Staging of brain pathology related to sporadic Parkinson’s disease
Introduction
Sporadic Parkinson’s disease (PD) is a progressive degenerative illness of the human nervous system that manifests itself clinically after the pathology already has reached an advanced stage [31], [32], [51]. A prerequisite for the post-mortem diagnosis of both the presymptomatic and symptomatic phases of the pathological process underlying PD is evidence of specific inclusion bodies, which develop as spindle- or thread-like Lewy neurites (LNs) in cellular processes, and in the form of globular Lewy bodies (LBs) in neuronal perikarya [33], [53], [54], [60]. In sporadic PD, only a few specific types of nerve cells are prone to develop the lesions. A major component of LNs and LBs is an aggregated form of the normally presynaptic protein α-synuclein. It is still unknown why this hydrophilic protein leaves its binding sites within synaptic boutons and, together with other components such as phosphorylated neurofilaments and ubiquitin, a heat shock protein required for the non-lysosomal ATP-dependent breakdown of abnormal proteins, gradually transforms into virtually insoluble LNs or LBs [1], [2], [15], [25], [29], [41], [49], [67], [70].
Damage to specific subnuclei of the substantia nigra, pars compacta, with severe obliteration of their neuromelanin-laden projection neurons, frequently is considered to be the most important hallmark of PD [20], [31], [38], [39], [43]. The nigral damage, however, always is accompanied by extensive extranigral pathology, including that in the dorsal motor nucleus of the glossopharyngeal and vagal nerves (i.e. dorsal IX/X motor nucleus) and adjoining intermediate reticular zone, in some subnuclei of the reticular formation and the raphe system, the coeruleus–subcoeruleus complex, the magnocellular nuclei of the basal forebrain, and many subnuclei of the thalamus and amygdala. Cases with severe damage usually show lesions reaching the neocortex [10], [13], [22], [23], [50], [53], [63].
The question arises as to whether the pathology evolves simultaneously at all of these nigral and extranigral induction sites or whether the various sites differ in their susceptibilities to develop the disease-related alterations and, accordingly, follow a coherent sequence. The present study, therefore, intentionally includes a spectrum of cases exhibiting LNs and LBs in a specific subset of neuronal types and predilection sites, which are known to be involved in clinical PD cases. In doing so, we assume it to be correct that nonsymptomatic and symptomatic cases can be ordered in such a manner that cases exhibiting the mildest pathology represent the starting point and those most heavily involved the terminus of a disease spectrum, with a tendency toward increasing severity on the part of the overall pathology (Table 2). According to this assumption, the neuronal damage does not develop randomly but, rather, follows a predetermined sequence marked by characteristic changes in topographical extent. The present study is aimed at working out a neuropathological staging procedure based upon the topography of these changes. It is not our intent here to correlate the proposed neuropathological stages with clinical symptoms. Furthermore, we would like to emphasize that the study sample does not include cases clinically diagnosed as diffuse LB disease. Likewise, we did not detail study cases which were neuropathologically classified as fully-developed Alzheimer’s disease (AD) with co-occurring LBs and LNs in prosencephalic areas. It remains to be seen whether deviations from the proposed staging scheme exist in cases of advanced AD with LBs or in cases of clinically assessed diffuse LB disease.
Section snippets
Materials and methods
Three groups of cases were studied. The first group consisted of brains obtained at autopsy from 41 individuals with clinical diagnoses of PD (19 females, 22 males, aged 75.7±7.2 years, Table 2). The clinical protocols of these cases noted the predominance of either tremor or rigidity combined with hypokinesia and postural instability. The brain tissue exhibited nigral LBs and severe loss of nigral neuromelanin-laden neurons [16], [30], [37], [62] (Fig. 2).
The second group included autopsy
Results
The brains of all of the incidental cases and of individuals with clinically overt sporadic PD display the presence of α-synuclein-immunoreactive LNs and LBs while at the same time being free of intracytoplasmic inclusions related to non-PD α-synucleinopathies [35], [41]. The concomitant AD-related pathology lies within the expected range of the respective age groups [9].
LBs usually are present as spherical or reniform, weakly acidophilic inclusion bodies with smooth surfaces, varying in shape
Discussion
The α-synuclein-containing inclusion bodies found in the incidental and symptomatic cases are pathological and usually not considered to be normal concomitants of brain aging [12], [24]. On account of their immunocytochemical profile, they hardly can be mistaken for the lesions occurring in other neurodegenerative disorders that do not belong to the group of synucleinopathies. The induction sites and cell types involved in multiple system atrophy or Hallervorden–Spatz disease differ from those
Acknowledgements
This study was supported by the Deutsche Forschungsgemeinschaft. The kind contribution of Dr. W.P. Gai was supported by funding from the NHMRC (Department of Human Physiology, Flinders Medical Centre, Bedford Park, Australia). Our thanks also go to I. Szász (graphics) and to A. Biczysko and M. Babl for their skillful laboratory technical assistance.
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