Brain Dopamine Biomarker

We have recently reported that visual electroencephalographic (EEG) processing of event related potentials (ERPs) is dysregulated in subjects with opioid use disorder (OUD) and that blue color cognitive processing is potentially robust enough to serve as a electrocortical biomarker for brain dopamine (DA) with a significance level of p<0.0001 (Cohen's d 0.89). Blue color processing in the retina is mediated by DA-containing amacrine cells and co-varies with brain DA. With the adoption of a more robust physiological approach, mainly electroretinographic (ERG) recordings combined with ERPs, this might be increased to sigma significance levels, towards the goal of achieving an accurate biomarker of brain DA. We are currently working on this approach using the S-cone ERG response blue cone ERG response, which is modulated by DA levels in the retina. This would be a physiological approach that can be accomplished in the clinic by primary and secondary health professionals quickly and non-invasively with FDA-approved ERG instruments typically used by ophthalmologists to determine the function of the retina. We will propose to record ERGs and ERPs in 25 Parkinson's (PD) subjects and 25 non-PD age-matched controls with a suite of light stimulation procedures to evaluate physiological and cognitive measures of blue color processing. This will be accomplished before and after administration of drug treatment for PD (e.g., Sinemet) in PD subjects.

Specific Aim: Assess feasibility and characterize a noninvasive electrocortical biomarker of brain DA by integrating blue cone S-cone ERG response ERG with ERPs, and test its specificity / sensitivity to DAergic modulation in PD and non PD controls. This aim will be accomplished by recording ERG and ERP responses to blue light stimulation in 25 PD subjects and 25 age matched controls, before and after pharmacologic with Levodopa/Carbidopa eyedrop intervention.

The core hypothesis of this proposal is that blue color processing, including cortical processing as we have recently reported, has the potential to be a psychophysical biomarker of brain DA and monitoring of treatment efficacy for treatment of PD, drug abuse, and other DA-dependent disorders.

Dopamine (DA) has many functions in the brain and is implicated in a host of psychiatric disorders including PD, schizophrenia, obsessive compulsive disorder, depression, sleep disturbances, restless legs syndrome, attention-deficit hyperactivity disorder, and drug addiction. These neuropsychiatric disorders are associated with both increased and decreased DA transmission in the brain. One goal for the treatment of lowered DA levels characteristic of addiction and PD is to enhance its release in the mesolimbic and nigrostriatal DA systems, which originate in the midbrain and project to the striatum. Currently, this is accomplished with drug therapies that enhance DA synthesis, metabolism, or receptor responses towards the goal of enhancing DA synthesis, transmission, and processing. An important component for any therapeutic individual multimodal addiction treatment plan would be to identify specific biological changes that could be used to diagnose, monitor and tailor treatment objectively. For over three decades, DA, its receptors, transporters, precursors, and metabolites in the mesolimbic and nigrostriatal DA pathways have been investigated as potential biomarkers for PD and drug abuse. The most established, albeit recently controversial, biomarker for brain DA is the quantity of a DA subtype-2 receptors (D2Rs) in the striatum, as measured by positron emission tomography (PET). The number of brain D2Rs are directly proportional to the levels of DA in the brain and its associated activity and transmission[4]. However, PET scans are cost-prohibitive for clinical practice. In addition to cost, invasiveness and radiation risk preclude PET scans as a routine clinical tool for assessment of D2R and DA levels in the brain. Interestingly, D2Rs are not only detectable in the brain but are also expressed in peripheral tissues where they play a role in a variety of physiological functions. It has been suggested that D2Rs in the blood may be a peripheral biomarker of brain DA. Accordingly, we have reported that blood DA levels, but not other catecholamines like norepinephrine or epinephrine, are enhanced in RLS with downregulation of lymphocyte and monocyte D2Rs. In PD subjects and in an animal model of PD, we have recently reported that D2Rs expressed on specific populations of blood leukocytes are a potential peripheral biomarker of brain DA in PD. Although this study revealed high significance levels[5] for expression of D2Rs on select leukocytes in PD and in the animal model of PD, an effective biomarker needs to approach sigma levels of significance levels to be considered reliable as an objective index of disease state. Thus, although D2R expression in the periphery remains a viable approach to monitoring brain DA, there is no reliable, non-invasive, or even well-accepted molecular, neurochemical, physiological, or perceptual biomarker of brain DA for diagnosis of DA-dependent brain disorders or for monitoring treatment efficacy currently in clinical use. The lack of an effective biomarker of brain DA has stalled innovations in treatment strategies for DA-dependent disorders and conditions. Ideally, a highly significant biological index based on molecular and/or physiological effects in the periphery that reflect brain DA accurately and could be accomplished with existing clinical tools and non-invasively would be a significant contribution to the field.

Other than that described above in our published study on cognitive measures of blue color processing in opioid addicts, we have not recorded ERGs or ERPs in PD subjects. However, we have recently purchased an LKC Technologies RETEval ERG instrument that is FDA-approved for clinical studies and we have recorded blue light flash ERGs in controls.

Inclusion criteria

• Parkinson's subjects will have received physician verified diagnosis of the disease and be on a dopaminergic medication for at least 3 months

Exclusion criteria

• Any movement, strength, or balance assessments that may pose a potential risk for injury
• Individuals with a history of photosensitive epilepsy or seizure activity triggered by visual stimuli
• Current use of antipsychotics, stimulants, or other medications known to affect central dopaminergic transmission
• Pregnancy
• Recent ocular surgery
• Phenylketonuria
• (PD participants) not cognitively intact and not able to consent for themselves
• (non-PD subjects) a pre-screening survey will assess medication use and neurological history
• Ophthalmologic or visual system conditions that may interfere with stimulus delivery or retinal function. These include significant cataract (defined as LOCS III ≥ NC2/NO2 or any media opacity that precludes adequate delivery of visual stimuli to the retina), active retinal or macular pathology (including age-related macular degeneration with significant drusen or geographic atrophy, diabetic retinopathy, retinal vein occlusion, or epiretinal membrane with foveal involvement), glaucoma, or any optic neuropathy.
• Individuals with congenital color vision deficiencies, particularly tritan-spectrum defects
• Ocular surgery within the past three months
• Use of medications known to affect retinal electrophysiology (e.g., chronic hydroxychloroquine, vigabatrin, deferoxamine, or isotretinoin)
• History of photosensitive epilepsy or visually triggered seizures (especially relevant given the use of bright visual stimuli and potential flicker paradigms)