MIND-MAPS: Mitochondria, Proteins & Synapses in Neurodegeneration

The hallmark of Parkinson’s disease pathology is the aggregation of misfolded α-synuclein in Lewy bodies, which leads to loss of neuronal synapses and consequently, loss of neurons. A common finding is a progressive mitochondrial dysfunction associated with α-synuclein aggregation, leading to energy deficits and synaptic loss, followed by cell death. Recent advances in positron emission tomography molecular imaging provide a unique opportunity for direct evaluation of mitochondria, proteins and synaptic function. We aim to provide in vivo evidence for the role of mitochondria, proteins and synapses in neurodegenerative diseases, and their relevance to disease burden. Our findings may provide novel molecular markers for drug development, and to monitor disease progression and the response to treatment.

Synaptopathy and neurodegeneration in vivo

PHAGO: Inflammation, Genetics and Alzheimer’s disease

As some people get older small amounts of damage can accumulate in their brain and may cause brain immune cells to become faulty, which may in turn lead to greater brain inflammation and an increased risk of developing diseases such as Alzheimer’s disease. Our goal is to develop a treatment for Alzheimer’s disease by modulating how brain immune cells respond to damage. Our study aims to produce new knowledge and tools about brain inflammation to help us achieve this. We know that certain genetic factors can influence brain immune cell behaviour in Alzheimer’s disease and other similar conditions and understanding this better may provide important clues for directing our efforts to find a treatment.

iMarkHD: In Vivo Longitudinal Imaging of HD Pathology

iMarkHD is an innovative longitudinal clinical imaging study and collaboration between the CHDI Foundation and NIG at KCL. The study is designed to assess longitudinal change in Huntington’ disease (HD) pathology with positron emission tomography (PET) molecular and multi-modal magnetic resonance (MR) imaging, and clinical observation for up to 3 years. This study will assess molecular pathology with highly specific PET radioligands, and structural and functional pathology with state-of-the-art MR imaging. The primary goal is to establish a series of PET readouts across the different stages of HD that could be used as markers of disease progression and treatment response in therapeutic development for HD.

Dopaminergic therapy and brain networks in Parkinson’s Disease

PD is a chronic neurodegenerative disorder primarily characterised by the loss of dopaminergic neurons in the basal ganglia. Although oral levodopa and dopamine agonists are still the most effective symptomatic treatment for PD patients, attempts to correct dopamine deficiencies appear to quickly produce a wide range of negative side effects, especially at high doses and after chronic treatment.  In this project, we aim to use several state-of-the-art MRI techniques to gain an insight into the mechanisms of dopaminergic therapy and relative restoration of brain networks and pathology in patients with PD, and to determine how it may be possible to prevent dopaminergic therapy’s unwanted adverse effects.

Synaptopathy and neurodegeneration in vivo

Mollecular Imaging of Synaptopathy and neurodegeneration in vivo

The mechanisms underlying neurodegeneration are still only partially understood. Synaptic vesicle glycoprotein  2A (SV2A) is a transmembrane protein expressed ubiquitously in secretory vesicles in all brain areas where it regulates neurotransmission by restoring synaptic vesicles Ca2+-induced exocytosis. Changes in SV2A expression affect glutamatergic and GABAergic transmission. Additionally, SV2A is expressed in mitochondria suggesting that modulating SV2A expression may improve mithocondrial dysfunction and play a potential role in the treatment of neurodegenerative disorders. In this study we will use PET with a novel and selective ligand for SV2A to assess synapse density and neurodegenerative mechanisms in vivo in patients with Parkinson’s disease.

Investigating the role of astrocytes in neurodegenerative disorders of movement

In neurodegenerative disorders such Parkinson’s and Huntington’s disease, astroglia can get over activated resulting in reactive astrogliosis, which is involved in the initiation and progression of neurodegeneration. The Imidazoline 2 binding sites (I2BS) are mainly located on astrocytes in cortex, hippocampus, basal ganglia and brainstem and play a fundamental role in the biology of reactive gliosis. Post-mortem data have shown a significant increase of I2BS and astrogliosis in the brains of Parkinson’s and Huntington’s disease patients. In this study, by using PET with a novel and selective ligand for I2BS, we aim to assess the role of astrogliosis in patients with Parkinson’s and Huntington’s disease. The successful application of I2BS PET imaging could also facilitate the development of potential new treatments and the development of diagnostic and/or prognostic markers.

Examining the Braak hypothesis in patients with familial Parkinson’s disease

According to Braak’s staging, the pathological process in Parkinson’s disease occurs in a gradual ascending fashion, starting from the olfactory nucleus and the medulla in presymptomatic stages and spreading to the pons and midbrain later. Several genes causing familial forms of Parkinson’s disease have been discovered in the last decade, providing important insights into the pathogenesis of Parkinson’s disease, allowing opportunity to also study presymptomatic stages. In this project we aim to use molecular PET and SPECT imaging together with MRI to assess brainstem and striatal pathology in familial cases with Parkinson’s disease that share common clinical phenomenology with idiopathic Parkinson’s disease patients.

Effect of AZD3241 in patients with Multiple System Atrophy

Multiple system atrophy is a rare, sporadic, progressive, adult-onset neurodegenerative disorder of the central and autonomic nervous systems. Current treatments for Multiple System Atrophy addresses only isolated symptoms (e.g. orthostatic hypotension) and are at best only modestly effective, with death occurring 8 years (median) from symptoms onset. There is a great need for novel drugs that modify disease outcomes and slow disease progression in patients with Multiple System Atrophy. In this study we have partnered with AstraZeneca USA in a multicentre international trial to assess the effect of AZD3241 in reducing neuroinflammation and improve outcomes in patients with Multiple System Atrophy.

The role of phosphodiesterase 10A in patients with Parkinson’s disease

Parkinson’s disease is a chronic neurodegenerative movement disorder. Phosphodiesterase 10A (PDE-10A) is a vital enzyme hydrolysing cAMP/cGMP signalling cascades, playing a key role in the basal ganglia circuit by regulating the direct and indirect striatal output pathways, promoting neuronal survival, and therefore having a crucial role in the regulation of motor control of movement. In this project, we are using PET imaging to explore the role of PDE-10A in patients with early, middle-stage, and advanced Parkinson’s disease. If our study is successful, PDE-10A could be targeted with novel pharmacotherapy with an aim to promoting neuronal survival and improving motor function in patients with Parkinson’s disease.

Tracking myelin changes with Αβ PET and MRI in patients with Multiple Sclerosis.

Multiple Sclerosis is a chronic debilitating disease characterised by the presence of neuroinflammation, demyelination and neurodegeneration at multiple sites throughout the central nervous system. Axonal loss arises in part due to disruption of the axon–myelin unit, implying that restoring myelin sheaths to these axons may provide a highly effective means of preserving long-term axonal survival, making remyelination and its translational potential a topic of increasing research activity. A major challenge in clinical studies of such remyelination-based therapies is to assess and quantify any changes in myelin content in vivo. In this study we aim to use Αβ PET and MR imaging to track myelin changes in vivo in patients with Multiple Sclerosis.

The role of phosphodiesterase 4 in patients with Parkinson’s disease.

Phosphodiesterase 4 (PDE-4) is an intracellular protein widely expressed in the brain, where it hydrolyzes the second messenger cyclic adenosine monophosphate (cAMP), mediating the striatal outputs and having a central role in the control of movement, immune response, mood and emotional memory. In this study, we aim to investigate in vivo the expression of PDE-4 enzyme in Parkinson’s disease patients using Positron Emission Tomography (PET) molecular imaging.

Quantification of misfolded proteins in vivo in movement and cognitive disorders

Αβ, tau and α-synuclein aggregates are core pathological characteristics for several neurodegenerative disorders leading to motor, cognitive and neuropsychiatric symptoms. Novel Positron Emission Tomography (PET) molecular imaging techniques are either establishing or under development and will allow in vivo quantification of misfolded proteins in patients suffering from amyloidopathies, tauopathies and α-synucleinopathies. The prevention of misfolded protein aggregation and propagation is the focus of attempts to develop disease-modifying treatments for patients with neurodegenerative disorders.

The role of phosphodiesterase 10A in early premanifest Huntington’s disease

Huntington’s disease is an inherited, progressive and fatal neurodegenerative disorder affecting motor, cognitive and neuropsychiatric functions. There is an urgent need of early biomarkers and novel disease-modifying therapies in Huntington’s disease. Phospodiesterase 10A (PDE-10A) hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. In this study we are using PET molecular imaging to investigate the role of PDE-10A in early premanifest Huntington’s disease gene carriers. If our study is successful, PDE-10A could serve as an early biomarker and could be a key therapeutic target in Huntington’s disease.

Dopaminergic stimulation in patients with advanced Parkinson’s disease

Oral levodopa remains the most common and effective symptomatic treatment for patients with Parkinson’s disease, however its chronic use is hampered by the development of motor and non-motor complications. A continuous drug delivery and less pulsatile form of dopaminergic stimulation delivered by novel preparations could result in a stable clinical response and may have a protective effect against the onset of motor and non-motor complications. PET molecular imaging with D2/D3 specific radioligands, following pharmacological challenges, has the ability to quantify in vivo synaptic dopamine levels, and therefore assess whether novel preparations could generate sustained and prolonged dopamine levels in the dopaminergically denervated striatum in patients with advanced Parkinson’s disease.

Central and peripheral immune response in Huntington’s disease gene carriers

A core feature of Huntington’s disease pathology involves the toxic effect of mutant huntingtin, which causes neuronal dysfunction and degeneration of striatal and cortical neurons and is associated with the cardinal Huntington’s disease clinical features of movement, cognitive, and psychiatric symptoms. Mutant huntingtin is highly expressed in both central nervous system and peripheral immune cells. Altered immune response may contribute to the pathogenesis of Huntington’s disease. In this study, we are investigating levels and associations between neuroinflammatory response and peripheral plasma cytokines in Huntington’s disease gene carriers. If we can provide evidence of a link between altered central and peripheral immune response, peripheral inflammatory cells may serve as an indirect marker of neuroinflammation in Huntington’s disease.

Addiction in patients with Parkinson’s disease

Impulse control disorders (ICDs) are a group of conditions (e.g. pathological gambling, hypersexuality, etc) commonly associated with dopaminergic therapy of Parkinson’ disease that involve repetitive, excessive and compulsive activities that interfere with life functioning. Parkinson’s patients who develop ICDs in the context of compulsive dopaminergic drug use are described as having dopamine dysregulation syndrome (DDS). We use functional and structural Magnetic Resonance (MR) imaging, and PET molecular imaging to investigate the pathophysiological mechanisms underlying these debilitating conditions.

The role of serotonergic system in Parkinson’s disease

With the use of PET imaging and specific radioligands tagging serotonergic targets, we are conducting fundamental work investigating the role of the serotonergic system in Parkinson’s disease. Our studies include in vivo staging of the serotonergic dysfunction across a wide clinical range of idiopathic Parkinson’s disease, and investigation of serotonergic pathology underlying motor and non-motor symptoms and complications that are challenging to treat in the clinic. A large body of our work has been dedicated to investigate the role serotonergic terminals in the development of levodopa- and graft-induced dyskinesias.

Neuroinflammation in patients with Multiple Sclerosis

Activated microglia play an important role in the pathophysiology of Multiple Sclerosis. In this project we are using PET imaging targeting translocator protein (TSPO), which is upregulated when microglia become activated. We aim for investigating microglial activation in cerebral nuclei, and cortical and subcortical areas of the brain in patients with different type of Multiple Sclerosis. TSPO PET could be also used as a tool to monitor neuroinflammatory response to disease-modifying treatment.