April 8, 2010 — Subjective memory impairment (SMI) or mild deficits in memory that may, or may not, worry an individual appear to predict progression to more advanced cognitive impairment and dementia, new research suggests.

A study by investigators at the University of Bonn, Germany, shows that individuals who had memory impairment with concern at the beginning of the study were at the highest risk for conversion to any dementia, or Alzheimer's disease (AD)–related dementia, at either 18-month or 5-year follow-up.

"Subjective memory impairment without worry was independently associated with increased risk for dementia," the study authors, led by Frank Jessen, MD, write. "This risk was roughly doubled by the presence of subjective memory impairment–related worry."

In addition, the results showed that having memory impairment at the beginning of the study and mild cognitive impairment (MCI) at the first follow-up increased the risk for conversion to any dementia or dementia related to AD at the second follow-up; these individuals had the greatest risk of developing dementia.

"Our data support the concept of SMI as a pre-MCI condition in AD. Furthermore, the risk increase associated with SMI-related worry indicates that this early memory decline in AD may vary and may be more subjectively dramatic than memory decline related to other factors such as normal aging even among subjects with equal performance on testing," the investigators write.

The study is published in the April issue of the Archives of General Psychiatry.

Longitudinal, Multicenter Study

The researchers used the German Study on Aging, Cognition and Dementia in Primary Care Patients of the German Competence Network Dementia, a longitudinal investigation of subjects initially without dementia. The subjects, recruited at 6 study sites in Germany, were 75 years or older.

Trained psychologists interviewed subjects at home. To assess SMI, subjects were asked whether they felt as though their memory function was worsening and whether this was a source of worry.

Subjects also completed a battery of neuropsychological tests, including the Structured Interview for Diagnosis of Dementia of Alzheimer’s Type, Multi-infarct Dementia and Dementia of Other Etiology (SIDAM).

The SIDAM interview, including the SIDAM cognitive (SISCO) score (which includes memory and nonmemory domains, such as orientation, language, and perception), and the Geriatric Depression Scale were performed at baseline and 1.5- and 5-year follow-up.

MCI was defined as 1-SD performance below age- and education-adjusted normal ranges in any of 4 SISCO score domains, the absence of dementia, and lack of impact on activities of daily living (ADL). Dementia, which requires cognitive impairment and impaired ADL, was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria.

MCI has an annual conversion rate to dementia of 10% to 20%.

From a baseline population of 2415 subjects, researchers tested a variety of different sequences of SMI and MCI at follow-up with regard to the prediction of dementia, including

• No SMI at baseline and no MCI at first follow-up;
• SMI at baseline and no MCI at first follow-up;
• No SMI at baseline and MCI at first follow-up; and
• SMI at baseline and MCI at first follow-up.

The researchers found that SMI with worry (P < .001) and SMI without worry (P = .02) were associated with increased risk for dementia at first and second follow-up.

Age (P = .003), ApoE4 genotype (P = .04), and baseline SISCO score (P < .001) were other significant risk factors. Sex, education, and Geriatric Depression Scale score were not associated with increased risk for dementia.

Incidence dementia in AD at follow-up 1 or 2 was associated with SMI with worry (P < .001), SMI without worry (P = .007), age (P = .003), and baseline SISCO score (P < .001). Sex, education, depression score, and ApoE4 genotype were not associated with incidence dementia.

The sensitivity and specificity for conversion to dementia in AD among subjects having SMI with worry at baseline were 69.0% and 74.3%, respectively

Subjects without SMI at baseline and without MCI at 18-month follow-up served as the reference category in a second analysis. The greatest risk for dementia was in subjects with SMI at baseline and with MCI at first follow-up.

At 5-year follow-up, the risk for conversion to any dementia was increased by an odds ratio (OR) of 8.92, whereas the risk for conversion to dementia in AD was increased by an OR of 19.33.

Worry Doubles Risk

The greatest risk for conversion to any dementia (OR, 29.24) was in subjects with SMI at baseline and with amnestic MCI at first follow-up. The risk was even greater (OR, 60.28) for conversion to dementia in AD at the second follow-up period.

The hazard ratio (HR) of conversion at follow-up 1 or follow-up 2 for SMI without worry at baseline was 1.83 (95% confidence interval [CI], 1.12 – 2.99) for any dementia and 3.04 (95% CI, 1.36 – 6.81) for dementia in AD. For SMI with worry at baseline, the corresponding HRs were 3.53 (95% CI, 2.07 – 6.03) for any dementia and 6.53 (95% CI, 2.82 – 15.20) for dementia in AD.

"Subjective memory impairment without worry was independently associated with increased risk for dementia. This risk was roughly doubled by the presence of subjective memory impairment–related worry," the study authors note.

Overall, these results provide "strong empiric support" for the recently suggested model of SMI as a pre-MCI syndrome in the clinical manifestation of AD, say investigators.

"The present data contribute to the current efforts toward a predementia diagnosis of AD. We suggest that biomarker studies (such as magnetic resonance imaging, positron emission tomography, and cerebrospinal fluid investigations) should address not only MCI but also earlier SMI as performed in some studies," they write.

They added that future evaluation of SMI in conversion to dementia may identify specific profiles of SMI that are particularly predictive.

Red Flag

Commenting on the findings for Medscape Psychiatry, Ronald Petersen, MD, PhD, director of the Mayo Clinic Alzheimer’s Disease Research Center, Rochester, Minnesota, and a member of the American Academy of Neurology, said subjective concerns on the part of patients are very important, especially now that researchers are investigating earlier stages of the disease process.

Although not every patient with a subjective concern is necessarily on the road to MCI and AD, such complaints should not be discarded or chocked up to normal forgetfulness in aging, said Dr. Petersen.

"Subjective memory concern raises a flag that clinicians should not ignore. It doesn’t mean you have to launch a million dollar workup on the patient, but don’t ignore it; explore it a little bit further, see what kinds of memory concerns the patient has, and then if you think this might be a genuine memory problem, then go ahead and pursue it with further evaluation," he said.

Assessing the element of worry may be a bit trickier, said Dr. Petersen. "It behooves the clinician to take it a step further and not only inquire about the type of memory impairment, the quality, but also look at things like anxiety, depression, and melancholy," which may, in fact, explain some subjective memory impairment.

The study authors and Dr. Petersen have disclosed no relevant financial relationships.

Arch Gen Psychiatry. 2010;67:414-422.