Tuesday, April 6, 2010

Predicting Alzheimer ’s Disease Progression Rate

Mental status exam - Mental status exams assess memory, concentration, and other cognitive skills. The most frequently used mental status exam is called the Mini-Mental State Exam (MMSE), a research-based set of questions that results in a score representing a person's general level of cognitive functioning.

The MMSE is generally a reliable and valid indicator of cognitive impairment that can correctly distinguish between individuals with dementia, individuals with pseudo-dementia due to depression, and individuals with depression and no cognitive impairment. However, the test must be used with caution in certain groups of people. For example, highly educated people frequently score high on the MMSE, even if they have Alzheimer's Disease (AD). Similarly, people with less than an eighth grade education or whose first language is not English often score poorly on the MMSE, even though they may not have cognitive impairment.

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The latest research states that not only the patient current mental status may be evaluated based on the MMSE assessment results, but also Alzheimer's disease (AD) progression rate. The new approach is able to reliably predict how quickly the individual patient will lose cognitive and other abilities with significant degree of reliability.

Rachelle Doody, MD, PhD, and colleagues from Baylor College of Medicine in Houston, Texas, report initial results using the prognosis indicator with 597 patients followed up for 15 years published online February 23, 2010 in Alzheimer's Research & Therapy.

“Patients and families frequently ask clinicians to predict expected rates of cognitive and functional decline, and clinicians currently have little basis for making such decisions," Dr. Doody told Medscape Neurology.

"We’ve found that a simple, calculated progression rate at the initial visit gives reliable information regarding performance over time," she said. "The slowest progression group also survives longer."

Calculating AD Progression Rate

The pre-progression rate is calculated using a standard assessment of symptom duration in years and the baseline Mini-Mental State Examination (MMSE) score. The estimate of duration includes a series of questions about the duration of specific symptoms that might be a sign of AD, medical records review, and informant interview.

The study authors explain, “Since a cognitively intact individual should obtain the maximum MMSE score of 30, the pre-progression rate is given by the formula: (30 baseline MMSE)/estimated duration of symptoms in years.”

Those with an MMSE score decrease of less than 2 points per year were classified as slow progressors. Intermediate progressors were defined as having a 2- to 4-point decrease per year and rapid progression as a 5 point or greater decrease per year in MMSE score.

Dr. Doody told Medscape Neurology, “The procedures for obtaining and using the information are not yet in common use, but they could be. With further refinement, physicians could use this work to tell patients whether they fall into a slow, intermediate, or rapidly progressing category with respect to the intrinsic progression of their AD. They might decide upon follow-up intervals and how aggressive to be with medications based upon the progression rate. Once started on therapy, it might be possible to alter the intrinsic rate, but this requires further study.”

The researchers examined outcomes for patients annually for up to 15 years using the MMSE, the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAScog – cognitive MMSE sub-scale), the Verbal Series Attention Test, the Clinical Dementia Rating Scale Sum of Boxes, and the Lawton and Brody Activities of Daily Living Scale, which combines the Physical Self-Maintenance Scale and the Instrumental Activities of Daily Living Scale.

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Slow Progressors Also Live Longer

The investigators found that patients in the slow and intermediate groups maintained better performance on tests of cognitive function, global function, and complex activities of daily living than the rapid progressors. For example, slow progressors gained 0.6 fewer points per year on the ADAScog and intermediate progressors 0.8 fewer points per year than rapid progressors.

At study entry, the slow progressors also had a longer estimated duration of symptoms than intermediate or fast progressors, as well as higher IQ and education.

Slow progressors also lived longer. Median survival was 4.7 years for slow, 4.1 years for intermediate, and 2.5 years for rapid progressors, adjusted for age, sex, education, and baseline severity (hazard ratio, 0.62 for slow vs. fast progressors).

“Our results suggest that prognostications based upon initial progression rate are most reliable for slow and fast progressors but that long duration reliability of an intermediate progression rate may depend upon the patient's age and life expectancy at diagnosis," the study authors conclude. "It would be safe to say that an intermediate progressor may remain so for several years, but that, if the patient lives for a long time after diagnosis, the rate may increase sufficiently to affect both abilities and survival."

Next Question: Can Drugs Alter Progression Rate?

Whether these “apparently intrinsic” progression rates can be modified by anti-dementia drug treatment is a key unanswered question that must be answered before the progression rate tool can be adopted for clinical use, the study authors say.

For now, Dr. Doody said, “Physicians could tell patients that people do not progress naturally at the same rate and that their individualized progression characteristics should be taken into account in planning their treatment and in monitoring their response to therapy. They could also say that the proposed rate requires some procedures that are not yet in everyday use (a standardized estimate of duration) and that they will decide over time whether or not to incorporate these procedures into what they do based upon continued studies of its utility.”

This study also has implications for AD clinical trial design. “Currently, parallel group studies count on randomization to yield comparable placebo and treatment groups," the study authors write. "Preprogression rates are not assessed, yet imbalances across the treatment groups in this important variable could obscure or create treatment differences. Future clinical trials may benefit from gathering systematic data regarding individual symptom onset in order to perform a formal estimate of duration and to calculate preprogression rates.”
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Not Ready for Routine Use

Cognitive neurologist Alireza Atri, MD, PhD, agreed that this might be useful. Dr. Atri, who recently analyzed long-term effectiveness of combination therapy in AD (Alzheimer Dis Assoc Disord. 2008;11:209-221), is director of the Memory Disorders & Special Dementia Units at the Veterans' Affairs Geriatric Research Education and Clinical Center in Bedford, Massachusetts, and assistant in neurology at Massachusetts General Hospital/Harvard Medical School in Boston.

Asked by Medscape Neurology to comment on this study, Dr. Atri said, “I think this is an important study with several exceptional strengths, including utilization of a large, well-characterized longitudinal clinical cohort with useful measure and endpoints and analysis using sophisticated methods guided by good clinical and scientific knowledge from a leader in the field who has an uncommon perspective and expertise, working at the interface of clinical care and clinical trials and utilizing quantitative methodology to address important questions with great practical implications that, thus far, have been mostly neglected, overlooked, and/or underappreciated.”

Dr. Atri noted that although this model for predicting risk and prognosis in AD is not yet ready for routine use, it “provides a very good enhancement/upgrade from previous work and prognostication models, including some of Dr. Doody's own work, that integrate patient demographics and clinical characteristics and measures, including test scores, type and duration of symptoms, and physical exam findings, at a first clinical visit to a neurologist/physician in order to better predict the highly variable individual course we see in patients with Alzheimer's disease.”

Dr. Atri said that the study raises questions that need to be addressed further, including the effect of antidementia medications, vitamins and dietary supplements, vascular risk factors, behavioral symptoms, physical findings, especially parkinsonism and extrapyramidal signs, and genetic susceptibility factors, such as APOE-e4 status.

“We are a ways away still, but we desperately need to be wiser and more efficient in our approaches to gathering and using clinical data," Dr. Atri said. "I agree that clinical trials should heed Dr. Doody’s findings and incorporate more data and approaches like this to minimize risk of imbalances between or within treatment groups that can easily obscure signals of efficacy in Alzheimer's disease trials.”

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