Pick disease

Definition

Pick disease is a rare neurodegenerative disorder that affects pre-senile adults. It is characterized by atrophy of the tissues in the frontal and temporal lobes of the brain and by the presence of aggregated tau protein that accumulates in Pick bodies in the neurons of the affected regions. Named for the German physician who studied patients who with the disease, Pick disease is grouped together with other non-Alzheimer's dementias, under the category of frontotemporal dementia (FTD), which is now the preferred term for Pick disease. FTD is classified by the Diagnostic and Statistical Manual of Mental disorders, Fourth Edition (DSM-IV) as a Dementia Due to Other General Medical Conditions.

Description

The disease is named after the German physician, Arnold Pick, but it was not named by him. German psychiatrist and pathologist Alois Alzheimer named the illness in 1923 following post-mortem examinations of Pick's patients. One of these patients was a 71-year old man who died following progressive mental deterioration. His autopsy revealed atrophy of the frontal cortex. This feature is seen nearly universally among patients with FTD. The disease is also referred to as frontotemporal lobar degeneration, progressive aphasia and semantic dementia.

The disease may be inherited through mutations associated with chromosomes 17, 9 and 3, or develop sporadically.

Demographics

Alzheimer's disease and other non-Alzheimer's dementias are much more common than FTD. The average age of onset is 54 years, and most cases arise between the ages of 40 and 60. Few diagnoses are made in individuals older than 75 years of age, but FTD has been diagnosed in people as young as 20.

At autopsy, 8–10% of all cases of pre-senile dementia meet the diagnostic criteria for FTD disease, although some estimates put the incidence of the disease in the United States at as much as 15% of individuals with dementia. Epidemiological studies have estimated that FTD affects as few as one in 100,000 people. The familial incidence of FTD disease may be higher in Europe; a Dutch study indicated a prevalence of 28 per 100,000 individuals. The incidence increases with age, affecting 10.7 per 100,000 in the 50–60-year age range and 28 per 100,000 in the 60–70-year age range. FTDs account for about 3% of dementias. One-fifth to one-half of individuals diagnosed with FTD has a first-degree relative that has also been diagnosed with dementia.

Discrepancies in neuropathological diagnosis have led some groups to suspect that its incidence is much greater than previously indicated. There is some suggestion that as imaging techniques improve the disease is becoming more frequently recognized in younger patients.

Causes and Symptoms

The molecular cause of Pick disease are a series of mutations linked to chromosomes 17, 9 and 3. One of these mutations is located on the long arm of chromosome 17 (17q35) at the locus known to hold the gene for the tau protein, and accounts for between 9–14% of all FTDs. This gene has also been implicated in Alzheimer's disease. Mutations on chromosomes 9 and 3 have not yet been identified. The gene encodes a scaffold protein that maintains the shape of brain neurons by stabilizing cellular microtubules. Mutations to the tau protein cause it to form clumps and limit its ability to assemble microtubules. The aggregates that form in the neurons of the affected regions of the brain are called Pick bodies. As in Alzheimer's disease, the tau protein is hyperphoshorylated in FTD.

The brain regions most severely affected by the tau mutation are the frontal and temporal lobes. These parts of the brain control reasoning and judgment, behavior and speech. In addition to the accumulation of tau protein, these regions atrophy over the course of the disease.

The clinical features of frontotemporal dementia includes changes in the patient's behavior, and may include additional emotional, neurological and language symptoms. Patients show poor reasoning, judgment and mental flexibility, but memory may not be affected.

Initially, patients become disinhibited and restless, and lose the ability to control their actions or to chose socially acceptable behavior. As the condition progresses, repetitive and ritualistic behaviors, such as hand rubbing or clapping, develop. Hyperoral behaviors are often associated with this phase, and may include overeating, hoarding or fixations on specific foods.

Later, apathy, uncaring and unsympathetic attitudes, and mood changes may develop. The patient may also develop language difficulties, including aphasia and reduced reading and writing comprehension, dysarthria and echolalia. Most patients with FTD eventually become mute.

Some patients with FTD will develop ALS, also known as Lou Gehrig's disease, parkinsonian, or psychiatric symptoms.

Diagnosis

Frontotemporal dementia is commonly misdiagnosed as Alzheimer's disease, because of the similarity in their clinical courses. However, FTD should be suspected if Alzheimer's-like symptoms are present in patients of a pre-senile age. Patients show early declines in social conduct, emotional expression and insight. Conversely, perception, spatial skills, memory generally remain intact or well preserved. The following behavioral disorders, altered speech and language, and physical signs also support FTD diagnosis.

The diagnostic criteria for FTD were reviewed and updated at a consensus conference in 1998. The criteria comprising the clinical profile are divided into two groups: core diagnostic features, which must be present, and supportive diagnostic features, which are present in many patients with FTD. Changes to character and altered social conduct are prominent features of the disease and prevalent at all stages.

Core Diagnostic Features

• insidious onset and gradual progression
• early decline in social conduct
• early impaired regulation of personal conduct
• early emotional blunting
• early loss of insight

Supportive Diagnostic Features

• altered behavior: decline in hygiene, mental rigidity, hyperorality and dietary changes, stereotyped behavior
• speech and language: less spontaneous and limited speech, sterotypy, echoalia, mutism
• physical signs: primitive reflexes, incontinence, rigidity and tremor, low blood pressure, frontal or anterior temporal abnormality

Neuropsychological tests reveal a lack of verbal fluency, ability to abstract and limited executive function. Because of the clinical similarities between FTD and Alzheimer's disease, it is difficult not to misdiagnose FTD as Alzheimer's disease. However, one study found that a word fluency test may be the best method of differentiating FTD from Alzheimer's disease.

Neuroimaging studies, such as CT scans , will generally show atrophy and reduced blood flow to the frontal and anterior temporal lobes, but will not be conclusive in all cases. Several studies suggest that functional imaging with single photon emission CT or positron emission tomography may be better at identifying FTD in its early stages, showing decreased blood flow to the frontal and temporal lobes. Electroencephalograms (EEG) may show non-specific changes in electrical activity, but are usually normal.

Like Alzheimer's disease, a diagnosis of FTD can be confirmed with autopsy. Gross inspection reveals significant atrophy of the cortex and the white matter of the frontal and anterior temporal lobes. Neuronal inclusions called "Pick bodies" are characteristic of the disease, but not always present or necessary for diagnosis. Pick bodies are cytoplasmic silver-staining masses made up of 10-to 20-nm filaments. Other investigators have further classified the pathology into three distinct subsets.

• FTD Type A: lobar atrophy with swollen poorly staining neurons and Pick bodies
• FTD Type B: lobar atrophy with swollen poorly staining neurons, but no Pick bodies
• FTD Type C: lobar atrophy, lacking swollen poorly staining neurons and Pick bodies

Differential Diagnosis

FTD is rare and other diseases, such as hydrocephalus , tumors, hypothyroidism, vascular dementia, and vitamin B12 deficiency should be ruled out. However, an accurate and rapid diagnosis saves well-intentioned but futile attempts to treat for other conditions such as depression or mania.

Treatment

There is no known treatment for frontotemporal dementia and no way to slow the progression of the disease. Treatment focuses on patient care, symptom management, monitoring symptom progression and providing assistance with daily activities and personal care.

During the early stages of the disease speech therapy, occupational therapy, and behavior modification may improve day-to-day functioning and improve autonomy. Disorders that contribute to confusion, such as heart failure, hypoxia , thyroid disorders, and infections should be treated appropriately.

Some medications, such as anticholinergics , analgesics, cimetidine, central nervous system depressants, and lidocaine may heighten confusion and non-essential ones should be discontinued. In addition, it is inadvisable to prescribe drugs used to treat Alzheimer's disease, as many may increase agitation and aggressivity.

As the disease progresses, a patient's capacity to care for himself will decline and he will become more dependent on caregivers. Around the clock care may be required in the most advanced stages or the disease; family members should consider hiring an in-home caregiver or consider institutional care to meet the patient's needs.

Clinical trials

As of early 2004, two NIH sponsored clinical trials were recruiting patients with frontotemporal dementia. Both were operating out of the National Institute of Neurological disorders and Stroke (NINDS) in Bethesda, MD. The Memory and Aging Center at the University of California, San Francisco is also conducting several diagnostic and genetic studies of FTD. Contact information is listed under resources, below.

Prognosis

Patients with frontotemporal dementia have a poor prognosis. The disease is much more aggressive than Alzheimer's disease. Total disability occurs early after diagnosis. Most patients die within two to 10 years after diagnosis, with median survival at three years from diagnosis and six years after symptom inception. Death is usually due to infection or from body system failure.

Resources

BOOKS

Goldman, L., and J. C. Bennett, eds. Cecil Textbook of Medicine, 21st ed. W. B. Saunders Company, 2000.

PERIODICALS

Coleman, L. W., K. B. Digre, G. M. Stephenson, et al. "Autopsy-Proven, Sporadic Pick Disease With Onset at Age 25 Years." Archives of Neurology 59 (May 2002): 856–859.

Hodges, J. R., R. Davies, J. Xuereb, et al. "Survival in frontotemporal dementia." Neurology 61 (2003): 349-354.

Gydesen, S., J. M. Brown, A. Brun, et al. "Chromosome 3 linked frontotemporal dementia (FTD-3)." Neurology 59 (2002): 1585-1594.

Munoz, D. G., D. W. Dickson, C. Bergeron, et al. "The Neuropathology and Biochemistry of Frontotemporal Dementia." American Neurological Association (June 23, 2003).

ORGANIZATIONS

The National Institute of Neurological Disorders and Stroke (NINDS). 9000 Rockville Pike, Bethesda, MD 20892. (800) 411-1222. prpl@mail.cc.nih.gov.

UCSF Memory and Aging Center. 350 Parnassus Avenue, Suite 706, San Francisco, CA 94143-1207. (415) 476-6880; Fax: (415) 476-4800. <http://memory.ucsf.edu>.

Pick's Disease Support Group. <http://www.pdsg.org.uk/>.

The Association for Frontotemporal Dementias. <http://www.ftd-picks.org>.

Hannah M. Hoag, MSc