Sporadic PD is one of the most reliable and stable neurological diagnoses with 92% of the clinical features remaining unchanged for 5-10 years (Jankovic et al., 2000). While the incidence of sporadic PD significantly increases with age, the average age of onset for levodopa-responsive motor symptoms is around 60 years old. Fewer studies have assessed the average age at death for sporadic PD patients, but recent large-scale risk analysis using death and mortality as outcomes suggest that patients survive to 76 years of age on average (Wirdefeldt et al., 2005). These data show that, in the relatively homogeneous group of patients with dopa-
Fig. 1. Stages identified for sporadic PD and average demographics compared with the stages identified in the Braak staging scheme for sporadic PD and the demographics of the cases fulfilling criteria for these pathological stages. Note the considerable overlap in demographics for the pathological stages suggesting that, potentially, only the cases in stages 5-6 are comparable with the majority of clinical cases analysed
Fig. 1. Stages identified for sporadic PD and average demographics compared with the stages identified in the Braak staging scheme for sporadic PD and the demographics of the cases fulfilling criteria for these pathological stages. Note the considerable overlap in demographics for the pathological stages suggesting that, potentially, only the cases in stages 5-6 are comparable with the majority of clinical cases analysed responsive deficits, the disease is very slowly progressive with several stages clearly defined (Fig. 1). The presymptomatic period is estimated at 5-10 years most commonly occurring prior to the age of 60 (Jankovic, 2005). There is a 5-10 year period of relatively stable motor deficits occurring for most patients in their 60s (Jankovic et al., 2000), which is followed by a 5-10 year period of functional decline to death.
Staging procedure for sporadic Parkinson's disease and pathological demographics
Braak and colleagues devised a neuropatho-logical staging scheme under the assumption that the abnormal intraneuronal accumulation of a-synuclein is the common pathology for sporadic PD. By analysing the distribution and severity of a-synuclein cytoplasmic inclusions in brain specimens from the population at large (168 cases selected for detailed analysis, including 41 PD cases, 69 with a-synuclein inclusions, and 58 controls; the last two groups derived from screening 413 cases), cases can be categorised according to different hierarchical stages of disease infiltra tion (Braak et al., 2003). The most mildly affected cases (7% of the population) displayed lesions in the dorsal motor nucleus of the vagus nerve, the intermediate reticular zone of the medulla oblongata, the magnocellular portions of the reticular formation, the locus coeruleus and, frequently, the anterior olfactory nucleus (stages 1-2). Cases with moderate involvement (11% of the population) exhibit additional lesions in select mesencephalic and prosencephalic nuclei (stages 3-4), and all cases with severe pathology (6% of the population) show additional deterioration of the neocortex (stages 5-6).
Analysis of the demographics of the pathological stages observed shows considerable overlap rather than progression (Fig. 1). While this may be expected in pathological series due to average life expectancies, it suggests that most cases dying with this type of stage 1-2 pathology may never have gone on to develop clinical symptoms due to the very late timing of their preclinical period, a finding recently validated (Parkkinen et al., 2005). Thus, it is now important to confirm the existence of the same preclinical phenomena in autopsy material from populations within the predicted preclinical age range, or determine the alternate preclinical pathologies at these predicted time points.
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