Article

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

ABSTRACT 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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    • "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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    • "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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    • "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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