FORT MYERS, FLA—Differentiating between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) remains a potentially difficult process given the overlap in clinical presentation. However, preliminary data from an ongoing University of Rochester study suggest that levels of tau in the cerebrospinal fluid (CSF) may serve as a biological marker for distinguishing the two diseases. The study, reported at the 11th Annual Meeting of the American Neuropsychiatric Association (ANPA), also revealed differences in the neuropsychiatric profile between patients with AD and those with DLB, mirroring previous findings.

"[Diagnosis] is problematic in all stages of these diseases," noted lead author Michelle Papka, PhD, an assistant professor of neurology at the University of Rochester Medical Center and codirector of the Memory and Cognitive Disorders Program at Saint Barnabas Health Care System's Institute of Neurology and Neurosurgery in West Orange, NJ. "As the diseases progress, it may become a little easier to differentiate the two, but overall I think it is difficult at any stage."

Several studies have cited fluctuations in cognitive function, parkinsonism, and visual hallucinations as characteristic features of DLB. However, these features are not uncommon in patients with AD and other forms of dementia, Dr. Papka noted, so that "on a case-by-case basis it is actually very difficult [to make a diagnosis]. Therefore, if we could identify a biological marker, we would really be making an advancement."

As part of their effort to identify such markers, Dr. Papka and colleagues have examined 11 patients with mild to moderate AD and eight with similarly staged DLB; the goal of the study is to eventually enroll 20 patients for each disorder and follow them until autopsy. All subjects undergo an extensive battery of cognitive and neuropsychiatric tests, including the Neuropsychiatric Inventory; CSF levels of tau and ß-amyloid1-42 are also being assessed, as is each subject's apolipoprotein E (APOE) genotype. Ubiquitin levels, which Dr. Papka hypothesizes should be higher in DLB patients than in those with AD, are being evaluated as well, although the results are not yet available.

In the initial sample, the two groups were similar on most demographic and cognitive measures, although patients with DLB were more likely to be dependent in their daily living skills. Mean scores for AD and DLB patients on the Mini-Mental State Examination (23.3 and 23.9, respectively) and the Clinical Dementia Rating Scale (1.0, 1.3) were consistent with the diagnosis of mild to moderate disease.

A FOURFOLD DIFFERENCE

In general, the two groups performed similarly on most cognitive measures, including tests of attention and memory. However, patients with DLB did more poorly on a test of executive functioning, which required subjects to identify whether a statement was logical. In addition, symptoms of agitation, depression, apathy, and sleep problems were more frequent and severe in the DLB group; the differences reached statistical significance despite the small sample sizes. Hallucinations and parkinsonian features were also more prominent in DLB than in AD patients, although this finding is not surprising given the inclusion of these features in the diagnostic criteria for DLB. In general, the clinical profile of the DLB patients "is suggestive of impaired functioning of basal ganglia and frontostriatal pathways," the researchers noted.

More striking, however, was the difference in tau levels between the two groups. While patients with AD had mean tau levels of more than 800 pg/mL (presumably due to the presence of neurofibrillary tangles), mean tau levels in DLB patients averaged only 200 pg/mL. Not only was this difference statistically significant, but within-group tau levels were so tightly clustered that there was no overlap in values between the DLB and AD groups. The groups did not differ in APOE genotype or CSF levels of ß-amyloid1-42.

A RELIABLE MARKER?

Will CSF tau levels allow clinicians to differentiate AD from DLB? "It's too early to make that conclusion," Dr. Papka cautioned. "The results would need to be replicated in a larger patient population and with autopsy-confirmed diagnoses. But if this finding persists through those steps, then I think that tau may be a valid and reliable biological marker for distinguishing AD from DLB."

If tau does prove a valid diagnostic marker, "the next stage would be to develop potential interventions," Dr. Papka said. Two cholinesterase inhibitors are currently approved for use in AD, she noted, and "there is reason to believe that these drugs may be more helpful in DLB patients than in AD because [DLB patients] have more healthy neurons remaining to benefit from the extra acetylcholine." Some researchers have even suggested that the 15% to 20% response rates seen with cholinesterase inhibitors in some AD trials are actually due to the inadvertent inclusion of patients with DLB. Studies are under way to test these hypotheses.

SEX DIFFERENCES IN AD: NEW SPECT FINDINGS

In other dementia news presented at the ANPA meeting, researchers at Brown University reported that the gender differences seen in patients with AD—notably the greater impairment of verbal abilities in female patients—may reflect lateralized differences in regional cerebral blood flow (rCBF). In a study using single photon emission computed tomography (SPECT), the researchers found that women with probable AD were more than three times as likely as male patients to have unilateral left hemisphere abnormalities.

"Several studies suggest that language abilities are more impaired in women with AD [than in men]," noted Brian R. Ott, MD, associate professor of medicine in the Department of Clinical Neurosciences at Brown University. "Our findings support this observation, since language is dominant in the left hemisphere in most individuals."

The study examined rCBF patterns in 174 women and 126 men evaluated for dementia or memory problems. Subjects' SPECT results were classified as having either unilateral left, unilateral right, or bilateral defects; the data were also stratified according to diagnosis (probable, possible, or unlikely AD). Dr. Ott found that in the total patient sample, unilateral left hemisphere defects were more than twice as common in women (24%) as in men (10%). Among the 165 subjects with probable AD, 26.2% of women but only 8.1% of men had unilateral left hemisphere abnormalities; unilateral right hemisphere defects were far less common but also favored women (3.9% versus 0.9%). In subjects with possible AD and those considered unlikely to have AD, the gender differences were far less dramatic, although women were still more likely than men to have left hemisphere abnormalities.

The role of these abnormal hemispheric asymmetries may extend beyond their hypothesized role in language deficits, Dr. Ott suggested. "Previous studies, including our own, suggest that men with AD are more likely to be apathetic and aggressive, while women are more likely to be depressed, emotionally labile, or psychotic. While the anatomic and physiologic substrates for these behaviors and psychiatric symptoms are no doubt quite complex, our SPECT observations raise the possibility that women with AD who have relative preservation of right hemisphere function may have better preserved insight and deficit awareness. If so, this could lead to greater distress over their condition among those women with asymmetric [defects]." To investigate these possibilities, the researchers plan to examine the cognitive and psychiatric correlates of SPECT asymmetries.

REDUCING AGITATION IN ELDERLY PATIENTS WITH DEMENTIA

In another study presented at the meeting, researchers at Dartmouth Medical School reported that olanzapine reduced symptoms of agitation in a third of elderly patients with dementia or other neuropsychiatric illness. Robert B. Williams, PhD, and colleagues examined the drug's impact on 20 geriatric patients (mean age, 76) who had agitation in addition to multiple psychiatric and medical diagnoses. Treatment was initiated with low doses of olanzapine that were increased to a maximum of 15 mg/day if necessary; symptoms were assessed via the Clinical Global Impressions (CGI) Scale before therapy and during the sixth week of treatment.

While the mean CGI score for the entire patient sample was reduced by nearly half with olanzapine therapy, from 5.7 to 2.95, individual responses varied. Seven patients (35%) showed "much improvement" while receiving olanzapine, whereas eight others (40%) had minimal improvement. The remainder showed no change or, in the case of one patient, did worse. Eleven patients showed benefits on the Abnormal Involuntary Movements Scale; adverse effects were rare.

No medication has received government approval for treating agitation in geriatric patients, and the new findings illustrate that "no single drug is reliably beneficial" in this population, according to Dr. Williams and colleagues. Nonetheless, they concluded, "the data support the clinical impression that olanzapine is safe and efficacious as a treatment for agitation in elderly patients with dementia and/or other psychiatric illnesses."

—Peter Doskoch

Suggested Reading
1. Hohl U, Tiraboschi P, Hansen LA, et al. Diagnostic accuracy of dementia with Lewy bodies. Arch Neurol.2000;57:347-351.

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