Noradrenergic deficits contribute to apathy in Parkinson's disease through the precision of expected outcomes

Apathy is a debilitating feature of many diseases, including Parkinson's disease. We tested the hypothesis that degeneration of the locus coeruleus-noradrenaline system contributes to apathy by modulating the relative weighting of prior beliefs about action outcomes. Participants with mild-to-moderate idiopathic Parkinson's disease (N=17) completed a double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinson's disease, subject to stratification according to locus coeruleus integrity.

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Calcium Channels as a Potential Target for Neuroprotection in Parkinson’s Disease

US Neurology ◽

10.17925/usn.2011.07.02.109 ◽

2011 ◽

Vol 07 (02) ◽

pp. 109 ◽

Cited By ~ 1

Author(s):

Tanya Simuni ◽

D James Surmeier ◽

◽

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuroprotective Effect ◽

Selective Vulnerability ◽

Phase Iii ◽

Substantia Nigra Pars Compacta ◽

Double Blind ◽

Finding Study

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1 % of the population above the age 65. The principal motor symptoms of PD are attributable to the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Recent studies demonstrate that dopaminergic (DA) neurons in the SNc, as well as many neurons in other regions affected by PD, have a distinctive physiologic phenotype. They are autonomous L-type Cav1.3 Ca2+channels pacemakers. Continuous Ca2+influx results in increased oxidative stress that may explain the selective vulnerability of these neurons. More importantly for PD, blocking these channels with isradipine, the most potent of the dihydropyridine (DHP) channel antagonists at L-type Ca2+channels with the Cav1.3 subunit, protects these neurons inin vitroandin vivomodels of parkinsonism. Neuroprotective effect is achieved at the serum concentrations that can be achieved with the doses approved for human use. Recent epidemiologic data also points to a reduced risk of PD with chronic use of specifically centrally acting DHP Ca2+channel antagonists. Isradipine is an approved agent for the treatment of hypertension. Our pilot data demonstrate acceptable dose-dependent tolerability of isradipine in early PD. A pilot Phase II multicenter, double-blind, placebo-controlled, safety, tolerability, and dosage finding study of isradipine in early PD has completed recruitment, with the results of the study to be available in the near future. Results of that study will inform the design of the planned Phase III pivotal efficacy trial of isradipine, as a disease modifying agent in early PD.

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Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson's disease

10.1101/2020.09.03.20176800 ◽

2020 ◽

Author(s):

Claire O'Callaghan ◽

Frank Hubert Hezemans ◽

Rong Ye ◽

Catarina Rua ◽

P Simon Jones ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Locus Coeruleus ◽

Response Inhibition ◽

Therapeutic Potential ◽

Reaction Times ◽

Stop Signal ◽

Stop Signal Task ◽

Double Blind ◽

Caudal Portion

Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson's disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomised crossover design, 19 people with Parkinson's disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7T imaging of the locus coeruleus using a neuromelanin-sensitive magnetisation transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in Parkinson's disease patients. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalised treatment approaches.

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Locus Coeruleus Degeneration Correlated with Levodopa Resistance in Parkinson’s Disease: A Retrospective Analysis

Journal of Parkinson s Disease ◽

10.3233/jpd-212720 ◽

2021 ◽

pp. 1-10

Author(s):

Cheng Zhou ◽

Tao Guo ◽

JingJing Wu ◽

Linbo Wang ◽

Xueqin Bai ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Locus Coeruleus ◽

Rating Scale ◽

Linear Regression Analysis ◽

Animal Experiments ◽

Network Synchronization ◽

Clinical Issue ◽

The Relationship

Background: The widely divergent responsiveness of Parkinson’s disease (PD) patients to levodopa is an important clinical issue because of its relationship with quality of life and disease prognosis. Preliminary animal experiments have suggested that degeneration of the locus coeruleus (LC) attenuates the efficacy of levodopa treatment. Objective: To explore the relationship between LC degeneration and levodopa responsiveness in PD patients in vivo. Methods: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a good indicator of LC and substantia nigra (SN) degeneration, and levodopa challenge tests were conducted in 57 PD patients. Responsiveness to levodopa was evaluated by the rates of change of the Unified Parkinson’s Disease Rating Scale Part III score and somatomotor network synchronization calculated from resting-state functional MRI before and after levodopa administration. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNRLC) and levodopa responsiveness. Multiple linear regression analysis was conducted to rule out the potential influence of SN degeneration on levodopa responsiveness. Results: A significant positive correlation was found between CNRLC and the motor improvement after levodopa administration (R = 0.421, p = 0.004). CNRLC also correlated with improvement in somatomotor network synchronization (R = –0.323, p = 0.029). Furthermore, the relationship between CNRLC and levodopa responsiveness was independent of SN degeneration. Conclusion: LC degeneration might be an essential factor for levodopa resistance. LC evaluation using NM-MRI might be an alternative tool for predicting levodopa responsiveness and for helping to stratify patients into clinical trials aimed at improving the efficacy of levodopa.

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In vivo quantification of the locus coeruleus and substantia nigra in parkinson's disease

Parkinsonism & Related Disorders ◽

10.1016/j.parkreldis.2020.06.069 ◽

2020 ◽

Vol 79 ◽

pp. e11-e12

Author(s):

J. Pape ◽

I. Galazky ◽

E. Düzel ◽

M.J. Betts

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Locus Coeruleus

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In vivo locus coeruleus imaging in Alzheimer’s and Parkinson’s disease

Alzheimer s & Dementia ◽

10.1002/alz.044587 ◽

2020 ◽

Vol 16 (S5) ◽

Author(s):

Matthew J. Betts ◽

Johanna Pape ◽

Annika Spottke ◽

Stefan J. Teipel ◽

Ingo Kilimann ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Locus Coeruleus

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Locus Coeruleus Integrity from 7T MRI Relates to Apathy and Cognition in Parkinson’s Disease and Progressive Supranuclear Palsy

10.1101/2021.04.19.21255762 ◽

2021 ◽

Author(s):

Rong Ye ◽

Claire O’Callaghan ◽

Catarina Rua ◽

Frank H. Hezemans ◽

Negin Holland ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Spatial Pattern ◽

Locus Coeruleus ◽

Progressive Supranuclear Palsy ◽

Neuropsychiatric Symptoms ◽

Test Group ◽

Cross Sectional ◽

Richardson’S Syndrome

AbstractBackground and ObjectivesThe loss of noradrenergic neurons in the locus coeruleus (LC) contributes to various cognitive and neuropsychiatric symptoms in Parkinson’s disease (PD) and progressive supranuclear palsy (PSP). The spatial precision of in vivo LC imaging is improved using a magnetisation transfer sequence combined with ultra-high field 7T MRI. This study aimed to test the sensitivity of LC imaging in PD and PSP, to characterise the spatial pattern of LC atrophy in patients, and its relationship to cognition and apathy.MethodsThis cross-sectional observational study recruited patients with idiopathic PD, probable PSP-Richardson’s syndrome and age-matched healthy controls (HC) via specialist clinics and volunteer registries. All participants underwent clinical assessments for cognition and apathy, and high-resolution (0.08 mm3) LC scans. To quantify LC integrity, the contrast-to-noise ratio (CNR) relative to a pons reference region was calculated and extracted using a probabilistic atlas. Subregional mean CNRs were summarised to test group differences and to correlate LC integrity with apathy and cognition scores. LC clusters were identified to confirm the spatial pattern of the effect (threshold free cluster enhancement, 10000 permutations, p<0.05, corrected for family-wise error).ResultsTwenty-five patients with PD, 14 with PSP and 24 controls with completed dataset were included in the study. Patients with PSP were more impaired on global cognition and apathy scores, compared to controls and PD. Clusters with reduced contrast were observed in the caudal LC for both PD and PSP patients relative to controls (HC>PD, right caudal LC, 37 voxels; HC>PSP, bilateral caudal LC, 206 voxels). PSP and PD patients showed similar levels of LC degeneration, but this was more extensive in PSP. Across both disease groups, LC integrity was associated with cognitive performance (MoCA: F(1,37)=5.339, p=0.027, bilateral LC, 200 voxels; ACE-R: F(1,37)=4.297, p=0.045, left LC, 70 voxels) and apathy (Apathy Scale: F(1,37)=4.335, p=0.044, left LC, 99 voxels).DiscussionWe confirm the sensitivity of 7T LC imaging to detect sub-regional LC changes in PD and PSP. The relationship between LC integrity and non-motor symptoms highlights the potential for noradrenergic therapeutic strategies to ameliorate cognitive and behavioural features of PD and PSP.

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