Early Biomarkers of Neurodegeneration in Parkinsonian Syndromes (SODIPARK)

Early Biomarkers of Neurodegeneration in Parkinsonian Syndromes: Analysis in Very High Field (7T) Brain MRI.

Parkinson's disease (PD) is the most common degenerative Parkinson's syndrome and is linked, among other things, to the excessive accumulation of an abnormally aggregating protein, alpha-synuclein. Progressive Supranuclear Palsy (PSP) is another Parkinson's syndrome, linked, among other things, to the abnormal accumulation of the protein Tau, and expressed clinically by falls, early cognitive impairment and oculomotor disorders, not present in PD. The onset of these disorders is so gradual that differential diagnosis between the two diseases is only possible at a late stage, on average 3 to 5 years after the onset of symptoms.

To date, there is a lack of validated imaging biomarkers for diagnosing and monitoring PD and PSP. There is therefore an urgent need for the development of robust biomarkers capable of detecting neurodegeneration at an early stage, in order to aid differential diagnosis as soon as symptoms appear, and to potentially enable these patients to be included in specific therapeutic trials (as these diseases are pathophysiologically different) with potential neuroprotective effects.

The development of cutting-edge technologies such as 7T MRI, combined with optimized image processing methods, now enable non-invasive in vivo exploration and analysis of these small structures in terms of ion homeostasis (sodium), microstructure (volumetry, amount of iron and neuromelanin) and connectivity.

Study Overview

• Status: Not yet recruiting
• Conditions: Parkinson Disease; Progressive Supranuclear Palsy
• Intervention / Treatment: Procedure: 7 Tesla MRI

• Study Type: Interventional
• Enrollment (Estimated): 63
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stephan Grimaldi, MD; Phone Number: 33 0491385266; Email: stephan.grimaldi@ap-hm.fr

Study Locations

• France
  • Aix-en-Provence, France, 13080
    • Ch Pays D'Aix
    • Contact: Silvia Di Legge, MD; Email: sdilegge@ch-aix.fr
  • Aubagne, France, 13400
    • Hôpital Privé La Casamance - Service de Neurologie
    • Contact: Emmanuelle Boutin-Grob; Email: boutinemmanuelle@gmail.com
  • Avignon, France, 84000
    • Centre Hospitalier Avignon - Service de Neurologie
  • Nice, France, 06000
    • CENTRE HOSPITALIER UNIVERSITAIRE NICE - Service de Neurologie
    • Contact: Cosmin Alecu, MD; Email: alecu.c@chu-nice.fr
  • Nimes, France, 30000
    • CENTRE HOSPITALIER NIMES - Service de Neurologie
    • Contact: Giovanni Castelnovo, MD; Email: giovanni.castelnovo@chu-nimes.fr
  • Toulon, France, 83000
    • CENTRE HOSPITALIER SAINTE MUSSE - Toulon
    • Contact: Elena Rusu; Email: elena-camelia.rusu@ch-toulon.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

For Parkinson Disease:

Inclusion Criteria:

1. Patients aged between 40 and 80
2. Fulfilling the diagnostic criteria for MPI (Postuma et al., 2015)
3. First motor symptom (rigidity, akinesia, tremor) less than 36 months ago
4. Patient entitled to or affiliated with a social security scheme
5. Patients who understood, completed and signed the consent form for study participation.

Exclusion Criteria:

1. Patient with a neurological disease of the central nervous system other than those studied (including history of stroke, repeated head trauma, documented encephalitis). In case of doubt, this criterion will be left to the discretion of the principal investigator, who is a neurologist.
2. Contraindications to 7T MRI: presence of an ocular metallic foreign body (accidental shrapnel or other), pacemaker (cardiac simulator) or neurostimulator (pain treatment), cochlear implants or any implanted electronic medical equipment in general, metallic heart valve, vascular clips implanted on a cranial aneurysm.
3. Claustrophobia or any other condition preventing full MRI.
4. Montreal Cognitive Assessment (MOCA) test < 25/30
5. Pregnant or breast-feeding woman or protected person (under guardianship, curatorship, deprived of liberty).

For Progressive Supra-nuclear Palsy:

Inclusion criteria:

1. Patients aged 40 to 80
2. Fulfilling the diagnostic criteria for soPSP (Höglinger et al., 2017) :
3. First motor symptom (rigidity, akinesia, tremor) or falls or cognitive impairment (frontal syndrome or language disorder or cortico-basal syndrome) occurring less than 36 months ago
4. Patients benefiting from or affiliated to a social security scheme
5. Patients who have understood, completed and signed the study participation consent form

Exclusion criteria:

1. Patient with a neurological disease of the central nervous system other than those studied (including history of stroke, repeated head trauma, documented encephalitis). In case of doubt, this criterion will be left to the discretion of the principal investigator, who is a neurologist.
2. Contraindications to 7T MRI: presence of an ocular metallic foreign body (accidental shrapnel or other), pacemaker (cardiac simulator) or neurostimulator (pain treatment), cochlear implants or any implanted electronic medical equipment in general, metallic heart valve, vascular clips implanted on a cranial aneurysm.
3. Claustrophobia or any other condition preventing MRI.
4. Pregnant or breast-feeding woman or protected person (under guardianship, curatorship, deprived of liberty).

For Control group:

Inclusion criteria:

1. Subjects aged between 40 and 80
2. Subjects benefiting from or affiliated with a social security plan
3. Subjects who have understood, completed and signed the study participation consent form

Exclusion criteria:

1. Subjects with a known history of neurological disease of the central nervous system (e.g. Parkinson's disease, Alzheimer's, stroke, brain tumor, multiple sclerosis, amyotrophic lateral sclerosis, repeated head trauma, documented encephalitis, etc.). In case of doubt, this criterion will be left to the discretion of the principal investigator, who is a neurologist.
2. Contraindications to 7T MRI: presence of an ocular metallic foreign body (accidental shrapnel or other), pacemaker (cardiac simulator) or neurostimulator (pain treatment), cochlear implants or any implanted electronic medical equipment in general, metallic heart valve, vascular clips implanted on a cranial aneurysm.
3. Claustrophobia or any other condition preventing MRI.
4. Pregnant or breast-feeding women or protected persons (under guardianship, curatorship, deprived of liberty).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Healthy volunteers	Procedure: 7 Tesla MRI; Patients will have a 7T MRI and questionnaires; Other Names: Questionnaires
Other: Patients with Parkinson Disease	Procedure: 7 Tesla MRI; Patients will have a 7T MRI and questionnaires; Other Names: Questionnaires
Other: Patients with Progressive Supranuclear Palsy	Procedure: 7 Tesla MRI; Patients will have a 7T MRI and questionnaires; Other Names: Questionnaires

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sodium accumulation between Parkinson disease patients and Progressive Supranuclear Palsy	Comparison of intracerebral sodium accumulation measured by very high-field (7T) cerebral MRI between subjects with Idiopathic Parkinson's Disease and subjects with early-stage Progressive Supra-Nuclear Palsy	Between month 0 and month 3 after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sodium accumulation between Parkinson disease patients (MPI) and control subjects	Comparison of intracerebral sodium accumulation between subjects with early-stage Parkinson's Disease (PD) and control subjects.	Between month 0 and month 3 after inclusion
Sodium accumulation between Progressive Supra-nuclear patients (soPSP) and control subjects	Comparison of intracerebral sodium accumulation between subjects with soPSP and control subjects.	Between month 0 and month 3 after inclusion
Brain atrophy between MPI and soPSP patients	3D mapping of brain atrophy differences measured in Voxel Based Morphometry (VBM), value in cm3	Between month 0 and month 3 after inclusion
Brain atrophy between MPI and control group	3D mapping of brain atrophy differences measured in Voxel Based Morphometry (VBM), value in cm3	Between month 0 and month 3 after inclusion
Brain atrophy between soPSP and control group	3D mapping of brain atrophy differences measured in Voxel Based Morphometry (VBM), value in cm3	Between month 0 and month 3 after inclusion
Iron accumulation between soPSP and control group	3D mapping of iron accumulation differences measured by Quantitative Susceptibility Mapping (QSM), values in ppm	Between month 0 and month 3 after inclusion
Iron accumulation between MPI and soPSP patients	3D mapping of iron accumulation differences measured by Quantitative Susceptibility Mapping (QSM), values in ppm	Between month 0 and month 3 after inclusion
Iron accumulation between soPSP patients and control group	3D mapping of iron accumulation differences measured by Quantitative Susceptibility Mapping (QSM), values in ppm	Between month 0 and month 3 after inclusion
Accumulation of neuromelanin between MPI and soPSP patients	3D mapping of neuromelanin differences (signal/MT ratio)	Between month 0 and month 3 after inclusion
Accumulation of neuromelanin between MPI patients and control group	3D mapping of neuromelanin differences (signal/MT ratio)	Between month 0 and month 3 after inclusion
Accumulation of neuromelanin between soPSP patients and control group	3D mapping of neuromelanin differences (signal/MT ratio)	Between month 0 and month 3 after inclusion
Movement of water molecules between MPI and soPSP patients	3D mapping of differences in mean diffusivity (DM), values in mm2/s	Between month 0 and month 3 after inclusion
Movement of water molecules between MPI patients and control group	3D mapping of differences in mean diffusivity (DM), values in mm2/s	Between month 0 and month 3 after inclusion
Movement of water molecules between soPSP patients and control group	3D mapping of differences in mean diffusivity (DM), values in mm2/s	Between month 0 and month 3 after inclusion
Structural connectivity between MPI and soPSP patients	3D mapping of anisotropy fraction (AF) differences, values between 0 and 1	Between month 0 and month 3 after inclusion
Structural connectivity between soPSP patients and control group	3D mapping of anisotropy fraction (AF) differences, values between 0 and 1	Between month 0 and month 3 after inclusion
Structural connectivity between MPI patients and control group	3D mapping of anisotropy fraction (AF) differences, values between 0 and 1	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and age	Correlation between sodium concentration (mmol/L) and age	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and sex	Correlation between sodium concentration (mmol/L) and sex	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and laterality	Correlation between sodium concentration (mmol/L) and laterality	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and sex	Measure by Voxel Based Morphometry (VBM) in cm3 and sex	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and age	Measure by Voxel Based Morphometry (VBM) in cm3 and age	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and laterality	Measure by Voxel Based Morphometry (VBM) in cm3 and laterality	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and age	Measure by Quantitative Susceptibility Mapping (QSM) in ppm and age	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and sex	Measure by Quantitative Susceptibility Mapping (QSM) in ppm and sex	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and laterality	Measure by Quantitative Susceptibility Mapping (QSM) in ppm and laterality	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and age	Correlation between ratio of signal/MT and age	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and sex	Correlation between ratio of signal/MT and sex	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and laterality	Correlation between ratio of signal/MT and laterality	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and age	Correlation between anisotropy fraction (AF) and age	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and sex	Correlation between anisotropy fraction (AF) and sex	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and laterality	Correlation between anisotropy fraction (AF) and laterality	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and duration of disease progression	Correlation between anisotropy fraction (AF) and duration of the disease	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and duration of disease progression	Correlation between ratio of signal/MT and duration of the disease	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and duration of disease progression	Measure by Quantitative Susceptibility Mapping (QSM) in ppm and duration of the disease	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and duration of disease progression	Measure by Voxel Based Morphometry (VBM) in cm3 and duration of disease progression	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and duration of disease progression	Correlation between sodium concentration (mmol/L) and duration of disease	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and sense of smell	Correlation between sodium concentration (mmol/L) and sense of smell (questionnaire)	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and sense of smell	Measure by Voxel Based Morphometry (VBM) in cm3 and sense of smell (questionnaire)	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and sense of smell	Measure by Quantitative Susceptibility Mapping (QSM) in ppm and sense of smell (questionnaire)	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and sense of smell	Correlation between ratio of signal/MT and sense of smell (questionnaire)	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and sense of smell	Correlation between anisotropy fraction (AF) and sense of smell (questionnaire)	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and severity of disease	Unified Parkinson's Disease Rating Scale (UPDRS), 0 to 199, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and quality of life	Schwab & England score, 0 to 100%, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and quality of life	Schwab & England score, 0 to 100%, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and quality of life	Schwab & England score, 0 to 100%, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and quality of life	Schwab & England score, 0 to 100%, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and quality of life	Correlation between Schwab & England score (Schwab & England score, 0 to 100%, 0 means better outcome) and sodium concentration (mmol/L)	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and severity of disease	Unified Parkinson's Disease Rating Scale (UPDRS), 0 to 199, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and severity of disease	Unified Parkinson's Disease Rating Scale (UPDRS), 0 to 199, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and severity of disease	Unified Parkinson's Disease Rating Scale (UPDRS), 0 to 199, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and Hospital Anxiety and Depression	HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and Hospital Anxiety and Depression	HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and Hospital Anxiety and Depression	HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and Hospital Anxiety and Depression	HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and Hospital Anxiety and Depression	HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and Sleep Behavior Disorder	REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and Sleep Behavior Disorder	REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and Sleep Behavior Disorder	REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and Sleep Behavior Disorder	REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and Sleep Behavior Disorder	REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and motivation scale	Starkstein motivation scale, 0 to 42, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and motivation scale	Starkstein motivation scale, 0 to 42, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and motivation scale	Starkstein motivation scale, 0 to 42, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and motivation scale	Starkstein motivation scale, 0 to 42, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and motivation scale	Starkstein motivation scale, 0 to 42, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and non-motor fluctuations	Number of non-motor fluctuations	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and non-motor fluctuations	Number of non-motor fluctuations	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and non-motor fluctuations	Number of non-motor fluctuations	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and non-motor fluctuations	Number of non-motor fluctuations	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and non-motor fluctuations	Number of non-motor fluctuations	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and cognitives functions	Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and cognitives functions	Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and cognitives functions	Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and cognitives functions	Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and cognitives functions	Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and quality of life	Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and quality of life	Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and quality of life	Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and quality of life	Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and quality of life	Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and hypotension	Blood pressure test for orthostatic hypotension	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and hypotension	Blood pressure test for orthostatic hypotension	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and hypotension	Blood pressure test for orthostatic hypotension	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and hypotension	Blood pressure test for orthostatic hypotension	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and hypotension	Blood pressure test for orthostatic hypotension	Between month 0 and month 3 after inclusion
Measurement of the dependency between structural connectivity and hallucinations	Miami Questionnaire, 0 to 70, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between accumulation of neuromelanin and hallucinations	Miami Questionnaire, 0 to 70, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between iron accumulation and hallucinations	Miami Questionnaire, 0 to 70, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between brain atrophy and hallucinations	Miami Questionnaire, 0 to 70, 0 means better outcome	Between month 0 and month 3 after inclusion
Measurement of the dependency between sodium accumulation and hallucinations	Miami Questionnaire, 0 to 70, 0 means better outcome	Between month 0 and month 3 after inclusion

Collaborators and Investigators

• Sponsor: Assistance Publique Hopitaux De Marseille
• Investigators: Study Director: François Cremieux, AP-HM

Study record dates

Study Major Dates

• Study Start (Estimated): January 15, 2024
• Primary Completion (Estimated): January 15, 2026
• Study Completion (Estimated): January 15, 2028

Study Registration Dates

• First Submitted: November 17, 2023
• First Submitted That Met QC Criteria: November 24, 2023
• First Posted (Estimated): December 5, 2023

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: November 24, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: MRI; biomarkers; Parkinson disease; progressive supranuclear palsy
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Tauopathies; Cranial Nerve Diseases; Ocular Motility Disorders; Paralysis; Ophthalmoplegia; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive; Nerve Degeneration
• Other Study ID Numbers: RCAPHM22_0291; ID-RCB (Other Identifier: ANSM)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No