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Thursday, August 26, 2010

How a Type of Electrical Brain Activity Relates to AD

Dear Readers,

The "hippocampal theta rhythm" is a specific type of electrical activity that can be observed in the hippocampus and other brain structures in numerous species of mammals including rodents, rabbits, dogs, cats, bats, and marsupials.

In the oldest EEG literature dating back to the 1920s, Greek letters such as alpha, beta, theta, and gamma were used to classify EEG waves falling into specific frequency ranges, with "theta" generally meaning a range of about 4–7 cycles per second (Hz).

In the 1930s–1950s, a very strong rhythmic oscillation pattern was discovered in the hippocampus of cats and rabbits. In rats, hippocampal theta is seen mainly in two conditions: first, when an animal is running, walking, or in some other way actively interacting with its surroundings; second, during REM. The presence of theta in the hippocampal EEG can be predicted on the basis of what an animal is doing, rather than why the animal is doing it. Theta-frequency EEG activity is also manifested during some short term memory tasks. Theta rhythms are very strong in rodent hippocampi during learning and memory retrieval, and are believed to be vital to the induction of long-term potentiation, a cellular mechanism of learning and memory.

In the August 18 Journal of Neuroscience, researchers led by Aline Stéphan at Paris Descartes University, France, report that Aß dampens the electrical theta oscillations of the rat hippocampus, and this modulation correlates with a decline in learning ability. This decline in theta is not due to cell death, but instead reflects a change in firing patterns. The findings point to another mechanism by which AD may disrupt normal cognitive functions, such as learning and memory.

Villette and colleagues assessed the memory of injected rats using a novel-object recognition test, a paradigm requiring intact hippocampal function. Rats were presented with a variety of objects every other day for three weeks, with one object always being the same. While rats injected only with placebo gradually spent less time exploring the familiar object and more time exploring the novel ones, Aß-injected rats showed the opposite tendency, an effect that grew worse two to three weeks after the injections. In other words, the ability of Aß-treated rats to distinguish between novel and familiar objects gradually declined.

Villette and colleagues also recorded electrical activity during object exploration, when theta oscillations are maximal in normal rats, and found that in the Aß-treated rats, the power of the theta frequencies decreased between days 9 and 21 after injections. In addition, when placebo-treated rats learned to discriminate between a novel and a familiar object, their peak theta frequency dropped from about 7.5 Hz to 7.1 Hz when exploring the novel object, an effect seen in other studies, but in Aß-treated rats, the theta frequency stayed constant at 7.6 Hz, correlating with a lack of learning.

This is an important paper for many reasons. First, it suggests that beta-amyloid is negatively impacting memory function even when the brain is still structurally intact (that is, no hippocampal atrophy has taken place). This form of beta-amyloid may be causing trouble before it has even deposited into plaques. More importantly, it opens up the possibility that by reinstating the theta frequency pharmacologically, we might have a new avenue to consider for early AD treatment.

Villette V, Poindessous-Jazat F, Simon A, Léna C, Roullot E, Bellessort B, Epelbaum J, Dutar P, Stéphan A. Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat. J Neurosci. 2010 August 18;30(33):10,991-11,003.

Michael Rafii, M.D., Ph.D
Associate Medical Director, ADCS
Author: Michael Rafii MD, PhD at 9:38 AM 0 Comments

Monday, August 23, 2010

Dementia in the Asian Community: Is it Due to Alzheimer's Disease or Vascular Disease?

Dear Readers,

Have you heard the saying "Things come in three's?" Well, that was the case this month when over a three week period, I was asked the following question three times, at three separate Asian community health events -- "Which type of dementia is more common in Asians -- Alzheimer's disease or vascular dementia?"

A similar question was posed in a recently published study that sought to examine the trends in prevalence (existing cases) of dementia, Alzheimer's disease and vascular disease from a Japanese population sample. Participants came from the town of Hisayama, which has had a stable population for the last 50 years, has similar age distributions, occupational status and nutrient intake almost identical to that of the rest of Japan. A total of four examinations for dementia were conducted on all persons 65 years or older between 1985 and 2005. Researchers reported that over 20 years, the prevalence of dementia (adjusted for age and sex) significantly increased with time -- from 6.0% in 1985 to 8.3% in 2005. A similar trend was also noted for Alzheimer's disease (1.1% in 1985 to 3.8% in 2005) but not for vascular dementia. Further, the prevalence of Alzheimer's disease was more likely to increase in those 75+ years or older.

This study nicely demonstrates that in Japan, a country that has one of the highest ratios of elderly persons to the general population, not only is the prevalence of dementia increasing but also that of Alzheimer's disease. Further studies will be needed to examine whether these trends are similar for the other Asian populations that are in the region.

Here are three articles you can refer to, to learn about this particular study or the Hisayama study in general.

Sekita A, Ninomiya T, Tanizaki Y et al. Trends in prevalence of Alzheimer's disease and vascular dementia in a Japanese community: the Hisayama Study, Acta Psychiatr Scand 2010

Tanizaki Y, Kiyohara Y, Kato I, et al. Incidence and risk factors for subtypes of cerebral infarction in a general population. The Hisayama Study. Stroke 2000

Yoshitake T Kiyohara Y, Kato I et al. Incidence and risk factors for vascular dementia and Alzheimer's disease in a defined Japanese population: the Hisayama Study. Neurology 1995

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS

Author: Neelum Aggarwal MD at 9:47 AM 0 Comments

Wednesday, August 18, 2010

What Does the Cessation of the Lilly Semagacestat Study Mean?


Eli Lilly and Company announced yesterday that it is halting development of semagacestat, a ?-secretase inhibitor being studied as a potential treatment for Alzheimer's disease. The decision was made after preliminary results from two separate phase 3 studies showed that the drug did not slow disease progression and worsened cognition and the ability to perform activities of daily living.

In the 2 trials, called IDENTITY (Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of AmyloId PaThologY) and IDENTITY-2, semagacestat was compared with placebo in more than 2600 patients with mild-to-moderate Alzheimer's disease. Endpoints for the trials were the Alzheimer's Disease Assessment Scale–Cognitive subscore and the Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory.

Analysis showed that cognition and the ability to complete activities of daily living worsened in placebo-treated patients, as expected. However, by these same measures, patients treated with semagacestat worsened to a statistically significantly greater degree than those treated with placebo. In addition, semagacestat was associated with an increased risk of skin cancer compared with placebo.

What does this mean for the Amyloid Hypothesis? And what does it mean for clinical trials of AD drugs?

I think the amyloid theory is still valid, but this clearly tells us that our current views may be too simple— clearing amyloid at the stage of mild-to-moderate AD may have little, if any impact on cognition. It must be kept in mind that amyloid deposition in the brain occurs over decades. By the time synapses are lost, administering a drug that decreases beta-amyloid may be too little, too late. In fact, if hippocampal atrophy is present, then there is clearly loss of brain tissue and amyloid had already done its damage.

I think a good analogy for AD is that of heart disease. If a patient presents with a heart attack, starting them on a cholesterol lowering drug will have little impact on their symptoms from the heart attack. But, if the cholesterol levels are checked 5 or even 10 years prior, then a cholesterol lowering drug would certainly reduce the risk of having a heart attack in the first place. By measuring beta-amyloid levels in the brain and cerebrospinal fluid, measuring hippocampal atrophy and trying to identify AD in its earliest stages, we will allow these drugs to have their greatest impact.

In fact, Bristol Myers Squibb is conducting such a trial. It is a phase II study of their gamma-secretase inhibitor in “prodromal” AD. Subjects must not have a diagnosis of dementia, and entry into the trial requires direct measurement of CSF amyloid. Their compound is even more selective for Amyloid Precursor Protein and may therefore be more likely to have a beneficial effect.

Michael Rafii, MD, Ph.D
Associate Medical Director, ADCS
Author: Michael Rafii MD, PhD at 12:22 PM 0 Comments

Tuesday, August 03, 2010

The Connection Between Amyloid, Tau and FYN


Amyloid plaques and neurofibrillary tangles (NFTs) are the two classic hallmarks of Alzheimer’s disease (AD), but the connection between their two respective proteins—beta-amyloid and tau—has remained mysterious. Now, a paper published on July 21 in the prestigious journal Cell details a molecular mechanism that links tau to beta-amyloid toxicity at the synapse. The groundbreaking new study was led by Professor Jürgen Götz and Dr Lars Ittner, based at the University of Sydney.

Back in 2004, scientists from the University of California at Irvine injected anti-beta-amyloid antibodies in the brains of transgenic mice that develop both beta-amyloid deposits and NFTs. This treatment led to a rapid reduction of beta-amyloid deposits and reversed the accumulation of abnormal tau (Oddo et al., 2004). When the anti-beta-amyloid antibodies were removed, the beta-amyloid pathology re-emerged. This was followed by the reappearance of tau pathology. These findings from animal models provided some proof that beta-amyloid and tau pathology were linked in that levels of beta-amyloid deposits influence levels of NFTs.

In the new findings*, researchers from the University of Sydney, show that tau is essential for the positioning of yet another protein, FYN, at the synapse, which then renders the neuron vulnerable to beta-amyloid. They demonstrate that tau functions at the synapse, and links beta-amyloid to toxicity at specific receptors, and that its effects are subsequent to beta-amyloid action. Tau-based treatments may indeed be critical in developing therapies aimed at slowing down the progression of AD.

Thanks for reading,
Michael Rafii, MD, PhD
Associate Medical Director, ADCS

*Ittner et al, Dendritic Function of Tau Mediates Amyloid-beta Toxicity in Alzheimer's Disease Mouse Models. Cell. 2010 Jul 21.

Author: Michael Rafii MD, PhD at 4:21 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.