1321
SCIENCE & PRACTICE Parkinson’s disease: pathophysiology
Idiopathic Parkinson’s disease is the only neurodegenerative disorder in which symptoms can be successfully treated long term. Nevertheless, despite the efficacy of levodopa and related compounds, patients experience increasing difficulties with time. They have to contend not only with drug-related abnormal movements, fluctuations in motor function, and psychological disturbances that may be improved by altering treatment, but also with drug-resistant complications such as gait disorders and intellectual deterioration that may be due to non-dopaminergic lesions. The major parkinsonian symptoms (akinesia, rigidity, tremor) result from massive destruction of nigrostriatal dopaminergic neurons. The selectivity of this lesion makes Parkinson’s disease an excellent model for the study of the mechanisms and causes of neuronal death in the ageing brain.
to
the substantia
neurons
nigra; and certain groups of adrenergic (dorsal vagal nucleus, sympathetic ganglia). This
list is not exhaustive. All of these neuronal systems deteriorate as the disease progresses but to different degrees. A complex clinical picture can result, which varies for each patient. The classic triad of motor symptoms develops mainly because of degeneration of ventral mesencephalic dopaminergic systems,s whereas early cognitive deficits (frontal syndrome and depression) probably arise from subcortical lesions. Later, damage to the cerebral cortex may contribute to a dementia syndrome in 15-20% of patients. Treatmentresistant postural and gait disorders probably result from loss of non-dopaminergic neurons, but which neurons are responsible remains to be identified.
Brain lesions Lesions and symptoms The nigrostriatal dopaminergic neurons that project to the putamen-the predominantly "motor" part of the striatum-are more affected (85 %) than those that project to more "cognitive" areas, such as the caudate nucleus and nucleus accumbens (75%). Dopaminergic neurons that project to cortical and limbic structures (mesocorticolimbic system) are less affected, as are those in the hypothalamus. The dopaminergic neurons in the central grey substance (near the aqueduct of Sylvius) and those extending to the spinal cord seem to be unaffected.2 Neuronal loss is therefore heterogeneous. Even in the most vulnerable structures, such as the substantia nigra, cell loss is never total, but evidence suggests that the process is continuous. HLA-DR-positive microglia are found in the substantia nigra,3 which suggests ongoing cell death; some dopaminergic neurons show altered morphology or reduced expression of certain neuron-specific genes (eg, for tyrosine hydroxylase);4 and neuronal loss in the substantia nigra is always less severe than dopamine depletion in the striatum, which suggests that cells may lose their capacity to synthesise dopamine before dying. Although striatal deficiency constitutes the bulk of parkinsonian abnormalities, other neuronal systems are also affected.2 These systems include noradrenergic (locus coeruleus), serotonergic (raphe), and cholinergic (nucleus basalis of Meynert) neurons that project to cortical and limbic structures; neurons containing peptides such as cholecystokinin-8 (substantia nigra), met-enkephalin, leuenkephalin, substance P (striatum and pallidum), somatostatin, and corticotrophin-releasing factor (cortex); unidentified cortical neurons showing Alzheimer-like neuropathological changes (about 50% of cases); cholinergic neurons
(pedunculopontine tegmental nucleus) projecting
Fig 1-Brain lesions in patients with parkinsonism. Motor symptoms may worsen despite treatment, perhaps because of increasingly complex combinations of dopaminergic and non-dopaminergic lesions. How these lesions contribute to symptoms becomes more evident when patients are categorised according to their response to levodopa. "Levodopa-responsive" patients show the first signs of an essentially akinetic-rigid syndrome before the age of 40, and derive considerable benefitfrom levodopa treatment. Motor scores at the time of maximum improvement with levodopa are mostly unchanged, although motor disability without treatment continues to increase. The continued response of these patients to treatment suggests that they have a severe but selective loss of dopamine in the striatum (fig 1 A), the output pathways ADDRESS: Neurology and Neuropsychology Service, and INSERM U 289, Hôpital de la Salpêtrière, 47 Boulevard de l’Hôpital, 75634 Paris Cédex 13, France. Correspondence to Prof Y.
Agid (MD, PhD).
1322
being essentially spared (fig 1 B). The response to levodopa in other patients decreases with time, with a subsequent parkinsonian syndrome that is largely drug-resistant, as in progressive supranuclear palsy. In this case, response to levodopa may be prevented by lesions of non-dopaminergic efferent neurons located downstream ("in series") from dopaminergic nerve terminals (fig 1 B). Most cases of idiopathic Parkinson’s disease lie between these extremes. Even in later stages of the diseaselevodopa still improves parkinsonian disablity, but not completely. Drug-resistant symptoms are mainly axial-eg, gait disorder and postural instability. In these patients, additional lesions cannot be downstream from nigrostriatal neurons or else they would antagonise effects on levodopa. They must, therefore, be situated "in parallel" with the dopaminergic lesion (fig 1 C).
Fig 2-Dopaminergic cell loss in the substantia nigra of patients with idiopathic Parkinson’s disease. The differences in the time
course of cell loss between idiopathic and disease point to causes for the idiopathic form that include both environmental and genetic factors.
postencephalitic Parkinson’s
Rate of degeneration of dopaminergic neurons
Dopaminergic neurons continue to be lost throughout the of Parkinson’s disease (fig 2). The rate of loss in the substantia nigra has been calculated at about 1 % per year (10 neurons per day), instead of 05% per year as in normal subjects.78 It is unclear whether loss is linear or exponential (dopamine depletion in the striatum approximates to an exponential model)but the rate differs between patients. Cell loss can range from being extremely severe (90%) after short periods of evolution to relatively mild (60%) after
Environmental factors
course
many years of illness.
hypothesis has received much attention since the discovery of the potent neurotoxin, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), which causes selective destruction of dopaminergic neurons in the substantia nigra of humans and primates. The motor symptoms and the extent to which monoaminergic neurons degenerate are indistinguishable from those in Parkinson’s disease, at least as it presents in early onset patients.5 Such findings suggest,
Regression analysis (fig 2) indicates that parkinsonian symptoms are seen only after dopaminergic neuronal loss has reached a certain threshold (70-80% nerve terminals in the striatum; 50-60% cell bodies in the substantia nigra). In the symptom-free period, when many cells have nonetheless been lost, dopaminergic transmission is maintained by increased activity of the remaining neurons and hypersensitivity of postsynaptic dopamine receptors.2 The chronic neuronal degeneration characteristic of Parkinson’s disease is not seen in postencephalitic parkinsonism, where rapid destruction of a large number of nigral dopaminergic neurons is followed by slow degeneration of those that remain, as in normal ageing (fig 2). To maintain chronic neuronal degeneration in Parkinson’s disease, the agent or factor responsible must be continuously present. The constant presence of an
but do not prove, that similar environmental agents may contribute to the idiopathic disease. The higher frequency of Parkinson’s disease in industrialised countries (chemicals, heavy metals, and pesticides) and rural areas (vegetable farming, well water, and wood pulp) supports such a view. 13 However, chronic intoxication by a specific compound is improbable because Parkinson’s disease is ubiquitous. The hypothesis that primary cell death, caused by an exogenous agent during the patient’s early or middle years, is followed by a gradual age-related decline in cell number, 14 although possible for postencephalitic parkinsonism, is not consistent with the idiopathic disease (fig 2). Combinations of genetic and environmental factors are also conceivable, such as genetically determined vulnerability to an exogenous agent that results in subacute toxic cell death or premature cell
environmental toxin would be consistent with this type of process, but permanent malfunction of neurons because of a genetic predisposition, resulting in either insufficient production of an essential protein or accumulation of toxic metabolites, must also be considered.
ageing.
This
Ageing Although it is logical that ageing should contribute to pathological cell death, one would expect the frequency of Parkinson’s
Death of
dopaminergic neurons
Genetic factors
Heredity does not seem to be important in Parkinson’s disease.9 The frequency of a positive family history and the prevalence of the disease among first-degree relatives are the same in patients and controls. Furthermore, the concordance rates for monozygotic and dizygotic twins are similar, althouth these data alone do not exclude a genetic component to the disease." Early onset Parkinson’s disease, where familial cases are more frequent," may have a stronger genetic basis. Autosomal dominant transmission of idiopathic-like parkinsonism has also been described,12 which suggests that a single genetic anomaly can cause all the essential symptoms associated with the disease.
disease to increase with age. Some epidemiological studies suggest that this may be so, but others report that disease frequency decreases after 80 years of age. It is, therefore, difficult to draw conclusions from these data.15 Necropsy studies have suggested that the rate of loss of dopaminergic innervation in the caudate nucleus is similar whether the disease develops before or after 60 years of age.8 Furthermore, neuronal loss in the substantia nigra is less severe in late onset patients than in early onset patients despite similar disease durations.16 Although ageing probably does not have a major effect on dopaminergic neuron degeneration, symptom expression may be altered. Unlike early onset patients, those whose disease begins later in life have more severe frontal-lobe-like symptoms gait disorders, and postural instability.18
1323
Mechanisms The
Lewy body
The presence of Lewy bodies (eosinophilic cytoplasmic inclusions), in addition to loss of pigmented neurons in the substantia nigra, is accepted as neuropathological confirmation of the diagnosis of Parkinson’s disease. These inclusions are also found in brain structures that are not necessarily catecholaminergic (such as the nucleus basalis of Meynert and the dorsal motor nucleus of the vagus). Lewy bodies are found in elderly patients who may have symptom-free Parkinson’s disease/9 in some patients with Alzheimer’s disease, and in diffuse Lewy-body disease, where inclusions are found disseminated throughout the brain. They may still have some specificity in Parkinson’s disease, however, since they are not found in the substantia nigra of patients with other parkinsonian syndromes where neurons degenerate (progressive dopaminergic supranuclear palsy, postencephalitic parkinsonism, and multisystem atrophy). It is unlikely that Lewy bodies, which contain normal cell constituents,2° cause degeneration of nigrostriatal or other neurons. An understanding of the process by which they are formed would help, however, to clarify the mechanism of neuronal degeneration.
Free radicals
Lipid peroxidation is selectively increased in the substantia nigra of patients with Parkinson’s disease,21 which suggests that free radicals are produced in excess and result in chronic local oxidative stress that may cause progressive degeneration of the nigral dopaminergic neurons. Free radicals are probably produced normally in large quantities in the human substantia nigra since there is an abundance of detoxifying enzymes, such as superoxide dismutase in dopaminergic neurons22 and glutathione peroxidase in glial cells. In parkinsonian patients, the activity of these enzymes is not especially abnormal .23 However, decreased concentrations of glutathione24 and increased activity of mitochondrial superoxide dismutase2’ suggest that excess free radicals may be
produced. Free radicals are formed during neuromelanin synthesis. Neuromelanin is found in most, but not all, mesencephalic dopaminergic neurons, these are the neurons that
degenerate in Parkinson’s disease, whereas unpigmented neurons (in the central grey substance) are spared.26 In addition, the more pigment these neurons contain, the more vulnerable they seem to be,27 an abundance of neuromelanin in a dopaminergic neuron could lead to its degeneration. However, less pigmented neurons degenerate as well, notably those in the ventrolateral part of the substantia nigra,28 which suggests that the pigment alone is not sufficient to cause cell death. Free radicals can also be generated in substantia nigra by oxidative degradation of dopamine by monoamine oxidase B, which is highly concentrated in this structure.29 This process may accelerate as remaining neurons increase their activity. Furthermore, iron concentrations are increased in the substantia nigra of parkinsonian patients,3O notably Lewy bodies,31 and may be related to an observed decrease in ferritin concentrations.32 Since iron facilitates formation of toxic hydroxyl (-OH) and superoxide (0’) radicals, as well as hydrogen peroxide, and has a predilection for neuromelanin,33 free radicals could be continuously produced in the substantia nigra.
Defective mitochondrial respiration A decreased activity of respiratory-enzyme complex 134,35 in the substantia nigra, but not in other brain regions36 of subjects with Parkinson’s disease, suggests that dopaminergic neurons might have defective mitochondrial energy metabolism. Complex-I activity has also been reported to be reduced in platelets from patients with Parkinson’s disease,37 but this observation has not been confirmed (Prof A. H. V. Schapira, personal communication). Complex-II activity is inhibited by MPP+, a metabolite of the neurotoxin MPTP, in laboratory animal models of Parkinson’s disease.38 An MPTP-like substance might, therefore, have a similar effect in parkinsonian patients. Alternatively, reduced complex-I activity could result from either a defective gene encoding abnormal complex-I proteins or a factor that regulates gene transcription. No deletions of mitochondrial DNA have been found,39 but further study of the mitochondrial genome is needed. Other hypotheses continue to be tested. The disease is not of viral origin,40 and is not an autoimmune disorder, although antibodies directed against substantia nigra have been found in cerebrospinal fluid of parkinsonian patients.41 The possibility that sulphur-conjugate metabolism is defective has also been proposed, since decreased thiolmethyltransferase activity has been reported in the blood of parkinsonian patients.’2 The fragility of irradiated fibroblasts may indicate impaired DNA repair mechanisms.43 A possible deficit in trophic factors essential for the survival of dopaminergic neurons is also being sought. The observation that brain-derived neurotrophic factor both increases the survival of mesencephalic dopaminergic neurons and reduces the cytotoxicity of MPP + in vitro may be crucial. 44 I thank Dr M.
Ruberg for her help with the text. REFERENCES
1.
Hornykiewicz O. Dopamine (3-hydroxytyramine)
and brain functions.
Pharm Rev 1966; 18: 925-64.
Agid Y, Jayoy-Agid F, Ruberg M. Biochemistry of neurotransmitters in Parkinson’s disease. In: Marsden CD, Fahn S, eds. Movement disorders 2. London: Butterworths, 1987: 166-230. 3. McGeer PL, Itagaki Q, Akiyama H, McGeer EG. Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 2.
1988; 24: 574-76. Javoy-Agid F, Hirsch E, Dumas S, Duyckaerts C, Mallet J, Agid Y. Decreased tyrosine hydroxylase messenger mRNA in the surviving dopamine neurons in Parkinson’s disease: an in situ hybridization study. Neuroscience 1990; 48: 245-53. 5. Langston JW. Mechanisms underlying neuronal degeneration in Parkinson’s disease: an experimental and theoretical treatise. Mov Disord 1989; 4: S15-S25. 6. Bonnet AM, Loria Y, Saint-Hilaire MH, Lhermitte F, Agid Y. Does long-term aggravation of Parkinson’s disease result from nondopaminergic lesions? Neurology 1987; 37: 1539-42. 7. Riederer P, Wuketich S. Time course of nigrostriatal degeneration in Parkinson’s disease. J Neurol Transm 1976; 38: 277-301. 8. Scherman D, Desnos C, Darchen F, Pollak P, Javoy-Agid F, Agid Y. Stratial dopamine deficiency in Parkinson’s disease: role of aging. Ann 4.
Neurol 1989; 26: 551-57. 9. Duvoisin RC. On heredity, twins, and Parkinson’s disease. Ann Neurol 1986; 4: 409-11. 10. Johnson WG, Hodge SE, Duvoisin R. Twin studies and the genetics of Parkinson’s disease: a reappraisal. Mov Disord 1990; 5: 187-94. 11. Alonso ME, Otero E, D’Regules R, Figueroa HH. Parkinson’s disease: a genetic study. Can J Neurol Sci 1986; 13: 248-51. 12. Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A large kindred with autosomal dominant Parkinson’s disease. Ann Neurol
1990; 27: 276-82. 13. Tanner CM. The role of environmental toxins in the Parkinson’s disease. Trends Neurosci 1989; 12: 49-54.
etiology
of
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14. Calne DB, Langston JW. Aetiology of Parkinson’s disease. Lancet 1983; ii: 1457-59. 15. Koller W, O’Hara R, Weiner W, et al. Relationship of aging to Parkinson’s disease. In: Yahr MD, Bergmann KJ, eds. Adv in Neurol
1986; 45: 317-21. 16. Gibb WRG, Lees AJ. A comparison of clinical and pathological featues of young- and old-onset Parkinson’s disease. Neurology 1988; 38: 1402-06. 17. Dubois B, Pillon B, Sternic N, Lhermitte F, Agid Y. Age-induced cognitive deficit in Parkinson’s disease. Neurology 1990; 40: 38-41. 18. Blin J, Bonnet AM, Vidailhet M, Brandabur M, Agid Y. Does aging aggravate parkmsonian disability? J Neurol Neurosurg Psychiatry (in
press). 19. Marsden CD. Parkinson’s disease. Lancet 1990; i: 948-52. 20. Jellinger K. New developments in the pathology of Parkinson’s disease. In: Streifler MB, Korczyn AD, Melamed E, Youdim MBH, eds. Parkinson’s disease: anatomy, pathology, and therapy. Adv Neurol 1990; 53: 1-16. 21. Dexter DT, Carter CJ, Wells FR, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 1989; 52: 381-89. 22. Ceballos I, Sinet PM, Nicole A, et al. Superoxide dismutase and Parkinson’s disease. Lancet 1990; 335: 1035-36. 23. Martilla RJ, Lorentz H, Rinne UK. Oxygen toxicity protecting enzymes in Parkinson’s disease. J Neurol Sci 1988; 86: 321-31. 24. Perry TL, Godin DV, Hansen S. Parkinson’s disease: a disorder due to nigral glutathione deficiency? Neurosci Lett 1982; 33: 305-10. 25. Saggu H, Cooksey J, Dexter D, et al. A selective increase in particulate superoxyde dismutase activity in parkinsonian substantia nigra. J Neurochem 1989; 53: 692-96. 26. Hirsch EC, Graybiel AM, Agid Y. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 1988; 334: 345-48. 27. Mann DMA, Yates PO. Possible role of neuromelanin in the pathogenesis of Parkinson’s disease. Mech Ageing Dev 1983; 21: 193-203. 28. Gibb WRG, Fearnley JM, Lees AJ. The anatomy and pigmentation of the human substantia nigra in relation to selective neuronal vulnerability. In: Streifler MB, Korczyn AD, Melamed E, Youdim MBH, eds. Advances in Neurology 1990; 53: 31-34. 29. Konradi C, Kornhuber J, Froelich L, et al. Demonstration of monoamine oxidase-A and B in the human brainstem by a histochemical technique. Neuroscience 1989; 33: 383-400. 30. Dexter DT, Wells FR, Lees AJ, et al. Increased nigral iron content and alterations in other metal ions occuring in brain in Parkinson’s disease.
J Neurochem 1989; 52: 1830-36. 31. Hirsch EC, Brandel JP, Javoy-Agid F, Agid Y. Iron and aluminium increase in the substantia nigra of patients with Parkinson’s disease: a X-ray microanalysis. J Neurochem 1991; 56: 446-51. 32. Dexter DT, Carayaon A, Vidailhet M, et al. Decreased ferritin levels in brain in Parkinson’s disease. J Neurochem 1990; 55: 16-20. 33. Ben-Sachar D, Youdim MBH. Selectivity of melanized nigra-striatal dopamine neurons to degeneration in Parkinson’s disease may depend on iron-melanin interaction. J Neural Transm 1990; 29 (suppl): 251-58.
Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990; 54: 823-27. 35. Mizuno Y, Ohta S, Tanaka M, et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Comm 1989; 163: 1450-55. 36. Schapira AHV, Mann VM, Cooper JM, et al. Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 1990; 55: 2142-45. 37. Parker WD, Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 1989; 26: 719-23. 38. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by MPP+, a metabolite of the neurotoxin MPTP. Life Sci 1985; 36: 2503-08. 39. Schapira AHV, Holt IJ, Sweeney M, Harding AE, Jenner P, Marsden CD. Mitochondrial DNA analysis in Parkinson’s disease. Mov Disord 34.
1990; 5: 294-97. 40. Elizan TS, Casals J. The viral hypothesis in Parkinson’s disease and Alzheimer’s disease: a critique. In: Kurstak E, Liposwki ZJ, Morozov PV, eds. Viruses, immunity and mental disorders. New York: Plenum, 1987: 47-59. 41. McRae-Degueurce A, Gottfries CS, Karlsson I, Svennerholm L, Dahlstrom A. Antibodies in the CSF of a Parkinson patient recognize neurons in rat mesencephalic regions. Acta Physiol Scand 1986; 126: 313-15. 42. Waring RH, Sturman SG, Smith MCG, Steventon GB, Heafield MTE, Williams AC. S-methylation in motorneuron disease and Parkinson’s disease. Lancet 1989; ii: 356-57. 43. Robbins JH, Otsuka F, Tarone RE, Polinsky RJ, Brumback RA, Nee LE. Parkinson’s disease and Alzheimer’s disease: hypersensitivity to X-rays in cultured cell lines. J Neurol Neurosurg Psychiatry 1985; 48: 916-23. 44. Hyman C, Hofer M, Barde YA, et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991; 350: 230-32.
Parkinson’s disease: management
Extensive recent research has led to renewed public interest in Parkinson’s disease and has consequently raised patients’ expectations about outcome of treatment. Such optimism is probably unjustified. Although the introduction of levodopa as replacement therapyl for the selective depletion of dopamine2 has been a qualified success, many long-term sequelae remain as insoluble difficulties for the clinician. Moreover, Parkinson’s disease mainly affects elderly people, whose quality of life may already be impaired by other disorders. Therapeutic failure, coexisting disease, and treatment-related complications are often forgotten in the excitement generated by the results of artificially controlled drug trials and descriptions of novel treatment strategies. I will begin by discussing the confounding factors that commonly limit the success of care given to Parkinson’s disease patients.
Treatment failures Confusional states
Attempts estimate the frequency of intellectual decline among patients with Parkinson’s disease have been largely to
unsuccessful. The first prospective community study of dementia associated with Parkinson’s diseaseshowed that 24-3% of patients were demented as defined by the Diagnostic and Statistical Manual-III Revised, and an unknown number were depressed and had milder signs of dementia. Most parkinsonian patients have mild intellectual disability as a result of frontal-lobe dysfunction;4 these deficits do not usually pose any difficulties in management. A substantial minority with progressive dementia are difficult to treat, and drug treatment itself may lead to hallucinosis. Other medical conditions such as thyroid disorders, syphilis, and intracerebral mass lesions may need to be excluded. Progressive intellectual decline raises the possibility of an incorrect initial diagnosis-Alzheimer’s disease,5 multisystem atrophyand cortical-Lewy-body disease must all be included in the differential diagnosis. Depression is common in Parkinson’s disease and can present as either physical or mental decline. ADDRESS Brook Regional Movement Disorder Clinic, Shooter’s Hill Road, Woolwich, London SE18 4LW, UK. Correspondence to Dr C G Clough (MRCP).
SCIENCE & PRACTICE Parkinson’s disease: pathophysiology
Idiopathic Parkinson’s disease is the only neurodegenerative disorder in which symptoms can be successfully treated long term. Nevertheless, despite the efficacy of levodopa and related compounds, patients experience increasing difficulties with time. They have to contend not only with drug-related abnormal movements, fluctuations in motor function, and psychological disturbances that may be improved by altering treatment, but also with drug-resistant complications such as gait disorders and intellectual deterioration that may be due to non-dopaminergic lesions. The major parkinsonian symptoms (akinesia, rigidity, tremor) result from massive destruction of nigrostriatal dopaminergic neurons. The selectivity of this lesion makes Parkinson’s disease an excellent model for the study of the mechanisms and causes of neuronal death in the ageing brain.
to
the substantia
neurons
nigra; and certain groups of adrenergic (dorsal vagal nucleus, sympathetic ganglia). This
list is not exhaustive. All of these neuronal systems deteriorate as the disease progresses but to different degrees. A complex clinical picture can result, which varies for each patient. The classic triad of motor symptoms develops mainly because of degeneration of ventral mesencephalic dopaminergic systems,s whereas early cognitive deficits (frontal syndrome and depression) probably arise from subcortical lesions. Later, damage to the cerebral cortex may contribute to a dementia syndrome in 15-20% of patients. Treatmentresistant postural and gait disorders probably result from loss of non-dopaminergic neurons, but which neurons are responsible remains to be identified.
Brain lesions Lesions and symptoms The nigrostriatal dopaminergic neurons that project to the putamen-the predominantly "motor" part of the striatum-are more affected (85 %) than those that project to more "cognitive" areas, such as the caudate nucleus and nucleus accumbens (75%). Dopaminergic neurons that project to cortical and limbic structures (mesocorticolimbic system) are less affected, as are those in the hypothalamus. The dopaminergic neurons in the central grey substance (near the aqueduct of Sylvius) and those extending to the spinal cord seem to be unaffected.2 Neuronal loss is therefore heterogeneous. Even in the most vulnerable structures, such as the substantia nigra, cell loss is never total, but evidence suggests that the process is continuous. HLA-DR-positive microglia are found in the substantia nigra,3 which suggests ongoing cell death; some dopaminergic neurons show altered morphology or reduced expression of certain neuron-specific genes (eg, for tyrosine hydroxylase);4 and neuronal loss in the substantia nigra is always less severe than dopamine depletion in the striatum, which suggests that cells may lose their capacity to synthesise dopamine before dying. Although striatal deficiency constitutes the bulk of parkinsonian abnormalities, other neuronal systems are also affected.2 These systems include noradrenergic (locus coeruleus), serotonergic (raphe), and cholinergic (nucleus basalis of Meynert) neurons that project to cortical and limbic structures; neurons containing peptides such as cholecystokinin-8 (substantia nigra), met-enkephalin, leuenkephalin, substance P (striatum and pallidum), somatostatin, and corticotrophin-releasing factor (cortex); unidentified cortical neurons showing Alzheimer-like neuropathological changes (about 50% of cases); cholinergic neurons
(pedunculopontine tegmental nucleus) projecting
Fig 1-Brain lesions in patients with parkinsonism. Motor symptoms may worsen despite treatment, perhaps because of increasingly complex combinations of dopaminergic and non-dopaminergic lesions. How these lesions contribute to symptoms becomes more evident when patients are categorised according to their response to levodopa. "Levodopa-responsive" patients show the first signs of an essentially akinetic-rigid syndrome before the age of 40, and derive considerable benefitfrom levodopa treatment. Motor scores at the time of maximum improvement with levodopa are mostly unchanged, although motor disability without treatment continues to increase. The continued response of these patients to treatment suggests that they have a severe but selective loss of dopamine in the striatum (fig 1 A), the output pathways ADDRESS: Neurology and Neuropsychology Service, and INSERM U 289, Hôpital de la Salpêtrière, 47 Boulevard de l’Hôpital, 75634 Paris Cédex 13, France. Correspondence to Prof Y.
Agid (MD, PhD).
1322
being essentially spared (fig 1 B). The response to levodopa in other patients decreases with time, with a subsequent parkinsonian syndrome that is largely drug-resistant, as in progressive supranuclear palsy. In this case, response to levodopa may be prevented by lesions of non-dopaminergic efferent neurons located downstream ("in series") from dopaminergic nerve terminals (fig 1 B). Most cases of idiopathic Parkinson’s disease lie between these extremes. Even in later stages of the diseaselevodopa still improves parkinsonian disablity, but not completely. Drug-resistant symptoms are mainly axial-eg, gait disorder and postural instability. In these patients, additional lesions cannot be downstream from nigrostriatal neurons or else they would antagonise effects on levodopa. They must, therefore, be situated "in parallel" with the dopaminergic lesion (fig 1 C).
Fig 2-Dopaminergic cell loss in the substantia nigra of patients with idiopathic Parkinson’s disease. The differences in the time
course of cell loss between idiopathic and disease point to causes for the idiopathic form that include both environmental and genetic factors.
postencephalitic Parkinson’s
Rate of degeneration of dopaminergic neurons
Dopaminergic neurons continue to be lost throughout the of Parkinson’s disease (fig 2). The rate of loss in the substantia nigra has been calculated at about 1 % per year (10 neurons per day), instead of 05% per year as in normal subjects.78 It is unclear whether loss is linear or exponential (dopamine depletion in the striatum approximates to an exponential model)but the rate differs between patients. Cell loss can range from being extremely severe (90%) after short periods of evolution to relatively mild (60%) after
Environmental factors
course
many years of illness.
hypothesis has received much attention since the discovery of the potent neurotoxin, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), which causes selective destruction of dopaminergic neurons in the substantia nigra of humans and primates. The motor symptoms and the extent to which monoaminergic neurons degenerate are indistinguishable from those in Parkinson’s disease, at least as it presents in early onset patients.5 Such findings suggest,
Regression analysis (fig 2) indicates that parkinsonian symptoms are seen only after dopaminergic neuronal loss has reached a certain threshold (70-80% nerve terminals in the striatum; 50-60% cell bodies in the substantia nigra). In the symptom-free period, when many cells have nonetheless been lost, dopaminergic transmission is maintained by increased activity of the remaining neurons and hypersensitivity of postsynaptic dopamine receptors.2 The chronic neuronal degeneration characteristic of Parkinson’s disease is not seen in postencephalitic parkinsonism, where rapid destruction of a large number of nigral dopaminergic neurons is followed by slow degeneration of those that remain, as in normal ageing (fig 2). To maintain chronic neuronal degeneration in Parkinson’s disease, the agent or factor responsible must be continuously present. The constant presence of an
but do not prove, that similar environmental agents may contribute to the idiopathic disease. The higher frequency of Parkinson’s disease in industrialised countries (chemicals, heavy metals, and pesticides) and rural areas (vegetable farming, well water, and wood pulp) supports such a view. 13 However, chronic intoxication by a specific compound is improbable because Parkinson’s disease is ubiquitous. The hypothesis that primary cell death, caused by an exogenous agent during the patient’s early or middle years, is followed by a gradual age-related decline in cell number, 14 although possible for postencephalitic parkinsonism, is not consistent with the idiopathic disease (fig 2). Combinations of genetic and environmental factors are also conceivable, such as genetically determined vulnerability to an exogenous agent that results in subacute toxic cell death or premature cell
environmental toxin would be consistent with this type of process, but permanent malfunction of neurons because of a genetic predisposition, resulting in either insufficient production of an essential protein or accumulation of toxic metabolites, must also be considered.
ageing.
This
Ageing Although it is logical that ageing should contribute to pathological cell death, one would expect the frequency of Parkinson’s
Death of
dopaminergic neurons
Genetic factors
Heredity does not seem to be important in Parkinson’s disease.9 The frequency of a positive family history and the prevalence of the disease among first-degree relatives are the same in patients and controls. Furthermore, the concordance rates for monozygotic and dizygotic twins are similar, althouth these data alone do not exclude a genetic component to the disease." Early onset Parkinson’s disease, where familial cases are more frequent," may have a stronger genetic basis. Autosomal dominant transmission of idiopathic-like parkinsonism has also been described,12 which suggests that a single genetic anomaly can cause all the essential symptoms associated with the disease.
disease to increase with age. Some epidemiological studies suggest that this may be so, but others report that disease frequency decreases after 80 years of age. It is, therefore, difficult to draw conclusions from these data.15 Necropsy studies have suggested that the rate of loss of dopaminergic innervation in the caudate nucleus is similar whether the disease develops before or after 60 years of age.8 Furthermore, neuronal loss in the substantia nigra is less severe in late onset patients than in early onset patients despite similar disease durations.16 Although ageing probably does not have a major effect on dopaminergic neuron degeneration, symptom expression may be altered. Unlike early onset patients, those whose disease begins later in life have more severe frontal-lobe-like symptoms gait disorders, and postural instability.18
1323
Mechanisms The
Lewy body
The presence of Lewy bodies (eosinophilic cytoplasmic inclusions), in addition to loss of pigmented neurons in the substantia nigra, is accepted as neuropathological confirmation of the diagnosis of Parkinson’s disease. These inclusions are also found in brain structures that are not necessarily catecholaminergic (such as the nucleus basalis of Meynert and the dorsal motor nucleus of the vagus). Lewy bodies are found in elderly patients who may have symptom-free Parkinson’s disease/9 in some patients with Alzheimer’s disease, and in diffuse Lewy-body disease, where inclusions are found disseminated throughout the brain. They may still have some specificity in Parkinson’s disease, however, since they are not found in the substantia nigra of patients with other parkinsonian syndromes where neurons degenerate (progressive dopaminergic supranuclear palsy, postencephalitic parkinsonism, and multisystem atrophy). It is unlikely that Lewy bodies, which contain normal cell constituents,2° cause degeneration of nigrostriatal or other neurons. An understanding of the process by which they are formed would help, however, to clarify the mechanism of neuronal degeneration.
Free radicals
Lipid peroxidation is selectively increased in the substantia nigra of patients with Parkinson’s disease,21 which suggests that free radicals are produced in excess and result in chronic local oxidative stress that may cause progressive degeneration of the nigral dopaminergic neurons. Free radicals are probably produced normally in large quantities in the human substantia nigra since there is an abundance of detoxifying enzymes, such as superoxide dismutase in dopaminergic neurons22 and glutathione peroxidase in glial cells. In parkinsonian patients, the activity of these enzymes is not especially abnormal .23 However, decreased concentrations of glutathione24 and increased activity of mitochondrial superoxide dismutase2’ suggest that excess free radicals may be
produced. Free radicals are formed during neuromelanin synthesis. Neuromelanin is found in most, but not all, mesencephalic dopaminergic neurons, these are the neurons that
degenerate in Parkinson’s disease, whereas unpigmented neurons (in the central grey substance) are spared.26 In addition, the more pigment these neurons contain, the more vulnerable they seem to be,27 an abundance of neuromelanin in a dopaminergic neuron could lead to its degeneration. However, less pigmented neurons degenerate as well, notably those in the ventrolateral part of the substantia nigra,28 which suggests that the pigment alone is not sufficient to cause cell death. Free radicals can also be generated in substantia nigra by oxidative degradation of dopamine by monoamine oxidase B, which is highly concentrated in this structure.29 This process may accelerate as remaining neurons increase their activity. Furthermore, iron concentrations are increased in the substantia nigra of parkinsonian patients,3O notably Lewy bodies,31 and may be related to an observed decrease in ferritin concentrations.32 Since iron facilitates formation of toxic hydroxyl (-OH) and superoxide (0’) radicals, as well as hydrogen peroxide, and has a predilection for neuromelanin,33 free radicals could be continuously produced in the substantia nigra.
Defective mitochondrial respiration A decreased activity of respiratory-enzyme complex 134,35 in the substantia nigra, but not in other brain regions36 of subjects with Parkinson’s disease, suggests that dopaminergic neurons might have defective mitochondrial energy metabolism. Complex-I activity has also been reported to be reduced in platelets from patients with Parkinson’s disease,37 but this observation has not been confirmed (Prof A. H. V. Schapira, personal communication). Complex-II activity is inhibited by MPP+, a metabolite of the neurotoxin MPTP, in laboratory animal models of Parkinson’s disease.38 An MPTP-like substance might, therefore, have a similar effect in parkinsonian patients. Alternatively, reduced complex-I activity could result from either a defective gene encoding abnormal complex-I proteins or a factor that regulates gene transcription. No deletions of mitochondrial DNA have been found,39 but further study of the mitochondrial genome is needed. Other hypotheses continue to be tested. The disease is not of viral origin,40 and is not an autoimmune disorder, although antibodies directed against substantia nigra have been found in cerebrospinal fluid of parkinsonian patients.41 The possibility that sulphur-conjugate metabolism is defective has also been proposed, since decreased thiolmethyltransferase activity has been reported in the blood of parkinsonian patients.’2 The fragility of irradiated fibroblasts may indicate impaired DNA repair mechanisms.43 A possible deficit in trophic factors essential for the survival of dopaminergic neurons is also being sought. The observation that brain-derived neurotrophic factor both increases the survival of mesencephalic dopaminergic neurons and reduces the cytotoxicity of MPP + in vitro may be crucial. 44 I thank Dr M.
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Parkinson’s disease: management
Extensive recent research has led to renewed public interest in Parkinson’s disease and has consequently raised patients’ expectations about outcome of treatment. Such optimism is probably unjustified. Although the introduction of levodopa as replacement therapyl for the selective depletion of dopamine2 has been a qualified success, many long-term sequelae remain as insoluble difficulties for the clinician. Moreover, Parkinson’s disease mainly affects elderly people, whose quality of life may already be impaired by other disorders. Therapeutic failure, coexisting disease, and treatment-related complications are often forgotten in the excitement generated by the results of artificially controlled drug trials and descriptions of novel treatment strategies. I will begin by discussing the confounding factors that commonly limit the success of care given to Parkinson’s disease patients.
Treatment failures Confusional states
Attempts estimate the frequency of intellectual decline among patients with Parkinson’s disease have been largely to
unsuccessful. The first prospective community study of dementia associated with Parkinson’s diseaseshowed that 24-3% of patients were demented as defined by the Diagnostic and Statistical Manual-III Revised, and an unknown number were depressed and had milder signs of dementia. Most parkinsonian patients have mild intellectual disability as a result of frontal-lobe dysfunction;4 these deficits do not usually pose any difficulties in management. A substantial minority with progressive dementia are difficult to treat, and drug treatment itself may lead to hallucinosis. Other medical conditions such as thyroid disorders, syphilis, and intracerebral mass lesions may need to be excluded. Progressive intellectual decline raises the possibility of an incorrect initial diagnosis-Alzheimer’s disease,5 multisystem atrophyand cortical-Lewy-body disease must all be included in the differential diagnosis. Depression is common in Parkinson’s disease and can present as either physical or mental decline. ADDRESS Brook Regional Movement Disorder Clinic, Shooter’s Hill Road, Woolwich, London SE18 4LW, UK. Correspondence to Dr C G Clough (MRCP).
