Morphometry of the human substantia nigra in ageing and Parkinson’s disease. Acta Neuropathol

Neuropathology, Johns Hopkins School of Medicine, Ross Research Building 555, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Acta Neuropathologica (Impact Factor: 10.76). 04/2008; 115(4):461-70. DOI: 10.1007/s00401-008-0352-8
Source: PubMed


To investigate the relation between the loss of substantia nigra (SN) neurons in normal ageing and Parkinson's disease (PD), we measured the total number and the cell body volume of pigmented (neuromelanin) neurons in the SN. We examined young (n = 7, mean age: 19.9), middle-aged (n = 9, mean age: 50.1), and older controls from the Baltimore Longitudinal Study of Aging (n = 7, mean age: 87.6), as well as PD cases (n = 8, mean age: 74.8). On random-systematically selected paraffin Nissl-stained sections, we used the Optical Fractionator to estimate the total number of neurons on one side of the SN. Using the Nucleator probe, we measured the volume of these neurons. In young and older controls, we also estimated the total number and volume of tyrosine hydroxylase (TH) positive (+) nigral neurons. We observed a significant loss of pigmented (-28.3%, P < 0.01) and TH (+) (-36.2%, P < 0.001) neurons in older controls compared with younger subjects. Analysis of the size distribution of pigmented and TH (+) neurons showed a significant hypertrophy in older controls compared to young controls (P < 0.01). In contrast, in PD we observed a significant atrophy of pigmented neurons compared to all control groups (P < 0.01). These data suggest that neuronal hypertrophy represents a compensatory mechanism within individual SN neurons that allows for normal motor function despite the loss of neurons in normal ageing. Presumably, this compensatory mechanism breaks down or is overwhelmed by the pathological events of PD leading to the onset of the characteristic motor disturbances.

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Available from: Alan Zonderman, Mar 03, 2014
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    • "The aforementioned findings are frequently used to support the possibility that the nigral DA cell (DAc) loss is a specific characteristic of PD. However, a similar degeneration has been observed in the SN of aged healthy subjects who also show a decrease in the number of: (1) total SN neurons (Hirai, 1968; McGeer et al., 1977; Stark and Pakkenberg, 2004; Morterá and Herculano-Houzel, 2012); (2) pigmented SN neurons (which decrease 7–10% per decade) (Ma et al., 1999; Stark and Pakkenberg, 2004; Rudow et al., 2008); (3) TH+ and DAT+ neurons (Kastner et al., 1993; Rudow et al., 2008; Kordower et al., 2013); (4) DD+ neurons (Lloyd and Hornykiewicz, 1970); and (5) MAO+ neurons (Saura et al., 1997). Thus, the nsDAc loss cannot be considered as a discriminating characteristic of PD. "
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    ABSTRACT: Available data show marked similarities for the degeneration of dopamine cells in Parkinson's disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as α-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression.
    Full-text · Article · Aug 2014 · Frontiers in Neuroanatomy
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    • "A recent study of over 750 elderly individuals (mean age 88.5 years) without clinically defined PD, has shown that nearly 1/3 showed mild to severe neuronal loss within the substantia nigra, with 10% also showing Lewy body pathology (Buchman et al. 2012). Cell loss within the SN has been shown to be extensive (Rudow et al. 2008) and was estimated to occur at a rate of 4.7% per decade (Fearnley and Lees 1991), while more recent stereological techniques estimate this loss of neurons to occur at a rate of 9.8% per decade (Ma et al. 1999b). "
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    ABSTRACT: As the second most common age related neurodegenerative disease after Alzheimer's disease, the health, social and economic impact resulting from Parkinson's disease will continue to increase alongside the longevity of the population. Ageing remains the biggest risk factor for developing idiopathic Parkinson's disease. Although research into the mechanisms leading to cell death in Parkinson's disease has shed light on many aspects of the pathogenesis of this disorder, we still cannot answer the fundamental question, what specific age related factors predispose some individuals to develop this common neurodegenerative disease. In this review we focus specifically on the neuronal population associated with the motor symptoms of Parkinson's disease, the dopaminergic neurons of the substantia nigra, and try to understand how ageing puts these neurons at risk to the extent that a slight change in protein metabolism or mitochondrial function can push the cells over the edge leading to catastrophic cell death and many of the symptoms seen in Parkinson's disease. We review the evidence that ageing is important for the development of Parkinson's disease and how age related decline leads to the loss of neurons within this disease, before describing exactly how advancing age may lead to substantia nigra neuronal loss and Parkinson's disease in some individuals.
    Full-text · Article · Feb 2014 · Ageing research reviews
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    • "During normal aging, design-based stereology studies of the brains of human and non-human primates report significant loss and compensatory hypertrophy of catecholaminergic neurons in SN PC and VTA (Siddiqi et al., 1999; Cabello et al., 2002; Rudow et al., 2008), while the numbers and size of catecholaminergic neurons in LC remain stable (Mouton et al., 1994; Ohm et al., 1997). "
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    ABSTRACT: Parkinson's disease (PD), an age-related movement disorder, is characterized by severe catecholaminergic neuron loss in the substantia nigra pars compacta (SN(PC))-ventral tegmental area (VTA) and locus coeruleus (LC). To assess the stability of these central catecholaminergic neurons following an acute episode of severe inflammation, 6 to 22 month old C57/Bl6 mice received a maximally tolerated dose of lipopolysaccharide (LPS) followed by euthanasia 2 hours later to assay peak levels of peripheral and central cytokines; and, 14 weeks later for computerized stereology of tyrosine hydroxylase-immunopositive (tyrosine hydroxylase-positive [TH+]) neurons in the SN(PC)-VTA and LC. Two hours after LPS, cytokine levels varied in an age-related manner, with the greatest peripheral and central elevations in old and young mice, respectively. Severe inflammation failed to cause loss of TH+ neurons in SN(PC)-VTA or LC; however, there was an age-related decline in these TH+ neurons in LPS-treated and control groups. Thus, unknown mechanisms in the B6 mouse brain appear to protect against catecholaminergic neuron loss following an acute episode of severe inflammation, while catecholaminergic neuron loss occurs during normal aging.
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