Skip Navigation LinksHome > ADCS > Alzheimer's Insights: an ADCS Blog  
 
    

Alzheimer's Insights:
an ADCS Blog

  Recent Post

Monday, May 13, 2013

Type 2 Diabetes Risk of Cognitive Impairment Among Older Mexican Americans

Dear Readers,

May is officially "Stroke Awareness " month and so I thought it would be appropriate to talk about cardiovascular risk factors and how they relate not only to stroke but to cognitive decline and dementia. Diabetes continues to be one of the most established and common risk factors for vascular disease, stroke and mortality not only in the US, but also globally. In addition, diabetes appears to increase the risk of dementia by two fold in many populations, yet little is known whether this increased risk is similar among racial and ethnic minorities. Let's take a look at a recent study that followed a specific population.

A total of 1,617 older Mexican Americans, aged 60-98 years, from the Sacramento Area Latino study on Aging were followed for 10 years. They were evaluated for metabolic and cardiovascular risk factors and their relation to cognitive decline and dementia. Enrollment began in 1998 and participants were evaluated and interviewed in their homes every 12-15 months, with phone calls made every 6 months between the home visits. Of the 1,617 persons in the sample, a total of 677 had diabetes during the study (n= 513 baseline diabetes cases, and 164 incident cases), with 940 remaining diabetes "free". Comparing those with treated diabetes to those without diabetes, those with diabetes were younger and more likely to be born in the US. There were no relationships between education level and diabetes status.

Among those who had diabetes, 62.2% met at least two criteria for diabetes in the study (elevated fasting glucose, anti-diabetic medications use or self report) and 37.8 % had one (13.3% fasting glucose, 3.4% anti-diabetic medication use and 21.1% self report). Of those participants who reported a physician diagnosis of diabetes at baseline, the median reported duration of diabetes was 10 years. Of this group, at baseline 64.7% of participants with diabetes were using anti-diabetic medications, 36.1% were using one medication and 28.7% were using two or more. The proportion of persons taking a diabetes medication remained constant throughout the follow up years.

Persons who were treated with diabetes had a two-fold increased incidence of dementia versus those with no diabetes. In addition, those persons with diabetes were more likely to die than those without a history of diabetes. Furthermore, there was an increased risk of death that occurred in those with diabetes and dementia.

This study is unique in that it is the only US population-based longitudinal study of Mexican Americans that was able to assess cognitive function, dementia and mortality. The results of this study demonstrated that among Mexican Americans, the rates of dementia risk was similar to that of studies with predominantly Caucasian participants, and that diabetes is a risk factor for not only cognitive decline and dementia, but also mortality. Further, treated diabetes appeared not to modify the dementia and mortality rates, thus suggesting that the relationship to diabetes and dementia is very robust. Whether the timing of treatment, or aggressiveness of treatment may have the potential to modify these outcomes remains to be investigated, however, this study further alerts public health officials and health care providers to not only screen and treat for diabetes, but also consider cognitive screening as part of their care management.

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

Mayeda ER, Haan MN, Kanaya AM, et al. Type 2 Diabetes and 10 year Risk of Dementia and Cognitive Impairment Among Older Mexican Americans. Diabetes Care 2013 pg 1-7

Cheng D, Noble J, Tang MX et al. Type 2 diabetes and late onset Alzheimer's disease. Dement Geriatr Cogn Disord 2011; 31;424-430

Chatterji P, Joo H, Lahiri K. Racial/ethnic and education related disparities in the control of risk factors for cardiovascular disease among individuals with diabetes. Diabetes Care 2012; 35; 305-312.

Thanks for reading.


Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL
 
Author: Neelum Aggarwal MD at 12:03 PM 0 Comments

Tuesday, May 07, 2013

Results of IGIV Study Disappointing But Not Discouraging

The first results from the GAP study of Intravenous Immunoglobulin (IGIV) for Alzheimer’s disease were just announced and are disappointing but not entirely discouraging. The primary results are clear - IGIV did not significantly slow decline of thinking abilities or preserve daily function in a large group of Alzheimer’s patients when compared to an inactive placebo. However, some positive responses were seen in certain subgroups of the participants who received IGIV.

The GAP study was a late-stage clinical trial of IGIV carried out by the ADCS over the past five years with support from Baxter Healthcare and the National Institute on Aging. It enrolled 390 patients with mild to moderate Alzheimer’s disease from 45 ADCS sites in the US and Canada. Participants were given either IGIV or placebo for 18 months. They were tested at regular intervals to see if IGIV was safe and effective in reducing dementia symptoms. The ADAS-Cog, a test of thinking abilities, and the ADCS-ADL, a measure of daily function, were the two primary endpoints measures. A host of other tests, scans and biomarker studies were carried out as secondary or exploratory outcomes to further examine IGIV’s effects. The study was carried out to a very high standard, setting goals that have not yet been reached by any medication for Alzheimer’s that is approved or under investigation.

After 18 months of treatment, the group of patients who received IVIG were not significantly different from those who were given a placebo on either of the two primary endpoints. This means that IGIV was not effective in slowing the progression of Alzheimer’s disease. The news was not all bad, however. IGIV was well-tolerated, and some positive effects were observed in at least two subgroups of participants treated with IGIV. While the subgroup results are encouraging, they do not negate the primary outcomes. A positive result that is limited to a subgroup of patients can be considered a justification for further study, but does not provide the kind of evidence necessary for IGIV to be considered a useful treatment for Alzheimer’s disease. Only positive outcomes on the primary measures could have led to IVIG being accepted as a new treatment for Alzheimer’s and in this case, the primary endpoints were negative.

What we stand to learn from the GAP study cannot be overstated. IGIV was chosen for study because it contains antibodies the human body produces naturally that react with clumps of beta amyloid protein and other molecules thought to be involved in the development of Alzheimer’s disease. In earlier phases of clinical study, IGIV showed considerable promise in slowing dementia-related decline, albeit in small numbers of patients. It was essential to determine whether or not IGIV could help most persons with Alzheimer’s and that is exactly what the GAP study has accomplished. While the negative primary results are undeniably a disappointment, the clear answers provided by the GAP study are a major step forward for Alzheimer’s research.

IVIG is approved to treat a number of disorders, but not Alzheimer’s disease. It is expensive and in limited supply. Over the past several years, some physicians have chosen to administer IVIG to their patients with Alzheimer’s disease in what is called “off label” treatment based on the positive findings from earlier studies. The GAP study’s primary findings should discourage this kind of off-label use of IGIV for treatment of Alzheimer’s for the foreseeable future. However, Alzheimer’s patients already receiving off label treatment with IGIV should discuss their options carefully with their physician, taking into account that there were some positive effects observed in subgroups of IVIG-treated participants in the GAP study.

The study results are still under analysis and a full study report will be presented to the medical and scientific community in July at the AAIC meeting in Boston. This will include some of the brain imaging results and biomarkers that were collected from blood and spinal fluid during the study. These additional analyses will help to put the study’s findings into better focus and may provide new directions for future studies.

As the GAP study leader, I want to acknowledge and express my gratitude to all of the participants in this study, especially the Alzheimer’s patients and their study partners for their invaluable and selfless contribution to Alzheimer’s research. I would also like to acknowledge the extraordinary efforts of the investigators and the research teams at the 45 ADCS sites that took part in the study as well as the many highly skilled persons at the ADCS, Baxter and the NIA that helped to bring this important study to fruition.


Norman Relkin MD, PhD
ADCS Project Leader
Gammaglobulin Alzheimer Partnership (GAP) Study
Associate Professor of Clinical Neurology and Neuroscience
Weill Cornell Medical College
New York, New York




 
Author: Jeffree Itrich at 2:38 PM 0 Comments

Wednesday, May 01, 2013

Phobic Anxiety and Cognitive Performance in Older Women

Dear Readers,

During the past month while at community presentations, I have been asked to comment more on the contribution of “personality characteristics” to decline in memory and cognitive function, than traditional medical or lifestyle characteristics. I am not sure as to why there is a sudden rash of these types of questions, however some participants mention that they are having feelings of uncertainty, or anxiousness about getting older and thinking about how they will manage financially, physically and emotionally as they age. These comments made me research the current literature on this topic, and led me to an interesting paper by Grodstein et al, that examined the relationship between anxiety and cognitive function.

In this paper, a total of over 16,000 women from the Nurses’ Health study answered questions from the phobic anxiety scale of the Crowne Crisp Index ( CCI). The average age at the time of questionnaire administration was 63 years. This index measured common symptoms of phobic anxiety, and consisted of self-rated questions of phobias and avoidance desire. Scores ranged from 0 to 16 (higher scores = higher anxiety). CCI scores were categorized into five groups 0-1 (reference group), 2, 3, 4, 5 and 6 or more (highest phobia score).

Cognitive function was measured by the Telephone Interview for Cognitive Status (TICS). 31 points or less are consistent with cognitive impairment in addition to four extra cognitive tests (East Boston Memory Test, fluency, delayed 10 word recall and digit span). All analyses took into account the participant’s age, education, anxiety level, body mass index, smoking history, post menopausal hormone use, hypertension and cholesterol history, heart disease diabetes and physical activity history.

Women in the highest phobic category were generally less healthy, i.e. they had higher BMI’s, increased history of hypertension, heart disease, diabetes and cholesterol, lower physical activity and were current smokers. In addition, those with higher phobic anxiety had lower levels of educational attainment. The findings also suggested that women with higher phobic anxiety also had lower cognitive scores not only on the global measure of all the tests, but also with tests on verbal memory, executive function and attention. Interestingly however, these cognitive scores did not appear to worsen or decline over time.

What could be the biological mechanism at work to explain these findings? One prominent theory states that stress, and the associated factors such as anxiety that may accompany stress, may lead to chronically elevated levels of pro-inflammatory cytokines and stress hormones that injure key brain regions such as the hippocampus, thus accounting for the poor performance on cognitive tests. Another theory implicates genetic vulnerability, the COMT polymorphism gene that has been associated with late life cognitive impairment in other cohorts. What is still unclear however is why the lower level of cognitive function associated with phobic anxiety did not decline over time as one would have expected.

Perhaps, phobic anxiety represents a different type of behavioral construct than other measures such as distress proneness or depression. Indeed research suggests that phobic anxiety and symptoms have an earlier age of onset and persistent course. This fact may be important, since treatments for anxiety exist, and thus earlier treatment, may delay the onset of cognitive impairment in old age.

Want to read more? Here are 3 articles that you should read to learn about this particular study or other research in this area.

Okereke OI, Grodstein F. Phobic Anxiety and Cognitive Performance Over 4 years among Community Dwelling Older Women in the Nurses’ Health Study. Am J Geriatr Psychiatry 2013

Crown S, Crisp AH. A short clinical diagnostic: self rating scale for psychoneurotic patients. The Middlesex Hospital Questionnaire Br. J Psychiatry 1966; 112:917-923

Bierman EJ, Comijs HC, Rijmen F, et al. Anxiety symptoms and cognitive performance in later life: results from the longitudinal aging study Amsterdam. Aging Ment Health 2008; 12 (4): 571-523.


Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Chicago, IL
 
Author: Neelum Aggarwal MD at 11:22 AM 0 Comments

Tuesday, April 23, 2013

Seeing the Brain with CLARITY

Dear Readers,

A team of engineers has developed a way to turn organs from mammals, such as lab mice or human bodies donated to science, transparent. Once transparent, scientists can add chemicals to the organs that attach to and highlight specific features, such as different cell types. The result is an intact organ that scientists can see inside and study.

The techniques, called CLARITY, involves a series of chemical treatments that replaces the fatty lipid membranes surrounding cells with a chemical mesh that keeps microscopic details intact without scattering light like lipid does. Neurotransmitters and other important molecules remain in place and can be visualized with a rainbow palette of fluorescent dyes.

Until now, neuroscientists typically had to cut a brain into ultra-thin slices to visualize such features. But that destroys one of the things they’re most interested in studying: the cable-like axons that carry signals from one part of the brain to another. The new method makes it possible to visualize these long-range connections as well as the fine-scale anatomy and molecular make up of neurons, the scientists reported last week in the journal Nature. This is probably one of the most important advances for understanding the structure of the brain in decades.

Although they developed the method in mouse brains, the team shows that it works on human post-mortem brain tissue too. In the Nature paper, they describe abnormal neural connections in an autistic boy whose brain had been stored in formalin for more than six years.

With this breakthrough, researchers plan to compare circuitry in banked tissue from people with other neurological diseases, including Alzheimer’s disease, and from controls whose brains were healthy. Such studies in living people are impossible, because most neuron-tracing methods require genetic engineering or injection of dye in living animals. Scientists might also revisit the many specimens in repositories that have been difficult to analyze because human brains are so large.

Chung et al, Structural and Molecular Interrogation of Intact Biological Systems, Nature 2013



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 2:34 PM 0 Comments

Thursday, April 11, 2013

Better Model of Alzheimer’s disease: From mice to rats

Dear Readers,

As you will recall, beta-amyloid is a fragment of a larger protein, known as APP, and is produced by enzymes that cut APP at two places as it secretes from neurons. Its deleterious effects on the brain and in plaques have been written about in previous blogs. Researchers often use rodents to study diseases. However, previous studies on transgenic mice and rats that have the mutations only partially reproduce the problems caused by Alzheimer’s. The animals have memory problems and many plaques, but none of the other hallmarks,especially neurofibrillary tangles and neuron loss.

Now, researchers led by Dr. Terrence Town at Cedars-Sinai Medical Center and UCLA, have engineered rats by mutating a combination of genes, which are known to play a role in the rare, early-onset form of Alzheimer’s. Behavioral studies showed that the rats indeed developed memory and learning problems with age, similar to AD. And, as predicted, the presence of beta-amyloid in the brains of the rats increased with age. However, unlike previous rodent studies, the rats also developed neurofibrillary tangles. That is, these rats manifest a complete repertoire of AD pathological features.

The researchers performed a variety of experiments confirming the presence of neurofibrillary tangles in brain regions most affected by Alzheimer’s such as the hippocampus and the cingulate cortex, which are involved in learning and memory. Further experiments showed that about 30 percent of neurons in these regions died with age, the largest amount of cell death seen in an Alzheimer’s rodent model. The researchers also found that there are increasing levels of beta-amyloid oligomers in the brain, before the neurofibrillary tangles develop.

The results of this work are two-fold. First, it further validates the idea that excessive production of beta-amyloid in the brain drives the development of neurofibrillary tangles inside of neurons that ultimately leads to their demise. In addition, it provides us with a new animal model to test drugs that may be effective in slowing down the progression of the underlying mechanisms seen in AD.
This new animal model of AD will undoubtedly serve as a critical tool to enable future drug studies in AD.


A Transgenic Alzheimer Rat with Plaques, Tau Pathology, Behavioral Impairment, Oligomeric Aß, and Frank Neuronal Loss, The Journal of Neuroscience, 10 April 2013


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 2:01 PM 0 Comments

Friday, April 05, 2013

Costs of Dementia in the United States

Dear Readers,

This week, the non-profit RAND corporation, published a study in the prestigious New England Journal of Medicine that represents the most accurate estimate of the financial costs associated with Alzheimer’s disease dementia. The study was funded by the National Institute on Aging and looked at costs for the disease in 2010.

These costs are, of course, in addition to the incalculable emotional losses caused by the disease, but are quite astonishing in themselves.

The new study is based on findings from the Health and Retirement Study, an ongoing survey of individuals in the United States age 51 and older that began in 1992, and is supported by the National Institute on Aging, as well as the Social Security Administration. A subset of that study group received a detailed in-home clinical assessment for dementia as part of the Aging, Demographics and Memory Study, a nationally representative examination of dementia in the United States.

The survey included an assessment of whether people could perform daily activities such as dressing themselves and preparing their own meals. Participants were also asked about their out-of-pocket health care expenses for services such as nursing home stays, home health care and other medical services. Other questions asked whether they received help from others for their daily living activities. Medicare spending information was linked to medical claims for most participants.

The estimated prevalence of dementia among persons older than 70 years of age in the United States in 2010 was 14.7%. The yearly monetary cost per person that was attributable to dementia was about $50,000. These individual costs suggest that the total monetary cost of dementia in 2010 was approximately $200 billion. Medicare paid approximately $11 billion of this cost.

The main component of the costs attributable to dementia is the cost for institutional and home-based, long-term care rather than the costs of medical services.

As readers of this blog will recall, if we could delay the dementia phase of AD by 5 years, we can cut the incidence by half. The fiscal imperative for finding a cure remains blindingly clear.


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 8:44 AM 0 Comments

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

Wednesday, February 27, 2013

Researchers Now Able to See Molecular Mechanisms Inside Living Neurons with Genetic AD Mutation

Dear Readers,

As you might recall, about 5 percent of all cases of AD are familial. That is, the disease occurs because of an inherited mutation in the gene for either the amyloid precursor protein (APP) or in genes for the enzymes that cleave APP. The end result is that the mutation causes an over production of beta-amyloid that is toxic to synapses and neurons, and patients develop dementia sometime around the age of 50. In addition, beta-amyloid builds up as the tell-tale amyloid plaques. Some researchers believe the plaques are a way that the brain sequesters toxic beta-amyloid.

Interestingly, in 2008, a paper was published describing a family with an inherited form of AD due to an unusual mutation in APP that results in dementia at a young age, but who have no amyloid plaques in the brain. The beta-amyloid is present, yet it cannot deposit into plaques, and exists only as a free-floating form.

Since then, researchers have genetically engineered mice that have the same exact mutation in APP. These mice also develop the signs of dementia, but also lack the plaques just as their human counterparts do. The explanation for this curious absence of plaques came a few years later by carefully examining the structure of beta-amyloid produced from the mutated APP. The mutation caused the beta-amyloid molecules to chemically repel each other, rather than stick to one another, and therefore could not form plaques. It was this finding, among others, that raised the possibility that plaques may be protective. This should not be too surprising, given that cholesterol plaques in arteries, are in essence, sequestering excessive, free-floating cholesterol and isolating it from depositing in other tissues.

Now, in a study published in the journal Cell - Stem Cell, researchers in Japan have generated neurons from stem cells derived from patients with this curious form of familial AD. They also generated such cells from two patients with the non-inherited form of AD for comparison. The accomplishment of this feat means that we can now look at the molecular mechanisms as they occur inside a living neuron that harbors a genetic mutation that affects the beta-amyloid pathway. The neural cells from one of the familial and one of the non-familial AD patients showed extensive cellular damage from beta-amyloid INSIDE neurons. This internal form of beta-amyloid has not been as extensively studied, and only by this type of experiment, can we hope to better understand how it is involved in AD. The team also found that the injuries were lessened with docosahexaenoic acid (DHA) treatment. Certainly this finding is very important, and needs to be better studied, but more importantly, this stem cell technique may one day allow us to test drugs for AD on neurons derived from patients with AD to efficiently obtain answers about mechanism of action and perhaps chance of success before launching larger scale studies.


Kondo et al. Modeling Alzheimer’s Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Aß and Differential Drug Responsiveness.




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 2:45 PM 0 Comments
<< 1 2 3 4 5  ... >> 

Archive

Helpful Sites

About Us

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.


 
 


| Contact Us |

By: TwitterButtons.com Find us on Facebook

Copyright 2008 Regents of the University of California.