- Email: [email protected]
Another trial, another hour
Comment
prevention study of a defined duration was small. Also, the neuropsychological battery used was designed to identify people with dementia and therefore might not have been sensitive to the earliest cognitive changes in the disease. Although measures that are more sensitive to early change in this population have been identified,5 the optimum choice of outcome measures is always highly dependent on the age of the population, the expected effect of the intervention, and the study duration. When using cognitive outcome measures, one must also consider sociocultural factors, and the low educational level of people in the present study (>50% had less than 6 years of education) limits the applicability of the results to people with familial AD in more industrialised societies. Increased knowledge about imaging and biochemical markers in AD6 and familial AD7–9 over the past 10 years has allowed their use as surrogate outcome measures in prevention studies, thus circumventing some of the limitations of clinical outcomes. Present efforts both in the Colombian population and in the international Dominantly Inherited Alzheimer Network10 aim to better define such biomarker changes so they too can be used to set the stage for prevention of familial AD.
John M Ringman Mary S Easton Center for Alzheimer’s Disease Research, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [email protected] I declare that I have no conflicts of interest. 1
2
3 4
5
6
7 8
9 10
Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, et al. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer’s disease: a retrospective cohort study. Lancet Neurol 2011; published online Feb 4. DOI:10.1016/S1474-4422(10)70323-9. Lopera F, Ardilla A, Martinez A, et al. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA 1997; 277: 793–99. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256: 183–94. Ringman JM, Grill J, Rodriguez-Agudelo Y, Chavez M, Xiong C. Commentary on “a roadmap for the prevention of dementia II: Leon Thal Symposium 2008.” Prevention trials in persons at risk for dominantly inherited Alzheimer’s disease: opportunities and challenges. Alzheimers Dement 2009; 5: 166–71. Parra MA, Abrahams S, Logie RH, Mendez LG, Lopera F, Della Sala S. Visual short-term memory binding deficits in familial Alzheimer’s disease. Brain 2010; 133: 2702–13. Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 2010; 9: 119–28. Ringman JM, Younkin SG, Pratico D, et al. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 2008; 71: 85–92. Klunk WE, Price JC, Mathis CA, et al. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci 2007; 27: 6174–84. Ridha BH, Barnes J, Bartlett JW, et al. Tracking atrophy progression in familial Alzheimer’s disease: a serial MRI study. Lancet Neurol 2006; 5: 828–34. Bateman RJ, Aisen PS, De Strooper B, et al. Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res Ther 2011; 2: 35.
Another trial, another hour Since the discovery of dopamine deficiency in Parkinson’s disease more than 50 years ago, almost all therapies have been focused on replacing or increasing concentrations of dopamine.1 Consequently, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, dopamine agonists, and levodopa improve Parkinson’s disease symptoms, whereas drugs that deplete or block dopamine cause or worsen parkinsonism. The only other neurotransmitter thought to have an important role in the treatment of Parkinson’s disease is acetylcholine, and there has been a long search for other neurotransmitters that might have a therapeutic role. Adenosine has received attention because the 2A class of its receptors (A2A) are selectively localised to the indirect basal ganglia pathway and, as such, offer the opportunity to modulate the abnormal effects of the striatum on the pallidum. The A2A receptor is predominantly found on www.thelancet.com/neurology Vol 10 March 2011
GABAergic enkephalin-expressing neurons, which also express D2 dopamine receptors, and the proposed hypothesis is that antagonism of GABA pathways via A2A receptors inhibits striatopallidal output.2 In this issue of The Lancet Neurology, Hauser and colleagues3 present findings of their multinational, double-blind, phase 2 trial of preladenant, an A2A antagonist, in patients with moderate-to-advanced Parkinson’s disease and at least 2 h off time per day. The preclinical basis for this trial was a study of an animal model of parkinsonism, in which motor performance improved with the use of the study drug without causing dyskinesias.2 In the trial, 253 patients were randomly assigned to receive 12 weeks of treatment with 1, 2, 5, or 10 mg preladenant twice per day, or placebo, and 246 received at least one dose of study treatment. The primary outcome was change in off time from
Published Online February 10, 2011 DOI:10.1016/S14744422(11)70021-7 See Articles page 221
201
Simon Fraser/Royal Victoria Infirmary, Newcastle upon Tyne/Science Photo Library
Comment
baseline to end of treatment, assessed by home diaries. Reductions in daily off time were significant only in the 5 mg preladenant group, by 1·0 h, and the 10 mg preladenant group, by 1·2 h. Preladenant was not associated with any significant safety issues. Although clinicians have a wide variety of options for the treatment of motor fluctuations in Parkinson’s disease,4 many patients remain troubled by off time. A new treatment to alleviate the problem is certainly welcome. However, A2A receptor antagonism is not a new idea: istradefylline, another A2A receptor antagonist, was tested in a similar clinical trial with a reduction in off time of 0·7 h.5 Despite istradefylline achieving so-called significance in clinical trials, the US Food and Drug Administration issued a not approvable letter expressing concern about the clinical usefulness of the drug.6 This response raises the important issue of clinical significance as opposed to statistical significance. Clinical significance is not simply a notion of common sense, but has a well formulated methodology to establish minimally important differences for patients’ reported outcomes.7 In the past 5 years, this idea has received much attention in assessment of Parkinson’s disease and response of the disease to treatment.8,9 202
Hauser and colleagues cite another study by Hauser and Auinger suggesting that a 1 h reduction in off time per day might be the minimum clinically important difference in patients who have Parkinson’s disease and motor fluctuations. Is 1 h less off time per day meaningful, and is a new drug the only way to achieve it? Patients in this trial were permitted to take all the drugs available to treat motor fluctuations. If patients were treated optimally but still having fluctuations, then introduction of a new class of drug resulting in decreased off time would be welcomed. However, many patients in this trial were not taking all of the available drugs. In the two preladenant groups that achieved the minimum clinically significant improvements in off time (5 and 10 mg twice daily), about a third of patients were not receiving a dopamine agonist, and about a quarter were on monoamine oxidase or catechol-O-methyltransferase inhibitors. In assessment of the potential usefulness of preladenant, an important issue is whether more extensive use of available antiparkinsonian drugs could achieve the same minimal results. The reduction in off time with preladenant is similar to that achieved from the addition of entacapone or rasagiline to levodopa.10 Acknowledged weaknesses of Hauser and colleagues’ study included fairly small treatment groups, the large percentage of imputed values for missing data (for 23% of patients, data were last-observation-carriedforward values), and the failure to correct for multiple hypothesis testing in examination of secondary outcomes. Therefore, the study has interesting findings, but is far from definitive. In this trial, scores did not improve for the motor part of the unified Parkinson’s disease rating scale, by contrast with the improvement in motor function recorded in preclinical studies, but dyskinesias did not increase. If this absence of an increase in dyskinesia can be replicated, preladenant will be a unique and potentially important advance in the treatment of Parkinson’s disease, because most available adjunctive therapies for off time have the potential to exacerbate dyskinesias. Finally, the demonstration that manipulation of a neurotransmitter other than dopamine or acetylcholine improves the symptoms of moderateto-severe Parkinson’s disease has broadened the scope of potential novel therapies. www.thelancet.com/neurology Vol 10 March 2011
Comment
William J Weiner, Stephen G Reich
5
University of Maryland School of Medicine Department of Neurology, 3-S-124 Baltimore, MD 21201, USA [email protected]
6
WJW receives research funding from Solvay and Boehringer-Ingelheim. SGR has served as consultant to Schering-Plough, and receives research funding from Chiltern. 1 2
3
4
Ahlskog JE. Beating a dead horse: dopamine and Parkinson disease. Neurology 2007; 69: 1701–11. Jenner P, Mori A, Hauser R, Morelli M, Fredholm BB, Chen JF. Adenosine, adenosine A2a antagonists, and Parkinson’s disease. Parkinsonism Relat Disord 2009; 15: 406–13. Hauser RA, Cantillon M, Pourcher E, et al. Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 2011; published online Feb 10. DOI:10.1016/S1474-4422(11)70012-6. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesias (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66: 983–95.
7
8
9
10
Hauser RA, Shulman LM, Trugman JM, et al, Istradefylline 6002-US-013 Study Group. Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord 2008; 23: 2177–85. PR Newswire. Kyowa Hakko receives not approvable letter from FDA for istradefylline (KW-6002). Feb 28, 2008. http://www.highbeam.com/ doc/1G1-175494321.html (accessed Feb 2, 2011). Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J Clin Epidemiol 2008; 61: 102–09. Schrag A, Sampaio C, Counsell N, Poewe W. Minimal clinically important change on the unified Parkinson’s disease rating scale. Mov Disord 2006; 21: 1200–07. Shulman LM, Gruber-Baldini AL, Anderson KE, Fishman PS, Reich SG, Weiner WJ. The clinically important difference on the unified Parkinson’s disease rating scale. Arch Neurol 2010; 67: 64–70. Rascol O, Brooks DJ, Melamed E, et al, for the LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365: 947–54.
Biochemical diagnosis of neurodegenerative diseases gets closer Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy—the most common synucleinopathies—are characterised by deposition of α-synuclein as the major constituent of intraneuronal Lewy body aggregates (in Parkinson’s disease and dementia with Lewy bodies) or glial cytoplasmic inclusions (in multiple system atrophy). But despite these characteristic pathological features, the antemortem diagnosis of these neurodegenerative diseases relies on classification criteria based only on clinical signs. In the case of parkinsonism, this attitude hampers early diagnosis—for example, the high specificity of the UK Brain Bank criteria for Parkinson’s disease is largely due to overt signs and symptoms of full-blown disease. Moreover, the UK Brain Bank criteria have a high predictive value only if applied by experts in movement disorders, the accuracy being much lower when applied by non-experts.1 For all disorders in which people have parkinsonism, similar clinical phenotypes can have heterogeneous pathological causes. CSF biomarkers offer the opportunity to improve the accuracy of early diagnosis of such disorders, as has already been achieved in another devastating neurodegenerative disorder, Alzheimer’s disease.2 In this issue of The Lancet Neurology, Brit Mollenhauer www.thelancet.com/neurology Vol 10 March 2011
and co-workers3 convincingly show that α-synuclein concentrations in CSF have a role as a reliable predictor of synucleinopathy. The investigators found that concentrations in the CSF are consistently lower in patients with Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy than in patients with non-synucleinopathies, including tauopathies (in this case Alzheimer’s disease and progressive supranuclear palsy). This claim stems from two large independent cohorts of patients, a training set of 273 participants resulting from cooperation of three donor centres, and a validation cohort of 407 participants recruited from a single centre. Analysis was also done in CSF from a group of patients with autopsy-confirmed dementia with Lewy bodies, Alzheimer’s disease, and other neurological disorders; low CSF α-synuclein concentrations were recorded in all individuals with definite dementia with Lewy bodies, with good discriminative power versus Alzheimer’s disease (p=0·019; area under the curve [AUC]=0·687). In the three series of samples assessed, the positive predictive value for an underlying synucleinopathy was invariably more than 90%. The major merits of the study by Mollenhauer and colleagues are the large sample size and the completeness of the range of synucleinopathies
Published Online February 14, 2011 DOI:10.1016/S14744422(11)70019-9 See Articles page 230
203
prevention study of a defined duration was small. Also, the neuropsychological battery used was designed to identify people with dementia and therefore might not have been sensitive to the earliest cognitive changes in the disease. Although measures that are more sensitive to early change in this population have been identified,5 the optimum choice of outcome measures is always highly dependent on the age of the population, the expected effect of the intervention, and the study duration. When using cognitive outcome measures, one must also consider sociocultural factors, and the low educational level of people in the present study (>50% had less than 6 years of education) limits the applicability of the results to people with familial AD in more industrialised societies. Increased knowledge about imaging and biochemical markers in AD6 and familial AD7–9 over the past 10 years has allowed their use as surrogate outcome measures in prevention studies, thus circumventing some of the limitations of clinical outcomes. Present efforts both in the Colombian population and in the international Dominantly Inherited Alzheimer Network10 aim to better define such biomarker changes so they too can be used to set the stage for prevention of familial AD.
John M Ringman Mary S Easton Center for Alzheimer’s Disease Research, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [email protected] I declare that I have no conflicts of interest. 1
2
3 4
5
6
7 8
9 10
Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, et al. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer’s disease: a retrospective cohort study. Lancet Neurol 2011; published online Feb 4. DOI:10.1016/S1474-4422(10)70323-9. Lopera F, Ardilla A, Martinez A, et al. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA 1997; 277: 793–99. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256: 183–94. Ringman JM, Grill J, Rodriguez-Agudelo Y, Chavez M, Xiong C. Commentary on “a roadmap for the prevention of dementia II: Leon Thal Symposium 2008.” Prevention trials in persons at risk for dominantly inherited Alzheimer’s disease: opportunities and challenges. Alzheimers Dement 2009; 5: 166–71. Parra MA, Abrahams S, Logie RH, Mendez LG, Lopera F, Della Sala S. Visual short-term memory binding deficits in familial Alzheimer’s disease. Brain 2010; 133: 2702–13. Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 2010; 9: 119–28. Ringman JM, Younkin SG, Pratico D, et al. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 2008; 71: 85–92. Klunk WE, Price JC, Mathis CA, et al. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci 2007; 27: 6174–84. Ridha BH, Barnes J, Bartlett JW, et al. Tracking atrophy progression in familial Alzheimer’s disease: a serial MRI study. Lancet Neurol 2006; 5: 828–34. Bateman RJ, Aisen PS, De Strooper B, et al. Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res Ther 2011; 2: 35.
Another trial, another hour Since the discovery of dopamine deficiency in Parkinson’s disease more than 50 years ago, almost all therapies have been focused on replacing or increasing concentrations of dopamine.1 Consequently, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, dopamine agonists, and levodopa improve Parkinson’s disease symptoms, whereas drugs that deplete or block dopamine cause or worsen parkinsonism. The only other neurotransmitter thought to have an important role in the treatment of Parkinson’s disease is acetylcholine, and there has been a long search for other neurotransmitters that might have a therapeutic role. Adenosine has received attention because the 2A class of its receptors (A2A) are selectively localised to the indirect basal ganglia pathway and, as such, offer the opportunity to modulate the abnormal effects of the striatum on the pallidum. The A2A receptor is predominantly found on www.thelancet.com/neurology Vol 10 March 2011
GABAergic enkephalin-expressing neurons, which also express D2 dopamine receptors, and the proposed hypothesis is that antagonism of GABA pathways via A2A receptors inhibits striatopallidal output.2 In this issue of The Lancet Neurology, Hauser and colleagues3 present findings of their multinational, double-blind, phase 2 trial of preladenant, an A2A antagonist, in patients with moderate-to-advanced Parkinson’s disease and at least 2 h off time per day. The preclinical basis for this trial was a study of an animal model of parkinsonism, in which motor performance improved with the use of the study drug without causing dyskinesias.2 In the trial, 253 patients were randomly assigned to receive 12 weeks of treatment with 1, 2, 5, or 10 mg preladenant twice per day, or placebo, and 246 received at least one dose of study treatment. The primary outcome was change in off time from
Published Online February 10, 2011 DOI:10.1016/S14744422(11)70021-7 See Articles page 221
201
Simon Fraser/Royal Victoria Infirmary, Newcastle upon Tyne/Science Photo Library
Comment
baseline to end of treatment, assessed by home diaries. Reductions in daily off time were significant only in the 5 mg preladenant group, by 1·0 h, and the 10 mg preladenant group, by 1·2 h. Preladenant was not associated with any significant safety issues. Although clinicians have a wide variety of options for the treatment of motor fluctuations in Parkinson’s disease,4 many patients remain troubled by off time. A new treatment to alleviate the problem is certainly welcome. However, A2A receptor antagonism is not a new idea: istradefylline, another A2A receptor antagonist, was tested in a similar clinical trial with a reduction in off time of 0·7 h.5 Despite istradefylline achieving so-called significance in clinical trials, the US Food and Drug Administration issued a not approvable letter expressing concern about the clinical usefulness of the drug.6 This response raises the important issue of clinical significance as opposed to statistical significance. Clinical significance is not simply a notion of common sense, but has a well formulated methodology to establish minimally important differences for patients’ reported outcomes.7 In the past 5 years, this idea has received much attention in assessment of Parkinson’s disease and response of the disease to treatment.8,9 202
Hauser and colleagues cite another study by Hauser and Auinger suggesting that a 1 h reduction in off time per day might be the minimum clinically important difference in patients who have Parkinson’s disease and motor fluctuations. Is 1 h less off time per day meaningful, and is a new drug the only way to achieve it? Patients in this trial were permitted to take all the drugs available to treat motor fluctuations. If patients were treated optimally but still having fluctuations, then introduction of a new class of drug resulting in decreased off time would be welcomed. However, many patients in this trial were not taking all of the available drugs. In the two preladenant groups that achieved the minimum clinically significant improvements in off time (5 and 10 mg twice daily), about a third of patients were not receiving a dopamine agonist, and about a quarter were on monoamine oxidase or catechol-O-methyltransferase inhibitors. In assessment of the potential usefulness of preladenant, an important issue is whether more extensive use of available antiparkinsonian drugs could achieve the same minimal results. The reduction in off time with preladenant is similar to that achieved from the addition of entacapone or rasagiline to levodopa.10 Acknowledged weaknesses of Hauser and colleagues’ study included fairly small treatment groups, the large percentage of imputed values for missing data (for 23% of patients, data were last-observation-carriedforward values), and the failure to correct for multiple hypothesis testing in examination of secondary outcomes. Therefore, the study has interesting findings, but is far from definitive. In this trial, scores did not improve for the motor part of the unified Parkinson’s disease rating scale, by contrast with the improvement in motor function recorded in preclinical studies, but dyskinesias did not increase. If this absence of an increase in dyskinesia can be replicated, preladenant will be a unique and potentially important advance in the treatment of Parkinson’s disease, because most available adjunctive therapies for off time have the potential to exacerbate dyskinesias. Finally, the demonstration that manipulation of a neurotransmitter other than dopamine or acetylcholine improves the symptoms of moderateto-severe Parkinson’s disease has broadened the scope of potential novel therapies. www.thelancet.com/neurology Vol 10 March 2011
Comment
William J Weiner, Stephen G Reich
5
University of Maryland School of Medicine Department of Neurology, 3-S-124 Baltimore, MD 21201, USA [email protected]
6
WJW receives research funding from Solvay and Boehringer-Ingelheim. SGR has served as consultant to Schering-Plough, and receives research funding from Chiltern. 1 2
3
4
Ahlskog JE. Beating a dead horse: dopamine and Parkinson disease. Neurology 2007; 69: 1701–11. Jenner P, Mori A, Hauser R, Morelli M, Fredholm BB, Chen JF. Adenosine, adenosine A2a antagonists, and Parkinson’s disease. Parkinsonism Relat Disord 2009; 15: 406–13. Hauser RA, Cantillon M, Pourcher E, et al. Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 2011; published online Feb 10. DOI:10.1016/S1474-4422(11)70012-6. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesias (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66: 983–95.
7
8
9
10
Hauser RA, Shulman LM, Trugman JM, et al, Istradefylline 6002-US-013 Study Group. Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord 2008; 23: 2177–85. PR Newswire. Kyowa Hakko receives not approvable letter from FDA for istradefylline (KW-6002). Feb 28, 2008. http://www.highbeam.com/ doc/1G1-175494321.html (accessed Feb 2, 2011). Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J Clin Epidemiol 2008; 61: 102–09. Schrag A, Sampaio C, Counsell N, Poewe W. Minimal clinically important change on the unified Parkinson’s disease rating scale. Mov Disord 2006; 21: 1200–07. Shulman LM, Gruber-Baldini AL, Anderson KE, Fishman PS, Reich SG, Weiner WJ. The clinically important difference on the unified Parkinson’s disease rating scale. Arch Neurol 2010; 67: 64–70. Rascol O, Brooks DJ, Melamed E, et al, for the LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365: 947–54.
Biochemical diagnosis of neurodegenerative diseases gets closer Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy—the most common synucleinopathies—are characterised by deposition of α-synuclein as the major constituent of intraneuronal Lewy body aggregates (in Parkinson’s disease and dementia with Lewy bodies) or glial cytoplasmic inclusions (in multiple system atrophy). But despite these characteristic pathological features, the antemortem diagnosis of these neurodegenerative diseases relies on classification criteria based only on clinical signs. In the case of parkinsonism, this attitude hampers early diagnosis—for example, the high specificity of the UK Brain Bank criteria for Parkinson’s disease is largely due to overt signs and symptoms of full-blown disease. Moreover, the UK Brain Bank criteria have a high predictive value only if applied by experts in movement disorders, the accuracy being much lower when applied by non-experts.1 For all disorders in which people have parkinsonism, similar clinical phenotypes can have heterogeneous pathological causes. CSF biomarkers offer the opportunity to improve the accuracy of early diagnosis of such disorders, as has already been achieved in another devastating neurodegenerative disorder, Alzheimer’s disease.2 In this issue of The Lancet Neurology, Brit Mollenhauer www.thelancet.com/neurology Vol 10 March 2011
and co-workers3 convincingly show that α-synuclein concentrations in CSF have a role as a reliable predictor of synucleinopathy. The investigators found that concentrations in the CSF are consistently lower in patients with Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy than in patients with non-synucleinopathies, including tauopathies (in this case Alzheimer’s disease and progressive supranuclear palsy). This claim stems from two large independent cohorts of patients, a training set of 273 participants resulting from cooperation of three donor centres, and a validation cohort of 407 participants recruited from a single centre. Analysis was also done in CSF from a group of patients with autopsy-confirmed dementia with Lewy bodies, Alzheimer’s disease, and other neurological disorders; low CSF α-synuclein concentrations were recorded in all individuals with definite dementia with Lewy bodies, with good discriminative power versus Alzheimer’s disease (p=0·019; area under the curve [AUC]=0·687). In the three series of samples assessed, the positive predictive value for an underlying synucleinopathy was invariably more than 90%. The major merits of the study by Mollenhauer and colleagues are the large sample size and the completeness of the range of synucleinopathies
Published Online February 14, 2011 DOI:10.1016/S14744422(11)70019-9 See Articles page 230
203