NEUROPATHOLOGY FOR MEDICAL STUDENTS
Presented by William I. Rosenblum, MD
CHAPTER 6-- DISEASES OF THE BASAL GANGLIA AND SUBSTANTIA NIGRA
PRETEST: Answers will be found in the text of this chapter or click on link at end of questions
In the diseases discussed here, the primary pathology within the brain is located either in the basal ganglia or in the substantia nigra. The student should review the anatomy of these structures.
The diseases involving the basal ganglia are Huntington's chorea and Wilson's disease, or hepatolenticular degeneration. The disease involving the substantia nigra is Parkinson's disease. The reason for grouping the latter disease together with the former is simple: the neuronal cell bodies in the substantia nigra are connected via their axons with cell bodies in the basal ganglia. The neurotransmitter released at the synapse in the basal ganglia is DOPamine (dihydroxyphenylethylamine), a catecholamine closely related to norepinephrine, and synthesized in the neurons of the substantia nigra. The transmitter travels in the axons to the basal ganglia. Hence destruction of the nigra results in depletion of DOPamine in the basal ganglia.
Treatment with LDOPA the precursor of the transmitter may increase transmitter synthesis by surviving neurons and improve disordered movement manifested by symptoms such as tremor, chorea, and rigidity.
In the normal adult, the substantia nigra (arrows) is a pigmented structure.
The pigment in the substantia nigra is dark (arrows) because of the presence of brown neuromelanin in neurons (below).
Neuromelanin is produced in the catabolism of DOPamine, the neurohumor synthesized by these neurons. The symptoms of Parkinsonism (e.g., tremor and rigidity) are produced when the substantia nigra is damaged, and its neurons can no longer influence the basal ganglia.
There is more than one cause of nigral degeneration, and hence more than one cause of Parkinson's disease. The two causes considered most common are viral encephalitis and "unknown." or "idiopathic". Most newly discovered cases of Parkinson's disease are idiopathic. However it is now known that patients may have abnormalities in the gene for the protein called Parkin. It is also known that the Lewy bodies which are characteristic of the idiopathic cases (see image below) contain alpha synuclein in an abnormal form. Cases of Parkinson's disease also have numerous neurites which are filled with alpha synuclein. The relationship of these developments to our understanding of the disease remains to be established.
Lewy bodies in the image above are the intracytoplasmic, eosinophilic inclusions with a clear halo around
In addition to the presence of Lewy bodies, Parkinson's disease is characterized by degeneration of the nigral neurons, with liberation of the neuromelanin into the adjacent tissue where it is phagocytosed and carried away by macrophages. This results, not only in destruction of the DOPamine factory, but also in depigmentation of the substantia nigra. Thus, in a patient with well-developed disease, the substantia nigra is pale, and no longer stands out like the dark band in the normal brain.
In the image below the susbtantia nigra on the left is normal while that on the right is relatively depigmented.
In the microscopic image below the loose pigment, liberated from destroyed neuronal cell bodies is seen as brown, granular clumps of neuromelanin between the intact neurons.
Lewy bodies and the other changes can also be seen in the locus ceruleus where norepinephrine rather than DOPamine is produced. The brown pigment found in neurons of the normal locus ceruleus results from degeneration of the norepinephrine rather than from DOPamine. In the picture below the brain stems of two patients are shown at the level of the anterior basis pontis. Just below the later , lower corners of the fourth ventricle, the darkly pigmented locus ceruleus can be seen. That on the left is normal. The patient on the right had Parkinson's disease and the locus ceruleus is much less prominent.
Many patients with Parkinsons's disease develop dementia. In addition there is a type of dementia known as diffuse Lewy body disease in which there are Lewy bodies not only in the areas which contain neuromelanin but in numerous other areas including temporal lobe and cingulate gyrus. In the latter locations they are not as well demarcated or as distinct as the typical Lewy bodies illustrated above. However, like all Lewy bodies, they can be stained with antibody against ubiquitin.
This makes them much easier to see and this test should be performed in any case of dementia whose where histology has ruled out Alzheimers disease and in which typical Lewy bodies have been recognized in substgantia nigra or locus ceruleus. The relationship of the dementia of Parkinson's disease to that of the "diffuse Lewy body disease" is a matter of some controversy. Moreover cases that apparently have both Alzheimer's diseases and diffuse Lewy body disease have been reported and in these the burden of senile plaques and neuropfibrillary tangles is less than that normally seen with dementia of the pure Alzheimer type.
Huntington's disease is characterized by degeneration of the caudate nucleus, the putamen, and to a lesser extent, the globus pallidus. The disease is hereditary, and transmitted by a dominant gene where expression is determined by the length of a triplet repeat. The gene codes for Huntingtin, a protein whose function is not known at present. Huntingtin accumulates within the nucleus of affected cells.The relationship of this to neuronal death is unknown. In addition to disturbances of movement, including chorea, mental derangement is observed.
The latter is thought due to neuronal loss in the cortex, which is observed in addition to the loss of neurons in basal ganglia. The latter loss is thought to cause the motor disturbances, though accompanying degeneration of other brain areas may also be responsible. Astrocytosis accompanies the neuronal loss.
Neuronal loss leads to atrophy of the basal ganglia, giving the caudate a straight or even a scooped out or convex shape. Because of the altered shape of the caudate, the lateral ventricles are enlarged, and their lateral margins are straight or bowed out. This is shown in the image below. The ventricular enlargement is characteristic and can be seen on pneumoencephalograms, CAT scans, or MRIs, which can then assist in making the correct diagnosis.
In the left side of the figure below we see a cross section of a brain from a Huntington's patient. The caudate is markedly reduced in size giving it a flattened appearance. On the right, in black and white, we see a normal caudeate in panels A & B and the markedly reduced, scooped out caudate of a patient in panels C & D.
In the image below the microscopic section was stained with the Holzer stain for astrocytes. The blue processes of the reactive astrocytes are stained in this caudate nucleus that has undergone degeneration and neuronal loss in Huntington's disease.
Wilson's disease is caused by high tissue levels of copper. The brain and the liver are principally affected. In the eye, copper deposited in the cornea produces a visible "Kayser-Fleisher" ring. Within the brain, the basal ganglia (lenticular nuclei) is affected and this, plus liver involvement, give the disease its other name, hepatolenticular degeneration. The relationship between the cirrhotic liver in this disease, and signs of cerebral dysfunction, is uncertain.
The neurologic deterioration (rigidity and tremor) appears to be based primarily on damage to the brain which is unrelated to the liver disease, though liver failure from other forms of cirrhosis is often associated with global cerebral dysfunction.