ScienceDaily (June 11, 2008) — A 115-year-old woman who remained mentally alert throughout her life had an essentially normal brain, with little or no evidence of Alzheimer's disease, according to a study in the August issue of Neurobiology of Aging.

The findings question the assumption that Alzheimer's disease or other forms of dementia will inevitably develop, if people live long enough. "Our observations suggest that, in contrast to general belief, the limits of human cognitive function may extend far beyond the range that is currently enjoyed by most individuals, and that improvements in preventing brain disorders of aging may yield substantial long-term benefits," according to a study led by Prof. dr. Gert Holstege of University Medical Centre Groningen, The Netherlands.

Dr. Holstege and colleagues had a unique chance to test the mental functioning of one of the world's oldest humans, and then to compare their findings with the condition of the subject's brain after death. The patient was a Dutch woman who, at age 82, made arrangements to donate her body to science after death. At age 111, she contacted the researchers to ask whether her body would still be useful for research or teaching purposes. They assured her that, contrary to what she thought, they were especially interested because of her age: "She was very enthusiastic about her being important for science," Dr. Gert Holstege and colleagues write.

The researchers found the patient to be "an alert and assertive lady, full of interest in the world around her, including national and international politics and sports." She had lived independently until moving to a residential care home at age 105, mainly because of poor eyesight. Ironically, she had been very small at birth and was not expected to survive.

A series of neurological and psychological examinations were performed when the patient was 112 and 113 years old. The results were essentially normal, with no signs of dementia or problems with memory or attention. In general, her mental performance was above average for adults aged 60 to 75.

As planned, her body was donated to science when she died at age 115. At the time, she was the world's oldest woman. Examination after death found almost no evidence of atherosclerosis (narrowing of the arteries) anywhere in her body. The brain also showed very few abnormalities--the number of brain cells was similar to that expected in healthy people between 60 and 80 years old.

A key finding was the absence of brain abnormalities typical of Alzheimer's disease. There were almost no deposits of a substance called beta-amyloid, which are characteristic of Alzheimer's patients. The other abnormalities present, including "neurofibrillary tangles," were very mild--too early to cause significant mental impairment.

The unique case lends new insights into the potential for preserving brain function in very elderly patients. Previous studies have found at least mild abnormalities in the brains of nearly all "cognitively normal" elderly people. As the number of people living to age 100 and beyond continues to increase, the findings suggest that deterioration of the brain is not inevitable.

Increasing rates of obesity have led to concerns about an epidemic of adverse health consequences. Obesity is most simply characterized by measuring waist circumference or waist to hip ratio (WHR). The frequent association of abdominal obesity, as determined by the WHR, with elevation of serum triglycerides, decline in HDL (the "good cholesterol"), hypertension and diabetes constitute a metabolic constellation often referred to as Syndrome X, or the Metabolic Syndrome. It is an important risk factor for cardiovascular disease and stroke.

Obesity has been linked to the development of Alzheimer disease and specific changes in brain structure. Based on the correlation between obesity, dementia and cardio-metabolic factors, investigations have focused on defining potential alterations in brain anatomy seen in this context. Magnetic Resonance Imaging (MRI) was chosen as the desired imaging modality because of its capacity for high spatial resolution and quantitative assessment.

MRI measures that have been previously linked to cognitive impairment and dementia include  hippocampal volume (HV) and white matter hyperintensities (WMH). The hippocampus is a region of the brain essential for memory processing and retrieval. Cerebral white matter consists of nerve cell processes that serve to connect distant clusters of neurons into functional networks. Decreases in HV and and increases in WMH have been shown to contribute independently to the risk of dementia. Because WHR is a component of the Metabolic Syndrome, associations between it and these structural brain changes were investigated.

A recent study was conducted in the Central Valley of California including 112 individuals in the Latino community. WHR determinations, MRI scans and metabolic assessments were performed.  In this cross-sectional analysis greater WHR was associated with a fall in HV and an increase in WMH. A one standard deviation increase in WHR was associated with a 27% increase in WMH. It is important to note that these relationships were not affected by adjustment for body mass index (BMI) (a measure of generalized obesity), total cholesterol level, fasting blood glucose, serum insulin levels or systolic blood pressure.

Although prior studies have shown correlations between HV and WMH with various metabolic and cardiovascular factors, in this study they did not explain the entire association. The authors suggested other potential etiologies such as inflammatory mechanisms linked to the central fat depots, stress and elevation of the stress hormone cortisol as additional factors.

These findings complement a large body of data that demonstrate the negative effects of obesity on cognitive function. They are also consistent with the emerging reports of the beneficial effects of exercise on cognition. One result of exercise may be improved weight regulation. Taken together, these findings provide further support for the suggestion that structural brain changes might be at least partially modifiable by lifestyle alterations.

The only drug approved by the FDA for the acute treatment of strokes is tPA. tPA is the "clot busting" drug that must be given very shortly after a stroke has started. It's major side effect is bleeding which may occur in the brain. If this happens, additional damage to the brain can occur. Because of the short time window during which it may be administered, many people don't get to the hospital soon enough to qualify for use of tPA.

A novel new function may breathe new life into an old drug. Minocycline, an antibiotic used to treat acne, may be an alternative treatment for stroke. It is a semisynthetic cousin of tetracycline. It has been shown to have neuroprotective effects in animal models of multiple sclerosis (MS), Parkinson disease, Huntington disease and ALS (Lou Gehrig's disease). The mechanisms responsible for the death of nerve cells in these diseases share many similarities with cell death pathways in stroke. This prompted investigators to evaluate minocycline in a rodent stroke model. Pyramidal neuron (a type of nerve cell) survival increased from 10 to 77% after administration of minocycline. In another animal stroke model, even when administered 48 hours after a stroke developed, minocycline reduced the size of the stroke.

The proposed mechanisms of minocycline's actions appear to have nothing to do with its antibiotic effects. It seems to have significant anti-inflammatory activities as well as a novel ability to inhibit what are referred to as cell death cascades (that cause nerve cells to essentially self destruct under adverse circumstances) triggered by stroke-like events.

In an open-label, evaluator-blinded study done at Edith Wolfson Hospital in Holon, Israel, minocycline was given to stroke patients for five days. It was started between 6 and 24 hours after onset of a stroke. One hundred fifty-one patients were enrolled in the study. They were followed for 90 days. Recovery rate and final neurological status were evaluated. Improvement was noted as early as day 7. No evidence of recurrent stroke or hemorrhage was noted during the follow-up period. Patients had significantly improved outcome with minocycline treatment in this open label study.

It appears that the beneficial actions of minocycline, especially its antagonism of cell death pathways, which are not engaged acutely during a stroke, make it a potentially useful candidate for stroke therapy with a wider therapeutic time window. Based on these promising preliminary findings, Dr. David Hess at the Medical College of Georgia will further study the efficacy of minocycline in acute stroke in a prospective double-blinded human trial. The current focus of the study is to determine drug safety, optimal dosing regimens and during of therapy.

If previous findings are upheld, minocycline may become a new "standard" therapy for patients experiencing symptoms of acute stroke.

The purpose of sleep is unknown. What is known is that it not only occurs in humans, but all mammals, and even as far back as box jelly fish and species such as the fruit fly Drosophila melanogaster. This suggests that sleep-like states are evolutionarily ancient. Now evidence suggests that a quiescent behavioral state exists in the nematode Caenorhabditis elegans, a round worm. This quiescent state develops during a developmental stage called lethargus, which temporally occurs before each of its four moults in larval stage transitions. 

Quiescence in C. elegans demonstrates certain specific characteristics of sleep. A key feature of sleep is reduced sensory responsiveness. This is manifested in C. elegans by decreased responses to abrupt mechanical and strident olfactory (smell) stimuli. This quiescent state is reversible, as is sleep. It also manifests a "homeostatic," or metabolically refreshing, quality when, after a period of enforced wakefulness, subsequent sleep occurs more rapidly and is deeper.

The temporal relationship between lethargus and the moult, which is essential for growth and development of the animal, is a period of enhanced biosynthetic activity. This is consistent with the sleep-like state playing a vital role in growth and development of the organism. Also related to lethargus are vital alterations in the nervous system and the connectivity between individual nerve cells. Connections between nerve cells are called synapses. The process of modification of these connections is called called plasticity. Plasticity is the basis for learning and memory and reflects what happens during the developmental stages in round worms. It is also a vital brain process in humans.

Strengthening of new neuronal connections is called consolidation and is necessary for the solidification of learning. This process requires expenditure of substantial amounts of cellular energy and must provide significant benefits. These synaptic modifications (plasticity and consolidation) associated with lethargus in C. elegans promote nervous system changes that are important in the organism's life cycle.  Such a role in nervous system development, maturation and function is notable in light of information suggesting that sleep, and sleep-like states, are necessary for the production of changes in the nervous system.

These findings highlight potential roles played by sleep in humans. It is well-known that sleep deprivation acutely diminishes mental functions. Chronic sleep deprivation is associated with elevations in the stress hormone cortisol. Cortisol, in excess, can cause shrinkage and loss of nerve cell connections (synapses). This occurs in association with aging and is more severe in dementing conditions such as Alzheimer disease. These findings are evidence of the importance of adequate sleep not only for provision of cognition, but also for the prevention of neuronal changes seen in severe memory loss states.

Autism is a neurodevelopmental disorder with genetic and environmental influences. It has increased dramatically in incidence over the past 25 years. A newly published study conducted by researchers at the University of Texas Health Science Center in San Antonio explored the link between industrial release of mercury and increased autism rates. Data documenting mercury release were from 39 coal-fired power plants and 56 industrial facilities in Texas. Autism rates were examined from 1,040 Texas school districts.

For every 1,000 pounds of mercury released by all industrial sources into the environment in Texas in 1998, there was a corresponding 2.6% increase in autism rates in the Texas school districts in 2002. For every 1,000 pounds of mercury released by Texas power plants in 1998, there was a corresponding 3.7% increase in autism rates in Texas school districts in 2002. The researchers found that autism prevalence is reduced by 1-2% with each 10 miles of distance from a pollution source.

The United States Environmental Protection Agency estimated annual environmental mercury releases to be 158 million tons nationwide in the late 1990s. Dr. Palmer, one of the investigators, said, "We need to be concerned about global mercury emissions since a substantial proportion of mercury releases are spread around the world by long-range air and ocean currents. Steps for controlling and eliminating mercury pollution on a worldwide basis may be advantageous."

These new findings are similar to a number of other studies that confirm the presence of higher amounts of bodily incorporation of mercury in plant species, animals and humans the closer they are to the pollution source. The authors noted, "We suspect low-dose exposures to various environmental toxicants, including mercury, that occur during critical windows of neural development among genetically susceptible children may increase the risk for developmental disorders such as autism." There is additional evidence from unrelated studies that children and other developing organisms are more susceptible to the neurobiological effects of mercury exposure.

Something new under the sun has been discovered! Novel findings are frequently associated with new technologies. Such was the case at hand. By utilizing a sophisticated computer algorithm that identified the simultaneous firing of geographically disparate nerve cells in human brains, a new functional brain system was identified. It is referred to as the "Default Mode Network" (DMN).  Examples of existing, well understood neural systems include the oculomotor system (that keeps our eyes tracking together in a way that focuses the visual image on the fovea, the central part of the retina where detailed image processing is performed), the auditory system (that allows us to make sense of the sounds we hear), the visual system (that enables us to compose a visual image from the electrical responses generated when light contacts our eyes) and the somato-motor system (that allows us to perform coordinated motor tasks such as writing and walking).

The anatomic underpinnings of the DMN comprise a disseminated group of nodes connected electrically by long, thin nerve fibers. Think of them like cities linked by superhighways. What fascinated researchers from the outset was the observation that when the brain was engaged in any one of a number of different task-oriented mental chores, the default mode became inactivated. However, during pensive non task-directed moments it became intensely stimulated. Examples of this type of non-task directed mental stimulation include introspective rumination, consideration of self-referential thoughts, reflection about past events, wondering what others might be thinking, mulling over the future, free-associating or what might be referred to as daydreaming. These are some of the most cogent mental functions the brain is called on to perform.

Components of the default mode network include portions of the medial prefrontal cortex and medial parietal cortex (called the precuneus). Not included in the default mode network, but intimately linked to it, is a small, yet vital region called the hippocampus. It plays a pivotal role in processing and calling up memories. A typical, hippocampally mediated association task is the assignment and recollection of the relationship between names and faces.  Being introduced to a stranger and then promptly forgetting his name is the prototypical senior moment. Understanding the role the DM network (especially the precuneus) and the hippocampus play in this frustrating scenario might help prevent it from happening in the future.

Let's walk through a typical social encounter. Consider a block party where there is a large crowd of unfamiliar people, noise and energy, and then throw in the anxiety and stress of meeting a host of new neighbors. For many persons this setting constitutes the "Perfect Storm" of circumstances that foment forgetting, especially when one's memory is not in top form to start with. What happens when you are tasked with remembering your next door neighbor's sister's name involves several steps. Number one is the deactivation of the DM system. This requires conscious input. You must clear your mind of the events of the day, what you need to do after the party, who else might be attending, what their agenda is and so forth. Some times it is helpful to use a note pad to write down what you need to buy at the grocery store, and to free up mental energy for other tasks such as remembering new names. Stress and anxiety make it difficult for the DM to disengage, as does sleep deficiency. When this is the case, the brain must "juggle' many mental balls simultaneously (default mode threads as well as the task at hand). Much like any multi-tasking situation, you probably perform poorly at each of the multiple things you try to do. So, freeing up your mind (allowing your DM to relax) is the first step to remembering.

The next thing that is required is to activate your hippocampus. That involves focusing your attention on the task at hand. You must concentrate, get actively engaged and remain focused. Start out by looking directly into the eyes of the person you have been introduced to. This issues a directive to your brain that this person is a high priority and must be attended to. After learning his name, repeat it to yourself and then again out loud by saying something like, "Frank, it is a pleasure to meet you. I have heard so much about you from you sister." This reinforces the connection and strengthens the memory trace you are establishing.

So hopefully the next time you find yourself in this type of social circumstance, you will think about what cutting-edge science has taught you about senior moments and how to avoid them. Just remember, that to remember you must turn off the default mode and turn on the hippocampus. 

Patients receiving chemotherapy for various types of cancer have long complained about neurological side effects they believed were related to the chemo treatments themselves. These symptoms included memory loss, headaches, difficulty concentrating, word-finding problems, mental fatigue and even learning disabilities. Until recently, these complaints were often dismissed as being unrelated to the chemotherapy. Doctors felt they were due to depression about being sick, having cancer, eating poorly, being stressed out, disturbed daily schedules or even "ICU syndrome." However, emerging information is documenting the full scope of the adverse cognitive impact chemotherapy has on the brain. 

In some studies, upwards of 80% of patients treated with chemotherapy reported that they suffer from some form of impaired cognition. This has come to be referred to as "Chemo Brain." These (usually delayed) consequences can compromise the quality of life in a significant portion of cancer survivors. Consistent with these observations is new research demonstrating that treatment with a single chemotherapeutic agent, 5-fluorouracil (5-FU), even when used by itself is able to cause a syndrome of delayed degeneration within the nervous system. 5FU is a widely prescribed chemo drug frequently used in combination with other agents for the treatment of many cancers including cancers of the colon, rectum, breast, stomach, pancreas, ovary and bladder.

Little is known about the brain-related side effects of chemotherapy. Why one patient may be affected and not another is not fully understood. Questions remain including whether these effects are related to dosing regimens, combinations, relationship to specific cancer types, prior brain damage, breakdown of the blood-brain barrier or inflammation. Researchers at the University of Rochester and Harvard Medical School demonstrated in mice studies that administration of 5-FU caused both acute central nervous system damage as well as damage that worsened over time. They discovered this damage was not self repairing. One of the manifestations was an impairment in the rate at which the animals were able to process information.

In addition to toxicity to the dividing cells within the brain, 5-FU damaged cells called oligodendrocytes. They are brain cells responsible for producing the myelin sheath of neurons. This is like the plastic coating on a lamp cord. When damaged, the wires short out and the lamp doesn't work. The same thing happens in the brain. Messages between nerve cells can't be transmitted.

In other studies, Mark Noble, PhD, exposed several different types of healthy brain cells as well as a variety of human cancer cell lines to three commonly used chemotherapy drugs - carmustine, cisplatin and cytosine arabinoside - at levels characteristically experienced in patients. These drugs are used to treat certain types of breast cancer, lung cancer, colon cancer, Hodgkin and non-Hodgkin lymphoma, leukemia and brain tumors.

Cancer treatments are partially based on the assumption that the drugs are less toxic to normal cells than to cancer cells. Normal cells also usually recover more rapidly from chemo than do cancerous cell types. It thus came as a big surprise that these drugs were far more toxic to healthy brain cells than to the cancer cells. Worse still, these drugs were found to be toxic to both non-dividing cells, dividing stem cells and precursors at even very low concentrations. Because neurogenesis (formation of new nerve cells) occurs in the hippocampus - a major hub in memory function - and it is interrupted by these drugs, this locus might be one area where the cognitive side effects of chemotherapy arise.

These findings provide some scientific rationale for the cognitive symptoms many patients receiving chemotherapy describe. However, because chemotherapy is a cornerstone of cancer treatment, no one should forego this potentially life-saving therapy. It should be discussed with your doctor ahead of time and mental function should be monitored during and after therapy. This information should also stimulate the development of strategies to protect brain cells from these drugs.

The principal mental disorders affecting late life are dementias such as Alzheimer disease (AD) and the primary mood disorder, depression. In addition to cognitive falloff, some of the most common symptoms in the dementing and neurodegenerative diseases are depressed mood, apathy and anxiety. There is overlap between these symptoms and those seen in depression. Loss of neurons and nerve cell connections is characteristically seen in AD. Many investigators have theorized that neuronal atrophy and death in these disorders results, in part, from a lack of of trophic support. For healthy existence, cells in every location in the body depend on chemicals called trophic factors that protect them and allow them to function optimally. In the brain, neurotrophins are the compounds neurons rely on for this cellular support. The primary one is called BDNF (Brain-Derived Neurotrophic Factor). BDNF is present in the highest concentrations in the hippocampus, a brain region with vital functions in both learning and memory.

Hippocampal BDNF levels fall in response to stress.  Stress plays a key role in the development of depression and other psychiatric illnesses. Shrinkage of the hippocampus associated with nerve cell loss and atrophy has been observed in animals exposed to chronic stress. These animals manifest behavioral alterations associated with a depressive state. Consistent with these observations is the fact that humans with a history of chronic, recurrent depression, or post-traumatic stress disorder have shown significant hippocampal atrophy (shrinkage) in brain imaging studies.

One approach used in treating depressive symptoms is the administration of antidepressant medication. Recent evidence suggests that these drugs produce a downstream elevation of BDNF in association with their mood elevating properties. In this context, it is interesting to note that current research studies provide evidence that our daily behavior and lifestyle choices influence the level of BDNF expression in the brain. Exercise and participation in an enlightened environment are often linked with up-regulation of synthesis of this important neurotrophin. They also modulate neurogenesis, or production of new nerve cells within the hippocampus.

The ability of exercise to improve the psychiatric status of depressed patients has been observed for some time. As has already been discussed in previous posts, physical activity upregulates the production of BDNF. This suggests that exercise and antidepressant therapy activate similar molecular pathways in the brain. 

Three recent articles have assessed the effects of exercise on patients with major depressive illness. Several conclusions can be made from these studies. One, that exercise improves the symptoms of depression. Second, exercise improves the outcome in patients being treated with antidepressants. Third, moderate intensity exercise is more effective than low intensity exercise in alleviation of depressive symptoms.

Another significant observation regarding the impact of exercise on depressive symptomatology is that its antidepressant effects endure after the period of exercise is terminated. Effects of depression on executive function are exceedingly problematic for many depressed patients. Exercise has been shown to improve reaction times and other parameters of executive function.

There are very few downsides to exercising. It is good for prevention of obesity, blood pressure control, improvement of cardiovascular risk profile and now it is known to be beneficial for mental health and cognition.