Compare and Contrast the Pathological Features of Alzheimer’s Disease and Pick’s Disease
Dementia has devastating effects on the central nervous system and is one of the most commonly encountered disorders in clinical neurology. The epidemiological of the most common dementia, Alzheimer’s disease, has long been known. However, retrospective autopsy studies have revealed that there are an increasing number of diseases that are responsible for dementia in addition to Alzheimer’s. Picks disease is a type of dementia that can be pathologically and clinically separated from Alzheimer’s, but it is often challenging to delineate the two due to numerous overlapping clinical and pathological features. This essay aims to compare and contrast the two diseases, but does not provide an exhaustive review. The individual pathological features of each disease are discussed separately before comparisons are made in order to provide a sufficient basis upon which more data can be added. More emphasis will be placed on differences between the two disorders rather than their similarities because this information has the greatest clinical value.
(1) Clinical Presentation
Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterised by early memory and cognitive dysfunction. Pick’s disease (PiD) is a rarer form of neurodegenerative disease, occurring approximately one-tenth as often as Alzheimer’s, typically exhibiting early personality changes and reduction in functional activity. Even though both Alzheimer’s and Pick’s disease are types of cerebral cortical degeneration they exhibit somewhat different clinical symptoms.
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Characteristically one of the first signs of Pick’s disease is behavioural abnormalities consistent with frontal lobe degeneration. Patients often demonstrate roaming, hyperoral and disinhibited behaviours, with decreased social propriety and impulsive sexual behaviour. In comparison, these behaviours are relatively infrequent in Alzheimer’s disease. Mendez et al (1993) reported that 76% of Pick’s patients had early personality change compared with only 31% of Alheimer’s patients. Contrastingly, Alzheimer’s patients commonly present with progressive memory loss, first of recent memory and then of more remote memory, highlighting the involvement of the hippocampus in disease pathology. In comparison, episodic memory is spared in Pick’s disease until relatively late in the disease course, with mathematical and visuospatial skills commonly well preserved. Even patients with advanced disease score well on the mini-mental state examination compared to AD (Folstein et al, 1975).
However, in advance stages both disorders exhibit memory impairments that are characteristic of dementia.
Another apparent difference is that early language impairment is seen in PiD that is out of proportion with impairments in other cognitive abilities. Although language is also impaired in AD, it usually occurs later in the disease course when there is also widespread cerebral dysfunction (Wechsler et al, 1982).
This also demonstrates the more severe involvement of left hemisphere in PiD compared to AD. However, within clinical settings the ability to differentiate the disorders based on contrasting symptoms is challenging as symptoms in both disorders are highly variable, depending upon the location of the cortical atrophy.
(2) Neuroimaging
The widely accepted view that Pick’s is too similar to Alzheimer’s disease to be reliable differentiated has inspired scientists to use modern technology in order to aid diagnosis. Computed tomographic and magnetic resonance imaging have shown that one of the cardinal features of Pick’s disease is circumscribed cortical atrophy, usually affecting the frontal and temporal lobes. Scans also show prominent widening of sulcal spaces in both the frontal and temporal lobes and the peri-Sylvian region. Often pathological changes are asymmetrical, whereby structural alterations are seen on one side more than the other (Munoz-Garcia & Ludwin,1984), with atrophy more commonly worse in the dominant hemisphere (usually the left).
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Sparing of occipital regions, parietal regions and the posterior two-thirds of the superior temporal gyrus is common (Dickson, 2001).
MRI studies of AD show global cerebral atrophy, predominantly affecting the temporal and parietal lobes early in disease progression. Atrophy of gyri and widening of sulci of the cerebral hemispheres is also evident. Atrophy is most apparent in the medial temporal lobe, particularly localised to the parahippocampal gyrus. The occipital lobe and motor cortex are generally spared.
Imaging techniques clearly show that in both disorders the cortex becomes shrunken or atrophied and is reduced in volume. However, in contrast to AD in which the atrophy is relatively diffuse and mild, the changes seen in PiD are usually more circumscribed and are often asymmetrical. In contrast to this, circumscribed cortical trophy is a rare finding in AD and changes are usually bilateral and symmetrical.
Frontal lobe involvement also differs between the two disorders. Early in the progression of AD the frontal lobes are less affected than the posterior cortex and do not demonstrate gross atrophy until later stages of the disease. In comparison, one the first signs of PiD is severe frontal lobe atrophy, leading to the observed behaviour abnormalities that are shown early in disease progression, but are not commonly seen in AD(Mendez et al, 1993).
(3) Gross Neuropathology
In agreement with the characteristics defined using imaging techniques, the hallmark of macroscopic findings in PiD is lobar or circumscribed cerebral atrophy affecting both the frontal and temporal lobes. In particular, the orbital frontal lobe and the medial and anterior temporal lobes are affected (for review see Dickson 1998).
The cerebral gyral atrophy in Pick’s disease is severe, producing gyri that are extremely thin and described as having a ‘’knife blade’’ appearance, with greatest cell loss in the 3 outer cortical layers (Corsellis, 1976).
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In contrast the pre-central gyrus and posterior two-thirds of the superior temporal gyrus are commonly preserved.
Atrophy is also apparent within limbic structures, most commonly affecting the amygdala, entorhinal cortex and cingulate gyrus. However, there appears to be confusion within the literature as to whether the hippocampus is relatively spared or profoundly atrophied in Picks disease. Bergeron’s review of Pick’s disease states that the hippocampus is often relatively preserved (Bergeron et al), but other case studies of Pick’s Disease report profound shrinkage of the hippocampus and associated structures (Wechsler et al, 1982).
In spite of this confusion the current data suggest that there is marked loss of small granular neurons in the dentate gyrus of the hippocampal formation within Pick’s disease.
In contrast, the most predominate atrophy in Alzheimer’s disease is seen in the posterior parietal areas, inferior temporal cortex and limbic cortex. The hippocampal region displays bilateral shrinkage of the hippocampal complex and compensatory enlargement of the temporal horn and of the lateral ventricles. Moderate to severe neuronal loss is also observed in the nucleus basalis of Meynert (Hirano & Zimmermann, 1962)
It can be seen that neuronal loss occurs in both Alzheimer’s and Picks disease alike. Studies have commonly demonstrated that the degree of neuronal and synaptic loss in PD is equal to or greater than is seen in AD. Further analysis of neuronal loss has demonstrated that that neuronal degeneration pattern in PD is clearly distinct from that in AD. Hyman and Hoesen’s analysis of the neuropathological changes of the temporal lobe in AD and PD suggests a greater neuronal loss in all cortical layers in comparison with a more pronounced laminar neuronal loss in AD (Hyman & Hoesen, 1994).
Widespread loss of dendritic spines in affected cortical areas resembled that seen in Alzheimer’s disease (12)
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It is also apparent that atrophy of limbic structures is evident in both diseases, but is often more pronounced in early stages of Alzheimer’s disease, where it correlates well with early cognitive deficits. The involvement of the hippocampus in AD is so pronounced that it has been suggested that the disease should be defined as a ‘hippocampal dementia’ (Ball et al, 1985).
However, it is hard to compare the two disorders with regards to hippocampal involvement as there appears to be a lack of consensus concerning the extent of hippocampal involvement in Picks disease. The changes seen in the hippocampus have been described as slight- to moderate (Heston et al, 1987) to severe (Wechsler et al, 1982).
Nevertheless, both dementias have in common a certain degree of degeneration of the hippocampus and amgydala, although the involvement of the hippocampus is less consistent and intense in PD compared to AD.
Furthermore, continual differences in neuronal degradation are also seen in the basal nucleus of Meynert. In contrast to Alzheimer’s disease, the basal nucleus of Meynert in PiD is relatively preserved (7), although there are reports of neuronal loss in a few cases. Hilt et al (1982), and Munoz-Garcia & Ludwin (1984) observed that the neuronal population in the nbM was reduced in patients suffering from PD. However, the pattern of neuronal loss was different from that observed in AD.
In AD there is a significant loss of cells in the nbM and this produces a deficit in cholinergic function as the nbM manufactures chloline acetyltransferase. This molecule is needed to join acetyl CoA to choline to make acetylcholine. Cummings reported the decrease in cholinergic activity to be between 80 and 90% in affected cortical regions of patients with AD. Therefore it is be reasonable to assume that if there was a similar neuronal loss in the nbM in PiD then there would be a corresponding decrease in ChAT production. The majority of studies investing the cortical cholinergic system in PiD have revealed relative preservation of cholinergic markers ( Wood et al, 1993).
Wood et al (1983) compared post-mortem material from the cortical cholinergic system in AD and PiD and found that ChAT was significantly decreased in Alzheimer’s but not in Pick’s dementia. The authors concluded that the cholinergic innervation of the cortex from the basal forebrain was intact in PiD but not in AD. Therefore it appears that the changes seen in the nbM are more varied in PiD.
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(4) Histopathological Findings
Microscopic inspection of neural tissue obtained from Pick’s patients shows a marked loss of pyramidal cells accompanied by globular, argentophillic inclusions (Pick Bodies), Hirano bodies and granulovacuolar degeneration. In areas of the neocortex which are more severely affected there is almost a complete loss of large pyramidal neurons with a corresponding collapse of the parenchyma, diffuse spongisosis and dense gliosis. White matter changes are commonly limited to demyelination and mild gliosis.
Pathological changes in AD include the presence of Hirano bodies and granulovacualr degeneration which are both found most prominently in the hippocampus. Glial cell reactions are also abundant, with astrocytes commonly observed in the grey and subcortical white matter appearing enlarged with increased size and number of processes and increased expression of GFAP (Esiri, 2000).
Agyrophillic plaques, neurofibrillary tangles and neuropil threads are also a consistent pathological finding.
Neuronal and synaptic loss accompanied by gliosis is seen in both disorders. On closer inspection the presence of Hirano bodies and granulovacuolar degeneration are also abundant in PiD and AD. Hirano bodies are eosinophillic intracytoplasmic inclusions, predominantly made up of aggregates of actin and actin associated proteins that affect the cytoskeletal structure of nerve cells. In both AD and PiD Hirano Bodies are found in CA1 area of the hippocampal formation and are often found near pyramidal cells which are affected by cytoplasmic granulovaculor degeneration.
Microglial cells are increased and activated in both AD and PiD, with abundant gliosis viewed in both disorders. Microglia are brain scavenger cells that respond to even minor neuronal alterations, therefore it is not surprising that they are abundant when massive neuronal degeneration occurs as seen in dementias like AD and PiD.
(5) Formation of Abnormal Structures
Two distinct neuronal changes are observed in degenerating areas in PiD: ballooned cortical neurons (BN) and spherical argrophillic inclusions known as Pick Bodies (PB).
Ballooned neurons, also referred to as swollen neurons are mainly composed of granulofilamentous material. (Dickson, 1998).
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They are differentiated from other neruons by swollen cytoplasm and laterally displaced nucleus in the cell. They are most abundant in areas of severe cortical atrophy, like the frontal cortex (9)
Pick bodies are spherical cytoplasmic inclusions that are well demarcated, amorphous and slightly basophilic on hematoxylin-eosin stain. They are argentophillic with Bielschowsky and Bodian silver stains but fail to react with Gallyas stain. They are primarily made up of abnormal aggregates of tau, a neuron specific protein usually associated with stabilization of microtubules. Studies of topographic distribution of Picks Bodies in cortex show that they are found in large numbers in the dentate fascia and pyramidal cell layer of the hippocampus, entorhinal cortex and frontal and temporal neocortices (Yasuhara et al, 1995) and are not uniformly or randomly distributed, but instead they are found in clusters.
The main lesions found in AD are neurofibrillary tangles and neuritic plaques. Neurofibrillary tangles (NFTs) are cytoplasmic bundles of paired helical filaments made from abnormally, hyperphosphorylated tau protein that are abundant in both the cerebral cortex and the hippocampus. NFT’s are most abundant in the hippocampus, entorhinal cortex and amyagdal as well as the areas that project into them. Neuritic plaques, often referred to as senile plaques, are spherical extracellular deposits of an insoluble form of β-amyloid peptide, surrounded by degenerating neurites and glial cells activated by inflammation processes. Insoluble Aβ, the main component of plaques, is a produced by abnormal cleavage near the transmembrane domain of Amlyoid Precursor Protein (APP).
This abnormal processing of APP produces peptides with 40 and 42 amino acids, instead of 40 amino acids, that rapidly aggregate to form fibrils with α-sheet structure.
In comparing the lesions found in both AD and PiD it is easy to identify the differences, but harder to distinguish similarities. Firstly, Pick bodies and ballooned neurons are rarely seen in AD (Dickson, 1998).
In comparison, amyloid plaques observed in AD are not seen in PiD and are believed to be relatively specific to AD and Downe Syndrome (Hasegaawa, 2004).
However, the N-terminal segment of APP (APPn), the precursor protein that amyloid plaques are made from, has been found in Pick’s Bodies (Yasuhara et al, 1994), but no plaques were found.
The main shared component between the two disorders is that they are both characterized by the presence of intracellular filamentous tau protein deposits. Both neurofibrillary tangles found in AD and Pick Bodies found in PiD are composed of tau that is both hyperphosphorylated and abnormally phosphorylated relative to tau from normal adult brains (King et al, 2001).
As a result tau is unable to bind to microtubules and the cytoskeleton in both diseases is disrupted. Both PB and NFTS will therefore immunostain with antibodies to tau as well as antibodies to ubiquitin (Jackson & Lowe, 1996) However, tau filamentous lesions in both AD and PiD differ in respect to distribution, morphology and pathology
Ultrastructural analysis of pathological tau in AD showed that the main component of NFTs are paired helical filaments (PHF) that are composed of two strands of filaments twisted around each other. Straight filaments are also present, but are not as abundant as PHF’s. In comparison, analysis of PB’s showed that they are predominantly made up of straight filaments, 10mm in diameter along with small amounts of intermediate filaments and PHF’s with periodicities longer than that found in AD (90 vs145nm) (King et al, 2001) Measurements of filament periodicities identified a single peak with an average of 80nm along long axis of PHF’s in AD. In comparison, two peaks where found for PiD filaments. The first peak was similar to PHF’s in AD with an average period of 90nm, however the second peak averaged 145 nm, longer than the filaments in AD (Buee & Delacourte, 1999).
Further analysis of purified PHF’s from AD brain by sodium-polyacrylamide gel electrophoresis has shown that in AD tau forms a major triplet band at 68, 64, and 60kDa, as well as a minor band at 72kDa (Greenberg & Davies, 1990, Greenberg et al, 1991).
In contrast, western blot analysis of tau in PB’s has shown that it is distinctively different from tau in AD in as it is made up of 2 major bands at 60 and 64kDa and a variable minor band 68kDa ( Liberman et al 1998).
Normal adult nervous systems contain 6 isoforms of tau with 3 or 4 microtubule binding repeats that are generated by alternative RNA splicing. It was initially thought that because the major bands in PB did not include the microtubule-binding repeat that is encoded by exon 10, that they were comprised of entirely 3R (Sergeant et al 1997).
However, recent research has revealed that 4-repeat tau is also present, but in smaller amounts and usually detected in glial cells (Zhukarera et al 2002).
In contrast, PHF in AD does not lack exon 10 and is comprised of approximately equal amounts of 3-repeat and 4-repeat tau (Hong et al, 1998).
More detail analysis of expression of tau in both Alzheimer’s and Pick’ disease shows that on a molecular level that highly specific dysfunction of certain kinases and phosphatase enzyme cascades may be altered. These are important at they serve to regulate the phosphorylation of tau. Interestingly, research has also show that the kinases and phosphatases involved may differ between Alzheimer’s and Picks disease, but more research is needed before conclusions can be made ( Hof et al, 1994).
Furthermore, the topographic distribution of PB in the hippocampus has a very similar distribution to NFT found in AD. However, the main difference observed between the two disorders is that the dentate fascia is more vulnerable to PB but not to NFTs. PB’s can be distinguished from NFTs by their more homogenous staining. In addition both NFTs and PBs are recognised by phosphorylation dependant antibodies like AT8 as they share a number of phosphorylated sites (Tolnay & Probst 1999).
However, the antibody 12E8 is not able to recognise tau in PBs because of the absence of phosphorylation of the exon 9 residue Ser262. Therefore on biochemical analysis PB’s are 12E8 negative, whereas NFTs are 12E8 positive.
Both dementias also have neuropil threads (NT) in pathological states. They are often present in larger numbers in NFT-containing neuropils in AD (Braak et al, 1986).
They also show variable distribution and density patterns in different areas and cortical layers in both diseases. Davis, Wang and Markesberg (1992) investigated neuropil threads in several dementing disorders. They observed that in AD 6.87% of the cortical area was occupied by neuropil threads and 0.3% in PiD versus 0.02% in controls. Therefore neuropil threads were present in both AD and PiD brains, but abundant numbers of NT are primary found in AD and not PiD.
It is evident that despite familiarity with the pathology of both Picks and Alzheimer’s disease that it is only recently that scientists are beginning to develop a true understanding of these neurodegenerative disorders. There is hope that with increasing ability to reliably differentiae the two diseases that clinicians will be able to capitalise on differences between disorders in order to promote effective diagnoses. Specific sets of Tau isoforms distinguish between typical neuronal inclusions and could be used in clinical practise to establish which inclusions are present and deduce the type of dementia. Overall the aim of researchers and clinicians alike should be to delineate neurodegenerative syndromes more accurately and hopefully in the near future to develop effective treatments as understanding about dementia continues to grow.
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