Pick's disease

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Overview
Pick's disease, also known as Pick disease and PiD, is a rare neurodegenerative disease. While the term Pick's disease was once used to represent a specific group of clinical syndromes with symptoms attributable to frontal and temporal lobe dysfunction, it is now used (at least among professionals in the field) to mean a specific pathology that is just one of the causes of the clinical syndrome now known as frontotemporal lobar degeneration. Some people still use the term Pick's disease to mean the more general clinical syndrome of frontotemporal lobar degeneration, but this has previously led to confusion among both professionals and patients and so its use should be restricted to the specific pathological subtype described below.

Pick's disease (the pathology) causes progressive destruction of nerve cells in the brain and causes tau proteins to accumulate into "Pick bodies" that are a defining characteristic of the disease.

Note
Pick's disease has two meanings that are often confused:

1) Pathology: Neurologists currently use the term "Pick's disease" to mean specifically one of the pathological subtypes of frontotemporal lobar degeneration (FTLD). The pathological hallmark of Pick's disease are Pick bodies. These are spherical cytoplasmic inclusions found within neurons in affected portions of the brain. They cause neurons to swell, taking on a "ballooned" appearance. Pick bodies contain the protein Tau, and hence the disease is also referred to as a tauopathy (along with progressive supranuclear palsy, corticobasal degeneration, and others).

2) Syndrome: Pick's disease is also the old name for the clinical syndrome frontotemporal dementia (FTD). Some neurologists now avoid this use of the term, however, because it is not possible to distinguish between FTD caused by Pick's disease pathology (definition 1) and other FTLD processes prior to autopsy.  However, it is important to note that a number of support groups for families of patients with frontotemporal dementia continue to use the name "Pick's disease" in their titles.

Note: This confusion has led some neurologists to suggest other names for FTLD. The most prominent is perhaps Kertesz' suggestion of the term "Pick Complex" to encompass not only the clinical syndromes associated with FTLD, but also the overlapping pathologic processes of corticobasal degeneration and progressive supranuclear palsy.

For more information on Pick's Disease, see the article on the pathologic process of frontotemporal lobar degeneration (FTLD) and its related clinical syndromes of frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia.

History
Pick's disease is named after Arnold Pick, a professor of psychiatry from the University of Prague who first discovered and described the disease in 1892 by examining the brain tissue of several deceased patients with histories of dementia. As a result, the characteristic histological feature of this disease - a protein tangle that appears as a large body in neuronal tissue - is named a Pick body. In 1911, Alois Alzheimer also noted the complete absence of senile plaques and neurofilbrillary tangles as well as the presence of Pick Bodies and occasional ballooned neurons.

Symptoms
Pick's disease is one of the causes of the clinical syndrome of frontotemporal lobar degeneration which has three subtypes. Pick's disease pathology is associated more with the frontotemporal dementia and progressive nonfluent aphasia subtypes than the semantic dementia subtype.

Causes
Whilst other pathologies causing frontotemporal lobar degeneration are associated with a genetic cause, there is no evidence in the modern literature that classical Pick's disease pathology can run in families or has a genetic cause.

Pathology and Biochemistry
PiD was first recognized as a distinct disease separate from other neurodegenerative diseases because of the presence of large, dark-staining aggregates of proteins in neurological tissue as well as the aforementioned ballooned cells, which are known as Pick cells. Pick bodies are almost universally present in patients with PiD, but some new cases of atypical Pick’s disease have come to light that lack noticeable Pick bodies. A variety of stains can aid in the visualization of Pick bodies and Pick cells, but immunohistochemical staining using anti-tau and anti-ubiquitin antibodies have proven the most efficient and specific. Hematoxylin and eosin staining allows visualization of another population of Pick cells, which are both tau and ubiquitin protein negative. Several different silver impregnation stains have been used, including the Bielschowsky, Bodian, and Gallyas methods. The latter two techniques are sensitive enough to allow PiD to be distinguished from Alzheimer's disease as the Bodian will bind preferentially to cells with PiD as compared to the Gallyas method, which preferentially binds to the cells with Alzheimer's.

Numerous different areas of the brain are affected by PiD, but the specific areas that are affected allow for differentiation between PiD and Alzheimer’s disease. Pick bodies are almost always found in several different places in the brain, including the dentate gyrus, the pyramidial cells of the CA1 sector and subiculum of the hippocampus, and the neocortex as well as a plurality of other nuclei. Interestingly, it is the location within the different layers of the brain as well as the anatomical location that demonstrates some of the unique features of PiD. A striking feature is that in the neocortex the Pick bodies are located in the II and IV layers of the cortex, which send neurons within the cortex and to thalamic synapses, respectively. While layers III and V have very few if any Pick bodies they show extreme neuronal loss that can, in some cases, be so severe as to leave a void in the brain. altogether. Other regions that are involved include the caudate, which is severely affected, the dorsomedial region of the putamen, the globus pallidus, and locus cerulus. The hypothalamic lateral tuberal nucleus is also very severely affected. The cerebellar elements that are important in receiving input, including the mossy fibers as well as the monodendritic brush cells in the granule cell layer, and generating output signals, most notably the dentate nucleus, are stricken with lots of tau protein inclusions. Strangely, the substantia nigra is most often uninvolved or only mildly involved, but cases of extreme degeneration do exist.

PiD has several unique biochemical characteristics that allow for unique identification of Pick’s disease as opposed to other pathological subtypes of frontotemporal lobar degeneration. The most striking of these is that this disease, which has tau protein tangles present in many affected neurons, contains only one or as many as two of the six different isoforms of the tau protein. All of these isoforms result from alternative splicing of the same gene. Pick bodies typically have the 3R isoform of tau proteins as not only the most abundant form but the only form of this protein, but a recent study has shown that a much greater number of different tau isoforms including 4R and mixed 3R/4R can be present in the Pick bodies. Not only do these tangles have the 3R tau protein predominately but they are also characteristically shaped with a round body and there is often an indentation in the area that faces the nucleus of the cell. The Pick bodies are also able to be labeled by N-terminal amyloid precursor protein segment, hyperphosphorylated tau, ubiquitin, Alz-50, neurofiliment proteins, clathrin, synaptophysin and neuronal surface glycoside (A2B5) specific stains. Moreover βII tubulin proteins are also suspected in playing a role in the formation of phosphor-tau aggregates that are seen in PiD as well as AD.

Differences from Alzheimer’s disease
In Alzheimer’s disease, all six isoforms of tau proteins are expressed. In addition, the presence of neurofibrillary tangles that are a hallmark of Alzheimer’s can be stained with antibodies to basic fibroblast growth factor, amyloid P, and heparan sulfate glycosaminoglycan.