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Is there a need to redefine Parkinson's disease?
Journal of the Neurological Sciences 310 (2011) 2–3
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Is there a need to redefine Parkinson's disease? Amos D. Korczyn ⁎ The Sieratzki Chair of Neurology, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv 69978, Israel
a r t i c l e
i n f o
Article history: Received 31 March 2011 Received in revised form 6 July 2011 Accepted 11 July 2011 Available online 16 August 2011 Keywords: Parkinson's disease Lewy bodies Synuclein etiology Pathogenesis Criteria Genetics
a b s t r a c t Parkinson's disease (PD) has initially been described as a clinical syndrome, although the exact definition has changed over the past centuries. The inclusion of the pathological changes added another level of complexity, with Lewy bodies, synuclein deposits and neuronal loss in the substantia nigra being used alternatively. A third level of complexity was added with the recognition of genetic mutations resulting in parkinsonism, sometimes with and sometimes without Lewy body deposition, and the identification of frequent additional important pre-motor manifestations. These different points of view on the definition of PD have important implications on the study of the etiology and even the therapy of PD. © 2011 Elsevier B.V. All rights reserved.
Introduction Parkinson's disease (PD) is a common neurodegenerative disease, affecting millions of people worldwide, affecting their life to a significant degree. Since its first description by James Parkinson in 1817 and until the present day, its diagnosis is primarily clinical. As such, the criteria for diagnosis have changed over the years. In the 19th century it has attracted the attention of Jean-Martin Charcot. This eminent and influential clinician was the first to redefine the disease. He named it after James Parkinson, a tradition we still honor today, but this was perhaps tongue-in-cheek gesture. The original term used by James Parkinson, Paralysis Agitans or the Shaking Palsy [1] required tremor to be part of the clinical phenotype. However Charcot included cases without tremor as well. During the twentieth century, the epidemic of encephalitis lethargica was another milestone. Although most patients were affected by an acute disease, it was hypothesized that most of PD cases are actually survivors of mild or preclinical encephalitis lethargica, and that as the cohort will die off the frequency of the disease will gradually diminish until it will once more become the rare disorder it used to be prior to the encephalitis epidemic [2]. The underlying distinction between PD and parkinsonism due to other causes has been a prominent feature of movement disorders research over the past decades. It has been well established that different etiologies (Table 1) and disease states can present with
⁎ Tel.: + 972 3 6974229; fax: + 972 3 6409113. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.07.011
overlapping clinical features, and it was up to the astute physician, usually a movement disorders specialist, to accurately diagnose PD. The need to have agreed clinical criteria to diagnose PD was evident, but it was up to the London school to propose such a set of criteria to diagnosis [3]. Their inclusion criteria (Table 2) have been rather arbitrary, but were supported by a pathological demonstration of Lewy bodies (LBs) in dopaminergic cells of the substantia nigra. The implication of this corroboration of the clinical diagnosis by the pathological findings is however subject to objection: Pathological changes are also a phenotype, and it is not immediately clear why the pathological phenotype is superior to a clinical diagnosis, and for which purpose. Pathological changes are the end-result of the underlying processes and it may well be that different abnormalities will result in similar or identical pathological pictures. Thus, we do not consider liver cirrhosis a disease because the same phenotype can occur as a result of exposure of toxic substances, metabolic abnormalities, infections etc. Biomarkers can partially help differentiate entities (such as hepatitis virus antibodies), but the pathological phenotype is the same or close to it. It should further be stressed that LBs do not accumulate in the substantia nigra so it is their mere existence, rather than number, which defines the disease pathologically (however, LBs can be found occasionally at autopsy in people who during life never had parkinsonian symptoms, and are than called “incidental” LBs). Other autopsy-driven data, like cell number in the substantia nigra or dopamine concentrations are rarely used. Although the UK Brain Bank Criteria are quoted times over as if they are being observed, they actually did not completely stand the test of time. Practically all the inclusion criteria have been neglected or altered. Familial cases are now included (see below), bradykinesia is not employed any more as a mandatory feature, the disease may start simultaneously on both sides of the body (even though
A.D. Korczyn / Journal of the Neurological Sciences 310 (2011) 2–3 Table 1 Etiological heterogeneity of Parkinsonian syndromes. • Infective (encephalitis lethargica) • Toxic (MPTP, Manganese, neuroleptic) • Traumatic (Boxer's parkinsonism) • Vascular • Degenerative (PD, MSA, PSP)
asymmetric onset is very common), and autonomic impairment may occur at presentation or before the motor symptoms occur [4]. Any response to dopamine replacement is not considered an important inclusion criterion since it exists in many parkinsonian syndromes (while a marked and sustained response, and definitely the development of appendicular dyskinesias later on, are more convincing evidence). This criterion is also unhelpful and had to be disregarded in many seminal papers where de-novo patients were recruited into drug studies of a new dopaminomimetic agent [5]. In fact, rather than clinical criteria for diagnosis, these criteria served to exclude other parkinsonian syndromes. The modern understanding of PD was heavily influenced by the identification of dopamine as a neurotransmitter, and its establishment as playing a central role in motor physiology, its gradual disappearance in PD, and later by the development of dopamine replacement therapy. However, this dopaminocentric view of PD had its disadvantages: It drew attention away from non-motor manifestations of the disease [6], while at the same time leading to the search for endogenous or exogenous factors responsible for the non-existent exclusive degeneration of substantia nigra cells, such as for agents neurotoxic to these neuron. In other words, the suggestion that PD is identified as a dopamine deficiency state was too narrow and at the same time nonspecific. The discovery of alpha-synuclein (aS) changed the picture dramatically [7]. The identification of genetic mutations in the aS gene, and the development of immunostaining methods which demonstrated a widespread deposition of this protein in the LBs and in several areas of the nervous system, were quick to move the field from a dopaminocentric view to one that focuses on aS. Although LBs have been identified outside the nigral system previously (such as in the myenteric plexus [8]), the new findings were helpful to provide a more complete explanation of the non-motor symptoms of PD. The existence of constipation, sleep problems, depression or dementia, previously thought to be coincidental or secondary, was now accepted as part of the more complex neural involvement in the disease. This development, importantly led by Braak et al. [9], was also used to formulate new theories of causation, such as the idea that the damage spreads from cell-to-cell. This theory of propagation of the disease, later insinuating a prion-like progression mechanism [10], once again shifted the definition of PD from a clinical entity to a pathologicallybased definition as a synucleinopathy, implicitly implying a causal role for synuclein in PD etiopathogenesis, and allowed dementia,
Table 2 Clinical diagnosis of PD: UK Brain Bank Criteria. • Slowly progressive, non-familial disease • Cardinal symptoms Bradykinesia and one of the following rigidity, rest tremor, postural instability • Asymmetric disease • No dementia at onset • No severe postural instability at onset • No prominent autonomic signs at onset • Response to dopamine replacement
3
typically as a late phenomenon but occasionally predating even motor manifestation, to be integrated into the spectrum. Although the new definition of PD as a synucleinopathy helped to exclude other parkinsonian syndromes (which have their own pathologic substrates), it is important to note that the fact that PD is associated with synuclein deposition does not necessarily lead to the conclusion that synuclein is to be incriminated in the primary causation of the disease. This conclusion, supported by aS mutations manifesting as PD, is based on the assumption that sporadic PD follows the same pathogenetic pathway as the genetic form all the way from the beginning (which is clearly not the case). The fact that a common phenotype occurs (clinically or pathologically) does not necessarily imply identical initial causative processes. The recognition of genetic–phenotypic discrepancies adds to the dilemma. Carriers of mutations in the PARKIN or LRRK2 genes may or may not develop synuclein depositions, and the clinical phenotypes may also vary [11,12]. Thus, the definition of PD is evasive. In order to establish scientifically the concept of a disease, the clinical and pathological manifestations are only part of the picture. Considerably more important to the definition of a disease is identification of the pathogenic mechanism and the underlying pathogenetic processes. As long as these requirements are not fulfilled, we can only speak of syndromes. Since the initial pathogenetic processes leading to PD are not yet known, at least in the sporadic cases, PD cannot be strictly classified as a disease. In this respect PD is not different from several adult-onset neurodegenerative disorders such as Alzheimer's disease or multiple sclerosis. Clearly, this purist definition of a disease is itself problematic because it assumes that PD is a unitary disorder with a single etiopathogenic factor. However it is more likely that PD is more complex in its causation, where each case is the result of a separate constellation of several individual factors, acting on a background of an individual genetic background. This much more complex situation calls for new thinking of PD, which is slowly evolving over the past decade. Thus, although a precise scientific definition of PD is not available, the practical necessities have to be met. Thus we need operationalized definitions of the topics of any research. These however would be different for epidemiologic, genetic or pathological investigations as well as for drug studies. References [1] Parkinson J. Essay on the Shaking Palsy. London: Sherwood, Neely and Jones; 1817. [2] Poskanzer DC, Schwab RS. Studies in the epidemiology of Parkinson's disease predicting its disappearance as a major clinical entity by 1980. Trans Am Neurol Assoc 1961;86:234–5. [3] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–4. [4] Korczyn AD. Autonomic nervous system dysfunction in Parkinson's disease. In: Calne DB, et al, editor. Parkinsonism and Aging. N.Y: Raven Press; 1989. p. 219–21. [5] Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342: 1484–91. [6] Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the a-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045–7. [7] Korczyn AD, Gurevich T. Parkinson's disease: before the motor symptoms and beyond. J Neurol Sci 2010;289:2–6. [8] Korczyn AD. Autonomic nervous system dysfunction in Parkinson's disease. Adv Neurol 1990;53:463–8. [9] Braak H, Del Tredici K, Rub U, de Vos RAI, Jansen Steur ENH, Braak E. Straging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24: 197–211. [10] Olanow WC. Parkinson's disease, proteins, and prions: milestones. Mov Disord 2011;26:1056–71. [11] Haugarvoll K, Wszolek ZK. Clinical features of LRRK2 parkinsonism. Parkinsonism Relat Disord 2009;15(Suppl 3):S205–8. [12] Wider C, Dickson DW, Wszolek ZK. Leucine-rich repeat kinase 2 gene-associated disease: redefining genotype-phenotype correlation. Neurodegener Dis 2010;7: 175–9.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Is there a need to redefine Parkinson's disease? Amos D. Korczyn ⁎ The Sieratzki Chair of Neurology, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv 69978, Israel
a r t i c l e
i n f o
Article history: Received 31 March 2011 Received in revised form 6 July 2011 Accepted 11 July 2011 Available online 16 August 2011 Keywords: Parkinson's disease Lewy bodies Synuclein etiology Pathogenesis Criteria Genetics
a b s t r a c t Parkinson's disease (PD) has initially been described as a clinical syndrome, although the exact definition has changed over the past centuries. The inclusion of the pathological changes added another level of complexity, with Lewy bodies, synuclein deposits and neuronal loss in the substantia nigra being used alternatively. A third level of complexity was added with the recognition of genetic mutations resulting in parkinsonism, sometimes with and sometimes without Lewy body deposition, and the identification of frequent additional important pre-motor manifestations. These different points of view on the definition of PD have important implications on the study of the etiology and even the therapy of PD. © 2011 Elsevier B.V. All rights reserved.
Introduction Parkinson's disease (PD) is a common neurodegenerative disease, affecting millions of people worldwide, affecting their life to a significant degree. Since its first description by James Parkinson in 1817 and until the present day, its diagnosis is primarily clinical. As such, the criteria for diagnosis have changed over the years. In the 19th century it has attracted the attention of Jean-Martin Charcot. This eminent and influential clinician was the first to redefine the disease. He named it after James Parkinson, a tradition we still honor today, but this was perhaps tongue-in-cheek gesture. The original term used by James Parkinson, Paralysis Agitans or the Shaking Palsy [1] required tremor to be part of the clinical phenotype. However Charcot included cases without tremor as well. During the twentieth century, the epidemic of encephalitis lethargica was another milestone. Although most patients were affected by an acute disease, it was hypothesized that most of PD cases are actually survivors of mild or preclinical encephalitis lethargica, and that as the cohort will die off the frequency of the disease will gradually diminish until it will once more become the rare disorder it used to be prior to the encephalitis epidemic [2]. The underlying distinction between PD and parkinsonism due to other causes has been a prominent feature of movement disorders research over the past decades. It has been well established that different etiologies (Table 1) and disease states can present with
⁎ Tel.: + 972 3 6974229; fax: + 972 3 6409113. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.07.011
overlapping clinical features, and it was up to the astute physician, usually a movement disorders specialist, to accurately diagnose PD. The need to have agreed clinical criteria to diagnose PD was evident, but it was up to the London school to propose such a set of criteria to diagnosis [3]. Their inclusion criteria (Table 2) have been rather arbitrary, but were supported by a pathological demonstration of Lewy bodies (LBs) in dopaminergic cells of the substantia nigra. The implication of this corroboration of the clinical diagnosis by the pathological findings is however subject to objection: Pathological changes are also a phenotype, and it is not immediately clear why the pathological phenotype is superior to a clinical diagnosis, and for which purpose. Pathological changes are the end-result of the underlying processes and it may well be that different abnormalities will result in similar or identical pathological pictures. Thus, we do not consider liver cirrhosis a disease because the same phenotype can occur as a result of exposure of toxic substances, metabolic abnormalities, infections etc. Biomarkers can partially help differentiate entities (such as hepatitis virus antibodies), but the pathological phenotype is the same or close to it. It should further be stressed that LBs do not accumulate in the substantia nigra so it is their mere existence, rather than number, which defines the disease pathologically (however, LBs can be found occasionally at autopsy in people who during life never had parkinsonian symptoms, and are than called “incidental” LBs). Other autopsy-driven data, like cell number in the substantia nigra or dopamine concentrations are rarely used. Although the UK Brain Bank Criteria are quoted times over as if they are being observed, they actually did not completely stand the test of time. Practically all the inclusion criteria have been neglected or altered. Familial cases are now included (see below), bradykinesia is not employed any more as a mandatory feature, the disease may start simultaneously on both sides of the body (even though
A.D. Korczyn / Journal of the Neurological Sciences 310 (2011) 2–3 Table 1 Etiological heterogeneity of Parkinsonian syndromes. • Infective (encephalitis lethargica) • Toxic (MPTP, Manganese, neuroleptic) • Traumatic (Boxer's parkinsonism) • Vascular • Degenerative (PD, MSA, PSP)
asymmetric onset is very common), and autonomic impairment may occur at presentation or before the motor symptoms occur [4]. Any response to dopamine replacement is not considered an important inclusion criterion since it exists in many parkinsonian syndromes (while a marked and sustained response, and definitely the development of appendicular dyskinesias later on, are more convincing evidence). This criterion is also unhelpful and had to be disregarded in many seminal papers where de-novo patients were recruited into drug studies of a new dopaminomimetic agent [5]. In fact, rather than clinical criteria for diagnosis, these criteria served to exclude other parkinsonian syndromes. The modern understanding of PD was heavily influenced by the identification of dopamine as a neurotransmitter, and its establishment as playing a central role in motor physiology, its gradual disappearance in PD, and later by the development of dopamine replacement therapy. However, this dopaminocentric view of PD had its disadvantages: It drew attention away from non-motor manifestations of the disease [6], while at the same time leading to the search for endogenous or exogenous factors responsible for the non-existent exclusive degeneration of substantia nigra cells, such as for agents neurotoxic to these neuron. In other words, the suggestion that PD is identified as a dopamine deficiency state was too narrow and at the same time nonspecific. The discovery of alpha-synuclein (aS) changed the picture dramatically [7]. The identification of genetic mutations in the aS gene, and the development of immunostaining methods which demonstrated a widespread deposition of this protein in the LBs and in several areas of the nervous system, were quick to move the field from a dopaminocentric view to one that focuses on aS. Although LBs have been identified outside the nigral system previously (such as in the myenteric plexus [8]), the new findings were helpful to provide a more complete explanation of the non-motor symptoms of PD. The existence of constipation, sleep problems, depression or dementia, previously thought to be coincidental or secondary, was now accepted as part of the more complex neural involvement in the disease. This development, importantly led by Braak et al. [9], was also used to formulate new theories of causation, such as the idea that the damage spreads from cell-to-cell. This theory of propagation of the disease, later insinuating a prion-like progression mechanism [10], once again shifted the definition of PD from a clinical entity to a pathologicallybased definition as a synucleinopathy, implicitly implying a causal role for synuclein in PD etiopathogenesis, and allowed dementia,
Table 2 Clinical diagnosis of PD: UK Brain Bank Criteria. • Slowly progressive, non-familial disease • Cardinal symptoms Bradykinesia and one of the following rigidity, rest tremor, postural instability • Asymmetric disease • No dementia at onset • No severe postural instability at onset • No prominent autonomic signs at onset • Response to dopamine replacement
3
typically as a late phenomenon but occasionally predating even motor manifestation, to be integrated into the spectrum. Although the new definition of PD as a synucleinopathy helped to exclude other parkinsonian syndromes (which have their own pathologic substrates), it is important to note that the fact that PD is associated with synuclein deposition does not necessarily lead to the conclusion that synuclein is to be incriminated in the primary causation of the disease. This conclusion, supported by aS mutations manifesting as PD, is based on the assumption that sporadic PD follows the same pathogenetic pathway as the genetic form all the way from the beginning (which is clearly not the case). The fact that a common phenotype occurs (clinically or pathologically) does not necessarily imply identical initial causative processes. The recognition of genetic–phenotypic discrepancies adds to the dilemma. Carriers of mutations in the PARKIN or LRRK2 genes may or may not develop synuclein depositions, and the clinical phenotypes may also vary [11,12]. Thus, the definition of PD is evasive. In order to establish scientifically the concept of a disease, the clinical and pathological manifestations are only part of the picture. Considerably more important to the definition of a disease is identification of the pathogenic mechanism and the underlying pathogenetic processes. As long as these requirements are not fulfilled, we can only speak of syndromes. Since the initial pathogenetic processes leading to PD are not yet known, at least in the sporadic cases, PD cannot be strictly classified as a disease. In this respect PD is not different from several adult-onset neurodegenerative disorders such as Alzheimer's disease or multiple sclerosis. Clearly, this purist definition of a disease is itself problematic because it assumes that PD is a unitary disorder with a single etiopathogenic factor. However it is more likely that PD is more complex in its causation, where each case is the result of a separate constellation of several individual factors, acting on a background of an individual genetic background. This much more complex situation calls for new thinking of PD, which is slowly evolving over the past decade. Thus, although a precise scientific definition of PD is not available, the practical necessities have to be met. Thus we need operationalized definitions of the topics of any research. These however would be different for epidemiologic, genetic or pathological investigations as well as for drug studies. References [1] Parkinson J. Essay on the Shaking Palsy. London: Sherwood, Neely and Jones; 1817. [2] Poskanzer DC, Schwab RS. Studies in the epidemiology of Parkinson's disease predicting its disappearance as a major clinical entity by 1980. Trans Am Neurol Assoc 1961;86:234–5. [3] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–4. [4] Korczyn AD. Autonomic nervous system dysfunction in Parkinson's disease. In: Calne DB, et al, editor. Parkinsonism and Aging. N.Y: Raven Press; 1989. p. 219–21. [5] Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342: 1484–91. [6] Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the a-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045–7. [7] Korczyn AD, Gurevich T. Parkinson's disease: before the motor symptoms and beyond. J Neurol Sci 2010;289:2–6. [8] Korczyn AD. Autonomic nervous system dysfunction in Parkinson's disease. Adv Neurol 1990;53:463–8. [9] Braak H, Del Tredici K, Rub U, de Vos RAI, Jansen Steur ENH, Braak E. Straging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24: 197–211. [10] Olanow WC. Parkinson's disease, proteins, and prions: milestones. Mov Disord 2011;26:1056–71. [11] Haugarvoll K, Wszolek ZK. Clinical features of LRRK2 parkinsonism. Parkinsonism Relat Disord 2009;15(Suppl 3):S205–8. [12] Wider C, Dickson DW, Wszolek ZK. Leucine-rich repeat kinase 2 gene-associated disease: redefining genotype-phenotype correlation. Neurodegener Dis 2010;7: 175–9.