Mark B. Moss

Neurobiological Bases of Age-Related Cognitive Decline in the Rhesus Monkey

The rhesus monkey offers a useful model of normal human aging because when monkeys are tested on a battery of behavioral tasks that can also be used to evaluate cognition in humans, it is found that the monkeys undergo an age-related decline in several domains of cognitive function as do humans. In monkeys these changes begin at about 20 years of age. To determine what gives rise to this cognitive decline, we have examined several parameters in the brains of monkeys. Some parameters do not change with age. Examples of this are the numbers of neurons in the neocortex and hippocampal formation, and the numbers of synapses in the hippocampal formation. Changes in other parameters can be positively correlated with chronological age; examples of this are numbers of neuritic plaques, a decrease in the numbers of neurons in the striatally projecting pars compacta of the substantia nigra, and a decrease in the thickness of layer I in primary visual cortex. But the most interesting changes are those that correlate either with cognitive decline alone, or with both cognitive decline and chronological age. Among these are a breakdown in the integrity of myelin around axons, an overall reduction in the volume of white matter in the cerebral hemispheres, thinning of layer I in area 46 of prefrontal cortex, and decreases in the cell density in cortically projecting brain stem nuclei. To date then, our studies suggest that the cognitive declines evident in the rhesus monkey may be a consequence of changes in layer I and in the integrity of myelinated axons, rather than an agerelated loss of cortical neurons or synapses, as has long been assumed.

Lack of correlation between plaque burden and cognition in the aged monkey

Abstract To assess whether amyloid plaque accumulation in the monkey brain can account for age-related cognitive impairment that begins at about 20 years of age, we measured plaque content in the brains of 14 rhesus monkeys aged 5–30 years. We used immunohistochemistry employing the monoclonal antibody 6E10, which is specific to amino acids 1–17 of the amyloid β peptide to identify amyloid plaques in serial coronal sections of the forebrain. Amyloid plaques accumulate with age, starting at 25 years of age and escalating after 30 years. Until the age of 30, plaques are only found in a few monkeys and are relatively sparse. Results from our group and others show that plaque content and the proportion of individuals afflicted with amyloid plaques increase with age. Although both cognitive dysfunction and plaque content increase with age, amyloid plaque content does not correlate with the cognitive dysfunction observed in elderly monkeys since even in very old subjects some cognitively impaired animals have few amyloid plaques and others with abundant plaques show only minor cognitive impairments. In summary, amyloid plaques appear to accumulate significantly only in monkeys over 25 years of age but do not appear to be a causal factor in age-related cognitive decline of the normal aging rhesus monkey.

MRI-guided focused ultrasound surgery in the brain: Tests in a primate model

MRI‐guided focused ultrasound was tested in the brains of rhesus monkeys. Locations up to 4.8 cm deep were targeted. Focal heating was observed in all cases with MRI‐derived temperature imaging. Subthreshold heating was observed at the focus when the ultrasound beam was targeted with low power sonications, and in the ultrasound beam path during high‐power exposures. Lethal temperature values and histologically confirmed tissue damage were confined to the focal zone (e.g., not in the ultrasound beam path), except when the focus was close to the bone. In that case, damage to the neighboring brain tissue was observed. Focal lesions were observed on histological examination and, in some cases, in MR images acquired immediately after the ultrasound exposures. The capabilities demonstrated in this study will be of benefit for clinical ultrasound therapies in the brain. Magn Reson Med 49:1188–1191, 2003.

Sex, Age, and Training Modulate Spatial Memory in the Rhesus Monkey (Macaca mulatta)

The authors tested 90 rhesus monkeys (Macaca mulatta) on a task of spatial memory, the spatial Delayed Recognition Span Test. The results showed that performance declined significantly with age, males had greater scores than females, and the rate of apparent decline with age was greater in males than in females. Both working and reference memory declined with age, but only working memory showed sex differences. The authors compared these data with that of 22 monkeys who were trained on a simpler version of the task before formal testing. Training had no effect on males but dramatically improved working memory in young females. The results confirm a male advantage in spatial working memory at a young age and confirm a greater decline with age in males than in females. It is important to note that prior training completely reverses the deficits of young females.

Age-Related Cognitive Decline in the Rhesus Monkey

It is only in the last 25 years that significant strides have been taken toward the development of primate models of normal human aging. Together with advances in the fields of molecular biology, neuroimaging, and behavioral neuroscience, these models have emerged as potentially important components in our understanding of the age-related cognitive decline in humans (Peters et al., 1996). This is not to say that studies using other species, particularly rodents, have provided a wealth of information on the neurobiological substrates of aging. However, the rich behavioral repertoire of the monkey, particularly the monkey’s remarkable ability to perform a variety of complex short-term memory tasks, many administered to normal humans in geriatric research studies, has made this species particularly suited to assess cognitive function at a level not possible in nonprimates.

A rhesus monkey reference label atlas for template driven segmentation

Backgroundu2002 We have acquired dual‐echo spin‐echo (DE SE) MRI data of the rhesus monkey brain since 1994 as part of an ongoing study of normal aging. To analyze these legacy data for regional volume changes, we have created a reference label atlas for the Template Driven Segmentation (TDS) algorithm.

A Primate Model of Hypertensive Cerebrovascular Disease

Cerebrovascular disease (CVD) in humans has been shown to produce a variety of cognitive impairments ranging from selective deficits to wide-range dementia. Among the risk factors for CVD (e.g., age, diabetes mellitus, serum lipids, obesity, cardiac disease), arterial hypertension has been identified as key(1) affecting more than 25% of the adult population of the United States (2). Gross effects of extreme hypertension are well known and include a four times greater risk for CVD than normotensive individuals(3). For the most part, hypertension is an asymptomatic disorder, but recently it has been the focus of attention on its possible detrimental effects on cognitive function. Indeed, over the past two decades, evidence has accumulated to suggest that hypertension in humans produces, in many cases, a significant impairment in several domains of cognitive function. But because of the inherent limitations of human research, even with recent advances in magnetic resonance and positron emission imaging technology, our understanding of the neurobiological basis for hypertensive related cognitive impairment is unknown. It is also unknown to what extent the changes in cognition that are associated with hypertension represent the first stage in the development of CVD and vascular dementia.

Early Features of Alzheimer’s Disease

Alzheimer’s disease (AD), the most common dementing disorder, ultimately produces severe impairments that affect all cognitive domains (e.g., memory, executive function, langauage, spatial ability, and attention.) Early in the course of disease, however, the pattern of deficits is more circumscribed. Memory changes are generally the earliest cognitive change seen in AD. Changes in executive function ability also shown significant declines early in the course of AD. Neuropathologic studies in autopsy-confirmed AD patients who had a range of severity during life provide strong evidence for neurobiologic changes responsible for the pattern of cognitive deficits seen early in the disease. Together with recent neuroimaging studies, they suggest that a brain network with multiple nodes is selectively vulnerable in AD and that the cognitve deficits are related to the involvement of this brain network. We will review the early cognitive changes associated with AD and their neurobiologic correlates.

Research in Alzheimer's disease: A progress report:

Although first identified over 80 years ago, it is only in the last ten years that Alzheimers disease has become the focus ofa major research effort. In this brief period, significant advances have been .made in the assessment, epidemiology, genetics and pathophysiology of the disease. However, despite these gains we are still far from understanding the cause or developing an effective treatment. With continued research efforts in the study of Alzheimers disease, as well as in normal aging, effective treatment and prevention may eventually be realized.

Neural transplantation: A panacea?

Abstract While the technique of neural transplantation represents an exciting therapeutic technology for the treatment of brain disorders, there are some issues concerning anatomical connectivity and functional recovery which must first be addressed.