Meeting Notes: ICAD 2009

The 2009 International Conference on Alzheimer's Disease (ICAD), held July 11-16 in Vienna, Austria, featured hundreds of presentations and posters covering a diverse range of topics in Alzheimer's disease (AD) research, diagnosis, and treatment. According to the ICAD website, this year's event "drew nearly 3,800 international attendees to Vienna to share the latest ideas, thoughts and theories in dementia science. Breaking research and new technology captured global media attention as the world's leading scientists explored innovative ways to unlock the mysteries of Alzheimer's disease." ICAD 2009 (www.alz.org/ icad) featured presentations from researchers and clinicians conducting cutting-edge research into novel imaging approaches to understanding early AD; disease mechanisms; new pathways and targets for drug therapy; investigations using animal and cellular models; epidemiology and risk factors; and many more important topics.

ICAD 2009 Poster Presentation Podcasts

Toward a Multidimensional Formulation of Alzheimer's Disease Pathogenesis and Pathophysiology

Presenter Rodrigo O. Kuljis discusses the challenges to our understanding of neurodegenerative disorders and to the development of effective treatments and prevention presented because we lack a "satisfactory, unanimously agreed and unifying conceptual scheme" for them. Dr. Kuljis proposes that resolving this will require researchers to address "in an integrated fashion the multiple dimensions and scales of organization of the central nervous system, that transcend the conventional boundaries of biochemistry/molecular biology, systems neuroscience, and nosology-among others-as well as going beyond the timescales usually considered in this approach."

Overcoming Recruitment Challenges for Brain Tissue Donation: The University of Wisconsin, Madison Alzheimer's Disease Brain Bank

Presenter Kara M. Erwin discusses the challenges faced by Alzheimer's disease researchers seeking to find brain donors. This study examined barriers and incentives for brain donation. Researchers created and distributed a survey designed to help learn more about patients' and caregivers' knowledge of and attitudes toward brain donation.

Preservation of Cognitive Functioning in Depressed, Demented Geriatric Patients with Cardiovascular Risk Factors: An Ongoing, Three-year Naturalistic Study

The presenter discusses objective, design, and results of this study, which was undertaken to examine the long-term effect of combined pharmacologic and non-pharmacologic interventions in geriatric patients with depression, mixed dementia, and cardiovascular comorbidities. The non-pharmacologic interventions included a unique home-based program that included mild exercises, cognitive training, memory training, stress management, dietary and other lifestyle modifi cations, and a program of hand movements designed especially for this fragile population.

Visit www.hcplive.com/hcplive to listen to these interviews from ICAD.

Abstracts of all 2009 ICAD poster presentations are available in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 5, Issue 4, Supplement (July 2009), online at www.alzheimersanddementia.org/issues/ contents. (You'll have to click the "Next issue" arrow to view the TOC for the Supplement.)

Online Resource for Patients with Alzheimer's Disease (AD)

DementiaGuide.com Enables Caregivers to Learn More about AD, Track Their Loved One's Symptoms and Progress, and Share Data with Physicians

MDNG is always on the lookout for new online resources for physicians and patients that promote more effective communication, enhances the physician- patient relationship, and helps patients and caregivers take a more active role in treatment. This resource (www.dementiaguide.com), developed by Dr. Kenneth Rockwood, President and Chief Scientifi c Offi cer, and the rest of the DementiaGuide team, is designed to help caregivers to better understand and manage the symptoms of dementia and Alzheimer's disease.

Cathy McNutt, vice president of product development, explained that caregivers can sign up for a free trial account and create a symptom profi le for their loved one with dementia or AD. The symptom profi le lets caregivers describe and track symptoms over time and determine whether individual symptoms have changed, improved, or deteriorated. Symptoms are organized into several pre-set categories, including "thinking and judgment," "personality changes," "memory and language," "behavior," and "physical changes." Within each category are listed specifi c symptoms; for example, "thinking and judgment" includes "decision making (problems with)," "attention/ concentration (lack of)," "insensitivity," "comprehension/understanding," "following instructions," and "inappropriate language and behaviors." Each individual symptom has a defi nition to help caregivers further understand and categorize content. They can also add their own custom symptoms. Then, each symptom has a list of pre-defi ned descriptors that help caregivers describe and rank behaviors and characteristics associated with the symptom. Finally, after recording the frequency with which each symptom presents, caregivers rank the symptoms in order of most important to least important to help determine which are having the most effect on the patient's life. The profi le is designed to "reflect the caregiver's and patient's background, living arrangements, medications, and general health history."

McNutt said that SymptomGuide, which includes the profi le creation and tracking tools, "walks you through the process of creating an individualized profi le of the symptoms that you are managing and how they are progressing over time. It gives you management techniques for each symptom. You can use your profi le report to communicate with doctors and family members to help them understand where you and the person you are caring for are and what you both need."

After creating a profile, caregivers can use DementiaGuide's reporting tools to record, track, and graph changes in symptoms over time. They can even print out a report to take with them to doctor visits, making it easier to communicate and modify treatment plans. McNutt also pointed out that in addition to the data-specifi c profi le and tracking tools, DementiaGuide also offers a "Journal" feature that lets caregivers write and record detailed descriptions of behavior changes and other observations, important details that can otherwise be forgotten when it comes time to visit the doctor.

DementiaGuide also features a detailed "Symptom Library" developed by Dr. Rockwell to provide caregivers with in-depth, reliable, and accurate information about the symptoms associated with dementia. Other features include a "Community" page that highlights key topics in dementia and AD, and a "Support" section where caregivers can browse answers to questions that are frequently asked by other caregivers.

Visit DementiaGuide.com to see if your patients with Alzheimer's disease and their caregivers would benefi t from the tools and information it offers. If you or one of your patients already uses this resource, contact Chris Cole at ccole@mdng.com, and share your experiences and insights.

Hot Topics at ICAD

APOE-3 and TOMM-40 Haplotypes Determine Inheritance of Alzheimer's Disease Independently of APOE-4 Risk

Noting that estimates for the heritability of apolipoprotein E-4 (APOE-4) for late-onset Alzheimer's disease (ranging from 58-79%) and the populationattributable risk due to the APOE-4 allele (ranging from 20-70%) suggest that "other genetic variants or interactions between variants incur additional risk and modify age of onset distributions." Also taking into account the "extraordinary association" for AD with the linkage disequilibrium (LD) region containing APOE, and that TOMM-40, the "protein translocase of the outer mitochondrial membrane," is also in high LD with APOE, Allen D. Roses, of Duke University and the Deane Drug Discovery Institute, and colleagues sought to identify new haplotypes with this LD region that may increase estimates of heritability. They studied the TOMM-40/APOE-4 LD region in 66 patients with AD and 66 age-matched controls. They found that "unique and distinct inherited families of different TOMM-40 variants are located on the same genetic interval as APOE-3," but not on the APOE-4 genetic region. These variants can "either increase or decrease the age of risk distribution of AD." They concluded that "the genetic inheritance of these TOMM-40 variants is independent of the inheritance of APOE-4, providing a differentiation of two distinct forms of APOE-3: those linked to TOMM-40 haplotypes that increase risk and decrease age of onset, and those that decrease risk."

Blood-borne Amyloid-beta Dimer Correlates with Clinical Markers of Alzheimer's Disease

As readers know, a diagnosis of Alzheimer's disease is made based on a clinician's judgment and observations following a variety of neuropsychological tests, lab work to rule out other causes of symptoms, and other assessments. A defi nitive diagnosis must wait until a post-mortem exam of the patient's brain tissue that reveals the presence of amyloid plaques and neurofi brillary (tau) tangles. Studies have shown these plaques (especially amyloid-beta) are associated with AD and progression of the disease. Kevin J. Barnham, of the University of Melbourne, and colleagues noted that studies attempting to target amyloid-beta processing have been thwarted by the lack of validated biomarkers. However, several studies have pointed to oligomeric forms of amyloid- beta as "the toxic species that induce the neuronal dysfunction associated with AD." These forms also include "synaptotoxic amyloid-beta dimers" that have been found post-mortem in AD brain tissue. Because there is currently no means of monitoring this promising target in live patients, Barnham and colleagues analyzed blood samples from a cohort of patients (43 with AD, 23 with mild cognitive impairment, and 52 healthy controls) using a form of mass spectroscopy to see if they could identify oligomeric forms of amyloidbeta and to see if there were differences in the level of those oligomers in healthy subjects vs. patients with AD and/or MCI. They found differences in the blood profi les between healthy patients and patients with AD and/or MCI that were consistent with the presence of two "distinct processing pathways" for amyloid precursor protein (APP) with "an amyloidogenic pathway favored in AD." This has potential diagnostic and therapeutic implications because this fi nding indicated "signifi cantly higher levels of amyloid-beta monomer and amyloid-beta dimer in the blood of AD subjects" (an increase of 16% and 35%, respectively, compared with controls). The researchers also reported that their fi ndings correlated with other clinical markers of AD, including MMSE scores. These results indicate that "fundamental biochemical events relevant to AD" can be monitored through routine blood analysis and may be useful clinical biomarkers for AD.

Can a Measure of the Amount of Assistance a Patient with Alzheimer's Disease Requires to Perform Daily Tasks Be Used to Evaluate Cost-effectiveness of Therapy?

A poster submitted for presentation at the 2009 International Conference on Alzheimer's Disease (ICAD) by Daniel L. Murman, MD, University of Nebraska Medical Center, and colleagues asks a key question in this era of managed care, tightening healthcare budgets, and possible comprehensive healthcare reform: could a tool that measures the level of care needed by patients with Alzheimer's disease (AD) be used to help evaluate the cost effectiveness of AD treatments and therapies?

This question is worth asking for a number of reasons, as formulary managers, PBMs, insurers, and other third-party payers must constantly weigh clinical effi cacy against cost-effectiveness when deciding whether to approve coverage of or payment for treatments. Because of this, Murman and colleagues note that it is important to "develop methods for translating clinical changes into economic outcomes."

One method for doing this and predicting resource use and cost may be to evaluate the level of assistance patients with AD require to perform daily tasks, using the Dependence Scale (DS), a well-established level-of-care measure in AD.

To determine the usefulness of DS score for predicting cost of care, the researchers performed a baseline assessment of a cohort of 133 caregiver/ AD patient pairs, with follow-up every 12 months for two years. AD patients were between age 50-85 years and met NINCDS-ADRDA criteria for AD. In addition to caregiver-assessed DS scores, patients were also assessed with MMSE, NPI, the Columbia University Parkinson's Rating Scale (at baseline), and the Comorbid Illnesses with Cumulative Illness Rating Scale. The study also recorded demographic data (age, marital status, education, etc), resource utilization during the previous 12 months (medication use, doctor visits, hospitalization, and other measures), and unpaid caregiving time (using the Caregiver Activity Time Survey).

Analysis of the data revealed that direct cost of care was "best predicted by DS summated score, [extent of] comorbid illness, and marital status." DS sum and extent of comorbid illness were the best predictors of total costs. By way of comparison, the annual total cost of care for a married patient with moderate comorbid illness and DS sum of 2 was $3,760; the cost for a patient with same marital status and comorbid illness, but with a DS sum of 12, was $50,476.

These findings show that "the DS is a signifi cant and important predictor of economic outcomes in AD." The authors conclude that "information such as this can assist in the development of pharmaco-economic models for evaluating the cost-effectiveness of new AD treatments."

Online Resource for Researchers: iFBAD

The Internet-based Forecasting of the Burden of Alzheimer's Disease (iFBAD) website (www.biostat.jhsph.edu/project/globalAD) was developed by Ron Brookmeyer, PhD, Elizabeth Colantuoni, PhD, and colleagues in the Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health (www.biostat.jhsph.edu).

The iFBAD website describes the application as "an internet-based system to forecast (F) the burden (B) of Alzheimer's disease (AD) and to evaluate the potential impact of interventions that delay AD onset and progression" (thus, the iFBAD acronym). The system produces projections of AD prevalence, incidence, DALYS, and cost.

To paraphrase the description provided at the website (and as explained at the conference by Dr. Colantuoni, who presented this information at ICAD as poster #P2-066 "Web-based Application to Estimate and Project the Burden of Alzheimer's Disease and Evaluate the Impact of Potential Interventions"), the iFBAD is based on a "multi-stage probabilistic model for the incidence and progression of Alzheimer's disease." According to the model, healthy individuals may transition to either mild or moderate and late stage Alzheimer's disease (referred to by the model as stage 1 and stage 2 disease, respectively). A person's annual probability of AD onset varies by age, gender, and calendar year. A person's annual probability of moving from stage 1 disease to stage 2 disease may vary by calendar year. The annual probability of onset of AD and the annual transition rate to stage 2 disease depend on calendar year to "allow for the introduction of interventions that delay disease onset or progression." The website does a better job of explaining this, along with the way in which probability of mortality is factored in and how the model generates age-, gender- and stage-specifi c prevalence rates of Alzheimer's disease. Go to www.biostat.jhsph.edu/project/globalAD/ourmodel.htm to read more about how iFBAD works.

Neuropsychological Assessment Remains Important Predictor of MCI Evolution to Dementia

By Timothy Tankosic, MD

Although neuropsychological impairment, reduced cerebral activity, brain atrophy and cerebrospinal fluid abnormalities are known to occur in "healthy elderly controls" who subsequently progress to dementia, comparisons of neuropsychological tests with biomarkers remain relatively rare in follow up studies of healthy subjects. In order to make these comparisons in larger samples, studies designed to predict the evolution from the pre-dementia to the dementia stage of AD must be reviewed. Such studies try to predict which subjects, among those classifi ed as "mild cognitive impairment" (MCI) or "questionable AD" convert to the diagnosis of AD. Eric Salmon, MD, PhD, of the University of Liège (Belgium), reviewed such comparative studies in a plenary session presentation at the 2009 Alzheimer's Association International Conference on Alzheimer's Disease, held in Vienna, Austria.

Dr. Salmon performed a literature review for support or refutation of three hypotheses. Hypothesis 1 posits that biomarkers are more useful than neuropsychological assessment in predicting conversion from MCI to AD. Hypothesis 2 argues that neuropsychological assessment is more useful than biomarkers for the same prediction. Hypothesis 3 suggests that there are signifi cant advantages in the use of a combination of markers.

Studies supporting each of the hypotheses were identified. Three reported that hippocampal atrophy or temporoparietal hypometabolism are slightly better predictors of evolution from MCI to AD than neuropsychological tests. A recent study in a large population of MCI subjects found that a combination of neuropsychological tests was superior to neuroimaging, while another showed that neuropsychological variables were better predictors than ApoE status. Four studies showed that a combination of medial temporal atrophy and cognitive impairment or a combination of brain activity and neuropsychological tests provided the most accurate classifi cation of converters and non-converters.

Most (but not all) studies showed that neuropsychological variables remain important predictors of evolution to dementia, even in populations where neuroimaging or other biomarkers are available. Neuropsychological tests are particularly sensitive to the early "changes of mind" that precede AD or even MCI. Decreased verbal fluency were observed 12 years before the diagnosis of AD was made in one study, and declines in episodic memory, executive function and semantic knowledge were observed two years before the diagnosis of MCI in another study.

Long-term memory remains the best neuropsychological predictor, and it is frequently associated with a measure of global cognition. However, combinations of neuropsychological tests are needed because a single test cannot fully evaluate subtle changes in networks. The best test for the detection of MCI is not necessarily the best test for the detection of progression from MCI to AD. Moving forward, it is anticipated that refi nements will be made in neuropsychological variables, as they will be in neuroimaging and other biomarkers.

[NB: The superiority of the combination of biomarkers and neuropsychological tests was apparent in an ICAD press conference presenting results from ADNI studies of early detection of AD. Two of the three studies included a neuropsychological test along with an imaging biomarker as part of their most accurate assessment protocol. The third study did not evaluate neuropsychological tests.]