Entorhinal Cortex: Antemortem Cortical Thickness and Postmortem Neurofibrillary Tangles and Amyloid Pathology.

BACKGROUND AND PURPOSE: The entorhinal cortex, a critical gateway between the neocortex and hippocampus, is one of the earliest regions affected by Alzheimer disease-associated neurofibrillary tangle pathology. Although our prior work has automatically delineated an MR imaging-based measure of the entorhinal cortex, whether antemortem entorhinal cortex thickness is associated with postmortem tangle burden within the entorhinal cortex is still unknown. Our objective was to evaluate the relationship between antemortem MRI measures of entorhinal cortex thickness and postmortem neuropathological measures. MATERIALS AND METHODS: We evaluated 50 participants from the Rush Memory and Aging Project with antemortem structural T1-weighted MR imaging and postmortem neuropathologic assessments. Here, we focused on thickness within the entorhinal cortex as anatomically defined by our previously developed MR imaging parcellation system (Desikan-Killiany Atlas in FreeSurfer). Using linear regression, we evaluated the association between entorhinal cortex thickness and tangles and amyloid-ß load within the entorhinal cortex and medial temporal and neocortical regions. RESULTS: We found a significant relationship between antemortem entorhinal cortex thickness and entorhinal cortex (P = .006) and medial temporal lobe tangles (P = .002); we found no relationship between entorhinal cortex thickness and entorhinal cortex (P = .09) and medial temporal lobe amyloid-ß (P = .09). We also found a significant association between entorhinal cortex thickness and cortical tangles (P = .003) and amyloid-ß (P = .01). We found no relationship between parahippocampal gyrus thickness and entorhinal cortex (P = .31) and medial temporal lobe tangles (P = .051). CONCLUSIONS: Our findings indicate that entorhinal cortex-associated in vivo cortical thinning may represent a marker of postmortem medial temporal and neocortical Alzheimer disease pathology.

Neuron numbers in the hypothalamus of the normal aging rhesus monkey: stability across the adult lifespan and between the sexes.

Normal aging is accompanied by changes in hypothalamic functions including autonomic and endocrine functions and circadian rhythms. The rhesus monkey provides an excellent model of normal aging without the potential confounds of incipient Alzheimer's disease inherent in human populations. This study examined the hypothalamus of 51 rhesus monkeys (23 male, 18 female, 6.5-31 years old) using design-based stereology to obtain unbiased estimates of neuron and glia numbers and the Cavalieri method to estimate volumes for eight reference spaces: total unilateral hypothalamus, suprachiasmatic nucleus (SCN), supraoptic nucleus (SON), paraventricular nucleus (PVN), dorsomedial nucleus (DM), ventromedial nucleus (VM), medial mammillary nucleus (MMN), and lateral hypothalamic area (LHA). The results demonstrated no age-related difference in neuron number, glia number, or volume in any area in either sex except the PVN of male monkeys, which showed a significant increase in both neuron and glia numbers with age. Comparison of males and females for sexual dimorphisms revealed no significant differences in neuron number. However, males had more glia overall as well as in the SCN, DM, and LHA and had a larger hypothalamic volume overall and in the SCN, SON, VM, DM, and MMN. These results demonstrate that hypothalamic neuron loss cannot account for age-related deficits in hypothalamic function and provides further evidence of the absence of neurodegeneration and cell death in the normal aging rhesus monkey.

Aging of intrinsic circadian rhythms and sleep in a diurnal nonhuman primate, Macaca mulatta.

There is growing evidence that alterations in the intrinsic circadian clock and sleep might affect the aging process. The rhesus monkey (Macaca mulatta) provides unique opportunities to explore the role of the clock in successful and unsuccessful physiological and cognitive aging in a diurnal primate with consolidated nighttime sleep, complex cognitive functions, long life span, and phylogenetic proximity to humans. A longitudinal study was conducted to characterize the effects of aging on the entrained and intrinsic circadian rhythms of activity, polysomnographic sleep patterns, and melatonin production in unrestrained male rhesus monkeys [6-9 (n=6) and 24-28 (n=4) years of age]. An age-dependent decline was found in the stability of circadian rhythms of activity and in peak melatonin levels. The range of individual intrinsic circadian periods (τ) is not age-dependent. Aged monkeys do not display clearly defined "morningness-eveningness" chronotypes and, unlike the young, show no correlation between the chronotype under entrained conditions and the length of intrinsic circadian period. The daily activity period (α) is reduced with age and this is associated with high day-to-day variability in sleep quantity and quality, fragmentation of nighttime sleep and daytime wakefulness, increased daytime sleep time, overall increase in stage 1 sleep, and reduced time spent in rapid-eye movement and slow-wave sleep. In the absence of environmental time cues, age-dependent changes in sleep and circadian rhythms are exacerbated and circadian patterns of sleep in young rhesus monkeys start resembling those in aged animals, together suggesting important role of circadian regulation in aging sleep phenotype. This first characterization of age-dependent changes in the intrinsic rhythms and sleep in rhesus monkeys, demonstrating major similarities to human aging phenotype, should assist in the search for the mechanisms involved and for effective prophylactic and therapeutic strategies.

Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults.

OBJECTIVE: Since Alzheimer disease (AD) neuropathology is thought to develop years before dementia, it may be possible to detect subtle AD-related atrophy in preclinical AD. Here we hypothesized that the "disease signature" of AD-related cortical thinning, previously identified in patients with mild AD dementia, would be useful as a biomarker to detect anatomic abnormalities consistent with AD in cognitively normal (CN) adults who develop AD dementia after longitudinal follow-up. METHODS: We studied 2 independent samples of adults who were CN when scanned. In sample 1, 8 individuals developing AD dementia (CN-AD converters) after an average of 11.1 years were compared to 25 individuals who remained CN (CN-stable). In sample 2, 7 CN-AD converters (average follow-up 7.1 years) were compared to 25 CN-stable individuals. RESULTS: AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05). Despite this small absolute difference, Cohen d effect sizes for these differences were very large (> 1). Of the 11 CN individuals with baseline low AD-signature thickness (≥ 1 SD below cohort mean), 55% developed AD dementia over nearly the next decade, while none of the 9 high AD-signature thickness individuals (≥ 1 SD above mean) developed dementia. This marker predicted time to diagnosis of dementia (hazard ratio = 3.4, p < 0.0005); 1 SD of thinning increased dementia risk by 3.4. CONCLUSIONS: By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.

Temporoparietal MR imaging measures of atrophy in subjects with mild cognitive impairment that predict subsequent diagnosis of Alzheimer disease.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) represents a transitional state between normal aging and Alzheimer disease (AD). Our goal was to determine if specific temporoparietal regions can predict the time to progress from MCI to AD. MATERIALS AND METHODS: MR images from 129 individuals with MCI were analyzed to identify the volume of 14 neocortical and 2 non-neocortical brain regions, comprising the temporal and parietal lobes. In addition, 3 neuropsychological test scores were included to determine whether they would provide independent information. After a mean follow-up time of 5 years, 44 of these individuals had progressed to a diagnosis of AD. RESULTS: Cox proportional hazards models demonstrated significant effects for 6 MR imaging regions with the greatest differences being the following: the entorhinal cortex (hazard ratio [HR] = 0.54, P < .001), inferior parietal lobule (hazard ratio [HR] = 0.64, P < .005), and middle temporal gyrus (HR = 0.64, P < .004), indicating decreased risk with larger volumes. A multivariable model showed that a combination of the entorhinal cortex (HR = 0.60, P < .001) and the inferior parietal lobule (HR = 0.62, P < .01) was the best predictor of time to progress to AD. A multivariable model reiterated the importance of including both MR imaging and neuropsychological variables in the final model. CONCLUSIONS: These findings reaffirm the importance of the entorhinal cortex and present evidence for the importance of the inferior parietal lobule as a predictor of time to progress from MCI to AD. The inclusion of neuropsychological performance in the final model continues to highlight the importance of using these measures in a complementary fashion.

MRI measures of temporoparietal regions show differential rates of atrophy during prodromal AD.

BACKGROUND: MRI studies have demonstrated differential rates of atrophy in the entorhinal cortex and hippocampus during the prodromal phase of Alzheimer disease (AD). The current study was designed to determine whether a broader set of temporoparietal regions show differential rates of atrophy during the evolution of AD. METHODS: Sixteen regions of interest (ROIs) were analyzed on MRI scans obtained at baseline and follow-up in 66 subjects comprising three groups: controls = individuals who were cognitively normal at both baseline and follow-up; nonconverters = subjects with mild cognitive impairment (MCI) at both baseline and follow-up; converters had MCI at baseline but had progressed to AD at follow-up. RESULTS: Annualized percent change was analyzed with multivariate analysis of variance (MANOVA), covaried for age. The MANOVA demonstrated an effect of group (p = 0.004). Post hoc comparisons demonstrated greater rates of atrophy for converters vs nonconverters for six ROIs: hippocampus, entorhinal cortex, temporal pole, middle temporal gyrus, fusiform gyrus, and inferior temporal gyrus. Converters showed differentially greater rates of atrophy than controls in five of the same ROIs (and inferior parietal lobule). Rates of change in clinical status were correlated with the atrophy rates in these regions. Comparisons between controls and nonconverters demonstrated no differences. CONCLUSION: These results demonstrate that temporoparietal regions show differential rates of atrophy on MRI during prodromal Alzheimer disease (AD). MRI data correlate with measures of clinical severity and cognitive decline, suggesting the potential of these regions of interest as antemortem markers of prodromal AD.

Detection of cortical thickness correlates of cognitive performance: Reliability across MRI scan sessions, scanners, and field strengths.

In normal humans, relationships between cognitive test performance and cortical structure have received little study, in part, because of the paucity of tools for measuring cortical structure. Computational morphometric methods have recently been developed that enable the measurement of cortical thickness from MRI data, but little data exist on their reliability. We undertook this study to evaluate the reliability of an automated cortical thickness measurement method to detect correlates of interest between thickness and cognitive task performance. Fifteen healthy older participants were scanned four times at 2-week intervals on three different scanner platforms. The four MRI data sets were initially treated independently to investigate the reliability of the spatial localization of findings from exploratory whole-cortex analyses of cortical thickness-cognitive performance correlates. Next, the first data set was used to define cortical ROIs based on the exploratory results that were then applied to the remaining three data sets to determine whether the relationships between cognitive performance and regional cortical thickness were comparable across different scanner platforms and field strengths. Verbal memory performance was associated with medial temporal cortical thickness, while visuomotor speed/set shifting was associated with lateral parietal cortical thickness. These effects were highly reliable - in terms of both spatial localization and magnitude of absolute cortical thickness measurements - across the four scan sessions. Brain-behavior relationships between regional cortical thickness and cognitive task performance can be reliably identified using an automated data analysis system, suggesting that these measures may be useful as imaging biomarkers of disease or performance ability in multicenter studies in which MRI data are pooled.

Hypertension-induced changes in monoamine receptors in the prefrontal cortex of rhesus monkeys.

Hypertension affects approximately 60 million people in the United States. Recent studies have demonstrated that hypertension may produce progressive changes in the CNS. The present study is focused on reports in the literature that hypertension may significantly alter neurotransmitter systems, particularly dopamine (DA) and norepinephrine (NE). To address this, DA and norepinephrine (NE) receptor binding was assessed in the prefrontal cortex (PFC) of 15 male rhesus monkeys using on-the-slide in vitro assays for the DA1, NE alpha1 and NE alpha2 receptors as well as for the DA and NE uptake transporters. Eight monkeys underwent surgical coarctation of the mid-thoracic aorta which produced sustained, untreated hypertension as defined by a systolic pressure above 150 mm Hg. Compared with normotensive controls, chronic, untreated hypertension produced a significant decrease in DA1 and NE alpha1 receptor binding and an increase in DA uptake (DAU) receptor binding in the prefrontal cortex. While the mechanisms by which untreated hypertension alters DA and NE receptors is not known, the use of this non-human primate model should provide the means to uncover neurobiological changes that occur with untreated hypertension.

MRI measures of entorhinal cortex vs hippocampus in preclinical AD.

BACKGROUND: MRI measures of the entorhinal cortex and the hippocampus have been used to predict which nondemented individuals with memory problems will progress to meet criteria for AD on follow-up, but their relative accuracy remains controversial. OBJECTIVES: To compare MRI measures of the entorhinal cortex and the hippocampus for predicting who will develop AD. METHODS: MRI volumes of the entorhinal cortex and the hippocampus were obtained in 137 individuals comprising four groups: 1) individuals with normal cognition both at baseline and after 3 years of follow-up (n = 28), 2) subjects with memory difficulty but not dementia both at baseline and after 3 years of follow-up (n = 73), 3) subjects with memory difficulty at baseline who were diagnosed with probable AD within 3 years of follow-up (n = 21), and 4) patients with mild AD at baseline (n = 16). RESULTS: Measures of both the entorhinal cortex and the hippocampus were different for each of the pairwise comparisons between the groups (p < 0.001) and were correlated with tests of memory (p < 0.01). However, the volume of the entorhinal cortex differentiated the subjects from those destined to develop dementia with considerable accuracy (84%), whereas the measure of the hippocampus did not. CONCLUSION: These findings are consistent with neuropathologic data showing substantial involvement of the entorhinal cortex in the preclinical phase of AD and suggest that, as the disease spreads, atrophic change develops within the hippocampus, which is measurable on MRI.

Effects of age on the thickness of myelin sheaths in monkey primary visual cortex.

The effect of age on myelin sheath thickness was determined by an electron microscopic examination of cross sections of the vertical bundles of nerve fibers that pass through primary visual cortex of the rhesus monkey. The tissue was taken from the cortices of young (4-9 years of age) and old (over 24 years of age) monkeys, and the sections were taken at the level of layer 4Cbeta. From the electron photomicrographs, the diameters of axons and the numbers of lamellae in their myelin sheaths were determined. No change was found in the diameters of axons with age, although the mean numbers of myelin lamellae in the sheaths increased from 5.6 in the young monkeys to 7.0 in the old monkeys. Much of this increase in mean thickness was due to the fact that, in the old monkeys, thick myelin sheaths with more than ten lamellae are more common than in the young monkeys. While this increase in the thickness of myelin sheaths is occurring in old monkeys, there are also age-related changes in some of the sheaths. Consequently, it seems that, with age, there is some degeneration of myelin but, at the same time, a continued production of lamellae.

Neuropathology of progressive cognitive decline in chronically hypertensive rhesus monkeys.

Hypertension is an identified major risk factor for cerebrovascular disease, which is second only to Alzheimer's disease as a cause of dementia in the elderly. In addition, hypertension has been associated with a more subtle, progressive decline in cognitive function for which the neuropathology is not well understood. The present study was undertaken to explore this relationship in an experimental, nonhuman primate model, with hypertension produced by a coarctation of the thoracic aorta. Since prior studies with this model have shown a progressive decline in memory function, similar to that seen in human hypertension, as well as scattered microinfarcts in the cerebral white and gray matter, this study was designed to explore the relationship between these two. In addition to microinfarcts, the hypertensive monkeys with the highest arterial blood pressure also showed minute areas of focal gliosis without infarction. The number of these focal lesions showed a significant correlation with the severity of the hypertension, but not with the behavioral deficit. For four of these hypertensive monkeys, immunostaining demonstrated a pervasive, widespread activation of microglial cells and astroglial cells in the white matter as well as evidence of leaks in the blood-brain barrier, providing a more logical substrate for the cognitive decline.

Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease.

We used magnetic resonance imaging (MRI) measurements to determine whether persons in the prodromal phase of Alzheimer's disease (AD) could be accurately identified before they developed clinically diagnosed dementia. Normal subjects (n = 24) and those with mild memory difficulty (n = 79) received an MRI scan at baseline and were then followed annually for 3 years to determine which individuals subsequently met clinical criteria for AD. Patients with mild AD at baseline were also evaluated (n = 16). Nineteen of the 79 subjects with mild memory difficulty "converted" to a diagnosis of probable AD after 3 years of follow-up. Baseline MRI measures of the entorhinal cortex, the banks of the superior temporal sulcus, and the anterior cingulate were most useful in discriminating the status of the subjects on follow-up examination. The accuracy of discrimination was related to the clinical similarity between groups. One hundred percent (100%) of normal subjects and patients with mild AD could be discriminated from one another based on these MRI measures. When the normals were compared with the individuals with memory impairments who ultimately developed AD (the converters), the accuracy of discrimination was 93%, based on the MRI measures at baseline (sensitivity = 0.95; specificity = 0.90). The discrimination of the normal subjects and the individuals with mild memory problems who did not progress to the point where they met clinical criteria for probable AD over the 3 years of follow-up (the "questionables") was 85% and the discrimination of the questionables and converters was 75%. The apolipoprotein E genotype did not improve the accuracy of discrimination. The specific regions selected for each of these discriminations provides information concerning the hierarchical fashion in which the pathology of AD may affect the brain during its prodromal phase.

Hippocampal formation lesions produce memory impairment in the rhesus monkey.

There is much debate over the role of temporal lobe structures in the ability to learn and retain new information. To further assess the contributions of the hippocampal formation (HF), five rhesus monkeys received stereotactically placed ibotenic acid lesions of this region without involvement of surrounding ventromedial temporal cortices. After surgery, the animals were trained on two recognition memory tasks: the Delayed Non-Match to Sample (DNMS) task, which tests the ability to remember specific trial unique stimuli, and the Delayed Recognition Span Task (DRST), which tests the ability to remember an increasing array of stimuli. Relative to normal control monkeys, those with HF lesions demonstrated significant impairments in both learning and memory stages of the DNMS task. Additionally, the HF group was significantly impaired on spatial, color, and object versions of the DRST. Contrary to suggestions that damage to the entorhinal and parahippocampal cortices is required to produce significant behavioral deficits in the monkey, these results demonstrate that selective damage to the HF is sufficient to produce impairments on tasks involving delayed recognition and memory load. This finding illustrates the importance of the HF in the acquisition and retention of new information.

Spatial cognition in rhesus monkeys: male superiority declines with age.

Twelve young (4-7 years of age) and 14 old (20-27 years of age) male and female rhesus monkeys were tested on seven cognitive tasks. Males and females performed similarly on tasks of object memory and executive function, but young males outperformed young females on a spatial memory task (Delayed Recognition Span Test) that requires the identification of a new stimulus among an increasing array of serially presented stimuli. This superior level of spatial ability in young males declined sharply with age, so that old males did not perform significantly better than old females. These findings in the nonhuman primate suggest that biological rather than sociocultural factors underlie the sex differences in cognition and their diminution with age.

Quantitative follow-up of patients with multiple sclerosis using MRI: reproducibility.

The reproducibility of an automated method for estimating the volume of white matter abnormalities on brain magnetic resonance (MR) images of multiple sclerosis (MS) patients was evaluated. Twenty MS patients underwent MR imaging twice within 30 minutes. Measurement variability is introduced mainly by MRI acquisition and image registration procedures, which demonstrate significantly worse reproducibility than the image segmentation. The correction of partial volume artifacts is essential for sensitive measurements of overall lesion burden. The average lesion volume difference (bias) between two MR exams of the same MS patient (N = 20) was 0.05 cm3, with a 95% confidence interval between -0.17 and +0.28 cm3, suggesting that the proposed measurement system is suitable for clinical follow-up trials, even in relatively small patient cohorts. The limits of agreement for lesion volume were between -1.3 and +1.5 cm3, implying that in individual patients changes in lesion load need to be at least this large to be detected reliably. This automated method for estimating lesion burden is a reliable tool for the evaluation of MS progression and exacerbation in patient cohorts and potentially also in individual patients.

Age-related decline in DHEAS is not related to cognitive impairment in aged monkeys.

To determine whether endogenous DHEAS level is related to cognitive performance in the rhesus monkey, we tested 9 young and 14 old monkeys on the acquisition and the 120 s delay condition of the delayed non-matching to sample and on the spatial delayed recognition span test. A single summary measure of cognitive ability, the cognitive performance index (CPI), was derived from these three tests. As expected, the mean level of DHEAS as well as the CPI declined with age. DHEAS level, however, was not significantly correlated with CPI, after controlling for the relationship of age to these two variables. Further, impaired and unimpaired aged monkeys did not differ in DHEAS level. These findings suggest that DHEAS is not independently associated with age-related cognitive decline in the rhesus monkey.

White matter changes with normal aging.

We evaluated brain tissue compartments in 72 healthy volunteers between the ages of 18 and 81 years with quantitative MRI. The intracranial fraction of white matter was significantly lower in the age categories above 59 years. The CSF fraction increased significantly with age, consistent with previous reports. The intracranial percentage of gray matter decreased somewhat with age, but there was no significant difference between the youngest subjects and the subjects above 59. A covariance adjustment for the volume of hyperintensities did not alter the foregoing results. The intracranial percentage of white matter volume was strongly correlated with the percentage volume of CSF. The finding of a highly significant decrease with age in white matter, in the absence of a substantial decrease in gray matter, is consistent with recent neuropathologic reports in humans and nonhuman primates.

Age-related neuronal loss in the nucleus centralis superior of the rhesus monkey.

The effect of age on the number of neurons in the nucleus centralis superior (NCS) was determined in 11 behaviorally tested rhesus monkeys of 7-32 years of age, There was a significant age-related decrease in both cell packing density and in the total number of neurons. This decrease in number of neurons appeared to effect two different populations of cell in the NCS, one of which corresponded in size to the serotonergic cells in this nucleus and the other to a smaller-sized cell. Comparisons of the changes in the cell packing density with behavioral testing, showed significant correlations with the overall test performance as well as with individual tests of memory function and of executive system functions. These findings suggest that neuronal loss in the NCS may play a significant role in mediating cognitive changes seen in normal aging.

Patterns of cognitive decline in aged rhesus monkeys.

Although cognitive decline has been well established as a consequence of aging in non-human primate models, the prevalence or frequency of impairment for specific age ranges has not been described. The first aim of this study was to estimate prevalence of cognitive impairment on each of the six tests of cognitive performance by comparing the performance of early-aged (19-23 years old), advanced-aged (24-28 years old), and oldest-aged (29+ years old) monkeys to that of young adults (< 15 years old). The second aim was to derive a single overall measure of cognitive performance to help classify behavioral function in our aged monkeys. Accordingly, we obtained performance measures for these age groups on six behavioral measures: (1) acquisition of the delayed non-matching-to-sample task (DNMS); (2) performance of the DNMS with a delay of 120 sec; (3) the spatial condition of the delayed recognition span test (DRST); (4) the color condition of the DRST; (5) spatial reversal learning; and (6) object reversal learning. Early-aged monkeys displayed prevalence rates of impairment significantly greater than zero on all tasks except the DRST-color. The highest prevalence of impairment was observed in this age group in a task measuring spatial memory (DRST). Significant trends toward progressively higher impairment rates in advanced-aged and oldest-aged monkeys were observed for DNMS-acquisition, DRST-color and spatial reversal learning tasks. A linear transformation of standardized scores on the six cognitive tests was derived by means of principal components analysis (PCA). The first PCA (PCA1) included data from 30 monkeys with available data on all six measures, and yielded a composite measure which declined linearly with increasing age (r = -0.74). A second PCA (PCA2) was performed on data from 53 monkeys for which three test scores (DNMS-acquisition, DNMS-120s delay, and DRST-spatial condition) were available. The composite score derived from this analysis was highly correlated (r = 0.93) with the composite score from PCA1, suggesting that a score based on only three tests may provide an adequate classification of global cognitive ability.

Recognition memory span in rhesus monkeys of advanced age.

Assessment of recognition memory was performed on eight rhesus monkeys of advanced age (25 to 27 years of age) using the delayed recognition span test (DRST). Their performance was compared to that of five young adult animals (5 to 7 years of age) on two stimulus conditions of the DRST: spatial position and color. Both trial unique and repeating series were used for each of the two conditions. As a group, aged monkeys were impaired on both the spatial and color conditions of the DRST, achieving about two-thirds of the span of the young adult group in each condition. Error analyses revealed that monkeys in the aged group also produced more perseverative responses (i.e., displacing the previously correct disk) than did young adults. Together the findings suggest that monkeys of advanced age are impaired on tasks with memory loading demand characteristics.