Parkinson’s disease research

Parkinson’s disease is the second most common neurodegenerative disorder, affecting more than 100,000 Australians and approximately 10 million people worldwide. It is characterised by the progressive loss of dopamine-producing neurons and the pathological accumulation of the protein alpha-synuclein.

While motor symptoms – including tremor, rigidity and slowness of movement – are the hallmarks of the disease, Parkinson’s also causes a wide range of non-motor problems including:

• autonomic dysfunction (when the automatic nervous system is not working properly)
• dementia
• hallucinations
• sleep disturbance.

There is currently no cure, and therapies to slow disease progression remain an urgent unmet need.

DLB is the second most common form of degenerative dementia and, like Parkinson’s disease, is characterised by the abnormal accumulation of alpha-synuclein in Lewy bodies. People living with DLB experience progressive cognitive decline alongside fluctuating attention, vivid visual hallucinations and Parkinsonism, often making diagnosis challenging and care complex.

Our program actively investigates how to:

• better distinguish DLB from Parkinson’s disease dementia and Alzheimer’s disease
• improve outcomes for patients and their families.

iRBD is a parasomnia (or sleep disorder) in which people act out vivid, often distressing dreams during REM sleep. It is now well-established that iRBD is a prodromal – or earliest identifiable – stage of Lewy body disease. The vast majority of people with iRBD will eventually develop either Parkinson’s disease or DLB.

Critically, this means that iRBD represents the earliest clinical window at which these diseases can potentially be identified and treated, before widespread neuronal loss has occurred.

Our program is actively pursuing biomarker development and early intervention strategies in this population.

We also provide specialist clinical assessment and research services for patients with conditions that can closely resemble PD but have distinct underlying biology and trajectories. Sometimes called Parkinson's disease mimics, these conditions include:

• Multiple System Atrophy (MSA) – a rapidly progressive disorder affecting movement, balance and autonomic function
• Progressive Supranuclear Palsy (PSP) – a tau-related disorder causing falls, eye movement abnormalities and cognitive decline.

Brain changes using neuroimaging and neurophysiology

Our program uses advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging to map the structural and functional changes that underlie the motor and non-motor symptoms of Parkinson’s disease and related conditions. In addition, we use electroencephalogram (EEG) and deep brain stimulation (DBS) to identify the pathophysiology of symptoms allowing us to develop new treatment approaches.

Current projects include international collaborations using functional neuroimaging and neurophysiology as biomarkers of brain dysfunction as predictors of disease progression.

Cellular changes associated with genetics

Understanding the genetic underpinnings of Parkinson’s disease and related conditions provides critical insight into disease mechanisms and potential therapeutic targets.

We employ human stem cells, organoids and primary patient cells to investigate pathogenic variants in genes such as LRRK2 and GBA1, exploring how mutations in these genes alter cellular biology – including immune responses, lipid handling and protein aggregation – to drive neurodegeneration.

This work informs the development of targeted, precision medicine approaches.

Discovering biomarkers for early diagnosis and prognosis

A central focus of our work is the identification and validation of biomarkers – measurable biological signals that can detect the cellular and molecular changes for the different disease pathologies. These biomarkers are needed to predict disease pathology at different stages and track treatment response.

We investigate biomarkers:

• using structural and functional neuroimaging (with MRI and PET)
• by developing fluid and tissue biomarkers across multiple matrices (including cerebrospinal fluid, blood and skin biopsy).

Our biomarker program directly supports the goal of diagnosing these diseases earlier – including at the prodromal iRBD stage – when neuroprotective interventions may be most likely to succeed.

Molecular changes associated with pathology

Understanding the molecular changes that define the pathology of these diseases in human tissue remains fundamental to progress. At present, the pathology of an individual’s disease can only be seen at a cellular level post-mortem. Professor Halliday leads the Global Brain Bank to Identify Data-Driven Molecular and Cellular Subtyping Underlying Disease Initiation and Progression in Lewy Body Diseases.

This program involves 18 institutions around the world aiming to improve diagnosis by identifying molecular biomarkers (including novel RNAs) that will guide personalised treatment strategies based on pathology-specific progression.

Professor Halliday also leads the NSW Movement Disorders Brain Donor Program which allows such research, as well as enables definitive post-mortem diagnosis for patients and families. Discovering molecular brain changes cannot occur without individuals' precious donated brain material to analyse.

Dysphagia

In neurodegenerative disorders, swallowing difficulties – or dysphagia – are highly common and affect up to 80% of patients. Dysphagia leads to dehydration, malnutrition, facilitates pneumonia and thereby determines quality of life and the prognosis of these diseases.

For most conditions, dysphagia-associated complications are the leading cause of death. Awareness and early identification of dysphagia allows for an early initiation of effective therapies to improve swallowing and thereby quality of life.

Freezing of gait

Freezing of gait is a sudden, episodic inability to initiate or continue walking that affects many people with Parkinson’s disease and PSP. It is a major contributor to falls and loss of independence.

Professor Lewis chairs the International Consortium for Freezing of Gait and our team leads world-class basic and translational research into the neural mechanisms of this debilitating symptom, with active clinical trials targeting its treatment.

Motor phenotypes

Our work has shown that patients with Parkinson’s can present with a variety of physical symptoms, such as tremor or slowness. Understanding the cause of these issues will extend our therapeutic strategies.

Sleep, cognition and non-motor symptoms

Sleep disturbances – including iRBD, excessive daytime sleepiness and insomnia – are among the most disabling non-motor features of Parkinson’s disease and often precede motor onset by many years.

Our team has a strong program investigating the mechanisms and management of sleep–wake dysfunction, as well as dementia, hallucinations and other non-motor symptoms that significantly affect quality of life.

Associate Professor Antony Cooper is a cell and molecular biologist and geneticist investigating the mechanisms that cause Parkinson's disease (PD), with the aim of identifying biomarkers and therapeutics that slow progression in idiopathic Parkinson's disease (iPD).

His group recently identified a genetic signature that stratifies PD patients into three subgroups, which show distinct disease trajectories in patient cohorts and divergent responses across two Phase III disease-modifying trials, providing evidence that iPD arises from multiple underlying mechanisms. These findings support a precision-medicine framework in which therapies are matched to the mechanism driving each patient's disease.

The next step is to define the cellular and molecular basis of each subgroup to enable mechanism-based drug development and patient stratification for precision-medicine clinical trials.

Professor Dzamko is a professor of neurobiochemistry whose research focuses on the molecular mechanisms underlying Parkinson’s disease, with particular expertise in:

• LRRK2 kinase biology
• alpha-synuclein pathology
• the genetics of neurodegeneration.

His work spans cell biology, biochemistry and translational biomarker research, and he plays a vital role in coordinating the biobanking infrastructure that underpins our precision medicine strategy.

His recent work includes investigations into:

• lipid dysregulation in PD serum
• genetic modulation of immune responses in Parkinson’s disease
• pathological targets for disease-modifying therapy development.

Associate Professor Florin Gandor is a neurologist and movement disorders specialist with 20 years of experience in treating and researching disorders of the voice and swallowing in Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP).

He is an expert in device-aided therapies for these movement disorders. Before his appointment at Macquarie University in 2024 he was head of the Department of Clinical Trials and the Dysphagia Research Centre at the Movement Disorders Hospital in Beelitz, Germany. He pioneered clinical research in dysphagia and voice dysfunction in movement disorders and discovered clinical biomakers that delineate movement disorders from one another.

In 2021, Associate Professor Gandor was awarded the Robert-Wartenberg award and lecture, the highest German non-academic research award. He is a member of the MSA Study Group’s Steering Committee of the Movement Disorders Society and a member of the Treatment Guidelines Committee for MSA of the European Academy of Neurology.

Professor Halliday is one of Australia’s most distinguished neuroscientists, with a career spanning more than four decades of research into:

• Parkinson’s disease
• dementia with Lewy bodies
• frontotemporal dementia.

She is:

• a Fellow of the Australian Academy of Science
• a Fellow of the Australian Academy of Health and Medical Sciences
• a Companion of the Order of Australia (AC) – awarded for eminent service to medical research in the field of neurodegenerative disorders
• an NHMRC Leadership Fellow.

She was named NSW Scientist of the Year in 2022 and was the 2021 recipient of the international Robert A Pritzker Prize for Leadership in Parkinson’s Research.

Her work has been instrumental in developing revised diagnostic criteria for Parkinson’s disease and in advancing our understanding of the neuropathology underlying Lewy body diseases.

Professor Lewis is a professor of cognitive neurology at Macquarie University Health and a consultant neurologist who has sub-specialised in Parkinson’s disease, dementia with Lewy bodies and related conditions.

He leads the Parkinson’s Disease Research Clinic and holds the chair of the International Consortium for Freezing of Gait.

His research integrates neuroimaging, neurophysiology, neuropathology, neurogenetics and clinical trials to understand and treat the full spectrum of neurodegenerative brain disease. He leads the NSW Movement Disorders Brain Donor Program and conducts active clinical trials targeting disease progression and symptom management.