Neurodegenerative disorders

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The neurodegenerative diseases are common disorders in which there is degeneration of specific groups of neurons or brain areas, causing characteristic clinical syndromes.

Motor neuron disease (amyotrophic lateral sclerosis) causes paralysis, due to death of motor neurons in the motor cortex, brain stem and spinal cord}.

Motor neuron disease is a progressive neurodegenerative disease. It is mainly seen in old age, a small number of patients presenting in middle age.
Disease typically begins as mild weakness in one limb. There is then progression to severe paralysis, with loss of swallowing and respiration leading to death in 2-3 years. The cause of the disease is unknown.

Different sub-types relate to the loss of different groups of motor neurons:

Amyotrophic lateral sclerosis is the most common pattern, showing loss both of cortical motor neurons and lower motor neurons in the spinal cord and brain stem.

Progressive bulbar palsy is common, shows loss of brain stem motor neurons

Progressive muscular atrophy is uncommon and shows loss restricted to spinal lower motor neurons.

Primary lateral sclerosis is rare and shows loss of neurons restricted to the motor cortex.

There is loss of motor neurons from cortex, brain stem and cord, and gliosis with secondary degeneration of motor tracts. Inclusion bodies containing the protein ubiquitin are found in surviving neurons.

Parkinson's disease results from loss of neurons from the substantia nigra.

Parkinson's disease is a movement disorder that mainly affects patients over the age of 45 years. It is clinically characterized by disturbance of movement with rigidity, slowness of voluntary movement (bradykinesis), and rest tremor. Severity of disease is related to loss of the neuromelanin-containing nerve cells from the substantia nigra in the midbrain; these cells normally produce dopamine, their loss reducing the amount of dopamine in the basal ganglia.

Macroscopically, there is loss of pigment from the substantia nigra, which is the result of death of the melanin-containing dopaminergic cells. The surviving cells in the substantia nigra contain spherical inclusions termed Lewy bodies.

The cause of Parkinson's disease is unknown. The disease may be symptomatically treated by administration of drugs that correct the neurotransmitter imbalance, e.g. l-dopa. The natural history of the disease is for patients to develop failure of response to treatment, with death eventually occurring from wasting and poor nutritional intake.

In this section through the midbrain, pigmented neurons have been lost from the substantia nigra (between lines), which is abnormally pale.
Lewy bodies are spherical inclusions seen in the melanin-containing neurons in Parkinson's disease. Typically they have a hyaline core and a pale halo. They are based on aggregated neurofilaments.

Huntington's disease is an autosomal dominant disease causing chorea and dementia

Huntington's disease is a neurodegenerative disease causing choreiform movements and dementia, with onset in middle life. The disease is an autosomal dominant disorder with a prevalence of approximately 1 in 20,000; the gene has been characterized at its location in the short arm of chromosome 4.

Macroscopically the brain shows atrophy of the caudate and putamen due to cell loss and gliosis, and careful measurements have shown subtle loss of neurons from the cerebral cortex.

The natural history of this disease is for affected individuals to develop progressive cognitive decline, with increase in severity of the movement disorder. Patients die as a result of their severe mental and physical incapacity.

Alzheimer's disease is the most common cause of dementia
Alzheimer's disease is the most common neurodegenerative disease and the most common cause of dementia.

The brain in Alzheimer's disease is smaller than normal and brain weight is reduced, evident as shrinkage of gyri and widening of sulci of the cerebral hemispheres.

Histologically, there are several main abnormalities seen in Alzheimer's disease. Amyloid, composed of b(A4) protein, is deposited in the cerebral cortex as spherical deposits termed senile plaques. Intraneuronal inclusions comprising bundles of abnormal filaments termed {\B neurofibrillary tangles} develop in cortical neurons.
Tangles are frequently flame-shaped and occupy much of the space within the neuronal cytoplasm, being composed of a microtubule-binding protein called Tau protein. Cortical nerve-cell processes become twisted and dilated (neuropil threads) due to accumulation of the same filaments that form the tangles. Neuronal loss ( 50%) is seen from the cortex, particularly in patients under the age of 80 years. The amyloid is often also deposited in cerebral arteries, causing an amyloid angiopathy.

Neuronal system atrophies are neurodegenerative diseases affecting several neuronal groups

A number of uncommon neurodegenerative diseases show loss of neurons from several nuclei in the brain, brain stem, cerebellum and spinal cord, and are given names according to the pattern of involvement. There are large numbers of such syndromes, each having different genetic and pathological causes. Clinically, patients have symptoms and signs that relate to the neuronal groups involved, including rigidity, chorea, cognitive decline and weakness. 

Among the main types of multisystem atrophy are spinocerebellar degenerations, a group of familial diseases with several inheritance patterns, which are characterized by loss of cerebellar cortical neurons and degeneration of spinal cord tracts. The best known of these is Friedreich's ataxia, a spastic cerebellar ataxia with degeneration of posterior columns and corticospinal and spinocerebellar tracts.
Cerebellar cortical atrophies are familial diseases in which the main abnormality is loss of Purkinje cells from the cerebellar cortex, with lesser involvement of other neuronal groups. Patients present with cerebellar ataxia, usually in the third decade. 

Olivopontocerebellar atrophies are familial diseases, many of which are autosomal dominant. Patients have prominent cerebellar ataxia, extrapyramidal rigidity and bulbar paresis, caused by loss of neurons from the cerebellar cortex, substantis nigra and pons respectively. In many cases, inclusions are seen in glial cells.

Idiopathic orthostatic hypotension (Shy-Drager syndrome) is a disorder dominated by the presence of orthostatic hypotension. This may occur in isolation, or, more usually, as part of a multiple-system atrophy involving the substantia nigra, motor neurons and cerebellum. The basis of hypotension is loss of neurons from the intermediolateral column in the thoracic spinal cord.

In cerebellar degeneration there is atrophy of the cerebellar folia. This case was a familial cerebellar degeneration causing a severe ataxia.
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Revised: 02-11-2014.