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Thursday, March 28, 2013

Deep Brain Stimulation for AD


Dear Readers,

Many of you are probably familiar with the concept of a pacemaker that stabilizes abnormal heart rhythms, such as atrial fribrillation. The implanted device sends electrical pulses to the heart muscle, resetting a normal heartbeat.

Now, a new study has been launched that will look specifically at whether electrical stimulation of the brain can help fight the memory loss of AD. This ‘brain pacemaker’ for AD is similar to the heart pacemaker. It, too, sends electrical pulses, but targets a region of the brain called the fornix—a bundle of about one million axons that normally serves as a superhighway for learning and memories. The fornix is also one of the first regions to be damaged by Alzheimer’s disease.

The first of up to 10 patients who will be enrolled in an FDA-approved study to determine if using a brain pacemaker can improve cognitive and behavioral functioning in patients with Alzheimer's disease, has undergone the neurosurgical procedure. This study actually employs the use of deep brain stimulation (DBS), the same ‘pacemaker’ technology used to successfully treat about 100,000 patients worldwide with movement disorders such as Parkinson's disease.

The current trial (called the ADvance Study) was inspired by an experiment done in Canada about five years ago in which stimulating the hypothalamus and fornix caused a surprising improvement in memory. This was followed in 2010 by a small Canadian trial of six patients with mild AD. When the researchers looked at the brains of these patients, they saw increased glucose metabolism in the temporal and parietal lobes of the brain over a 13-month period—a sign of healthy functioning neurons. Typically, in Alzheimer’s patients, glucose metabolism in the brain decreases as the disease progresses—so the increase in metabolism is promising.

To implant the pacemaker, surgeons drill two small holes in the skull and implant two ultrathin wires into the fornix on both sides of the brain. The wires are then connected to a matchbox-size control device that is inserted beneath the collarbone. After surgery, the device is completely invisible. The wires deliver 130 pulses every second. These pulses, referred to as deep brain stimulation, deliver just a few volts of electricity, such that the patients are completely unaware of them. The hypothesis is that these pulses will activate the ailing neurons, making them function more effectively.

This is certainly not a cure, but if successful it might delay the steady advance of memory loss that otherwise characterizes Alzheimer’s disease.



Thanks for reading,


By 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 8:37 AM 0 Comments

Monday, March 25, 2013

Gender Differences in Clinical Symptoms & Outcomes in Hospitalized Dementia Patients


Dear Readers,

As dementia rates continue to rise worldwide, many governments are examining their long term care strategies and establishing care systems and facilities to support people with dementia in and outside of the hospital systems. Within the hospital systems, admissions due to dementia often center on worsening of behavioral symptoms that could not be managed in the community. As the frequency of admissions continues to increase both nationally and internationally, interest has focused on potential differences between men and women regarding risk of mortality and aggressiveness. Whether or not differences in symptoms or outcomes were present in men and women hospitalized for disruptive behaviors due to dementia was recently examined in a paper by Kitamura T et al.

Patients admitted to the acute pyschogeriatric ward were enrolled in this study from 2006-2008. All patients were admitted due to severe behavioral symptoms, such that they could not be taken care of in their home or other settings. Data obtained from all participants was demographic data, their living situation before admission (own home, group home, care facility or medial hospital), types of symptoms and reasons for hospitalization, type of dementia (using the BEHAVE-AD) scale, cognitive function(mini mental state examination - MMSE) and functional activities of daily living.

Of the 292 patients in the study (170 women, 122 men, average age 80.5 yrs) the prevalence of vascular dementia was greater in men than in women and men were also more likely to live with only their partner. The partner was more frequently the spouse as opposed to a daughter or son. Both MMSE and activity of daily living scores were lower in men than women (MMSE men= 7 (7.4), women 10 (8.3)). Aggression and combative behavior was most frequently the reason for hospitalization among men, while apathy or depression was the most common reason for admission in women. In addition, women tended to present with more paranoia and delusional ideation than men. Medications used also differed among men and women. Cholinesterase inhibitors were used more in women, while anti-psychotics were used more in men. Men had longer hospitalizations on average than women and women on average were discharged at a higher rate to home than men.

This study was important as it sheds light on the potential gender differences not only in prevalence of behavioral symptoms/signs seen in Alzheimers’ disease, but it also examined various factors apart from gender that could affect the manifestation of behavioral symptoms. Home environment, caregiver relationship to the patient, cognitive and physical functioning all were examined in this study. After controlling for these variables, paranoid ideation, delusions and anxiety were more common in women than in men, while aggressiveness was more common in men. The higher incidence of aggression in men has been well documented and may be associated with genetic predisposition and hormonal levels of testosterone, whereas the etiology of delusions, paranoia and anxiety in women is less clear.

Although this study was conducted in Japan and would need to be replicated in larger samples with more diverse populations, it continues the conversation on sex and gender differences in dementia: presentation and outcomes, and results could potentially impact treatment strategies in hospital and outpatient care management plans.

Want to read more? Here are three articles that you may read to learn about this particular study or other research in this area.

KitamuraT, Kitamura M, Hino S. et al. Gender differences in Clinical Manifestations and Outcomes among hospitalized patients with Behavioral and Psychological Symptoms of Dementia. J. Clin Psychiatry 2012: 73 (12): 1548-1554.

Lovheim H, Sandman PO, Karlsson S, et al. Sex differences in the prevalence of behavioral and psychological symptoms of dementia. Int Psychogeriatr 2009 : 21 ( 3) 469- 475

Ono T, Tamai A, Takeuchi D, et al. Predictors of length of stay in a ward for demented elderly: gender differences. Psychogeriatrics 2010; 10 (3) 153- 159.

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Chicago, IL
 
Author: Neelum Aggarwal MD at 2:37 PM 0 Comments

Thursday, March 14, 2013

Beta-amyloid: oligomers, dimers, trimers and other species


Dear Readers,

Although the exact cause of AD is unknown, it is widely believed to be triggered by abnormal aggregates of the protein, beta-amyloid. This protein is produced as a by-product when the amyloid precursor protein is cut by enzymes as it is secreted by brain cells. Once produced, beta-amyloid molecules are called oligomers, which can exist as a single molecule, or monomer. When two monomers bind to each other, they form a dimer; if three bind, we call it a trimer. It turns out that in the presence of certain beta-amyloid oligomers, specifically the trimers, the scaffolding protein tau (which is inside of brain cells), becomes abnormal and leads to a breakdown of the cellular scaffolding to produce widespread brain cell degeneration and dysfunction. It is thought that this toxic species of beta-amyloid is the culprit in the AD process. And we now know that this disease process begins one or two decades prior to the onset of overt symptoms.

These beta-amyloid oligomers deserve a bit more discussion. You see, the monomers not only form dimers and trimers, but the trimers themselves can bind to other trimers. In fact, when four trimers bind to each other, they form a species called beta-amyloid*56. The 56 refers to the unique molecular weight of this complex protein. The exact role of beta-amyloid*56 in AD is not known.

Researchers at the University of Minnesota, led by Dr. Karen Ashe, have been trying to understand beta-amyloid*56 for quite some time and have recently made a breakthrough. In a recent study, they looked at 107 adults -- 48 with either Alzheimer's or mild cognitive impairment, 49 cognitively normal older adults, and 10 younger cognitively normal volunteers. Their goal was to assess the molecular basis of early pathophysiology and to see how beta-amyloid is involved. Specifically, they hypothesized beta-amyloid trimers and beta-amyloid*56 -- were both pathogenic. In previous animal studies, beta-amyloid*56 has been associated with loss of cognition.

In this study, the researchers measured CSF levels of beta-amyloid trimers and beta-amyloid*56, as well as the beta-amyloid oligomer, total tau protein, and the abnormal phospho-tau. What they found was that in cognitively intact older adults, trimers and beta-amyloid*56 were both elevated in individuals at risk for AD, and they showed stronger relationships with tau than did beta-amyloid monomers.

What does this all mean? This means beta-amyloid*56 does indeed play a role in AD pathogenesis and targeting it may be just as important to the treatment of Alzheimer’s disease as is targeting the other beta-amyloid species.

For more information please read: Handoko M, et al "Correlation of specific amyloid-ß oligomers with tau in cerebrospinal fluid from cognitively normal older adults" Arch Neurol 2013; 70: 1-6.


Thanks for reading,


By 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 10:43 AM 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.