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Friday, July 29, 2011

Formal Guidelines Issued for Alzheimer’s Genetic Testing

By Michael Rafii, MD, PhD
Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego

Dear Readers:
Published in the June edition of Genetics in Medicine, and jointly issued by the American College of Medical Genetics and the National Society of Genetic Counselors, new guidelines have been developed for the field of Alzheimer’s disease.
The guidelines distinguish between genetic testing for dominantly inherited AD genes and that for the Alzheimer’s susceptibility gene - ApoE . The three early-onset familial AD genes—presenilin-1 (PS1), presenilin-2 (PS2), and amyloid precursor protein (APP)—confer almost 100 percent risk of developing AD, usually before the age of 60. Children of parents with the disease have a 50 percent chance of inheriting the gene, and may request pre-symptomatic testing. The guidelines lay out several strong recommendations for this type of predictive testing.
In contrast to dominantly inherited genes, testing for the AD susceptibility gene ApoE is a completely different case. The fourth gene, APOE-e4 on chromosome 19, is linked to a greater risk of susceptibility for developing late-onset Alzheimer’s. Late-onset AD is the more common form of the disease manifested after the age of 55 and generally associated with old age. APOE-e4 is a variant form of a gene that encodes the production of a protein called apolipoprotein E, which may play a role in repairing connections between brain cells. People with one copy of APOE-e4 have a greater risk of getting Alzheimer’s than people with other forms of the gene, and people with two copies of APOE-e4 have an even greater risk. Although carrying a copy of the ApoE4 risk allele increases the odds of getting AD by several fold, many people with the risk allele do not get the disease, while others without the allele do develop AD. The guidelines do not advocate for such testing.
The authors hope the guidelines will help to ensure that genetic testing for AD is performed in situations where it will provide useful information, and that patients and family remembers receive accurate information on the meaning of the results.
Goldman JS, Hahn SE, Catania JW, Larusse-Eckert S, Butson MB, Rumbaugh M, Strecker MN, Roberts JS, Burke W, Mayeux R, Bird T. Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011 Jun;13(6):597-605.
Author: Michael Rafii MD,PhD at 10:13 AM 0 Comments

Wednesday, July 20, 2011

Cardiovascular Risk Factors, Alzheimer's Disease, and Native Americans

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush University ADC

Dear Readers:

I was recently asked by a community health services nurse about whether the risk factors for Alzheimer's disease were the same for members of the Native American community. Before answering, I asked her for some information regarding the Native American community here in Chicago. I was surprised to hear that Chicago is often considered an "Urban Indian" city, as there are approximately 30,000 people in the greater metro Chicago area who claim Native blood/heritage with over 70,000 persons residing in various regions of the State. In addition to the Great Lakes Tribes- Illinois is also home to persons from tribes from the Plains, Western Mountain region, Sou hwest and Northeast regions of the country. Lastly, the American Indian Center in Chicago (AIC), located in the north part of the city, is the oldest urban Indian Center in the US.

Armed with that background information, I proceeded to tell her about the recent study published in the American Journal of Geriatric Psychiatry. In this study, researchers examined the role of common cardiovascular risk factors (CRF) to Alzheimer's disease (AD) in a group of Choctaw Indians - with and without Alzheimer's disease - and age-matched caucasians. The participants were recruited by employees of the Choctaw Nation Health Care Authority in Talihina, Oklahoma.

Baseline demographic variables were obtained by self report. In addition to questions regarding history of hypertension, diabetes, high cholesterol/use of an anti-cholesterol agents and myocardial infarction; family history of AD and blood samples for homocysteine (HC) and APOe4 were obtained. The diagnosis of AD was based on the NINCDS/ADRDA criteria and neuropsychological testing included the Trail Making test, Clock drawing test in addition to the CERAD battery.

A total of 39 Choctaw Indians with AD, 39 Choctaw Indians without AD and 39 white persons with AD - all age matched as close as possible - comprised the sample. In cross group comparisons, the white persons with AD had a significantly greater level of education and significantly lower HC levels compared to Choctaw Indians with AD, whereas Choctaw Indians with AD and those without AD were similar on these variables. With regards to CRF, there were no significant differences between Choctaws with and without AD in gender, history of high cholesterol, or MI. Both white and Choctaw Indian AD groups had a significant higher percent of affected first degrees relatives than the Choctaw Indian controls ( 44% or 31% versus 8%).

ApoE4 status was available on 37 Choctaw Indians with AD, 39 without AD, and 14 of the white persons with AD. White persons with AD had a significantly higher proportion of one or more apoe E4 allele than either Choctaw group. There was no relationship between the number of CRF's in comparing Choctaw Indians with AD to Choctaw Indians without AD however overall, Choctaw Indians with AD had a significantly higher number of CRF's than white persons with AD. The level of HC was not associated with the number of CRF's in both white and Choctaw Indians, however, there was a significant relationship between HC concentration and age of onset of AD seen only in the Choctaw Indians.

This study examined and contrasted the relationship between modifiable CRF's, homocysteine levels , APOe4 and AD in Choctaw Indians and whites. The main finding suggests that in Choctaw Indians with AD, homocysteine levels, rather than modifiable risk factors or APOe4 status, may have more of a role in the disease pathogenesis of AD than previously thought. Although the sample size for this study was small, and the ascertainment of CRF's relied on self report as opposed to blood samples for glucose and lipid levels, the results are intriguing. Further studies in persons with Native American heritage are needed to replicate these findings and examine how possibly lowering of HC levels may influence the clinical course of AD in persons in this race/ethnicity group.

To learn more about this study or related research in Native Americans, please refer to:

Weiner MF, Hynan LS, Rossetti H et al. The Relationship of Cardiovascular Risk Factors to Alzheimer Disease in Choctaw Indians Am J Geriatric Psychiatry. 2011; 19: 423-429

Weiner MF, Rosenberg RN, Womack KB, et al. Atherosclerosis risk factors in American Indians with Alzheimer's Disease. Alzheimer Disease Assoc Disorder 2008; 22:245-248

Thanks for reading.

Neelum T. Aggarwal, MD
Author: Neelum Aggarwal MD at 3:40 PM 0 Comments

Thursday, July 14, 2011

Recent Developments in Amyloid Imaging

The use of positron emission tomography (PET) imaging to diagnose Alzheimer's disease (AD) appears to be closer to becoming a clinical tool, based on results from two articles published online in the Archives of Neurology.

In one study, Adam S. Fleisher, M.D., from Banner Alzheimer's Institute in Phoenix, and colleagues, evaluated PET imaging using the tracer florbetapir F 18. The study population included 68 individuals with probable AD, 60 individuals with mild cognitive impairment, and 82 healthy individuals who served as controls. PET scanning was used to monitor activity of the agent being studied. Dr. Fleisher and colleagues found differences in the brain uptake of florbetapir F 18, between the three groups, and in the detection of amyloid plaque; the differences may be large enough to help distinguish between the conditions, and between impaired versus unimpaired brains.

In another study, David A. Wolk, M.D., from the Penn Memory Center in Philadelphia, and colleagues, evaluated use of a tracer called fluorine 18-labeled flutemetamol for imaging the brain. The study involved conducting PET scans on seven patients who were given the tracer. All had previously undergone a biopsy for normal pressure hydrocephalus, a progressive condition that includes dementia and can be difficult to distinguish from AD. Researchers found correspondence between readings of the PET scans and evidence of amyloid lesions -- the plaque associated with AD -- provided by microscopic evaluation of the biopsied tissue.

The greatest use of such scans may ultimately be to help rule out Alzheimer's disease, instead of rule it in. That is, in the physician's office, having a negative scan (meaning no detectable amyloid buildup in the brain) may be helpful to clinicians in ruling out Alzheimer's disease as the cause of the memory and thinking changes a person is experiencing. However, a positive scan (showing that there is amyloid buildup in the brain) has limited utility at this point.

Having amyloid buildup does not mean for certain that one has Alzheimer's dementia, especially in a patient who may not have symptoms. About 30 percent of elderly people have plaque, but not Alzheimer's dementia. It is believed that having a positive amyloid scan may reflect the early stages of Alzheimer’s disease (prior to the dementia phase) and increase one's risk of developing Alzheimer’s dementia in the future.

1. D. A. Wolk, I. D. Grachev, C. Buckley, H. Kazi, M. S. Grady, J. Q. Trojanowski, R. H. Hamilton, P. Sherwin, R. McLain, S. E. Arnold. Association Between In Vivo Fluorine 18-Labeled Flutemetamol Amyloid Positron Emission Tomography Imaging and In Vivo Cerebral Cortical Histopathology. Archives of Neurology, 2011

2. A. S. Fleisher, K. Chen, X. Liu, A. Roontiva, P. Thiyyagura, N. Ayutyanont, A. D. Joshi, C. M. Clark, M. A. Mintun, M. J. Pontecorvo, P. M. Doraiswamy, K. A. Johnson, D. M. Skovronsky, E. M. Reiman. Using Positron Emission Tomography and Florbetapir F 18 to Image Cortical Amyloid in Patients With Mild Cognitive Impairment or Dementia Due to Alzheimer Disease. Archives of Neurology, 2011
Author: Michael Rafii MD,PhD at 12:42 PM 0 Comments

Tuesday, July 05, 2011

Oldest Old Women and Cognitive Impairment

It is well known that people over the age of 85 years - often referred to as the oldest old - comprise the fastest growing segment of the US population. What is less known however, is whether cognitive differences regarding prevalent mild cognitive impairment (MCI) or its subtypes, exist between the “young old” and the “oldest old” groups. This question was posed by Yaffe et al, in a recent article published in the Archives of Neurology.

Data for this study was obtained from women who were enrolled in a large, ongoing Study of Osteoporotic Fractures (SOF). This multicenter study enrolled women aged 65 years or older from 1986-1988 and who had clinical visits every 2 to 4 years. At the 9th clinic visit (2006-2008), cognitive testing was offered to the women, and a total of 1,338 women were enrolled in the Women’s Cognitive Impairment Study of Exceptional Aging (WISE) study. Of these women, 1,299 were 85y or older and comprise the present sample for this study.

At the baseline clinic visit, information regarding age, education, race/ethnicity and type of residence were obtained. Other information obtained included body mass index, self reported poor memory symptoms, medication usage, and history of stroke, transient ischemic attack, dementia or Alzheimer’s disease (AD), diabetes or Parkinson’s disease.

Depression was measured using the Geriatric Depression scale. Information regarding functional assessment (activities of daily living – ADL -- and instrumental ADLs) was obtained. Initially, cognitive abilities were measured with the 26 point or 30 point Mini Mental State Examination (MMSE) and the Trail Making B test at each clinic visit. At the 9th visit an expanded version of the cognitive tests was administered. (Modified Mini Mental State Examination (3MS), tests for verbal learning, verbal fluency and digit span)

All women at visit 9 were initially screened for cognitive impairment utilizing a set of criteria and scores regarding cognitive and functional performance, clinical diagnostic criteria and type of residence. Women who screened negative were deemed cognitively normal. Those who screened positive in one or more of these criteria, were further evaluated by a team of experts. The diagnosis of dementia (based on DSM IV criteria) and the likely cause of dementia (i.e. AD, vascular dementia, dementia due to multiple causes [mixed] or other) was ascertained. MCI was diagnosed using the modified Peterson criteria, and those diagnosed with MCI were further classified as to having amnestic versus non amnestic and single versus multiple impaired domains.

Of the 1,299 women in the study (mean age 88.2 y, mean education 12.8y), 17.8 % were diagnosed with dementia, 23.2 % were diagnosed with MCI, with 59% were cognitively normal. The prevalence of MCI was higher in women 90 y or older than in women 85-89 years. Amnestic, multiple domains was the most common subtype of MCI, followed by non-amnestic, single domain and amnestic, single domain. The prevalence of dementia in those 90 y or older was double those aged 85-89 y. Features consistent with AD and mixed dementia were most common, accounting for 40% of the dementia cases. Compared with those with normal cognition, those with dementia or MCI were older, more likely to be depressed, to live in a nursing home and have a history of stroke.

This study suggests that cognitive impairment is common in women of the oldest old; with Alzheimer’s disease and mixed dementia appearing to be the most common types of dementia, and amnestic multiple domain and amnestic single domain the most common subtype of MCI. These results are important as they attempt to characterize the prevalence of dementia and MCI in this group of elderly. As epidemiological projections continue to suggest that the numbers of the “oldest old” will increase by 40% during the next decade – information as provided in this article, may inform us on public health planning and aid in future projections for health care costs.

If you would like to read more on this topic please check out the following articles:

Yaffe K, Middleton LE, Li-Yung L et al. Mild Cognitive Impairment, Dementia, and their subtypes in Oldest Old Women. Archives of Neurology 2011; 68 (5): 631-636

Rapp SR, Legault C, Henderson VW, et al. Subtypes of mild cognitive impairment in older postmenopausal women: the Women’s Health Initiative Memory study. Alzheimer Dis Assoc Disord. 2010; 24(3): 248-255

Busse A, Hensel A, Buehne U, Angermeyer MC et al. Mild cognitive impairment: long term course of four clinical subtypes. Neurology 2006; 67(12): 2176-2185

Thanks for reading.

Neelum T. Aggarwal, MD
ADCS Steering Committee Member
Rush Alzheimer’s Disease Center
Rush Institute for Healthy Aging
Chicago, Illinois
Author: Neelum Aggarwal MD at 3:37 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.