To our knowledge, this represents the largest study of LBP in longitudinally evaluated normal control subjects to date. The major finding in this study is that 23% of elderly subjects with normal cognition and no clinical evidence of PD, DLB, or other CNS disorders contained alpha-synuclein positive LBP in one or more regions of the central nervous system. While others have described LBP in normal elderly subjects, none have used longitudinally evaluated elderly normal controls and focused only on LBP in normal aging. In the pre-immunocytochemistry era, Lipkin (4
) reported LB in 4.9% of control subjects and Forno (5
) found them in 4.7% of routine autopsies. Gibb and Lees (6
) found LBP increased from 3.8% to 12.8% between the sixth and ninth decade in 273 patients dying of diseases other than PD. Many of them had other neurological diseases. Since the beginning of alpha-synuclein immunohistochemistry use, Tsuboi et al (7
) found LBP in 9.2% of normal elderly subjects, Parkkinen et al found LBP in 11% in one study (8
) and 13% in another (12
), and Wakisaka et al (13
) found them in 15% (13
). Jellinger (14
) showed that 31% of aged controls had alpha-synuclein positive LB in the basal nucleus and in medulla, pons, or midbrain. In a series of 904 autopsied subjects, Parkkinen et al. (12
) found LBP in the brainstem or basal forebrain nucleus of 106 subjects (13%), but only 32 (30%) did not have any neurologic impairment and were considered normal. In a community-based Japanese population (the Hisayama Study), LBP was present in 15% (11 / 73) of nondemented subjects without PD (13
). Sengoku (28
) found LBP in 31.9% of consecutive autopsied patients from a general geriatric hospital. In the only two studies of small numbers of longitudinally followed cognitively normal elderly individuals, Knopman et al (11
) described LBP in 13% (5/39) and Mikolaenko et al (15
) found LBP in 8.3% (3/36).
In a study of 30 incidental LBP cases from 413 autopsies, Del Tredici et al (9
) found that LBP begins in the dorsal glossopharyngeal-vagal complex, locus ceruleus/subceruleus complex, caudal raphe nuclei, gigantocellularis reticular nucleus, olfactory bulb, tract and anterior olfactory nucleus but not in the substantia nigra. These subjects were not followed longitudinally but did not have PD, AD, or other neurological or psychiatric diseases. Of our 7 cases limited to the brainstem, four involved medullary nuclei alone supporting the findings of Del Tredici et al (9
). Nine other cases had brainstem and amygdala only involvement.
It is difficult to compare our results with the other studies because of case selection and study design. None of the other studies used longitudinally followed systematically evaluated controls except as noted above (11
). Some studies calculated the percentage of alpha-synuclein positive normals in all alpha-synuclein positive cases rather than the whole autopsy series. Some were designed to compare dementia with nondementia controls without regard for movement disorders. Other studies used only specific brain areas and not a broad spectrum of brain regions. However, the percentage of normal elderly controls with LBP in our study (23%) is higher than most other studies except for the report by Jellinger (14
) who found LBP in 31% of controls and Sengoku et al (28
) who found it in 31.9%.
The reason for the high prevalence of LBP in our study is not clear. Several authors have suggested that aging and severe AD pathology have a major effect in the evolution of LBP (8
). Two of these studies showed an age-related increase in LBP between the eighth and tenth decade (8
). Although our subjects with LBP were old (mean age > 80 yrs), no significant difference in mean age of those with and without LBP was present. However, in the LBP group, LBP was slightly increased in the eighth and ninth decades compared to the seventh decade.
Our study did not show an association with AD pathology as indicated by statistically insignificant mean Braak scores of 2.1 in subjects with LBP compared to 1.80 in controls without LBP. In addition, NP counts between controls with and without LBP were not significantly different. Thus, it would appear from our study that AD pathology does not have a strong effect on the evolution of LBP as suggested by others (13
), and synergism between LBP and tau or Aβ lesions is not present as indicated by Mikolaenko et al (15
). In addition, the presence of LBP does not indicate a transition to the mixed form of AD/DLB in our study. Those with neocortical and allocortical LBP had Braak stage scores (for neurofibrillary pathology) from 0 to II. None of our LBP subjects showed clinical manifestations of DLB or a decline in cognitive function, even at a late stage of life, suggesting that they were not developing DLB yet. Synergy between AD and DLB pathology may be restricted to subjects experiencing progressive clinical symptoms and cognitive decline rather than the asymptomatic, cognitively normal subjects presented here.
Lewy bodies were initially described in the amygdala in AD using α-synuclein immunohistochemistry by Lippa et al (29
) and have been reported to occur in this site in 43% to 60% of AD patients (30
). The amygdala was a common site of LBP in our controls, occurring in 24 out of 33 cases with LBP. Interestingly, almost two-thirds of those with brainstem LBP also had amygdala involvement. Although LBP was prominent in the amygdala, none had cognitive impairment, which would suggest that LBP in amygdala is not always related to cognitive impairment as suggested by Parkkinen et al (12
) suggested that the burden of alpha-synuclein pathology was significantly greater in demented patients versus nondemented subjects Most neuropathologists would agree with that conclusion. However, several of our cases had neocortical and allocortical LBP and met the original neuropathological criteria for DLB (26
) but were not demented. Six of our cognitively normal control subjects had developed Parkinson signs or early neuropsychiatric manifestations of DLB and were excluded from this study. Each of these met the latest neuropathologic criteria for DLB (32
) and probably had preclinical or early DLB. The details of these subjects are presented in a separate publication (33
Braak and Del Tredici (34
) developed a staging procedure for LBP associated with PD that begins in the medulla and olfactory structures and continues in a topographical predictable sequence in 6 stages progressively involving olfactory, autonomic, limbic, and somatosensory systems. One of our cases involved the olfactory bulb alone. Braak and Del Tredici (34
) indicate that the earliest LBP may develop more or less simultaneously in the medulla and olfactory bulb (Stage 1). Perhaps our single case represents one instance where the change occurs first in the olfactory bulb and would have been followed by LBP in the medulla if the patient had lived longer. In the cases with brainstem only LBP, 4 had medulla involvement alone and the pathological changes were mild and predominantly limited to the dorsal glossopharyngeal/vagal nuclear complex and the nucleus gigantocellularis. One case involved medulla and the locus ceruleus, the former more extensively than the latter. These cases conformed to Braak stages 1 and 2 (35
). Three cases had medulla, locus ceruleus/subceruleus and substantia nigra LBP and conform to Braak stage 3 except that the amygdala was not involved. Eight cases had LBP in the amygdala, medulla, locus ceruleus, and substantia nigra fulfilling complete Braak stage 3 criteria. It would be expected that some of these cases may have clinical findings such as motor symptoms, autonomic, or cognitive decline but they were not detected. Perhaps they had subtle undetected clinical findings. Another explanation is that possibly the burden of LBP and neuron loss was not large enough to cause symptoms. Regardless of whether they were in the presymptomatic or undetected symptomatic phase of PD, it seems clear that these individuals had a relatively uniform pathological process advancing in the predictable manner described by Braak et al (35
). However, 2 subjects had amygdala and substantia nigra involvement and one had amygdala and medulla only and do not fit the criteria well. It would be expected that not every case would fit precisely into the Braak staging scheme and variation may occur in a small percentage of cases.
All 6 cases with allocortical or neocortical involvement had LBP in the medulla, pons, midbrain, and amygdala. All had involvement of the temporal neocortex and two had involvement of the anterior cingulate gyrus. Because of mild LBP scores they would not have met the Braak stage 5 criteria for PD (35
). Two would have met the initial criteria for pathological diagnosis of DLB (26
) or the recently amended criteria (27
). None of these cases showed significant cognitive decline, neuropsychiatric, or Parkinsonism signs by history or neurological examination.
A limitation of our study is that it is a sample of convenience. All subjects were white except two, of advanced age, and most were well educated. Many had professional, educational, or business occupations and most were of middle class socio-economic status. Thus, our study is not applicable to the general population. However, it is a relatively uniform sample whose subjects showed excellent compliance to our longitudinal evaluation process. We purposely excluded those with other neurological disease, especially PD and cognitive decline or major psychiatric features to gain insight into alterations in the aging brain.
Our study shows that the presence of LBP in elderly control subjects is not always accompanied by neurologic clinical manifestations. There is no clear explanation for this, but it is possible that the burden of LBP was not large enough to cause symptoms in some cases or that our cases had strong “brain reserve” to withstand the effects of LBP. Perhaps the high level of education in our subjects (mean = 16 years) plays a role in this regard. Thus, in evaluating elderly, well educated subjects with no cognitive decline at autopsy, one should consider that the threshold of LBP causing clinical symptoms may be higher than in the average population.
It is also possible that some of these subjects developed clinical or cognitive changes between the last evaluation and autopsy, although this seems unlikely for the majority because of the short interval between the last exam and death of the subjects with LBP (8.94 ± 6.12 months).
A more likely explanation for our findings is based on the recognition that diseases such as PD, AD, and DLB have pathological manifestations long before the classic clinical findings appear. In some PD cases, autonomic, olfactory, and sleep disorders (36
) antedate motor symptoms and signs by many years. Del Tredici et al (9
) and others (6
) suggest that LBP in the brainstem represents the precursor of PD. It is unlikely that our findings represent nonspecific alterations found in the aging brain. DelleDonne et al (16
) showed that subjects with incidental Lewy body disease had diminished immunoreactivity for tyrosine hydroxylase and vascular monoamine transporter 2 in the putamen compared to normal controls. This decline in dopaminergic immunoreactivity correlated inversely with substantia nigra neuron loss and PD stages. Their findings suggest that incidental Lewy body disease most likely represents preclinical PD. It is possible that most, if not all of our subjects, were in the presymptomatic phase of PD, PDD, or DLB and, if they had lived longer, they would have demonstrated clinical neurological impairment. Our study also suggests that a large number of normal elderly are probably at risk for developing these disorders.