Associations between neuromelanin depletion and cortical rhythmic activity in Parkinson’s disease
Authors: Wiesman Alex I , Madge Victoria , Fon Edward A , Dagher Alain , Collins D Louis , Baillet Sylvain ,   PREVENT-AD Research Group and Quebec Parkinson Network, Villeneuve Sylvia , Poirier Judes , Breitner John C S , Badawy Mohamed , Baillet Sylvain , Baril Andrée-Ann , Bellec Pierre , Bohbot Véronique , Bzdok Danilo , Chakravarty Mallar , Collins Louis , Dadar Mahsa , Ducharme Simon , Evans Alan , Gauthier Claudine , Geddes Maiya R , Hoge Rick , Ituria-Medina Yasser , Montembeault Maxime , Multhaup Gerhard , Münter Lisa-Marie , Rajah Natasha , Rosa-Neto Pedro , Schmitz Taylor , Soucy Jean-Paul , Spreng Nathan , Tardif Christine , Vachon-Presseau Etienne , Javanray Mohammadali , Ai Meishan , Amouyel Philippe , Ao Jiarui , Ashton Nicholas , Aumont-Rodrigue Gabriel , Bailly Julie , Baracchini Guilia , Beauchesne Charles , Blennow Kaj , Bocti Christian , Boisvert Lianne , Westman Ann Brinkmalm , Cunningham Nolan-Patrick , Dagher Alain , Dai Xing , Dang-Vu Thien Thanh , Das Samir , Dauar-Tedeschi Marina , De Beaumont Louis , Dery Christine , Descoteaux Maxime , Valdez Alfonso Fajardo , Fonov Vladimir , Morgan David G , Gallago Jonathan , Garrone Aurelie , Hudon Louise , Hull Adam , Jean Gabriel , Labonté Anne , Laforce Robert , Lalancette Marc , Lambert Jean-Charles , Leoutsakos Jeannie-Marie , Bruneau Laurence Maligne , Menes Julien , Misic Bratislav , Mohammediyan Bery , Capota Eugenia Nita , Noly-Gandon Alix , de la Colina Adrian Eduardo Noriega , Orban Pierre , Ourry Valentin , Picard Cynthia , Binette Alexa Pichet , Prenevost Nathalie , Qiu Ting , Quesnel Marc James , Ramassamy Charles , Raoult Jean-Michel , Remz Jordana , Rothman Erica , Sarty Isabel , Sylvain Elisabeth , Tikasz Andras , Tremblay Stefanie , Tremblay-Mercier Jennifer , Tullo Stephanie , Turcotte Jacob , Ulku Irem , Vitali Paolo , Wearn Alfie , Williams Kayla , Yakoub Yara , Zatorre Robert , Zetterberg Henrik , Etienne Pierre , Gauthier Serge , Nair Vasavan , Pruessner Jens , Aisen Paul , Anthal Elena , Appleby Melissa , Arbour Nathalie , Auld Daniel , Ayranci Gülebru , Barkun Alan , Beaudry Thomas , Bedetti Christophe , Beland Marie-Lise , Benbouhoud Fatiha , Boutin Sophie , Brandt Jason , Carmo Leopoldina , Carrier Charles Edouard , Chapleau Marianne , Cheewakriengkrai Laksanun , Chen Yalin , Chokr Tima , Courcot Blandine , Couture Doris , Craft Suzanne , Cuello Claudio , Dansereau Christian , Daoust Leslie-Ann , Dea Doris , Debacker Clément , Desautels René , Dubuc Sylvie , Duclair Guerda , Dufour Marianne , Dunlop Alana , Eisenberg Mark , El-Khoury Rana , Élie MarieJosée , Farzin Sarah , Faubert Anne-Marie , Ferdinand Fabiola , Fontaine David , Frappier Josée , Frenette Joanne , Gagné Guylaine , Gervais Valérie , Giles Renuka , Gonneaud Julie , Gordon Renee , Greco Claudia , Intzandt Brittany , Jack Clifford R , Jutras Benoit , Kat Justin , Kazazian Christina , Khachaturian Zaven S , Knopman David S , Köbe Theresa , Kostopoulos Penelope , Lafaille-Magnan Marie-Elyse , Lapalme Felix , Lazarenco Corina , LeblondBaccichet Gloria , Lee Tanya , Lefebvre Marilou , Lemay David , Lepage Claude , Leppert Illana , Li Cai , Madjar Cécile , Mahar Laura , Maillet David , Maltais Jean-Robert , Mathieu Axel , Mathotaarachchi Sulantha , Mayrand Ginette , McSweeney Melissa , Meyer Pierre-François , Michaud Diane , Miron Justin , Montine Thomas J , Morris John C , Near Jamie , NewboldFox Holly , Nilsson Nathalie , Ozlen Hazal , Pagé Véronique , Pascoal Tharick A , Peillieux Sandra , Petkova Mirela , Pishnamazi Morteza , Pogossova Galina , Poirier Alexandre , Poline Jean-Baptiste , Rabipour Sheida , Richer Marie-Josée , Rioux Pierre , Sager Mark A , Saint-Fort Eunice Farah , Salaciak Alyssa , Savard Mélissa , Settimi Matthew , Sperling Reisa A , St-Onge Frederic , Strikwerda-Brown Cherie , Subramaniapillai Sivaniya , Tabrizi Shirin , Tam Angela , Tariot Pierre N , Teigner Eduard , Théroux Louise , Thomas Ronald G , Toussaint Paule-Joanne , Tremblay Christina , Tuwaig Miranda , Vallée Isabelle , Venugopalan Vinod , Verfaillie Sander C J , Vogel Jacob , Wan Karen , Wang Seqian , Yu Elsa , Beaulieu-Boire Isabelle , Blanchet Pierre , Bogard Sarah , Bouchard Manon , Chouinard Sylvain , Cicchetti Francesca , Cloutier Martin , Dagher Alain , Das Samir , Degroot Clotilde , Desautels Alex , Dion Marie Hélène , Drouin-Ouellet Janelle , Dufresne Anne-Marie , Dupré Nicolas , Duquette Antoine , Durcan Thomas , Fellows Lesley K , Fon Edward , Gagnon Jean-François , Gan-Or Ziv , Genge Angela , Jodoin Nicolas , Karamchandani Jason , Lafontaine Anne-Louise , Langlois Mélanie , Leveille Etienne , Lévesque Martin , Melmed Calvin , Monchi Oury , Montplaisir Jacques , Panisset Michel , Parent Martin , Pham-An Minh-Thy , Poline Jean-Baptiste , Postuma Ronald , Pourcher Emmanuelle , Rao Trisha , Rivest Jean , Rouleau Guy , Sharp Madeleine , Soland Valérie , Sidel Michael , Sun Sonia Lai Wing , Thiel Alexander , Vitali Paolo 
Published: September 2024

Abstract
Parkinson’s disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in the substantia nigra (SN) and the locus coeruleus (LC), respectively, resulting in motor and cognitive impairments. Although SN dopamine dysfunction has clear neurophysiological effects, the association of reduced LC norepinephrine signalling with brain activity in PD remains to be established.
We used neuromelanin-sensitive T1-weighted MRI (PD, n = 58; healthy control, n = 27) and task-free magnetoencephalography (PD, n = 58; healthy control, n = 65) to identify neuropathophysiological factors related to the degeneration of the LC and SN in patients with PD. We found pathological increases in rhythmic alpha-band (8–12 Hz) activity in patients with decreased LC neuromelanin, which were more strongly associated in patients with worse attentional impairments. This negative alpha-band–LC neuromelanin relationship is strongest in fronto-motor cortices, where alpha-band activity is inversely related to attention scores. Using neurochemical co-localization analyses with normative atlases of neurotransmitter transporters, we also show that this effect is more pronounced in regions with high densities of norepinephrine transporters. These observations support a noradrenergic association between LC integrity and alpha-band activity. Our data also show that rhythmic beta-band (15–29 Hz) activity in the left somatomotor cortex decreases with lower levels of SN neuromelanin; the same regions where beta activity reflects axial motor symptoms.
Together, our findings clarify the association of well-documented alterations of rhythmic neurophysiology in PD with cortical and subcortical neurochemical systems. Specifically, attention-related alpha-band activity is related to dysfunction of the noradrenergic system, and beta activity with relevance to motor impairments reflects dopaminergic dysfunction.