Unravelling the Alteration of Brain Structure and Function in Parkinson´s Disease With Ultra-high Field MRI

NCT03866044 | Unknown DMC

• 1 other identifier: H-18021857
• Study Type: observational
• Target: 90
• Locations: 1 country
• Sites: 2

Brief Summary

Parkinson's Disease (PD) is a neurodegenerative disease characterized by a range of disabling motor- and non-motor symptoms caused by a loss of neurons in neuromodulatory brainstem nuclei. Typical motor symptoms include bradykinesia, rigidity and tremor. Non-motor symptoms are diverse and include REM sleep behaviour disorder, hyposmia, autonomic dysfunction, depression, apathy and cognitive impairment. The motor symptoms can in some degree be attributed to degeneration of the substantia nigra (SN) and a deficiency of dopamine (DA) availability, and DA replacement therapy can partially alleviate motor symptoms. The role of nigral degeneration on non-motor symptoms is however less clear. In addition to nigral degeneration, the noradrenergic (NA) locus coeruleus (LC) also undergoes severe degeneration in PD. Again, it is unclear how LC degeneration contributes to motor and non-motor symptoms. Ultra-high resolution structural magnetic resonance imaging (MRI) provides the opportunity to assess alterations of the affected nuclei in detail and functional MRI (fMRI) can map activation in the neuronal populations as a measure of DA and NA function.

Conditions

Parkinson Disease

Outcome Measures

Primary Outcomes (23)

• SN contrast ratio on neuromelanin sensitive images

  Mean SI(SN)/mean SI(cerebral peduncles), SI=signal intensity. We expect that PD patients will have decreased SN contrast ratio compared with age-matched healthy participants and that SN contrast ratio will correlate with UPDRS-3 subscore.

  Baseline

• SN volume on neuromelanin sensitive images

  Voxels in SN with mean SI \> SI+2 standard deviations(cerebral peduncles) , SI=signal intensity). We expect that PD patients will have decreased SN volume compared with age-matched healthy participants and that SN volume will correlate with UPDRS-3 subscore.

  Baseline

• LC contrast ratio on neuromelanin sensitive images

  Mean SI(LC)/mean SI(pontine tegmentum), SI=signal intensity. We expect that PD patients will have decreased LC contrast ratio compared with age-matched healthy participants and that LC contrast ratio will correlate with NMSS, LARS and BDI-II scores.

  Baseline

• LC volume on neuromelanin sensitive images

  Voxels in LC with mean SI \> SI+4 standard deviations(pontine tegmentum), SI=signal intensity). We expect that PD patients will have decreased LC volume compared with age-matched healthy participants and that LC volume will correlate with NMSS, LARS and BDI-II scores.

  Baseline

• Total SN iron accumulation: SWI

  SN mean signal intensity on SWI. We expect that PD patients will have lower mean SN SWI signal intensity compared to healthy.

  Baseline

• Total SN iron accumulation: R2*

  SN mean R2\* values (unit=1/s). We expect that PD patients will have higher mean SN R2\* values compared to healthy.

  Baseline

• Total SN iron accumulation: QSM

  SN mean QSM values (unit=ppb). We expect that PD patients will have higher mean SN QSM values compared to healthy.

  Baseline

• Nigrosome-1 iron accumulation: SWI

  Nigrosome-1 signal visibility on SWI assessed by blinded raters. We expect that iron accumulation in nigrosome-1 will be greater in PD patients leading to a loss of discrimination on SWI.

  Baseline

• Nigrosome-1 iron accumulation: R2*

  Mean R2\* values in the nigrosome-1 region (unit=1/s). We expect that PD patients will have higher R2\* values in the nigrosome-1 region.

  Baseline

• Nigrosome-1 iron accumulation: QSM

  Mean QSM values in the nigrosome-1 region (unit=ppb). We expect that PD patients will have higher QSM values in the nigrosome-1 region.

  Baseline

• Functional brain activation pattern in the LC, SN, VTA, and striatum

  Revealed by task related blood oxygenation level dependent (BOLD) signal changes. We expect that functional activation in these regions will be attenuated in PD patients corresponding to their loss of brainstem nuclei integrity (see hypotheses).

  ON & OFF PD medication in a period within 24 weeks from baseline.

• Motor disease severity

  Unified Parkinson's Disease Rating Scale (UPDRS)-3 subscore (Motor severity, range 0-108, higher values = worse outcome). Measured while subjects are taking their usual medication.

  Baseline

• Overall disease severity

  Total Unified Parkinson's Disease Rating Scale (UPDRS) score (sum of all 4 subscores listed below, range 0-199, higher values = worse outcome), UPDRS-1 (Cognitive and mental disease severity, range 0-16, higher values = worse outcome), UPDRS-2 (disease severity in relation to activities of daily living, range 0-52, higher values = worse outcome) and UPDRS-3 (Motor severity, range 0-108, higher values = worse outcome), UPDRS-4 (Complications of therapy, range 0-23, higher values = worse outcome) subscores. Measured while subjects are taking their usual medication.

  Baseline

• Non-motor disease severity

  Total Non-Motor Symptom Scale (NMSS) score (range 0-360, higher values = worse outcome). Measured while subjects are taking their usual medication.

  Baseline

• Modified Hoehn and Yahr Staging

  Modified Hoehn and Yahr Staging (Crude measure of disease severity, range 0-5, higher score = worse outcome). Measured while subjects are taking their usual medication.

  Baseline

• Schwab and England Activities of Daily Living Scale

  Schwab and England Activities of Daily Living Scale (Measure of ADL function, range 100-0%, higher score = better outcome). Measured while subjects are taking their usual medication.

  Baseline

• Apathy

  Total Lille Apathy Rating Scale (LARS) score (range -36-36, higher score = better outcome).

  Baseline

• Mood

  Total Beck's Depression Inventory-II (BDI-II) score (range 0-63, lower score = better outcome).

  Baseline

• Autonomic emotional-arousal response: Pupillary response

  Change in pupil size in response to arousing stimuli compared with non-arousing stimuli (unit=difference in mm). We expect that PD patients will have a smaller pupillary response following arousing stimuli compared to healthy participants.

  ON & OFF PD medication in a period within 24 weeks from baseline.

• Autonomic emotional-arousal response: Skin conductance response

  Change in skin conductance (unit=micro Siemens) in response to arousing stimuli compared with non-arousing stimuli. We expect that PD patients will show an attenuated skin conductance response to arousing stimuli compared to healthy participants.

  ON & OFF PD medication in a period within 24 weeks from baseline.

• Behavioural outcome measures: Choices

  Learning in reinforcement learning paradigm: Choices, reaction times, parameters describing degree of action-value vs. stimulus value learning from computational model.

  ON & OFF PD medication in a period within 24 weeks from baseline.

• Behavioural outcome measures: Reaction times

  Learning in reinforcement learning paradigm: Reaction times (unit=ms) describing degree of action-value vs. stimulus value learning from computational model.

  ON & OFF PD medication in a period within 24 weeks from baseline.

• Behavioural outcome measures: Model parameters

  Learning in reinforcement learning paradigm: Model parameters describing degree of action-value vs. stimulus value learning from computational model.

  ON & OFF PD medication in a period within 24 weeks from baseline.

Study Arms (2)

Parkinson's Disease (PD)

Patients with Parkinson's Disease meeting the following criteria: Inclusion criteria: * Aged 18 or more. * Clinically established or probable PD according to the MDS Clinical Diagnostic Criteria for Parkinson's Disease * Signed informed consent Exclusion criteria: * Pregnancy or breastfeeding * History of other neurologic or psychiatric disease * Pacemaker or other implanted electronic devices * Claustrophobia

Healthy participants

Healthy participants age- and sex-matched to the PD group. Inclusion criteria: * Age- and sex-matched to PD group (aged 18 or more) * Signed informed consent Exclusion criteria: * Pregnancy or breastfeeding * History of neurologic or psychiatric disease * Pacemaker or other implanted electronic devices * Claustrophobia

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Participants will be recruited from the ambulatory care at the Department of Neurology, Bispebjerg Hospital and through private practicing neurologists. As part of the clinical assessment relevant patients with PD will be asked if they would be interested in participating in the study. Also, letters with invitation to participate in the study will be sent to patients with PD in treatment at the clinics. Participants will also be recruited from the general population via advertisements.

You may qualify if:

• Aged 18 or more.
• Clinically established or probable PD according to the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's Disease
• Signed informed consent

You may not qualify if:

• Pregnancy or breastfeeding
• History of other neurologic or psychiatric disease
• Pacemaker or other implanted electronic devices
• Claustrophobia
• Healthy participants age- and sex-matched to the PD group:
• Age- and sex-matched to PD group (aged 18 or more)
• Signed informed consent
• Pregnancy or breastfeeding
• History of neurologic or psychiatric disease
• Pacemaker or other implanted electronic devices
• Claustrophobia

Sponsors & Collaborators

• Danish Research Centre for Magnetic Resonance: lead
• Bispebjerg Hospital: collaborator

Study Sites (2)

Department of Neurology, Copenhagen University Hospital Bispebjerg

Copenhagen, 2400, Denmark

RECRUITING

Danish Research Centre For Magnetic Resonance, Copenhagen University Hospital Hvidovre

Hvidovre, 2650, Denmark

RECRUITING

MeSH Terms

Conditions

Parkinson Disease

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Study Officials

• Hartwig R Siebner, DMSci

  Danish Research Centre for Magnetic Resonance

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Christopher F Madelung, MD

CONTACT

38620436; christopher.fugl.madelung.01@regionh.dk

Hartwig R Siebner, DMSci

CONTACT

38626541; hartwig.roman.siebner@regionh.dk

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 7, 2019
• First Posted: March 7, 2019
• Study Start: September 19, 2018
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: May 18, 2022

Record last verified: 2022-05

Locations

DK (2)