A brief history of brain iron accumulation in Parkinson disease and related disorders

Abstract

Iron has a long and storied history in Parkinson disease and related disorders. This essential micronutrient is critical for normal brain function, but abnormal brain iron accumulation has been associated with extrapyramidal disease for a century. Precisely why, how, and when iron is implicated in neuronal death remains the subject of investigation. In this article, we review the history of iron in movement disorders, from the first observations in the early twentieth century to recent efforts that view extrapyramidal iron as a novel therapeutic target and diagnostic indicator.

Keywords: Parkinson disease; history of neuroscience; iron; substantia nigra.

Fig. 1

Timeline of some of the major developments in iron and Parkinson disease (PD) research

Fig. 2

Depiction by Spatz (1922a, b) of macroscopic distribution of iron staining in coronal sections of unfixed human brain, visualized with the ammonium sulfide method. Abb. 1. 42-year-old woman, section through rear left frontal lobe; concentrated ammonium sulfide for one minute: supra- and infra-commissural pallidum gray, otherwise no reaction. Abb. 2. 16-year-old boy, slightly caudal to plane of Abb. 1; ½ hour in 2% ferrocyanide solution, 15 h in dilute hydrochloric acid. Abb. 3. 62-year-old man, section through medial mammillary body; ¼ hour in 2% ferrocyanide solution, ¼ hour in hydrochloric acid. The blue coloration of the white matter is more intensive in the image than in reality. Abb. 5. 37-year-old woman, section through the caudal basal ganglia; several days in ammonium sulfide in alcohol. The strongest reaction is in the substantia nigra, then the nucleus ruber, the nucleus caudatus, and the caudal part of the putamen (the pallidum is not included in this section). Cl. = claustrum; C. L. = corpus Luysi; C. m. = corpus mamillare; C. a. = commissura anterior; C. i. = capsula interna; G. p. = globus pallidus (infrac. = pars infracommissuralis; p. suprac. = pars supracommissuralis); G. g. l. = ganglion geniculatum laterale; J. = lnsula; N. c. = nucleus caudatus; N. am. = nucleus amygdalae; N. r. = nucleus ruber; N. II. = nervus opticus; N. s. i. = nucleus substantiae innominatae; P. = putamen; S. n. = substantia nigra; Th. = thalamus; S. p. a. = substantia perforata anterior; V. A. = Vicq d’Azyr tract

Fig. 3

An early histopathological assessment of iron in the Parkinson disease brain using Perls Prussian blue staining described by Lhermitte et al. (1924). a, b Deposition of non-heme iron was found in globules lining the vessel walls of the globus pallidus (arrows; both with hematoxylin and Van Giesen stain; ×60 magnification for (a); ×180 for (b). c These deposits were also observed as extracellular globules with a high fat content (arrows; Scharlach R and hematoxylin stain; ×200 magnification) in globus pallidus tissue. d The substantia nigra showed no abnormal iron deposition, though pigmented cells were noted to be shrunken (Nissl stain; ×140 magnification). Figures reproduced with permission from BMJ Publishing.

Fig. 4

Iron metabolism in Parkinson disease. Proposed mechanism of iron accumulation in dopaminergic neurons and sources of oxidative stress. Reproduced with permission from Hare and Double,

Fig. 5

Early T2-weighted magnetic resonance imaging using a 1.5 T field strength of iron in a multiple system atrophy. White arrows in a, b denote decreased signal intensity, indicating iron deposits, in the putamen and caudate nucleus compared to the globus pallidus (open arrows, (b)). Hypointensity marked with the white arrowhead (c) was interpreted as indicative of specific iron accumulation in the substantia nigra pars compacta. Reproduced from Drayer et al. with permission from the Radiological Society of North America (copyright 1986)

Fig. 6

Transcranial ultrasonogram showing progressive hyperechogenicity of the substantia nigra pars compacta in Parkinson disease. a Initial examination revealed an area of 0.23 cm² hyperechogenicity in the substantia nigra pars compacta (white arrows). b Follow-up examination at five years showed hyperechogenicity had not changed. c Schematic representation of the ipsilateral mesencephalon, with the substantia nigra pars compacta marked with white arrows. Reproduced from (Berg et al. 2005) with permission from John Wiley and Sons (copyright 2005)