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Thursday, October 27, 2011

Mild to Moderate Alzheimer's Disease in Koreans: Findings from the CREDOS Study


Dear Readers,

In a recent article from the Journal of Korean Medical Sciences, Park and colleagues examined the prevalence of cognitive and behavioral characteristics in Korean patients with Alzheimer's disease from a large nationwide hospital based study. The data from this study comes from the CREDOS study ( Clinical Research for Dementia of South Korea), which has been funded by the Ministry of Health, Welfare and Family Affairs since 2005. The multiple centers included in CREDOS started a longitudinal registry of patients who were diagnosed with mild to moderate AD and the aim of this particular paper, was to examine and describe unique behavioral and social characteristics of those patients with mild to moderate AD in Korea.

A total of 31 different CREDOS participating centers were consecutively included in this study, and a total of over 1,700 patients were selected based on the following inclusion/exclusion criteria. All patients met the criteria for probable AD by the NINCDS-ADRDA and the DSM IVcritiera. Severity of dementia was assessed by the Clinical Dementia (CDR) rating scale and mild to moderate dementia was defined as CDR 0.5, 1 or 2. Patients who had clinical evidence of stroke, were those who had severe white matter hyperintensities, hemorrhages, brain tumors or hydrocephalus on neuroimaging scans.

The interviews consisted of structured questions that obtained data for demographic characteristics, lifestyle and family history, and past medical history including vascular risk factors such as hypertension, diabetes, heart disease, hyperlipidemia, alcohol and smoking . A Caregiver questionnaire form was also included, in addition to the Korean dementia screening questionnaire , Korean-mini mental state examination, activities of daily living and the Korean version of the neuropsychiatric inventory (NPI). Cognitive tests were assessed by the neuropsychological battery of the Seoul Neuropsychologic screening battery ( SNSB). The SNSB tested for visuoconstructive function, frontal executive function, attention, language, praxis and four elements of the Gerstmann syndrome.

A total of 1,786 participants formed the sample size for the majority of the analyses. The most prevalent group was the 8th decade, which had 926 patients (51.8%), and female patients comprised 67% of the sample. Approximately 19% of the patients were categorized as having early onset AD (EOAD, 65 years old), and of those who had APOE genotyping performed, 410/ 957 were positive for e4 (7.1 % homozygous, 35.8% heterozygous). The average age of onset of AD was 71.4 years (SD = 7.9) and average years of education was 7.1 years (SD= 5.0).

As expected, among the vascular risk factors, hypertension (48%) and diabetes (22 %) were were frequently found, followed by current alcohol drinker (19.4%), family history of stroke (18.5%) and cardiac disease (14.6%). Cognitively, the mean K- MMSE was 19.2. Overall 85.7% of the patients had neuropsychiatric symptoms, with the most common symptoms:, depression, anxiety and irritability (50.6% had noted depression on the NPI). Neuroimaging correlates (using a scale to grade severity of white matter hyperintensities) revealed that approximately 77% of patients were shown to have some degree of white matter hyperintensities on scans, most characterized as having moderate deep/periventricular white matter changes.

This clinical based study adds valuable demographic/clinical/neuroimaging data to the existing data from population-based studies in Korea. First, the percentage of early onset AD cases was higher than expected by population projections, and thus this suggests that many cases may have been missed, as screening may not be routinely performed for those under the age of 65yrs. Further, the association of vascular risk factors to cognitive impairment continues to be a major factor for cognitive impairment, crossing all ethnicities, and underscoring the importance for medical management to limit their deleterious effects.

Lastly, depression appears to be more common than thought of previously in this population, as reflected by the low reporting of depression by caregivers (3.7%) compared to the high proportion of depressive symptoms as measured by the NPI (50.6%). This discrepancy may be due to cultural influences/norms or perhaps suggest that test administration/explanation of the terms used to assess this behavior may not be accurate. In any case, this study provides interesting clinical based data that may aid in government policy making decisions regarding diagnosing and managing the care for individuals with Alzheimer's in Korea.

Here are 3 articles you can refer to, to learn about this study or the latest research on Alzheimer's disease in Korea.

Park HK, NA DL, Han SH et al. Clinical Characteristics of a Nationwide Hospital based Registry of Mild to Moderate Alzheimer's Disease in Korea: A CREDOS ( Clinical Research Center for Dementia of South Korea) Study. Journal of Korean Medical Sciences, 2011; 26: 1219-1226

Jhoo JH, Kim KW, Huh Y et al. Prevalence of dementia and its subtypes in an elderly urban Korean population: Results from the Korean Longitudinal Study on Health and Aging ( KLoSHA). Dement Geriatr Cogn Disord 2008:26: 270-6

Lee DY, Lee JH, Ju YS et al. The prevalnce of dementia in older people in an urban poulation of Korea: The Seoul study. J Am Geriatr Soc 2002;50: 1233-9.

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 11:37 AM 0 Comments

Wednesday, October 19, 2011

Gantenerumab and Beta-amyloid Plaque Removal


Gantenerumab, an antibody that binds to beta-amyloid, clears plaques in a matter of months, report scientists at F. Hoffmann-La Roche Ltd., Basel, Switzerland, in a study published online in the October 10 Archives of Neurology.

The Phase I study of 16 Alzheimer's patients tested gantenerumab at two doses against a placebo over six months of treatment. Senior author Luca Santarelli and colleagues used positron emission tomography (PET) scans to visualize and compare levels of amyloid plaques in the brain before and after intravenous antibody treatments, and found the decreases. The current study did not evaluate cognition. Many researchers suspect the build-up of such plaques may be a cause of this memory robbing disease.

There are, in fact, almost a dozen anti-beta-amyloid antibodies in clinical testing, including solanezumab, developed by Eli Lilly and Company, Indianapolis, Indiana, which, along with bapineuzumab, is furthest along in clinical development.

An earlier small study of the Elan Pharmaceuticals/Wyeth antibody bapineuzumab (now developed by Janssen Alzheimer Immunotherapy, Dublin, Ireland) also used PET scans to compare plaque levels in the brain before and after intravenous antibody treatment. This antibody lowered brain amyloid levels in Alzheimer's patients by an average of 8.5 percent over 18 months, compared with a 16.9 percent increase in untreated patients.

In the current study, 18 patients, aged 50-90, who had mild to moderate AD, received either placebo or gantenerumab (60 mg or 200 mg) in up to seven monthly intravenous infusions. At the end of the study, PET scans indicated that the six patients in the low-dose group lost 15.9 percent of their plaques, while the six in the high-dose group dispatched 35.7 percent. If this holds up, it would indicate faster amyloid removal than reported for bapineuzumab.

It is unclear whether beta-amyloid clearance by gantenerumab prevents or slows cognitive decline. We await results of Phase 3 trials of solanezumab and bapineuzumab next year, which will reveal whether clearance of beta-amyloid provides any cognitive benefit in mild to moderate AD. Of course, studies are being planned for prodromal Alzheimer's disease. Prodromal AD is a condition in which a person's memory loss is worse than can be expected by the normal aging process, while their ability to engage in daily activities is not affected to the extent that dementia would be diagnosed. Research sites around the world are preparing to enroll patients for the SCarlet RoAD study, to evaluate efficacy and safety of gantenerumab in patients with prodromal AD.

Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu Z, Loetscher H, Santarelli L. Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab. Arch Neurol. 2011 Oct 10




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 12:28 PM 0 Comments

Thursday, October 06, 2011

Is Alzheimer’s Disease Contagious?


A prion is an infectious agent composed of protein in a misfolded form. The word prion was coined in 1982 by Dr. Stanley B. Prusiner, and is derived from the words protein and infection. Normal prion proteins are produced naturally in the brain, but can cause disease when they come into contact with an infectious form of the protein that folds into an unusual conformation. These infectious prions convert innocuous prion proteins into the infectious form, which forms clumps and leads to neurodegenerative diseases, such as variant Creutzfeldt-Jakob disease, the human form of mad cow disease. Prions slowly destroy the brain tissue of infected people by causing a cascade of misshapen proteins. They're known to spread via consumption of contaminated food, by getting a transfusion of blood or tissue transplant from someone who is infected.

In 2009, researchers led by Dr. Stephen Strittmatter at Yale, showed that prion proteins produced naturally in the brain interact with the amyloid-ß peptides that are hallmarks of Alzheimer's disease. Blocking this interaction in preparations made from mouse brains halted some neurological defects caused by the accumulation of amyloid-ß peptide.

Now, researchers led by Dr. Caludio Soto at the University of Texas Health Science Center, have shown that, in fact, Alzheimer's disease itself, may be a prion-like disease. His team injected the brain tissue of a confirmed Alzheimer’s patient into mice and compared the results to those from injected tissue of a control without the disease. None of the mice injected with the control showed signs of Alzheimer’s, whereas all of those injected with Alzheimer’s brain extracts developed plaques and other brain alterations typical of the disease.

These findings suggest that in an experimental setting, misfolded beta-amyloid can behave in a similar way as infectious prions. It remains to be proven whether at least a proportion of human AD cases could be due to a transmissible prion-like mechanism. And it must be kept in mind, that prions are not contagious via normal human contact.




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 9:11 AM 0 Comments

Monday, October 03, 2011

Racial differences in Cognitive and Physical Function from a Large Community-Based Cohort


Dear Readers,

In a recent article from the Journal of Gerontology Series B, Barnes and colleagues examined the association of education with cognitive and physical function in a large group of older individuals. The data from this study comes from the Chicago Health and Aging Project (CHAP), a large longitudinal population based study of risk factors for Alzheimer's disease and other common age related conditions.

The study started with a complete census of all households in three contiguous neighborhoods on the South Side of Chicago. All residents aged 65 years and older were asked to participate, and of the 7813 eligible residents, over 6000 participated. In-home baseline interviews were conducted from 1993-1997 and successive interview cycles occurred at three year intervals. As persons turned 65 years in the community they were also asked to participate. The interviews consisted of structured questions that obtained data for demographic characteristics, psychosocial variables, medical history and cognitive performance tests.

Physical function was assessed by three performance tests that focused on lower extremity strength, balance, and gait- including tandem stand, measured walk and repeated chair stands. Higher scores on each tests ( range 0-5) indicated better physical function and the tests were summed to create an overall composite measure of function. Cognitive tests were based on four tests that included, tests of immediate and delayed memory, perceptual speed, the oral version of the Symbol Digit Modalities Test, and the Mini Mental State Examination test. Other variables assessed were race, education in years ( range 0-30), and the history or presence of seven medical conditions (heart disease, stroke, hypertension, diabetes, cancer, thyroid disease and shingles or herpes zoster).

A total of 9534 participants formed the sample size for these analyses (65% Black and 60.4% women). The average age was 73.0 yrs (SD= 6.9 yrs and 12.2 yrs of education ( SD= 3.5). Blacks on average were younger and had fewer years of education and performed lower on physical function and cognitive performance based tests.

The association of education with markers of physical and cognitive health was similar in both Blacks and Whites with low levels of education, however at higher levels of education, there was a significantly more positive association between years of education and both health outcomes among Black than among Whites. This positive association became stronger for each year of education beyond 12 yrs of education in Blacks only. Adjusting for differences in chronic disease between Blacks and Whites did not change the results suggesting that common disease related pathways do not account for racial differences in the relationship between years of education and late life functional health outcomes. Further controlling for overall physical function in the analyses did not change these results.

This study adds to the current research examining the complex association of education, health, physical function and cognitive function to race. As the US population is becoming more and more racially and ethnically diverse, the role of race/ethnicity to cognitive health and physical functioning is becoming increasingly important. This study highlights interesting associations of education to functioning, suggesting that continuing education beyond a high school level may be helpful in reducing late life health disparities in aging minority populations. Whether these trends are noted for other racial/ethnic minorities in the US population will need to be investigated.

Here are three articles you can explore to learn about the CHAP study or the latest research on cognitive health outcomes in racial and ethnic minorities.

Barnes LL, Wilson RS, Hebert LE et al. Racial Differences in the Association of Education With Physical and Cognitive Function in Older Blacks and Whites. The Journals of Gerontology, Series B: Psychological Sciences and Social Sciences, 66(3) 354-363

Bienias JL, Beckett LA, Bennett DA et al. Design of the Chicago Health and Aging Project (CHAP). Journal of Alzheimer's Disease, 5, 349-355.

Everson Rose SA, Mendes de Leon, Bienias JL et al. Early life conditions and cognitive function in later life. American Journal of Epidemiology, 158-1083-1089

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 12:06 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.