Rate Of Hippocampal Volume Loss Research Articles

Hippocampal volume across age: Nomograms derived from over 19,700 people in UK Biobank.

Measurement of hippocampal volume has proven useful to diagnose and track progression in several brain disorders, most notably in Alzheimer's disease (AD). For example, an objective evaluation of a patient's hippocampal volume status may provide important information that can assist diagnosis or risk stratification of AD. However, clinicians and researchers require access to age-related normative percentiles to reliably categorise a patient's hippocampal volume as being pathologically small. Here we analysed effects of age, sex, and hemisphere on the hippocampus and neighbouring temporal lobe volumes, in 19,793 generally healthy participants in the UK Biobank. A key finding of the current study is a significant acceleration in the rate of hippocampal volume loss in middle age, more pronounced in females than in males. In this report, we provide normative values for hippocampal and total grey matter volume as a function of age for reference in clinical and research settings. These normative values may be used in combination with our online, automated percentile estimation tool to provide a rapid, objective evaluation of an individual's hippocampal volume status. The data provide a large-scale normative database to facilitate easy age-adjusted determination of where an individual hippocampal and temporal lobe volume lies within the normal distribution.

REST rs3796529 Genotype and Rate of Functional Deterioration in Alzheimer's Disease.

Recently, REST (RE1-silencing transcription factor) gene has been shown to be lost in Alzheimer’s disease (AD), and a missense minor REST allele rs3796529-T has been shown to reduce the rate of hippocampal volume loss. However, whether the REST rs3796529 genotype is associated with the rate of functional deterioration in AD is unknown. A total of 584 blood samples from Taiwanese patients with AD were collected from January 2002 to December 2013. The diagnosis of AD was based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria. The allele frequency of rs3796529-T was compared between the AD cohort and 993 individuals from the general population in Taiwan. Kaplan-Meier analysis, the log rank test and a multivariate Cox model were then used to evaluate the association between rs3796529-T and functional deterioration in the AD cohort. The allele frequency of rs3796529-T was significantly lower in the AD cohort compared to the general population cohort (36.82% vs. 40.73%, p=0.029). Kaplan-Meier analysis and the log rank test showed that the AD patients carrying the rs3796529 T/T genotype had a longer progression-free survival than those with the C/C genotype (p=0.012). In multivariate analysis, the rs3796529 T/T genotype (adjusted HR=0.593, 95% CI: 0.401-0.877, p=0.009) was an independent protective factor for functional deterioration. The rs3796529 T/T genotype was associated with slower functional deterioration in patients with AD. This finding may lead to a to better understanding of the molecular pathways involved, and prompt further development of novel biomarkers to monitor AD.

Increased Alzheimer's risk during the menopause transition: A 3-year longitudinal brain imaging study.

Two thirds of all persons with late-onset Alzheimer’s disease (AD) are women. Identification of sex-based molecular mechanisms underpinning the female-based prevalence of AD would advance development of therapeutic targets during the prodromal AD phase when prevention or delay in progression is most likely to be effective. This 3-year brain imaging study examines the impact of the menopausal transition on Alzheimer’s disease (AD) biomarker changes [brain β-amyloid load via 11C-PiB PET, and neurodegeneration via 18F-FDG PET and structural MRI] and cognitive performance in midlife. Fifty-nine 40–60 year-old cognitively normal participants with clinical, neuropsychological, and brain imaging exams at least 2 years apart were examined. These included 41 women [15 premenopausal controls (PRE), 14 perimenopausal (PERI), and 12 postmenopausal women (MENO)] and 18 men. We used targeted minimum loss-based estimation to evaluate AD biomarker and cognitive changes. Older age was associated with baseline Aβ and neurodegeneration markers, but not with rates of change in these biomarkers. APOE4 status influenced change in Aβ load, but not neurodegenerative changes. Longitudinally, MENO and PERI groups showed declines in estrogen-dependent memory tests as compared to men (p < .04). Adjusting for age, APOE4 status, and vascular risk confounds, the MENO and PERI groups exhibited higher rates of CMRglc decline as compared to males (p ≤ .015). The MENO group exhibited the highest rate of hippocampal volume loss (p’s ≤ .001), and higher rates of Aβ deposition than males (p < .01). CMRglc decline exceeded Aβ and atrophy changes in all female groups vs. men. These findings indicate emergence and progression of a female-specific hypometabolic AD-endophenotype during the menopausal transition. These findings suggest that the optimal window of opportunity for therapeutic intervention to prevent or delay progression of AD endophenotype in women is early in the endocrine aging process.

The effects of sequential treatments on hippocampal volumes in malignant glioma patients.

Malignant gliomas (MG) are very aggressive tumors. In an effort to improve the outcome, the patients receive multi-modal therapies such as surgery, radiation and chemotherapy (temozolomide followed in many cases by bevacizumab). The survivors are affected by multiple learning and memory deficits. Greater deterioration over time in hippocampal specific cognitive tasks was shown in patients receiving bevacizumab in addition to radiation and temozolomide for a longer period of time (RTOG 0825). The rate of hippocampal atrophy in patients treated with radiation and temozolomide followed by bevacizumab is not yet determined, and is the goal of the present study. We used the serial MRIs obtained as parts of standard clinical care in patients with MG. Measurements were done using the Medical Image Processing, Analysis and Visualization (MIPAV) software. The hippocampus in the contralateral hemisphere was manually traced and measured, to avoid morphological structure changes induced by the tumor, radiation fields or surgical markers. We determined a longitudinal progression of hippocampal atrophy-with the maximum volume loss (33.26 %) for the patients that were on treatment for 5years. There was no detectable hippocampal atrophy during the chemo-radiation followed by adjuvant temozolomide. A significant decrease in the absolute hippocampus volume was noted after 6months of continuous bevacizumab treatment (p < 0.05). The hippocampal volume loss progressed over the next 3years, and was higher than the one previously reported in Alzheimer disease patients. The hippocampal volume loss is minimal during the 1month after diagnosis, when the patients receive chemo-radiation and adjuvant temozolomide. However, prolonged treatment including bevacizumab is associated with a significant rate of hippocampal volume loss.

Protective variant for rate of hippocampal volume loss identified by whole exome sequencing in APOE-ε3ε3 males with MCI

Protective variant for rate of hippocampal volume loss identified by whole exome sequencing in APOE-ε3ε3 males with MCI

Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

Effects of ApoE-ɛ4 allele load and age on the rates of grey matter and hippocampal volumes loss in a longitudinal cohort of 1186 healthy elderly persons

In a sample of 1186 healthy subjects aged 65 to 89 years who were scanned twice with MRI 3.6 years apart, we studied the effects of age and ApoE-ɛ4 allele load on the rate of atrophy of grey matter and hippocampus. Rates of grey matter and hippocampal volumes loss were computed from T1-weighted magnetic resonance images using voxel-based morphometry and region of interest analysis. Longitudinal analysis showed that an age-related annual rate of grey matter volume loss was only seen in ɛ4 homozygotes only (n=14) whereas no age effect was seen ɛ4 heterozygotes (n=239) and in noncarriers (n=933). ApoE-ɛ4 homozygotes also had a significantly larger rate of hippocampal volume loss than heterozygotes or noncarriers. During the same period, no effect or interaction of ApoE genotype and age was observed on cognitive decline, as assessed by the Mini Mental State Examination (MMSE). These data do not suggest an ɛ4 gene dose effect on the rate of hippocampal volume loss in healthy elderly subjects as most of the effect was limited to homozygotes. Hippocampal volume loss may not be a good imaging marker to understand the effect of the ApoE-ɛ4 allele on the risk of dementia in a population-based setting. It could be hypothesized that the impact of a single ApoE-ɛ4 allele on brain structures is largely delayed in time.

Hippocampal volume loss and Alzheimer disease progression

The progression of Alzheimer disease might be monitored by measuring the rate of hippocampal volume loss by means of MRI. Research suggests that a reduction in hippocampal volume can be detected over a period as short as 6 months, and that such volume loss is associated with cognitive decline and other indicators of Alzheimer disease neuropathology.

IC-P2-150: Comparing rates of change versus cross-sectional hippocampal measure in early DAT

Background: In cross-sectional studies comparing subjects with and without very mild dementia of the Alzheimer type (DAT), we showed that deformities of hippocampal surface shape and volume could discriminate groups. While this suggests that irregularities of hippocampal structure are a feature of early AD, they could represent an early form of neurodegeneration or a long-standing “anatomic” vulnerability to disease. In this study, we compared the volume and shape of the hippocampus over time in very mildly demented and nondemented subjects, and determined whether the rate of changes in structural measures would improve the discrimination of subject groups based on cross-sectional (baseline) measures. Methods: MR scans were collected from 54 CDR 0.5 subjects and 69 CDR 0 subjects on multiple occasions (Table 1). Large-deformation high-dimensional brain mapping was applied to all scans to generate hippocampal surfaces in each subject scan. An average hippocampal surface constructed from 86 healthy subjects from a previous study was used as a reference to compute displacements from this reference for all surfaces. Mean displacements for hippocampal surface zones corresponding to the CA1, subiculum and remainder subfields were computed for each subject as shape measures. Mixed models with baseline CDR status as fixed factor and between-scan interval as random factor were used to test for group differences in rates of change in the hippocampal variables. Gender was used as a covariate. Results: At baseline, CDR 0.5 subjects had smaller volumes and more inwardly deformed hippocampal surfaces as compared with CDR 0 subjects. In particular, the surface zone associated with the CA1 hippocampal subfield deformed inwardly at a faster rate in the CDR 0.5 subjects than in the CDR 0 subjects. However, the effect size of the longitudinal comparison was smaller than the effect size of the cross-sectional comparison at baseline. See Table 2. Conclusions: These results suggest that while very mild DAT subjects show a more rapid rate of hippocampal volume loss and shape deformation than nondemented subjects, the degree of hippocampal deformation at the onset of dementia is already substantial and is as good or better than measures of changes in structure for group discrimination. P01-AG026276,P01-AG03991, P50-AG05681,R01-MH60883, R01-MH56584,P41-RR15241.

Small baseline volume of left hippocampus is associated with subsequent conversion of MCI into dementia: The Göteborg MCI study

Earlier studies have reported that hippocampal atrophy can to some extent predict which patients with mild cognitive impairment (MCI) will subsequently convert to dementia, and that converters have an enhanced rate of hippocampal volume loss. To further validate the hypothesis that hippocampal atrophy predicts conversion from MCI to dementia, to relate baseline hippocampal volume to different forms of dementia, and to investigate the role of hippocampal side differences and rate of volume loss over time. The subjects (N=68) include patients with MCI at baseline and progression to dementia at the two-year follow-up (N=21), stable MCI patients (N=21), and controls (N=26). Among the progressing patients, 13 were diagnosed as having AD. The Göteborg MCI study is a clinically based longitudinal study with biannual clinical assessments. Hippocampal volumetry was performed manually on the MRI investigations at baseline and at the two-year follow-up. Hippocampal volumetry could predict conversion to dementia in both the AD and the non-AD subgroup of converters. Left hippocampal volume in particular discriminated between converting and stable MCI. Cut off points for individual discrimination were shown to be potentially useful. The converting MCI group had a significantly higher rate of hippocampal volume loss as compared to the stable MCI group. In MCI patients, hippocampal volumetry at baseline gives prognostic information about possible development of AD and non-AD dementia. Contrary to earlier studies, we found that left hippocampal volume has the best predictive power. Reliable predictions appear to be possible in many individual cases.

Does Donepezil Treatment Slow the Progression of Hippocampal Atrophy in Patients With Alzheimer’s Disease?

The only approved pharmacological approach for the symptomatic treatment of Alzheimer's disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer's disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression. In a prospective cohort study, 54 patients with Alzheimer's disease who received donepezil treatment and 93 control patients with Alzheimer's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer's Disease Assessment Scale score were comparable between the treated and control groups. The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer's Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant. Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer's disease.

Small hippocampal size in cognitively normal subjects with coronary artery disease

Objective: Hippocampal size reduction detected by three-dimensional structural magnetic resonance imaging (3D-MRI) represents an important hallmark of Alzheimer's disease (AD). Recently, epidemiological and neuropathological studies have associated coronary artery disease (CAD) and cardiovascular risk factors with AD. The present study aimed to assess whether small hippocampal size is also a feature of CAD. Methods: Hippocampal volumes were assessed in 20 men with CAD and 20 healthy matched control subjects by use of 3D-MRI. Subjects with a history of neurological or psychiatric disorder, or signs of cognitive impairment were rigorously excluded. Results: Compared with controls, subjects with CAD had significantly smaller (−14%) hippocampal volumes. Cardiovascular risk factors were not related to hippocampal volumes of CAD subjects. Conclusions: Our results demonstrate small hippocampal size in CAD subjects without any cognitive impairment. Future studies should clarify whether the annual rate of hippocampal volume loss of persons with CAD is greater than that of healthy individuals and predicts later cognitive decline or dementia.

Differential aging of the medial temporal lobe: a study of a five-year change.

To test the hypothesis that entorhinal cortex (EC) volume decreases at a slower rate than the hippocampal (HC) volume in healthy adults, and to examine whether the rate of shrinkage increases with age. Volumes of the HC and EC were measured twice on MRI scans of 54 healthy adults (aged 26 to 82 years), with an average interval of 5 years. Markedly different age trends were noted in the examined regions. The EC showed no age-related differences on both occasions and only minimal age-related change (0.33%/y). By contrast, the HC exhibited significant age-related differences at baseline and at follow-up evaluation and decreased at a faster pace of 0.86%/y. Older participants (aged > or = 50 years) showed increased annual shrinkage of the HC (1.18%) and EC shrinkage (0.53%/y). The rate of HC volume loss significantly exceeded that of the EC. No EC shrinkage and modest HC volume reduction were observed in people aged <50 years. Age-related shrinkage occurs in the medial temporal lobes of healthy adults, with significant hippocampal decline and minimal entorhinal changes. In both regions, the rate of decline accelerates with age, although the role of pathologic factors in age-related increase of volume loss merits further investigation.

Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women.

To determine whether the presence of a single epsilon4 allele of the APOE gene is associated with an increased rate of hippocampal volume loss or decline in cognition in healthy women in their sixth decade of life. Nine APOE-epsilon4 allele-negative (mean age +/- SD, 60.6 +/- 10.2 years) and 16 APOE-epsilon4 allele-positive (mean age +/- SD, 55.1 +/- 6.0 years) healthy women underwent neurocognitive testing and MRI at the time of entry into the study (baseline) and 2 years later. Neurocognitive testing consisted of the Buschke-Fuld Free Recall, verbal fluency tests, the Rey Figure Test, the Wechsler Memory Scale-Revised, and the Wechsler Adult Intelligence Survey-Revised Block Design. Hippocampal volume determinations were based on manual outlining of sagittal slices aided by axial, coronal, and three-dimensional views of high-resolution 124-slice whole-brain scans; the scans were obtained with a 1.5-tesla scanner using a T1-weighted three-dimensional gradient echo sequence with RF spoiling (TR/TE/flip angle, 24 msec/3 msec/30 degrees ). The percent change in hippocampal volume per year was greater in the APOE-epsilon4 allele-positive group (mean +/- SD, 2.32 +/- 1.75%) than in the APOE-epsilon4 allele-negative group (mean +/- SD, 0.77 +/- 1.02%; t = 2.41; p < 0.03, two-tailed test). There were no significant differences between the two groups in terms of any of the cognitive measures, and hippocampal volume loss was not correlated with changes in any of the above-mentioned cognitive measures. The presence of a single APOE-epsilon4 allele is associated with an increased rate of hippocampal volume loss in healthy women in their sixth decade of life that is not related to any detectable memory changes.

Rate of medial temporal lobe atrophy in typical aging and Alzheimer's disease.

To determine the annual rates of volumetric change of the hippocampus and temporal horn in cognitively normal elderly control subjects and individually matched patients with AD, and to test the hypothesis that these rates were different. Cross-sectional studies consistently reveal cerebral atrophy in elderly nondemented subjects compared with healthy young adults, and greater atrophy in patients with AD relative to elderly control subjects. However, rates of atrophy are estimated most accurately by performing serial measurements in the same individuals. MRI-based volumetric measurements of the hippocampi and temporal horns were performed in 24 cognitively normal subjects aged 70 to 89 years who were individually matched with respect to gender and age with 24 patients with AD. Each subject underwent an MRI protocol twice, separated by 12 months or more. The mean annual rate of hippocampal volume loss among control subjects was -1.55+/-1.38% and the temporal horns increased in volume by 6.15+/-7.69% per year. These rates were significantly greater among AD patients: hippocampus, -3.98+/-1.92% per year, p < 0.001; temporal horn, 14.16+/-8.47% per year, p = 0.002. A statistically significant yearly decline in hippocampal volume and an increase in temporal horn volume was identified in elderly control subjects who represent typical aging individuals. These rates were approximately 2.5 times greater in patients with AD than in individually age- and gender-matched control subjects.