Early detection and treatment of Parkinson’s disease

Prodromal Parkinson’s disease: A focus on REM sleep behaviour disorder

By the time Parkinson’s disease (PD) is diagnosed, there is large loss (50−89%) of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta (SNPc). Loss of dopaminergic markers and transporters in the dorsal putamen and of melanised neurons in the SNPc are modest at this stage but progress to gross loss.¹

These findings, discussed Professor Pavese, mean that disease modifying agent administration needs to be far earlier than time of diagnosis, but, he posed, how do you recognise symptoms early enough to make a difference?

Several years before PD diagnosis, ‘pre-motor’ symptoms include rapid eye movement (REM) sleep behaviour disorder (RBD),² involving disruptive or abnormal behaviours during REM sleep. This typically first presents from age 50, with a higher prevalence in males, and is associated with an increased risk of developing PD.³

There are several corresponding pathological findings between PD and RBD. In early PD there is a build-up of α-synuclein aggregates in the brain or peripheral organs, which may represent two different prodromal stages.⁴ This is reflected by decreased acetylcholinesterase (ACh) in the small intestine, indicating a reduction in parasympathetic innervation, a known factor in PD.⁵ In RBD, there is decreased ACh density in the transverse colon, which is significantly different from controls but not from people with PD.⁶ This, said Professor Pavese, suggests that in people with RBD who develop PD, initial insult is in the periphery while in people with PD without prodromal RBD, initial insult is in the brain.⁴

There are pathological correlates between REM sleep behaviour disorder and Parkinson’s disease

Additionally, cholinergic denervation has been found in the neocortex of people with RBD⁷ along with monoaminergic innervation dysfunction in the thalamus. This latter finding potentially reflects dysfunction of locus coeruleus projecting neurons,⁸ part of the network involved in the abolisment of muscle tone during REM sleep.^6,9 Also shown is significantly higher cholinergic neuronal integrity in brainstem areas, which was suggested to be compensatory for neurodegenerative processes.¹⁰

In PD there is decreased SNPc neuromelanin compared to controls, with people with RBD showing intermediate decreases between the two.¹¹ Reduced neuromelanin has also been shown in the locus coeruleus in RBD.¹² Increased echogenicity (assessed by ultrasound) is found in the substantia nigra in both PD¹³ and RBD,¹⁴ although this has not proved useful for identifying who with RBD will develop PD.¹⁵ Finally, widespread microgliosis in PD¹⁶ is reflected in RBD in some areas of the substantia nigra,¹⁷ linked to reduced cortical ACh activity.¹⁸

The role of α-synuclein in Parkinson’s disease pathology

Potential mechanisms that lead to neurodegeneration in PD include misfolded α-synuclein.¹⁹ Indeed, PD is characterised by accumulation of α-synuclein deposits in Lewy bodies.²⁰ However, PD does not have a simple, single gene pattern of genetic influence and while multiplications have been found in the α-synuclein gene (SNCA), this finding is not universal.²¹

α-synuclein aggregation prior to Lewy body formation may cause cell loss

Spreading of α-synuclein pathology is the basis of Braak staging of PD,²² although the picture is not as simple as this as Lewy body distribution can be variable and without correlation with disease stage²³ or neuronal loss.²⁴ As such, Professor Fleming Outeiro questioned which stage between initial α-synuclein aggregation and Lewy body formation is the most toxic with regard to cell loss as it is hypothesised that pre-fibrillar oligomeric forms can cause cell loss, with Lewy bodies being the aftermath.²⁵

Upcoming disease modifying treatments

Despite therapy, discussed Professor Antonini, PD progression is unaffected by all current medications, including levodopa.^26,27 With the large focus on α-synuclein, he questioned whether targeting events that lead to aggregation may help delay progression.²⁸ One way of inhibiting protein aggregation may be with the use of blood brain barrier (BBB)-penetrating small molecule-based colloidal nanoparticles.²⁹ One such molecule, UCB0599, inhibits α-synuclein folding and a Phase 1b clinical trial, including people with PD, showed that orally-administered UCB0599 is generally well-tolerated and can cross the BBB.^30-32

Parkinson’s disease modifying treatments include those targeting α-synuclein aggregation

A number of therapies in clinical trials revolve around immune system components including monoclonal antibodies that have the potential to clear α-synuclein brain aggregates.³³ These have been shown to clinically impact motor signs in people with early PD over a period of 1 year.³⁴ Nanobodies derived from antigen binding fragments of dromedary heavy-chain antibodies are also being produced that can be directed against α-synuclein and block fibril aggregation, as has been shown in vitro.³⁵As we have natural antibodies against α-synuclein,³⁶ another strategy is to boost this immunity, with early studies showing such therapies can produce a humoral immune response.³⁷

Genetic analysis of people with PD have confirmed four genes with a positive association to PD, including GBA1.³⁸ Treatments that can increase glucocerebrosidase activity are in clinical trials to ascertain their effects on motor symptoms in PD, with a noncontrolled trial indicating potential use in this realm.³⁹ Another PD-associated gene, LRKK2, is also being targeted with the use of an LRRK2 kinase inhibitor that has been shown to cross the BBB.⁴⁰