# Neurovascular Effects of Dopamine Replacement Therapy in Parkinson's Disease

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2020 · $589,961

## Abstract

PROJECT SUMMARY
The overarching goal of this revised project is to understand the evolution of levodopa-induced dyskinesias
(LID), a disabling and refractory side-effect of the gold standard treatment for Parkinson's disease (PD). Nearly
all PD patients will acquire LID within 10 years of beginning the drug. Once LID sets in, usually as advancing
disease requires higher doses of levodopa, PD becomes extremely difficult to manage. Most research on LID
has focused on the neuronal level, where LID is associated with a variety of pre- and post-synaptic changes [1].
The relationship of these changes to the transition to LID, however, remains elusive. We have therefore
undertaken a systems-level approach in human PD patients and in a rodent model of LID. Using multi-tracer
PET imaging to measure both glucose metabolism and regional blood flow, we discovered that levodopa
administration is associated with significant neurovascular dysregulation: the vasomotor and metabolic
responses to levodopa dissociate from one another, with blood flow increasing and metabolism diminishing in
areas of dopaminergic denervation. This dissociation is greatest in the putamen and particularly prominent in
subjects with LID, who also have elevated metabolic activity in the sensorimotor cortex (SMC) in the off-
medication state. We subsequently found that, when scanned in the unmedicated state, LID subjects show
abnormal increases in hypercapnic vasoreactivity, an index of capillary density, in the putamen dissociation
region. Hypothesizing that chronic levodopa treatment potentiates angiogenesis in dissociation regions, we
collaborated with Dr. Angela Cenci (Lund, Sweden) to use microPET in the rodent LID model. We found
evidence of levodopa-mediated neurovascular dysregulation and altered blood-brain-barrier (BBB)
permeability in the basal ganglia, which correlates with the severity of dyskinesia and with histopathological
evidence of angiogenesis in the same animals. Thus, data from both human patients and rodents suggest LID-
related neurovascular changes occur at the systems level and develop gradually over time. Whether LID is also
associated with local gliovascular reactions such as neuroinflammation remains unknown, as does the time
course of changes leading up to the onset of LID. Given that this information will be necessary if we are to slow
or prevent the development of LID, we propose to: (1) trace the evolution of localized neurovascular
dysfunction in PD patients as they transition to LID; (2) delineate longitudinal changes in neurovascular unit
function in uncoupling regions; and (3) identify mechanisms underlying neurovascular changes in a rat model
of LID.

## Key facts

- **NIH application ID:** 10019416
- **Project number:** 5R01NS105979-02
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** DAVID EIDELBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $589,961
- **Award type:** 5
- **Project period:** 2019-09-16 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019416

## Citation

> US National Institutes of Health, RePORTER application 10019416, Neurovascular Effects of Dopamine Replacement Therapy in Parkinson's Disease (5R01NS105979-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10019416. Licensed CC0.

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