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Keywords:

  • multiprotein;
  • neurodegeneration;
  • Brain Bank

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED

The prevalence of neurodegenerative disorders increases dramatically with advancing age. Although in recent decades the study of many neurodegenerative disorders has evolved greatly, the concept of neurodegeneration still remains elusive. Although neurodegenerative disorders are classified according to the major components of protein deposits, coexpression of several abnormal proteins in the brain tissue is more common than that was previously thought. The aim of this report is to describe the type of protein deposits found in brains with neuropathological diagnosis of neurodegenerative disease. The report shows the experience obtained in the Brain Bank of Navarra (Spain). The target population for this retrospective descriptive study comprised 178 brains autopsied in the “Hospital of Navarra” in Pamplona between 1994 and 2004 and 201 brains donated to the Brain Bank of Pamplona between 2004 and 2009. The diagnosis of the 201 brains from the Brain Bank was 62 (30.8%) Alzheimer's disease (AD), 43 (21.3%) multiprotein deposit, 31 (15.4%) α-synucleinopathies, 31 (15.4%) frontotemporal lobar degeneration (FTLD), 17 (8.4%) tauopathies, 9 (4.4%) prion disease, 6 (2.9%) vascular dementia (VD), and 2 (0.9%) Huntington's disease. Among the 43 cases with multiprotein deposits, we found 35 brains with deposits of 3 proteins (tau, β-amyloid, and α-synuclein). In these two series of brains, the high incidence of deposition of multiple proteins in neurodegenerative disorders is shown. Our results are in agreement with previous findings showing that tau, β-amyloid, and α-synuclein are the proteins most frequently deposited together. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

The average life expectancy of many populations throughout the world now extends late into the eighth decade, and the prevalence of most neurodegenerative disorders increases dramatically with advancing age. Although in recent decades the study of many neurodegenerative disorders has evolved greatly, the concept of neurodegeneration still remains elusive (Taylor et al., 2002; Forman et al., 2004). In particular, the molecular events leading to the formation of the neuropathological hallmarks of the specific illnesses (e.g., senile plaques, neurofibrillary tangles, and Lewy bodies) are only partially understood (Sorrentino and Bonavita, 2007). It is known that the deposit of abnormal proteins is a common feature shared by all neurodegenerative disorders (Taylor et al., 2002; Ramchandani, 2004). Presently, neurodegenerative disorders are classified according to known genetic mechanisms or the major components of protein deposits. Nevertheless, coexpression of several abnormal proteins in the brain tissue is more common than that has previously been thought. Recent reports have shown that neurodegenerative dementia may be characterized by deposition of different proteins occurring together (Armstrong et al., 2005; Galpern and Lang, 2006; Schneider et al., 2007; Kovacs et al., 2008; Arai et al., 2009; Dickson, 2009; Jellinger, 2009). The main proteins involved in the pathogenesis of neurodegenerative diseases are β-amyloid, tau, and α-synuclein. Abnormalities of these three proteins account for 70% of all dementias and more than 90% of all neurodegenerative dementias (Cummings, 2003). The most common of the neurodegenerative disorders is Alzheimer's disease (AD), which is characterized by deposits of β-amyloid and tau protein. Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and amyotrophic lateral sclerosis–parkinsonism dementia complex, in past collectively designated as tauopathy, are related to abnormalities in the tau protein metabolism (Goedert, 2004). Nowadays, not only tau but also TAR DNA-binding protein 43 (TDP-43) is admitted as cause of frontotemporal lobar degeneration (FTLD). Parkinson's disease, dementia with Lewy bodies (DLB), and multiple system atrophy, grouped together under the term synucleinopathy, are related to abnormal α-synuclein metabolism (Galvin et al., 2001). Abnormal deposit of less common proteins is involved in other neurodegenerative diseases such as Huntington's disease (huntingtin). Furthermore, recent molecular biology and genetic studies suggest that there are both overlap and intraindividual diversities between different phenotypes. This is believed to be related to synergistic mechanisms between major pathologic proteins (Forman et al., 2004).

The aim of this report is to describe the type of protein deposits in brains with neuropathological diagnoses of neurodegenerative disease. The report shows the experience obtained in the Brain Bank of Navarra (Spain). Two series form the object of the study: the former, coming from patients who died during 1994–2004 whose brains are stored in the Department of Pathology, and the latter from the Tissue Brain Bank. We expect to find more than one misfolded or abnormal protein in same brain tissue.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED

The target population of this retrospective descriptive study comprised 178 brains autopsied in the “Hospital de Navarra” in Pamplona between 1994 and 2004 and 201 brains donated to the Brain Bank of Pamplona between 2004 and 2009. All cases had a neuropathological diagnosis of neurodegenerative disorder. All the donors from the Brain Bank in this study were patients with clinical diagnosis of neurodegenerative disorders. Control cases without neurological disorders were also microscopically studied but not included in the study. Necropsy permission or informed consent was obtained respectively in both groups. Part of the study was carried out in the Department of Pathology at the “Hospital de Navarra,” where both hemispheres of the brain were used. Given standard practices in place at the neurological tissue banks whereby the left hemisphere is frozen, in such cases the study was carried out on the right cerebral hemisphere. Following fixation in formaldehyde (10%) for ∼3 weeks, the brain was sectioned. The procedure for fixing and sectioning is recommended by BrainNet Europe (Bell et al., 2008). The macroscopic study of the brains included photographs, weight, pH measurement, cerebrospinal fluid samples (where possible), and macroscopic description. The samples examined and immunohistochemical stains used in each case are shown in Table 1. Each paraffin block was stained with hematoxylin and eosin (H&E). The antibody dilutions were: tau, 1:100; β-amyloid, 1:200; TDP-43, 1:1700; PrP, 1:100; α-synuclein, 1:50; ubiquitin, 1:700; and α,β-crystallin, 1:100. The criteria used in carrying out the following diagnoses were drawn from other studies: vascular dementia (VD; O'Brien et al., 2003), mixed dementia (Zekry et al., 2003), AD (Braak and Braak, 1991), dementia with Lewy bodies (DLB) (McKeith et al., 2005), Huntington's disease (Vonsattel et al., 1985), hippocampal sclerosis (Kalaria et al., 2004), FTLD, FTLD with TDP-43 positive inclusions (Cairns et al., 2007), prion diseases (Budka et al., 1995), PSP (Hauw et al., 1994), and CBD (Dickson et al., 2002). In the multideposit group, we included all the cases with deposits of different proteins fitting major neuropathological criteria for at least two different neurodegenerative disorders.

Table 1. Immunostains and regions
Regionsα-Synucleinβ-AmyloidTauTDP-43Ubiquitinα,β-CrystallinPrP
Cingulate gyrusxx     
Motor gyrus xx    
Frontal gyrusxxxxxx 
Anterior thalamus xx    
Putamen  x    
Globus pallidus  x    
Hippocampusxxxxx  
Superior temporal gyrusxxxxx  
Medio temporal gyrusxxxxx  
Parietal gyrusxxx   x
Occipital gyrus xx    
Substantia nigraxxx    
Ponsxxx    
Medulla oblongataxxx    
Amygdalaxxx  x 
Caudate-acumbens xxxx  
Olfactory bulbxxxxx  
Nucleus basalis of Meynertx x    
Cerebellum (vermis) x    x

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED

The mean age of cases was 81 years old. The diagnoses of the 201 brains from the Brain Bank were 62 (30.8%) AD, 43 (21.3%) multiprotein deposit, 31 (15.4%) α-synucleinopathies, 31 (15.4%) FTLD, 17 (8.4%) tauopathies, 9 (4.4%) prion disease, 6 (2.9%) VD, and 2 (0.9%) Huntington's disease. Among the 43 cases with multiprotein deposits, we could find (Fig. 1) 35 brains with deposit of three proteins (tau, β-amyloid, and α-synuclein), four brains with deposit of four proteins (tau, Figs. 2 and 3; β-amyloid, Figs. 4 and 5; α-synuclein, Figs. 6 and 7; and TDP-43, Figs. 8 and 9), two with deposit of TDP-43 and tau, and two with deposit of α-synuclein and tau. The characteristics of the 43 cases from the Brain Bank with multiprotein deposits were as follows: from the 35 brains with deposit of 3 proteins (tau, β-amyloid, and α-synuclein), 1 of them fitted criteria for PSP. The remaining 34 fitted criteria for both DLB and AD. The four brains with deposit of four proteins (tau, β-amyloid, α-synuclein, and TDP-43) fitted criteria for AD and DLB and FTLD with TDP-43 positive inclusions. These four TDP-43 positive cases showed intracytoplasmic inclusions in neurons in the hippocampus, temporal cortex, and striate nucleus. One of them showed intracytoplasmic inclusions in glial cells, two of them showed intranuclear (“cat-eye-like”) inclusions and none of them showed inclusions in motoneurons. From the two with deposit of TDP-43 and tau both fitted criteria for AD, showed TDP-43 positive intracytoplasmic inclusions in neurons in the hippocampus, temporal cortex, striate nucleus, and motor neurons in the anterior horn of the spinal cord. The two cases with deposits of α-synuclein and tau fitted DLB criteria, one of them also CBD criteria and the other one also PSP. All the cases from this sample of brains with multiprotein deposit that fitted criteria for AD had experienced cognitive impairment during life. From the 35 cases that fitted DLB criteria, 30 of them (85%) had parkinsonism when alive. The two cases diagnosed with PSP and the one with DCB had parkinsonism and of the six cases that fitted criteria for FTLD with TDP-43 positive inclusions, two had had clinical symptoms of motor neurone disease. According to the pattern of regional involvement described by McKeith et al. (1996, 2005), all the cases diagnosed with DLB had a limbic or diffuse neocortical pattern. This means that all the brains showed brainstem involvement (IX–X cranial nerves, locus ceruleus, and substantia nigra) and the degree of limbic involvement was at least moderate in the amygdala and basal Meynert nucleus, and at least mild in the transentorhinal and cingulate cortex. According to the different stages in the gradual accumulation of neurofibrillary tangles and neuropil threads defined by Braak and Braak (1991), all brains diagnosed with AD showed at least one stage out of IV, and according to the different stages in the gradual accumulation of amyloid deposits defined by Braak and Braak (1991), brains diagnosed with AD could be at any of the three possible stages (A, B, or C). The diagnosis of the 178 brains from the autopsies of “Hospital de Navarra” was 88 (49.3%) AD or Alzheimer-related changes (neurofibrillary tangles or amyloid plaques), 35 (19.6%) α-synucleinopathies, 30 (16.8%) multiprotein deposits, 14 (7.8%) tauopathies, 6 (3.3%) prion diseases, 1 (0.5%) hippocampal sclerosis, and 4 (2.2%) other diagnoses.

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Figure 1. Number of multiple protein deposits. Sample from the Brain Bank of Navarre.

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Figure 2. Hyperphosphorylated tau protein inside and outside neurons forming neurofibrillary tangles (arrow) and dystrophic neurites (head arrow), respectively.

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Figure 3. Protein tau hyperphosphorylated at higher magnification in a case of AD.

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Figure 4. Immunohistochemistry for Aβ-42 in temporal cortex at low magnification. "Cotton-like" deposits in diffuse sensile plaques.

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Figure 5. Amyloid deposition in meningeal and cortical arteries (arrow) in frontal cortex.

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Figure 6. Patient of Figs. 4 and 5 showed not only Aβ-42 but also Lewy bodies (arrow) stained by α-synuclein.

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Figure 7. Lewy body and dystrophic neurites (arrow) in a patient whose brain expressed not only α-synuclein but also tau and amyloid.

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Figure 8. Abnormal TDP-43 distribution in a case of frontotemporal degeneration. Note that the protein is not inside the nucleus but inside the cytoplasm.

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Figure 9. FTLD. "Cat-eye" like TDP-43+ intranuclear inclusion (arrow).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED

In these two series of brains, the high incidence of deposits of multiple proteins in neurodegenerative disorders is shown. We know that the use of antibodies in immunohistochemistry has led to an improvement in the diagnosis of various disorders and has also contributed to our knowledge of new entities. As early as 1991, Prusiner (1991) after an outbreak of spongiform encephalopathy pointed out the important role of deposition of proteins in the pathogenesis of neurodegenerative disorders. Presently, neurodegenerative diseases are classified according to the predominant protein that is deposited. But widespread application of these immunohistochemical and biochemical investigations is now revealing that disease forms characterized by the accumulation of a single protein are rather the exception than the rule. A spectrum of disorders characterized by the deposition of various modified proteins in certain locations has been demonstrated. The concomitant presence of pathologically altered proteins defines a spectrum rather than pure disease forms and protein deposits may influence the involvement of other proteins (Andersen, 2004; Beal, 2005; Roy et al., 2005; Esiri, 2007). In the central nervous system, when a protein is not well synthesized, is synthesized in excess, changes its shape, is deposited in an abnormal way, is misfolded or not removed if it is denatured, the same reaction ensues in the other proteins and the toxic effect of each one of them is added (synergistic effect). This leads to neurone death. This was defined by Kovacs as the orchestral concept of protein deposition (Kovacs et al., 2010). Our results stress the importance of providing insight into the degeneration programs common to this group of disorders. Our study is also in agreement with previous findings showing that tau, β-amyloid, and α-synuclein are the proteins more frequently deposited together. There is evidence that tau and α-synuclein can promote each other's fibrillization in vitro and in vivo (Wirths et al., 2000; Giasson et al., 2003; Popescu et al., 2004; Clinton et al., 2010) and that the misfolding and aggregation of a disease protein may disrupt normal cellular mechanisms, thereby predisposing other proteins to aggregate (Gidalevitz et al., 2006). More specifically, Obi et al. (2008) hypothesized that unidentified factors induce aggregation of either tau or α-synuclein, potentially enhanced by Aβ deposition, which may shift toward different disease entities (AD or DLB) or mixed forms (AD + DLB). According to the bibliography, although in AD, Lewy bodies may be detected in a high proportion in various locations (Uchikado et al., 2006b), the frequency of Lewy bodies is not increased in PSP as compared with controls, and the presence of tauopathy does not alter significantly the distribution of Lewy bodies; thus, in this case, Lewy body pathology most probably represents an independent disease process (Uchikado et al., 2006a). Regarding coaccumulation of TDP-43, tau, β-amyloid, and α-synuclein deposits, our study is also in agreement with previous reports. TDP-43 pathology has been shown to occur in entorhinal and hippocampal sections of 30% of all AD brains (Amador-Ortiz et al., 2007) and also in 30% of brains with concomitant AD and DLB pathology (Nakashima-Yasuda et al., 2007). Moreover, in our study, TDP-43 positive deposits were not restricted to the limbic system but also involved basal ganglia and neocortical areas in several cases. The extent to which AD pathology versus α-synuclein lesions drive the accumulation of TDP-43 pathology—in the limbic system—in DLB + AD remains to be determined.

One important aspect that remains unclear is the impact of these findings on the clinical manifestations of the pathological processes. The revised consensus criteria (McKeith et al., 2005) have recommended taking AD-related pathology into account when assessing subjects with DLB. We only studied a gross clinical correlation between AD and cognitive impairment and between DLB and parkinsonism, but not between cognitive impairment and DLB, as the pathological hallmarks leading to the cognitive expression of DLB are still a matter of discussion. Although the diagnosis of multiprotein deposits in our study mixes different pathologies that can potentially cause cognitive impairment, we can suggest that, as expected according to the literature (Nelson et al., 2007), all cases fitting AD criteria had cognitive impairment when alive. On the other hand, although one of the main symptoms of DLB is parkinsonism (McKeith et al., 2005), not all the cases with DLB showed parkinsonism in our study. This is in agreement with Parkkinen et al. (2008), whose study emphasized that abundant α-synuclein pathology may be detected in subjects without clinical symptoms.

The fact that many proteins may interact and promote the formation of disease-associated variants in the same brain, irrespective of how we name a disease in neuropathology, was named by Trojanowski and Lee (2003) the “fatal attraction or proteins.” This leads to the question as to whether neurodegenerative disorders are considered by some to form a continuum (Armstrong et al., 2005).

We would like to conclude this article by stressing that further understanding of mechanisms regulating protein processing and aggregation is needed, if we want to facilitate development of therapies designed to treat and prevent these disorders. These therapies should be focused on the process that follows each one of the proteins and look for the point where this process was unleashed.

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  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED
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