Pick's disease

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 ^[1] 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"^[2] 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. ^[3]

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History

Pick 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 ^[4][2]. 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. ^[4]

Controversy Over Disease Nomenclature

Pick’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^[4][5]. In 1974,^[6] 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.

• Group A: These brains had both Pick bodies and ballooned neurons in various areas of the limbic system, the cortical regions that had undergone atrophy, and the hippocampus. Gliosis (atrophy and death of glial cells) was also profound throughout the affected region.

• Group B: These brains had ballooned neurons in the frontal cortical regions; however, Pick effects were also seen other regions including the precentral gyrus, the pallidum, and the substantia nigra. In this group gliosis was only seen in the pallidum and substantia nigra. The effects were far less pronounced in other regions including the thalamus and neostriatum.

• Group C1: Brains in this group, known as the "temporal" group, showed significant gliosis and atrophy at the temporal pole, the amygdaloid nucleus acumens nucleus stria terminalis complex, and the juxta-allo-cortical temporal cortex.
• Group C2: Brains in this group, known as the "frontal" group, showed significant gliosis and atrophy in the frontal lobe. This effect was also present in other regions including the precentral gyrus, the cingular, orbital, insular, and sometimes temporal regions of the brain.

While this set of diagnostic criteria seems fairly straightforward, there are a number of different problems including the wide use of different histological staining techniques by different labs which show different affinities for different types of inclusions and protein subtypes. Furthermore this diagnostic set of criteria makes is unable to distinguish between different neurological disorders that can confound a proper diagnosis^[5]. Thus to date there is no universally accepted morphological definition that can lead to a definitive diagnosis of PiD^[4]. Thus clinical symptoms and histological analysis are the current standard for PiD diagnosis.

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,^[7] 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^[7], rudeness^[7], 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^[2] 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^[8] 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:

• Macroscopic atrophy in the temporal or frontal lobe.
• Characteristic preservation of the first temporal gyrus, traverse gyrus and Ammon’s horn.
• Primary degenerative changes in the cortical gray matter, with concomitant involvement in the corresponding white matter.
• Neuronal depletion accentuated in the superficial cortical layers I-IIIa.
• Occasional presence of ballooned neurons.
• Absence of atherosclerosis, inflammatory changes, neurofibrillary tangles, and senile plaques.

While the patient is still alive, the mini mental state examination will allow clinicians to see deficiencies in functioning that can aid in a correct diagnosis. There are some patients that allow a pre-mortem brain biopsy and when combined with subsequent histological analysis can allow clinicians to make a definitive diagnosis of PiD prior to death. Thus the definitive diagnosis is still completed using histological analysis however the advent of highly sensitive and accurate noninvasive functional neuroimaging technologies like Positron Emission Tomography,^[9] SPECT, MRI ^{[7] [2]} and fMRI have allowed clinicians unprecedented understanding of the real time functional deficiencies that are seen in patients with PiD.

Histological Hallmarks of Pick’s Disease

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; however, some new cases of atypical Pick’s disease have come to light that lack noticeable Pick bodies^[7]. 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^[1]. 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^[5][7]. 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^[5].

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 ^[2]. 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 ^[2].

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.^[10] All of these isoforms result from alternative splicing of the same gene.^[11] 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.^[12] 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^[1] and neuronal surface glycoside (A2B5) ^[12] 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.^[13]

Differences from Alzheimer’s disease

While 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 ^[3]. 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 ^[3]. However the areas where the cognitive function differences significantly between the two diseases are mainly personality alterations and speech problems ^[9]. 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^[12].

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.

• Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophylic grain disease (AGD) these are associated tauopathies unlike PiD have tau isoforms that contain mainly if not exclusively the 4R tau repeat ^[10].
• Limbic neurofibrillary tangle dementia (LNTD), diffuse neurofibrillary tangles with calcification (DNTC) both show the full range of all six isoforms of tau proteins in a very similar manner to AD ^[10].
• Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has been identified by the genetic mutations that are present in the tau gene. Thus because the genotype and phenotype of an organism can be known this has served as a model for trying to understand other tauopathies ^[10].
• Dementia with Lewy bodies (DLB) which includes diffuse Lewy body disease (DLBD), senile dementia of Lewy body type, and Lewy body variant of AD all have characteristic α-synuclein present. Thus these diseases have come to be known as synucleinopathies. Picks disease does not have quantifiable levels of α-synuclein present ^[10]
• Dementia Lacking Distinctive Homology (DLHD) has recently been linked to chromosome 3 and Frontotemporal dementia associated motor neuron disease (FTD-MND) has recently been linked to chromosome 9. These diseases have ubiquitin positive neuronal inclusions present without any presence of tau deposits. At current there is no known uniformly present genetic link to PiD ^[12]

• Progressive subcortical gliosis shows, as the name implies, severe gliosis without much loss of white matter. Picks disease typically has marked the aforementioned atrophy of the frontal and temporal lobes with severe loss of white matter in the brain, as well as possible gliosis^[7].

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)^[14]

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. ^[3].

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.

References

1. ^ ^{a b c} Armstrong, RA; Cairns NJ, Lantos, PL (1998). "A comparison of histological and immunohistochemical methods for quantifying the pathological lesions of Pick’s disease". Neuropathology 18 (4): 295-300. PMID 16006664.
2. ^ ^{a b c d e f} Wang, LN; Zhu MW, Feng YQ, Wang JH. (2006). "Pick's disease with Pick bodies combined with progressive supranuclear palsy without tuft-shaped astrocytes: a clinical, neuroradiologic and pathological study of an autopsied case.". Neuropathology 26 (3): 222-230. PMID 16771179.
3. ^ ^{a b c d} {{name=About Picks Disease>Pick's Disease: Frontal Lobe Dementia.
4. ^ ^{a b c d} Amano, N; Iseki, E (1999). "Introduction: Pick’s disease and frontotemporal dementia". Neuropathology 19 (1): 417-421.
5. ^ ^{a b c d} Uchihara, T; Ikeda K, Tsuchiya K. (2003). "Pick body disease and Pick syndrome.". Neuropathology 23 (4): 318-326. PMID 14719549.
6. ^ Constatinidis, J; Richard J, Tissot R. (1974). "Pick's disease". European Neurology 11 (1): 208-217.
7. ^ ^{a b c d e f g} Yamakawa, K; Takanashi M, Watanabe M, Nakamura N, Kobayashi T, Hasegawa M, Mizuno Y, Tanaka S, Mori H (2006). "Pathological and biochemical studies on a case of Pick disease with severe white matter atrophy.". Neuropathology 26 (6): 586-591. PMID 17203597.
8. ^ Onari, K; Spatz H (1926). "Anatomische Beiträge zur Lehre von der Pickschen umschriebene Grobhirnrinden- Atrophie (‘Picksche Krankheit’).". Z Ges Neurol Psychiatrie 101 (1): 470-511.
9. ^ ^{a b} Shibuya-Tayoshi, S; Tsuchiya K, Seki Y, Arai T, Kasahara T. (2005). "Presenile dementia mimicking Pick's disease: an autopsy case of localized amygdala degeneration with character change and emotional disorder.". Neuropathology 25 (3): 235-240. PMID 16193841.
10. ^ ^{a b c d e} Iskei, E; Arai, H (2006). "Progress in the classification of non-Alzheimer-type degenerative dementias". Psychogeriactrics 6 (1): 41-42.
11. ^ Arai, T; Ikeda K, Akiyama H, Tsuchiya K, Iritani S, Ishiguro K, Yagishita S, Oda T, Odawara T, Iseki E. (2003). "Different immunoreactivities of the microtubule-binding region of tau and its molecular basis in brains from patients with Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration.". Acta Neuropathol. 105 (5): 489-498. PMID 12677450.
12. ^ ^{a b c d} Munoz, DG; Dickson DW, Bergeron C, Mackenzie IR, Delacourte A, Zhukareva V. (2003). "The neuropathology and biochemistry of frontotemporal dementia.". Ann Neurol 54 supp. S5 (1): S24-S28. PMID 12833365.
13. ^ Puig, B; Ferrer I, Ludueña RF, Avila J. (2005). "βII-tubulin and phospho-tau aggregates in Alzheimer's disease and Pick's disease". J Alzheimers Dis. 7 (1): 213-220. PMID 16006664.
14. ^ Pick Disease - Medications. eMedicineHealth. Retrieved on 2007-12-21.

See also

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.