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Thursday, June 23, 2011

Dietary Effects on Beta-amyloid and Cognition

A low-fat diet led to improvements in a putative biomarker of Alzheimer's disease risk in patients with mild cognitive impairment, but it had the opposite effect in healthy older adults, a small, short-term trial found.

In a randomized 49-person trial, mean levels of the 42-amino-acid form of amyloid-beta protein in cerebrospinal fluid (CSF AB42) increased in the cognitively impaired patients after eating the low-fat diet for four weeks, whereas mean levels of this marker declined in healthy adults on the same diet, according to a report in the June issue of Archives of Neurology.

Declines in CSF AB42 have been associated with worsening cognitive function and increased risk of Alzheimer's disease in some earlier studies. In the study by Craft and colleagues, 29 patients with amnestic mild cognitive impairment and 20 cognitively normal controls -- mean age in both groups was just under 70 -- were randomized to either a high or low-fat diet. The low-fat diet was designed to have 25% of calories from fat, with less than 7% from saturated fat and a glycemic index of less than 55. The high-fat diet had 45% of calories from fat with saturated fat accounting for more than 25% of calories and a glycemic index of more than 70. In addition to CSF AB42, levels of other factors such as insulin, tau protein, and apolipoprotein E in CSF were measured, along with blood lipids and insulin.

Effects of the two diets on serum cholesterol and insulin profiles were as expected, with relatively unhealthy changes seen with the high-fat diet in both groups of participants, versus improvements with the low-fat diet. No significant differences in these parameters were seen in the cognitively impaired patients relative to controls. On the other hand, changes in CSF AB42 and insulin both differed significantly between the two participant groups.

In response to the low-fat diet, cognitively impaired patients had increases in CSF insulin and AB42, whereas decreases were seen in the healthy controls (P=0.05 for CSF insulin, P=0.001 for CSF AB42). The high-fat diet seemed to affect the CSF biomarkers only in the normal controls. CSF insulin declined dramatically in controls with this diet but no mean change was seen in the patients. A similar pattern was seen for CSF levels of apolipoprotein E.

Relative to those on the high-fat diet, those on the low-fat diet -- among both cognitively impaired patients and controls -- improved their performance on a test of delayed visual memory (P=0.05). Little change from baseline was seen in either group with the high-fat diet, but scores increased substantially from baseline in patients and controls.

The study supports further investigation into the possibility that consumption of a diet high in saturated fat and simple carbohydrates may increase the risk of AD. Conversely, diets low in saturated fat and simple carbohydrates may offer protection against AD and enhance brain health.

Bayer-Carter, et al. Diet Intervention and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment. Archives of Neurology, June 2011.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego

Author: Michael Rafii MD,PhD at 11:37 AM 0 Comments

Thursday, June 16, 2011

Cinnamon and AD

Plants have a long history as a rich source of new compounds for drug discovery. Cinnamon is widely used by humans, both as a spice and as a traditional medicine. It is, perhaps, one of the oldest herbal medicines, having been mentioned in the Bible and in Chinese texts as long as 4,000 years ago.

Previous studies have already demonstrated the potential for herbal extracts to interact with beta-amyloid, and perhaps slow down or even prevent AD. As we move towards earlier identification of Alzheimer's disease pathology in minimally symptomatic individuals, such therapies will undoubtedly become areas of intense research. Examples for extensively studied naturally occurring compounds are the (-)-epigallocatechin-3-gallate (EGCG) from green tea and Curcumin, which is derived from the natural turmeric.

Now, a research team headed by Michael Ovadia from Tel Aviv University, has isolated one of the ingredients in cinnamon, CEppt, and used it in a series of tests conducted on two-month-old lab mice that were raised with five aggressive strains of Alzheimer’s-inducing genes. The experiment’s results, recently published in the PLoS ONE scientific journal, were impressive. Laboratory rodents, genetically altered to develop dementia, received either the cinnamon extract or an inert treatment for four months. The extract improved the rats' performance on learning and memory tasks. It also reduced the amount of plaque formed in the brain. The animals were fed drinking water containing a CEppt solution over four months, and researchers found that the disease’s development was delayed, with additional trials showing that existing amyloids had been dissolved. The results show the ability of CEppt to inhibit the progress of beta-amyloid aggregation. CEppt is actually comprised of several molecules, and it remains to be found which molecule is exerting this effect.

Supplements such as Curcumin, EGCG, DHA and CEppt will likely be evaluated in clinical trials in patients who have minimal symptoms, but are on the path towards developing AD. That is, patients with amyloid building up in the brain, but not yet showing symptoms as assessed by Amyloid scans (for example. From studies such as ADNI, we believe that there is a 15 year window during which amyloid is building up in the brain, while there are minimal symptoms, such as memory loss present. This window may be the best time to initiate anti-amyloid therapy.

Anat Frydman-Marom, et al, Orally Administrated Cinnamon Extract Reduces ß-Amyloid Oligomerization and Corrects Cognitive Impairment in Alzheimer's Disease Animal Models; PLoS One Jan. 28, 2011

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego
Author: Michael Rafii MD,PhD at 11:30 AM 0 Comments

Friday, June 10, 2011

Depression, Brain Volumes and Subclinical Cerebrovascular Disease in Women

Dear Readers,

A recent report from the Women's Health Initiative MRI study - examined the relationship between depressive symptoms and regional brain volumes and determined whether depressive symptoms were associated with increased subclinical cerebrovascular disease in post menopausal women.

A total of over 1300 community dwelling post menopausal women (mean age of 70 years) were enrolled in the study. Baseline demographic information and medical history on lifestyle variables were obtained by self report and clinical measurements using standardized forms. In addition to questions regarding depression, body mass index and baseline cognitive function was assessed by administration of the modified mini mental state (3MS) examination.

Depression was measured using the Burnam screening algorithm that consists of the six items from the 20 item CES-D scale and two items from the National Institute of Mental Health's Diagnostic Interview Schedule ( DIS). Questions on depression were as follows:

Over the past week ( 1) Did you feel depressed? (blue or down), (2) Did you have restless sleep? (3) Did you enjoy life? (4) Did you have crying spells? (5) Did you feel sad? (6) Did you feel that people disliked you? Each item was scored as 0 (rarely or none of the time, less than 1 day), 1 (some or a little of the time; 1-2 days), 2 ( occasionally or a moderate amount of time; 3-4 days), or 3 ( most or all of the time; 5-7 days).

MRI scans (performed on average 8 years later) were obtained and volumes of gray matter, white matter and cerebrospinal volumes were determined. Volumes were further classified as hippocampal, amygdala, frontal lobe, and total brain volumes. Areas of special interest within the frontal lobe were lateral orbital gyrus, medial orbital gyrus, medial frontal gyrus, inferior frontal gyrus, middle frontal gyrus, superior frontal gyrus and precentral gyrus. Basal ganglia lesion volume and the combination of white and gray matter lesion volume were calculated and defined as "ischemic lesion volume."

At baseline, a total of 18% (n= 253) of the women met the Burnam score cut point signifying elevated depression. At baseline, depressed compared with non-depressed women had lower global cognitive function and were more likely to have a history of prior hormone therapy. Elevated depressive signs were associated with lower mean superior frontal, middle frontal, inferior frontal and lateral orbital volumes, relative to the reference cohort. No differences in the mean total brain, frontal lobe, amygdala and hippocampal volumes, were noted between depressed and non-depressed women.

After controlling for multiple variables that included demographic, lifestyle, baseline cognitive function, cardiovascular risk factors, hormone replacement therapy, and antidepressant use, brain volumes in the frontal, middle and inferior lobes remained significant between the depressed and non-depressed groups. There were no significant differences in basal ganglia, and non basal ganglia gray matter and white matter volumes.

This study examined the relationship between depressive symptoms to volumes in multiple brain regions, and found that volumes in specific regions of the frontal lobes were associated with depressive symptoms, whereas specific regions associated with the hippocampus and basal ganglia were not. The authors acknowledge that perhaps the older age of the sample in addition to the lack of information on the age of onset or total duration of depressive symptoms may have limited their ability to detect any associations in these areas. Nevertheless, this study adds to the increasing body of evidence that late life depression is associated with brain volumes in regions related to frontal lobe structures and these associations are not modified by cardiovascular risk factors or lifestyle conditions. Further studies should examine how longitudinal changes in these areas may play a prominent role in the development of cognitive impairment and conversion to dementia.

To learn more about this study or the latest research on depression and women, please refer to:

Goveas JS, Espeland MA, Hogan P et al. Depressive symptoms, brain volumes and subclinical cerebrovascular disease in post-menopausal women: The Women's Health Initiative MRI study. (2011) J Affect Disord. 2011 Jul;132(1-2):275-84.

O'Brien JT, Firbank MJ, Krishnan MS et al. LADIS Group, 2006. White matter hyperintensities rather than lacunar infarcts are associated with deppresive symptoms in older people: the LADIS study. Am J. Geriatr Psychiatry 14, 834-841

Frodl TS, Koutsouleris N, Bottlender R et al. 2008. Depression related variation in brain morphology over 3 years: effects of stress? Arch Gen. Psychiatry 65, 1156-1165

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 3:12 PM 0 Comments

Wednesday, June 08, 2011

Possible Therapy That May Work in Prion Diseases As Well as AD

Last month, I wrote about the relationship between prions and Alzheimer's disease and reviewed some work by researchers at Trinity College in Dublin, Ireland. Now, there has been an important paper published looking at a possible therapeutic strategy that may work in prion diseases as well as Alzheimer's disease. The work was carried out at the Medical Research Council Prion Unit at University College London, in collaboration with colleagues at the Laboratory for Neurodegeneration at University College Dublin, and Trinity College Dublin.

The researchers have identified two antibodies which could help block the onset of Alzheimer’s disease in the brain. The antibodies, ICSM-18 and ICSM-35, are already known to play a crucial role in preventing ‘protein misfolding’, the main cause of Creutzfeldt–Jakob disease (CJD), the human form of mad cow disease.

The study, published yesterday in Nature Communications, has shown, using mice, that these antibodies can block damaging effects on brain tissue caused by beta amyloid. The researchers carried out experiments in brain slices from mice, which were taken from a region of the brain called the hippocampus. This is the area affected in Alzheimer’s disease. They tested the effects of beta amyloid on neurons in these brain slices. They looked at the effect on a type of neuron signalling called “long-term potentiation” (LTP), which involves strengthening connections between neurons and is involved in learning and memory. Here, they confirmed that beta amyloid negatively affects LTP. They then tested whether prion protein needed to be present for beta amyloid to have its effect. To do this, they repeated their experiments using brain slices from mice that were genetically engineered to lack prion protein. In addition to using their laboratory-generated beta-amyloid, they also repeated these experiments using amyloid beta extracted from the brain of a patient with Alzheimer’s disease. And in fact, prion protein does need to be present for beta amyloid to have this effect.

They then turned to how the prion protein and amyloid beta interact. They did this to identify key parts of the proteins that allow interaction to occur, so they could target these with antibodies to see if this would stop the interaction. The researchers subsequently tested a range of antibodies against different parts of the prion protein to see whether this would stop it binding to amyloid beta.

Once they identified antibodies that blocked this binding, they asked whether these antibodies could halt the effects of beta amyloid on long-term potentiation. Finally, they tested the effects of these antibodies in living rats. Again, they looked at the effects on long-term potentiation. They injected the rats’ brains with beta amyloid extracted from a human brain with Alzheimer’s and looked at the effect on long-term potentiation. They then tested whether pre-injecting the brains with the antibody before injecting amyloid beta blocked it from having an effect. The researchers found that two anti-prion antibodies, called ICSM-18 and ICSM-35, that have been tested in human prion disease, could block the binding of amyloid beta and prion protein in the laboratory. These antibodies were also able to stop amyloid beta from having an effect on long-term potentiation in mouse brain slices. ICSM-18 was also shown to stop the effect of amyloid beta on long-term potentiation in live rats.

Clinical trials to see whether drugs based on these antibodies can mitigate the damage caused to the human brain as a treatment for patients with CJD are due to begin in 2012.

Freir DB, Nicoll AJ, Klyubin I et al. Interaction between prion protein and toxic amyloid ß assemblies can be therapeutically targeted at multiple sites. Nature Communications, June 7, 2011.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego
Author: Michael Rafii MD,PhD at 1:06 PM 0 Comments

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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.