Pick Disease

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

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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.

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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.

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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.

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Patient Education

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

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