BACKGROUND: Recent studies have suggested that melatonin-a hormone produced by the pineal gland under circadian control-contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group. METHODS: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24-hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme-linked immunosorbent assays. RESULTS: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients. CONCLUSION: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.The authors would like to acknowledge the study funders: the Big Lottery Fund (C498A738) and Parkinson’s UK (J-0802). The research was supported by a National Institute of Health Research Biomedical Research Award (to Addenbrooke’s Hospital/University of Cambridge), the Wellcome Trust (103838, 100333/Z/12/Z) and a Raymond and Beverly Sackler Studentship (to DPB). We would like to thank staff at the Wellcome Trust Clinical Research Facility in Addenbrooke’s Hospital, Cambridge for performing the melatonin blood sampling.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/mds.2659

Barker, Roger A

Breen, David P

Brooks, David J

Burn, David J

Fisher, Kate

Jones, P Simon

Nombela, Cristina

Reddy, Akhilesh B

Rowe, James B

Vuono, Romina

Movement Disorders

PubMed

© 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder SocietyBackground: Recent studies have suggested that melatonin—a hormone produced by the pineal gland under circadian control—contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group. Methods: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24-hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme-linked immunosorbent assays. Results: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients. Conclusion: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Breen, DP

Nombela, C

Vuono, R

Jones, PS

Fisher, K

Burn, DJ

Brooks, DJ

Reddy, AB

Rowe, JB

Barker, RA

Spiral - Imperial College Digital Repository

Hypothalamic Volume Loss IsAssociated With ReducedMelatonin Output inParkinson’s DiseaseDavid P. Breen, MRCP, PhD,1* Cristina Nombela, PhD,1Romina Vuono, PhD,1 P. Simon Jones, MSc,2Kate Fisher, PhD,1 David J. Burn, FRCP, MD,3David J. Brooks, MD, DSc,4,5Akhilesh B. Reddy, PhD, MRCP,6James B. Rowe, MRCP, PhD,2,7,8 andRoger A. Barker, MRCP, PhD11John van Geest Centre for Brain Repair, University of Cambridge,Cambridge, UK 2Department of Clinical Neurosciences, University ofCambridge, Cambridge, UK 3Institute of Neuroscience, NewcastleUniversity, Newcastle, UK 4Division of Neurology, Imperial College,London, UK 5Institute of Clinical Medicine, Aarhus University,Aarhus, Denmark 6Institute of Metabolic Science, University ofCambridge, Cambridge, UK 7Behavioural and Clinical NeuroscienceInstitute, University of Cambridge, Cambridge, UK 8Medical ResearchCouncil Cognition and Brain Sciences Unit, Cambridge, UKABSTRACTBackground: Recent studies have suggested that mel-atonin—a hormone produced by the pineal glandunder circadian control—contributes to PD-relatedsleep dysfunction. We hypothesized that degenerativechanges to the neural structures controlling pinealfunction (especially the suprachiasmatic nuclei of theanterior hypothalamus) may be responsible for reducedmelatonin output in these patients. We comparedhypothalamic volumes in PD patients with matchedcontrols and determined whether volume loss corre-lated with reduced melatonin output in the PD group.Methods: A total of 12 PD patients and 12 matchedcontrols underwent magnetic resonance imaging todetermine hypothalamic volume. In addition, PDpatients underwent 24-hour blood sampling in a con-trolled environment to determine serum melatonin con-centrations using enzyme-linked immunosorbentassays.Results: PD patients had significantly reduced hypo-thalamic gray matter volume when compared withmatched controls. Melatonin levels were significantlyassociated with hypothalamic gray matter volume anddisease severity in PD patients.Conclusion: Melatonin levels are associated with hypo-thalamic gray matter volume loss and disease severityin PD patients. This provides anatomical and physiolog-ical support for an intrinsic sleep and circadian pheno-type in PD. VC 2016 The Authors. Movement Disorderspublished by Wiley Periodicals, Inc. on behalf of Inter-national Parkinson and Movement Disorder SocietyKey Words: melatonin; hypothalamus; suprachias-matic nucleus; Parkinson’s; circadianSleep disturbances are one of the most commonnonmotor complaints in Parkinson’s disease (PD) andhave been attributed to a variety of factors. Under-standing the relative contribution of each is crucial toidentify the most effective treatment strategies for indi-vidual patients. Some of these relate to the clinicallyidentified features of the disease such as motor impair-ment, nocturia, pain, or neuropsychiatric symptoms.Dopaminergic and other medications may also exacer-bate patients’ sleep problems. However, the sleep dys-function in PD may be a result of neuronal loss in keystructures and circuits involved in the regulation ofthe sleep-wake cycle.Two recent studies have reported that reduced mela-tonin output in PD patients is associated with alteredsleep architecture, including reduced slow wave andrapid eye movement sleep1 and excessive daytimesleepiness.2 Altered melatonin patterns have also beenobserved in Huntington’s disease3 and Alzheimer’s dis-ease,4 both of which have prominent sleep and circa-dian abnormalities. Because melatonin is a hormoneproduced by the pineal gland under circadian control,------------------------------------------------------------This is an open access article under the terms of the CreativeCommons Attribution License, which permits use, distribution andreproduction in any medium, provided the original work is properlycited.*Correspondence to: Dr. David P. Breen, John van Geest Centre forBrain Repair, University of Cambridge, ED Adrian Building, Forvie Site,Robinson Way, Cambridge, CB2 0PY, UK; dpbreen1@gmail.comPresent address for Cristina Nombela: School of Medicine, UniversidadPolitecnica de Cartagena, Murcia, Spain.Present address for Kate Fisher: School of Chemistry, University ofEdinburgh, Edinburgh UK.David P. Breen and Cristina Nombela contributed equally to themanuscript.Funding agencies: The authors acknowledge the study funders: the BigLottery Fund (C498A738) and Parkinson’s UK (J-0802). The researchwas supported by a National Institute of Health Research BiomedicalResearch Award (to Addenbrooke’s Hospital/University of Cambridge),the Wellcome Trust (103838, 100333/Z/12/Z), and a Raymond and Bev-erly Sackler Studentship (to D.P.B.).Relevant conflicts of interests/financial disclosures: The authorsreport no conflicts of interest.Received: 23 August 2015; Revised: 1 February 2016; Accepted: 3February 2016Published online 00 Month 2016 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.26592B R I E F R E P O R TMovement Disorders, Vol. 00, No. 00, 2016 1we hypothesised that degenerative changes to the neu-ral structures controlling pineal function (especiallythe suprachiasmatic nuclei [SCN] of the hypothala-mus) may reduce melatonin output and contribute tocertain aspects of sleep dysfunction in PD.This study compared hypothalamic volumes in PDpatients with matched controls and determinedwhether volume loss correlated with reduced melato-nin output in the PD group.MethodsPatientsA total of 12 PD patients were selected from a pre-viously studied sleep cohort.1 All of the patients whohad also undergone magnetic resonance imaging(MRI) as part of the parallel Incidence of CognitiveImpairment in Cohorts with Longitudinal Evaluation–Parkinson’s Disease (ICICLE-PD) study were includedin the analysis, in addition to 12 unrelated matchedcontrols from the Medical Research CouncilCognition and Brain Sciences Unit healthy volunteerpanel. The ICICLE-PD protocol has been publishedelsewhere.5 All participants provided written consent,the study was performed according to the Declarationof Helsinki, and the protocol was approved by thelocal research ethics committee.In brief, patients underwent a battery of clinicaltests including the Unified Parkinson’s Disease RatingScale (MDS-UPDRS), Addenbrooke’s Cognitive Exam-ination (ACE-R), and the Beck Depression Inventory(BDI). Levodopa equivalent dose (LED) was calculatedusing the conversion factors proposed by Tomlinsonand colleagues.6 Matching was based on age, gender,years of education, and ACE-R.Imaging Acquisition and AnalysisMRI data were acquired using a Siemens TIM Trio3T scanner (Siemens Medical Systems, Erlangen, Ger-many). Patients underwent T1-weighted magnetisationprepared rapid gradient echo scanning: pulse repeti-tion 5 2250 ms, echo time 5 2.98 ms, flip angle 5 9 8,time delay 5 900 ms, 256 3 256 mm2 field of view,192 3 1 mm slices). Images were preprocessed accord-ing to a pipeline in SPM8 (http://www.fil.ion.ucl.ac.uk/spm) run on Matlab 7 (Mathworks, Natick, Mas-sachusetts). T1-weighted images were segmented intogray matter and white matter tissue and registeredthrough the Diffeomorphic Anatomical RegistrationThrough Exponentiated Lie Algebra scheme. Theresulting study-specific template was registered toMontreal Neurological Institute space, and individualmodulated images were smoothed with an 8 mm, fullwidth at half-maximum Gaussian kernel. A hypothala-mic region of interest (dilated by 3 mm) from theWFU Pick Atlas (http://fmri.wfubmc.edu/software/pickatlas) was used to obtain an individual hypothala-mic volume per participant (Fig. 1A,B). Gray mattervolume in the region of interest (measured in voxels)was calculated using the FMRIB Software Library(FSL) tool “fslstats” within FSL version 4.1.7 (www.fmrib.ox.ac.uk). Thereafter, relative hypothalamicgray matter volume was calculated by dividing bywhole brain volume (the sum of the gray and whitematter segments).Serum Melatonin MeasurementPD patients were admitted to a single room at theWellcome Trust Clinical Research Facility at Adden-brooke’s Hospital in Cambridge. A peripheral venouscannula was inserted 30 minutes before the start ofsampling at 1:00 PM. During the next 24 hours, partic-ipants adhered to their habitual bed times, and bloodsamples were collected every 90 minutes using a 3-way valve that was attached to a 0.9% sodium chlo-ride infusion to prevent the cannula from clotting.Sampling was performed through a long line to pre-vent disruption to the patient’s sleep. Participantsremained sedentary apart from bathroom visits. Mealtimes were consistent between participants, and nodaytime naps were allowed. Temperature was constantat 21 8C. Patients were not strictly shielded from exter-nal light, but lighting levels were less than 5 lux fol-lowing lights off. Serum melatonin concentrationswere measured using enzyme-linked immunosorbentassays as previously described.1 Based on hormoneconcentrations at each 90-minute time point, total 24-hour melatonin output was defined as the area underthe curve (calculated using the trapezoid rule).Statistical AnalysisAll data were approximately normally distributedbased on Shapiro-Wilk testing; therefore, unpaired ttests were used to compare clinical parameters andvolumetric values between patients and controls. Pear-son rank correlation testing was used to study therelationship between melatonin output and relativehypothalamic gray matter volume, as well as the rela-tionship between melatonin output and disease sever-ity (adjusted for LED).ResultsAge, gender, duration of education, and ACE-Rwere not significantly different between PD patientsand controls (Table 1). PD patients had a mean dis-ease duration of 3.3 years, mean LED of 366 mg, andmean UPDRS part III score of 23.9. None of the par-ticipants were taking hypnotics. The mean durationbetween melatonin testing and MRI in the PD groupwas 1.9 months (SD 3.4).B R E E N E T A L2 Movement Disorders, Vol. 00, No. 00, 2016When compared with controls, PD patients had sig-nificantly reduced relative hypothalamic gray mattervolume (2.56 3 1027 [SD 2.78 3 1027] vs 2.69 3 1027[SD 2.07 3 1027]; P 5 .005) (Fig. 1C).Having verified that there were significant differen-ces between patients and controls in terms of hypo-thalamic volume, we found that melatonin levels weresignificantly associated with relative hypothalamicgray matter volume in the PD group (r 5 .591,P 5 .028) (Fig. 1D).Partial correlation between melatonin levels and dis-ease severity, correcting for LED, showed a significantinverse relationship (r 5 2.681, P 5 .021). There wasno significant relationship between melatonin outputand LED (r 5 .180, P 5 .76).DiscussionThere is increasing evidence from clinical and ani-mal studies that there is circadian dysregulation in avariety of neurodegenerative diseases.7 We previouslyreported significant reductions in melatonin concentra-tion in 30 early-stage PD patients.1 Videnovic and col-leagues also found a significantly diminishedamplitude of melatonin secretion in serum samples of20 PD patients on dopaminergic therapy under modi-fied constant routine conditions.2There is evidence from neuropathological8 andimaging9 studies that the hypothalamus is directlyaffected by PD. The central clock within the hypothal-amus, the SCN, is likely to contribute to this volumeloss because it has been shown that mice overexpress-ing alpha-synuclein exhibit a reduced SCN firingrate.10 This could weaken their ability to communicateneural and hormonal signals from the central clock tothe pineal gland, which secretes melatonin into theblood.TABLE 1. Clinical characteristics of PDpatients and controlsVariable PD Controls P valuedNumber of participants 12 12 naGender ratio (male:female) 6:6 6:6 1.0Age (years) 66.7 (5.5) 66.3 (5.2) 0.92Duration of education (years) 18.3 (2.9) 17.2 (2.8) 0.33ACE-R 95.2 (3.1) 96.1 (3.0) 0.48Disease duration (years)a 3.3 (1.1) na naLEDD (mg)b 366 (161) na naMDS-UPDRS part IIIc 23.9 (9.0) na naBDI 7.3 (17.8) 3.3 (3.6) 0.011**Significant difference at .05 level.LEDD, levodopa equivalent daily dose; ACE-R, Addenbrooke’s CognitiveExamination-Revised; MDS-UPDRS, Unified Parkinson’s Disease RatingScale; BDI, Beck Depression Inventory; na, not applicable.Results expressed as mean (SD) unless stated otherwise*Significant difference at .05 level.aDisease duration from date of diagnosis.bAll but two PD patients were taking dopaminergic medication.cBased on MDS-UPDRS assessments performed within the last 6 months.dUnpaired t tests performed.FIG. 1. A and B: Panels show the region of interest used to calculate the hypothalamic volume for each participant. C: Panel is a graphical representa-tion of the significant reduction in relative hypothalamic gray matter volume in PD patients when compared with matched controls (with standard errorof the mean error bars). D: Panel demonstrates the significant correlation between relative hypothalamic gray matter volume and total 24-hour melato-nin output (with both axes showing partial residuals). In both graphs, relative hypothalamic gray matter volume was calculated by dividing gray mattervolume by whole brain volume (both measured in voxels). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]H Y P O T H A L A M I C V O L U M E A N D M E L A T O N I N O U T P U T I N P DMovement Disorders, Vol. 00, No. 00, 2016 3This study thus adds to the existing literature bysuggesting that hypothalamic volume loss—which wehave now shown in this new PD cohort—may beresponsible for reduced melatonin output, which hasbeen linked to sleep disturbances in PD.The major limitation of this study is the relativelysmall number of patients, which precluded the use oflinear regression and adjustment of confounders. Fur-thermore, patients were not strictly shielded from exter-nal light during the melatonin sampling period, whichmay have influenced the results. Although we lackedserum melatonin measurements in the control group,the critical test for our hypothesis was the correlationbetween hypothalamic volume and melatonin levels inPD patients. It is not yet possible to perform dedicatedimaging of the SCN within the hypothalamus using3Tesla MRI; therefore, ultra-high field imaging orclinico-pathological studies will be required to allowmore thorough dissection of the relative role of the dif-ferent hypothalamic nuclei to this deficit.In summary, we have shown that melatonin levels areassociated with hypothalamic gray matter volume lossand disease severity in PD patients. This provides anatom-ical and physiological support for an intrinsic sleep andcircadian phenotype in PD and the fact that this is relatedto the disease itself rather than being an indirect conse-quence of other symptoms or treatments.Acknowledgments: We would like to thank Dr. Saber Sami forhis assistance with imaging acquisition and Dr. Noham Wolpe for histechnical support. We would also like to thank the staff at the WellcomeTrust Clinical Research Facility in Addenbrooke’s Hospital, Cambridge,for performing the melatonin blood sampling.References1. Breen DP, Vuono R, Nawarathna U, et al. Sleep and circadianrhythm regulation in early Parkinson disease. JAMA Neurol 2014;71:589-595.2. Videnovic A, Noble C, Reid KJ, et al. Circadian melatonin rhythmand excessive daytime sleepiness in Parkinson disease. JAMA Neu-rol 2014;71:463-466.3. Kakkiolia E, Silajdzic E, Nambron R, et al. Plasma melatonin isreduced in Huntington’s disease. Mov Disord 2014;29:1511-1515.4. Mishima K, Tozawa T, Satoh K, et al. Melatonin secretion rhythmdisorders in patients with senile dementia of Alzheimer’s type withdisturbed sleep-waking. Biol Psychiatry 1999;45:417-421.5. Nombela C, Rowe JB, Winder-Rhodes SE, et al. Genetic impact oncognition and brain function in newly diagnosed Parkinson’s dis-ease: ICICLE-PD study. Brain 2014;137:2743-2758.6. Tomlinson CL, Stowe R, Patel S, et al. Systematic review of levo-dopa dose equivalency reporting in Parkinson’s disease. Mov Dis-ord 2010;25:2649-2653.7. Videnovic A, Lazar AS, Barker RA, et al. ‘The clocks that timeus’—circadian rhythms in neurodegenerative disorders. Nat RevNeurol 2014;10:683-693.8. Langston JW, Forno LS. The hypothalamus in Parkinson disease.Ann Neurol 1978;3:129-133.9. Politis M, Piccini P, Pavese N, et al. Evidence of dopamine dysfunc-tion in the hypothalamus of patients with Parkinson’s disease: an invivo 11C-raclopride PET study. Exp Neurol 2008;214:112-116.10. Kudo T, Loh DH, Truong D, et al. Circadian dysfunction in amouse model of Parkinson’s disease. Exp Neurol 2011;232:66-75.B R E E N E T A L4 Movement Disorders, Vol. 00, No. 00, 2016

Hypothalamic volume loss is associated with reduced melatonin output in Parkinson's disease

Apollo (Cambridge)

Hypothalamic volume loss is associated with reduced melatonin output in Parkinson's disease.

Background: Recent studies have suggested that melatonin—a hormone produced by the pineal gland under circadian control—contributes to PD‐related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group.

Methods: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24‐hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme‐linked immunosorbent assays. Results: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients. Conclusion: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD

Hypothalamic volume loss is associated with reduced melatonin output in Parkinson's disease.

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