Letters
BBB imaging as a reliable diagnostic tool, and potentially targeting the BBB for the prevention of post-mTBI complications. Itai Weissberg, Bmed Ronel Veksler, Bmed, Bsc Lyn Kamintsky, Msc Rotem Saar-Ashkenazy, Msc Dan Z. Milikovsky, Bmed Ilan Shelef, MD Alon Friedman, MD, PhD Author Affiliations: Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel (Weissberg, Veksler, Kamintsky, Milikovsky, Friedman); Department of Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel (Saar-Ashkenazy, Shelef, Friedman); Department of Medical Imaging, Soroka University Medical Center, Beer-Sheva, Israel (Shelef); Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada (Friedman). Corresponding Author: Alon Friedman, MD, PhD, Department of Medical Neuroscience, Dalhousie University, 5850 College St, PO Box 15000, Halifax, NS B3H 4R2, Canada ([email protected]). Author Contributions: Drs Shelef and Friedman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Messrs Weissberg and Veksler served as co-first authors, each with equal contribution to the manuscript. Study concept and design: Weissberg, Milikovsky, Friedman. Acquisition, analysis, or interpretation of data: Weissberg, Veksler, Kamintsky, Saar-Ashkenazy, Shelef. Drafting of the manuscript: Weissberg, Veksler, Kamintsky, Saar-Ashkenazy, Milikovsky. Critical revision of the manuscript for important intellectual content: Weissberg, Kamintsky, Shelef, Friedman. Statistical analysis: Weissberg, Veksler, Kamintsky, Saar-Ashkenazy, Milikovsky. Obtained funding: Friedman. Administrative, technical, or material support: Kamintsky, Saar-Ashkenazy. Study supervision: Shelef, Friedman. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by the European Union’s Seventh Framework Program (FP7/2007-2013; grant agreement 602102, EPITARGET, to Dr Friedman) and the Israel Science Foundation (grant 713/11 to Dr Friedman). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We thank the Negev Football (Black Swarm) team for their participation in this study and Hadar Shalev, MD, and Sharon Naparstek, MsC, of the Department of Psychiatry, Soroka University Medical Center, for their advice on the study design. They did not receive compensation for the contributions. 1. DeKosky ST, Blennow K, Ikonomovic MD, Gandy S. Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nat Rev Neurol. 2013;9(4):192-200. 2. Koerte IK, Ertl-Wagner B, Reiser M, Zafonte R, Shenton ME. White matter integrity in the brains of professional soccer players without a symptomatic concussion. JAMA. 2012;308(18):1859-1861. 3. McAllister TW, Ford JC, Flashman LA, et al. Effect of head impacts on diffusivity measures in a cohort of collegiate contact sport athletes. Neurology. 2014;82(1):63-69. 4. Shlosberg D, Benifla M, Kaufer D, Friedman A. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol. 2010;6(7):393-403. 5. Marchi N, Bazarian JJ, Puvenna V, et al. Consequences of repeated blood-brain barrier disruption in football players. PLoS One. 2013;8(3):e56805. 6. Chassidim Y, Veksler R, Lublinsky S, Pell GS, Friedman A, Shelef I. Quantitative imaging assessment of blood-brain barrier permeability in humans. Fluids Barriers CNS. 2013;10(1):9.
COMMENT & RESPONSE
The Central Clock in Patients With Parkinson Disease To the Editor The regulation of sleep-wakefulness behavior involves 2 physiological processes. A circadian process, based in the suprachiasmatic nucleus, is responsible for the timing of sleep and wakefulness, and a homeostatic process that monitors and responds to the quality and quantity of prior sleep and wakefulness.1 In patients with Parkinson disease (PD), sleep disturbances are among the most debilitating nonmotor symptoms.2 The underlying neuropathology is multifactorial and involves complex diseasemedication interactions.2 Given this complex pathophysiology, the contribution of a dysfunctional suprachiasmatic nucleus clock has remained elusive. In a study published in JAMA Neurology, Breen et al3 assessed sleep architecture and the circadian profile of cortisol, melatonin, and peripheral clock gene expression in 30 patients diagnosed as having PD. In addition to confirming the well-established alterations of sleep in PD,2 a significant reduction in the amplitude of melatonin secretion, hypercortisolemia, and altered peripheral clock gene expression were found in patients with PD. Videnovic et al4 also reported a 4-fold reduction in the amplitude of melatonin secretion in 20 patients with PD housed in a constant-routine protocol. Videnovic et al4 went further by showing that patients with PD with excessive daytime sleepiness had a significant 2.5-fold reduction in the melatonin rhythm amplitude compared with patients with PD without excessive daytime sleepiness. However, in both the Breen et al3 and Videnovic et al4 studies, no alterations in the markers of the circadian phase were reported in patients with PD. This is surprising given that in both studies, patients with PD were receiving dopaminergic therapy. Previous studies that investigated the phase of the melatonin rhythm in medicated and unmedicated patients with PD found a phase-advanced melatonin rhythm in patients receiving dopamine therapy.5 Indeed, Bolitho et al6 confirmed the alteration of the phase angle of entrainment of the melatonin rhythm in 16 treated compared with untreated de novo patients with PD and healthy control participants. Additionally, Bolitho et al6 reported a 3-fold increase in melatonin secretion, contrasting the decrease reported by Breen et al3 and Videnovic et al.4 The reasons behind these discrepancies are not clear. As stated by Videnovic et al,4 the experimental protocols of the earlier studies did not control for environmental conditions. Consequently, the melatonin rhythm phase and amplitude may have been influenced by external factors such as light exposure. However, this may not account for the results of Bolitho et al6 given that melatonin samples were collected under controlled conditions. A more plausible explanation is that these differences reflect an intrinsic neuropathophysiological variability in the PD cohorts investigated. This conclusion is supported by significant differences in multiple features of the sleep/wake cycle between patients studied by Breen et al3 and Bolitho et al.6 Furthermore, the patients in both studies did not show an increase in total sleep duration, which departs from the hypersomnia characterizing sleep in PD.2
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JAMA Neurology November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
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Letters
Collectively, these studies show that alterations in the circadian system are a potential causative factor in disturbed sleep in PD. However, a remaining question is whether alterations in peripheral circadian markers reflect a dysfunctional central clock. The reported alterations in hormonal and molecular markers measured to assess the circadian system could also reflect dysfunctional efferent or afferent pathways of the suprachiasmatic nucleus. Detailed assessments of the different components of the neuronal networks governing circadian rhythms regulation using, for example, functional magnetic resonance imaging, are needed to resolve this remaining conundrum. Karim Fifel, PhD Tom DeBoer, PhD Author Affiliations: Laboratory of Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands. Corresponding Author: Karim Fifel, PhD, Laboratory of Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center Mailbox S5-P, PO Box 9600, 2300 RC Leiden, the Netherlands ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: Dr Fifel received a postdoctoral fellowship from Fondation Fyssen. Role of the Funder/Sponsor: Fondation Fyssen had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. 1. Achermann P, Borbély AA. Sleep homeostasis and models of sleep regulation. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 5th ed. St Louis, MO: Saunders; 2011:431-444. 2. Chaudhuri KR, Healy DG, Schapira AH; National Institute for Clinical Excellence. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 2006;5(3):235-245. 3. Breen DP, Vuono R, Nawarathna U, et al. Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol. 2014;71(5):589-595. 4. Videnovic A, Noble C, Reid KJ, et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol. 2014;71(4): 463-469. 5. Bordet R, Devos D, Brique S, et al. Study of circadian melatonin secretion pattern at different stages of Parkinson’s disease. Clin Neuropharmacol. 2003; 26(2):65-72. 6. Bolitho SJ, Naismith SL, Rajaratnam SM, et al. Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease. Sleep Med. 2014;15(3):342-347.
In Reply We read with interest the letter to the editor by Fifel and DeBoer. Their comments focus on 3 published studies that shed light on circadian function in Parkinson disease (PD) and its possible link to frequently disrupted sleep-wake cycles in the PD population. Videnovic et al1 studied 24-hour circadian secretion of melatonin in serum samples of 20 patients with PD taking dopaminergic therapy under modified constant-routine conditions. They found diminished amplitude of melatonin secretion in patients with PD and a strong correlation with excessive daytime sleepiness.1 No alterations in other circadian markers were found. Similarly, Breen et al2 reported significant reductions in melatonin levels in 30 patients with early-stage PD, along with increased cortisol levels and flattening of the circadian Bmal1 rhythm (one of the core clock genes). In contrast to these findings, Bolitho and 1456
colleagues3 found increased melatonin secretion and prolonged phase angle of entrainment in medicated patients with PD (n = 16) but not in unmedicated patients (n = 13) or matched control individuals (n = 28). One reason for the observed differences in melatonin rhythms across these studies may relate to the experimental designs and the patient cohorts studied. Important method aspects of the study by Bolitho et al3 are the use of saliva as the source for melatonin measurements and the restricted sample collection to 8 hours in the evening. These aspects make comparison with the findings of the Videnovic et al1 and Breen et al2 studies challenging because, first, there are no comparative data looking at melatonin concentrations in saliva and serum in PD and, second, there are no data by which to compare full 24-hour melatonin secretion profiles. Furthermore, Bolitho et al3 excluded 21 of 78 study participants owing to an absent salivary melatonin signal. Another reason may relate to the heterogeneity within the PD population including differences in circadian function, sleep timing, and light exposure history. A dysfunction of the autonomic system, frequently present in the PD population, may have impacted melatonin concentrations variably in the study cohorts. Finally, the timing of the dopaminergic medications may be another significant factor influencing melatonin rhythms in studied patients with PD. In fact, the relationship between the timing of dopaminergic medications, circadian function, and sleep is unexplored and may be an area for future research because chronopharmacological approaches to the treatment of PD have been neglected compared with other diseases.4 Collectively, these 3 studies have demonstrated that there is impaired circadian rhythmicity of melatonin secretion across the clinical spectrum of PD. While the significance of these findings and mechanisms linking circadian dysfunction to PD needs to be clarified by further studies, these observations have opened up a novel research direction that is centered on the circadian system and its role in the biology of PD. Aleksandar Videnovic, MD, MSc David P. Breen, MRCP Roger A. Barker, MRCP, PhD Phyllis C. Zee, MD, PhD Author Affiliations: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (Videnovic); University of Cambridge, John van Geest Centre for Brain Repair, Cambridge, England (Breen, Barker); Department of Neurology, Northwestern University, Chicago, Illinois (Zee). Corresponding Author: Aleksandar Videnovic, MD, MSc, Neurological Clinical Research Institute, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 165 Cambridge St, Ste 600, Boston, MA 02114 ([email protected]). Conflict of Interest Disclosures: None reported. Correction: This article was corrected online November 10, 2014, for incorrect information in the second paragraph. 1. Videnovic A, Noble C, Reid KJ, et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol. 2014;71(4): 463-469. 2. Breen DP, Vuono R, Nawarathna U, et al. Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol. 2014;71(5):589-595.
JAMA Neurology November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 05/29/2015
jamaneurology.com
Letters
3. Bolitho SJ, Naismith SL, Rajaratnam SM, et al. Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease. Sleep Med. 2014;15(3):342-347.
6, 2014, in JAMA Neurology (doi:10.1001/jamaneurol.2014.2343), the first author’s name should have been given as John W. Krakauer. This article was corrected online.
4. Dallmann R, Brown SA, Gachon F. Chronopharmacology: new insights and therapeutic implications. Annu Rev Pharmacol Toxicol. 2014;54:339-361.
CORRECTION Error in Byline: In the Viewpoint entitled “The Future of Stroke Treatment: Bringing Evaluation of Behavior Back to Stroke Neurology,” published online October
Error in Byline: In the Original Investigation entitled “Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease: A Genome-Wide Association Study,” published online September 8, 2014, in JAMA Neurology (doi:10.1001 /jamaneurol.2014.1491), the Alzheimer Disease Genetics Consortium coauthors were inadvertently listed as collaborators but should have been identified as coauthors. This article was corrected online and in print.
jamaneurology.com
JAMA Neurology November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 05/29/2015
1457
BBB imaging as a reliable diagnostic tool, and potentially targeting the BBB for the prevention of post-mTBI complications. Itai Weissberg, Bmed Ronel Veksler, Bmed, Bsc Lyn Kamintsky, Msc Rotem Saar-Ashkenazy, Msc Dan Z. Milikovsky, Bmed Ilan Shelef, MD Alon Friedman, MD, PhD Author Affiliations: Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel (Weissberg, Veksler, Kamintsky, Milikovsky, Friedman); Department of Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel (Saar-Ashkenazy, Shelef, Friedman); Department of Medical Imaging, Soroka University Medical Center, Beer-Sheva, Israel (Shelef); Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada (Friedman). Corresponding Author: Alon Friedman, MD, PhD, Department of Medical Neuroscience, Dalhousie University, 5850 College St, PO Box 15000, Halifax, NS B3H 4R2, Canada ([email protected]). Author Contributions: Drs Shelef and Friedman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Messrs Weissberg and Veksler served as co-first authors, each with equal contribution to the manuscript. Study concept and design: Weissberg, Milikovsky, Friedman. Acquisition, analysis, or interpretation of data: Weissberg, Veksler, Kamintsky, Saar-Ashkenazy, Shelef. Drafting of the manuscript: Weissberg, Veksler, Kamintsky, Saar-Ashkenazy, Milikovsky. Critical revision of the manuscript for important intellectual content: Weissberg, Kamintsky, Shelef, Friedman. Statistical analysis: Weissberg, Veksler, Kamintsky, Saar-Ashkenazy, Milikovsky. Obtained funding: Friedman. Administrative, technical, or material support: Kamintsky, Saar-Ashkenazy. Study supervision: Shelef, Friedman. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by the European Union’s Seventh Framework Program (FP7/2007-2013; grant agreement 602102, EPITARGET, to Dr Friedman) and the Israel Science Foundation (grant 713/11 to Dr Friedman). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We thank the Negev Football (Black Swarm) team for their participation in this study and Hadar Shalev, MD, and Sharon Naparstek, MsC, of the Department of Psychiatry, Soroka University Medical Center, for their advice on the study design. They did not receive compensation for the contributions. 1. DeKosky ST, Blennow K, Ikonomovic MD, Gandy S. Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nat Rev Neurol. 2013;9(4):192-200. 2. Koerte IK, Ertl-Wagner B, Reiser M, Zafonte R, Shenton ME. White matter integrity in the brains of professional soccer players without a symptomatic concussion. JAMA. 2012;308(18):1859-1861. 3. McAllister TW, Ford JC, Flashman LA, et al. Effect of head impacts on diffusivity measures in a cohort of collegiate contact sport athletes. Neurology. 2014;82(1):63-69. 4. Shlosberg D, Benifla M, Kaufer D, Friedman A. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol. 2010;6(7):393-403. 5. Marchi N, Bazarian JJ, Puvenna V, et al. Consequences of repeated blood-brain barrier disruption in football players. PLoS One. 2013;8(3):e56805. 6. Chassidim Y, Veksler R, Lublinsky S, Pell GS, Friedman A, Shelef I. Quantitative imaging assessment of blood-brain barrier permeability in humans. Fluids Barriers CNS. 2013;10(1):9.
COMMENT & RESPONSE
The Central Clock in Patients With Parkinson Disease To the Editor The regulation of sleep-wakefulness behavior involves 2 physiological processes. A circadian process, based in the suprachiasmatic nucleus, is responsible for the timing of sleep and wakefulness, and a homeostatic process that monitors and responds to the quality and quantity of prior sleep and wakefulness.1 In patients with Parkinson disease (PD), sleep disturbances are among the most debilitating nonmotor symptoms.2 The underlying neuropathology is multifactorial and involves complex diseasemedication interactions.2 Given this complex pathophysiology, the contribution of a dysfunctional suprachiasmatic nucleus clock has remained elusive. In a study published in JAMA Neurology, Breen et al3 assessed sleep architecture and the circadian profile of cortisol, melatonin, and peripheral clock gene expression in 30 patients diagnosed as having PD. In addition to confirming the well-established alterations of sleep in PD,2 a significant reduction in the amplitude of melatonin secretion, hypercortisolemia, and altered peripheral clock gene expression were found in patients with PD. Videnovic et al4 also reported a 4-fold reduction in the amplitude of melatonin secretion in 20 patients with PD housed in a constant-routine protocol. Videnovic et al4 went further by showing that patients with PD with excessive daytime sleepiness had a significant 2.5-fold reduction in the melatonin rhythm amplitude compared with patients with PD without excessive daytime sleepiness. However, in both the Breen et al3 and Videnovic et al4 studies, no alterations in the markers of the circadian phase were reported in patients with PD. This is surprising given that in both studies, patients with PD were receiving dopaminergic therapy. Previous studies that investigated the phase of the melatonin rhythm in medicated and unmedicated patients with PD found a phase-advanced melatonin rhythm in patients receiving dopamine therapy.5 Indeed, Bolitho et al6 confirmed the alteration of the phase angle of entrainment of the melatonin rhythm in 16 treated compared with untreated de novo patients with PD and healthy control participants. Additionally, Bolitho et al6 reported a 3-fold increase in melatonin secretion, contrasting the decrease reported by Breen et al3 and Videnovic et al.4 The reasons behind these discrepancies are not clear. As stated by Videnovic et al,4 the experimental protocols of the earlier studies did not control for environmental conditions. Consequently, the melatonin rhythm phase and amplitude may have been influenced by external factors such as light exposure. However, this may not account for the results of Bolitho et al6 given that melatonin samples were collected under controlled conditions. A more plausible explanation is that these differences reflect an intrinsic neuropathophysiological variability in the PD cohorts investigated. This conclusion is supported by significant differences in multiple features of the sleep/wake cycle between patients studied by Breen et al3 and Bolitho et al.6 Furthermore, the patients in both studies did not show an increase in total sleep duration, which departs from the hypersomnia characterizing sleep in PD.2
jamaneurology.com
JAMA Neurology November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 05/29/2015
1455
Letters
Collectively, these studies show that alterations in the circadian system are a potential causative factor in disturbed sleep in PD. However, a remaining question is whether alterations in peripheral circadian markers reflect a dysfunctional central clock. The reported alterations in hormonal and molecular markers measured to assess the circadian system could also reflect dysfunctional efferent or afferent pathways of the suprachiasmatic nucleus. Detailed assessments of the different components of the neuronal networks governing circadian rhythms regulation using, for example, functional magnetic resonance imaging, are needed to resolve this remaining conundrum. Karim Fifel, PhD Tom DeBoer, PhD Author Affiliations: Laboratory of Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands. Corresponding Author: Karim Fifel, PhD, Laboratory of Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center Mailbox S5-P, PO Box 9600, 2300 RC Leiden, the Netherlands ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: Dr Fifel received a postdoctoral fellowship from Fondation Fyssen. Role of the Funder/Sponsor: Fondation Fyssen had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. 1. Achermann P, Borbély AA. Sleep homeostasis and models of sleep regulation. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 5th ed. St Louis, MO: Saunders; 2011:431-444. 2. Chaudhuri KR, Healy DG, Schapira AH; National Institute for Clinical Excellence. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 2006;5(3):235-245. 3. Breen DP, Vuono R, Nawarathna U, et al. Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol. 2014;71(5):589-595. 4. Videnovic A, Noble C, Reid KJ, et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol. 2014;71(4): 463-469. 5. Bordet R, Devos D, Brique S, et al. Study of circadian melatonin secretion pattern at different stages of Parkinson’s disease. Clin Neuropharmacol. 2003; 26(2):65-72. 6. Bolitho SJ, Naismith SL, Rajaratnam SM, et al. Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease. Sleep Med. 2014;15(3):342-347.
In Reply We read with interest the letter to the editor by Fifel and DeBoer. Their comments focus on 3 published studies that shed light on circadian function in Parkinson disease (PD) and its possible link to frequently disrupted sleep-wake cycles in the PD population. Videnovic et al1 studied 24-hour circadian secretion of melatonin in serum samples of 20 patients with PD taking dopaminergic therapy under modified constant-routine conditions. They found diminished amplitude of melatonin secretion in patients with PD and a strong correlation with excessive daytime sleepiness.1 No alterations in other circadian markers were found. Similarly, Breen et al2 reported significant reductions in melatonin levels in 30 patients with early-stage PD, along with increased cortisol levels and flattening of the circadian Bmal1 rhythm (one of the core clock genes). In contrast to these findings, Bolitho and 1456
colleagues3 found increased melatonin secretion and prolonged phase angle of entrainment in medicated patients with PD (n = 16) but not in unmedicated patients (n = 13) or matched control individuals (n = 28). One reason for the observed differences in melatonin rhythms across these studies may relate to the experimental designs and the patient cohorts studied. Important method aspects of the study by Bolitho et al3 are the use of saliva as the source for melatonin measurements and the restricted sample collection to 8 hours in the evening. These aspects make comparison with the findings of the Videnovic et al1 and Breen et al2 studies challenging because, first, there are no comparative data looking at melatonin concentrations in saliva and serum in PD and, second, there are no data by which to compare full 24-hour melatonin secretion profiles. Furthermore, Bolitho et al3 excluded 21 of 78 study participants owing to an absent salivary melatonin signal. Another reason may relate to the heterogeneity within the PD population including differences in circadian function, sleep timing, and light exposure history. A dysfunction of the autonomic system, frequently present in the PD population, may have impacted melatonin concentrations variably in the study cohorts. Finally, the timing of the dopaminergic medications may be another significant factor influencing melatonin rhythms in studied patients with PD. In fact, the relationship between the timing of dopaminergic medications, circadian function, and sleep is unexplored and may be an area for future research because chronopharmacological approaches to the treatment of PD have been neglected compared with other diseases.4 Collectively, these 3 studies have demonstrated that there is impaired circadian rhythmicity of melatonin secretion across the clinical spectrum of PD. While the significance of these findings and mechanisms linking circadian dysfunction to PD needs to be clarified by further studies, these observations have opened up a novel research direction that is centered on the circadian system and its role in the biology of PD. Aleksandar Videnovic, MD, MSc David P. Breen, MRCP Roger A. Barker, MRCP, PhD Phyllis C. Zee, MD, PhD Author Affiliations: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (Videnovic); University of Cambridge, John van Geest Centre for Brain Repair, Cambridge, England (Breen, Barker); Department of Neurology, Northwestern University, Chicago, Illinois (Zee). Corresponding Author: Aleksandar Videnovic, MD, MSc, Neurological Clinical Research Institute, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 165 Cambridge St, Ste 600, Boston, MA 02114 ([email protected]). Conflict of Interest Disclosures: None reported. Correction: This article was corrected online November 10, 2014, for incorrect information in the second paragraph. 1. Videnovic A, Noble C, Reid KJ, et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol. 2014;71(4): 463-469. 2. Breen DP, Vuono R, Nawarathna U, et al. Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol. 2014;71(5):589-595.
JAMA Neurology November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 05/29/2015
jamaneurology.com
Letters
3. Bolitho SJ, Naismith SL, Rajaratnam SM, et al. Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease. Sleep Med. 2014;15(3):342-347.
6, 2014, in JAMA Neurology (doi:10.1001/jamaneurol.2014.2343), the first author’s name should have been given as John W. Krakauer. This article was corrected online.
4. Dallmann R, Brown SA, Gachon F. Chronopharmacology: new insights and therapeutic implications. Annu Rev Pharmacol Toxicol. 2014;54:339-361.
CORRECTION Error in Byline: In the Viewpoint entitled “The Future of Stroke Treatment: Bringing Evaluation of Behavior Back to Stroke Neurology,” published online October
Error in Byline: In the Original Investigation entitled “Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease: A Genome-Wide Association Study,” published online September 8, 2014, in JAMA Neurology (doi:10.1001 /jamaneurol.2014.1491), the Alzheimer Disease Genetics Consortium coauthors were inadvertently listed as collaborators but should have been identified as coauthors. This article was corrected online and in print.
jamaneurology.com
JAMA Neurology November 2014 Volume 71, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 05/29/2015
1457
