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Wednesday, May 30, 2012

Cognitive Function, Retinal & Ischemic Brain Changes



Dear Readers,

I recently read an article in the American Academy of Neurology’s green journal that examined the association of retinopathy to cognitive function and brain changes. The study included 511 women aged 65 years and older who were participating in the Women’s Health Initiative Memory study (WHIMS) and the Sight Examination study (WHISE). The women in the WHISE study were recruited between 2000 and 2002 from an existing study – the Women’s Health Initiative study. Over 4000 persons participated in the WHISE study and of them, a total of 511 WHISE participants also participated in the WHIMS- MRI study. Each woman who enrolled in the WHISE study, had a comprehensive eye examination (including visual acuity) and completed a questionnaire which collected ocular and medical history on conditions such as cataracts, glaucoma, diabetes, early and late age-related macular degeneration (AMD). In addition fundus photography was obtained to visualize the optic disc, macula, temporal, superior, inferior and nasal areas.

As part of the procedures for the parent study- the Women’s Health Initiative -cognitive testing was assessed annually using the 3MSE. The 3MSE was obtained in 505 women of the 511 women, with an average of 4.5 3MSE evaluations performed prior to fundus photography and 5.9 3MSE evaluations performed after fundus photography. MRI evaluations were performed using standard imaging techniques that characterized ischemic lesions (white matter hyper intensities), infarcts and total brain volumes.

The average ages of the women in this study was 69 +/-4 yrs, and were evaluated in WHISE for retinopathy 3.8 +/- 0.8 yrs after they had enrolled in the WHI. MRI images in WHIMS were obtained an average of 8 yrs after their WHI enrollment and 4.2 +/- 0.5 yrs after the WHISE eye examinations. The overall race/ethnic composition of this was group was predominantly white. (0.8% Asian, n= 4, 4.1%African American, n= 21; 2.1% Hispanic, n= 10; white 91.9%; n=470; other/multiple race/ethnicity 0.9%, n=5)

A total of 39 women from the entire sample were classified as having retinopathy and the diagnosis of retinopathy status was related to diabetes and hypertension status. Women with retinopathy had greater levels of total lesion volumes, with more frontal lobe lesion volumes as compared to those women with no retinopathy. Regional differences in lesion volumes by retinopathy status were present in the parietal and temporal lobes but not in the occipital lobe.

Across follow up, analyses conducted controlling for education, smoking status, body mass index, hypertension, diabetes, cardiovascular disease, demonstrated that 3MSE scores were significantly lower for women with retinopathy compared to those without retinopathy. Women with retinopathy performed worse on both the vision dependent and non vision dependent items over time.

The findings from this study add to the existing research that seeks to link early markers of micro vascular changes (i.e. retinopathy) to markers of ischemia and brain changes. Retinopathy was associated not only with greater deficits over time in global cognitive function, but also with larger ischemic lesion volumes. These findings suggest that retinopathy evaluations may provide a mechanism to estimate vascular pathology directly. One limitation of this study however, was the lack in precision regarding the assessment of white matter hyperintensity lesions/infarcts. In addition, the global measure for cognitive function was the only measure used, and as such, no comment on changes in specific cognitive systems could be discussed.

Here are 3 articles you can refer to, to learn about this particular study or the latest research on dementia in India.

Haan M, Espeland MA, Klein BE et al. Cognitive function and retinal and ischemic brain changes: The Women’s Health Initiative. Neurology 2012; 78: 942

Wong TY, Klein R, Sharrett AR, et al. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002; 288: 67-74

Lindley RI, Wang JJ, Wong MC et al. Retinal microvascularature in acute lacunar stroke: a cross sectional study. Lancet Neurol 2009; 8: 628-634

Thanks for reading.


Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Co-Leader-Clinical Core, Rush Alzheimer’s Disease Center
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL












 
Author: Neelum Aggarwal MD at 3:18 PM 0 Comments

Wednesday, May 23, 2012

ApoE Damages Blood Vessels


Dear Readers,

New evidence appearing in this week’s issue of the prestigious journal Nature implicates the ApoE4 gene, the primary genetic risk factor for late-onset Alzheimer’s disease, as a prime culprit in damaging brain blood vessels. The researchers describe a detailed pathway through which ApoE4 triggers the breakdown of the blood brain barrier in genetically engineered mice. This breakdown causes toxic proteins to accumulate in the brain and provokes neuronal degeneration.

Readers of this blog may recall that the blood brain barrier is a physical separation of circulating blood from the brain. It restricts the diffusion of microscopic objects such as bacteria and toxic molecules into the central nervous system.

To study the role of ApoE, the researchers used mice in which the mouse version of ApoE protein was replaced with human ApoE2, 3, or 4, as well as ApoE knockout animals which have been genetically engineered in such a way that a gene has been removed from its DNA. In two-week-old mice with ApoE4 or no ApoE, cerebral blood vessels leaked profusely, capillary length declined, and cerebral blood flow dropped. These changes grew worse with age. Moreover, brains of ApoE4 and knockout mice accumulated proteins that damage neurons. ApoE4 mice had less neuronal activity and lost synaptic connections. The researchers used a combination of molecular and imaging techniques to show these changes in mice. What does this mean for humans with ApoE 4?

People with the ApoE4 form of the ApoE gene are known to have higher levels of cerebral amyloid angiopathy, a condition where toxic beta-amyloid deposits directly into the blood vessels, thereby weakening their structural integrity and making individuals more susceptible to bleeding in the brain compared to non-carriers. This study leads us to believe that not only does ApoE promote deposition in the brain rather than its removal from the brain, it also damages the blood brain barrier in such a way to allow other toxic molecules to injure the brain as well.


Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 17.



Thanks for reading,

Michael


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 4:38 PM 0 Comments

Wednesday, May 16, 2012

Exciting Developments on the AD Research Front


Dear Readers,

Yesterday at the Alzheimer’s Disease Research Summit 2012, a conference hosted by the National Institute on Aging, Dr. Francis Collins director of the NIH, announced the first-ever therapeutic prevention trial in cognitively healthy people at high risk for AD. The decision is part of the National Plan to Address Alzheimer’s Disease (NAPA), which I have recently blogged about. The unprecedented trial will be run by an international collaboration of researchers in academia and industry to prevent dementia due to AD by treating patients with a drug before any cognitive symptoms appear.

The trial, called the Alzheimer's Prevention Initiative (API) is led by Dr. Eric Reiman, Dr. Pierre Tariot, and Dr. Jessica Langbaum at the Banner Alzheimer’s Institute in Phoenix, Arizona, and Dr. Francisco Lopera and his colleagues at the University of Antioquia in Colombia. Over the past two years, these scientists and other colleagues have enrolled members of the world’s largest kindred afflicted with a mutation that leads to early onset AD.

The trial will look at the efficacy of the drug crenezumab in preventing dementia. Genentech licensed crenezumab from the Swiss biotech company AC Immune. Similar to bapineuzumab, solanezumab, and gantenerumab, three AD immunotherapies currently in Phase 3 and Phase 2 trials, respectively, crenezumab is a monoclonal antibody that binds beta-amyloid. By virtue of binding beta-amyloid, early on the the course of the disease, it may prevent the widespread injury that occurs in the brain 10-15 years before patients with AD develop any memory symptoms.

Three hundred people in Colombia will participate in the trial. One hundred mutation carriers will receive monthly injections of crenezumab, 100 will get placebo, plus 100 non-carriers will receive placebo to ensure that study participants will not know whether they carry the pathogenic mutation or not. All participants will be asymptomatic. The trial is intended not as an exploratory study, but as a registration trial, meaning a positive outcome might form the basis for a new drug application.

While this trial is gearing up, the AD researchers are planning for the next one, which aims to test investigational drugs in ApoE carriers at elevated risk of developing Alzheimer’s. The hope is that this initial trial will stimulate more presymptomatic treatment trials throughout the field.

Thanks for reading,

Michael


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 10:37 AM 0 Comments

Tuesday, May 15, 2012

CBS Evening News Story on the Lack of Volunteers for ADNI


If you missed the CBS Evening News broadcast on Monday, May 14 you can view the story here. http://www.cbsnews.com/8301-18563_162-57434083/promising-alzheimers-research-delayed-by-shortage-of-volunteer-patients/?tag=contentBody;cbsCarousel They provided an excellent overview of the problems facing AD researchers today -- the lack of study volunteers that ultimately leads to AD research studies taking much longer than anticipated. And the longer it takes to recruit volunteers the longer it takes to eventually find a cure.


Jeffree Itrich, M.S.W., M.J.
Sr. Clinical Trials Communications & Recruitment Specialist
Alzheimer's Disease Cooperative Study
University of California San Diego
Tel: 858-246-1317

jitrich@ucsd.edu www.adcs.org

Have you subscribed to our monthly e-newsletter yet? If not, subscribe here: http://adcs.org/Research/registry.aspx & read past issues here:
http://adcs.org/Research/InformationNewsletters.aspx
 
Author: Jeffree Itrich at 9:48 AM 0 Comments

Wednesday, May 09, 2012

Midlife Versus Late-Life Depressive Symptoms and Risk of Dementia


Readers,

There has been an ongoing debate in the field as to whether the association between depression and dementia reflects a causative relationship or whether depression is an early symptom of impending dementia. The results of a large study that has just been published, suggest that the answer may differ depending on the dementia subtype. Depression that presents for the first time in late life may reflect the earliest symptoms of dementia, particularly AD.

The paper, published in the May issue of Archives of General Psychiatry, adds to the evidence that late-in-life depression is likely an early sign of Alzheimer's disease. To look at this relationship between depression and dementia, Dr. Rachel Whitmer, an investigator at the Kaiser Permanente Northern California Division of Research and her colleagues, looked at 13,535 long-term Kaiser Permanente members who had enrolled in a larger study in the period from 1964 to 1973 at ages ranging from 40 to 55 years old. Health information, including a survey that asked about depression, was collected at the time.

The researchers looked at whether the same people were depressed late in life, in the period from 1994 to 2000, and then looked at whether they were diagnosed with dementia or Alzheimer's disease in 2003. The participants' average age in 2003 was 81 and 57.9% were women. The study found depression present in 14.1% of subjects in midlife only, in 9.2% in late life only and in 4.2% in both.

When looking at those patients who later developed dementia, the study found 20.7% of study participants without depression developed dementia, compared with 23.5% of people who reported depression in midlife only and 31.4% of those who were depressed later in life. Among those who were depressed at both mid- and late-life, 31.5% developed dementia.

The researchers also found that people who were depressed in midlife but not late in life had no increased risk of developing Alzheimer's disease or vascular dementia. People who were depressed late in life were more likely to develop Alzheimer's while those depressed at both mid- and late life were three times as likely to develop vascular dementia.

Depression can be devastating by itself, but, in late-life, it can also be associated with increased risk of developing dementia as an important early sign.


Deborah E. Barnes et al, Midlife vs Late-Life Depressive Symptoms and Risk of Dementia: Differential Effects for Alzheimer Disease and Vascular Dementia. Arch Gen Psychiatry. 2012;69(5):493-498.




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 12:55 PM 0 Comments

Wednesday, May 02, 2012

Association between Serum 25 (OH) Vitamin D and the Risk of Cognitive Decline in Older Women



Dear Readers,

It is very rare in the course of a community talk on lifestyle factors as it relates to women’s health, that I don’t discuss the latest on Vitamin D research. Most women discuss vitamin D in terms of its relationship with calcium and bone health. Few realize however, the role of vitamin D in brain health. This topic was recently discussed in a recent article from Slinin and colleagues, where the authors attempted to characterize the relationship between lower vitamin D levels and cognitive impairment and cognitive decline.

The Study of Osteoporotic Fractures initially recruited over 9,000 community dwelling Caucasian women from four areas in the US -- Baltimore, MD; Minneapolis, MN; Portland, OR; and Monongahela Valley, PA. A total of 6350 women from the Year six cycle served as the “baseline” visit for this study (1992-1994) and underwent cognitive assessments and serum vitamin D measurements (ergocalciferol and cholecalciferol). Other demographic characteristics that were assessed were level of education, cardiovascular risk factors [hypertension, smoking, history of stroke, heart disease, diabetes, alcohol intake], history of lung and kidney disease and depression. Functional status was measured by a modified version of the Stanford Health Assessment Questionnaire, which assesses independence in six instrumental activities of daily living. Cognitive testing at year six (Visit six), year eight (Visit eight) and year 10(Visit 10) included the Modified Mini-mental State Examination (mMMSE) and Trails B test (a measure of executive function). Women who reported having a physician diagnosis of dementia or who were cognitively impaired at Year six (defined by the mMMSE score or Trail B) were excluded from longitudinal analyses.

At baseline evaluation, approximately 7% of the women were classified as being severely deficient for vitamin D and only 21% were classified as being sufficient for vitamin D. The remaining women were classified as either deficient or borderline sufficient for vitamin D levels. The authors found an association between low vitamin D levels and greater odds of cognitive impairment, as noted by the mMMSE scores. Although in simple statistical models, an association was found between the various categories of vitamin D levels and cognitive impairment as noted on the Trails B test, this relationship was no longer present when adjusted for age and education.

Longitudinal analyses revealed that there was an association between lower vitamin D levels and higher odds of incident cognitive decline as noted by the mMMSE performance. There was no evidence of an association between vitamin D levels and cognitive decline on performance of the Trails B test.

This study examined the association of vitamin D levels to cognitive function, in a large group of older women. The results suggest that low levels of vitamin D are associated with cognitive decline in women, and add to the existing population based literature that supports this finding. One potential mechanism of how vitamin D may “protect cognition” is by preventing the development of vascular dementia and the development of white matter hyperintensities on MRI scan. The role of vitamin D to cognitive function in elderly subjects participating in specifically designed trials to examine this relationship, have been mixed. Some have found no effect on cognition while others have shown a positive effect not only on cognitive function, but also on physical function tests.

The findings from this study are important as they add to the literature that suggests low levels of Vitamin D may signal the beginning of cognitive decline and dementia. Thus identification and treatment early on may prevent the development of cognitive decline in advancing age. The major limitation of this study as suggested by the authors was that it was done in Caucasian women only, thus not generalizable to the racially and ethnically diverse population in the U.S. Unfortunately, only one baseline measurement of vitamin D was available for analysis and this may have influenced the longitudinal findings. Lastly, the cognitive tests employed were relatively brief and no widely accepted criteria for cognitive impairment based on these tests are known at this time.

Here are 3 articles you can read to learn about this study, and other studies examining the oldest old.

Slinin Y, Paudel M, Taylor BC et al. Association Between Serum 25 (OH) Vitamin D and the Risk of Cognitive Decline in Older Women. Journal of Gerontology: Medical Sciences. 2012 Epub

Annweiler C, Allali G, Allain P, et al. Vitamin D and Cognitive Performance in Adults: a systematic review. Eur J. Neurol 2009; 16:1083-1089.

McGrath J, Scragg R, Chant D, et al. No Association Between Serum 25-hydroxyvitamin D3 level and performance on psychometrics tests in NHANES III. Neuroepidemiology 2007: 29, 49-54..

Thanks for reading.


Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Rush University Medical Center
Chicago, IL











 
Author: Neelum Aggarwal MD at 2:01 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.