MDC Publication Highlights - January 2020

Ambroxol for the Treatment of Patients with Parkinson's: outcomes from the first clinical trial

One of the most important risk factors for developing Parkinson’s disease are mutations in the Glucocerebrosidase (GCase) gene, also referred to as GBA1. The GCase protein plays an important role in the cells’ process of removing waste in a more effective manner. As such it has been suggested that increasing the levels of this protein in the cells may also enhance the waste removal process and thereby keep cells healthy for longer, providing a neuroprotective effect. Previous studies using Ambroxol, a drug commonly found in cough medication for individuals suffering from respiratory disease, showed that this common drug does exactly this. The current study, led by MDC researcher Prof. Tony Schapira, was designed to explore the safety and potential effectiveness of engaging the intra-cellular targets of Ambroxol in people with Parkinson’s. This was a single-center open-label non-controlled clinical trial with 18 participants who received an escalating dose of Ambroxol (up to 1.26 g per day) for up to 6 months.
Outcomes of the trial indicated that Ambroxol was safe and well tolerated. Ambroxol was also shown to cross the blood-brain barrier, a common obstacle in the treatment of diseases of the nervous system, bind to its targeted GCase enzyme and increase its expression levels. The trial’s positive outcomes merit an additional investigation, via a larger-scale placebo-controlled trial, of Ambroxol as a potential way to slow down Parkinson’s disease progression.

• Mullin et al. ‘Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial’. JAMA Neurology, First Published: 13 January 2020, DOI: 10.1001/jamaneurol.2019.4611.

Experience of health services and unmet care needs of people with late-stage Parkinson’s in England

It is estimated that in the UK, one in 50 people over the age of 65 have a form of Parkinsonism, a number that is predicted to double by 2030. Current treatment options can address some of the motor and non-motor symptoms Parkinsonism in the early and middle stages of the disease, but later disease stages are associated with increased disability, complex care needs and greater need for support from health and social services. International guidelines have stated the need for multidisciplinary, holistic and palliative approaches to care for this group, however, the implementation of these has shown to be variable and there can be a lack of integrated care.  
Little is known of the needs and care of those with Parkinson’s from their own perspective, particularly in the late stages when disability is greatest and communication is most difficult. This study, led by Prof. Schrag from the MDC, sought to explore experiences of service use and unmet care needs of those with late stage Parkinson’s who have high degrees of disability. This information may help address their care needs in the English healthcare system where different healthcare professionals are variably employed in community or secondary care, with some local and regional differences in availability of health and social care. In this qualitative research, ten people with advanced Parkinson’s living in the UK were interviewed using semi-structured open-ended questions.
Findings showed that the most common reports of unmet care needs by the participants were lack of flexibility of healthcare structure and service provision that accommodated their complex and individual needs. Emphasis was put on the need for support in their own home and the positive relationship with healthcare providers. These were highlighted as important for people with Parkinson’s for maintaining a degree of personal identity and normality. In addition, the provision of information was also important for these patients to maintain a level of control over their own care. Overall, findings indicated that there is a need for a more informed discussion on future care planning for this specific group of people with late stage Parkinson’s.

• Read et al. ‘Experiences of health services and unmet care needs of people with late-stage Parkinson’s in England: A qualitative study’.  PLoS ONE, First Published: 30 December 2019, DOI: 10.1371/journal.pone.0226916.

Diagnosis across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

Progressive Supranuclear Palsy (PSP), Corticobasal syndrome (CBS) and multiple system atrophy (MSA) are generally called atypical parkinsonian syndromes (APS). Although these conditions may resemble Parkinson’s disease (PD) upon initial presentation and at early disease stages, they are characterised by a more rapid deterioration and poorer response to Parkinson’s medication (such as levodopa). Currently, the only way to confirm the diagnosis of any of the atypical parkinsonian conditions is through post mortem neuropathological examination. This lack of disease-specific diagnostic markers causes delays in diagnosis (in about 50% of people living with PSP) as individuals are often given the wrong initial diagnosis. With the growing number of clinical trials testing new treatments that could potentially stop or slow the progression of disease, the need for an early and accurate diagnosis is critical for proper assignment of patients and trials and in the future, for timely initiation or the correct course of treatment.
The longitudinal research programme, PROSPECT, led by MDC researcher Prof Huw Morris, is looking at patterns of clinical, cognitive, MRI and blood protein in individuals with atypical parkinsonian syndromes. The aim of this study is to identify markers that can differences between subgroups of PSP and CBS patients and assess their usefulness in facilitating early diagnosis and separation from Parkinson’s. The first phase of this project has been completed and the current publication explored the PS in depth. The researchers found that PSP was massively underdiagnosed: Applying the Movement Disorder Society PSP diagnostic criteria to all study participants almost doubled the number of patients diagnosed with PSP. The researchers also identified a large number of patients with specific sub-types of CBS and PSP who had longer diagnostic latency and relatively benign clinical trajectories, making them more likely to be misdiagnosed based on existing clinical criteria. The researchers were able to identify new biomarkers (including clinical features and CSF markers) that could enhance early diagnosis for PSP and CBS. Overall, the study indicates that PSP may be twice as common as initially expected, highlighting the importance of early and accurate diagnosis and proposing new diagnostic tools.

• Jabbari et al. ‘Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome’. JAMA Neurology, First Published: 20 December 2019, DOI: 10.1001/jamaneurol.2019.4347

Brain genetic mosaicism in synuclein-related pathologies

Disorders such as Parkinson’s disease, Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) all belong to a group of conditions called synucleinopathies. These conditions are characterized by the formation of abnormal clusters (or aggregates) of a particular protein called alpha-synuclein in the brain. Synucleinopathies very rarely have a genetic background, and in most cases do not have a clear underlying genetic (or other) cause. In recent years, MDC researcher Dr. Christos Proukakis has been investigating the role of mosaicism in Synucleinopathies. Mosaicism is a condition in which different body parts within a single person may actually have different DNAs and therefore express different proteins. The researchers have previously shown that people with synucleopathies are more likely to show genetic mosaicism of the alpha-synuclein gene (SNCA). Patients were more likely to show multiplication of the alpha-synuclein gene in DNA expressed in their brain, but not in DNA taken from other body tissues. In the current publication, the researchers used a technique called single cell whole genome sequencing, allowing them to investigate the function of individual cells at a high resolution, to further characterize SNCA mosaicism in synucleopathies. The study found that levels of SNCA copies in the brain were higher in neurons from individuals with PD and MSA than in control samples. In MSA samples, this was this was also found in non-neuronal brain cells, which is in line with the known pathology pattern of the disease. This suggests that the number of SNCA copies in the brain may contribute to the development of these conditions, and that the involvement of other genes that show brain-specific variations should be further investigated.

• Perez-Rodriguez et al. ‘Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing’. Acta Neuropathologica Communications, First published: 23 December 2019, DOI: 10.1186/s40478-019-0873-5.