Hippocampal volume moderates the association between cerebrospinal fluid growth-associated protein 43 and episodic memory performance in older adults

Age-related hippocampal atrophy is associated with memory loss in older adults, and certain hippocampal subfields are more vulnerable to age-related atrophy than others. Cardiorespiratory fitness (CRF) may be an important protective factor for preserving hippocampal volume, but little is known about how CRF relates to the volume of specific hippocampal subfields, and whether associations between CRF and hippocampal subfield volumes are related to episodic memory performance. To address these gaps, the current study evaluates the associations among baseline CRF, hippocampal subfield volumes, and episodic memory performance in cognitively unimpaired older adults from the Investigating Gains in Neurocognition Trial of Exercise (IGNITE) (NCT02875301). Participants (N = 601, ages 65-80, 72% female) completed assessments including a graded exercise test measuring peak oxygen comsumption (VO2peak) to assess CRF, cognitive testing, and high-resolution magnetic resonance imaging of the hippocampus processed with Automated Segmentation of Hippocampal Subfields (ASHS). Separate linear regression models examined whether CRF was associated with hippocampal subfield volumes and whether those assocations were moderated by age or sex. Mediation models examined whether hippocampal volumes statistically mediated the relationship between CRF and episodic memory performance. Covariates included age, sex, years of education, body mass index, estimated intracranial volume, and study site. Higher CRF was significantly associated with greater total left (B = 5.82, p = 0.039) and total right (B = 7.64, p = 0.006) hippocampal volume, as well as greater left CA2 (B = 0.14, p = 0.022) and dentate gyrus (DG; B = 2.34, p = 0.031) volume, and greater right CA1 (B = 3.99, p = 0.011), CA2 (B = 0.15, p = 0.002), and subiculum (B = 1.56, p = 0.004) volume. Sex significantly moderated left DG volume (B = -4.26, p = 0.017), such that the association was positive and significant only for males. Total left hippocampal volume [indirect effect = 0.002, 95% CI (0.0002, 0.00), p = 0.027] and right subiculum volume [indirect effect = 0.002, 95% CI (0.0007, 0.01), p = 0.006] statistically mediated the relationship between CRF and episodic memory performance. While higher CRF was significantly associated with greater total hippocampal volume, CRF was not associated with all underlying subfield volumes. Our results further demonstrate the relevance of the associations between CRF and hippocampal volume for episodic memory performance. Finally, our results suggest that the regionally-specific effects of aging and Alzheimer's disease on hippocampal subfields could be mitigated by maintaining higher CRF in older adulthood.

Interactive effects of chronic cigarette smoking and age on hippocampal volumes

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.

While cortical processes play an important role in controlling locomotion, the underlying structural brain changes associated with slowing of gait in aging are not yet fully established. Our study aimed to examine the relationship between cortical gray matter volume (GM), white matter volume (WM), ventricular volume (VV), hippocampal and hippocampal subfield volumes, and gait velocity in older adults free of dementia. Gait and cognitive performance was tested in 112 community-residing adults, age 70 years and over, participating in the Einstein Aging Study. Gait velocity (cm/s) was obtained using an instrumented walkway. Volumetric MRI measures were estimated using a FreeSurfer software. We examined the cross-sectional relationship of GM, WM, VV, and hippocampal total and subfield volumes and gait velocity using linear regression models. In complementary models, the effect of memory performance on the relationship between gait velocity and regional volumes was evaluated. Slower gait velocity was associated with smaller cortical GM and total hippocampal volumes. There was no association between gait velocity and WM or VV. Among hippocampal subfields, only smaller presubiculum volume was significantly associated with decrease in gait velocity. Addition of the memory performance to the models attenuated the association between gait velocity and all volumetric measures. Our findings indicate that total GM and hippocampal volumes as well as specific hippocampal subfield volumes are inversely associated with locomotor function. These associations are probably affected by cognitive status of study population.

Studies have shown that patients with schizophrenia have smaller hippocampi than healthy comparison subjects. There are, however, inconsistencies regarding the relationship between clinical characteristics and topographical differences in hippocampal volumetry. The authors investigated hippocampal volumes in minimally treated patients with first-episode schizophrenia spectrum disorders, relative to comparison subjects. Thirty-nine consecutive patients and 29 matched comparison subjects were scanned using 1.5 tesla MR system. Patients had significantly smaller right anterior, right, and anterior hippocampal volumes than comparison subjects. There was a gender by diagnosis effect: female patients showed significantly smaller anterior and right hippocampal volumes than female comparison subjects, an effect not seen in male patients. Our results suggest that smaller hippocampal volumes are present even in early stages of the illness.

Hippocampal Volumes in First-Episode Psychosis

BackgroundPhysical exercise in cancer patients is a promising intervention to improve cognition and increase brain volume, including hippocampal volume. We investigated whether a 6-month exercise intervention primarily impacts total hippocampal volume and additionally hippocampal subfield volumes, cortical thickness and grey matter volume in previously physically inactive breast cancer patients. Furthermore, we evaluated associations with verbal memory. MethodsChemotherapy-exposed breast cancer patients (stage I-III, 2–4 years post diagnosis) with cognitive problems were included and randomized in an exercise intervention (n = 70, age = 52.5 ± 9.0 years) or control group (n = 72, age = 53.2 ± 8.6 years). The intervention consisted of 2x1 hours/week of supervised aerobic and strength training and 2x1 hours/week Nordic or power walking. At baseline and at 6-month follow-up, volumetric brain measures were derived from 3D T1-weighted 3T magnetic resonance imaging scans, including hippocampal (subfield) volume (FreeSurfer), cortical thickness (CAT12), and grey matter volume (voxel-based morphometry CAT12). Physical fitness was measured with a cardiopulmonary exercise test. Memory functioning was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R total recall) and Wordlist Learning of an online cognitive test battery, the Amsterdam Cognition Scan (ACS Wordlist Learning). An explorative analysis was conducted in highly fatigued patients (score of ≥ 39 on the symptom scale ‘fatigue’ of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), as previous research in this dataset has shown that the intervention improved cognition only in these patients. ResultsMultiple regression analyses and voxel-based morphometry revealed no significant intervention effects on brain volume, although at baseline increased physical fitness was significantly related to larger brain volume (e.g., total hippocampal volume: R = 0.32, B = 21.7 mm3, 95 % CI = 3.0 – 40.4). Subgroup analyses showed an intervention effect in highly fatigued patients. Unexpectedly, these patients had significant reductions in hippocampal volume, compared to the control group (e.g., total hippocampal volume: B = −52.3 mm3, 95 % CI = −100.3 – −4.4)), which was related to improved memory functioning (HVLT-R total recall: B = −0.022, 95 % CI = −0.039 – −0.005; ACS Wordlist Learning: B = −0.039, 95 % CI = −0.062 – −0.015). ConclusionsNo exercise intervention effects were found on hippocampal volume, hippocampal subfield volumes, cortical thickness or grey matter volume for the entire intervention group. Contrary to what we expected, in highly fatigued patients a reduction in hippocampal volume was found after the intervention, which was related to improved memory functioning. These results suggest that physical fitness may benefit cognition in specific groups and stress the importance of further research into the biological basis of this finding.

Sex-Dependent Hippocampal Volume Reductions in Schizophrenia Relate to Episodic Memory Deficits

Major depressive episodes over the course of 7 years and hippocampal subfield volumes at 7 tesla MRI: The PREDICT-MR study

IntroductionAnimal studies have shown that male but not female offspring exposed to maternal obesity have abnormal hippocampal development. Similar sex differences were observed in animal models of developmental programming by prenatal stress or maternal diabetes. We aimed to translate this work into humans by examining sex‐specific effects of exposure to maternal obesity on hippocampal volume in children.MethodsEighty‐eight children (37 boys and 51 girls) aged 7–11 years completed the study. Maternal prepregnancy body mass index (BMI) was obtained from electronic medical records. A high‐resolution anatomical scan was performed using a 3‐Tesla magnetic resonance imaging (MRI) scanner. Total hippocampal volume and hippocampal subfield volumes were analyzed using FreeSurfer 6.0. Linear regression was used to investigate sex differences in relationships between maternal prepregnancy BMI and child hippocampal volume.ResultsMaternal prepregnancy BMI ranged from 19.0 to 50.4 kg/m2. We observed a significant interaction between maternal prepregnancy BMI and sex on total hippocampal volume (p < .001) such that boys (r = −.39, p = .018) but not girls (r = .11, p = .45) had a significant negative relationship between maternal prepregnancy BMI and total hippocampal volume. This relationship in boys remained significant after adjusting for child and maternal covariates (β = −126.98, p = .012). The sex interactions with prepregnancy BMI were consistently observed in hippocampal subfields CA1 (p = .008), CA2/3 (p = .016), CA4 (p = .002), dentate gyrus (p < .001), and subiculum (p < .001).ConclusionsOur results support findings in animal models and suggest that boys may be more vulnerable to the adverse effects of exposure to maternal obesity on hippocampal development than girls.

High field structural MRI reveals specific episodic memory correlates in the subfields of the hippocampus

IntroductionEven though seasonal and sex‐dependent changes in hippocampal and subfield volumes are well known in animals, little is known about changes in humans. We hypothesized that changes in photoperiod would predict changes in hippocampal subfield volumes and that this association would be different between females and males.MethodsA total of 10,033 participants ranging in age from 45 to 79 years were scanned by MRI in a single location as part of the UK Biobank project. Hippocampal subfield volumes were obtained using automated processing and segmentation algorithms using the developmental version of the FreeSurfer v 6.0. Photoperiod was defined as the number of hours between sunrise and sunset on the day of scan.ResultsPhotoperiod correlated positively with total hippocampal volume and all subfield volumes across participants as well as in each sex individually, with females showing greater seasonal variation in a majority of left subfield volumes compared with males. ANCOVAs revealed significant differences in rate of change in only left subiculum, CA‐4, and GC‐ML‐DG between females and males. PLS showed highest loadings of hippocampal subfields in both females and males in GC‐ML‐DG, CA1, CA4, subiculum, and CA3 for left hemisphere and CA1, GC‐ML‐DG, CA4; subiculum and CA3 for right hemisphere in females; GC‐ML‐DG, CA1, subiculum, CA4 and CA3 for left hemisphere; CA1, GC‐ML‐DG, subiculum, CA4 and CA3 for right hemisphere in males.ConclusionThe influence of day length on hippocampal volume has implications for modeling age‐related decline in memory in older adults, and sex differences suggest an important role for hormones in these effects.

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

This cross-sectional study examined associations between multiple fluid biomarkers of neuronal and glial dysfunction (plasma neurofilament light chain, CSF growth-associated protein 43 and CSF soluble triggering receptor expressed on myeloid cells 2), total white matter hyperintensity volume and episodic memory and executive function performance in the context of Alzheimer's disease biomarker status. A total of 563 participants (mean age = 71.9 years, standard deviation = 7.2) from the Alzheimer's Disease Neuroimaging Initiative were classified by the amyloid-β/tau/neurodegeneration framework into no Alzheimer's disease pathology (n = 176), suspected non-Alzheimer's disease pathophysiology (n = 87) or Alzheimer's disease continuum (n = 300) groups. Participants completed baseline neuropsychological assessment, plasma/CSF biomarker collection and MRI. Analyses explored the relative contributions of biomarkers to episodic memory and executive function performance and whether relationships varied by amyloid-β/tau/neurodegeneration group status. Across all participants, neurofilament light chain ( = -0.14, P < 0.001) and growth-associated protein 43 ( = -0.13, P < 0.001) were the strongest biomarkers associated with episodic memory performance, such that greater levels were associated with worse episodic memory. There was a group by growth-associated protein 43 interaction with episodic memory: greater growth-associated protein 43 was associated with lower episodic memory performance in participants classified as Alzheimer's disease continuum relative to the no Alzheimer's disease pathology group ( = -0.26, P < 0.001). No robust associations between biomarkers and executive function performance or between soluble triggering receptor expressed on myeloid cells 2, white matter hyperintensity volume and cognition were observed. Biomarkers of neuro-axonal injury and synaptic dysfunction may independently contribute to episodic memory performance across participants with differing amyloid-β/tau/neurodegeneration profiles. Growth-associated protein 43 may predict worse episodic memory performance in participants with greater Alzheimer's disease pathology. These biomarkers of neuronal dysfunction may serve as domain-specific cognitive correlates in the context of Alzheimer's disease biomarker status.

Preterm birth (< 37weeks gestation) has been associated with memory deficits, which has prompted investigation of possible alterations in hippocampal volume in this population. However, existing literature reports varying effects of premature birth on hippocampal volume. Specifically, it is unclear whether smaller hippocampal volume in preterm-born individuals is merely reflective of smaller total brain volume. Further, it is not clear if hippocampal volume is associated with episodic memory functioning in preterm-born individuals. Meta-analysis was used to investigate the effects of premature birth on hippocampal volume and episodic memory from early development to young adulthood (birth to 26). PubMed, PsychINFO, and Web of Science were searched for English peer-reviewed articles that included hippocampal volume of preterm and term-born individuals. Thirty articles met the inclusion criteria. Separate meta-analyses were used to evaluate standardized mean differences between preterm and term-born individuals in uncorrected and corrected hippocampal volume, as well as verbal and visual episodic memory. Both uncorrected and corrected hippocampal volume were smaller in preterm-born compared to term-born individuals. Although preterm-born individuals had lower episodic memory performance than term-born individuals, the limited number of studies only permitted a qualitative review of the association between episodic memory performance and hippocampal volume. Tested moderators included mean age, pre/post-surfactant era, birth weight, gestational age, demarcation method, magnet strength, and slice thickness. With this meta-analysis, we provide novel evidence of the effects of premature birth on hippocampal volume.