NEWS & VIEWS PARKINSON DISEASE
Can dopamine transporter imaging define early PD? Angelo Antonini and Roberta Biundo
Dopaminergic brain imaging might aid early diagnosis of Parkinson disease (PD), but some patients with mild symptoms show no evidence of dopaminergic dysfunction at baseline, and apparently do not progress. Although some of these patients may have been misdiagnosed, others continue to fulfil PD diagnostic criteria despite normal follow-up brain scans. Antonini, A. & Biundo, R. Nat. Rev. Neurol. advance online publication 8 July 2014; doi:10.1038/nrneurol.2014.123
Accurate diagnosis of Parkinson disease (PD) is particularly challenging in patients who are in the early stages in the disease process, with short symptom duration and before treatment initiation.1 A recent study by Marek and co-authors further highlights such difficulties, and also sheds new light on the contribution of dopamine transporter (DAT) imaging as a surrogate biomarker for early diagnosis.2 The results confirm that up to 15% of patients entering clinical trials for early untreated PD might not exhibit dopaminergic defects in the basal ganglia either at baseline or at follow-up, yet almost 50% of these patients would still have clinical features in line with PD diagnostic criteria.
‘‘
…DAT imaging at study baseline can be used as a predictor of clinical and imaging progression
’’
For many decades, neurologists have been reporting all disorders manifesting with slowness of movement, resting tremor and gait disturbances as PD, attributing relatively little diagnostic relevance to nonmotor features including cognitive impairment.3 Following the introduction of neuropathological analysis, however, it became obvious that the rate of misdiagnosis of PD could be quite high, particularly if patients had short disease duration and were examined by non-experts. Operational diagnostic criteria for PD were defined on the basis of a series of brain examinations at the UK Brain Bank, and
these criteria became the gold standard in routine clinical practice.1 To confirm a clinical diagnosis of PD, some suggested that patients should be followed for at least 5 years after the initial diagnosis—a timescale that would enable most atypical conditions to be excluded. Although this approach suited clinical needs, it was inadequate to fit the strict requirements of clinical trials of symptomatic and disease-modifying interventions that targeted patients in the early stages of PD. Furthermore, the recognition that the disease has a relatively long premotor phase, and can be heralded by a number of nonmotor red flags, has substantially influenced our view of PD.4 The International Parkinson and Movement Disorders Society commissioned a task force to consider a redefinition of PD that reflects the profound changes in our understanding of the disorder, and concluded that new diagnostic criteria are required.5 Marek and colleagues examined the role of DAT imaging in the evaluation of patients displaying the early symptoms of PD. DAT single-photon emission CT (DAT-SPECT) and 18F-fluoro‑l-dopa PET imaging of the dopaminergic system have been available for many years, and could potentially provide suitable surrogate biomarkers to improve diagnostic accuracy in uncertain cases by detecting progressive loss of nigro-striatal nerve terminals in the basal ganglia. DAT-SPECT is commercially available in Western Europe and North America, and is widely used in the clinical arena.6–8 Many clinical trials in newly diagnosed and untreated patients with PD have used
NATURE REVIEWS | NEUROLOGY
DAT imaging in addition to clinical evaluation to assess PD progression. In these studies, an appreciable number of patients presenting with clinically subtle extra pyramidal features had scans without evidence of dopaminergic deficit (SWEDD). Therefore, it is unclear whether these patients—in some cases enrolled within 9 months of diagnosis—actually had PD, and whether their clinical and imaging profiles would show typical evolution (that is, worsening motor symptoms and a future scan showing striatal dopamine dysfunction). This problem is important because efficacy measures are based on the entire treated population, and patients with SWEDD might not respond to a given treatment like the other patients. Moreover, if patients with SWEDD have been misdiagnosed as having PD, what is the alternative diagnosis? Marek and co-authors tried to address some of the questions surrounding patients with SWEDD by analysing data collected in the context of PRECEPT (Parkinson Research Examination of CEP-1347 Trial), a multicentre, randomized, double-blinded, placebo-controlled study examining the efficacy and long-term safety of CEP-1347 as a potential disease-modifying treatment for patients with early PD. Patients with SWEDD were compared with those who had abnormal striatal DAT scans, both at study baseline and after follow-up almost 2 years later.2
‘‘
…we do not fully understand the relationship between [dopamine] and the clinical manifestations of PD
’’
Compared with 707 patients showing abnormal DAT imaging, 90 patients with SWEDD had milder parkinsonism with lesssevere resting tremor at baseline, and showed little clinical and imaging progression over the observation period. When the investigators were asked to reassess clinical diagnosis at follow-up, approximately 44% of the patients with SWEDD continued to fulfil PD diagnostic criteria, and 17% required dopaminergic therapy. A further 10 of the 90 patients had other degenerative parkinsonisms, such as multiple system ADVANCE ONLINE PUBLICATION | 1
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS atrophy. By contrast, in the cohort with DAT deficit, 86% of patients were confirmed to have PD, 8% had atypical parkinsonism, and 6% had nondegenerative parkinsonism. Although the possibility remains that the PRECEPT investigators might have ‘pushed’ a PD diagnosis in some cases to meet recruitment requirements, it is surprising to find such a large mismatch between clinical and imaging profiles—that is, positive PD or atypical parkinsonism diagnoses despite normal striatal DAT binding—persisting at follow-up. Moreover, these results refute a previous suggestion that the majority of patients with SWEDD have dystonic or essential tremor rather than PD:9 only 15% of patients were reported to have nondegenerative tremor disorders. Marek and colleagues reasonably conclude that DAT imaging at study baseline can be used as a predictor of clinical and imaging progression. However, we disagree with their view that patients with SWEDD can simply be discarded as unlikely to have PD. Genetic testing has offered us the opportunity to observe a number of individuals with mutations in PD-associated genes, such as LRKK2, who have normal motor function but abnormal DAT-SPECT, and
so far have not developed PD. These cases indicate that we do not fully understand the relationship between dopaminergic dysfunction and the clinical manifestations of PD. For future drug trials, and also in clinical practice, use of the current diagnostic criteria should be enforced, as they already include definitions of the cardinal motor manifestation of PD. At the same time, however, more attention should be devoted to instructing neurologists on how to properly examine patients. In addition, we should be careful to distinguish criteria to be used in research from more-stringent criteria for the clinical arena.10 Parkinson and Movement Disorders Unit, IRCCS Hospital San Camillo, Viale Alberoni 70, Venice, Italy (A.A., R.B.). Correspondence to: A.A. [email protected] Acknowledgements R.B. was supported by the Italian National research grant N: RF‑2009‑153017 Competing interests The authors declare no competing interests. 1.
Hughes, A. J., Daniel, S. E., Kilford, L. & Lees, A. J. Accuracy of clinical diagnosis
2 | ADVANCE ONLINE PUBLICATION
of idiopathic Parkinson’s disease: a clinicopathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181–184 (1992). 2. Marek, K. et al. Longitudinal follow-up of SWEDD subjects in the PRECEPT Study. Neurology 82, 1791–1797. 3. Chaudhuri, K. R. et al. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 5, 235–245 (2006). 4. Mollenhauer, B. et al. Non-motor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort. Neurology 81, 1226–1234 (2013). 5. Berg, D. et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov. Disord. 29, 454–462 (2014). 6. Antonini, A. Imaging for early differential diagnosis of parkinsonism. Lancet Neurol. 9, 130–131 (2010). 7. Scherfler, C. et al. Role of DAT-SPECT in the diagnostic work up of parkinsonism. Mov. Disord. 22, 1229–1238 (2007). 8. Antonini, A. et al. Complementary PET studies of striatal neuronal function in the differential diagnosis between multiple system atrophy and Parkinson’s disease. Brain 120, 2187–2195 (1997). 9. Bajaj, N. P. et al. Accuracy of clinical diagnosis in tremulous parkinsonian patients: a blinded video study. J. Neurol. Neurosurg. Psychiatry 81, 1223–1228 (2010). 10. Berardelli, A. et al. EFNS/MDS-ES recommendations for the diagnosis of Parkinson’s disease. Eur. J. Neurol. 20, 16–34 (2013).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
Can dopamine transporter imaging define early PD? Angelo Antonini and Roberta Biundo
Dopaminergic brain imaging might aid early diagnosis of Parkinson disease (PD), but some patients with mild symptoms show no evidence of dopaminergic dysfunction at baseline, and apparently do not progress. Although some of these patients may have been misdiagnosed, others continue to fulfil PD diagnostic criteria despite normal follow-up brain scans. Antonini, A. & Biundo, R. Nat. Rev. Neurol. advance online publication 8 July 2014; doi:10.1038/nrneurol.2014.123
Accurate diagnosis of Parkinson disease (PD) is particularly challenging in patients who are in the early stages in the disease process, with short symptom duration and before treatment initiation.1 A recent study by Marek and co-authors further highlights such difficulties, and also sheds new light on the contribution of dopamine transporter (DAT) imaging as a surrogate biomarker for early diagnosis.2 The results confirm that up to 15% of patients entering clinical trials for early untreated PD might not exhibit dopaminergic defects in the basal ganglia either at baseline or at follow-up, yet almost 50% of these patients would still have clinical features in line with PD diagnostic criteria.
‘‘
…DAT imaging at study baseline can be used as a predictor of clinical and imaging progression
’’
For many decades, neurologists have been reporting all disorders manifesting with slowness of movement, resting tremor and gait disturbances as PD, attributing relatively little diagnostic relevance to nonmotor features including cognitive impairment.3 Following the introduction of neuropathological analysis, however, it became obvious that the rate of misdiagnosis of PD could be quite high, particularly if patients had short disease duration and were examined by non-experts. Operational diagnostic criteria for PD were defined on the basis of a series of brain examinations at the UK Brain Bank, and
these criteria became the gold standard in routine clinical practice.1 To confirm a clinical diagnosis of PD, some suggested that patients should be followed for at least 5 years after the initial diagnosis—a timescale that would enable most atypical conditions to be excluded. Although this approach suited clinical needs, it was inadequate to fit the strict requirements of clinical trials of symptomatic and disease-modifying interventions that targeted patients in the early stages of PD. Furthermore, the recognition that the disease has a relatively long premotor phase, and can be heralded by a number of nonmotor red flags, has substantially influenced our view of PD.4 The International Parkinson and Movement Disorders Society commissioned a task force to consider a redefinition of PD that reflects the profound changes in our understanding of the disorder, and concluded that new diagnostic criteria are required.5 Marek and colleagues examined the role of DAT imaging in the evaluation of patients displaying the early symptoms of PD. DAT single-photon emission CT (DAT-SPECT) and 18F-fluoro‑l-dopa PET imaging of the dopaminergic system have been available for many years, and could potentially provide suitable surrogate biomarkers to improve diagnostic accuracy in uncertain cases by detecting progressive loss of nigro-striatal nerve terminals in the basal ganglia. DAT-SPECT is commercially available in Western Europe and North America, and is widely used in the clinical arena.6–8 Many clinical trials in newly diagnosed and untreated patients with PD have used
NATURE REVIEWS | NEUROLOGY
DAT imaging in addition to clinical evaluation to assess PD progression. In these studies, an appreciable number of patients presenting with clinically subtle extra pyramidal features had scans without evidence of dopaminergic deficit (SWEDD). Therefore, it is unclear whether these patients—in some cases enrolled within 9 months of diagnosis—actually had PD, and whether their clinical and imaging profiles would show typical evolution (that is, worsening motor symptoms and a future scan showing striatal dopamine dysfunction). This problem is important because efficacy measures are based on the entire treated population, and patients with SWEDD might not respond to a given treatment like the other patients. Moreover, if patients with SWEDD have been misdiagnosed as having PD, what is the alternative diagnosis? Marek and co-authors tried to address some of the questions surrounding patients with SWEDD by analysing data collected in the context of PRECEPT (Parkinson Research Examination of CEP-1347 Trial), a multicentre, randomized, double-blinded, placebo-controlled study examining the efficacy and long-term safety of CEP-1347 as a potential disease-modifying treatment for patients with early PD. Patients with SWEDD were compared with those who had abnormal striatal DAT scans, both at study baseline and after follow-up almost 2 years later.2
‘‘
…we do not fully understand the relationship between [dopamine] and the clinical manifestations of PD
’’
Compared with 707 patients showing abnormal DAT imaging, 90 patients with SWEDD had milder parkinsonism with lesssevere resting tremor at baseline, and showed little clinical and imaging progression over the observation period. When the investigators were asked to reassess clinical diagnosis at follow-up, approximately 44% of the patients with SWEDD continued to fulfil PD diagnostic criteria, and 17% required dopaminergic therapy. A further 10 of the 90 patients had other degenerative parkinsonisms, such as multiple system ADVANCE ONLINE PUBLICATION | 1
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS atrophy. By contrast, in the cohort with DAT deficit, 86% of patients were confirmed to have PD, 8% had atypical parkinsonism, and 6% had nondegenerative parkinsonism. Although the possibility remains that the PRECEPT investigators might have ‘pushed’ a PD diagnosis in some cases to meet recruitment requirements, it is surprising to find such a large mismatch between clinical and imaging profiles—that is, positive PD or atypical parkinsonism diagnoses despite normal striatal DAT binding—persisting at follow-up. Moreover, these results refute a previous suggestion that the majority of patients with SWEDD have dystonic or essential tremor rather than PD:9 only 15% of patients were reported to have nondegenerative tremor disorders. Marek and colleagues reasonably conclude that DAT imaging at study baseline can be used as a predictor of clinical and imaging progression. However, we disagree with their view that patients with SWEDD can simply be discarded as unlikely to have PD. Genetic testing has offered us the opportunity to observe a number of individuals with mutations in PD-associated genes, such as LRKK2, who have normal motor function but abnormal DAT-SPECT, and
so far have not developed PD. These cases indicate that we do not fully understand the relationship between dopaminergic dysfunction and the clinical manifestations of PD. For future drug trials, and also in clinical practice, use of the current diagnostic criteria should be enforced, as they already include definitions of the cardinal motor manifestation of PD. At the same time, however, more attention should be devoted to instructing neurologists on how to properly examine patients. In addition, we should be careful to distinguish criteria to be used in research from more-stringent criteria for the clinical arena.10 Parkinson and Movement Disorders Unit, IRCCS Hospital San Camillo, Viale Alberoni 70, Venice, Italy (A.A., R.B.). Correspondence to: A.A. [email protected] Acknowledgements R.B. was supported by the Italian National research grant N: RF‑2009‑153017 Competing interests The authors declare no competing interests. 1.
Hughes, A. J., Daniel, S. E., Kilford, L. & Lees, A. J. Accuracy of clinical diagnosis
2 | ADVANCE ONLINE PUBLICATION
of idiopathic Parkinson’s disease: a clinicopathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181–184 (1992). 2. Marek, K. et al. Longitudinal follow-up of SWEDD subjects in the PRECEPT Study. Neurology 82, 1791–1797. 3. Chaudhuri, K. R. et al. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 5, 235–245 (2006). 4. Mollenhauer, B. et al. Non-motor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort. Neurology 81, 1226–1234 (2013). 5. Berg, D. et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov. Disord. 29, 454–462 (2014). 6. Antonini, A. Imaging for early differential diagnosis of parkinsonism. Lancet Neurol. 9, 130–131 (2010). 7. Scherfler, C. et al. Role of DAT-SPECT in the diagnostic work up of parkinsonism. Mov. Disord. 22, 1229–1238 (2007). 8. Antonini, A. et al. Complementary PET studies of striatal neuronal function in the differential diagnosis between multiple system atrophy and Parkinson’s disease. Brain 120, 2187–2195 (1997). 9. Bajaj, N. P. et al. Accuracy of clinical diagnosis in tremulous parkinsonian patients: a blinded video study. J. Neurol. Neurosurg. Psychiatry 81, 1223–1228 (2010). 10. Berardelli, A. et al. EFNS/MDS-ES recommendations for the diagnosis of Parkinson’s disease. Eur. J. Neurol. 20, 16–34 (2013).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
