Comprehensive Multimodal Analysis of Neuroimmunological Diseases of the Central Nervous System

Objective: The goal of this study is to define the pathophysiological mechanisms underlying
the development of disability in immune-mediated disorders of the central nervous system
(CNS) and to distinguish these from physiological (and often beneficial) responses of the
human immune system to CNS injury. The long-term objective of the study is to acquire
knowledge that would allow us to therapeutically inhibit the pathogenic mechanisms and
enhance repair mechanisms in immune-mediated CNS diseases, thereby minimizing the extent of
CNS tissue damage and promoting recovery.

The protocol also serves as a screening tool for NDU clinical trials and enables development
of clinically-useful tools such as diagnostic tests and new, sensitive scales of neurological
disability, disease severity and CNS tissue destruction.

Study Population: Patients with evidence, or suspicion of immune-mediated CNS injury will be
enrolled. In addition, healthy volunteers will be included as controls for immunological and
imaging and biomarkers and to obtain normative data for development of new clinical scales
and smartphone apps.

Design: We will collect, in a standardized manner, multimodal data (standardized
clinical/functional, neuroimaging and molecular/immunological data) during the diagnostic
work-up of patients with varied disorders of the CNS in which immunemediated

processes are expected to play a pathophysiological role.

For the patient cohort, a comprehensive initial evaluation will be performed to establish a
definitive diagnosis or confirm diagnosis and subtype of multiple sclerosis (MS) as a
pre-requisite for enrollment into NDU clinical trials, but also to collect consistent
multimodal research data. Additional diagnostic tests, tailored to individual patients, may
be performed if required for the diagnostic process. The protocol stipulates a mandatory
follow-up visit for all adult patients inclusive of clinical, functional and MRI
examinations. Depending on the specific diagnosis, treatment decisions and clinical/research
needs, patients may be offered additional follow-up visits. The maximum frequency of the
follow-up visits and research samples to be collected is specified to ensure patient safety
is not compromised. Patients age 12-17 may also be included in the patient cohort to
establish a definitive diagnosis, or to provide non-standard assays to help with diagnostic
and therapeutic decisions as part of extraordinary clinical care.

The volunteer cohort will provide sex and age-matched (to adult patients) normative values.

Additionally, we will also enroll patients from whom only biological samples collected by
outside clinicians will be processed. This will be done to provide non-standard assays to
help with diagnostic and therapeutic decisions as a part of extraordinary clinical care.

Outcome Measures: Clinical, MRI and immunological measures will be the outcome measures.
However, no pre-defined research questions will be addressed other than to establish the
diagnosis, determine the level of disease activity, and monitor the natural history.

- PATIENT INCLUSION CRITERIA (for participation in the whole protocol):

1. Presentation with a clinical syndrome consistent with immune-mediated CNS
disorder and/or

2. Neuroimaging evidence of inflammatory and/or demyelinating/ dysmyelinating CNS
disease

3. At least 12 years old at the time of enrollment

4. Adults: Able to give informed consent on their own or via a Legally Authorized
Representative (LAR) or Durable Power of attorney (DPA), or Minors: parent or
legal guardian able to give consent, with child willing to give assent, if
reasonable based on their age and assent capacity, able to give assent with
consent given by their parent or legal guardian

5. Able to undergo the required procedures for diagnostic work-up, including lumbar
puncture MRI and clinical/functional evalautions.

HEALTHY VOLUNTEER INCLUSION CRITERIA:

1. At least 18 years old at the time of enrollment

2. Vital signs are found within normal range at the time of the screening visit

3. Able to give informed consent

4. Able to undergo related research procedures, such as blood draw, lumbar puncture or
lymphocytapheresis for collection of peripheral blood mononuclear cells (PBMC) samples

PATIENT INCLUSION CRITERIA for processing of collected biological samples:

1. Presentation with a clinical syndrome consistent with immune-mediated CNS disorder
and/or

2. Neuroimaging evidence of inflammatory and/or demyelinating/ dysmyelinating CNS disease

3. Ability to obtain either direct or surrogate informed consent for sample processing
and storage

PATIENT EXCLUSION CRITERIA (for participation in the whole protocol):

1. Significant medical condition that would make participation in diagnostic and research
part of evaluation impossible or risky

2. Medical contraindications for MRI (ie- any non-organic implant or other device such as
a cardiac pacemaker or infusion pump or other metallic implants, objects or body
piercings that cannot be removed)

3. Unable to provide informed consent

4. Unwilling to consent for collection of biological samples or their cryopreservation

HEALTHY VOLUNTEER EXCLUSION CRITERIA:

1. Systemic inflammatory disorder or inflammatory or non-inflammatory nurological
diseases.

2. Previous or current history of alcohol and substance abuse

3. Medical contraindications for MRI (i.e. any non-organic implant or other device such
as a cardiac pacemaker or infusion pump or other metallic implants, objects or body
piercings that cannot be removed)

4. Medical contraindication for lumbar puncture

5. Psychological contraindications for MRI (i.e. claustrophobia). This will be assessed
at the time the medical history is collected.

6. Pregnancy or current breastfeeding

7. Any contraindications to having study procedures done

8. History of auditory disorder (i.e. hearing impairment, known impaired acoustic reflex,
tinnitus)

HEALTHY VOLUNTEER SUB STUDY TO OBTAIN NORMATIVE DATA FOR THE SMARTPHONE APPS:

1. Because this sub study collects no personal identifiable information (PII), there are
no inclusion/exclusion criteria.

2. Participating subjects are self-declared as not having any neurological deficit, which
would be the same population that would provide normative data if the apps were freely
available via App store.