Chromatic Pupillometry to Assess the Melanopsin-Light Pathway in Progressive Supranuclear Palsy (PMPSP)

• ClinicalTrials.gov Identifier: NCT03330353
• Recruitment Status: Unknown
• First Posted: November 6, 2017
• Last Update Posted: November 7, 2017
• Sponsor: Massachusetts General Hospital
• Collaborators: NeurOptics Inc.; University of Toronto
• Information provided by (Responsible Party): Shirley Wray, Massachusetts General Hospital

Study Description

Brief Summary:

The specific aim of this study is to investigate rod, cone and melanopsin driven pupillary light response in individuals with progressive supranuclear palsy (PSP), age-matched healthy controls and individuals with other neurodegenerative diseases using chromatic pupillometry, with special interest in assessing melanopsin-driven post-illumination pupil response (PIPR) as an identifier for PSP.

The study addresses the following hypotheses:

1. Chromatic pupil responses, including rod/cone-driven rapid phase constriction and melanopsin-driven PIPR, are reduced in subjects with PSP compared to age-matched normal healthy control subjects,
2. Pupil parameters of the melanopsin-driven PIPR are abnormal in PSP subjects without supranuclear palsy, which is indicative of a subclinical physiological deficit of the OPN in the early stages of PSP.

If these hypotheses are upheld, chromatic pupillometry to measure the PIPR promises to be a reliable in vivo, non-invasive, convenient and inexpensive technique to detect asymptomatic pupillomotor impairment in advance of diagnostic oculomotor signs and deterioration of cognitive function.

Condition or disease	Intervention/treatment
PSP - Progressive Supranuclear Palsy; PD - Parkinson's Disease; AD - Alzheimer's Disease; ALS (Amyotrophic Lateral Sclerosis)	Diagnostic Test: Pupillometry

Detailed Description:

In 1963, Richardson, Steele and Olszewski published a landmark clinical report on 8 cases of supranuclear ophthalmoplegia, pseudobulbar palsy, nuchal dystonia and dementia and established the syndrome of heterogeneous system degeneration as a clinicopathological entity now known as PSP. The disease has a characteristic onset in the sixth decade (range 45 to 75 years) with some combination of impaired balance, abrupt falls, visual disturbances, slurred speech, dysphasia and vague changes in personality.

Slowing of voluntary vertical saccades, either down, up or both are a diagnostic marker of PSP and later impairment of voluntary horizontal saccades are characteristic in more than half of the cases. However, a proportion of PSP patients do not demonstrate these eye signs for a year or more after the onset of the disease.

This pilot study will use chromatic pupillometry to determine whether such a novel methodology may be used as an objective in vivo identifier of PSP. The rationale for the study is based in part on:

1. Clinicopathological correlation between the key clinical signs of a supranuclear gaze palsy with pathological verification that the degenerative process affects the pretectum and rostral midbrain,
2. The melanopsin-signaling pathway from ipRGCs (intrinsically photosensitive retinal ganglion cells) in the eye projects to the OPN (olivary pretectal nucleus) in the midbrain,
3. Chromatic pupillometry is a non-invasive technique suitable for elderly subjects with or without dementia.

Study Design

• Study Type: Observational
• Estimated Enrollment: 56 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Functional Assessment of the Melanopsin-Containing Retinal Ganglion Cells in Progressive Supranuclear Palsy Using Chromatic Pupillometry
• Actual Study Start Date: November 1, 2017
• Estimated Primary Completion Date: October 1, 2019
• Estimated Study Completion Date: October 1, 2019

Groups and Cohorts

Group/Cohort	Intervention/treatment
Neurodegenerative Diseases; Individuals with neurodegenerative diseases	Diagnostic Test: Pupillometry; Use of pupillometry to assess melanopsin-light pathway in patients with neurodegenerative diseases

Outcome Measures

Primary Outcome Measures :

1. Maximal Pupil Constriction [ Time Frame: 2 years ]
   The smallest pupil size following light stimulation. This parameter primarily represents rapid phase extrinsic ipRGC activity driven by rods and cones through synaptic input.
2. Post-illumination pupil response (PIPR) [ Time Frame: 2 years ]
   Measured pupil diameter over a period of 20 seconds, from 10 to 30 seconds after the offset of light stimulation.

Eligibility Criteria

• Ages Eligible for Study: 55 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Subjects diagnosed with PSP and age-matched control subjects

Criteria

Inclusion Criteria:

1. Individuals that meet the clinical criteria for PSP. Core features include:

   • Recurrent falls and unsteady gait
   • Axial and nuchal rigidity
   • Pseudobulbar palsy
   • Bilateral lid retraction
   • Supranuclear vertical gaze palsy
   • Atrophy of the midbrain tegmentum (the hummingbird sign on brain MRI,
2. Individuals that fit the criteria for the second PSP phenotype (which resembles PD) that has asymmetric findings, tremors and poor responses to treatment with Levodopa,

3. Individuals that meet the clinical criteria for PD with:

   • Progressive bradykinesia
   • Postural instability and frequent falls
   • Festinating gait with loss of associated movements
   • Cogwheel rigidity and mask-like face
   • Rest tremor,
4. Individuals who carry a diagnosis of Alzheimer' disease who present with progressive impairment of memory and cognitive domains such as language and visuospatial perception.

Diagnoses will be confirmed by the review of health/medical records of patients recruited from the Frontotemporal Disorders Unit clinic. In the case of participants recruited from research studies, diagnoses will be confirmed by the review of the research diagnoses indicated on the individuals' research records.

Exclusion Criteria:

1. Individuals who are frail or in questionable health,
2. Individuals with cataracts or with posterior pole ocular pathology such as age-related macular degeneration and optic neuropathies, including open angle high intraocular pressure glaucoma,
3. Individuals with photophobia (i.e., painful light sensitivity) when exposed to bright light, including those with ophthalmological conditions such as keratitis (herpes simplex), uveitis or Achromatopsia,
4. Individuals with advanced dementia with inability to sit erect, hold the eyes open, incontinence,
5. Individuals with epilepsy,
6. Individuals diagnosed with major depression or other severe psychiatric disorders

Contacts and Locations

Contacts

Contact: Shirley H Wray, MD, PhD; 617-726-5539; wray@helix.mgh.harvard.edu

Locations

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Shirley H Wray, MD, PhD, FRCP 617-726-5539 wray@helix.mgh.harvard.edu

Sponsors and Collaborators

Massachusetts General Hospital

NeurOptics Inc.

University of Toronto

Investigators

• Principal Investigator: Shirley H Wray, MD, PhD; Massachusetts General Hospital

  Study Documents (Full-Text)

Documents provided by Shirley Wray, Massachusetts General Hospital:

Study Protocol and Statistical Analysis Plan  [PDF] September 18, 2017

Informed Consent Form  [PDF] October 20, 2017

More Information

• Responsible Party: Shirley Wray, Professor of Neurology, Harvard Medical School, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT03330353
• Other Study ID Numbers: 2017p001603
• First Posted: November 6, 2017
• Last Update Posted: November 7, 2017
• Last Verified: November 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Coded data will be shared with co-investigators

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

Additional relevant MeSH terms:

Parkinson Disease; Alzheimer Disease; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Supranuclear Palsy, Progressive; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Neurocognitive Disorders; Mental Disorders; Paralysis; Neurologic Manifestations; Neuromuscular Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Ophthalmoplegia; Ocular Motility Disorders; Cranial Nerve Diseases; Eye Diseases