# Analysis of Olfactory Dysfunction for Early Diagnosis of Parkinson's Disease

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2021 · —

## Abstract

More than one million Americans suffer from Parkinson’s disease (PD), of whom at least 80,000 are
Veterans. Although PD is currently diagnosed on the basis of motor signs, these manifestations are preceded
by a period that lasts several years to decades, in which neurodegeneration spreads to many brain regions. The
earlier we can detect PD, the longer the window of opportunity to treat it before disabling symptoms appear.
Learning how to prevent disabling symptoms will require identifying markers that not only enable accurate early
diagnosis, but also enhance understanding of disease pathogenesis, paving the way for the development of
early intervention with disease-modifying drugs. Sense of smell is the first casualty of PD. Although the possibility
of using olfaction as a biomarker for PD has garnered increased interest in recent years, it will only be possible
once we have achieved a better understanding of the mechanisms of this olfactory loss and its cause-and-effect
relationship to -synuclein pathology, a hallmark of PD.
 Our over-arching hypothesis is that olfactory damage in PD is an early event directly linked to upstream -
synuclein toxicity and based on specific neuroanatomical changes with measurable functional impact. By
capitalizing on a well-established transgenic mouse model overexpressing human wild-type -synuclein in the
brain, we showed in our current VAMR a causative role for -synuclein pathology in cerebral blood flow (CBF)
deficit and olfactory dysfunction in PD. To develop further the potential of olfactory dysfunction as a multi-faceted
biomarker, we seek in-depth understanding of the role of CBF alterations in olfactory dysfunction, including its
mechanistic relationship to -synuclein pathology. Using the -synuclein transgenic mouse, we will assess how
progressive accumulation of -synuclein leads to disruption of the counter-regulatory mechanism between the
brain renin-angiotensin system (RAS) and dopamine, leading to abnormal local upregulation of the RAS and
deficits in CBF. In addition, we will elucidate the role of progressive -synuclein accumulation in metabolic
dysregulation, altered energy homeostasis, mitochondrial dysfunction, oxidative stress, and neuroinflammation,
as well as the relationships of these processes to CBF deficit and olfactory dysfunction. Our approach features
immunohistochemistry, biochemistry, behavioral assessments, and advanced neuroimaging modalities (arterial
spin-labeling MRI, diffusion tensor imaging, and fMRI) that are readily translatable to patients.
 Focusing on progressive -synucleinopathy in transgenic mice at 4, 9, and 16 months of age, representing
prodromal, preclinical, and clinical stages of PD, respectively, our specific objectives are:
 1. To elucidate the relationship between abnormal-synuclein aggregation and CBF deficit in PD-related
 olfactory dysfunction;
 2. To understand the mechanism of -synuclein overexpression-induced oxidative stress and
 neuroinflammat...

## Key facts

- **NIH application ID:** 10254880
- **Project number:** 2I01BX003157-05A2
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** ROBERT A CLARK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2016-04-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10254880

## Citation

> US National Institutes of Health, RePORTER application 10254880, Analysis of Olfactory Dysfunction for Early Diagnosis of Parkinson's Disease (2I01BX003157-05A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10254880. Licensed CC0.

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