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Using neuromelanin-sensitive ultra-high field (7\u2005T) MRI, we previously identified a reduction in neuromelanin signal in the caudal LC, indicating a rostro-caudal gradient of noradrenergic cell loss. Caudal LC degeneration was associated with greater severity of non-motor symptoms such as orthostatic hypotension and apathy.<\/jats:p>\n                  <jats:p>In the current case\u2013control study, we expanded the PD cohort to further corroborate the structure\u2013symptom relationships within the LC and investigate how degeneration along the rostro-caudal LC axis affects arousal-related functional responsivity. To this end, 71 people with PD in the ON-medication state and 40 age- and sex-matched healthy controls underwent clinical assessments and 7\u2005T magnetization transfer-weighted (MTw) MRI to quantify structural changes along the rostro-caudal LC axis. A subgroup of 30 people with PD and 27 controls underwent 7\u2005T functional MRI to assess LC responsivity to arousing auditory and visual stimuli in two functional MRI sessions on separate days. Healthy controls were scanned twice without medication, while people with PD were studied on and off dopaminergic medication in counterbalanced order.<\/jats:p>\n                  <jats:p>In the PD group, MTw MRI confirmed a significant reduction of the regional neuromelanin signal in the caudal LC relative to the control group (P = 0.010). This structural disintegration correlated with orthostatic hypotension (P = 0.009) and cognitive impairment (P = 0.036), corroborating its clinical relevance. Functional MRI revealed reduced activation of the caudal LC to arousing visual and auditory stimuli in people with PD relative to controls (P = 0.012). This difference reached statistical significance only in the ON-medication state, with a similar but non-significant trend in the OFF-medication state (P = 0.105). In an exploratory analysis of a smaller subsample, structural and functional caudal LC signals were significantly correlated in both people with PD and healthy controls (P = 0.007).<\/jats:p>\n                  <jats:p>Together, the findings provide evidence for a rostro-caudal gradient of LC pathology in PD at both structural and functional levels. While structural MRI provides fine-grained insights into spatial gradients of disease-related pathology, functional MRI captures the impaired functional responsivity of the caudal LC. The presence of arousal-induced hypoactivation of the caudal LC in the ON-medication state indicates that LC dysfunction extends beyond dopamine deficits in PD, highlighting complex interactions between dopaminergic and noradrenergic systems.<\/jats:p>","DOI":"10.1093\/brain\/awag106","type":"journal-article","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T12:38:07Z","timestamp":1774096687000},"source":"Crossref","is-referenced-by-count":2,"title":["Blunted response of caudal locus coeruleus to arousing stimuli in Parkinson\u2019s disease"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2213-6617","authenticated-orcid":false,"given":"Anders E","family":"Lund","sequence":"first","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital Amager and Hvidovre , 2650 Hvidovre ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher F","family":"Madelung","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital Amager and Hvidovre , 2650 Hvidovre ,","place":["Denmark"]},{"name":"Department of Neurology, Copenhagen University Hospital Bispebjerg and Frederiksberg , 2400 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristoffer H","family":"Madsen","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital Amager and Hvidovre , 2650 Hvidovre ,","place":["Denmark"]},{"name":"Department of Applied Mathematics and Computer Science, Technical University of Denmark , 2800 Kgs. Lyngby ,","place":["Denmark"]},{"name":"Department of Radiology, Zealand University Hospital , 4000 Roskilde ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitte L C","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital Amager and Hvidovre , 2650 Hvidovre ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemette","family":"L\u00f8kkegaard","sequence":"additional","affiliation":[{"name":"Department of Neurology, Copenhagen University Hospital Bispebjerg and Frederiksberg , 2400 Copenhagen ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , 2200 Copenhagen 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