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, | ICD9 = | ICDO = | OMIM = 172700 | MedlinePlus = | eMedicineSubj = neuro | eMedicineTopic = 311 | MeshID = D020774 | Pick’s disease, also known as Pick disease and PiD, is a rare fronto-temporal neurodegenerative disease. It causes about 0.4-2% of all dementia and affects women more than men. Moreover, this disorder causes progressive destruction of nerve cells in the brain and causes tau proteins to accumulate into the "Pick bodies" that are a defining characteristic of the disease.On average, Pick's disease occurs at a somewhat younger age than Alzheimer disease. In Pick's disease, the first symptoms typically appear in middle age, in people aged 40-60 years. However, it can occur in adults of any age.
HistoryPick 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 Alzheimer also noted the complete absence of senile plaques, and neurofilbrillary tangles as well as the presence of Pick Bodies and occasional ballooned neurons.
Controversy Over Disease NomenclaturePick’s disease is controversial because there remains significant disagreement about what are the hallmarks of this disease. There have been several different attempts to generate subtypes of this disease; however, none have been universally adopted. In 1974, numerous different cases of what was called Pick’s lobar atrophy were categorized based on the location of the different Pick bodies and ballooned neurons. This lead to the development of three groups: A, B, and C; group C was further subdivided into C1 and C2.
Symptoms Symptoms of PiD can strike adults of any age. The symptoms that are the most common include the decreased ability to produce language both spoken and written aphasia, decreased planning capacity, mood swings, and one or more of the following personality changes: apathy (indifference) or withdrawal, severe depression in a person who has never been depressed before, blunting or dullness of emotions, loss of inhibition, impulsive behavior in a usually cautious person, bad manners, rudeness, saying or doing inappropriate things in public, impatience, becoming extroverted or very talkative in a normally introverted person, inappropriate joking, aggression, restlessness or agitation, poor judgment especially with regards to financial matters, paranoia, selfishness, difficulty coping with changes from a routine, development of obsessive routines, and finally childlike behavior.
Causes Both Genetic and Environmental While there have been a few cases where this disease has run in families, there is no known pattern of inheritance. The vast majority of cases arise spontaneously with no known genetic or environmental link. There have been two mutations that have been identified in the tau protein gene in families with a history of PiD including a glycine-to-arginine at codon 389 and a lysine-to-threonine at codon 257 However, not all familial cases of PiD carry these mutations.
Diagnosis The diagnosis of PiD is not done in the traditional manner, as this disease has no test that can be done in vivo that will differentially allow a clinician to definitively say that a person has PiD. Instead, a series of specific tests are performed so as to rule out all other possible explanations of the aforementioned symptoms. Moreover, as the symptomatology for this disease is very nonspecific, integration of all of the tests allows for a diagnosis to be made once the other syndromes are ruled out. Tests are performed so as to allow for differentiation from other neurological disorders; however, true confirmation can only come via histological analysis that examines neurological tissue for the presence of Pick bodies. In 1926 Onari and Spatz generated a definition of PiD that relied heavily on histological analysis however these elements are still used to the present day in identifying PiD either pre or postmortem including:
Histological Hallmarks of Pick’s DiseasePiD 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; however, some new cases of atypical Pick’s disease have come to light that lack noticeable Pick bodies. There are a variety of stains that can allow for visualization however at current immunohistochemical staining using anti-tau and anti-ubiquitin antibodies have proven the most efficient and specific for aiding the visualization of Pick bodies, and Pick cells. Hematoxylin and Eosin staining also serves to allow for 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 AD as the Bodian will bind preferentially to cells with PiD as compared to the Gallyas method which preferentially binds to the cells with AD.
The Pathology and Biochemistry of Pick’s Disease There are numerous different areas of the brain that are affected by PiD however, upon closer inspection the specific areas that are affected allow for differentiation between PiD and Alzheimer’s disease (AD). The aforementioned 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 demonstrate 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. Furthermore 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 however cases of extreme degeneration do exist .PiD has several very unique biochemical characteristics that allow for unique identification of Pick’s disease as opposed to other fronto-temporal dementias (FTD’s).
The most striking of these is that this disease which has tau protein tangles present in many affected neurons only contains 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 however a recent study has shown that there are a much greater number of different tau isoforms including 4R and mixed 3R/4R that 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 diseaseWhile both of these diseases present in a similar fashion, there are some key differences that can be noted from previous longitudinal studies that have been performed, including cognitive testing on patients with Alzheimer’s disease as opposed to PiD . Interestingly, while there is some memory impairment of patients with PiD, it is far less common than the deficiencies that are seen with Alzheimer’s disease . However the areas where the cognitive function differences significantly between the two diseases are mainly personality alterations and speech problems . However on a biochemical level these differences become even more apparent. It is well known that in AD all six isoforms of tau proteins expressed. In addition the presence of neurofibrillary tangles that are a hallmark of AD are able to be stained with antibodies to basic fibroblast growth factor, amyloid P, and heparin sulfate glycosaminoglycan.
Differences from other Fronto-temporal Dementias Pick’s disease can be differentiated from other FTDs via the location of the neuronal loss and the different immunoreactive protein profiles.
Treatment At current there is no effective treatment that can be used to treat or prevent PiD. However some medications are used in order to lessen the clinical symptoms including:Cholinesterase inhibitors - Donepezil (Aricept) (may worsen agitation and aggression), rivastigmine (Exelon), and galantamine/galanthamine (Reminyl). These drugs have in effect replaced an older drug called tacrine (Cognex).Antidepressants/anxiolytics – Mirtazapine (Remeron), venlafaxine (Effexor), fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa),Antipsychotics – Haloperidol (Haldol), risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa)
Prognosis After Diagnosis In general the prognosis for the patient is very poor. Death usually occurs within 2-6 years however some patients have lasted as long as 17 years post-diagnosis. .
Ongoing Research Most current research is aimed at trying to understand if there is a genetic link that can be predictive in disease development or if the disease is caused by somatic mutation. Currently the formations of the 3R tau protein aggregates are also being investigated in the hopes of developing a pharmacologically active treatment.
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