Nigral pathology and parkinsonian signs in elders without Parkinson disease.

Rush Alzheimer's Disease Center, Chicago, IL, USA.
Annals of Neurology (Impact Factor: 11.91). 02/2012; 71(2):258-66. DOI: 10.1002/ana.22588
Source: PubMed

ABSTRACT Motor symptoms such as mild parkinsonian signs are common in older persons, but little is known about their underlying neuropathology. We tested the hypothesis that nigral pathology is related to parkinsonism in older persons without Parkinson disease (PD).
More than 2,500 persons participating in the Religious Orders Study or the Memory and Aging Project agreed to annual assessment of parkinsonism with a modified version of the Unified Parkinson Disease Rating Scale and brain donation. Brains from 744 deceased participants without PD were assessed for nigral neuronal loss and α-synuclein immunopositive Lewy bodies.
Mean age at death was 88.5 years. Mean global parkinsonism was 18.6 (standard deviation, 11.90). About ⅓ of cases had mild or more severe nigral neuronal loss, and about 17% had Lewy bodies. In separate regression models that adjusted for age, sex, and education, nigral neuronal loss and Lewy bodies were both related to global parkinsonism (neuronal loss: estimate, 0.231; standard error [SE], 0.068; p < 0.001; Lewy bodies: estimate, 0.291; SE, 0.133; p = 0.029). Employing a similar regression model that included both measures, neuronal loss remained associated with global parkinsonism (neuronal loss: estimate, 0.206; SE, 0.075; p = 0.006). By contrast, the association between Lewy bodies and global parkinsonism was attenuated by >60% and was no longer significant (Lewy bodies: estimate, 0.112; SE, 0.148; p = 0.447), suggesting that neuronal loss may mediate the association of Lewy bodies with global parkinsonism.
Nigral pathology is common in persons without PD and may contribute to loss of motor function in old age.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic inflammation is a major characteristic feature of Parkinson's disease (PD). Studies in PD patients show evidence of augmented levels of potent pro-inflammatory molecules e.g., TNF-α, iNOS, IL-1β whereas in experimental Parkinsonism it has been consistently demonstrated that dopaminergic neurons are particularly vulnerable to activated glia releasing these toxic factors. Recent genetic studies point to the role of immune system in the etiology of PD, thus in combination with environmental factors, both peripheral and CNS-mediated immune responses could play important roles in onset and progression of PD. Whereas microglia, astrocytes and infiltrating T cells are known to mediate chronic inflammation, the roles of other immune-competent cells are less well understood. Inflammation is a tightly controlled process. One major effector system of regulation is HPA axis. Glucocorticoids (GCs) released from adrenal glands upon stimulation of HPA axis, in response to either cell injury or presence of pathogen, activate their receptor, GR. GR regulates inflammation both through direct transcriptional action on target genes and by indirectly inhibiting transcriptional activities of transcriptional factors such as NF-κB, AP-1 or interferon regulatory factors. In PD patients, the HPA axis is unbalanced and the cortisol levels are significantly increased, implying a deregulation of GR function in immune cells. In experimental Parkinsonism, the activation of microglial GR has a crucial effect in diminishing microglial cell activation and reducing dopaminergic degeneration. Moreover, GCs are also known to regulate human brain vasculature as well as blood brain barrier (BBB) permeability, any dysfunction in their actions may influence infiltration of cytotoxic molecules resulting in increased vulnerability of dopamine neurons in PD. Overall, deregulation of glucocorticoid receptor actions is likely important in dopamine neuron degeneration through establishment of chronic inflammation.
    Frontiers in Neuroanatomy 01/2015; 9:32. DOI:10.3389/fnana.2015.00032 · 4.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of both parkinsonian signs and Parkinson's disease (PD) per se increases with age. Although the pathophysiology of PD has been studied extensively, less is known about the functional changes taking place in the basal ganglia circuitry with age. To specifically address this issue, 3 groups of rhesus macaques were studied: normal middle-aged animals (used as controls), middle-aged animals with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, and aged animals (>20 years old) with declines in motor function. All animals underwent the same behavioral and pharmacologic magnetic resonance imaging (phMRI) procedures to measure changes in basal ganglia function in response to dopaminergic drug challenges consisting of apomorphine administration followed by either a D1 (SCH23390) or a D2 (raclopride) receptor antagonist. Significant functional changes were predominantly seen in the external segment of the globus pallidus (GPe) in aged animals and in the striatum (caudate nucleus and putamen) in MPTP-lesioned animals. Despite significant differences seen in the putamen and GPe between MPTP-lesioned versus aged animals, a similar response profile to dopaminergic stimulations was found between these 2 groups in the internal segment of the GP. In contrast, the pharmacologic responses seen in the control animals were much milder compared with the other 2 groups in all the examined areas. Our phMRI findings in MPTP-lesioned parkinsonian and aged animals suggest that changes in basal ganglia function in the elderly may differ from those seen in parkinsonian patients and that phMRI could be used to distinguish PD from other age-associated functional alterations in the brain. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 10/2014; 36(2). DOI:10.1016/j.neurobiolaging.2014.10.014 · 4.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is generally considered that Parkinson's disease is induced by specific agents that degenerate a clearly defined population of dopaminergic neurons. Data commented in this review suggest that this assumption is not as clear as is often thought and that aging may be critical for Parkinson's disease. Neurons degenerating in Parkinson's disease also degenerate in normal aging, and the different agents involved in the etiology of this illness are also involved in aging. Senescence is a wider phenomenon affecting cells all over the body, whereas Parkinson's disease seems to be restricted to certain brain centers and cell populations. However, reviewed data suggest that Parkinson's disease may be a local expression of aging on cell populations which, by their characteristics (high number of synaptic terminals and mitochondria, unmyelinated axons, etc.), are highly vulnerable to the agents promoting aging. The development of new knowledge about Parkinson's disease could be accelerated if the research on aging and Parkinson's disease were planned together, and the perspective provided by gerontology gains relevance in this field. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 02/2015; 14(3). DOI:10.1111/acel.12312 · 5.94 Impact Factor

Full-text (2 Sources)

Available from
Jun 2, 2014

Joshua M Shulman