Staging/typing of Lewy body related α-synuclein pathology: A study of the BrainNet Europe Consortium

Department of Neuroscience and Neurology, Kuopio University, Kuopio, Finland.
Acta Neuropathologica (Impact Factor: 10.76). 04/2009; 117(6):635-52. DOI: 10.1007/s00401-009-0523-2
Source: PubMed


When 22 members of the BrainNet Europe (BNE) consortium assessed 31 cases with alpha-synuclein (alphaS) immunoreactive (IR) pathology applying the consensus protocol described by McKeith and colleagues in 2005, the inter-observer agreement was 80%, being lowest in the limbic category (73%). When applying the staging protocol described by Braak and colleagues in 2003, agreement was only 65%, and in some cases as low as 36%. When modifications of these strategies, i.e., McKeith's protocol by Leverenz and colleagues from 2009, Braak's staging by Müller and colleagues from 2005 were applied then the agreement increased to 78 and 82%, respectively. In both of these modifications, a reduced number of anatomical regions/blocks are assessed and still in a substantial number of cases, the inter-observer agreement differed significantly. Over 80% agreement in both typing and staging of alphaS pathology could be achieved when applying a new protocol, jointly designed by the BNE consortium. The BNE-protocol assessing alphaS-IR lesions in nine blocks offered advantages over the previous modified protocols because the agreement between the 22 observers was over 80% in most cases. Furthermore, in the BNE-protocol, the alphaS pathology is assessed as being present or absent and thus the quality of staining and the assessment of the severity of alphaS-IR pathology do not alter the inter-observer agreement, contrary to other assessment strategies. To reach these high agreement rates an entity of amygdala-predominant category was incorporated. In conclusion, here we report a protocol for assessing alphaS pathology that can achieve a high inter-observer agreement for both the assignment to brainstem, limbic, neocortical and amygdala-predominant categories of synucleinopathy and the Braak stages.

Download full-text


Available from: Dietmar Thal, Oct 01, 2015
1 Follower
124 Reads
  • Source
    • "Abasic sites are a type of DNA damage, often arising from oxidative stress, in which there is loss of a purine or a pyrimidine base. Given that polymorphisms in DNA repair genes, including a protein involved in the repair of abasic sites (Alafuzoff et al., 2009), were recently reported to be risk factors for developing PD, we investigated the role of abasic sites in human PD brain postmortem tissue. Coded midbrain and cortex brain sections from control and PD cases were obtained for abasic site detection, and only after analysis were samples unblinded (Supplemental Table 1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: DNA damage can cause (and result from) oxidative stress and mitochondrial impairment, both of which are implicated in the pathogenesis of Parkinson's disease (PD). We therefore examined the role of mitochondrial DNA (mtDNA) damage in human postmortem brain tissue and in in vivo and in vitro models of PD, using a newly adapted histochemical assay for abasic sites and a quantitative polymerase chain reaction (QPCR)-based assay. We identified the molecular identity of mtDNA damage to be apurinic/apyrimidinic (abasic) sites in substantia nigra dopamine neurons, but not in cortical neurons from postmortem PD specimens. To model the systemic mitochondrial impairment of PD, rats were exposed to the pesticide rotenone. After rotenone treatment that does not cause neurodegeneration, abasic sites were visualized in nigral neurons, but not in cortex. Using a QPCR-based assay, a single rotenone dose induced mtDNA damage in midbrain neurons, but not in cortical neurons; similar results were obtained in vitro in cultured neurons. Importantly, these results indicate that mtDNA damage is detectable prior to any signs of degeneration - and is produced selectively in midbrain neurons under conditions of mitochondrial impairment. The selective vulnerability of midbrain neurons to mtDNA damage was not due to differential effects of rotenone on complex I since rotenone suppressed respiration equally in midbrain and cortical neurons. However, in response to complex I inhibition, midbrain neurons produced more mitochondrial H2O2 than cortical neurons. We report selective mtDNA damage as a molecular marker of vulnerable nigral neurons in PD and suggest that this may result from intrinsic differences in how these neurons respond to complex I defects. Further, the persistence of abasic sites suggests an ineffective base excision repair response in PD.
    Neurobiology of Disease 06/2014; 70. DOI:10.1016/j.nbd.2014.06.014 · 5.08 Impact Factor
  • Source
    • "Cases were further confirmed neuropathologically for α-synucleinopathy. Using BNE’s staging protocol for α-synuclein pathology [38,39], 10 cases from Braak stage 6, 6 cases each from stages 4 and 5, and 5 cases from stage 3 were used in this study. The frontal cortex, cingulate cortex, striatum, nucleus basalis of Meynert (NBM), hippocampus, midbrain, pons, and medulla were obtained from each case. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Microglial activation is a pathological feature common to both Alzheimer's and Parkinson's diseases (AD and PD). The classical activation involves release of pro-inflammatory cytokines and reactive oxygen species. This is necessary for maintenance of tissue homeostasis and host defense, but can cause bystander damage when the activation is sustained and uncontrolled. In recent years the heterogeneous nature of microglial activation states in neurodegenerative diseases has become clear and the focus has shifted to alternative activation states that promote tissue maintenance and repair. We studied the distribution of CD163, a membrane-bound scavenger receptor found on perivascular macrophages. CD163 has an immunoregulatory function, and has been found in the parenchyma in other inflammatory diseases e.g. HIV-encephalitis and multiple sclerosis. In this study, we used immunohistochemistry to compare CD163 immunoreactivity in 31 AD cases, 27 PD cases, and 16 control cases. Associations of microglia with pathological hallmarks of AD and PD were investigated using double immunofluorescence. Parenchymal microglia were found to be immunoreactive for CD163 in all of the AD cases, and to a lesser extent in PD cases. There was prominent staining of CD163 immunoreactive microglia in the frontal and occipital cortices of AD cases, and in the brainstem of PD cases. Many of them were associated with Ass plaques in both diseases, and double staining with CD68 demonstrates their phagocytic capability. Leakage of fibrinogen was observed around compromised blood vessels, raising the possibility these microglia might have originated from the periphery. Increase in microglia's CD163 immunoreactivity was more significant in AD than PD, and association of CD163 immunoreactive microglia with Abeta plaques indicate microglia's attraction towards extracellular protein pathology, i.e. extracellular aggregates of Abeta as compared to intracellular Lewy Bodies in PD. Double staining with CD163 and CD68 might point towards their natural inclination to phagocytose plaques. Fibrinogen leakage and compromise of the blood brain barrier raise the possibility that these are not resident microglia, but systemic macrophages infiltrating the brain.
    02/2014; 2(1):21. DOI:10.1186/2051-5960-2-21
  • Source
    • "Additionally, the striatum receives serotonergic input from the oral raphe nuclei and noradrenergic innervations from the locus coeruleus. Both of these nuclei show degenerative changes in a variety of neurodegenerative diseases (amongst others PD) and contribute to the clinical picture (Braak et al., 2003; Alafuzoff et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuropathology of hyperkinetic movement disorders can be very challenging. This paper starts with basic functional anatomy of the basal ganglia in order to appreciate that focal lesions like for instance tumor or infarction can cause hyperkinetic movement disorders like (hemi)ballism. The neuropathology of different causes of chorea (amongst others Huntington's disease, neuroacanthosis, and HLD-2) and dystonia (DYT1, PD, and Dopa-Responsive Dystonia) are described. Besides the functional anatomy of the basal ganglia a wider anatomical network view is provided. This forms the basis for the overview of the neuropathology of different forms of tremor.
    Frontiers in Neurology 02/2013; 4:7. DOI:10.3389/fneur.2013.00007
Show more