of association with lower left middle temporal cortex thickness in the younger Avon participants (P = 0.034; beta = -0.013, CI -0.025, -0.001) and in the older UK Biobank participants (P = 0.019; beta = -0.003, CI -0.005, -4.56 × 10-4). Pathway scores were associated with smaller subcortical volumes, such as smaller hippocampal volume, in UK Biobank older adults. There was also evidence of positive association between subcortical volumes in Avon younger adults. For example, the tau protein-binding pathway score was negatively associated with left hippocampal volume in UK Biobank (P = 8.35 × 10-05; beta = -11.392, CI -17.066, -5.718) and positively associated with hippocampal volume in the Avon study (P = 0.040; beta = 51.952, CI 2.445, 101.460). The immune response score had a distinct pattern of association, being only associated with reduced thickness in the right posterior cingulate in older and younger adults (P = 0.011; beta = -0.003, CI -0.005, -0.001 in UK Biobank; P = 0.034; beta = -0.016, CI -0.031, -0.001 in the Avon study). The immune response score was associated with smaller subcortical volumes in the older adults, but not younger adults. The disease pathway scores showed greater evidence of association with imaging phenotypes than the genome-wide score. This suggests that pathway-specific polygenic methods may allow progress towards a mechanistic understanding of structural changes linked to polygenic risk in pre-clinical Alzheimer's disease. Pathway-specific profiling could further define pathophysiology in individuals, moving towards precision medicine in Alzheimer's disease.