Freezing of Gait: Clinical, Cognitive, and Imaging Features

Freezing of gait (FOG) is among the most disabling motor features of Parkinson disease (PD) and is present in other forms of parkinsonism as well. FOG is a brief (usually lasting \<30 seconds) episode of absence or a greatly reduced forward movement of the feet despite intention to walk. It typically occurs when patients initiate gait (so-called "start hesitation") and when attempting to turn. It is a leading cause of falls and often results in a wheelchair-dependent state. FOG greatly interferes with activities of daily living, causes social isolation and poor quality of life.

FOG is one of the least understood features of PD. It possibly may develop independent of the other motor features of the disease, and be caused by specific pathological changes in the brain. Previous studies on FOG have shown conflicting information and have not lead to clear understanding of the pathophysiology. One key reason for this is that there appears to be multiple subtypes which have rarely been taken into account.

The purpose of this study is to show that different types of FOG exist and to see if there is a connection to cognitive differences or gait patterns.

This study is an observational study to assess FOG via using multiple methods such as: clinical features, imaging, cognition and dopamine blood levels. The study consists of four parts (plus an optional fifth part) that will be completed over two-three separate days within a 30 day span. The four parts will not necessarily be performed in this order. Part one will be clinical and written questionnaire assessments of PD and FOG followed by 3D motion capture evaluations. Part two are cognitive or neuropsychiatric assessments. Part three is a magnetic resonance image (MRI) to examine the brain structure. Part four is Positron Emission Tomography (PET) imaging scan that measures norepinephrine transporter levels. The optional part 5 is a lumbar puncture that will measure cerebrospinal fluid catecholamines and proteomics.

Eligibility Criteria:
Inclusion Criteria for Parkinson disease (PD) subjects with freezing of gait (FOG):

* Diagnosis of PD by United Kingdom Brain bank criteria
* Hoehn \& Yahr stage I-IV
* Levodopa treated and responsive
* Able to manage 12 hours off dopaminergic medication
* Age 18-85 years
* Presence of FOG by history and seen by examiner at their clinical office visit or in a video taken at home
* Able sign a consent document and willing to participate in all aspects of the study
* Able to have an MRI scan (no pacemakers or history of claustrophobia)

Exclusion Criteria for Parkinson disease (PD) subjects with freezing of gait (FOG):

* Dementia that precludes completing study protocol
* Stage V PD - unable to walk independently when "off"
* History of FOG without ever being seen to have it
* Atypical parkinsonism: Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), Corticobasal Degeneration (CBD), Vascular Parkinsonism
* Treatment with medications that cause parkinsonism: drug-induced parkinsonism
* Any neurological or orthopedic disorders that interfere with gait
* Treatment with medications that will interfere with NET-PET (norepinephrine transporter-positron emission tomography) ligand binding

  a. Noradrenergic drugs: methylphenidate, atomoxetine, serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine)
* Absence or loss of levodopa response
* Any contraindications for MRI scan including pacemaker, deep brain stimulator, bladder stimulator, etc.

Inclusion Criteria for Parkinson disease (PD) subjects but no freezing of gait (FOG):

* Diagnosis of PD by United Kingdom Brain bank criteria
* Hoehn \& Yahr stage I-IV
* Levodopa treated and responsive
* Able to manage 12 hours off dopaminergic medication
* Age 18-85 years, age, gender and duration matched to the PD with FOG recruits
* Absence of FOG by history and by exam, confirmed by caregiver and FOG-Q item 3 score of 0.
* Able sign a consent document and willing to participate in all aspects of the study
* Able to have an MRI scan (no pacemakers or history of claustrophobia)

Exclusion Criteria for Parkinson disease (PD) subjects but no freezing of gait (FOG):

* Dementia that precludes completing study protocol
* Stage V PD - unable to walk independently when off.
* History of FOG at any time
* Atypical parkinsonism: Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), Corticobasal Degeneration (CBD), Vascular Parkinsonism
* Treatment with medications that cause parkinsonism: drug-induced parkinsonism
* Any neurological or orthopedic disorders that interfere with gait
* Treatment with medications that will interfere with NET-PET ligand binding
* Absence or loss of levodopa response
* Any contraindications for MRI scan including pacemaker, deep brain stimulator, bladder stimulator, etc.

Inclusion Criteria for subjects with freezing of gait (FOG) but not Parkinson disease (PD):

* Diagnosis of Primary Progressive Freezing gait by accepted Criteria 71
* Diagnosis of atypical parkinsonism; Progressive Supranuclear Palsy (PSP) or Multiple System Atrophy (MSA) with predominant and early onset FOG.
* Hoehn \& Yahr Stage I-IV parkinsonism
* Limited response to Levodopa but FOG unresponsive, but may be on levodopa or other dopaminergic medications
* Age 18-85 years
* Presence of FOG by history and seen by examiner at their clinical office visit or in a video taken at home
* MRI scan demonstrating no structural lesions: stroke, tumor or hydrocephalous
* Able sign a consent document and willing to participate in all aspects of the study
* Able to have an MRI scan (no pacemakers or history of claustrophobia).

Exclusion Criteria for subjects with freezing of gait (FOG) but not Parkinson disease (PD):

* Dementia that precludes completing study protocol
* Stage V Parkinsonism - unable to walk independently.
* Treatment with medications that cause parkinsonism: drug-induced parkinsonism
* MRI scan demonstrating structural lesions or hydrocephalous
* Notable levodopa response suggesting a diagnosis of PD including motor fluctuations or dyskinesia.
* Any neurological or orthopedic disorders that interfere with gait.
* Treatment with medications that will interfere with NET-PET ligand binding.
* Any contraindications for MRI scan including pacemaker, deep brain stimulator, bladder stimulator, etc.