Diseases with Akinetic Rigidity Idiopathic Parkinsons Disease

Idiopathic Parkinson's disease (iPD), the most common movement disorder and a major cause of neurologic

TABLE 5.10.

Extrapyramidal Diseases

Akinetic-rigid form Parkinson's disease Progressive supranuclear palsy

Dementia with parkinsonism linked to chromosome 17 Striatonigral degeneration Corticobasal degeneration Postencephalitic parkinsonism Parkinsonism-dementia complex of Guam

Hyperkinetic form Huntington's disease Dystonias

Chorea-acanthocytosis disability in the elderly, may affect individuals of 40 to 60 years of age, but it is seen primarily in those in their sixth decade. The annual incidence is 7 to 10 per 100,000 population, and this figure increases with age. A slight male preponderance is noted. About 1% to 3% of the population over the age of 65 years is afflicted. A rare juvenile form has an onset between 20 and 40 years of age. The disease occurs sporadically, but a considerable number of familial incidences have been identified. Both environmental and genetic etiologies are considered. The role of environmental factors is suggested by the clinical resemblance of iPD to the parkinsonism induced in humans by the neurotoxin MPTP (a pyridine derivative). However, no known environmental toxins have yet been associated with iPD. The identification so far of three different genes supports the role of genetic factors: a-synuclein gene (Park1) on chromosome 4, parkin (Park2) on chromosome 6, and ubiquitin c terminal hydroxylase-L1 (UCH-L1) on chromosome 4. Seven more loci have been identified (Parks 3 through 9) on chromosomes 2, 4, 1, and 12. Mutations in the a-synuclein and UCH-L1 genes are implicated in autosomal dominant disease; parkin is implicated in early-onset autosomal recessive inheritance.

Clinical Features

Combinations of extrapyramidal disorders and auto-nomic dysfunctions, frequently accompanied by neuro-psychiatric symptoms, define the disease. The cardinal motor symptoms are cogwheel rigidity of muscle tone, bradykinesia/akinesia, postural instability, and pill-rolling tremor at rest. A stooped posture, shuffling and festinating gait, lack of facial expression, micrographia, weak monotonous speech, and dysphagia are additional characteristic features. In some patients, akinetic-rigidity predominates; in others, resting tremor. Characteristic autonomic dysfunctions include orthostatic hypotension, seborrhea, sialorrhea, hyperhydrosis, constipation, bladder disorder, sleep disorder, and, rarely, sexual dysfunction. Anxiety, depression, psychosis, hallucination, and cognitive decline may emerge at any time during the course of the disease, which ranges from 10 to 20 years. No specific diagnostic tests are available. PET and SPECT show diminished striatal dopamine uptake.

Cogwheel Rigidity

FIGURE 5.23

Idiopathic Parkinson's disease (iPD). A 66-year-old man suffered from Parkinson's disease from the age of 50 years. The brain shows (A) discoloration of the substantia nigra compared to (B) normal control.

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Lewy Body Pathology

FIGURE 5.24

Idiopathic Parkinson's disease. Substantia nigra shows (A) severe neuronal losses and melanin pigments freely dispersed in the parenchyma. Lewy bodies immunoreact for (B) a-synuclein and (C) ubiquitin (immunostains). D. Hyalin body is present in a pigmented neuron (HE). E. Locus ceruleus shows a Lewy body (HE).

Pathology

The pathology of iPD encompasses nigral and widespread extranigral neuronal degenerations. A discoloration of the substantia nigra and locus ceruleus is a distinctive gross feature (Fig. 5.23). The essential histology is a degeneration of the melanin-containing neurons in the compact zone of the substantia nigra and the presence of Lewy bodies in remaining neurons (Fig. 5.24). As the neurons degenerate, melanin pigments are found within macrophages or dispersed freely in the neuropil. An astrocytic gliosis eventually forms at the site of neuronal losses. Surviving neurons display Lewy bodies and pale hyaline bodies. The Lewy bodies, histological hallmarks of iPD, are intracytoplasmic, eosinophilic, laminated inclusions often surrounded by a halo. Their molecular components are a-synuclein, a synaptic protein, and ubiquitin, a cellular stress protein (Table 5.11). a-Synuclein-positive dystrophic Lewy neu-rites are also present. The hyaline bodies are pale, eosin-ophilic, granular structures that displace the melanin and the nucleus (Fig. 5.24).

Common sites of neuronal degenerations and of Lewy bodies and Lewy neurites outside the substantia nigra are the locus ceruleus, dorsal nucleus of vagus, hypothalamus, midbrain raphe nuclei, pedunculopontine and ventral tegmental nuclei, basal nucleus of Meynert,

TABLE 5.11.

Idiopathic Parkinson's Disease

Molecular Pathology

Lewy bodies: Eosinophilic a-Synuclein-positive

Ubiquitin-positive amygdala, hippocampus, intermediolateral column of the spinal cord, and autonomic ganglia. Recent reports indicate astrocytic and oligodendrocytic involvement with argyrophilic and a-synculein-positive cytoplasmic inclusions in areas of neuronal degeneration.

Several factors are considered in the pathomecha-nism of neuronal degeneration, including apoptosis, excitotoxic neurodegeneration, mitochondrial dysfunction, and the formation of free radicals derived from the auto-oxidation of dopamine into neuromelanin.

Neurochemical Pathology and Clinical Correlates The pigmented nigral neurons synthesize the neurotrans-mitter dopamine and transport it to the striatum along the nigrostriatal pathway. In the striatum, the dopamine acts on the neurons possessing D1 and D2 receptors. The striatum also contains GABAergic spiny neurons and cholinergic interneurons. The inhibitory neurotransmit-ter y-aminobutyric acid (GABA) and the excitatory neurotransmitters acetylcholine (ACh) and glutamate are involved in complex neural circuits subserving motor activities. Depletion of the mostly inhibitory dopamine in the striatum upsets the balance between the excitatory and the inhibitory neurotransmitters, resulting in the motor manifestations of iPD. The akinetic rigidity is attributed directly to dopamine deficiency in the stria-tum, whereas the tremor at rest is related to neuronal activity in the globus pallidus. It is estimated that a greater than 50% loss of nigral neurons and a 50% to 80% reduction in striatal dopamine results in clinical symptoms.

Neurons in several extranigral sites synthesize specific neurotransmitters and transmit them to the meso-limbic cortex, neocortex, and deep gray structures. Deficiencies of these neurotransmitters are implicated in some of the neuropsychiatric and autonomic features of iPD. Degeneration of dopaminergic neurons in the ventral tegmental nuclei is associated with cognitive decline. The degeneration of noradrenergic neurons in the locus ceruleus is associated with affective changes and autonomic symptoms, and the degeneration of sero-tonergic neurons in the brainstem correlates with depression and sleep disorder. Neuronal degeneration in the noradrenergic dorsal vagus nucleus accounts for auto-nomic dysfunction, and degeneration of cholinergic forebrain basal nucleus adds to cognitive decline.

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