Key themes in Parkinson's disease research in 2021

Parkinson’s disease (PD) research in 2021 has focused on deepening our understanding of the intricacies of disease in order to optimize, revise, and personalize current approaches.

Are we focused on the correct targets? Are our trials optimally designed for the best chance of success? Can we better predict who will benefit from a given treatment approach? These are just some of the central questions driving today’s investigations. The International Congress of Parkinson’s Disease and Movement Disorders (MDS), 2021, shared state-of-the-art developments in the movement disorder field from experts across the world dedicated to addressing these questions.

In this feature, we spotlight hot topics in PD research, from improving deep brain stimulation targets to uncovering nuances in the genetic architecture of disease across the world. Read on to hear from MDS 2021 presenters on their work to optimize and personalize treatment in PD.

Lesion network mapping to identify & optimize neuromodulation targets

Observations from lesion studies have provided a wealth of knowledge on the functional architecture of the human brain. By examining the impairments resulting from injury to a certain brain region, a causal relationship between region and function can be inferred.¹ Over the last decade, voxel-based lesion mapping has flourished, enabling neurological symptoms to be mapped to specific brain regions by identifying overlap in lesions that cause similar symptoms. While this approach has led to several foundational discoveries, it is well recognized that many individual functions rely on the combined action of a network of connected brain areas, rather than a single region.

In 2015, Boes et al. expanded on this approach to account for the impact of neural networks.² Aptly named lesion network mapping, the technique maps brain lesions onto the normative functional connectome to assess the functional connectivity of each lesion location and overlaps lesion-associated networks to highlight regions common to a specific neurological symptom. The approach has been used to map causal circuits of hemichorea, freezing of gait, and several neuropsychiatric symptoms including depression.¹

Michael Fox, MD, PhD, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA, discussed his work on lesion and deep brain stimulation (DBS) network mapping in the movement disorder space and beyond at the International Congress of Parkinson’s Disease and Movement Disorders (MDS), 2021. VJNeurology caught up with Dr Fox on how the approach got to where it is today.

In 2018, Dr Fox and colleagues applied this novel approach to 29 cases of lesion-induced parkinsonism compiled from the literature.¹ Parkinsonism, typically defined as bradykinesia, rigidity, and tremor, is not specific to Parkinson’s disease (PD) and can occur outside of the context of nigrostriatal degeneration. Parkinsonism is seen in other neurological disorders, such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), and can occur in patients suffering lesions to locations outside the nigrostriatal tract, suggesting these symptoms may stem from other brain regions.¹

In this study, it was clear that despite causing common symptomatology, the lesion locations were heterogeneous, notably with only a third occurring in the substantia nigra. Using human connectomic data, the lesions were mapped onto brain networks, which revealed disruption of common connectivity networks. In 28 of 29 cases, the lesion affected networks that connected through the claustrum. The claustrum, thought to play a role in motor, perceptual and cognitive functioning, is not typically associated with parkinsonism and thus, the clinical relevance of these findings to patients was investigated. Atrophy patterns seen in patients with Parkinson’s disease, PSP and MSA were found to match the connectivity circuits identified by lesion network mapping.

Furthermore, investigators conducted DBS network mapping in patients with electrodes implanted in the subthalamic nucleus. It was shown that where the electrodes were placed within networks that flowed through the claustrum, better outcomes were achieved with DBS.

Overall, these results demonstrate the promise of lesion network mapping as a valuable tool to identify new targets for DBS, as well as highlighting the potential the claustrum as a region of importance in Parkinsonism.

Is clearing α-synuclein enough to treat Parkinson’s disease?

Alpha-synuclein (α-syn) is widely believed to be the key player in Parkinson’s disease (PD) pathology, responsible for the defining neurodegeneration through toxic aggregation. Aggregated α-syn is a pathological hallmark of PD, enabling a definitive diagnosis, and several lines of evidence support the critical importance of α-syn in PD pathogenesis. Observations of mutations in the SNCA gene provided the first link between PD and α-syn, supported by the subsequent discovery of α-syn as the major component of Lewy bodies and Lewy neurites.^3,4 Additionally, higher copy numbers of SNCA resulting from genetic overexpression were shown to associate with a more aggressive disease, implying a relationship between expression levels and disease severity.⁵ The identification of α-syn mutations in a number of inherited forms of PD, as well as polymorphisms implicated in sporadic PD, has led to the belief that α-syn plays an important, potentially causative, role in PD.

Over the decades since this link was first described, α-syn has continued to be investigated in the initiation and progression of neurodegeneration. As of June 2021, five anti-synuclein aggregation therapies are in clinical trials, with a further two agents recently discontinued.⁶ Strategies include monoclonal antibodies, active vaccination, and small molecules that aim to block aggregation or enhance extracellular clearance.

Despite the substantial focus that has been given to α-syn aggregation, for many, doubts remain regarding its true significance. A debate held at the International Congress of Parkinson’s Disease and Movement Disorders (MDS), 2021, discussed if clearing of α-syn aggregates is an adequate therapeutic strategy in PD. Arguing against this, Alberto Espay, MD, FAAN, University of Cincinnati, Cincinnati, OH, discussed why he believes α-syn pathology represents a consequence of disease rather than a cause. In our recent interview, Prof. Espay explains why he thinks the α-syn focus needs to shift from the idea of a toxic gain of function to a loss of function model.

The loss of function hypothesis argues that α-syn is critical to neuronal cell survival and incorporation of α-syn into aggregates reduces the functional α-syn pool.⁷ As the disease progresses, the available α-syn continues to be depleted until it reaches a threshold below which the cell can no longer survive. Intrinsic or extrinsic mechanisms may augment this process. In this way, the hallmark α-syn aggregation simply represents a consequence of the loss-of-function mechanism of toxicity.

Prof. Espay notes that studies have shown no correlation between Lewy pathology and degeneration levels in the subthalamic nucleus (STN) or with clinical severity of PD.⁸ Additionally, there is no support for a spread of Lewy pathology that precedes neurodegeneration and the onset of clinical symptoms. There is a lack of definitive evidence of a causal relationship between α-syn aggregation and neurodegeneration.

After over 50 years of use, and despite its numerous adverse effects, levodopa is still the gold standard for PD treatment. The development of disease-modifying treatments is the greatest unmet therapeutic need in PD, and thus, critical analysis of the approaches under investigation is of the utmost importance. If α-syn aggregation is neither necessary nor sufficient for the onset of neurodegeneration or clinical parkinsonism, perhaps it is important to instead look at the normal proteins that have been lost.

The Global Parkinson’s Genetic Program (GP2)

The genetic architecture of Parkinson’s disease (PD) is complex, with both rare and common genetic variants contributing to disease susceptibility, onset, and progression. The list of highly penetrant rare variants continues to grow, with more than 20 genes reported to cause PD to date.⁹ On top of this, 90 independent risk-associated variants have been identified in genome-wide association studies (GWAS). Despite substantial growth in our understanding of PD genetics, much remains to be uncovered. The majority of common genetic variability remains unidentified, our understanding of the biological functions of identified risk variants is limited, and the link between genetic changes and an individual’s risk of disease is not clear.

Furthermore, nearly all our genetic information from large GWAS comes from European populations. Very little data has been collected from underrepresented populations and thus, findings based on genetic discoveries may not be applicable to all patients with PD. There is a great need for the inclusion of patients from diverse ethnic backgrounds in genetic studies to understand genomic differences in minority populations, discover new influential genes, and enable equal opportunities for appropriate care across the globe. This is the goal of the Global Parkinson’s Genetic Program (GP2).

As a member of the GP2 Steering Committee, Enza Maria Valente, MD, PhD, IRCCS Mondino Foundation & University of Pavia, Pavia, Italy, shares an overview of the GP2 project, which aims to push the boundaries of genetic research by genotyping over 150,000 volunteers from all over the world in the next 5 years. GP2 will use state-of-the-art technology to sample and analyze patients with PD, individuals at risk of PD, and healthy volunteers from Africa, Asia, Europe, and America.¹⁰ The project will consist of a complex disease genetics group, to explore the genetic basis of typical sporadic PD, as well as a monogenic disease arm to identify new causes of monogenic PD.

The efforts of GP2 will deepen our understanding of the genetic basis of PD and tackle gaps in current knowledge by including underrepresented populations. It is hoped analyses will uncover new PD genes, protective variants, relationships between mutations, and variability across individuals of diverse ancestry. GP2 will also provide training and resources on data collection and analysis to ensure standardized methodology is employed across the world, enabling the creation of valuable datasets for the research and therapeutic development community.¹⁰

Why do PD trials keep failing? Seven solutions for neuroprotection

Despite a plethora of attempted strategies and much preclinical success, no neuroprotective agent has demonstrated efficacy in clinical trials for Parkinson’s disease (PD). Disease modifying treatments are the major unmet need in PD despite numerous targets being investigated, including mitochondrial dysfunction, neuroinflammation, cell survival pathways, a-synuclein aggregation, and dopaminergic signaling.¹¹ With almost 50 ongoing trials of PD treatments, it is important to understand why trials to date may have been unsuccessful, and how we can improve current approaches.⁶

Etienne Hirsch, PhD, Institut du Cerveau-ICM, Inserm, Sorbonne Université, Paris, France, outlines seven solutions for neuroprotection in Parkinson’s disease (PD), which he presented in the C. David Marsden presidential lecture at the the International Congress of Parkinson’s Disease and Movement Disorders (MDS),2021.

Of critical importance is the need to select defined patient subgroups with underlying biology that would make them suitable for the intervention being assessed. PD encompasses many subtypes, each with different underlying biology and thus, applying the same approach to treat all patients cannot be successful. A strategy revision is needed: include carefully molecularly and clinically characterized patients in trials to reduce patient variability and improve the accuracy of outcomes.¹¹ To achieve this, objective biomarkers that can segregate patients into clinically meaningful subgroups are needed.

The second solution is to combine pharmacological agents that target multiple pathways. Numerous mechanisms are postulated to be involved in the neurodegenerative process in PD and thus, targeting a single pathway is not sufficient. By targeting several parallel pathways at the same time, there is a better chance of success.¹¹
Late intervention is another aspect of current approaches that need addressing. By the time patients present with clinical symptoms of PD, 80% of their striatal dopamine has been lost. Introducing neuroprotective strategies much earlier in the disease course, when there are more healthy neurons to protect, is likely to improve the efficacy of novel investigational agents. Imaging studies have suggested there is a decade-long prodromal period in PD – longer in younger patients – representing the optimal opportunity to intervene.¹¹ With this comes the need for better prodromal markers.

The 4th issue raised by Prof. Hirsch is the dissonance between typical clinical trial methodology and the slowly progressive nature of neurodegeneration in PD. Due to the location of dysfunction in PD, determining if a drug reaches its target and positively affects disease at a cellular level is difficult. Combined with a lack of reference drugs and reliable biomarkers, trials must rely heavily on clinical measures of success. This does not fit with the slow progression typical of PD.

Disease-relevant designs for neuroprotection trials are needed. Furthermore, the time and expenses inherently associated with drug development hinder progress. Strategies to reduce the risk of drug development in PD are needed, starting with repurposing existing drugs.

Sixth is the issue of the central nervous system (CNS). The requirement of blood-brain-barrier penetration can lead to low and unpredictable biodistribution in the CNS, and typically, parenchymal concentrations are not assessed. Drugs designed for improved penetration, as well as detailed pharmacokinetic studies are required.

The final solution outlined is to adapt preclinical models to improve their predictive value.¹¹ Agents shown to elicit protective effects in animal models have consistently failed to slow disease progression in clinical settings. Moving forward, it is crucial to consider genetic background, immune status, and age in animal models, as well as accounting for the time delay between onset of degeneration and treatment initiation.

Written by Juliet Lawrence