Pick Disease 

Updated: Nov 18, 2019
Author: Monica Saini, MBBS, MD; Chief Editor: Jasvinder Chawla, MD, MBA 

Overview

Background

Pick disease (ICD-10 code G31.01)[1] is now best understood as a neuropathological construct presenting with either of two well-recognized phenotypic forms of cognitive dysfunction: behavioral variant frontotemporal dementia (bvFTD; 60–80%) and  semantic variant of primary progressive aphasia (svPPA). (See Presentation and Workup.)[2, 3]

Pick disease is a taupathy. Taupathies are syndromes that occur secondary to deposition of  abnormal forms of tau protein in the brain. Various taupathies can be differentiated based on preferential areas of brain involvement and /or involvement of specific cells/cellular compartments. The frontotemporal subtypes include: 

  1. Picks disease
  2. corticobasal degeneration (CBD)
  3. progressive supranuclear palsy (PSP)
  4. globular glial tauopathy (GGT)
  5. argyrophilic grain disease (AGD)
  6. primary age-related tauopathy (PART)

The majority of bvFTD patients mainly have FTLD-tau pathology (42%) rather than the other FTD proteinopathies (TDP-43, FUS) [32], with pick disease being the the most common FTLD-tau subtype (55–70%). Though previously considered rare, Picks disease is reported in up to 30% of  frontotemporal dementia (FTLD)-tau autopsy cases.[4]   

In contrast, most patients diagnosed with svPPA have TDP-43 pathology (70–90%); amongst the rest, half have FTLD-tau pathology, including PiD.[5]

Histopathological characteristics

Pick disease is morphologically distinct from other FTLD-tau subtypes and is characterized by presence of Pick bodies.

Histopathological findings include:

  1. Pick bodies. These are 3-repeat tau-immunopositive bodies predominantly located in granular neurons in the hippocampal dentate gyrus, hippocampal CA1 pyramidal neurons, and layer II of frontal and temporal cortices. Pick bodies are argyrophilic on some silver stains (modified Bielschowsky silver), but are not observed with Gallyas silver. [6]
  2. Marked neuronal loss and cortical atrophy, especially in right ventral and dorsal frontal and anterior temporal regions. [7]
  3. Ramified astrocytes, characterized by tau-immunopositive deposits in the proximal astrocytic processes usually localized to one side of the astrocyte. However, these are not a hallmark neuropathological feature of Pick disease.
  4. Other features, which are not pathognomic, include presence of balloon neurons, threads and oligodendroglial globular cytoplasmic inclusions and coiled bodies.

Pick disease pathology (majority with bvFTD) has been staged as follows:

  • Phase I: limbic and frontotemporal involvement
  • Phase II: involves subcortical structures including basal ganglia, thalamus and brainstem
  • Phase III: involvement of the primary motor cortex and precerebellar nucle
  • Phase IV: widespread pathology including the primary visual cortex [8, 9]

See Figure 1 in Boxer et al (2013) for an illustration of the neuropathologic subtypes of Pick disease/FTD.[10]

Etiology

Pick disease is a taupathy, with accumulation of abnormal tau protein in the brain.

Tau protein is a highly soluble microtubule-associated protein (MAPT) and promotes microtubule polymerization and stabilization. Tau protein in the brain is heterogeneous, due to alternative splice forms and post-translational modifications. “3R” and “4R” tau refer to the products of the alternative splicing of the MAPT gene (chromosome 17), which generates tau species with either three or four conserved ~32 amino acid repeats in the microtubule binding domain.

The tau protein in Pick disease is unique. It consists of residues K254-F378 of 3R tau, while other taupathies (including Alzheimer’s disease, progressive supranuclear palsy, and corticobasal ganglionic degeneration) either have 4Rtau or a combination of 3R and 4Rtau.[11] Tau filaments in Pick disease are characterized by 15–18 nm diameter straight tubules and 22–24 nm diameter twisted filaments.  

Accumulation of abnormal protein leads to progressive neuronal dysfunction and loss.

Genetic associations

3-repeat Pick disease has been shown to be associated with mutations in MAPT on exons and introns 9 and 10. Three missense mutations in exon 9 (L257 T, L226 V, and G272 V), one mutation in intron 9 (IVS9-15), one deletion mutation in exon 10 (△K280), and one mutation in intron 10 (IVS10 + 4) and exon 12 (P364S) have been reported.[12]

The exon 9 missense mutations reduce the binding of tau to microtubules, enhancing 3-repeat tau assembly, while the deletion in exon 10 and mutations in intron 10 have been proven to disrupt exon 10 splicing causing decrease of 4-repeat tau mRNA transcripts and increase of 3-repeat tau.[13]

C9orf72, GRN, and MAPT gene mutations are the most common in FTD, and together explain at least 17–40% of the familial FTLD. MAPT mutations present with significant variability in clinical expression even in the same family.

Epidemiology

Occurrence in the United States

Frontotemporal dementias as a group are the fourth most common cause of dementia. In most parts of the United States, among patients younger than 60 years, the frontotemporal dementias are the first or second most common cause of dementia. In patients older than 60 years, the incidence and prevalence of Alzheimer disease begins to take off, with Alzheimer disease becoming by far the most prevalent form of dementia.[14]

International occurrence

Familial forms of Pick disease may occur more frequently in Europe (particularly in Scandinavian nations). The estimated frequency ranges from 7 to 43 cases per 100,000 population.[15] In a study in the Netherlands, the prevalence was 28 per 100,000 persons.[16]

Epidemiological data for svPPA is relatively limited. In one epidemiology study that reported prevalence of FTD as 10.8/100,000, svPPA accounted for approximately one-third of the cases.[17]

Race-, sex-, and age-related demographics

Familial forms of Pick-complex dementias, linked to chromosome arm 17q, may be particularly common in people of Scandinavian origin/descent. It may represent as many as 17% of dementias in this population.

More men than women may be affected by Pick disease.

Pick disease occurs in a younger age group than dementia of the Alzheimer type, with peak incidence occurring in individuals aged 55–65 years.[18, 19]

bvFTD cases tend to have a variable onset; onset has been reported as early as the second decade and as late as the tenth decade. About 40% of FTD patients present with a positive family history for dementia, which is significantly higher than most other neurodegenerative diseases.

Prognosis

Like most dementias, Pick disease is slowly progressive, leading to increased vocational and personal disability. However, a small number of people who have behavioral disturbance consistent with the behavioral variant of FTD may not progress—this has been called the phenocopy variant. In past studies, slow or no progression occurs only in patients with nonlinguistic symptoms—none had primary progressive aphasia.

Some patients can progress slowly over extremely long periods. Some may develop artistic or other talents during the course of their dementia, a phenomenon that is perhaps related to disinhibition of "creative" brain areas. Musical or artistic tastes also may change (eg, the patient may develop a sudden interest in music intended for much younger listeners).

Some patients may be capable of acquiring new knowledge or skills, such as the use of a computer-assisted, simple communication system. This relative sparing of ability to “do things” (process-oriented rather than content-oriented memory) may be helpful in implementing behavioral training techniques to optimize social and daily activity competence.

Patients with svPPA typically survive 7–8 years after onset of disease, but survival can range from 2 to 15 years.[20]

Mortality and morbidity

Pick disease runs a shorter course than Alzheimer disease, on average about 6 years.[18, 21] In some individuals whose main symptoms are a disturbance of speech and language (primary progressive aphasia), the clinical course can be slow. In one small series, these patients survived an average of 5 years longer than patients with behavioral symptoms (behavioral variant).[22] A patient with primary progressive aphasia may preserve the ability to function at home for 10 or more years after onset.

Patient Education

For patient education information, see the Brain and Nervous System Center, as well as Pick Disease and Dementia Medication Overview.

 

Presentation

History

Frontotemporal lobar degeneration (FTLD) is a neuropathologic designation that encompases a group of neurodegenerative diseases of the frontal and anterior temporal lobes, associated with specific pathologies, including Pick pathology. Clinical syndromes associated with FTLD are classified under the rubric of FTD.

In FTD, the primary impairment in cognition does not involve an abnormal level of consciousness or distractibility. Such a finding is more consistent with an attentional dementia[23] or a confusional state and/or dementia. The onset of behavioral and cognitive dysfunction in individuals with Pick disease can be difficult to identify. In many cases, individuals with Pick disease perform well on quick cognitive screening tests, such as the Mini-Mental Status Examination (MMSE).[15]

Clinical features

bvFTD behavioral variant

The most common clinical subtype of FTLD is the behavioral variant frontotemporal dementia (bvFTD), which accounts for roughly more than half of FTLD cases. bvFTD is characterized by early and often severely disabling changes in personality and behavior,  which may be preceded by a long phase of subclinical behavioral changes and social disruption, often occurring in the absence of cognitive impairment. Psychiatric abnormalities that seem to respect the pattern of the classic frontal lobe syndromes are present.[24] “Possible bvFTD” criteria include only behavioral symptoms and thus bvFTD can be easily confused with psychiatric disorders.

Changes in attention, executive function, and social cognition have been reported in presymptomatic patients, especially MAPT mutation carriers.[25]

Patients with orbitofrontal dysfunction can become aggressive and socially inappropriate. Individuals become overly friendly, and may seem inappropriately explicit in their conversations.T hey become more impulsive, addiction prone, irritable, and are likely to exhibit antisocial behaviors.

Obsessive-compulsive or repetitive stereotyped behaviors may be noted. Obsessive–compulsive behavior correlates with dysfunction in networks involving orbitofrontal and anterior cingulate cortexes, basal ganglia, and thalamus.

Patients with dorsomedial or dorsolateral frontal dysfunction may demonstrate a lack of concern, apathy, or decreased spontaneity. Patients can demonstrate an absence of self-monitoring, abnormal self-awareness, and an inability to appreciate meaning.[24] They present with lack of spontaneity and motivation, which may progress to mutism and immobility in the end stages of the disease. Apathy seems to correlate anatomically with dysfunction of brain circuits involving the right anterior cingulate and caudate. Loss of empathy correlates with dysfunction in the right anterior temporal and medial frontal regions.

Patients with gray matter loss in the bilateral posterolateral orbitofrontal cortex and right anterior insula may demonstrate changes in eating behaviors, such as a pathologic sweet tooth. Patients with more focal gray matter loss in the anterolateral orbitofrontal cortex may develop hyperphagia.[26]

Though amnestic deficits are not prominent in bvFTD, in 60% of cases  patients and their caregivers report episodic memory disturbances.[27] Patients usually have relatively little limb apraxia and/or visuospatial dysfunction, thus distinguishing them from patients with diffuse, bihemispheric impairment. Cognitive symptoms of bvFTD are related to poor judgment, inattentiveness, distractibility, loss of planning ability, and disorganization. This executive dysfunction correlates with atrophy in the dorsolateral and medial prefrontal cortex.

Incontinence can occur; it tends to occur earlier as compared to Alzheimer disease.

Parkinsonism, with its concomitant history of rigidity and gait impairment, can occur. Severe or early parkinsonism indicates an alternate diagnosis, such as corticobasal ganglionic degeneration, diffuse Lewy body disease, or progressive supranuclear palsy.

Psychotic symptoms, including delusions and hallucinations, tend to occure more frequently in inherited bvFTD with MND features.[28]

svPrimary progressive aphasia

The first systematic description of a PPA case was published in 1982 by Marsel Mesulam.[29]

Age at onset of svPPA varies; commonest is between 55 and 70 years.[30]

In the semantic variant of PPA, preferential involvement of language and semantic processing is noted. A progressive loss of stored knowledge of word meaning is characteristic of svPPA, clinically evident as a multimodal loss of semantic knowledge.

Single-word naming and comprehension deficits are noted. This tends to affect low-frequency items (less familiar) in the early stages. Semantic paraphasia (e.g., clock for watch, brush for comb) are common. Anomia may be noted.

With progression, object recognition is impaired and this extends to all sensory modalities (e.g, visual agnosia). Surface dyslexia (difficulty in pronouncing irregular words, e.g, pronounce “yacht” as“yatsht”) and surface dysgraphia is noted.

Features extend beyond the realm of language. Patients may have difficulty in understanding concrete concepts. Some patients may have difficulty in facial recognition (loss of person knowledge).[31]

In mid-late phases, behavior changes may be prominent. These include disinhibition, irritability, changes in food taste, lack of empathy, and mental inflexibility.[32] Compulsive behavior is frequently seen and patients may show excessive preoccupation with normal bodily sensations.[33]

Memory impairment is relatively less severe and episodic memory tends to be better preserved. Typically, recent autobiographical memory tends to be better than remote autobiographical memory (reverse temporal gradient).[34]

Physical Examination

The general physical examination often shows the patient to be unkempt at an earlier stage than in comparably impaired patients with Alzheimer disease.

Abnormal spontaneous behaviors observed during examination may include the following:

  • Witzelsucht or inappropriate jocularity

  • Echolalia (repeating the examiner's words), echopraxia (imitating the examiner's gestures),[35, 36] and other disinhibited approach or utilization behaviors

A general neurologic examination may include some of the following abnormalities:

  • Primitive reflexes, such as grasp, suck, and snout (not the palmomental reflex, which is often present in healthy individuals[37] )

  • Akinesia, plastic rigidity, or paratonia on motor examination[38]

  • Resting tremor - Uncommon; its presence suggests Parkinson disease or a Parkinson-plus syndrome

Mental status/neuropsychological examination may reveal the following:

  • Verbal output that is often nonfluent - Most patients have difficulty in naming common objects or pictures (anomia); spontaneous speech can be sparse, yet fluent, in character, with preserved grammar (logopenia)

  • Perseveration - Cognitive and motor (see the image below)

    Motor perseveration in a patient with Pick disease Motor perseveration in a patient with Pick disease. The patient was asked to copy loops (as demonstrated by the examiner in the first line).
  • Relatively preserved visuospatial and visual orientation skills

 

DDx

Diagnostic Considerations

Diagnostic guidelines for svPPA specify the following criteria:[39]

  • [A] Core features: anomia and single-word comprehension deficits (both essential for diagnosis), plus
  • [B] at least 3 of the following other diagnostic features:
    1. impaired object knowledge, particularly for low- frequency or low-familiarity items
    2. surface dyslexia or dysgraphia
    3. spared repetition; and
    4. spared speech production (grammar and motor speech).

The diagnosis of FTD requires a clinical and neuropsychologic approach, supported by neuroimaging and/or genetic studies. Diagnostic criteria for bvFTD were revised and published in 2011.[40]

For a correct clinical diagnosis of FTD, it is useful to see patient and caregiver first together, and then separately, to apply consensus criteria clinically, and to utilize scales that elicit symptoms that are indicative of FTD rather than AD.

Conditions to consider in the differential diagnosis of Pick disease include the following:

  • Rarely, subcortical stroke, for example affecting the striatum

  • Primary brain tumors of the frontal lobe, pituitary, or related regions

  • Adult polyglucosan body disease

  • Chronic meningitis

  • Hashimoto encephalopathy

  • Hemochromatosis (controversial)

  • Creutzfeldt-Jakob disease

  • Olfactory groove meningioma

  • Sequential bilateral thalamic strokes

  • Herpes simplex encephalitis

Differential Diagnoses

 

Workup

Approach Considerations

As in any dementia evaluation, initial workup includes avitamin B-12 and folic acid levels, thyroid function studies, antinuclear antibodies,[23] and fluorescent treponemal antibody testing for syphilis. The American Academy of Neurology, in their practice guidelines for the evaluation of dementia, indicate that the incidence of syphilis as a cause of dementia is low in the typical American patient and that routine screening for syphilis is not necessary.[41] However, the index of suspicion should be high in patients with human immunodeficiency virus (HIV) and in patients from geographic regions where the prevalence of syphilis is high. A second-line workup includes cerebrospinal fluid (CSF) examination (for chronic meningitis or elevated pressure) and HIV serology. As Alzheimer disease is almost always in the differential diagnosis, CSF analysis for Abeta1-42 may be indicated.

If prominent inattention is observed, the patient may have a toxic and/or metabolic encephalopathy rather than a true dementia. In such patients, and also in patients with a rapid onset or progression of cognitive complaints, obtain a urine toxicology screen, serum chemistry panel, complete blood count (CBC) and differential count, liver function tests, ammonia level, and erythrocyte sedimentation rate. Malignancy workup, electroencephalogram (EEG), and Lyme disease serology may be indicated in select cases.

If the patient has parkinsonism or a movement disorder, the following tests can be added, as indicated:

  • Ceruloplasmin (serum) and serum or urinary copper to exclude Wilson disease
  • Manual peripheral blood smear for acanthocytes
  • Genetic testing – Not commercially available for screening for mutations associated with frontotemporal dementias, but genetic testing may be obtained from research laboratories. Consideration and discussion of genetic counseling and testing may especially be relevant in patients where family history suggestive of genetic taupathy is obtained (dementia, behavior disturbance, motor neuronopathy, parkinsonism, or a combination of these syndromes in >1 relative, one of whom is a first-degree relative).

Excellent information is available at Association for FTD.

All patients suspected to have Pick disease require a detailed cognitive assessment.  Evaluation by a neuropsychologist, behavioral neurologist, or neuropsychiatrist may be needed.

  • Language assessment: For svPPA, tests include confrontational naming (e.g, Boston Naming test), tests of semantic association (e.g., Pyramids and Palm Trees test), and knowledge (e.g, naming famous faces), reading and spelling of irregular words, evaluation of spontaneous speech, repetition and syntactic comprehension.

  • Frontal lobe function should be assessed in all patients suspected with Pick disease.

  • Characteristic behavioral features in bvFTD patients may be measured with scales such as frontal behavioral inventory (FBI), neuropsychiatric inventory (NPI), and Cambridge behavioral inventory (CBI). Neuropsychological tools such as theory of mind (ToM) tasks and social cognition and emotional assessment (SEA) have been demonstrated to be able to detect and distinguish bvFTD at an early stage from Alzheimer’s disease (AD).[42]

Imaging Studies

Brain CT scanning and MRI

Order a computed tomography (CT) scan if magnetic resonance imaging (MRI) is contraindicated in the patient (eg, if the patient has a pacemaker or metallic ocular implants).

If not contraindicated, an MRI scan is preferred. Metastatic lesions and subcortical infarction (eg, caudate, thalamic) can easily be missed on a CT scan. Frontal lobe atrophy out of proportion to atrophy in other brain regions can sometimes be detected. 

Typically, semantic impairment is associated with greater left-sided anterior temporal atrophy. Naming difficulties are correlated with involvement of the superior portions of the left temporal pole, while loss of person knowledge and behavioral changes are associated with more extensive right temporal atrophy. PPA appears to be associated not only with grey matter but also with significant white matter degeneration.[43]

Patients with FTD show earliest structural changes in the insula and temporal and frontal areas. They may have increased T2 signal in frontal lobe white matter, especially on fluid-attenuated inversion recovery (FLAIR) sequences.[14]

 

Functional brain and physiologic imaging

Functional brain imaging, eg, with single-photon emission CT (SPECT) scanning, or physiologic imaging with positron emission tomography (PET) scanning may be appropriate in some patients.

In some patients with relatively isolated social-behavioral dysfunction, employers or others may require evidence of a medical disorder. Such patients may appear cognitively normal on objective neuropsychological tests, yet may be unable to function due to acquired brain disease. A SPECT scan may demonstrate relative hypometabolism in frontal and temporal areas (when other neuroimaging is normal), thus providing evidence of brain dysfunction.

Semantic impairment is associated with greater left-sided anterior temporal  hypometabolism-on fluorodeoxyglucose (FDG) PET.[44] In these patients, resting-state functional magnetic resonance imaging has shown decreased functional connectivity along the ventral language pathway and increased functional connectivity along the dorsal language pathway,[45] which corresponds well with the clinical deficits in this syndrome. In patients with svPPA, a decrease in Fractional Anisotropy has been demonstrated in the longitudinal, uncinate, cingulum, and external capsule fasciculi.[46]

In patients with bvFTD, uni- or bilateral hypometabolism is noted in the prefrontal cortex, anterior temporal lobe, anterior cingulate, and basal ganglia (FDG PET).[47]

Lumbar Puncture

Lumbar puncture (CSF examination) is performed in patients with atypical features or rapidly progressive cognitive impairment. Cerebrospinal fluid is usually examined for cell count, protein, cryptococcal antigen, acid-fast bacillus (AFB), cultures, VDRL, and cytology,  if the clinical situation warrants such testing. Elevated levels of phosphorylated tau protein and low levels of Abeta1-42 are found in the CSF of patients with Alzheimer disease. Data on levels of tau and beta-amyloid in CSF from patients with frontotemporal dementias has been inconsistent.[48, 49] Studies have suggested that FTLD patients (including bvFTD) display higher levels of CSF NfL and/or lower ratio of phospho-tau/tau compared to healthy controls or patients with other neurodegenerative or psychiatric diseases, including, for example, AD.[50] However, there are no routinely used or guideline-mandated CSF biomarkers for the diagnostics of bvFTD or svPPA. 

Markers for Creutzfeldt-Jakob disease, central nervous system (CNS) Whipple disease, progressive multifocal leukoencephalopathy, and herpes encephalitis also can be ordered from the spinal fluid. Indication for such tests is determined by the clinical picture and differentials being considered for an individual patient.

Complications

Headache is the commonest complication following LP, and tends to self-resolve within 24–48 hours. Symptomatic intracranial hypotension, secondary to a persistent CSF leak, is less common and may in rare cases be complicated by development of subdural hematomas.

Observe the patient for headache or change in mental status for several days after this procedure (some physicians admit the patient for 23-hr observation). If patient has persistent headache, signs of low intracranial pressure, or you suspect a subdural hematoma, perform a CT scan with and without contrast or an MRI scan with contrast.

Brain Biopsy

Brain biopsy may be considered in exceptional circumstances if the diagnosis is in doubt and use of a treatment depends on the results. Usually, this occurs in setting of atypical features or a very rapid progression, where treatable pathologies need exclusion. 

Occasionally, spinal fluid markers can obviate the need for a brain biopsy, even in these patients.

 

Treatment

Approach Considerations

Currently, there are no treatments available for changing the course of bvFTD and svPPA. There is no class I evidence regarding any drug in bvFTD or svPPA.

The aim of medical therapy is symptomatic relief.

Individualized management plans, including nonpharmacologic and pharmacologic interventions, are best suited for patients with Pick disease.

Non-pharmacological treatment

This requires a multidisciplinary approach.

  • Patient safety and well-being: This may include driving restrictions, restriction of financial access (where required), environmental safety (home modification) and adaptation, caregiver training and counseling for families.
  •  Exercises and physical therapy: These are useful especially for patients with concomitant problems with movements. Appropriate referrals to physical and occupational therapists should be considered. Such interventions may also improve mood.
  • Dietary interventions: High-sugar-content foods may need to be restricted in some patients with carbohydrate craving. Some patients may require special care to prevent placement of inedible objects in the mouth. At initial presentation and follow-up the weight of the patient should be monitored.
  • Speech therapy: Though not curative, speech interventions have been shown to help patients with PPA cope with their speech deficits. Speech and language therapists have developed several impairment-based interventions and compensatory strategies for use. Speech therapist assessment is also indicated for swallowing assessment and management of dysphagia.

Pharmacological treatment

Because dysfunction of cortical cholinergic systems does not occur in Pick disease, the use of acetyltransferase inhibitors in this condition is not indicated. Cholinesterase inhibitors can even exacerbate behavioral disturbance in patients with FTD. Memnatine, though tolerated well, has no clinical benefit in FTD.[51]

Studies in the neurochemistry of bvFTD have shown a serotoninergic and dopaminergic network disruption. Consequently, studies have shown that serotonin selective reuptake inhibitors (SSRIs) (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram) are effective in helping with various symptoms of FTD (disinhibition, impulsivity, eating disorders). For  severe neurobehavioral symptoms where SSRIs are not useful, careful and limited use of antipsychotic medications (preferably quetiapine or olanzapine) may be considered, with close monitoring for extrapyramidal side effects. However, avoid the use of neuroleptics as much as possible.

Inpatient care

Most of the dementia workup above is now recommended as outpatient management. However, a one-day hospital stay may accomplish the second and third steps above under rare conditions (eg, potential need for epilepsy monitoring, if the diagnosis might include chronic meningitis or encephalitis, or if the need for brain biopsy is suspected). However, think carefully about the high risk of hospital-acquired delirium, with potential sundowning and agitation; this complication (see below) is associated with increased mortality and poor quality of life. Occasionally, hospitalization may be required to an appropriate ward in case of violent or totally disruptive behavior.

Outpatient care

Periodic follow-up care is indicated to manage problem behaviors or clinical problems of the patient, to support the caregiver, or to reevaluate the diagnosis if it is in doubt.

If paranoia, depression, or other behavioral problems manifest, pharmacologic treatments can be tailored to address these problems.

Decompensation/risk of hospital-acquired delirium

Like all people with dementia, people with Pick disease who are relatively high functioning are at very high risk of hospital-acquired delirium. If they decompensate while in a hospital or other unfamiliar setting during illness or medical intervention, this medical complication may adversely affect the outcome of the hospitalization as well as their general health. This should be considered when contemplating elective surgery or other nonessential interventions (eg, cataract removal).

Medicolegal concerns

Loss of social-emotional abilities must be taken into account when making recommendations about continuing work, especially when responsibility for others is part of the work role. People with FTD may retain intellectual capability of performing tasks, but they may make social or interpersonal errors that are unacceptable or even dangerous to themselves or others.

Surgical care

At this time, surgical treatments are not demonstrated to benefit people with frontotemporal dementias or Pick disease.

Consultations

Neuropsychologist, behavioral neurologist, geriatric psychiatrist, or neuropsychiatrist

Patient care can include consultations with a neuropsychologist, behavioral neurologist, geriatric psychiatrist, or neuropsychiatrist. For patients with progressive aphasia, consultation with a speech pathologist for family and patient education and, in rare cases, referral for a computerized communication assistive device, can be beneficial.

Consultation with a nurse practitioner or a geriatric or psychiatric case manager (social worker) experienced with dementia is indicated. If needed, such professionals can be located through a local chapter of the Alzheimer's Association or the state Department of Aging. While the patient is able to participate, a family contact (eg, durable power of attorney) can be designated to decide care-giving and/or end-of-life issues.

The nurse or case manager also can assist caregivers with stress management, teach behavioral techniques, provide referral to day programs, and assess a patient who may need to be admitted for short- or long-term management of behavioral problems.

Genetic counselor

In situations in which a strong family history of frontotemporal dementia or Pick disease is present, unaffected family members may desire genetic testing. It cannot be overstressed that this should be performed only after informed genetic counseling, preferably in a specialty center familiar with the genetics of dementing disorders. In this setting, testing may be of benefit.[52]

Brain injury specialist

If the patient and family have difficulty accepting the idea of social-emotional dysfunction and disability, and, for example, continue to assign the patient responsibility such as caring for small children, it can be helpful to consult with a job coach, cognitive specialist, or psychologist or social worker experienced with people with traumatic brain injury. Such specialists are experienced with recognizing and explaining the deficits encountered in people with FTD, because of the frequency of orbital-frontal cortical deficits after traumatic brain injury.

 

Medication

Medication Summary

Unfortunately, no available drugs arrest or reverse Pick disease. Currently, practitioners use a combination of neuroprotective and symptomatic therapies—including the administration of vitamins, antidepressants, cholinergic agents, and/or dopaminergic agents—in patients with the disorder.

Research studies suggest that a number of agents may actively inhibit neurodegeneration in animals, cellular models, or other disorders (see Scott and Barrett for a review[53] ), but none of these drugs are currently standard for use in Pick disease.

Vitamins

Class Summary

These are cofactors that are needed in metabolic reactions and that are essential for normal deoxyribonucleic acid (DNA) synthesis, with some vitamins providing antioxidant effects.

Vitamin E (E-Gem, Gamma-E-Gems, Aqua Gem-E, Aquasol E)

Vitamin E may protect polyunsaturated acid in membranes from attack by free radicals.

Thiamine

Thiamine is an essential coenzyme that combines with adenosine triphosphate (ATP) to form thiamine pyrophosphate.

Antidepressants

Class Summary

Although selective serotonin reuptake inhibitors (SSRIs) have been suggested for behavioral symptoms (eg, a craving for sweets, hypersexual behavior) in these patients,[54, 55] exercise care in using these agents in patients with parkinsonism, who may develop adverse effects of akathisia or dyskinesias.

Agents with mixed noradrenergic and serotonergic action may be helpful in treating patients with depression and frontal cognitive disorder.

Mirtazapine (Remeron)

Mirtazapine may be sedating, especially at the lower 15mg dose, and may be useful for patients with agitation or disinhibition and depression.

Venlafaxine (Effexor, Effexor XR)

Venlafaxine may be helpful for abulic patients who also have symptoms of depression or decreased initiative.

Trazodone (Oleptro)

Trazodone is a 5-HT2–receptor antagonist that inhibits the reuptake of 5-HT. It has a negligible affinity for cholinergic, adrenergic, dopaminergic, or histaminic receptors. Trazodone has good hypnotic properties and is effective in reducing agitation in patients with head trauma or dementia. This agent is also useful for sleep disturbances. It is structurally unrelated to tricyclic antidepressants (TCAs), tetracyclics, or monoamine oxidase inhibitors (MAOIs). The cardiac conduction effects of trazodone are qualitatively dissimilar to and quantitatively less pronounced than those of TCAs and so are less toxic in cases of trazodone overdose.[29]

Acetylcholinesterase Inhibitors, Central

Class Summary

Cholinergic therapy may be helpful for patients with aphasia,[56] and preliminary studies indicate that cholinesterase inhibitors may be useful for aphasia in Pick disease,[57] as well as for other dementia-related symptoms in this disorder.[58]

Donepezil (Aricept)

Donepezil is an acetylcholinesterase inhibitor that is used in dementia of the Alzheimer type. Cholinergic stimulation may improve naming[30] and increase neuronal plasticity[33] ; thus, it is reasonable to attempt therapy in patients with primary progressive aphasia. Unfortunately, no clinical studies are available on the effect of donepezil in patients with Pick disease.

Ergot Derivatives

Class Summary

Although these agents may worsen sexual or behavioral disinhibition, they may improve executive function, perseveration, and abulia.[59, 60, 61]

Bromocriptine (Parlodel, Cycloset)

Bromocriptine is a semisynthetic ergot alkaloid derivative. It is a strong dopamine D2-receptor agonist and a partial dopamine D1-receptor agonist. Bromocriptine inhibits prolactin secretion, with no effect on other pituitary hormones. It may be given with food to minimize the possibility of gastrointestinal (GI) irritation.

Approximately 28% of this agent is absorbed from the GI tract and metabolized in liver. Bromocriptine's approximate elimination half-life is 50 hours, with 85% excreted in feces and 3-6% eliminated in urine.

Initiate this drug at a low dosage; slowly increase the dosage to individualize therapy. Assess the dosage titration every 2 weeks. Gradually reduce the dose in 2.5-mg decrements if severe adverse reactions occur.

Antiparkinson Agents, Dopamine Agonists

Class Summary

Although these agents may worsen sexual or behavioral disinhibition, they may improve executive function, perseveration, and abulia.

Amantadine

Amantadine inhibits N-methyl-D-aspartic acid (NMDA) receptor–mediated stimulation of acetylcholine release in rat striatum. It may enhance dopamine release, inhibit dopamine reuptake, stimulate postsynaptic dopamine receptors, or enhance dopamine receptor sensitivity.