Mean Hippocampal Volume Research Articles

Hippocampal Structures Among Japanese Adolescents Before and After the COVID-19 Pandemic

Few studies have used a large-sample, longitudinal, population-based cohort study to examine whether the COVID-19 pandemic as a global major life event is associated with structural plasticity of the adolescent hippocampus. To examine whether Japan's first state of emergency (SoE) during the COVID-19 pandemic was associated with alterations in the macrostructures and microstructures of the hippocampus during its development. The population-neuroscience Tokyo TEEN Cohort study is a prospective cohort study with 4 consecutive waves in Tokyo, Japan. Due to the SoE, data collection was suspended between March 27, 2020, and July 30, 2020. Analyzed data, comprising 1149 brain structural scans obtained from 479 participants, of whom 336 participants had undergone 2 or more scans, were collected between October 2013 and November 2021. Data were analyzed from August 2022 to December 2023. Japan's first SoE (April 7 to May 25, 2020). Hippocampal volume, 12 hippocampal subfield volumes, and 7 microstructural measures of the hippocampus. A total of 1060 brain scans from 459 participants (214 female participants [47%]) including 246 participants from wave 1 (median [IQR] age, 11.3 [11.1-11.7] years), 358 from wave 2 (median [IQR] age, 13.8 [13.3-14.5] years), 304 from wave 3 (median [IQR] age, 15.9 [15.4-16.5] years), and 152 from wave 4 (median [IQR] age, 17.9 [17.5-18.4] years) were included in the final main analysis. The generalized additive mixed model showed a significant associations of the SoE with the mean hippocampal volume (β = 102.19; 95% CI, 0.61-203.77; P = .049). The generalized linear mixed models showed the main associations of the SoE with hippocampal subfield volume (granule cell and molecular layer of the dentate gyrus: β = 18.19; 95% CI, 2.97-33.41; uncorrected P = .02; CA4: β = 12.75; 95% CI, 0.38-25.12; uncorrected P = .04; hippocampus-amygdala transition area: β = 5.67; 95% CI, 1.18-10.17; uncorrected P = .01), and fractional anisotropy (β = 0.03; 95% CI, 0.00-0.06; uncorrected P = .04). After the first SoE, a volumetric increase in the hippocampus and trend increase in 3 subfield volumes and microstructural integration of the hippocampus were observed, suggesting that the transient plasticity of the adolescent hippocampus was affected by a major life event along with the typical developmental trajectory.

Dosimetric Comparison of Hippocampal Sparing Whole Brain Radiotherapy by Volumetric Modulated Arc Therapy, Linac-based Intensity-modulated Radiation Therapy and 3-D Conformal Radiation Therapy: A Cross-sectional Study

Introduction: Brain metastases are treated with Whole-Brain Radiotherapy (WBRT) using the 3-D Conformal Radiation Therapy (3DCRT) technique. Attempts have been made to perform dosimetric analysis of WBRT with hippocampal sparing using 3DCRT, Volumetric Modulated Arc Therapy (VMAT), and Linac-based Intensity Modulated Radiation Therapy (linac-based IMRT), anticipating technical challenges during contouring and treatment planning. Aim: To perform a dosimetric analysis and comparison ofhippocampal sparing cranial irradiation by 3DCRT, VMAT, and IMRT treatment plans in brain metastases patients. Materials and Methods: The analytical cross-sectional dosimetric study was conducted from November 2022 to September 2023 at Government Medical College, Kottayam, Kerala, India. Ten patients treated for brain metastases with WBRT using 3DCRT were considered for dosimetric analysis. The Planning Target Volume (PTV) dosimetry and hippocampal dosimetry were studied for all ten patients. The important dosimetric parameters included volume receiving 100% dose, Target Coverage (TC), Homogeneity Index (HI) in PTV dosimetry, the mean hippocampal dose, and maximal hippocampal dose in hippocampal dosimetry. The hippocampus and hippocampal avoidance volume were contoured. Treatment plans for 3DCRT, VMAT, and Linac-based IMRT were generated for each patient’s prescription dose of 30 Gy in 10 fractions. The non-parametric Kruskal-Wallis test was used for data analysis. Results: The mean whole brain Planned Target Volume (PTV) was 1190 cm3 . The mean hippocampal avoidance volume was 30 cm3 , which occupied 2.5% of the whole brain PTV. The average median dose received by the hippocampus was 30.05 Gy, 17.1 Gy, and 17.5 Gy for 3DCRT, Linac-based IMRT, and VMAT, respectively. The mean dose for the hippocampus was 31.03 Gy, 17.7 Gy, and 17.5 Gy for 3DCRT, Linac-based IMRT, and VMAT, respectively (p<0.001). VMAT offered better hippocampal sparing compared to IMRT and 3DCRT. On average, VMAT offered a 2% improvement, and 3DCRT offered a 5% improvement in TC compared to IMRT. The HI of 3DCRT was 0.09, IMRT 0.199, and VMAT 0.150. Conclusion: VMAT and LINAC-based IMRT permit hippocampal-sparing WBRT with adequate target volume coverage and acceptable homogeneity when compared to 3DCRT plans. Thus, the dosimetric study suggests that modern radiotherapy techniques should be advocated for hippocampal-sparing WBRT.

The relationships between hippocampal cerebrovascular reactivity, hippocampal volume, and episodic memory in healthy ageing

AbstractBackgroundCerebrovascular biomarkers such as cerebrovascular reactivity (CVR) have previously been associated with episodic memory. However, the relationship between memory and regional CVR within the hippocampus is not well studied. Moreover, whether this association is affected by hippocampal volume remains to be investigated. This study investigated the associations between hippocampal physiology, structure, and memory in ageing.MethodData from 104 participants (Age: Mean = 77±4.9 years) of the ongoing Oxford Heart and Brain Study was analysed for this study. CVR was assessed by a compensatory change in the blood oxygenation level dependent magnetic resonance imaging (MRI) signal in response to a 5% CO2 challenge, hippocampus volume was measured by structural MRI, and episodic memory was assessed with the Hopkins Verbal Learning Test Revised (HVLT‐R).ResultMean hippocampal CVR decreased with age (β = ‐0.004, p = 0.006). Mean hippocampal CVR was positively associated with mean hippocampal volume (β = 0.11, p = 0.010), and this association was driven by the left hippocampus after correcting for age and sex. Higher hippocampal CVR was also associated with better performance on the HVLT (β = 13.8, p = 0.035). This association was fully mediated by hippocampal volume, suggesting a path from cerebrovascular reactivity to episodic memory (Sobel’s z = 2.16, p = 0.030, see Figure 1).ConclusionThis study presents novel findings showing that hippocampal CVR was associated with episodic memory, and this association was mediated by hippocampal volume. This suggests a pathway by which impairments in hippocampal CVR are associated with worse episodic memory via smaller hippocampal volumes.

Association of cancer history with structural brain aging markers of Alzheimer's disease and related dementias risk.

Cancer survivors are less likely than comparably aged individuals without a cancer history to develop Alzheimer's disease and related dementias (ADRD). In the UK Biobank, we investigated associations between cancer history and five structural magnetic resonance imaging (MRI) markers for ADRD risk, using linear mixed-effects models to assess differences in mean values and quantile regression to examine whether associations varied across the distribution of MRI markers. Cancer history was associated with smaller mean hippocampal volume (b=-19 mm3 , 95% CI=-36, -1) and lower mean cortical thickness in the Alzheimer's disease signature region (b=-0.004 mm, 95% CI=-0.007, -0.000). Quantile regressions indicated individuals most vulnerable to ADRD were more affected by cancer history. Some brain MRI markers associated with ADRD risk were elevated in adults with a history of cancer. The magnitude of the adverse associations varied across quantiles of neuroimaging markers, and the pattern suggests possible harmful associations for individuals already at high ADRD risk. We found no evidence of an inverse association between cancer history and ADRD-related neurodegeneration. Cancer history was associated with smaller mean hippocampal volume and lower mean cortical thickness in the Alzheimer's disease signature region. Quantile regressions indicated individuals most vulnerable to ADRD were more affected by cancer history.

Effect of Late-Stage Meniere's Disease and Vestibular Functional Impairment on Hippocampal Atrophy.

We investigated correlations among clinical features, degree of inner ear endolymphatic hydrops (EH), and hippocampal volume (HV) in different stages of Meniere's disease (MD). From February 2021 to April 2022, clinical data were collected from 99 patients (39 males, 60 females, mean age: 50.4 ± 10.0 [range: 26-69] years) with unilateral MD admitted to the Department of Vertigo Disease of Shandong ENT Hospital. The left and right ears were affected in 64 and 35 patients, respectively. There were 50 and 49 cases in early (Stages 1, 2) and late stages (Stages 3, 4), respectively. Fifty healthy participants were included as controls. Audiovestibular function test results, EH grading using gadolinium-enhanced magnetic resonance imaging (MRI), and HV determined on MRI were analyzed for patients at different stages of MD. Between-group comparisons of early and late MD revealed significant differences in the disease course, vestibular function (VF), degree of EH, and HV. There were no significant between-group differences based on age, sex, affected side, subjective degree of dizziness, hospital anxiety, or depression. Mean HV in patients with early-stage MD was correlated with the canal paresis value of the caloric test and pure tone hearing threshold, HV in late-stage patients was correlated with vestibular EH. Patients with late-stage MD exhibited severe auditory and VF impairments, increased EH, and atrophy of the HV. More advanced disease was associated with greater vestibular damage and degree of EH. 3 Laryngoscope, 134:410-418, 2024.

Mediation of Reduced Hippocampal Volume by Cerebral Amyloid Angiopathy in Pathologically Confirmed Patients with Alzheimer's Disease.

Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer's disease (AD). To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer's Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. The study included 231 patients with no (n = 45), mild (n = 70), moderate (n = 67), and severe (n = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p = 0.023) but this was not significant when adjusted for APOE ɛ4 (p = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p = 0.04); but (b) had no evidence of correlation with CDRsb score (p = 0.57). Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype.

Volumetric hippocampal changes in glioblastoma: a biomarker for neuroplasticity?

PurposeThe pleiotropic effect of gliomas on the development of cognitive disorders and structural brain changes has garnered increasing interest in recent years. While it is widely accepted that multimodal therapies for brain cancer can foster cognitive impairment, the direct effect of gliomas on critical cognitive areas before anti-tumor therapies is still controversial. In this study, we focused on the effect of IDH1 wild-type glioblastoma on the human hippocampus volume.MethodsWe carried out a case-control study using voxel-based morphometry assessment, analyzed with the Computational Anatomy Toolbox software. Glioblastoma diagnosis was performed according to the latest 2021 WHO classification. Due to stringent inclusion criteria, 15 patients affected by IDH1 wild type glioblastoma were included and compared to 19 age-matched controls.ResultsWe observed a statistically significant increase in the absolute mean hippocampal volume (p = 0.017), as well as in the ipsilateral (compared to the lesion, p = 0.027) and the contralateral hippocampal volumes (p = 0.014) in the group of patients. When the data were normalized per total intracranial volume, we confirmed a statistically significant increase only in the contralateral hippocampal volume (p = 0.042).ConclusionsTo the best of our knowledge, this is the first study to explore hippocampal volumetric changes in a cohort of adult patients affected by IDH1 wild-type glioblastoma, according to the latest WHO classification. We demonstrated an adaptive volumetric response of the hippocampus, which was more pronounced on the side contralateral to the lesion, suggesting substantial integrity and resilience of the medial temporal structures before the initiation of multimodal treatments.

Magnetic resonance volumetric analysis of hippocampal lobe in children aged 6 years or younger presenting with seizures

Background: Magnetic Resonance (MR) imaging studies are sufficient for detection of gross Hippocampal Atrophy (HA), subtle HA that may characterize early disease is often missed. Quantitative MR imaging/ MR volumetry can depict the presence and laterality of HA in epilepsy with accuracy rates that may exceed those achieved with visual inspection of clinical MR imaging studies. Materials and Methods: The study comprised of Children at or below 6 years of age admitted in pediatric ward for seizure from July 2019 to December 2020 in Mahatma Gandhi Medical College Hospital and Research Institute presenting with seizures, admitted to pediatric department, and referred to radiodiagnosis for MRI. Complete case history including the socio-demographic data and other medical conditions of the patient was recorded. Results: The maximum no of patients were recorded in the age range of 13-24 years, with a slight male predominance. 44.76% patients suffering from generalized seizures, followed by 35.24% with focal seizures & 20% with undetermined form of seizures. Mean right & left hippocampal volume was found to be 2.572 & 2.4168 respectively. The mean right hippocampal volume in patients suffering from focal, generalized & undetermined patients was found to be 2.56, 2.53 & 2.67, & on left side it was 2.34, 2.42 & 2.45 respectively. The mean right hippocampal volume in patients as per the frequency/episode of 1-3, 4-6, 1-9 & 10 & above per month was found to be 2.6, 2.48, 2.41 & 2.685 & on left side it was 2.44, 2.33, 2.35 & 2.65. Conclusion: The use of MRI has been well-established as a reliable marker for the assessment of the mean volume of the hippocampus which is commonly seen to be involved in patients with seizures. We found a correlation between the mean hippocampal volume against the frequency of seizures wherein there was an increase in the volume with an increase in the frequency of seizures. We recommend more studies to understand these associations as there are deficit in terms of these parameters.

Nighttime behaviors, but not insomnia, correlates with cognition and biomarkers of dementia

AbstractBackgroundWhile sleep disturbances appear to be risk factors in the progression of Alzheimer’s disease (AD) and other dementias, little is known about the prevalence across dementia severity and the potential influence on the trajectory of cognitive decline.MethodWe used the prospective National Alzheimer Coordinating Center Uniform Data Set to evaluate the hypotheses that the prevalence of insomnia differs by definition and by stage of cognitive impairment, that certain sleep features track with established biomarkers of AD, and that longitudinal changes in sleep disorders affect cognition and AD biomarkers. We conducted cross‐sectional analyses to determine the prevalence of clinician‐determined insomnia and nighttime behaviors (nighttime restlessness, agitation, daytime sleepiness) in normal, mild cognitive impairment (MCI), and demented individuals, as defined by Montreal Cognitive Assessment (MoCA) cut‐off scores obtained during the patient’s first visit. We evaluated mean MoCA scores, hippocampal volumes, and CSF phosphorylated tau:beta amyloid ratios obtained near the first visit using Analysis of Variance (ANOVA) with age as a covariate. In longitudinal evaluations, we classified changes in insomnia and nighttime behaviors as “none”, “remitted”, “acquired”, or “steady” between the first and last visits. Similar changes in MoCA scores and hippocampal volumes were assessed with repeated‐measure ANOVA.ResultThe prevalence of clinician‐identified insomnia at initial visits was 15%, 17%, and 13% for normal, MCI, and dementia groups respectively. Prevalence of clinician‐identified nighttime behaviors was 13%, 19%, and 27% respectively. Insomnia was significantly associated with higher MoCA scores, larger hippocampal volumes, and higher pTau:Beta values, indicating those with clinician‐identified insomnia had better cognition and less neurodegeneration than individuals who clinicians identified to be without insomnia. In contrast, the presence of nighttime behaviors were associated with significantly worse cognition, smaller hippocampal volumes, and lower pTau:Beta. Similar findings were seen between longitudinal associations of sleep disorders and cognition and hippocampal volumes.ConclusionOur findings suggest that the clinician determination of insomnia may be under‐recognized in patients with cognitive impairment seen in memory disorders clinics, and that nighttime behaviors especially when reported by family members may better reflect sleep disturbances, the biological underpinnings of AD, and have diagnostic specificity in AD over insomnia.

Neuroimaging Findings in a Racially and Ethnically Diverse Cohort of Oldest‐Old Individuals: The LifeAfter90 Study

AbstractBackgroundNeuroimaging biomarkers are important and widely used in dementia research. Such studies, however, are rare in the oldest‐old and essentially non‐existent in ethnically diverse oldest‐old populations where the prevalence of cognitive impairment is greatest and dementia due to multiple pathologies. Here we present initial neuroimaging findings in the LifeAfter90 Study, a racially and ethnically diverse cohort of oldest‐old individuals.MethodsLifeAfter90 is a cohort of long‐term members of a health‐care system aged 90+ without a dementia diagnosis in their medical record at recruitment and clinical assessments every 6 months. Of the >800 participants enrolled, a subset agreed to brain imaging (MRI and amyloid PET). Hippocampal volume (HV) and white matter hyperintensities (WMH) were normalized to intracranial volume and WMH was log transformed. Amyloid burden was quantified as the mean SUVR values of 4 regions and dichotomized with an SUVR cutpoint of 1.10. Mean neuroimaging marker levels were compared between ethnoracial groups with analysis of covariance adjusting for age.ResultsTo date, 99 individuals have undergone an MRI and 90 an amyloid PET scan. The average age at the time of scan was 93 years, 60% of participants were women, and 43% had college education or higher (Table 1). Unadjusted values of neuroimaging findings are in Table 1 and adjusted means in Table 2 and Figure. In our preliminary data, we see 44% amyloid positivity overall. Black individuals have the lowest proportion of amyloid positivity (32%) but among the highest WMH mean volume, whereas Latino individuals have the highest proportion of amyloid positivity (64%) and lowest WMH mean volume. Asian individuals had the highest mean hippocampal volume. Except for SUVR differences in Black vs Latino individuals (p=.04), there were no group differences in mean levels (Figure).ConclusionsWe present neuroimaging findings from a first‐of‐its kind multi‐ethnic cohort study of oldest‐old individuals. Although too early to test for differences due to the small number of individuals, we have indications of ethnoracial differences in levels of neuropathologies consistent with those of younger elderly. Determining the utility of neuroimaging biomarkers for identifying future disease in these individuals is essential for advancing cognitive research.

Sleep Disturbances, Cognitive Status, and Biomarkers of Dementia.

While sleep disturbances appear to be risk factors in Alzheimer's disease (AD) progression, information such as the prevalence across dementia severity and the influence on the trajectory of cognitive decline is unclear. We evaluate the hypotheses that the prevalence of insomnia differs by cognitive impairment, that sleep disturbances track with AD biomarkers, and that longitudinal changes in sleep disorders affect cognition. We used the National Alzheimer's Coordinating Center Database to determine the prevalence of clinician-identified insomnia and nighttime behaviors in normal, mild cognitive impairment (MCI), and demented individuals. We evaluated mean Montreal Cognitive Assessment (MoCA) scores, hippocampal volumes (HV), and CSF phosphorylated tau:amyloid-β ratios at first visit using analysis of variance with age as a covariate. In longitudinal evaluations, we assessed changes in MoCA scores and HV in insomnia and nighttime behaviors between the first and last visits. Prevalence of insomnia was 14%, 16%, and 11% for normal, MCI, and dementia groups. Prevalence of nighttime behaviors was 14%, 21%, and 29% respectively. Insomnia patients had higher MoCA scores, larger HV, and lower pTauBeta than individuals without insomnia, indicating less neurodegeneration. In contrast, nighttime behaviors were associated with worse cognition, smaller HV, and higher pTauBeta. Similar findings were seen between longitudinal associations of sleep disorders and cognition and HV. Our findings suggest that insomnia is unreliably recognized in patients with cognitive impairment. Nighttime behaviors may better indicate the presence of sleep disturbances and have diagnostic specificity in AD over insomnia.

Quadratic relationship between systolic blood pressure and white matter lesions in individuals with hypertension.

There is a well documented relationship between cardiovascular risk factors and the development of brain injury, which can lead to cognitive dysfunction. Hypertension (HTN) is a condition increasing the risk of silent and symptomatic ischemic brain lesions. Although benefits of hypertension treatment are indisputable, the target blood pressure value where the possibility of tissue damage is most reduced remains under debate. Our group performed a cross-sectional ( n = 376) and longitudinal ( n = 188) study of individuals without dementia or stroke (60% women n = 228, age 68.5 ± 7.4 years; men n = 148, age 70.7 ± 6.9 years). Participants were split into hypertensive ( n = 169) and normotensive ( n = 207) groups. MR images were obtained on a 3T system. Linear modeling was performed in hypertensive and normotensive cohorts to investigate the relationship between systolic (SBP) and diastolic (DBP) blood pressure, white matter lesion (WML), and brain volumes. Participants in the hypertensive cohort showed a quadratic relationship between SBP and WML, with the lowest amounts of WML being measured in participants with readings at approximately 124 mmHg. Additionally, the hypertensive cohort also exhibited a quadratic relationship between DBP and mean hippocampal volume; participants with readings at approximately 77 mmHg showing the largest volumes. Longitudinally, all groups experienced WML growth, despite different BP trajectories, further suggesting that WML expansion may occur despite or because of BP reduction in individuals with compromised vascular system. Overall, our study suggests that in the hypertensive group there is a valley of mid-range blood pressures displaying less pathology in the brain.

SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility

Mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures is associated with common variation at rs7587026, located in the promoter region of SCN1A. We sought to explore possible underlying mechanisms. SCN1A expression was analysed in hippocampal biopsy specimens of individuals with mesial temporal lobe epilepsy with hippocampal sclerosis who underwent surgical treatment, and hippocampal neuronal cell loss was quantitatively assessed using immunohistochemistry. In healthy individuals, hippocampal volume was measured using MRI. Analyses were performed stratified by rs7587026 type. To study the functional consequences of increased SCN1A expression, we generated, using transposon-mediated bacterial artificial chromosome transgenesis, a zebrafish line expressing exogenous scn1a, and performed EEG analysis on larval optic tecta at 4 day post-fertilization. Finally, we used an in vitro promoter analysis to study whether the genetic motif containing rs7587026 influences promoter activity. Hippocampal SCN1A expression differed by rs7587026 genotype (Kruskal–Wallis test P = 0.004). Individuals homozygous for the minor allele showed significantly increased expression compared to those homozygous for the major allele (Dunn’s test P = 0.003), and to heterozygotes (Dunn’s test P = 0.035). No statistically significant differences in hippocampal neuronal cell loss were observed between the three genotypes. Among 597 healthy participants, individuals homozygous for the minor allele at rs7587026 displayed significantly reduced mean hippocampal volume compared to major allele homozygotes (Cohen’s D = − 0.28, P = 0.02), and to heterozygotes (Cohen’s D = − 0.36, P = 0.009). Compared to wild type, scn1lab-overexpressing zebrafish larvae exhibited more frequent spontaneous seizures [one-way ANOVA F(4,54) = 6.95 (P < 0.001)]. The number of EEG discharges correlated with the level of scn1lab overexpression [one-way ANOVA F(4,15) = 10.75 (P < 0.001]. Finally, we showed that a 50 bp promoter motif containing rs7587026 exerts a strong regulatory role on SCN1A expression, though we could not directly link this to rs7587026 itself. Our results develop the mechanistic link between rs7587026 and mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures. Furthermore, we propose that quantitative precision may be important when increasing SCN1A expression in current strategies aiming to treat seizures in conditions involving SCN1A haploinsufficiency, such as Dravet syndrome.

Epigenome-wide association study of hippocampal volume.

Decreased hippocampal volume has been associated with age-related memory decline as well as several neurodegenerative and neuropsychiatric disorders. However, the molecular determinants of hippocampal volume are still poorly understood. Epigenetic changes alter the expression of many neurotrophic genes and may mediate the effects of gene/environment interactions on age-related hippocampal atrophy. Therefore, we aimed toidentify the epigenetic signatures associated with hippocampal volume through genome-wide DNA methylation profiling. We based our study onthe first 4,000 participantsof the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. Left, right, and mean hippocampalvolumeswere obtained from 3T MRI scans using standard FreeSurfer6.0 pipeline (Fischl et al. 2002). Besides, a volumetric asymmetry index, defined as the difference between the left and right hippocampal volumes divided by their sum, was calculated. DNA methylation levels were quantified using Infinium MethylationEPIC(850K)BeadChip.Multivariable regression models were used to examine the association betweenDNA methylation levels and hippocampal volume or asymmetry, while adjusting for age, sex, intracranial volume, batch information, population stratification, smoking, and education. False discovery rate (FDR)-adjusted p-values were applied to account for multiple comparisons. A total of 2295 participants (57.3% female, age 54.3± 14.0years (range 30 - 95 years)) with both brain imaging and methylation data were included in the analyses. Methylation at a probe mapping to ERCC6L2was associated with higher mean hippocampal volume (ß =0.006 ± 0.001, FDR-adjusted p=0.011), whereas methylation at two other probes, mapping to INTS8 and KIAA0564, was associated with the hippocampal asymmetry index (ß =-0.122 ± 0.019, FDR-adjusted p= 0.007, and ß =0.062 ± 0.011, FDR-adjusted p=0.023, respectively). In silico pathway analyses revealed that ERCC6L2is associated with DNA repair, mitochondrial function, and response to reactive oxygen species, while INTS8 andKIAA0564 have been associated with neurodevelopmental disorders. We discovered three novel DNA methylation markers of hippocampal volume and asymmetry, which could be instrumental in the further elucidation of the molecular basis of neurodevelopmental variations in hippocampal volume as well as age-and disease-related hippocampal atrophy. Reference: Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, et al. 2002. Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain. Neuron 33:341-355.

Investigating the relationship between BMI across adulthood and late life brain pathologies

BackgroundIn view of reported associations between high adiposity, particularly in midlife and late-life dementia risk, we aimed to determine associations between body mass index (BMI), and BMI changes across adulthood and brain structure and pathology at age 69–71 years.MethodsFour hundred sixty-five dementia-free participants from Insight 46, a sub-study of the British 1946 birth cohort, who had cross-sectional T1/FLAIR volumetric MRI, and florbetapir amyloid-PET imaging at age 69–71 years, were included in analyses. We quantified white matter hyperintensity volume (WMHV) using T1 and FLAIR 3D-MRI; β-amyloid (Aβ) positivity/negativity using a SUVR approach; and whole brain (WBV) and hippocampal volumes (HV) using 3D T1-MRI. We investigated the influence of BMI, and BMI changes at and between 36, 43, 53, 60–64, 69 and 71 years, on late-life WMHV, Aβ-status, WBV and mean HV. Analyses were repeated using overweight and obese status.ResultsAt no time-point was BMI, change in BMI or overweight/obese status associated with WMHV or WBV at age 69–71 years. Decreasing BMI in the 1–2 years before imaging was associated with an increased odds of being β-amyloid positive (OR 1.45, 95% confidence interval 1.09, 1.92). There were associations between being overweight and larger mean HV at ages 60–64 (β = 0.073 ml, 95% CI 0.009, 0.137), 69 (β = 0.076 ml, 95% CI 0.012, 0.140) and 71 years (β = 0.101 ml, 95% CI 0.037, 0.165). A similar, albeit weaker, trend was seen with obese status.ConclusionsUsing WMHV, β-amyloid status and brain volumes as indicators of brain health, we do not find evidence to explain reported associations between midlife obesity and late-life dementia risk. Declining BMI in later life may reflect preclinical Alzheimer’s disease.

Association of Intensive vs Standard Blood Pressure Control With Magnetic Resonance Imaging Biomarkers of Alzheimer Disease

Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control. To evaluate the association of intensive blood pressure control on AD-related brain biomarkers. This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020. Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317). Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle. Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy. Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment. ClinicalTrials.gov Identifier: NCT01206062.

Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure-the COGNITION.MATTERS-HF cohort study.

AimsWe quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in patients with chronic heart failure (HF) over a period of three years.Methods and resultsA total of 148 patients with mild stable HF entered this monocentric prospective cohort study: mean age 64.5 (10.8) years; 16.2% female; 77% in New York Heart Association functional classes I–II; 128 and 105 patients attended follow-up visits after 1 and 3 years, respectively. The assessment included cardiological, neurological, psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small: −62 mm3 [95% confidence interval (CI) −81 to −42, P < 0.0001). This corresponded to a relative change of −1.8% (95% CI −2.3 to −1.2), which was similar in magnitude as observed with physiological aging. Moreover, the load of white matter hypointensities increased within the limits of normal aging. Cognitive function during the 3-year observation period remained stable, with ‘intensity of attention’ as the only domain declining (LSmean −1.82 points, 95% CI −3.05 to −0.58, P = 0.004). After 3 years, performance in all domains of cognition remained associated with hippocampal volume (r ≥ 0.29).ConclusionIn patients with predominantly mild HF, the markedly reduced hippocampal volume observed at baseline was associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy became evident over a mid-term period of three years.

Magnetic Resonance Imaging Characterization of the Hippocampi in Temporal Lobe Epilepsy: Correlation of Volumetry and Apparent Diffusion Coefficient with Laterality and Duration of Seizures.

Background and Purpose It is estimated that hippocampal damage is seen in 50 to 70% of patients with temporal lobe epilepsy (TLE). Although most magnetic resonance imaging (MRI) studies are adequate to detect gross hippocampal atrophy, subtle changes that may characterize early disease in TLE, such as visually nonappreciable volume loss, may often be missed if objective volumetric analysis is not undertaken. Materials and Methods We conducted a hospital-based prospective analytical study in which 40 patients with partial seizures of temporal lobe origin were included and their hippocampal volumes (HVs) were determined by manual volumetric analysis. The findings were recorded and correlated with the side of seizure and its duration. The quantitative assessment was allotted different grades accordingly. Also, the apparent diffusion coefficient (ADC) values of bilateral hippocampi were estimated and their correlation with the side of seizure was determined. Results Most patients in the study were in the age group of 11 to 20 years (37.5%). In total, 57.5% had seizures for a period of 1 to 5 years. While 67.5% ( n = 27) had seizure on the right, 32.5% ( n = 13) had on the left. The mean HV estimated on the right and left were correlated with the side of seizure and found to be statistically significant ( p < 0.001 in those with right-sided seizures and p = 0.02 in those with left-sided seizures). Simultaneously the ADC values estimated were found to correlate with the laterality of seizures with a statistical difference ( p < 0.01) . Duration of seizures however did not show a positive correlation with the HV. Conclusion MRI with quantitative estimation of HV and ADC values can depict the presence and laterality in TLE with accuracy rates that exceed those achieved by visual inspection alone. Thus, quantitative MRI provides a useful means for translating volumetric analysis into clinical practice.

Vitamin D deficiency is associated with decreased cognition independent from the disease status and AD morphology

AbstractBackground25(OH)D deficiency was associated with cognitive impairment and altered brain volumes, namely reduction in white matter and medial temporal lobe and enlargement of lateral ventricles. 25(OH)D deficiency was also associated with the development of Alzheimer's disease (AD). In this study, we aimed to investigate whether 25(OH)D levels are independently associated with cognitive performance and AD‐associated morphology in a mixed sample.MethodThe study was conducted at Hacettepe University Faculty of Medicine, Ankara, Turkey. The participants were chosen from our dementia research database.Demographic variables, 25(OH)D levels, standardized Modified Mini Mental Test (3MS) z‐scores, 1.5 T brain MRI, the data for comorbid medical conditions and current prescription drugs were used as pertinent variables. FreeSurfer v.6.0 was used for automated structural neuroimaging analysis. Based on the previous literature, AD cortical signature, predictive cortical thickness, medial temporal lobe gray matter and mean hippocampal volumes were calculated and used independently to assess AD‐related morphological changes. Cut‐off for 25(OH)D deficiency was accepted as 20 ng/ml. Statistical analyses were conducted using IBM SPSS Statistics 23 for Windows. To assess the predictive power of 25(OH)D, regression models were used with standardized 3MS scores and AD‐related areas as dependent variables. Statistical assumptions were met for all models presented. Funded by TUBITAK 214S048 and Hacettepe University THD 2018‐17363.ResultA total of 210 patients over 55 years of age (47 AD, 15 nonAD dementia, 74 Mild and Subjective Cognitive Impairment, 74 cognitively intact) were included. Mean 25(OH) level was 22.48 ±15.8 ng/ml. 108 participants (51.4%) had 25(OH)D deficiency (AD 57%, nonAD Dementia 60%, SCI/MCI 51%, Control 46%, p&gt;0.5). 25(OH)D deficiency was significantly associated with 3MS scores (χ2 =5.608,df=1,p=0.018). The association was also marginally significant when adjusted for age, diagnosis and medial temporal lobe gray matter volume (Exp(β): 2.472, p=0.05). 25(OH)D levels were not associated with AD‐related morphological changes on multivariate analyses.ConclusionPlasma 25(OH)D levels are associated with cognitive performance regardless of the diagnosis. The effect seems to be independent of AD‐related brain morphological changes. Our results suggest an independent effect of 25(OH)D levels on cognition.

White Matter Hyperintensity Burden Is Associated With Hippocampal Subfield Volume in Stroke.

White matter hyperintensities of presumed vascular origin (WMH) are a prevalent form of cerebral small-vessel disease and an important risk factor for post-stroke cognitive dysfunction. Despite this prevalence, it is not well understood how WMH contributes to post-stroke cognitive dysfunction. Preliminary findings suggest that increasing WMH volume is associated with total hippocampal volume in chronic stroke patients. The hippocampus, however, is a complex structure with distinct subfields that have varying roles in the function of the hippocampal circuitry and unique anatomical projections to different brain regions. For these reasons, an investigation into the relationship between WMH and hippocampal subfield volume may further delineate how WMH predispose to post-stroke cognitive dysfunction. In a prospective study of acute ischemic stroke patients with moderate/severe WMH burden, we assessed the relationship between quantitative WMH burden and hippocampal subfield volumes. Patients underwent a 3T MRI brain within 2–5 days of stroke onset. Total WMH volume was calculated in a semi-automated manner. Mean cortical thickness and hippocampal volumes were measured in the contralesional hemisphere. Total and subfield hippocampal volumes were measured using an automated, high-resolution, ex vivo computational atlas. Linear regression analyses were performed for predictors of total and subfield hippocampal volumes. Forty patients with acute ischemic stroke and moderate/severe white matter hyperintensity burden were included in this analysis. Median WMH volume was 9.0 cm3. Adjusting for intracranial volume and stroke laterality, age (β = −3.7, P < 0.001), hypertension (β = −44.7, P = 0.04), WMH volume (β = −0.89, P = 0.049), and mean cortical thickness (β = 286.2, P = 0.006) were associated with total hippocampal volume. In multivariable analysis, age (β = −3.3, P < 0.001) and cortical thickness (β = 205.2, P = 0.028) remained independently associated with total hippocampal volume. In linear regression for predictors of hippocampal subfield volume, increasing WMH volume was associated with decreased hippocampal-amygdala transition area volume (β = −0.04, P = 0.001). These finding suggest that in ischemic stroke patients, increased WMH burden is associated with selective hippocampal subfield degeneration in the hippocampal-amygdala transition area.