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Depression, subcortical dementia and normal aging: all three may have similar neurobehavioral manifestations. So how does a clinician make a differential diagnosis?

Speaking at the recent U.S. Psychiatric & Mental Health Congress, Wilfred G. Van Gorp, Ph.D., associate professor and director of the neuropsychology program at Cornell University, offered some guidelines. He began by reviewing the neuropsychological changes associated with normal aging. Crystallized intelligence-those verbal abilities that deal with long-held knowledge-tends to be resistant to change following any kind of brain perturbation or central nervous system (CNS) stressor, he said. This remains relatively stable until a person reaches their mid-60s. In contrast, fluid intelligence-psychomotor speed and nonverbal, often visuospatial tasks-is more susceptible to CNS changes. These nonverbal abilities, typically those that are timed and involve psychomotor speed, have a more precipitous decline, beginning after age 40. The fragility of certain cognitive tasks, as measured by the timed performance subtests on IQ tests, has been called the classic aging pattern, Van Gorp said.

He presented study data showing that changes in the frontal part of the brain and the subcortical structures are likely responsible for this cognitive decline of aging. To further explore this pattern, he and his colleagues compared normal elderly individuals to patients with AIDS dementia complex. They reported a remarkable similarity of both pattern and level of performance on every neuropsychological test. The normal elderly, who had an average age of around 75, resembled, in both level and pattern of cognitive functioning, the 35- and 40-year-old patients with HIV dementia.

What does this mean? When evaluating an elderly patient, the clinician first has to determine whether the symptoms are caused by normal aging. This means embarking upon a battery of neuropsychological tests with norms to compare with other people in the same age group. The clinician experienced in working with older adults can also give a mental exam and compare to see if it is a deviation from normal aging or not.

Before surveying the literature about the cognitive manifestations of depression and comparing these manifestations to dementia symptoms, Van Gorp stressed the difficulty of interpreting that literature. The majority of the cognition and depression studies conducted around the world have looked at depressed patients who have neurologic illnesses, such as Parkinson's disease, stroke or progressive supranuclear palsy, any of which may have caused the depression. Ruling those out leaves only 13 qualified studies that focus solely on cognition and depression.

Van Gorp pointed out three other issues to consider when reviewing the literature:

The first is the severity of the illness (dementia and depression). Severity of depression tended to be a key factor in whether or not a study found that a major depressive disorder had a significant impact upon cognition. Studies in which the subjects were inpatients almost always found significant neurocognitive deficits, whereas studies in which subjects were outpatients often failed to find an effect.

Second, results are affected by the instrument used to measure depression. Van Gorp's group conducted its own study (unpublished), that looks at elderly individuals with syndromal depression.

"We looked at people who were either high or low on the Beck Depression Inventory [BDI] and compared their performance on a battery of neurocognitive tests. We found numerous differences on measures of memory, psychomotor speed and attention," he said.

When they repeated the study using the same subjects assessed with the Geriatric Depression Scale (GDS), which asks patients their view about themselves and their future, the researchers found absolutely no relationship between the measure of depression and cognitive test performance.

Third, sensitivity and breadth of examination are important.

"The study that tends to separate dementia and depression based on some of the more superficial mental status exams is in for a lot of trouble because, in a sense, we get what we pay for," Van Gorp said. "You can't administer a five-minute screening test to examine a complex question. I think that clinicians who don't work in this area have the illusion that it's an easier question than it is."

The Studies

Van Gorp cited a recent meta-analytic study that compared depressed subjects who had nonneurologic illnesses and looked at how depression impacts cognition. This study was superior to other meta-analytic studies, he said, because only patients with non-CNS illnesses were used, and because the size of the effect and the variability across studies were factored in. The study offered an empirically based opinion on how depression affects cognition. He described some of the results.

Using inattentiveness as a key index of depression is a mistake because patients with depression did not largely have attentional disturbance. "This goes against the convention that depressed patients are uniformly inattentive," he said.

Verbal fluency is a slightly better indicator when trying to separate depression from normal aging; 10% of depressed subjects were in the clinically impaired range as compared with control subjects. Verbal learning-the acquisition of new information-was impacted in 14.5% of the depressed patients as compared to control subjects. In nonverbal learning acquisition, about 15% were impaired.

Almost 20% of the depressed patients scored in the impaired range on tasks of scanning and visual motor tracking relative to normal controls. Visual-spatial abilities showed a high degree of variability. Many clinicians have been taught that depressed patients could draw but that demented patients could not; that a patient who could not copy a complex figure had dementia and not depression. "That has not been borne out in the literature," Van Gorp said. "In fact, 15% of the depressed patients scored in the impaired range relative to the normals."

In memory recall tests, 15.5% of the depressed individuals scored in the impaired range, and their rates of forgetfulness were twice as high as control subjects.

Mental inflexibility proved to be a key factor. If there's one cognitive defect that is characteristic of people with major depression, said Van Gorp, it is the disturbance of mental flexibility.

Half of all depressed subjects scored in the impaired range relative to normal controls, showing great difficulty in tasks of mental flexibility, perseveration, set shifting and response inhibition. This finding was consistent with the findings of imaging studies, which revealed altered metabolic or blood-flow activity in the frontal lobes, particularly the left, of patients with syndromal depression.

In drawing conclusions from these various studies about depression, Van Gorp said, "There's little effect, surprisingly-and this goes contrary to our clinical intuition-on measures of attention and concentration. We see the largest effect on tasks of mental flexibility and frontal lobe functions, and an intermediate effect on many other cognitive tasks, such as memory. But the results do indicate clear deficits in a subgroup of depressed individuals, ranging from about 10% to 15% of depressed individuals."

What if, even after testing, it looks like a patient has all three: depression, dementia and normal aging?

"In cases where there is no clear-cut differential between a subcortical dementia, let's say, and depression affecting cognition, the rule is: treat and reevaluate," he said.

To see whether all elderly, depressed patients looked alike on neuropsychological testing or whether there were identifiable subgroups which might help clinicians recognize patterns, Van Gorp and colleagues conducted a study.

In the study were 111 elderly depressed subjects in their mid-70s, whose age of onset ranged from 40 to 60. They had no prior history of psychiatric disorder that could account for their disturbance. After administering neuropsychological tests for memory, frontal lobe function, depression and attention, the researchers performed a cluster analysis to look for subgroups and found three: those without neurocognitive impairment, those who had a frontal lobe presentation with a common memory impairment, and those with memory impairment alone.

The group least cognitively impaired had the youngest age of onset and the lowest level of disability. Remember, Van Gorp explained, that depression does not necessarily mean cognitive impairment.

The second group scored low on tasks of frontal lobe function and memory-the prototypal profile of depression. They had the latest age of onset and the greatest level of disability.

"These are the patients who come into your office and say, 'Help me.' The family comes in and says, 'I think she may be demented. She's not doing anything; she's not getting up off the couch.' These people have the greatest level of disability and this may be simply a reflection of their depression," Van Gorp said.

A third group, which had the highest levels of depression, but not the highest levels of disability, had memory impairment alone. Van Gorp plans on conducting a longitudinal study of this group and in the meantime hypothesizes that they are the ones who, over time, are at highest risk for irreversible dementia-ultimately Alzheimer's disease. "Could it not be," he queried, "that one reason it's hard for us as clinicians to differentiate between dementia and depression is because, in time, the depression in some older adults could be the first sign of what will emerge as a full-blown dementia syndrome?"

Three studies that have already looked at dementia and depression show that older adults with major depression are between two and three times more likely, over a three-year period, to develop Alzheimer' disease or another irreversible dementia. For this reason, follow-up is essential.

To Simplify and Summarize

Patients with cortical dementia (irreversible dementia) have normal speech volume but their language is impaired by a transcortical sensory aphasia-like syndrome, where they have severe anomia-the inability to name objects-and great circumlocution. Their comprehension, however, is relatively preserved. In terms of memory function, patients with cortical dementia have a defect in both recall and recognition; in subcortical dementia, recall is impaired while recognition is relatively intact. These patients cannot learn new information-every meeting with the patient is a new experience for the patient-and their cognition is impaired in many spheres. They often will have normal motor function and gait. They are cheerfully indifferent to their condition.

Patients with depression (reversible dementia) can be hypophonic but will have normal language. They have a forgetful memory pattern but can learn new information. They exhibit differential frontal lobe impairment, but not across all cognitive domains. They show psychomotor slowing and poor performance on effortful tasks. And they are pessimistic and brooding because they are painfully aware of their cognitive failures.

Differentiating depression from dementia in the elderly is extremely complicated, Van Gorp concluded: "I believe that any clinician attempting to put an imprimatur upon a patient, and write on their forehead 'pseudo dementia' or 'dementia syndrome of depression'-without a follow-up over time-is irresponsible and perhaps below the standard of care, and possibly will be wrong. When in doubt, treat."