Compensatory Mechanisms in Degenerative Neurologic Diseases Insights
From Parkinsonism
Donald B. Calne, DM, Michael J.
Zigmond, PhD
\s=b\ In animal models of parkinsonism, the ability to lose a substantial proportion of dopaminergic neurons without behavioral deficits does not derive from other systems taking over function of the dopaminergic pathway. The surviving nigrostriatal projec-
tion increases both the rate of synthesis and the release of dopamine, as compensatory adjustments. This capacity allows at least a fivefold rise in dopamine delivery per neuron, and this enhancement is potentiated further by receptor up-regulation. Decreased reuptake, due to loss of nerve endings, may also lead to augmented occupancy of dopamine receptors, and so constitute yet another compensatory mechanism. In humans, positron emission tomography has revealed subclinical impairment of the dopaminergic nigrostriatal pathway in subjects at risk for parkinsonism caused by 1-methyl-4-phenyl\x=req-\ 1,2,3,6-tetrahydropyridine and Lytico-Bodig (the amyotrophic lateral sclerosis-parkin-
seeking the cause of a degenerative disease, a first stage is the develop¬ ment of a conceptual model of pathogen¬ esis. To formulate such a model, it is
desirable to have information on the neurobiological adjustments that take Accepted for publication October 5,1990. From the Neurodegenerative Disorders Center, Department of Medicine, University of British Columbia, University Hospital, Vancouver, Canada (Dr Calne), and the Departments of Behavioral Neuroscience and Psychiatry, University of Pittsburgh (Pa) (Dr Zigmond). Reprint requests to Neurodegenerative Disorders Center, Department of Medicine, University of British Columbia, University Hospital, U.B.C. Site, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T1W5 (Dr Calne).
sonism dementia complex of Guam). However, the separation of patients with clinically overt idiopathic parkinsonism from controls is less marked in vivo (by positron emission tomography) than in postmortem analysis (by neurochemical assay). This disparity may be attributable to the reduction in the number of nigrostriatal nerve endings, leading, in vivo, to a relative increase of extracellular dopamine because active reuptake into the nerve endings is an important mechanism for removing dopamine from the synaptic cleft. In contrast, in a postmortem setting, dopamine that is not sequestered in the storage vesicles of nerve endings is readily available for biochemical degradation during the interval between death and brain analysis. Finally, it is also possible that differences may derive, in part, from dissimilar kinetic systems for handling exogenous and endogenous levodopa. (Arch Neurol. 1991 ;48:361-363)
place in the nervous system when some neurons
have died and others
are
at¬
tempting to compensate and to maintain function. The most extensively studied pathway in this context is the dopamin¬ ergic component of the nigrostriatal
bundle, and for this system, relevant
animal observations can be correlated with phenomena observed in idiopathic parkinsonism.12 In addition, since the dopaminergic cells ofthe zona compacta of the substantia nigra are selectively vulnerable to attrition with normal ag¬ ing,3 exploration of compensatory ad¬ justments in these neurons should con¬ tribute to the elucidation of neurologic
Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/07/2015
in this review we fo¬ and human studies of ad¬ to lesions of nigrostriatal do¬
Thus,
senescence. cus on animal
aptations pamine neurons.
ANIMAL STUDIES
6-Hydroxydopamine is a highly electroactive molecule that is concentrated by high-affinity transport systems of ca-
techolaminergic
neurons, particularly in the nerve terminals. Subsequent oxi¬ dation of this molecule produces highly toxic products, with resulting degener¬ ation.4 Injection of 6-hydroxydopamine into the brain of many experimental ani¬ mals, either via the cerebrospinal fluid or directly along the nigrostriatal bun¬ dle, results in the death of dopaminergic neurons. The extent of the lesion de¬ pends on route of administration, dos¬' age, and pharmacologie pretreatment. Gross behavioral changes do not oc¬ cur following the administration of 6-hydroxydopamine unless the destruc¬ tion ofthe nigrostriatal bundle is almost complete, and even' then, the deficits are often transient. Electrolytic lesions of the nigrostriatal system may also re¬ sult in neurologic impairments that im¬ prove spontaneously,5,6 and the same has been reported following administra¬ tion of the toxin l-methyl-4-phenyl1,2,3,6-tetrahydropyridine to subhu¬
primates.4 ability to undergo major loss of dopaminergic cells without clinical ef¬ man
The
fects and the spontaneous improvement that commonly occurs when the lesions are severe enough to induce initial be¬ havioral deficits do not reflect a transfer
of function from the nigrostriatal bundle to other pathways. Neurologic deficits can readily be reestablished in lesioned animals by pharmacologie manipula¬ tions that compromise dopaminergic function still further. Indeed, lesioned animals are supersensitive to such treatments. Moreover, a minimal num¬ ber of dopamine neurons must survive the lesion for recovery to occur. ' These observations suggest the continued im¬ portance of the remaining elements of
*3*-*(H
the nigrostriatal bundle. The relation between size of an ex¬ perimental lesion and neurologic deficit does not appear to derive from simple redundancy in the nigrostriatal system. The dopamine neurons that are spared by the injury have been shown to in¬ crease their synthesis and release of
3~f
""
tr(-
due to
degeneration of neighboring do¬ paminergic terminals"" and, after ex¬ tensive lesions, by an increase in the number of postsynaptic dopamine re¬
receptor up-regulation. Taken togeth¬ er, these mechanisms may allow each
surviving nigrostriatal
neuron
to
com¬
pensate for the death of many similar
cells before any functional deficit would be expected. Experimental observa¬ tions at both the behavioral and the cel¬ lular levels are consistent with this pre¬ diction, and studies of damage to other monoaminergic systems in the brain and the periphery indicate that the capacity for such adaptation is
widespread.1
It is possible that these compensatory processes exact a toll, however. The greatly enhanced turnover of dopamine could lead to the accumulation of toxic by-products of dopamine oxidation simi¬ lar to those formed by 6-hydroxydopa¬ mine, thereby contributing to the ulti¬ mate degeneration of surviving elements of the nigrostriatal bundle. Furthermore, comparable toxic sub¬ stances could accumulate in the extra¬ cellular space as a result of impaired removal of dopamine from the synaptic cleft consequent on loss of the nerve endings that possess an active reuptake mechanism. This vicious circle would generate more injury, to both dopamin¬ ergic and nondopaminergic cellular
components.
Extreme Lesion
Larger Lesion
transmitter, suggesting an active, com¬ pensatory elevation in their functional activity. The impact of this hyperac¬ tivity is augmented by the loss of sites for dopamine inactivation by reuptake
ceptors1" (Figure). Indeed, experiments have suggested that after partial ni¬ grostriatal lesions, surviving dopamin¬ ergic neurons can increase their capaci¬ ty to deliver transmitter by at least fivefold, and that the impact of this do¬ pamine can be increased still further by
Moderate Lesion
Normal
'
{
•f il —
^L
11
(
' „
compensatory changes after lesions of the nigrostriatal bundle (from Zigmond and Under normal conditions synaptic transmission takes place with relatively little Interaction between neighboring synapses. In addition, some synapses may be Inactive. Top right,
A model for
Strieker1). Top left,
Moderate lesions have little or no functional Impact for one or more reasons. Transmitter released at one synapse may act at a denervated site owing to the loss of inactlvatlon via high-afflnlty uptake in that region (shown). There may also be some redundancy in the intact system, and previously silent synapses may become active (not shown). Bottom left, A larger lesion may require an Increase In the synthesis and release of dopamine to keep postsynaptlc function under dopaminer¬ gic control. A rise In the production of dopamine, together with the loss of high-afflnlty uptake sites, would result in a further increase in the field of Influence of residual dopamine neurons (shown) and/or an Increase In the postsynaptlc response of Innervated sites (not shown). Bottom right, After still larger lesions, rapid compensatory processes would be Inadequate to restore function
Immediately. As a result, transmission would Initially fail (A). However, a delayed compensation and recovery of function may occur (B). These additional compensations could Include a gradual Increase in the availability of tyrosine hydroxylase enzyme, a rise In the number of postsynaptlc dopamine receptors, and the growth of new dopaminergic terminals. OBSERVATIONS ON HUMAN SUBJECTS
As in the
case
of the animal
models,
postmortem analyses have indicated
that neurologic deficits do not appear in idiopathic parkinsonism until the loss of" striatal dopamine exceeds about 80%. Moreover, concurrent measurements of the dopamine metabolite homovanillic acid suggest that degeneration of the nigrostriatal bundle is accompanied by an increase in dopamine turnover in hu¬ mans as in laboratory animals.1" Obser¬ vations with positron emission tomog¬ raphy (PET) also indicate the presence of a substantial loss of nigrostriatal nerve endings in patients with clinically overt parkinsonism. "'':' It is of interest from the viewpoint of documenting the com¬ pensatory potential of the human ni-
Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/07/2015
grostriatal pathway that PET has re¬ vealed subclinical damage to the nigro¬ striatal system in subjects with an increased risk of developing certain
forms of parkinsonism.1617 Postmortem analysis and PET also show normal age-related trends that are similar to, but less severe than, the changes found in idiopathic parkinson¬ ism.1""' With this background, it has been proposed that the appearance and progression of clinical parkinsonism might result from age-related decom¬ pensation of an old subclinical nigro¬ striatal lesion.2"'21 Positron emmision tomographic stud¬ ies support the notion that animal ex¬ periments are clinically relevant. More¬ over, the observations on animals also facilitate interpretation ofPET. Since its
inception, a persistent paradox has ob¬ scured the interpretation of PET with fluorodopa. Whereas human postmor¬ tem analyses of brains have revealed
marked differences between striatal do¬ pamine concentrations in normal and parkinsonian subjects, in vivo studies with PET have yielded less striking sepa¬ ration. This conflict may be resolved by taking into account the finding that in animals with partial lesions of the ni¬ grostriatal bundle, the removal of dopa¬ mine from the synaptic cleft is substan¬ tially impaired because the decreased number of dopaminergic nerve endings means that active reuptake is de¬ creased. Thus, whereas the intracellular content of striatal fluorodopamine formed from the exogenous fluorodopa PET tracer would be reduced by lesions ofthe nigrostriatal bundle, the accumu¬ lation of extracellular fluorodopamine might be enhanced. These predictions have recently been confirmed by direct neurochemical measurements in 6-hydroxydopamine-lesioned animals treat¬ ed with L-dopa.22 Since PET cannot dis¬ tinguish between intracellular and extracellular pools of labeled com¬ pounds, the technique can be expected to provide an index of the parkinsonian striatal deficit that is consistently closer to normal values than estimates ob¬ tained from postmortem studies. Fur¬ thermore, in the postmortem setting, dopamine that is not sequestered in the storage vesicles of nerve endings is more readily available for biochemical degradation during the interval be¬ tween death and brain analysis. This is conducive to increasing the separation of neurochemical findings between pa¬ tients with idiopathic parkinsonism and normal subjects. Finally, it is also possi¬ ble that the difference may derive, in part, from dissimilar kinetic systems for handling exogenous and endogenous
levodopa.
COMMENT
The considerable power of adaptive mechanisms in certain neural pathways has implications for the search for the pathogenesis of neurodegenerative dis¬ ease. In the case of degeneration of the nigrostriatal dopamine neurons, sub¬ stantial compensatory events may oc¬ cur and could interfere with the detec¬ tion of functional impairments for an extended period of time. If a similar situation obtains in the other common neurodegenerative dis¬ orders, there may be a shared category of pathogenesis in which early causal events occur without recognition be¬ cause compensatory mechanisms pre¬ clude clinical expression. Moreover, the compensatory activity may have longterm deleterious effects. Further analy¬ sis ofthe neurobiology of compensatory adjustments might allow the develop¬ ment of improved methods for the de¬ tection and treatment of a variety of neurologic disorders. References 1. Zigmond MJ, Stricker EM. Animal models of parkinsonism using selective neurotoxins: clinical and basic implications. Int Rev Neurobiol.
1989;31:1-79. 2. Kopin IJ, Markey SP. MPTP toxicity: implica-
tions for research in Parkinson's disease. Ann Rev Neurosci. 1988;11:81-96. 3. McGeer EG. Neurotransmitter systems in aging and senile dementia. Prog Neuropsychopharmacol Biol Psychiatry. 1981;5:435-445. 4. Heikkila RE, Cohen G. Further studies on the generation of hydrogen peroxide by 6-hydroxydopamine: potentiation by ascorbic acid. Mol Pharmacol. 1972;8:241-248. 5. Teitelbaum P, Epstein AN. The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychol Rev.
1962;69:74-90.
6. Marshall JF, Richardson JS, Teitelbaum P. Comp Physiol Psychol. 1974;87:808-830.
J
7. Hefti F, Melamed E, Wurtman RJ. Partial lesions of the nigrostriatal system in rat brain: biochemical characterization. Brain Res. 1980;195: 123-137.
Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/07/2015
8. Zigmond MJ, Acheson AL, Stachowiak MK, Stricker EM. Neurochemical compensation after nigrostriatal bundle injury in an animal model of preclinical parkinsonism. Arch Neurol. 1984;41: 856-861. 9. SnyderGL, Keller RWJr, Zigmond MJ. Dopamine efflux from striatal slices after intracerebral 6-hydroxydopamine: evidence for compensatory of residual terminals. hyperactivity J Pharmacol Exp Ther. 1990;253:867-876. 10. Creese I, Snyder SH. Nigrostriatal lesions enhance striatal [3H] spiroperidol binding. Eur J Pharmacol. 1979;56:277. 11. Bernheimer H, Birkmayer W, Hornykiewicz 0, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington: clinical, morphological and neurochemical correlations. J Neurol Sci. 1973;20:415-455. 12. Hornykiewicz 0, Kish SJ. Biochemical pathophysiology of Parkinson's disease. Adv Neurol. 1986;45:19-34. 13. Martin WRW, Calne DB. Imaging techniques and movement disorders. In: Marsden CD, Fahn JS, eds. Movement Disorders 2. Stoneham, Mass: Butterworths; 1987:4-16. 14. Garnett ES, Firnau G, Nahmias C. Dopamine visualized in the basal ganglia of living man. Nature. 1983;305:137-138. 15. Leenders KL. PET tracer studies of striatal dopaminergic function. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson's Disease. New York, NY: Macmillan Publishing Co Inc; 1987:105-121. 16. Calne DB, Langston JW, Martin WRW, et
al.PositronemissiontomographyafterMPTP:observations relating to the cause of Parkinson's disease.
Nature. 1985;317:246-248. 17. Snow B, Guttman M, Peppard RF, et al. Asymptomatic nigrostriatal lesions in five patients with Guamanian ALS. Neurology. 1989;39:399. 18. Martin WRW, Palmer MR, Patlak CS, Calne DB. Nigrostriatal function in humans studied with positron emission tomography. Ann Neurol.
1989;26:535-542. 19. Carlsson A, Winblad B. Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. J Neural Transm. 1976;38:271-276. 20. Calne DB, Langston JW. Aetiology of Par-
kinson's disease. Lancet. 1983;2:1457-1459. 21. Calne DB, Eisen A, McGeer E, Spencer P. Alzheimer's disease, Parkinson's disease, and motoneuron disease: abiotrophic interaction between ageing and environment? Lancet. 1986;2:1067\x=req-\ 1070. 22. Abercrombie ED, Bonatz AE, Zigmond MJ. Effects of L-dopa on extracellular dopamine in striatum of normal and 6-hydroxydopamine\x=req-\ treated rats. Brain Res. 1990;525:36-44.
From Parkinsonism
Donald B. Calne, DM, Michael J.
Zigmond, PhD
\s=b\ In animal models of parkinsonism, the ability to lose a substantial proportion of dopaminergic neurons without behavioral deficits does not derive from other systems taking over function of the dopaminergic pathway. The surviving nigrostriatal projec-
tion increases both the rate of synthesis and the release of dopamine, as compensatory adjustments. This capacity allows at least a fivefold rise in dopamine delivery per neuron, and this enhancement is potentiated further by receptor up-regulation. Decreased reuptake, due to loss of nerve endings, may also lead to augmented occupancy of dopamine receptors, and so constitute yet another compensatory mechanism. In humans, positron emission tomography has revealed subclinical impairment of the dopaminergic nigrostriatal pathway in subjects at risk for parkinsonism caused by 1-methyl-4-phenyl\x=req-\ 1,2,3,6-tetrahydropyridine and Lytico-Bodig (the amyotrophic lateral sclerosis-parkin-
seeking the cause of a degenerative disease, a first stage is the develop¬ ment of a conceptual model of pathogen¬ esis. To formulate such a model, it is
desirable to have information on the neurobiological adjustments that take Accepted for publication October 5,1990. From the Neurodegenerative Disorders Center, Department of Medicine, University of British Columbia, University Hospital, Vancouver, Canada (Dr Calne), and the Departments of Behavioral Neuroscience and Psychiatry, University of Pittsburgh (Pa) (Dr Zigmond). Reprint requests to Neurodegenerative Disorders Center, Department of Medicine, University of British Columbia, University Hospital, U.B.C. Site, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T1W5 (Dr Calne).
sonism dementia complex of Guam). However, the separation of patients with clinically overt idiopathic parkinsonism from controls is less marked in vivo (by positron emission tomography) than in postmortem analysis (by neurochemical assay). This disparity may be attributable to the reduction in the number of nigrostriatal nerve endings, leading, in vivo, to a relative increase of extracellular dopamine because active reuptake into the nerve endings is an important mechanism for removing dopamine from the synaptic cleft. In contrast, in a postmortem setting, dopamine that is not sequestered in the storage vesicles of nerve endings is readily available for biochemical degradation during the interval between death and brain analysis. Finally, it is also possible that differences may derive, in part, from dissimilar kinetic systems for handling exogenous and endogenous levodopa. (Arch Neurol. 1991 ;48:361-363)
place in the nervous system when some neurons
have died and others
are
at¬
tempting to compensate and to maintain function. The most extensively studied pathway in this context is the dopamin¬ ergic component of the nigrostriatal
bundle, and for this system, relevant
animal observations can be correlated with phenomena observed in idiopathic parkinsonism.12 In addition, since the dopaminergic cells ofthe zona compacta of the substantia nigra are selectively vulnerable to attrition with normal ag¬ ing,3 exploration of compensatory ad¬ justments in these neurons should con¬ tribute to the elucidation of neurologic
Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/07/2015
in this review we fo¬ and human studies of ad¬ to lesions of nigrostriatal do¬
Thus,
senescence. cus on animal
aptations pamine neurons.
ANIMAL STUDIES
6-Hydroxydopamine is a highly electroactive molecule that is concentrated by high-affinity transport systems of ca-
techolaminergic
neurons, particularly in the nerve terminals. Subsequent oxi¬ dation of this molecule produces highly toxic products, with resulting degener¬ ation.4 Injection of 6-hydroxydopamine into the brain of many experimental ani¬ mals, either via the cerebrospinal fluid or directly along the nigrostriatal bun¬ dle, results in the death of dopaminergic neurons. The extent of the lesion de¬ pends on route of administration, dos¬' age, and pharmacologie pretreatment. Gross behavioral changes do not oc¬ cur following the administration of 6-hydroxydopamine unless the destruc¬ tion ofthe nigrostriatal bundle is almost complete, and even' then, the deficits are often transient. Electrolytic lesions of the nigrostriatal system may also re¬ sult in neurologic impairments that im¬ prove spontaneously,5,6 and the same has been reported following administra¬ tion of the toxin l-methyl-4-phenyl1,2,3,6-tetrahydropyridine to subhu¬
primates.4 ability to undergo major loss of dopaminergic cells without clinical ef¬ man
The
fects and the spontaneous improvement that commonly occurs when the lesions are severe enough to induce initial be¬ havioral deficits do not reflect a transfer
of function from the nigrostriatal bundle to other pathways. Neurologic deficits can readily be reestablished in lesioned animals by pharmacologie manipula¬ tions that compromise dopaminergic function still further. Indeed, lesioned animals are supersensitive to such treatments. Moreover, a minimal num¬ ber of dopamine neurons must survive the lesion for recovery to occur. ' These observations suggest the continued im¬ portance of the remaining elements of
*3*-*(H
the nigrostriatal bundle. The relation between size of an ex¬ perimental lesion and neurologic deficit does not appear to derive from simple redundancy in the nigrostriatal system. The dopamine neurons that are spared by the injury have been shown to in¬ crease their synthesis and release of
3~f
""
tr(-
due to
degeneration of neighboring do¬ paminergic terminals"" and, after ex¬ tensive lesions, by an increase in the number of postsynaptic dopamine re¬
receptor up-regulation. Taken togeth¬ er, these mechanisms may allow each
surviving nigrostriatal
neuron
to
com¬
pensate for the death of many similar
cells before any functional deficit would be expected. Experimental observa¬ tions at both the behavioral and the cel¬ lular levels are consistent with this pre¬ diction, and studies of damage to other monoaminergic systems in the brain and the periphery indicate that the capacity for such adaptation is
widespread.1
It is possible that these compensatory processes exact a toll, however. The greatly enhanced turnover of dopamine could lead to the accumulation of toxic by-products of dopamine oxidation simi¬ lar to those formed by 6-hydroxydopa¬ mine, thereby contributing to the ulti¬ mate degeneration of surviving elements of the nigrostriatal bundle. Furthermore, comparable toxic sub¬ stances could accumulate in the extra¬ cellular space as a result of impaired removal of dopamine from the synaptic cleft consequent on loss of the nerve endings that possess an active reuptake mechanism. This vicious circle would generate more injury, to both dopamin¬ ergic and nondopaminergic cellular
components.
Extreme Lesion
Larger Lesion
transmitter, suggesting an active, com¬ pensatory elevation in their functional activity. The impact of this hyperac¬ tivity is augmented by the loss of sites for dopamine inactivation by reuptake
ceptors1" (Figure). Indeed, experiments have suggested that after partial ni¬ grostriatal lesions, surviving dopamin¬ ergic neurons can increase their capaci¬ ty to deliver transmitter by at least fivefold, and that the impact of this do¬ pamine can be increased still further by
Moderate Lesion
Normal
'
{
•f il —
^L
11
(
' „
compensatory changes after lesions of the nigrostriatal bundle (from Zigmond and Under normal conditions synaptic transmission takes place with relatively little Interaction between neighboring synapses. In addition, some synapses may be Inactive. Top right,
A model for
Strieker1). Top left,
Moderate lesions have little or no functional Impact for one or more reasons. Transmitter released at one synapse may act at a denervated site owing to the loss of inactlvatlon via high-afflnlty uptake in that region (shown). There may also be some redundancy in the intact system, and previously silent synapses may become active (not shown). Bottom left, A larger lesion may require an Increase In the synthesis and release of dopamine to keep postsynaptlc function under dopaminer¬ gic control. A rise In the production of dopamine, together with the loss of high-afflnlty uptake sites, would result in a further increase in the field of Influence of residual dopamine neurons (shown) and/or an Increase In the postsynaptlc response of Innervated sites (not shown). Bottom right, After still larger lesions, rapid compensatory processes would be Inadequate to restore function
Immediately. As a result, transmission would Initially fail (A). However, a delayed compensation and recovery of function may occur (B). These additional compensations could Include a gradual Increase in the availability of tyrosine hydroxylase enzyme, a rise In the number of postsynaptlc dopamine receptors, and the growth of new dopaminergic terminals. OBSERVATIONS ON HUMAN SUBJECTS
As in the
case
of the animal
models,
postmortem analyses have indicated
that neurologic deficits do not appear in idiopathic parkinsonism until the loss of" striatal dopamine exceeds about 80%. Moreover, concurrent measurements of the dopamine metabolite homovanillic acid suggest that degeneration of the nigrostriatal bundle is accompanied by an increase in dopamine turnover in hu¬ mans as in laboratory animals.1" Obser¬ vations with positron emission tomog¬ raphy (PET) also indicate the presence of a substantial loss of nigrostriatal nerve endings in patients with clinically overt parkinsonism. "'':' It is of interest from the viewpoint of documenting the com¬ pensatory potential of the human ni-
Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/07/2015
grostriatal pathway that PET has re¬ vealed subclinical damage to the nigro¬ striatal system in subjects with an increased risk of developing certain
forms of parkinsonism.1617 Postmortem analysis and PET also show normal age-related trends that are similar to, but less severe than, the changes found in idiopathic parkinson¬ ism.1""' With this background, it has been proposed that the appearance and progression of clinical parkinsonism might result from age-related decom¬ pensation of an old subclinical nigro¬ striatal lesion.2"'21 Positron emmision tomographic stud¬ ies support the notion that animal ex¬ periments are clinically relevant. More¬ over, the observations on animals also facilitate interpretation ofPET. Since its
inception, a persistent paradox has ob¬ scured the interpretation of PET with fluorodopa. Whereas human postmor¬ tem analyses of brains have revealed
marked differences between striatal do¬ pamine concentrations in normal and parkinsonian subjects, in vivo studies with PET have yielded less striking sepa¬ ration. This conflict may be resolved by taking into account the finding that in animals with partial lesions of the ni¬ grostriatal bundle, the removal of dopa¬ mine from the synaptic cleft is substan¬ tially impaired because the decreased number of dopaminergic nerve endings means that active reuptake is de¬ creased. Thus, whereas the intracellular content of striatal fluorodopamine formed from the exogenous fluorodopa PET tracer would be reduced by lesions ofthe nigrostriatal bundle, the accumu¬ lation of extracellular fluorodopamine might be enhanced. These predictions have recently been confirmed by direct neurochemical measurements in 6-hydroxydopamine-lesioned animals treat¬ ed with L-dopa.22 Since PET cannot dis¬ tinguish between intracellular and extracellular pools of labeled com¬ pounds, the technique can be expected to provide an index of the parkinsonian striatal deficit that is consistently closer to normal values than estimates ob¬ tained from postmortem studies. Fur¬ thermore, in the postmortem setting, dopamine that is not sequestered in the storage vesicles of nerve endings is more readily available for biochemical degradation during the interval be¬ tween death and brain analysis. This is conducive to increasing the separation of neurochemical findings between pa¬ tients with idiopathic parkinsonism and normal subjects. Finally, it is also possi¬ ble that the difference may derive, in part, from dissimilar kinetic systems for handling exogenous and endogenous
levodopa.
COMMENT
The considerable power of adaptive mechanisms in certain neural pathways has implications for the search for the pathogenesis of neurodegenerative dis¬ ease. In the case of degeneration of the nigrostriatal dopamine neurons, sub¬ stantial compensatory events may oc¬ cur and could interfere with the detec¬ tion of functional impairments for an extended period of time. If a similar situation obtains in the other common neurodegenerative dis¬ orders, there may be a shared category of pathogenesis in which early causal events occur without recognition be¬ cause compensatory mechanisms pre¬ clude clinical expression. Moreover, the compensatory activity may have longterm deleterious effects. Further analy¬ sis ofthe neurobiology of compensatory adjustments might allow the develop¬ ment of improved methods for the de¬ tection and treatment of a variety of neurologic disorders. References 1. Zigmond MJ, Stricker EM. Animal models of parkinsonism using selective neurotoxins: clinical and basic implications. Int Rev Neurobiol.
1989;31:1-79. 2. Kopin IJ, Markey SP. MPTP toxicity: implica-
tions for research in Parkinson's disease. Ann Rev Neurosci. 1988;11:81-96. 3. McGeer EG. Neurotransmitter systems in aging and senile dementia. Prog Neuropsychopharmacol Biol Psychiatry. 1981;5:435-445. 4. Heikkila RE, Cohen G. Further studies on the generation of hydrogen peroxide by 6-hydroxydopamine: potentiation by ascorbic acid. Mol Pharmacol. 1972;8:241-248. 5. Teitelbaum P, Epstein AN. The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychol Rev.
1962;69:74-90.
6. Marshall JF, Richardson JS, Teitelbaum P. Comp Physiol Psychol. 1974;87:808-830.
J
7. Hefti F, Melamed E, Wurtman RJ. Partial lesions of the nigrostriatal system in rat brain: biochemical characterization. Brain Res. 1980;195: 123-137.
Downloaded From: http://archneur.jamanetwork.com/ by a Western University User on 06/07/2015
8. Zigmond MJ, Acheson AL, Stachowiak MK, Stricker EM. Neurochemical compensation after nigrostriatal bundle injury in an animal model of preclinical parkinsonism. Arch Neurol. 1984;41: 856-861. 9. SnyderGL, Keller RWJr, Zigmond MJ. Dopamine efflux from striatal slices after intracerebral 6-hydroxydopamine: evidence for compensatory of residual terminals. hyperactivity J Pharmacol Exp Ther. 1990;253:867-876. 10. Creese I, Snyder SH. Nigrostriatal lesions enhance striatal [3H] spiroperidol binding. Eur J Pharmacol. 1979;56:277. 11. Bernheimer H, Birkmayer W, Hornykiewicz 0, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington: clinical, morphological and neurochemical correlations. J Neurol Sci. 1973;20:415-455. 12. Hornykiewicz 0, Kish SJ. Biochemical pathophysiology of Parkinson's disease. Adv Neurol. 1986;45:19-34. 13. Martin WRW, Calne DB. Imaging techniques and movement disorders. In: Marsden CD, Fahn JS, eds. Movement Disorders 2. Stoneham, Mass: Butterworths; 1987:4-16. 14. Garnett ES, Firnau G, Nahmias C. Dopamine visualized in the basal ganglia of living man. Nature. 1983;305:137-138. 15. Leenders KL. PET tracer studies of striatal dopaminergic function. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson's Disease. New York, NY: Macmillan Publishing Co Inc; 1987:105-121. 16. Calne DB, Langston JW, Martin WRW, et
al.PositronemissiontomographyafterMPTP:observations relating to the cause of Parkinson's disease.
Nature. 1985;317:246-248. 17. Snow B, Guttman M, Peppard RF, et al. Asymptomatic nigrostriatal lesions in five patients with Guamanian ALS. Neurology. 1989;39:399. 18. Martin WRW, Palmer MR, Patlak CS, Calne DB. Nigrostriatal function in humans studied with positron emission tomography. Ann Neurol.
1989;26:535-542. 19. Carlsson A, Winblad B. Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. J Neural Transm. 1976;38:271-276. 20. Calne DB, Langston JW. Aetiology of Par-
kinson's disease. Lancet. 1983;2:1457-1459. 21. Calne DB, Eisen A, McGeer E, Spencer P. Alzheimer's disease, Parkinson's disease, and motoneuron disease: abiotrophic interaction between ageing and environment? Lancet. 1986;2:1067\x=req-\ 1070. 22. Abercrombie ED, Bonatz AE, Zigmond MJ. Effects of L-dopa on extracellular dopamine in striatum of normal and 6-hydroxydopamine\x=req-\ treated rats. Brain Res. 1990;525:36-44.
