LA JOLLA, CALIF— Given the overlap in cognitive and behavioral symptoms, diagnosing the various non-Alzheimer’s disease dementias can be a difficult process. This is certainly true for frontotemporal dementia (FTD), although the challenge of identifying FTD is perhaps exceeded by the challenge of keeping track of the ever-shifting changes in terminology and diagnostic criteria. In the past eight years, at least three different sets of criteria, each featuring a somewhat different taxonomy, have been published. (Part of the problem is that FTD is a clinical syndrome rather than a single disease with a unitary pathology.)

Nonetheless, navigating through the potential confusion to obtain a correct diagnosis is important, as the course, presentation, and treatment of FTD differs from that of other dementias. At the annual meeting of the American Neuropsychiatric Association, Tiffany Chow, MD, an Assistant Professor of Clinical Neurology at the University of Southern California in Los Angeles, described the key manifestations of FTD and suggested tips that can aid diagnosis. She also offered advice on how to treat the behavioral and cognitive components of the syndrome.

FTD IN A NUTSHELL

As the name suggests, patients with FTD have dysfunction of the brain’s prefrontal regions, temporal lobes, or both. In many cases, there may be significant atrophyæeasily visible with magnetic resonance imagingæspecific to the affected regions; in other instances, the abnormalities may be functional rather than structural. Mild ischemic white matter changes consistent with normal aging may be present as well. Although some patients have Pick bodies, most do not. It is controversial whether those with semantic deficits have atrophy of the anterior hippocampus to the degree seen in Alzheimer’s disease, Dr. Chow noted.

The frontal-subcortical circuits affected by FTD are important in self-monitoring (orbitofrontal areas), motivation (the anterior cingulate), and executive functions (the dorsolateral prefrontal cortex); many patients have impairment to some degree in all three of these areas. Patients with a predominantly behavioral clinical presentation may have subjective and/or objective memory disturbances but do not have an amnestic syndrome, and they generally remain oriented to time and place.

When only one temporal lobe is involved, the presentation depends on which hemisphere is affected. Patients with primarily left temporal lobe dysfunction typically behave in a socially appropriate manner but present with aphasia and decreased facial expressiveness; these patients are often diagnosed as having semantic dementia. These are the FTD syndrome patients who are most like Alzheimer’s disease patients, because they can also suffer short-term memory loss. Those with predominantly right temporal abnormalities are more likely to exhibit antisocial behavior, bizarre dress, apathy, and hyperorality (patients may routinely put inedible items in their mouths, much as young children do).

EVOLVING CRITERIA

Given the wide range of behaviors mediated by the frontal and temporal lobes, it is not surprising that the process of determining the core diagnostic features of FTD has been an ongoing endeavor. The Lund-Manchester criteria, published in 1994,1 required the presence of at least two of the following features: loss of personal awareness, strange eating habits, perseveration, and mood change. In addition, patients had to have one or more of the following: frontal executive dysfunction, reduced speech, and preserved visuospatial ability. (In contrast, patients with Alzheimer’s disease generally develop impaired visuospatial ability as memory declines.) Finally, the authors of the criteria cited several important supporting features, including onset before age 65, a family history of FTD, early urinary incontinence, motor neuron disease, and (in the late stages) akinesia, rigidity, and tremor.

The criteria published by Neary and colleagues four years later2 incorporated most of the above features and added some others. However, the authors subdivided patients into three separate clinical presentations: frontotemporal dementia (characterized primarily by personality change and disordered social conduct), progressive nonfluent aphasia (in which patients have difficulty with initiation but not comprehension of speech), and semantic aphasia (distinguished by impaired understanding of word meaning and/or object identity). The general term frontotemporal lobar degeneration was used to refer to any of the three syndromes.

Although both the Neary and Lund-Manchester criteria emerged from consensus meetings, their purpose was more to establish a common set of standards for researchers than to aid clinical diagnosis. Thus, a third set of criteria, developed by the Work Group on Frontotemporal Dementia and Pick’s Disease, was published last year with the specific aim of helping clinicians diagnose FTD.3 The criteria, listed in the box at right, are considerably simpler than the Neary criteria and lump together all patients under the umbrella of FTD, although the authors did note that patients will have either a “behavioral presentation” or a “language presentation.” (Detailed descriptions of these “core clinical phenotypes” were not included in the formal criteria but appeared elsewhere in the paper.) The work group summarized the diverse pathological abnormalities that have been observed in FTD but opted not to incorporate these findings into the descriptions for the two phenotypes because neuropathology and clinical features do not always correlate.

In summary, Dr. Chow said, clinicians should consider any of the following to be a “red flag” for possible FTD in a patient with dementia:

• onset in the sixth decade (the mean age of onset among Dr. Chow’s patients is 56);

• onset of disinhibited or criminal behavior;

• loss of social awareness. This, Dr. Chow said, “is the [symptom] that your receptionist will tell you about”—the patient who, for example, might come up to the receptionist’s window and not leave;

• compulsive behavior;

• distractibility or impulsivity (these are also seen in Alzheimer’s but are more characteristic of FTD);

• disordered mood (usually depression but sometimes euphoria);

• stereotyped speech.

Moreover, Dr. Chow added, patients tend to be “environmentally dependent”—during an office visit “they can’t leave the stuff on your desk alone.”

TREATMENT STRATEGIES

Several biochemical abnormalities have been identified in patients with FTD. These include loss of serotonin receptors in the frontal and temporal cortices and the brainstem, and low cerebrospinal fluid levels of the homovanillic acid. Similar abnormalities are also seen in Alzheimer’s disease. Compared with Alzheimer’s, however, FTD results in higher levels of 4-hydroxy-3-methoxy-phenylglycol, and there are no cholinergic deficits.

Given the present lack of disease-modifying interventions, the treatment of FTD is necessarily symptomatic. Unfortunately, not all of the behavioral and cognitive problems respond equally well to pharmacotherapy.

For example, because FTD patients with executive dysfunction in some ways resemble individuals with attention-deficit/hyperactivity disorder (ADHD)—both groups have difficulty with attention and concentration—some investigators have hypothesized that alpha-2 agonists, which are helpful in ADHD, might be effective in treating FTD. However, findings from a recent open-label guanfacine study did not reveal impressive benefits. The 11 participants, all with moderate to advanced FTD, received 1 mg qam for most of the four-month trial; the dose was lower for the first two weeks of the study (0.5 mg qam) and higher for the final month (1 mg bid). The results, presented by Dr. Chow in a poster at the neuropsychiatry meeting, failed to show objective benefits on any cognitive measure, though she noted that “there were some subjective reports of improvement that are encouraging.” The next step, she added, “is to try higher doses, to use different instruments to monitor efficacy, and to get other centers involved in placebo-controlled crossover trials.”

Because patients with frontotemporal dementia do not have cholinergic abnormalities, medications targeting this neurotransmitter system, such as cholinesterase inhibitors, are not effective. Patients with deficits in expressive language (ie, those classified by the Neary criteria as having non-fluent primary progressive aphasia) who are treated with amantadine show subjective increases in fluency for three to six months, although the improvement on objective measures has not been compelling. Some patients may respond to bromocriptine, Dr. Chow suggested, but she noted that the drug has not been evaluated in a double-blind trial and that patients generally do not tolerate it as well as they do amantadine.

Depression can be common in patients with primary progressive aphasia, perhaps in part because patients continue to retain a good degree of self-awareness; this insight may foster reactive mood changes. Unfortunately, Dr. Chow said that she has had little success in treating this problem with selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants.

Nearly all patients with FTD will exhibit obsessive-compulsive behavior at some point during their illness, and these behaviors are much more responsive to treatment. Dr. Chow has found the SSRIs to be very useful for reducing obsessive-compulsive symptoms; she particularly favors paroxetine, starting at 10 mg/d and increasing the dosage if necessary to 20 or 40 mg/d. Sertraline and citalopram are reasonable alternatives. SSRIs may also be helpful for reducing anxiety and sexual disinhibition.

For agitation or psychosis, Dr. Chow advises against the use of typical neuroleptics, which can worsen motor symptoms. She said she has found the atypical antipsychotics to be useful, particularly quetiapine, which she starts at 25 mg/d and increases as needed up to 50 mg/d. Risperidone is also an option, but dosages higher than 1 mg/d may produce parkinsonism, Dr. Chow noted. Valproic acid can be a useful adjunct to the atypicals; trazodone is worth considering if sundowning is a problem. Agitation and confusion may be worsened by benzodiazepines.

Insomnia is often refractory in patients with FTD and may be related to the involvement of serotonergic neurons in REM sleep. The effects of zolpidem and zaleplon in this population are transient at best, according to Dr. Chow, but trazodone is sometimes helpful. If the patient is receiving an atypical antipsychotic for agitation or other reasons, a bedtime dose may provide a “bonus” of improved sleep.

The motoric disturbances that tend to appear in the later stages of FTD respond to levodopa/carbidopa in some cases; dopamine agonists can be helpful but the clinician should be alert for the possibility of psychosis.

Finally, behavioral interventions may be helpful for patients who are compliant and have good cognitive function, though any benefits will likely be lost as the disease progresses. One investigator has reported success using behavioral interventions to reduce obsessive-compulsive symptoms, and patients with aphasia may benefit from learning Amerind sign language.

Dr. Chow’s review of the diagnosis and treatment of FTD will be published in an upcoming issue of the Journal of Neuropsychiatry and Clinical Neurosciences.

—Peter Doskoch

Suggested Reading
1. The Lund and Manchester Groups. Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry. 1994;57:416-418.
2. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51:1546-1554.
3. McKhann GM, Albert MS, Grossman M, et al. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol. 2001;58:1803-1809.

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