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Estimating Progression Rate and Distinguishing Parkinsonian Syndromes Using Imaging and Deep Learning

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ClinicalTrials.gov Identifier: NCT03872102
Recruitment Status : Not yet recruiting
First Posted : March 13, 2019
Last Update Posted : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Richard Dewey, University of Texas Southwestern Medical Center

Brief Summary:
The goal of this study is to develop a model to predict the progression rate of Parkinson disease (PD) and use this model to distinguish between similar diseases such as PD, Progressive Supranuclear Palsy (PSP), and Multiple System Atrophy (MSA).

Condition or disease
Parkinson Disease Multiple System Atrophy Progressive Supranuclear Palsy

Detailed Description:

Management of patients with parkinsonian symptoms has two critical gaps: (1) there is no clinical test to objectively predict the disease progression rate in an individual with Parkinson disease (PD), and (2) no trustworthy test exists for the early differential diagnosis of conditions that exhibit parkinsonian symptoms and signs. This 2-year study develops a multi-modal neuroimaging biomarker that enables the prediction of disease progression rate in PD and an imaging biomarker that enables the differential diagnosis of PD, multiple systems atrophy (MSA), progressive supranuclear palsy (PSP), and healthy controls.

This study consists of two parts; multimodal imaging of a defined population of PD subjects previously followed as part of the Parkinson disease biomarker program at UT Southwestern, and recruitment of new study subjects with PD, MSA, and PSP who will be followed clinically over 2 years and who will undergo multimodal imaging 3 times during follow-up.

Participants will be asked to undergo an MRI, EEG, and DaTscan while on PD medications and will additionally repeat the MRI and EEG while in a 12-hour off state following withholding of the usual morning dose of levodopa.

At each study visit of the newly recruited cohorts, appropriate clinical scales will be performed based on their diagnosis and used to track and measure disease severity.

Objectives:

  1. To predict progression rate of PD using functional signatures from MEG, EEG, MRI and DaT to distinguish fast versus slow PD progressors using a deep learning predictive model.
  2. To use this deep learning model to differentiate between similar diseases such as Parkinson's disease, Progressive Supranuclear Palsy and Multiple System Atrophy.

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Study Type : Observational
Estimated Enrollment : 90 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Quantitative Diagnostics of Parkinsonian Syndromes Using Multi-modal Neuroimaging and Deep Learning
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : May 2021


Group/Cohort
Parkinson Disease
PD subjects will be recruited in accordance with the MDS Clinical Diagnostic Criteria for PD.
PSP
PSP subjects will be recruited in accordance with the MDS Criteria for Diagnosis of Progressive Supranuclear Palsy and must meet the designation of "probable PSP" for inclusion.
MSA
MSA subjects will be recruited in accordance with the Second Consensus Statement on Diagnosis of Multiple System Atrophy
Controls
Control subjects will be roughly age and sex matched with the subjects in the PD cohort, with no history or examination findings suggestive of any neurodegenerative disease.



Primary Outcome Measures :
  1. Change from baseline in MDS-UPDRS score at 24 months. [ Time Frame: 2 years ]

    The Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is the standard measure of PD severity used in multiple trials. This consists of four sub scales, Part I: non-motor experiences of daily living (13 items), Part II: motor experiences of daily living (13 items), Part III: motor examination (18 items), and Part IV: motor complications (six items). Each subscale has a five-point scale ranging from 0-4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.

    The total score is the sum of the subscale scores for all four parts and ranges from 0 (no disability) to 200 (total dependence). Negative change from baseline scores indicate improvement.


  2. Change from baseline in Unified Multiple System Atrophy Rating Scale (UMSARS) score at 24 months. [ Time Frame: 2 years ]
    The Unified Multiple System Atrophy Rating Scale (UMSARS) is the standard scale for measuring disease severity in MSA. This scale is composed of 2 sub-scales: Part I: Historical Review that includes 12 items and Part II: Motor Examination that includes 14 items. All items range from 0 to 4. Each subscale score is the sum of its items and the total UMSARS score is the sum of all 26 items. Hence the total UMSARS score can range from 0 to 104, with 0 meaning no impairment and 104 indicating severe impairment. Negative change from baseline scores indicate improvement.

  3. Change from baseline in Progressive Supranuclear Palsy Rating Scale (PSPRS) score at 24 months [ Time Frame: 2 years ]
    The Progressive Supranuclear Palsy Rating Scale (PSPRS) is the standard scale used to quantitate severity in PSP. This is a quantitative measure of disability in participants with PSP. The PSPRS comprises 28 items in 6 areas. The available total score ranges from 0 (normal) to 100. Six items are rated on a 3-point scale (0-2) and 22 are rated on a 5-point scale (0-4) The History/Daily Activities area includes 7 items with ta total maximum of 24 points, the mentation area 4 items with 16 points, the bulbar area 2 items with 8 points, the ocular motor area 4 items with 16 points, the limb motor are 6 items with 16 points, and the gait area 5 items with 20 points. Negative change from baseline scores indicate improvement.

  4. Change levodopa equivalent daily dose (LEDD) from baseline at 24 months [ Time Frame: 2 years ]
    The LEDD is calculated according to Tomlinson, et. and updated for newer dopaminergic drugs. This number is achieved by adjusting for relative clinical potency of various dopaminergic agents such that the LEDD is an approximation of the dopaminergic stimulation were the patient treated with only levodopa. Negative change from baseline scores indicate improvement.


Secondary Outcome Measures :
  1. Parkinson disease questionnaire, 39 item [ Time Frame: 2 years ]
    The Parkinson's Disease Questionnaire (PDQ-39) assesses to what degree PD subjects experience difficulties across 8 dimensions of daily living. The 39-question PDQ provides scores (expressed as a percentage) for each of the 8 scales: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. Individual items are rated on a 5-point scale (0-4). Higher percentages represent worse quality of life, and a reduction in score over time represents improvement.

  2. Montreal Cognitive Assessment [ Time Frame: 2 years ]
    The Montreal Cognitive Assessment (MoCA) is a cognitive screening test that has shown superior ability to detect both mild cognitive impairment and dementia in PD. There are validated cut-offs in published literature separating normal cognitive function, mild cognitive impairment, and dementia. The scale ranges from 0-30 with the the highest score representing normal cognition. An increase in the MoCA over time would indicate improvement in cognitive function.

  3. Schwab and England Activities of Daily Living Scale [ Time Frame: 2 years ]
    The Schwab and England Activities of Daily Living Scale (S&E) is a commonly used measure of daily function for Parkinson's disease (PD). The S&E Scale rates a PD patient's function on a scale from 0 indicating worst possible function to 100 indicating no impairment. An increase in the score over time indicates clinical improvement.



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population

There are 4 cohorts:

  1. Subjects with PD
  2. Subjects with PSP
  3. Subjects with MSA
  4. Control subjects
Criteria

Inclusion Criteria:

For part 1:

  • Previous participation in the PDBP study at UT Southwestern
  • Existence of sufficient participation in PDBP to determine fast or slow progressor status by clinical scoring tests
  • Availability of suitable matched participant in the alternate progression group
  • Willingness to participate in the imaging studies required for this study and to provide written informed consent

For part 2:

  • PD subjects will be recruited in accordance with the MDS Clinical Diagnostic Criteria for PD.

    • Duration of PD (since diagnosis) is < 5 years
    • MIBG SPECT indicative of cardiac sympathetic denervation
    • Datscan indicative of presynaptic dopaminergic neuronal loss
    • Willing to participate in imaging and clinical scoring visits, and provide written informed consent
    • Subject and investigator agree that it is highly likely subject will be able to participate throughout the 2-year study period (no plans to move)
  • MSA subjects will be recruited in accordance with the Second Consensus Statement on Diagnosis of Multiple System Atrophy.

    • No evidence of cardiac sympathetic denervation on MIBG SPECT
    • Duration of MSA (since diagnosis) is < 5 years
    • Willing to participate in imaging and clinical scoring visits, and provide written informed consent
    • Subject and investigator agree that it is highly likely subject will be able to participate throughout the 2-year study period (no plans to move away during the study)
  • PSP subjects will be recruited in accordance with the MDS Criteria for Diagnosis of Progressive Supranuclear Palsy and must meet the designation of "probable PSP" for inclusion.

    • Willing to participate in imaging and clinical scoring visits, and provide written informed consent
    • Subject and investigator agree that it is highly likely subject will be able to participate throughout the 2-year study period (no plans to move away during the study)
  • Control subjects will be recruited who meet the following criteria:

    • Roughly age and sex matched with the subjects in the PD cohort
    • No history or examination findings suggestive of any neurodegenerative disease
    • Normal gait, balance, and eye movements for age
    • No clinical evidence for symptomatic orthostatic hypotension
    • Willing to participate in imaging and clinical scoring visits, and provide written informed consent
    • Subject and investigator agree that it is highly likely subject will be able to participate throughout the 2-year study period (no plans to move away during the study)

Exclusion Criteria:

  • For parts 1 and 2:

    • Any contraindications to having a MRI, MEG, EEG
    • Any contraindications to having a DaTscan
    • All females of child-bearing potential, between the ages of 18-55, will be excluded from the study, unless they are confirmed to be not pregnant with a pregnancy test prior to scanning
    • This study will require constant clear communication throughout the duration of the study; therefore, non-English speakers will be excluded
    • Has clinically significant liver, kidney, lung, metabolic or hormone disturbances which pose safety risk
    • Has a current clinically significant heart disease that poses a safety risk
    • Has a current clinically significant infectious disease or a medical comorbidity which poses a safety risk
    • Has a history of relevant severe drug allergy or hypersensitivity
    • Have a history of drug, alcohol, or substance dependence or abuse within the last year, or prior prolonged history of dependence or abuse
    • Currently undergoing chemotherapy or radiation for cancer
    • Recreational drug use in past six months
    • Central nervous systems disease or brain injury that would preclude participation in this study
    • Psychiatric or neurological disorder that would preclude participation in this study
    • Inability to keep or maintain research appointments

For part 1:

  • Inability to calculate progression status due to insufficient data from PDBP
  • Severe disease progression such that participation in the imaging tests would be impossible or difficult
  • Non-availability of a suitable matched participant in the alternate progression group
  • A history of severe allergic reaction to iodine

For part 2:

  • PD subjects

    1. No cardiac denervation seen on MIBG SPECT
    2. Unequivocal cerebellar abnormalities
    3. Downward vertical gaze limitation or slowing of downward saccades
    4. Diagnosis of behavioral variant frontotemporal dementia or primary progressive aphasia
    5. Parkinsonian features restricted to the lower limbs for > 3 years
    6. Treatment with dopamine blockers or depleters in a time course consistent with drug induced parkinsonism
    7. Absence of an observable response to high dose levodopa despite moderate disease severity
    8. Normal DatScan (presynaptic neuronal loss NOT seen)
    9. Expert considers a diagnosis of alternative syndrome more likely than PD
    10. Rapid progression of gait impairment requiring wheelchair within 5 years of onset
    11. Complete absence of progression of motor symptoms over 5 years unless due to treatment
    12. Early bulbar dysfunction within the first 5 years since diagnosis
    13. Inspiratory respiratory dysfunction (stridor or frequent sighs)
    14. Severe autonomic failure in the first 5 years
    15. Recurrent falls (>1 per year) because of impaired balance in the first 3 years
    16. Disproportionate dystonic anterocollis or hand contractures of hands or feet within 10 years
    17. Absence of any of the common non-motor features of PD despite 5 years of disease
    18. Otherwise unexplained pyramidal tract signs (weakness, hyperreflexia, or extensor toe signs)
    19. Bilateral symmetric parkinsonism
  • MSA subjects

    a. Evidence for cardiac sympathetic denervation on MIBG SPECT

  • PSP subjects

    1. Predominant, otherwise unexplained impairment of episodic memory, suggestive of AD
    2. Predominant, otherwise unexplained autonomic failure, e.g., orthostatic hypotension (orthostatic reduction in blood pressure after 3 minutes standing > 30 mm Hg systolic or > 15 mm Hg diastolic), suggestive of multiple system atrophy or Lewy body disease
    3. Predominant, otherwise unexplained visual hallucinations or fluctuations in alertness, suggestive of dementia with Lewy bodies
    4. Predominant, otherwise unexplained multisegmental upper and lower motor neuron signs, suggestive of motor neuron disease (pure upper motor neuron signs are not an exclusion criterion)
    5. Sudden onset or step-wise or rapid progression of symptoms, in conjunction with corresponding imaging or laboratory findings, suggestive of vascular etiology, autoimmune encephalitis, metabolic encephalopathies, or prion disease
    6. History of encephalitis
    7. Prominent appendicular ataxia
    8. Identifiable cause of postural instability, e.g., primary sensory deficit, vestibular dysfunction, severe spasticity, or lower motor neuron syndrome
  • Control subjects

    1. In the investigator's opinion, an unsuitable candidate to serve as a control

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03872102


Contacts
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Contact: Ashley Gerald, MA 2146480212 ashley.gerald@utsouthwestern.edu

Sponsors and Collaborators
University of Texas Southwestern Medical Center
Investigators
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Principal Investigator: Richard B Dewey, MD UT Southwestern Medical Center

Publications:
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Responsible Party: Richard Dewey, Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT03872102     History of Changes
Other Study ID Numbers: Bioinformatics Study
First Posted: March 13, 2019    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Multiple System Atrophy
Shy-Drager Syndrome
Brain Diseases
Parkinson Disease
Atrophy
Supranuclear Palsy, Progressive
Parkinsonian Disorders
Basal Ganglia Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Pathological Conditions, Anatomical
Primary Dysautonomias
Autonomic Nervous System Diseases
Hypotension
Vascular Diseases
Cardiovascular Diseases
Ophthalmoplegia
Ocular Motility Disorders
Cranial Nerve Diseases
Tauopathies
Paralysis
Neurologic Manifestations
Eye Diseases
Signs and Symptoms