From active to apathetic

Differential diagnosis. FTD is most often mistaken for AD. In one study, FTD was found at autopsy in 18 of 21 patients who had been diagnosed with AD.⁵ Cerebrovascular dementia, Huntington’s disease, Lewy body dementia, and Creutzfeldt-Jakob disease are other differential diagnoses.

Suspect FTD if behavioral symptoms become more prominent than cognitive decline. In one study,⁶ patients with FTD exhibited:

• early loss of social awareness
  
• early loss of personal awareness
  
• progressive loss of speech
  
• stereotyped and perseverative behaviors
  
• and/or hyperorality.
  

Using these criteria, sensitivity for detecting FTD was 63.3% to 73.3%; specificity was 96.7% to 100%.⁶

The authors’ observations

Clinical evaluation for FTD should include a neuropsychiatric assessment, neuropsychological testing, and neuroimaging.

Neuropsychiatric assessment. Unlike AD, cholinergic acetyltransferase and acetylcholinesterase activity is well-preserved in FTD. Serotonergic disturbances are more common in FTD than in AD and are linked to impulsivity, irritability, and changes in affect and eating behavior.

On neuropsychological testing, memory is relatively intact. Orientation and recall of recent personal events is good, but anterograde memory test performance is variable. Patients with FTD often do poorly on recall-based tasks. Spontaneous conversation is often reduced, but patients perform well on semantic-based tasks and visuospatial tests when organizational aspects are minimized.

The MMSE is unreliable for detecting and monitoring patients with FTD. For example, some who require nursing home care have normal MMSE scores.⁴ Frontal executive tasks—such as the Wisconsin Card Sorting Test, Stroop Test, and verbal fluency examinations—can uncover dorsolateral dysfunction. Quantifiable decision-making and risk-taking exercises can reveal orbitobasal dysfunction.⁴

Neuroimaging. MRI shows left temporal lobe atrophy in patients with primary progressive aphasia; both frontal lobes are atrophic in frontal variant FTD. By contrast, the mesial temporal lobes are atrophic in AD.⁷ Frontal and anterior temporal lobe atrophy become more apparent in the latter stages of frontal variant FTD.⁴

Single-photon emission computed tomography (SPECT) using technetium and hexylmethylpropylene amineoxine can detect ventromedial frontal hypoperfusion before atrophy is evident. Order SPECT when the diagnosis is uncertain or the presentation or disease course is unusual.

Treatment: Taking aim at apathy

Donepezil, 10 mg/d, was continued to address Mr. A’s cognitive decline. Bupropion, 100 mg/d, was added to deal with his apathy and low energy. We saw him every 4 months.

Table 2

Medications shown beneficial for treating FTD

Drug	Targeted symptoms	Possible side effects
Donepezil	Cognition functions including memory	Nausea, anorexia, diarrhea, weight loss, sedation, confusion
Dopamine agonist (bromocriptine)	Behavioral disturbances*	Confusion, agitation, hallucinations
SSRIs (sertraline, fluoxetine)	Behavioral disturbances	Nausea, anorexia, diarrhea, weight loss, sexual dysfunction
Stimulants (methylphenidate)	Behavioral disturbances, somnolence	Insomnia, increased irritability, poor appetite, weight loss
Trazodone	Behavioral disturbances	Sedation, orthostasis, priapism
* Apathy, carbohydrate craving, disinhibition, irritability
SSRI: Selective serotonin reuptake inhibitor

Eight months later, Mr. A’s memory has worsened and he has lost several vital skills, such as operating the shower. His wife and daughter confiscated his car keys after he had driven on the wrong side of the road.

On follow-up, Mr. A’s gait is slower, and he has “shakiness” and mild finger clumsiness. Physical exam shows no problems and he is fully oriented, but his MMSE score (17/30) indicates further cognitive loss and he still lacks insight into his condition. Neuropsychological tests reveal:

• marked delays in processing and acting on information
  
• diminished working memory
  
• trouble understanding spatial functions
  
• decreased speech
  
• moderate to severe executive function impairments
  
• severe impairments in fine-motor dexterity, receptive and expressive language, and verbal and visual memory.
  

We also noticed several perseverative behaviors.

Bupropion alleviated Mr. A’s apathy at first, but an increase to 200 mg/d led to tremors and disrupted sleep. Bupropion was decreased to 150 mg/d; we would add a selective serotonin reuptake inhibitor (SSRI) if apathy persisted. We advised his wife and daughter to take him to adult day care and to make sure he does not drive. Follow-up interval is reduced to 2 months.

Eight weeks later, Mr. A is confused and anxious and his affect is remarkably flat, but he behaves appropriately in day care. We stopped bupropion because it did not resolve his apathy.

The authors’ observations

Treat apathy, avolition, anhedonia, social withdrawal, irritability, and/or inappropriate behaviors if these symptoms compromise quality of life for the patient and caregiver. Also try to preserve cognitive function.

Few large-scale clinical trials have addressed FTD pharmacotherapy (Table 2). In an open-label trial, 11 patients with FTD took sertraline, 50 to 125 mg/d, paroxetine, 20 mg/d, or fluoxetine, 20 mg/d. After 3 months, no one’s symptoms worsened and nine patients (82%) had reduced disinhibition, depressive symptoms, carbohydrate craving, and/or compulsions.⁵

In another open-label, uncontrolled trial, behavioral symptoms improved in eight patients with FTD who took paroxetine, up to 20 mg/d for 14 months. Baseline global performance, cognition, and planning scores remained stable, but attention and abstract reasoning were decreased. Side effects were tolerable.⁸