FreeSurfer vs. Manual Tracing: Distinguishing Stable from Cognitively Declining Elders Using Prospectively Measured Hippocampal Volume

Objective: Alzheimer’s disease (AD) pathology is thought to begin years before symptom onset. Hippocampal volume is sensitive to age-related cognitive decline and conversion from MCI to AD. Measurement of hippocampal volumes has used either automated methods such as FreeSurfer (FS) or manual tracing (MT). We compared the ability of FS and MT in detecting baseline volume differences in cognitively intact older individuals who subsequently showed significant cognitive decline. Participants and Methods: Seventy-five cognitively intact elders underwent baseline and 18-month follow-up structural MRI scan and neuropsychological testing. Participants were classified as Declining (n=27) or Stable (n=48) based on the baseline to 18-month changes on a listlearning task and a measure of general cognitive functioning. A 2 (left, right) x 2 (anterior, posterior) x 2 (Declining, Stable) repeated measures ANOVA was conducted for both the MT and FS hippocampal volumes derived at baseline. Results: MT identified significantly smaller left and right hippocampal volumes and smaller anterior than posterior hippocampal volumes in Declining compared to Stable subjects. In contrast, no group differences in hippocampal volumes were observed using FS. Notably, MT included more subiculum and entorhinal cortex, while FS included more of the amygdala and the CA region of the hippocampus. Conclusions: MT was superior to FS for detecting prospective volumetric differences associated with cognitive decline in cognitively intact older participants. MT afforded more unique coverage of the anterior hippocampus than FS. The differences in regional coverage of the mesial temporal lobe between MT and FS may account for the different findings in discriminating Stable and Declining groups

In Vivo Hippocampal Measurement and Memory: A Comparison of Manual Tracing and Automated Segmentation in a Large Community-Based Sample

While manual tracing is the method of choice in measuring hippocampal volume, its time intensive nature and proneness to human error make automated methods attractive, especially when applied to large samples. Few studies have systematically compared the performance of the two techniques. In this study, we measured hippocampal volumes in a large (N = 403) population-based sample of individuals aged 44–48 years using manual tracing by a trained researcher and automated procedure using Freesurfer (http://surfer.nmr.mgh.harvard.edu) imaging suite. Results showed that absolute hippocampal volumes assessed with these methods were significantly different, with automated measures using the Freesurfer software suite being significantly larger, by 23% for the left and 29% for the right hippocampus. The correlation between the two methods varied from 0.61 to 0.80, with lower correlations for hippocampi with visible abnormalities. Inspection of 2D and 3D models suggested that this difference was largely due to greater inclusion of boundary voxels by the automated method and variations in subiculum/entorhinal segmentation. The correlation between left and right hippocampal volumes was very similar by the two methods. The relationship of hippocampal volumes to selected sociodemographic and cognitive variables was not affected by the measurement method, with each measure showing an association with memory performance and suggesting that both were equally valid for this purpose. This study supports the use of automated measures, based on Freesurfer in this instance, as being sufficiently reliable and valid particularly in the context of larger sample sizes when the research question does not rely on ‘true’ hippocampal volumes

Relationship between hippocampal structure and memory function in elderly humans

With progressing age, the ability to recollect personal events declines, whereas familiarity-based memory remains relatively intact. It has been hypothesized that age-related hippocampal atrophy may contribute to this pattern because of its critical role for recollection in younger humans and after acute injury. Here, we show that hippocampal volume loss in healthy older persons correlates with gray matter loss (estimated with voxel-based morphometry) of the entire limbic system and shows no correlation with an electrophysiological (event-related potential [ERP]) index of recollection. Instead, it covaries with more substantial and less specific electrophysiological changes of stimulus processing. Age-related changes in another complementary structural measure, hippocampal diffusion, on the other hand, seemed to be more regionally selective and showed the expected correlation with the ERP index of recollection. Thus, hippocampal atrophy in older persons accompanies limbic atrophy, and its functional impact on memory is more fundamental than merely affecting recollection

Higher estrogen levels are not associated with larger hippocampi and better memory performance

BACKGROUND: Estrogens may prevent cognitive decline and Alzheimer disease. Animal study findings have shown beneficial effects of estrogen on the brain, particularly on the hippocampus, a structure related to memory performance and early Alzheimer disease. OBJECTIVE: To investigate whether higher levels of endogenous estradiol in older women and men are associated with larger hippocampal volumes on magnetic resonance imaging and better memory performance. DESIGN AND SETTING: Cross-sectional analysis within the Rotterdam Scan Study, a population-based study in the Netherlands of elderly subjects who do not have dementia. PARTICIPANTS: Two hundred ten women and 202 men, aged 60 to 90 years, with plasma levels of total estradiol and, in part, 162 women and 149 men also with levels of bioavailable and free estradiol. MAIN OUTCOME MEASURE: Hippocampal volumes on magnetic resonance imaging and memory performance (delayed recall). RESULTS: Women with higher total estradiol levels had smaller hippocampal volumes and poorer memory performance -0.29 mL (95% confidence interval, -0.57 to -0.00) and -0.4 (95% confidence interval, -1.3 to 0.5) fewe

Automated hippocampal segmentation in patients with epilepsy: Available free online

Hippocampal sclerosis, a common cause of refractory focal epilepsy, requires hippocampal volumetry for accurate diagnosis and surgical planning. Manual segmentation is time-consuming and subject to interrater/intrarater variability. Automated algorithms perform poorly in patients with temporal lobe epilepsy. We validate and make freely available online a novel automated method

Cerebral atrophy in mild cognitive impairment and Alzheimer disease: rates and acceleration.

OBJECTIVE: To quantify the regional and global cerebral atrophy rates and assess acceleration rates in healthy controls, subjects with mild cognitive impairment (MCI), and subjects with mild Alzheimer disease (AD). METHODS: Using 0-, 6-, 12-, 18-, 24-, and 36-month MRI scans of controls and subjects with MCI and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we calculated volume change of whole brain, hippocampus, and ventricles between all pairs of scans using the boundary shift integral. RESULTS: We found no evidence of acceleration in whole-brain atrophy rates in any group. There was evidence that hippocampal atrophy rates in MCI subjects accelerate by 0.22%/year2 on average (p = 0.037). There was evidence of acceleration in rates of ventricular enlargement in subjects with MCI (p = 0.001) and AD (p < 0.001), with rates estimated to increase by 0.27 mL/year2 (95% confidence interval 0.12, 0.43) and 0.88 mL/year2 (95% confidence interval 0.47, 1.29), respectively. A post hoc analysis suggested that the acceleration of hippocampal loss in MCI subjects was mainly driven by the MCI subjects that were observed to progress to clinical AD within 3 years of baseline, with this group showing hippocampal atrophy rate acceleration of 0.50%/year2 (p = 0.003). CONCLUSIONS: The small acceleration rates suggest a long period of transition to the pathologic losses seen in clinical AD. The acceleration in hippocampal atrophy rates in MCI subjects in the ADNI seems to be driven by those MCI subjects who concurrently progressed to a clinical diagnosis of AD

Recognition of Famous Names Predicts Cognitive Decline in Healthy Elders

Objective: The ability to recognize familiar people is impaired in both Mild Cognitive Impairment (MCI) and Alzheimer’s Dementia (AD). In addition, both groups often demonstrate a time-limited temporal gradient (TG) in which well known people from decades earlier are better recalled than those learned recently. In this study, we examined the TG in cognitively intact elders for remote famous names (1950–1965) compared to more recent famous names (1995–2005). We hypothesized that the TG pattern on a famous name recognition task (FNRT) would predict future cognitive decline, and also show a significant correlation with hippocampal volume. Method: Seventy-eight healthy elders (ages 65–90) with age-appropriate cognitive functioning at baseline were administered a FNRT. Follow-up testing 18 months later produced two groups: Declining (≥ 1 SD reduction on at least one of three measures) and Stable (\u3c 1 SD). Results: The Declining group (N = 27) recognized fewer recent famous names than the Stable group (N = 51), although recognition for remote names was comparable. Baseline MRI volumes for both the left and right hippocampi were significantly smaller in the Declining group than the Stable group. Smaller baseline hippocampal volume was also significantly correlated with poorer performance for recent, but not remote famous names. Logistic regression analyses indicated that baseline TG performance was a significant predictor of group status (Declining vs. Stable) independent of chronological age and APOE ε4 inheritance. Conclusions: The TG for famous name recognition may serve as an early preclinical cognitive marker of cognitive decline in healthy older individual

Altered hippocampal function in major depression despite intact structure and resting perfusion

Background: Hippocampal volume reductions in major depression have been frequently reported. However, evidence for functional abnormalities in the same region in depression has been less clear. We investigated hippocampal function in depression using functional magnetic resonance imaging (fMRI) and neuropsychological tasks tapping spatial memory function, with complementing measures of hippocampal volume and resting blood flow to aid interpretation. Method: A total of 20 patients with major depressive disorder (MDD) and a matched group of 20 healthy individuals participated. Participants underwent multimodal magnetic resonance imaging (MRI): fMRI during a spatial memory task, and structural MRI and resting blood flow measurements of the hippocampal region using arterial spin labelling. An offline battery of neuropsychological tests, including several measures of spatial memory, was also completed. Results: The fMRI analysis showed significant group differences in bilateral anterior regions of the hippocampus. While control participants showed task-dependent differences in blood oxygen level-dependent (BOLD) signal, depressed patients did not. No group differences were detected with regard to hippocampal volume or resting blood flow. Patients showed reduced performance in several offline neuropsychological measures. All group differences were independent of differences in hippocampal volume and hippocampal blood flow. Conclusions: Functional abnormalities of the hippocampus can be observed in patients with MDD even when the volume and resting perfusion in the same region appear normal. This suggests that changes in hippocampal function can be observed independently of structural abnormalities of the hippocampus in depression

Subregional hippocampal morphology and psychiatric outcome in adolescents who were born very preterm and at term

Background: The hippocampus has been reported to be structurally and functionally altered as a sequel of very preterm birth ( < 33 weeks gestation), possibly due its vulnerability to hypoxic-ischemic damage in the neonatal period. We examined hippocampal volumes and subregional morphology in very preterm born individuals in mid- and late adolescence and their association with psychiatric outcome. Methods: Structural brain magnetic resonance images were acquired at two time points (baseline and follow-up) from 65 ex-preterm adolescents (mean age = 15.5 and 19.6 years) and 36 termborn controls (mean age=15.0 and 19.0 years). Hippocampal volumes and subregional morphometric differences were measured from manual tracings and with three-dimensional shape analysis. Psychiatric outcome was assessed with the Rutter Parents' Scale at baseline, the General Health Questionnaire at follow-up and the Peters Delusional Inventory at both time points. Results: In contrast to previous studies we did not find significant difference in the cross-sectional or longitudinal hippocampal volumes between individuals born preterm and controls, despite preterm individual having significantly smaller whole brain volumes. Shape analysis at baseline revealed subregional deformations in 28% of total bilateral hippocampal surface, reflecting atrophy, in ex-preterm individuals compared to controls, and in 22% at follow-up. In ex-preterm individuals, longitudinal changes in hippocampal shape accounted for 11% of the total surface, while in controls they reached 20%. In the whole sample (both groups) larger right hippocampal volume and bilateral anterior surface deformations at baseline were associated with delusional ideation scores at follow-up. Conclusions: This study suggests a dynamic association between cross-sectional hippocampal volumes, longitudinal changes and surface deformations and psychosis proneness. Copyright

Five-Year Changes in Brain Volume and Episodic Memory in Cognitively Intact Elders with and without an Apolipoprotein ε4 Allele

The apolipoprotein ε4 allele is a risk factor for Alzheimer\u27s disease. ε4 carriers diagnosed with AD or MCI exhibit an increased rate of atrophy on MRI relative to non-carriers. Few longitudinal studies have examined the rate of atrophy and cognitive change in older ε4 carriers who were cognitively intact at study entry. In this study, structural MRI and episodic memory testing were administered on two occasions separated by 5 years to 45 cognitively intact older adults, ages 65-90 years, divided into two groups: (1) carriers with one or both ε4 alleles (n=24) and (2) demographically-matched non-carriers (n=21). Longitudinal analysis of whole brain gray matter, whole brain white matter, and hippocampal volumes were derived from Freesurfer software. Analysis of variance indicated a significant group x time interaction for both left and right cortical gray matter (p\u27s \u3c .05; 2% decrease) and left hippocampus (p \u3c .001; 5.6% decrease); right hippocampus showed a marginal effect (p=.086; 4.9% decrease). In all instances, the ε4 group showed greater atrophy over the five-year interval than non-carriers. White matter brain volume significantly decreased over retest intervals (3.5%), but did not differ between groups. Over the same retest interval, the ε4 group also showed significantly greater decline than non-carriers on delayed word recall and percent retention on a list-learning task. These data suggest that the presence of an ε4 allele carries an increased risk for cortical gray matter and hippocampal atrophy and memory loss among older participants who were cognitively intact at study entry