Brain Aging Research Research Articles

Automated neurosphere sorting and plating by the COPAS large particle sorter is a suitable method for high-throughput 3D in vitro applications

Existing guidelines for testing developmental neurotoxicity (DNT) propose investigations in rodents, which are ethically questionable as well as time and cost intensive. Thus, there is international agreement that predictive in vitro methods are needed to increase efficiency of testing and limit the number of animals used. One of a variety of novel approaches for DNT testing utilizes neurospheres, three-dimensional aggregate cultures of primary normal neural progenitor cells (NPCs). Because sorting and plating of single neurospheres is one of the most time-consuming steps within the assay, the aim of this study was to evaluate if the complex object parametric analyzer and sorter (COPAS PLUSTM, Union Biometrica Inc.) is a suitable tool for automated sorting and plating of neurospheres. The results of the comparison of NPC viability, proliferation, migration, differentiation and intracellular oxidative stress between manually and COPAS sorted and plated neurospheres of different species show that the automation by the COPAS instrument does not influence the basic performance of neurospheres. Therefore, we consider the COPAS instrument as a useful tool for higher throughput neurosphere research in toxicology, neuroregeneration, brain development, drug development and brain aging research.

Primate aging in the mammalian scheme: the puzzle of extreme variation in brain aging.

At later ages, humans have high risk of developing Alzheimer disease (AD) which may afflict up to 50% by 90 years. While prosimians and monkeys show more substantial changes, the great apes brains examined show mild neurodegenerative changes. Compared with rodents, primates develop and reproduce slowly and are long lived. The New World primates contain some of the shortest as well as some of the longest-lived monkey species, while the prosimians develop the most rapidly and are the shortest lived. Great apes have the largest brains, slowest development, and longest lives among the primates. All primates share some level of slowly progressive, age-related neurodegenerative changes. However, no species besides humans has yet shown regular drastic neuron loss or cognitive decline approaching clinical grade AD. Several primates accumulate extensive deposits of diffuse amyloid-beta protein (Aβ) but only a prosimian-the gray mouse lemur-regularly develops a tauopathy approaching the neurofibrillary tangles of AD. Compared with monkeys, nonhuman great apes display even milder brain-aging changes, a deeply puzzling observation. The genetic basis for these major species differences in brain aging remains obscure but does not involve the Aβ coding sequence which is identical in nonhuman primates and humans. While chimpanzees merit more study, we note the value of smaller, shorter-lived species such as marmosets and small lemurs for aging studies. A continuing concern for all aging studies employing primates is that relative to laboratory rodents, primate husbandry is in a relatively primitive state, and better husbandry to control infections and obesity is needed for brain aging research.

The Geneva brain collection.

The University of Geneva brain collection was founded at the beginning of the 20th century. Today, it consists of 10,154 formaldehyde- or buffered formaldehyde-fixed brains obtained from the autopsies of the Department of Psychiatry and, since 1971, from the Department of Geriatrics. More than 100,000 paraffin-embedded blocks and 200,000 histological slides have also been collected since 1901. From the time of its creation, this collection has served as an important resource for pathological studies and clinicopathological correlations, primarily in the field of dementing illnesses and brain aging research. These materials have permitted a number of original neuropathological observations, such as the classification of Pick's disease by Constantinidis, or the description of dyshoric angiopathy and laminar sclerosis by Morel. The large number of cases, including some very rare conditions, provides a unique resource and an opportunity for worldwide collaborations.

The effects of aging on dopaminergic neurotransmission: a microPET study of [11C]-raclopride binding in the aged rodent brain

Rodent models are frequently used in aging research to investigate biochemical age effects and aid in the development of therapies for pathological and non-pathological age-related degenerative processes. In order to validate the use of animal models in aging research and pave the way for longitudinal intervention-based animal studies, the consistency of cerebral aging processes across species needs to be evaluated. The dopaminergic system seems particularly susceptible to the aging process, and one of the most consistent findings in human brain aging research is a decline in striatal D2-like receptor (D2R) availability, quantifiable by positron emission tomography (PET) imaging. In this study, we aimed to assess whether similar age effects can be discerned in rat brains, using in vivo molecular imaging with the radioactive compound [ 11C]-raclopride. We observed a robust decline in striatal [ 11C]-raclopride uptake in the aged rats in comparison to the young control group, comprising a 41% decrement in striatal binding potential. In accordance with human studies, these results indicate that substantial reductions in D2R availability can be measured in the aged striatal complex. Our findings suggest that rat and human brains exhibit similar biochemical alterations with age in the striatal dopaminergic system, providing support for the pertinence of rodent models in aging research.

Outcome over seven years of healthy adults with and without subjective cognitive impairment

Background Subjective cognitive impairment (SCI) in older persons without manifest symptomatology is a common condition with a largely unclear prognosis. We hypothesized that (1) examining outcome for a sufficient period by using conversion to mild cognitive impairment (MCI) or dementia would clarify SCI prognosis, and (2) with the aforementioned procedures, the prognosis of SCI subjects would differ significantly from that of demographically matched healthy subjects, free of SCI, termed no cognitive impairment (NCI) subjects. Methods A consecutive series of healthy subjects, aged ≥40 years, presenting with NCI or SCI to a brain aging and dementia research center during a 14-year interval, were studied and followed up during an 18-year observation window. The study population (60 NCI, 200 SCI, 60% female) had a mean age of 67.2 ± 9.1 years, was well-educated (mean, 15.5 ± 2.7 years), and cognitively normal (Mini-Mental State Examination, 29.1 ± 1.2). Results A total of 213 subjects (81.9% of the study population) were followed up. Follow-up occurred during a mean period of 6.8 ± 3.4 years, and subjects had a mean of 2.9 ± 1.6 follow-up visits. Seven NCI (14.9%) and 90 SCI (54.2%) subjects declined ( P < .0001). Of NCI decliners, five declined to MCI and two to probable Alzheimer's disease. Of SCI decliners, 71 declined to MCI and 19 to dementia diagnoses. Controlling for baseline demographic variables and follow-up time, Weibull proportional hazards model revealed increased decline in SCI subjects (hazard ratio, 4.5; 95% confidence interval, 1.9–10.3), whereas the accelerated failure time model analysis with an underlying Weibull survival function showed that SCI subjects declined more rapidly, at 60% of the rate of NCI subjects (95% confidence interval, 0.45–0.80). Furthermore, mean time to decline was 3.5 years longer for NCI than for SCI subjects ( P = .0003). Conclusions These results indicate that SCI in subjects with normal cognition is a harbinger of further decline in most subjects during a 7-year mean follow-up interval. Relevance for community populations should be investigated, and prevention studies in this at-risk population should be explored.

Brain aging research

The last three decades produced a striking increase in investigations of the neurobiological basis of brain aging and aging-related changes in neural and cognitive function. Experimental and clinical studies of aging have become more valuable as the population, at least in industrialized countries, has become ‘greyer’. The increase in adult life expectancy that occurred in the twentieth century produced the motivation and necessity to invest resources in increasing ‘health span’ as well as lifespan, in order to maximize quality of life and minimize the financial and social burdens associated with disability in the later years of life. Specific interest in the aging nervous system is driven by recognition that increased longevity has little appeal for most people unless it is accompanied by maintenance of cognitive abilities. Indeed, surveys of older individuals routinely show that loss of mental capacity is among their greatest fear. In recent years, neuroscientists and gerontologists, with a variety of training and experimental approaches, have applied increasingly powerful quantitative methods to investigate why neural function declines with age. New animal model systems have been developed and old ones have become better characterized and standardized. The necessary and important descriptive studies that dominated the field in earlier years are increasingly supplemented by more hypothesis-driven research, resulting in sophisticated investigations and models of the mechanisms of brain aging. This review provides a selective overview of recent and current research on brain aging. The focus throughout will be on normal brain aging and the moderate cognitive changes that often accompany it, not on aging-related neurodegenerative diseases that result in dementia. To provide a context for studies of neurobiological changes in the aging brain, a brief overview of the types of cognitive changes that are commonly seen in aging humans is first provided. The remainder of the review focuses on animal studies that are progressively overcoming the unique challenges of aging research to reveal the neurobiological mechanisms of aging-related cognitive dysfunction, and suggest new targets for therapies to prevent or ameliorate cognitive decline.

Rodent models of brain aging and neurodegeneration

Laboratory rats and mice have long been considered to be convenient models for the study of aging in various mammalian systems. With regard to functions of the central nervous system, rodents have anatomical, cellular, and molecular characteristics that are similar to humans, and they can be tested for behavioral analogues of basic human motivational, reflexive and psychomotor functions, as well as for higher-order brain functions such as learning, memory and cognition. Behavioral studies of rodents conducted in the 1970’s and 1980’s provided confirmation that rodents indeed exhibit age-related declines in cognitive and psychomotor functions across their relatively short life spans. While it was clear that these declines did not reflect neurodegenerative conditions like Alzheimer’s or Parkinson’s diseases, it nevertheless became feasible to study the biological basis of the age related impairments in higher-order brain functions of these species. Moreover, rodent models of brain aging were recognized as potentially useful for predicting the effectiveness of therapeutic interventions on functional aging in humans. Research focused on age-related neurodegenerative diseases moved in a different direction, employing anatomical, pharmacological, and genetic manipulations to mimic neurodegenerative conditions. However, the behavioral characterization of the rodent models at different ages has been an essential element in both types of research, and has provided the most critical evidence needed to evaluate hypotheses about the neurobiological basis of brain aging and neurodegenerative disease. Efforts employing rodent models to identify the causes of brain aging and neurodegenerative conditions gained significant momentum in the 1990s, and many research programs and their methods of investigation have matured during the first half of the current decade. Three of the papers in the current issue discuss methodological approaches based on an earlier observation that age-related declines of cognitive function in rodents differ in severity among individuals, as appears to be the case in human subjects. Such trends are often reflected in an age-related increase of variability between test subjects, or as the presence of an apparent subset of aged animals that show reliable cognitive impairment. The application of methods to identify the specific neurobiological substrates that correlate with individualized cognitive performance of old rodents has led to significant advances in understanding of the effects and potential causes of brain aging. In particular, one article in this issue illustrates some novel insights gleaned through implementation of this type of methodology in conjunction with microarray profiling. A traditional approach to understanding processes of biological aging has been to study models or conditions in which the timetables of various age-related endpoints appear to be decelerated or accelerated. Such approaches have been equally attractive in brain aging and neurodegeneration research, as illustrated in two review articles in the current issue. These reviews provide new insights with regard to the potential influence of cerebral ischemia and disrupted circadian rhythms on cognitive function during aging. Long-standing practical and theoretical issues regarding the use of rodent models in aging research are widely considered in this issue. The availability of aged mice and rats as a critical resource has permitted a remarkable growth in brain aging research programs, but has simultaneously (and quite unavoidably) influenced the nature of the investigations by virtue of the specific genotypes that have been available. Articles in the current issue illustrate the use of a variety of different mouse and rat genotypes and discuss the extent to which they are appropriate models when used in different types of brain aging or neurodegeneration research. Additionally, one article illustrates assessment of decline in cognitive and psychomotor function in aging non-human primates, and addresses theoretical issues having a significant impact on the validity of various rodent models of brain aging. The common element among the articles appearing in this issue is a focus on behavioral assessment of aging in higher-order functions of the brain, the organ that must be considered closely linked to many important components of successful aging. While the life span has been considered a “gold standard” for evaluating potential anti-aging interventions in rodents, assessment of life span alone may fail to fully address the critical question of whether or not the productive, independent periods of life can be extended. While diverse in their individual focus, the articles in this issue are all reflective of progress toward an improved “standard” for understanding and predicting successful aging.

Regional Brain Changes in Aging Healthy Adults: General Trends, Individual Differences and Modifiers

Brain aging research relies mostly on cross-sectional studies, which infer true changes from age differences. We present longitudinal measures of five-year change in the regional brain volumes in healthy adults. Average and individual differences in volume changes and the effects of age, sex and hypertension were assessed with latent difference score modeling. The caudate, the cerebellum, the hippocampus and the association cortices shrunk substantially. There was minimal change in the entorhinal and none in the primary visual cortex. Longitudinal measures of shrinkage exceeded cross-sectional estimates. All regions except the inferior parietal lobule showed individual differences in change. Shrinkage of the cerebellum decreased from young to middle adulthood, and increased from middle adulthood to old age. Shrinkage of the hippocampus, the entorhinal cortices, the inferior temporal cortex and the prefrontal white matter increased with age. Moreover, shrinkage in the hippocampus and the cerebellum accelerated with age. In the hippocampus, both linear and quadratic trends in incremental age-related shrinkage were limited to the hypertensive participants. Individual differences in shrinkage correlated across some regions, suggesting common causes. No sex differences in age trends except for the caudate were observed. We found no evidence of neuroprotective effects of larger brain size or educational attainment.

Behavioural study of the d-galactose induced aging model in C57BL/6J mice

Rodent chronically injected with d-galactose ( d-gal) has been used as an animal aging model for brain aging or anti-aging pharmacology research. However, the dosage of d-gal used to establish this model in mice has been reported in a wide range. To study the dose-dependent effect of d-gal on rodent behaviour, we investigated the learning and memory ability of C57BL/6J (C57) mice after 8-week subcutaneous injection of d-gal at different doses by Morris water maze (MWM) and object recognition test (ORT). In addition, locomotor activity test (LAT) was also performed to examine the neuromuscular function. In comparison of vehicle (0.9% saline)-treated mice, d-gal-treated mice at dose of high (200 mg/kg per day) and middle (100 mg/kg per day) doses showed significant longer latency to platform and less target quadrant search time and distance in MWM In ORT, d-gal at high and middle doses reduced the discrimination index (DI) of mice more significantly than low dose (50 mg/kg per day), although all three doses of d-gal reduced the DI of mice significantly. Furthermore, d-gal at high and middle doses significantly decreased locomotor activity of the mice in LAT. Throughout three tests, d-gal induced behavioural impairments in C57 mice at high and middle doses tended to be in the same degree. These results indicate that d-gal can induce the behavioural impairment of C57 mice in a dose-dependent manner from 50 to 100 mg/kg, higher dose than 100 mg/kg cannot further deteriorate its behavioural performance.

Brain aging research at the close of the 20th century: from bench to bedside

Remarkable and continued growth in the field of brain aging research has been fueled by a confluence of factors. Developments in molecular biology, imaging, and genetics coupled with the imperative caused by the aging of the population has created fertile ground for improved understanding of the interaction between brain function and behavior. Aging changes in neurochemical systems may account for the spectrum of cognitive and behavioral states of successfully aged pen sons, but may also contribute to enhanced vulnerability to depressive or dementing illness. In particular, the refinement of in vivo imaging approaches to investigating the structure and function of the aging brain has provided the opportunity to strengthen our knowledge of the biological substrate of the aging brain and neuropsychiatrie disorders, and translate these into therapeutics.

Individual differences in hypothalamic-pituitary-adrenal activity in later life and hippocampal aging.

Variation in magnitude of cognitive decline in later life is a central feature of human aging. The more severe forms of dementias, such as Alzheimer's disease, clearly define one end of the spectrum. However, among those showing no obvious signs of clinical dementia there are considerable individual differences. Thus, although evidence for learning, memory, and language loss appears in some individuals as early as 50-55 years of age, many people continue to function alertly well into their 90s. These individuals exemplify what Rowe and Kahn (1987) have termed "successful" aging. The wide variability in CNS aging, often a nuisance factor in studies, are becoming a major focus for brain aging research (e.g., Gage et al., 1984;Gallager and Pelleymounter, 1988; Aitken and Meaney, 1990; Issa et al., 1990). Our studies over the past few years have added support to the idea that individual differences in hypothalamic-pituitary-adrenal (HPA) activity can account for part of the variation seen in neurological function among the elderly. In this article we discuss the evidence for the idea that adrenal glucocorticoids can compromise hippocampal function and, thus, produce cognitive impairments, as well as the potential mechanisms for these effects.