Most of our (83%) αS-positive cases could be assigned to one of the six PD stages as described by Braak and also into the brainstem, limbic or diffuse neocortical neuropathological category as recommended by McKeith and colleagues [4
]. Braak and colleagues depicted the topographical distribution of αS-IR structures by assessing 110 αS-positive subjects (69 incidental and 41 symptomatic PD patients) [4
]. The initial intent of Braak and colleagues was not to correlate the designated neuropathological stages with clinical symptoms, however this was later contemplated [5
]. Stages 1 and 2, i.e. stages where αS pathology is confined to the dmV and/or LC, are considered to be presymptomatic, whereas EPS appear and the cognitive decline increases with each stage. In stage 3, when SN is affected, EPS appear and subsequently in stage 4 when amygdaloid complex, transentorhinal region and temporo-occipital gyrus become involved, moderate cognitive impairment is observed (MMSE scores 21–24) and finally in stage 5 and 6 when the neocortex succumbs to the pathology, severe cognitive impairment is evident (MMSE scores 11–20 and 0–10, respectively) [5
]. Our results also suggest that the risk of EPS increases with disease progression though not to the same extent as earlier reported. In our study, we found one subject with EPS already in stage 2, whereas none of our cases in stage 4 displayed EPS, and more importantly no EPS had been reported in 55% of subjects who exhibited widespread pathology (Braak stages 5–6), i.e. this being compared with the 14% previously reported by Braak and colleagues [4
The initial decline in cognition was postulated to occur already during stages 3 and 4 i.e. around the same time when the initial manifestation of somatosensor dysfunction start to appear. When assessing 88 subjects, Braak and colleagues reported, that 36% of their subjects in stage 3, 67% in stage 4, 94% in stage 5 and 100% in stage 6 were demented [5
]. This is clearly in odds with our results where the percentage of demented increased from none to 50% between stages 3–6. It is noteworthy that when only demented subjects were included, 91% were assigned to PD-related Braak stages 5–6 and when only subjects with EPS were included, 94% were in the PD-related Braak stages 5–6. Thus the key difference between our study when compared to most other clinico-pathological correlation studies that have reported good correlation between risk of disease and progression of pathology is the study design [5
]. Consequently, when we only included subjects with clinical signs in our analysis the correlation between stage/severity of αS pathology and EPS/dementia was excellent in line with previous reports.
PD and DLB are distinguished as separate clinical entities and in 1996 the consortium of the DLB international workshop subdivided the neuropathological features of DLB into three categories: brainstem predominant, limbic and diffuse neocortical type [27
]. The foundation of these three categories is also based on the progressive propagation of αS pathology along a caudo-striatal axis. Similarly to the Braak staging [4
], when applying this categorization it is presumed that 100% of subjects with widespread αS pathology, i.e. in the diffuse neocortical stage all will be demented and display EPS. When we followed the classification strategy proposed by McKeith and colleagues [28
], our results also differed from those expected, i.e. only a subset of our subjects who were classified to be in the diffuse neocortical category displayed dementia and/or EPS (57 and 47%, respectively). In line with the above, when only demented subjects were included in the analysis the correlation between αS pathology and dementia was close to excellent (85%).
The clinical relevance of cortical αS pathology in relation to dementia is a matter of intense debate. Some authors have emphasized their key causative role [1
], whereas others have reported that there may be abundant cortical pathology in non-demented PD patients [8
] as well as in neurologically unimpaired subjects [10
]. It is noteworthy that the current study differs significantly from most other studies since it is based on neuropathologiacal findings rather than on clinical presentation. Our results emphasize that abundant pathology may be detected in many subjects without notable signs of dementia (MMSE >26) (43%), if it is sought. This has one unexpected consequence, i.e. a detailed regional assessment of αS pathology cannot reliably predict the clinical status observed premortem [33
There has been much discussion concerning the significance and influence of concomitant AD-related pathology, particularly as this is quite frequently seen in aged subjects. Therefore, the revised consensus criteria have recommended taking AD-related pathology into account while assessing subjects with suspected DLB [28
]. It was presumed that this would increase the diagnostic specificity since it was believed that the pathological substrate behind DLB was indeed αS pathology. When we assessed our unique material, we found, that within the neuropathological high likelihood categories of DLB, i.e. those cases where limbic/diffuse neocortical αS pathology is combined with mild/moderate AD-related changes, 56% of subjects remained cognitively intact. However, when we examined only demented subjects without severe AD-related pathology (Braak’s AD stage V-VI), 85% were assigned to a high likelihood category of DLB. This shows that when αS pathology is examined in clinically demented subjects, the correlation received between particular pathologic change and dementia is good. It is noteworthy that with respect of AD-related neurofibrillary pathology, all cases in the neocortical stage (Braak stage V-VI) were indeed demented.
One important issue with respect to the pathogenesis of synucleinopathies is not only to understand the molecular mechanisms behind the intracytoplasmic aggregation of αS, but also to appreciate where this process first appears and how it may progress through the brain. Thus, many recent studies have attempted to localize the most vulnerable neuronal populations. In this study, dmV and SN were found to be equally susceptible nuclei, but even earlier affected structures have been reported to appear in the spinal cord, dmV, olfactory bulb and AC [2
]. Thus, mapping out the “trigger site” for αS pathology appears to depend on the screening process i.e. if one screens medulla alone, those cases where lesions are restricted to other areas (e.g. SN) are not found and vice versa.
At variance to the studies of Del Tredici and Braak [4
] we identified a number of subjects where dmV and/or LC were not affected but αS-IR inclusions were found in the SN, BFB and or other cortical regions, and thus, the distribution of αS pathology did not strictly follow the caudo-rostral propagation pattern described by Braak and colleagues [4
]. Thus, the proposed ascending pathway is not the only possible route and our results indicate that pathology can emerge simultaneously in subcortical and cortical regions. Jellinger has also reported subjects with multiple αS-IR inclusions but with preservation of medullary nuclei [20
]. Furthermore, in some subjects we found the AC to be devoid of pathology although αS-IR structures were detected elsewhere in the neocortex. This refutes the proposal that in order to have neocortical involvement then the subcortical lesions have to expand through the basal forebrain nuclei. In addition, according to Braak and colleagues [4
], the αS pathology in previously involved regions should become exacerbated with disease progression. It is difficult to evaluate this proposal when one takes into account the increasing neuronal loss. If these two pathological hallmarks are linked in a causative chain, the load of αS-IR structures should show an inverted u-shape distribution over time where the number of inclusions would increases with the progression of the disease until the neurons start to die [12
We observed some cases with severe αS pathology in AC and in that situation this structure was either only involved region or was affected together with BFB and SN. All these subjects were demented and exhibited coexistent severe AD-related pathology (Braak AD stage V-VI [6
]). In one case, the dementia was considered to be vascular in origin. This is in line with the results of Uchikado and colleagues who have reported the AC predominant form to be common finding among patients with AD [35
In conclusion, our results confirm that the current staging/categorization systems can readily be applied to most of the subjects when assessing regional distribution of αS-pathology. It is noteworthy, however, that outliers do exist and in these cases the presumed distribution may have been modified by other coexisting pathologies or genetic factors [23
]. It is intriguing that around every second subject displaying abundant pathology did remain neurologically intact. It is noteworthy that these results were seen when a rather unselected sample of cases was investigated. It has been suggested that the key lesions begin to develop a considerable time prior to the appearance of clinical symptoms [13
], but based on our results there do seem to be some subjects who can tolerate substantial amounts of pathology. As only 50% of subjects with widespread αS pathology were demented (MMSE < 26) and displayed EPS, the clinical relevance of αS-IR inclusions as such still remains to be resolved. Hitherto, the aggregation of αS has been thought to lead to neuronal death but recent evidence has suggested that the formation of large inclusions may actually represent a protective process [3
]. Many biophysical studies have suggested that it is a protofibrillar form of αS rather than the “mature” fibrils that are responsible for the cell death [7
], and moreover, the fibrillar form that is typically observed at autopsy may actually be a sign of a well functioning neuroprotection [31
]. Thus, when we are assessing regional distribution of αS pathology, the question arises if we are really evaluating a stage of degeneration or conversely monitoring the level of functional neuroprotection.