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Thursday, August 29, 2013

Is AD Really Linked to Poor Dental Health?


Dear Readers,
British scientists recently reported finding signs of the gum-disease bacterium Porphyromonas gingivalis (P. gingivalis) in the brains of Alzheimer’s patients. The new study is being widely reported as adding to a growing body of evidence linking periodontal (gum) disease to an increased risk for AD.

However, such data needs to be considered very carefully.

In fact, what the study found was that substances on the surface of the bacterium (lipopolysaccharides) were present in the brain tissue of 4 out of 10 recently deceased people who had Alzheimer's. It was found in 0 out of 10 age matched patients who did not have AD. The bacteria itself was not found in the brain tissue of any people.

The theory behind linking gum disease with AD is that the presence of gum bacteria lipopolysaccharides in the brain may cause inflammation. This in turn could trigger a biological cascade that may be linked to the brain changes associated with Alzheimer's disease.

We already know that P. gingivalis is commonly found in chronic periodontal (gum) disease, and, if there is significant dental disease, can enter the bloodstream through such everyday activities as eating, brushing, and invasive dental treatments. While in the bloodstream, the bacteria can settle on heart valves and damage them. Hence, patients with mitral valve prolapse and other heart anomalies often take an antibiotic before dental procedures to prevent the bacteria from depositing within the heart. However, no bacteria have been reported in the brains of patients with gum disease, as the brain is an immunologically, well-protected organ, more so than any other.

It is important for readers to know that these types of studies show an association between gum disease and AD, but do not prove causation. For example, the number of subjects is extremely small to make a definitive conclusion, and the finding could have occurred simply by statistical chance. In addition, only 4 out of 10 subjects with AD had such changes, not 10 out of 10. If the gum disease was causative, one would expect more than just a minority of patients exhibiting the lipopolysaccharides. Finally, what if very early stage dementia caused people to actually brush their teeth less often, or altered their dietary intake? They would be at risk of developing gum disease and then progress through the early stages of AD to develop dementia. Then there would be a perceived strong correlation between gun disease and dementia. But the gum disease would have resulted from the early dementia, not vice versa. It is also important to note that previous studies have shown links between gum disease and other illnesses including heart disease and certain forms of cancer; that these findings are not specific to AD. The study is important and should be followed up with larger sample sizes, but given the above limitations, the study does not show that "brushing teeth reduces the risk of dementia" or that "gum disease can lead to dementia."



Thanks for reading.


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 3:06 PM 0 Comments

Thursday, August 22, 2013

Potential Biomarker for Preclinical AD


Dear Readers,

As many of you are aware, in addition to direct visualization of elevated amyloid levels in the brain using PET scans, there are two biochemical markers currently accepted to precede the appearance of symptoms of dementia:

1) Brain accumulation of beta-amyloid or low beta-amyloid levels in cerebrospinal fluid (CSF)

2) Elevated CSF total tau (t-tau) and phosphorylated-tau (p-tau).

Low concentrations of beta-amyloid in CSF are associated with AD and correlate with accumulation of beta-amyloid in the brain. High CSF concentrations of t-tau and p-tau are associated with increased neurofibrillary tangles seen inside of neurons. Such changes appear to be necessary, but not sufficient to produce the clinical signs of AD because postmortem studies indicate that a considerable amount (10-30%) of people without dementia exhibit such changes.

A study published last week reported the identification of what may be the earliest known biomarker associated with the risk of developing AD. The researchers, based in Barcelona Spain, demonstrated that a decrease in the level of mitochondrial DNA (mtDNA) in CSF may be a preclinical indicator for AD; moreover, there may be a directly causative relationship. Mitochondrial DNA is the genetic sequence located inside organelles called mitochondria, structures within cells that convert chemical energy from food into a form that cells can use.

The study involved CSF analysis of over 200 subjects, and was validated in separate cohorts from two different research centers. The researchers found that patients with a genetic form of early onset AD, as well as those with sporadic, or late-onset AD had decreased levels of mtDNA in their CSF, as compared to normal controls and patients whose dementia was not due to AD.

The hypothesis is that decreased mtDNA levels in CSF reflect the diminished ability of mitochondria to power the brain's neurons, triggering their death. The changes in circulating mtDNA levels in these patients, including those with mutations in the amyloid pathway, occurred before any alterations in the CSF beta-amyloid and p-tau proteins were detected.

The potential use of mtDNA as a marker of preclinical Alzheimer's disease provides unique advantages over beta-amyloid and p-tau: the detection of DNA is technically much easier than protein detection. Also, mtDNA can also be very readily quantified. In fact, the researchers identified cut off levels of mtDNA such that 364 pg/mL was the average in the asymptomatic at risk patients, 302 pg/mL in the symptomatic Alzheimer's patients, 718 pg/mL for the FTLD patients, and 883 pg/mL in the normals.

The findings in this paper are quite significant. They results allow for consideration of mtDNA as a potential biomarker for the earliest stages of AD.

Thanks for reading.


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 9:51 AM 0 Comments

Friday, August 09, 2013

The Effect of Exercise on Cognition and Physical Functioning in Older Women


Dear Readers,

Alzheimer’s disease is well known to be a multi-factorial and progressive neurodegenerative disease. As the incidence of AD continues to rise globally, the impact on social, economic and health delivery systems is becoming apparent. In response, clinically focused activities and research has not only shifted on establishing biomarkers for predicting the development of Alzheimer’s disease, but also to prevention studies that aim to delay one of the common symptoms of aging - cognitive decline. This week’s blog focuses on the role of exercise to cognitive function and describes an ongoing randomized clinical study in Australia.

In a study by Vaughn et al. published in BMC Geriatrics, women aged 65 – 75 years were recruited to a randomized controlled study for 16 weeks. The study was designed to assess the effect of an exercise intervention combining physical fitness training (aerobic /strength) and motor fitness training (balance, coordination, agility, reaction time and flexibility). Physical measurements were taken two weeks prior to the beginning of the trial and one week after completing the 16 week exercise program including blood serum levels for brain derived neurotrophic factor (BDNF). BDNF is thought to have a key role in brain plasticity by regulating the growth and survival of neurons in the adult brain, and most recently appears to be involved in brain changes that accompany exercise.

The classes were conducted for 60 minutes twice a week, and included an increased intensity and variation of the key components in the program. Strength training included progressive weight training and weight bearing exercises, in addition to motor training which included coordination, agility and balance. Sessions were conducted with fitness trainers, with a maximum of 20 participants to a class. One group of persons received the “intervention” while the other group received the “wait list”. The “wait list” group received no exercise intervention but was invited at the end of the 16 week period to attend the exercise program. Prior to enrollment, participants were screened by phone, with a TICS battery and Pre Activity Readiness Questionnaire, and for the ability to walk 20 meters unaided.

The primary outcome measures for this study were neurocognitive test performance related to the processes of working memory, inhibition, shifting, verbal fluency and simple and complex reaction times. The secondary outcomes were measurement in the blood of serum levels of BDNF, physical and functional capacity testing including the 6 minute walk test, the timed up and go test and one foot stance test of balance. Waist and hip circumferences, resting heart rate and blood pressure were obtained on all participants.

Although no results of this unique trial have been reported, the results will be informative in that they may shed light into the effect of a multimodal approach to exercise. Adding motor exercise training that is thought to involve the cognitive functions of attention and concentration in addition to traditional exercise regimens could provide valuable information on how to design future studies to prevent cognitive decline, if positive results are found.

Here are 3 articles you can refer to, to learn about this particular study or the latest research on exercise and cognitive function.

Vaughan S, Morris N, Shurn D. et al. Study protocol: a randomized controlled trial of the effects of a multimodal exercise program on cognition and physical functioning in older women. BMC Geriatrics 2012, 12:60

Rasmussen P, Brassard P, Adser H., et al. Evidence for a release of brain derived neurotrophic factor from the brain during exercise. Exp Physiol 2009 94: 10 1062-1069

Ratey JJ, Loehr F. The positive impact of physical activity on cognition during adulthood a review of underlying mechanisms, evidence and recommendations. Rev Neuroscience 2011; 22 (2) 171-185

Thanks for reading.
 
Author: Neelum Aggarwal MD at 4:32 PM 0 Comments

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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.