There is a working assumption that iLBD represents an early stage in the PD neurodegenerative process, either as a precursor or an aborted pathological state. Indeed, iLBD cases have striatal dopaminergic deficits consistent with this assumption. (Beach et al., 2008a
; DelleDonne et al., 2008
) In fact, a presymptomatic state is a necessary assumption given the known slow progression of PD, plus the fact that symptoms develop only after substantial neuronal damage.
This begs the question of the presymptomatic pathological substrate for the other major Lewy body disorder, DLB. DLB manifests with symptoms referable to cortex (i.e. dementia), but usually with concurrent parkinsonism. This issue is directly relevant to the current findings where a substantial proportion of our iLBD cases had α-synuclein pathology affecting one or more cortical regions, although the density of pathology was considerably less than in similar stage cases with clinically overt DLB.(Fujishiro et al., 2008
) Thus, although approximately a third of our cases had isolated brainstem α-synuclein pathology (consistent with premotor PD), another third had neuropathology that one might predict is a precursor to DLB (i.e. Braak PD stages 5–6). The remaining third of our cases were in between, and could arbitrarily be placed into one or the other category. Also consistent with a pre-DLB state, Parkkinen, et al. (Parkkinen et al., 2008
) noted that about half of their Braak Stage 5–6 cohort was asymptomatic, similar to our Diffuse group in . Restated, we propose that iLBD is dichotomous, with some cases representing the earliest stage of PD (or eventually PDD), and others, DLB. Whether each reflects a preclinical, precursor stage, or a state where the pathogenic process has been aborted or compensated remains to be determined.
Fully developed DLB may manifest as one of two neuropathological phenotypes: (1) diffuse cortical LBs with concurrent Alzheimer type pathology (NIA-Reagan intermediate to high); (2) minimal or no Alzheimer type pathology (NIA-Reagan low) and either transitional or diffuse cortical LBs.(Fujishiro et al., 2008
) Our Diffuse, asymptomatic cases may primarily represent the precursor to the latter type of DLB, since they had limited Alzheimer type pathology.
We identified no cases where Lewy-related pathology was predominantly in the amygdala (Leverenz, et al, 2008
), a common form of α-synuclein pathology in the setting of advanced AD. (Uchikado et al., 2006
) The amygdala is the nucleus that is most consistently affected among cases with concurrent AD pathology.(Hamilton, 2000
) Since the NIA-Reagan scores for all of our cases was 0–2 (no more than intermediate AD probability), the absence of amygdala-predominant Lewy-related pathology is not surprising. Parenthetically, the reason for the relatively low NIA-Reagan scores in these cases likely relates to the careful screening of medical records and exclusion of cases with documented cognitive impairment.
Consistent with multiple prior studies,(Bloch et al., 2006
; Halliday et al., 2008
; Jellinger, 2003
; Jellinger, 2008
; Kalaitzakis et al., 2008
; Parkkinen et al., 2005
; Parkkinen et al., 2008
; Zaccai et al., 2008
) we noted a minority of cases (21%) where the topographical caudal-to-rostral continuity of the Braak PD staging scheme was violated. This is not crucial to the Braak scheme, per se; however, it has implications for the proposal that a neurotrophic pathogen, such as a virus, ascends from gut or descends from olfactory bulb.(Hawkes et al., 2007
) Obviously, such a transsynaptically traveling pathogen might not leave evidence at every level, accounting for the skipped regions. Or, we and others might have missed Lewy pathology that would have been detected with intensive serial sectioning through all the relevant nuclei. On the other hand, there is not much of a precedent for such a process playing a role in neurodegenerative disease.
Skipped regions in the Braak PD scheme also suggest that the underlying pathogenic process may be multifocal in origin, rather than starting from one or two regions (e.g. dorsal motor nucleus or olfactory bulb), and subsequently ascending or descending. This pathological evidence, in the aggregate, would suggest a multifocal initiation as the more likely pathogenic scenario, and this has recently been emphasized. (Burke et al., 2008
One might take a different view of these data and argue that Braak PD staging has no validity and that the concept of an ascending caudal-to-rostral evolution of PD pathology should be abandoned; this view has recently gotten traction.(Burke et al., 2008
) However, the Braak caudal-to-rostral scheme does have support, although not necessarily with the precise neuroanatomic contiguity initially postulated. Thus, prior work has documented that clinically-established PD without dementia largely spares limbic cortex and neocortex, whereas advanced PD patients of similar age, but with levodopa-refractory motor syndromes and dementia, have transitional or neocortical Lewy-related pathology.(Apaydin et al., 2002
) Other investigations similarly support the proposal that PDD differs from PD without dementia by way of Lewy-related cortical pathology. (Aarsland et al., 2005
; Hurtig et al., 2000
) Pathological assessment stratified by PD duration also suggests an ascending process not simply explained by age; thus, short PD durations are associated with primarily brainstem pathology, whereas much longer PD durations include Lewy-related pathology at higher levels.(Halliday et al., 2008
The widespread Lewy-related pathology (Braak Stages 5–6) among some of our patients, as well as those in other studies(Parkkinen et al., 2008
; Zaccai et al., 2008
) obviously does not necessarily imply clinical consequences. LBs and LNs are markers of a disease process, but in the context of iLBD, may not necessarily reflect neuronal dysfunction, which in some cases may be minimal, compensated or controlled. Clinical symptoms in neurodegenerative disease presumably correlate with loss of neurons and perhaps more importantly synapses.(Kramer and Schultz-Schaeffer, 2007
; Terry, 2000
) However, comparative assessment of synapse and neuronal loss is extremely laborious and fraught with methodologic issues; hence, the nearly universal reliance on Lewy-related pathology, per se, to mark PD stages.
One possible criticism is the potential for case selection bias that is common among post-mortem investigations. However, not only were the iLBD cases identified blinded to the clinical data, they were derived from a large cohort of seniors dying without evidence of neurodegenerative disease; thus, selection bias relevant to the outcomes should not be substantial. Note also that autopsy rates for our local population are nearly twice the national average.(Nemetz et al., 1989
; Nemetz et al., 1987
This investigation also may be criticized for the retrospective design that is nearly universal among iLBD series. Obviously, without a comprehensive neurologic examination shortly before death, there can be no assurance of complete neurologic normality among the iLBD cases. However, to accomplish this with a prospective design would be extremely labor-intensive, require up to two decades to complete, and prohibitively expensive. Tending to offset this concern, the Mayo medical records were detailed, spanned a minimum of 5 years before death in our iLBD cases, and with the stipulation that all patients had been evaluated by a Mayo physician within the last year (median 20 physician visits the last 5 years). A neurologist, blinded to the neuropathological diagnoses, confirmed medical record-absence of dementia, tremor, parkinsonism or other evidence of neurodegenerative disease. Moreover, the incidence of iLBD in our series (14.5%) is nearly ten times greater than the lifetime risk (1.6%) for PD in the Olmsted County population.(Elbaz et al., 2002
) Thus, although mild parkinsonism, tremor or cognitive impairment could have been overlooked, this highly disproportionate frequency of iLBD suggests that most of these cases were not simply undetected PD.
In conclusion, two points deserve reiteration. First, incidental, but diffuse Lewy-related pathology (Braak PD stages 5–6) is a plausible precursor to DLB. Neurodegenerative disorders do not start abruptly and a preclinical pathological state is expected. This complements the current Braak PD staging scheme, which as currently written, is directly applicable only to PD. Second, we and other investigators have documented iLBD cases where brain regions that are integral to the ascending Braak scheme were skipped; this is contrary to the proposal of a neurotrophic pathogen passing transsynaptically.(Braak et al., 2006
; Hawkes et al., 2007
) The exceptions suggest that the beginnings of PD may reflect multifocal susceptibility, as has recently been emphasized,(Burke et al., 2008
) rather than one to two regions of origin.