John R. Wherrett, MD, PhD, FRCPC, Department of Medicine (Neurology), Toronto Western Hospital and University of Toronto, Toronto, ON.

Contemporary technologies, including digital imaging of the brain during life and quantative microscopy (unbiased stereology) for estimating histological features postmortem, have resulted in important new knowledge about changes in the brain that accompany healthy aging, including evidence that grey matter atrophies with an anterior-posterior gradient. Neurons shrink but numbers are preserved; however, there is moderate reduction in dendritic spines and in synapses that have altered function. This is to be interpreted in the light of evidence for neurogenesis continuing into late life. White matter volume increases into maturity, but in aging there is a marked reduction due mostly to a loss of small myelinated fibres. Cell inclusions characteristic of neurodegenerative disease are commonly found postmortem in the healthy aged.
Key words: brain, aging, morphometry, imaging.

A novel brain mapping technique has provided the first quantitative, dynamic visualization of the spreading wave of cortical atrophy in the brains of living patients with Alzheimer disease (J Neurosci 2003;23:994-1005).

Using this unique mapping method, Australian neuroscientists were able to visualize dynamic patterns of atrophy in 52 high-resolution MRI scans of 12 patients with AD and 14 elderly matched controls. Based on these scans, dramatic time-lapse videos were created, showing sequential loss of gray matter in four dimensions as it spread over time from temporal and limbic cortices into frontal and occipital brain regions, while sparing sensori-motor areas. The visualized patterns of cortical atrophy correlated with the AD patients' progressively declining cognitive ability and mirrored the sequence of neurofibrillary tangle accumulation observed at autopsy. AD patients were found to lose an average of 5.3% grey matter per year compared to a loss of only 0.9% in the healthy volunteers.

In the future, such images may offer researchers a potent tool for assessing the impact of therapies on dementia as well as for evaluating the spread of the disease.

Elise J. Levinoff, BSc^1,2, Howard Chertkow, MD, FRCPC^1,2,3
1Bloomfield Centre for Studies in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University
²Department of Neurology and Neurosurgery, McGill University
³Division of Geriatric Medicine, Dept. of Medicine, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, PQ.

Alzheimer disease (AD) is a neurodegenerative disease of elderly patients, pathologically characterized by the presence of senile plaques and neurofibrillary tangles in the brain. This pathology occurs in the cerebral cortex, specifically within the temporal lobes, resulting in impairment in cognitive domains such as short-term memory, attention, semantics, as well as aphasia and apraxia.¹ Patients also show marked changes in behaviour and are impaired in activities of daily living (ADLs). The causes of AD are unknown, but age is a major risk factor. Women are at a higher risk of developing AD, although this may be due, in part, to increased longevity. Additionally, mechanisms of neuronal injury, such as the presence of cerebral infarcts and consequences of head trauma, increase the risk of developing AD. Expression of the APOE-e4 genotype has also been associated with an increase in the risk of developing AD.¹

Presently, there is no cure for AD.

Mark P. Mattson
Laboratory of Neurosciences,
National Institute on Aging Gerontology Research Center, and
Department of Neuroscience,
Johns Hopkins University School of Medicine,
Baltimore, MD, USA.

As in other industrialized countries, as the average age of the population increases, the number of Canadians that suffer from neurodegenerative conditions such as Alzheimer disease (AD), Parkinson's disease (PD) and stroke is rapidly increasing. On a more positive note, the number of people that enjoy a healthy brain as they age is also increasing. The genetic and environmental factors that determine how the brain adapts to aging are beginning to be identified, and their mechanisms of action at the cellular and molecular levels are being elucidated. Although degeneration and death of neurons occur in some brain regions during normal aging, the brain is able to adapt to the cell loss by increasing the growth and synaptic connections of the remaining neurons.¹ In contrast, age-related neurodegenerative disorders occur when the death of neurons is accelerated and adaptive responses are impaired or overwhelmed. During the early years of life, the brain has a remarkable ability to adapt to adversity, such that although large regions of the brain may be damaged, normal function can be restored.² As we age, the brain loses its ability to adapt to an insult.

Brain Regeneration in Humans: Can We Manipulate This Process?

Multiple evidence collected over the past 30 years supports the notion of brain neurogenesis in animals. Until recently, however, regeneration of neurons in humans seemed impossible. Proof that humans are not unique came from the laboratory of Fred Gage of the Salk Institute for Biological Studies in California in November 1998.

The brains of five cancer patients, who were injected with bromodeoxyuridine (BrdU) to tract their tumor cells, were analyzed post mortem. BrdU is a non-specific marker of DNA replication and, thus, tracts any dividing cell. The researchers found ample evidence of cell division in neurons of the dentate gyrus of hippocampus, a region involved in learning and memory.

Dentate gyrus is the first relay station for sensory information entering the hippocampus. It gets hit with a lot of glutamate, an excitatory neurotransmitter that damages brain cells. Thus, neurogenesis in dentate gyrus may be part of brain repair. The new neurons are short-lived (only a few weeks) and could play a role in new memory formation. These memories may then be stored elsewhere for the long term.

If brain neurons can regenerate, what are the factors potentiating or retarding this process? Studies of mice that suffered a stroke showed that exercise speeds up the recovery. Interestingly, exercising had to be absolutely voluntary or else it did not induce neuronal proliferation. Also, living in spacious well-equipped cages resulted in the doubling of the number of new brain cells. Surprisingly, learning did not induce neuronal formation in mice, unlike in rats.

Neurogenesis can be chemically manipulated. For example, increasing serotonin raises the number of neurons in rodents. Importantly, this happens even if serotonin is increased by an anti-depressant such as Prozac. Estrogen also increases neurogenesis. This is expected since for a long time it has been theorized that hormone replacement therapy protects older women against mental decline. In contrast, corticosteroids (stress hormones) stunt neuronal regeneration and survival. Stress is well known to impair memory. Also, the levels of corticosteroids are three times higher in the elderly than in young people. Interestingly, when corticosteroid levels are lowered in older rats, cell division of neurons is increased.

Thus, neuronal regeneration appears to be a reality. On going studies are looking into various ways of manipulating and controlling this process. Hopefully, this will enable us to induce neuronal recovery in cases where brain damage has occured.

Suggested Reading

1. Motluk A. Grow your own. New Scientist, 12 February 2000, p. 24.
2. Zigova T, Sanberg PR. Neural stem cells for brain repair. Science & Medicine, Sep/Oct 1999, p.18.

Elana Lavine, BSc

As the elderly population becomes an increasingly larger proportion of society, a key focus of scientific research will be the process of normal brain aging. Exactly what processes are considered to be a part of normal aging? Much of the literature examines the pathological changes observed in the brain of patients with such diseases as Alzheimer's and Parkinson's. However, the changes in brain morphology during senescence, as evidenced by studies of the healthy elderly, help shed light on what is truly attributable to aging and what is attributable to disease. The distinction between the two may be blurred by influences of lifestyle, such as diet and exercise. Individual variation in outcome measures, such as short-term memory, may create a wide range of what may be categorized as "normal" function. In addition, there exists a relative absence of neuropathological data from well-characterized healthy aged adults studied over extended periods of time.¹

Brain Size & Morphological Change
By 80 years of age, the average brain has decreased 15% in weight, and is noted as having smaller gyri, separated by wider sulci.² Specific research has focused on finding out exactly which parts of the human brain contribute to the decrease in weight. Supratentorial brain atrophy has been shown to progress with aging, and specifically with a reduction in the volume of gray matter.

Chris Daniels

Canada's only national brain bank is "functioning at 50 per cent capacity right now", says the medical director of the bank.

Because of the recession and provincial cuts to research agencies, the bank went from collecting 120 brains a year to 60, director Dr. John Wherrett said of Canada's largest provider of brain tissues.

For fifteen years, the brain bank at the Toronto General Hospital, Western Division, has provided researchers brain tissue for studying neurodegenerative diseases like Alzheimer's Disease (AD) and Parkinson's Disease.

But for the last few years, the bank has been experiencing growing pains. Its main sources of income, the Medical Research Council, voluntary agencies, and the Ontario Mental Health board, had to reduce their commitment because of difficulty raising funds. This lack of funding has left the bank with fewer tissues for researchers and, without diseased tissues as well as controls for the studies, research has been moving more slowly, said Dr. Wherrett.

"We've had to pick and choose what we do," he said. "There has been a slow down in research in recent years because of massive cutbacks on top of the recession."

It's a trend he thinks will soon change.

Rhonda Witte, BSc

The process of aging is familiar to every individual. Yet, despite this familiarity, it remains one of the greatest biological mysteries. We embark on the aging journey from the very moment we are born and proceed passively until our deaths. It is a concept that some find difficult to comprehend, perhaps because it is seemingly inevitable--beyond one's control.

A multitude of theories has been proposed regarding the aging process. The question "Why do we age?" has sparked interest in many research disciplines. Of particular interest are the neurological aspects of aging. Numerous examinations of the aging brain have been performed, particularly those concerning the neurodegenerative diseases of the elderly. Interestingly, studies using animal models have suggested that estrogen replacement therapy may have a role in both the treatment and prevention of dementia by assisting the regeneration and preservation of neuronal structures.¹ Close attention has also been given to the "normal" aging brain and the events that occur over a lifetime.

Along with the heart and striated muscle, the brain is the oldest part of the mammalian body. The neurons of the brain are postmitotic once differentiated and are unable to renew themselves. Thus, the brain is highly susceptible to any cellular damage that may occur with age.