Recent advances in treating Parkinson's disease

Abstract

This article summarizes (1) the recent achievements to further improve symptomatic therapy of motor Parkinson's disease (PD) symptoms, (2) the still-few attempts to systematically search for symptomatic therapy of non-motor symptoms in PD, and (3) the advances in the development and clinical testing of compounds which promise to offer disease modification in already-manifest PD. However, prevention (that is, slowing or stopping PD in a prodromal stage) is still a dream and one reason for this is that we have no consensus on primary endpoints for clinical trials which reflect the progression in prodromal stages of PD, such as in rapid eye movement sleep behavior disorder (RBD) -a methodological challenge to be met in the future.

Keywords: Parkinson's disease; disease modifying treatment; motor symptoms; non-motor symptoms; prodromal stage.

Figure 1.. Scheme of a dopaminergic synapse with the different sites of actions for symptomatic Parkinson’s disease therapy.

COMT, catechol-O-methyl-transferase (inhibitor: entacapone, opicapone ^a, tolcapone); D1, D1 receptor: agonist (new compound in phase III); D2, D2/D3 receptor (non-ergot agonist: apomorphine, piribedil, pramipexole, ropinirole, rotigotine); D2b, presynaptic D2-autoreceptor; DDC, L-DOPA-decarboxylase; DOPAC, dihydroxyphenylacetic acid; L-DOPA ^a, L-dihydroxyphenylalanine (extended release); MAO-A, monoaminooxidase A; MAO-B, monoaminooxidase B (inhibitor: rasagiline, safinamide ^a, selegiline); TH, tyrosine hydroxylase; 3MT, 3 methoxy-tyramine; *, effect of L-DOPA (converted into dopamine); **, effect of dopamine agonists (mimics dopamine at D1 or D2/3 receptor and at D2b autoreceptor); ***, effect of MAO-B-inhibitor (blocks centrally degradation of dopamine, enhances and prolongs dopamine action); ****, effect of COMT-inhibitor (blocks peripherally degradation of L-DOPA, enhances and prolongs presence of L-DOPA in blood and thus enhances and prolongs action of central dopamine action); , vesicle; the round structure represents the symbol for the vesicle , the arrow represents the uptake mechanism - dopamine reuptake mechanism. ^aRecently approved for therapy of Parkinson’s disease ( Table 1).

Figure 2.. Braak’s hypothesis: staging of Parkinson’s disease.

This simplified hypothetical scheme shows how Parkinson’s disease may develop based on the hypothesis of the Braak staging and the “dual hit theory” . OB, olfactory bulb, SLD, sublaterodorsal nucleus of the subcoeruleus/coeruleus complex; lesion of the SLD leads to rapid-eye-movement sleep behavior disorder (RBD). The orange line illustrates the afferent connection from the substantia nigra to the olfactory bulb. The α-synuclein (aSYN) aggregates (red-circled icon) may retrogradely spread from the GIT via the dorsal motor nucleus of the vagal nerve to the locus coeruleus and subsequently ascend to the substantia nigra (Hit 1). It is discussed that the later propagation may either take place by means of direct anterograde transport (thin light blue arrow with question mark – from the LC to the SN) or retrograde transport from the LC to the SN (empty arrow with question mark), or via an intermediate structure (orange circle) such as the amygdala complex (asterix). Likewise the aSYN aggregates (red-circled icon) may retrogradely spread from the OB to the substantia nigra (Hit 2). Dopamine transporter single-photon emission computed tomography (DAT-SPECT): On the right side, images of the striatal presynaptic terminals of the nigrostriatal pathway are visualized by DAT-SPECT. In Braak stage 1, the DAT-SPECT is normal. In Braak stage 2, the DAT-SPECT is still normal (Locus coeruleus −). In Braak stage 3, the nigrostriatal pathway is partially degenerated but less than necessary to cause parkinsonian motor symptoms and signs. The image shows a partial loss of the nigrostriatal dopaminergic terminals in the dorsolateral aspect of the striatum (Locus coeruleus +). The red line indicates the threshold for the extent of the nigrostriatal lesion associated with parkinsonian motor symptoms. In Braak stage 4, the loss of the nigrostriatal terminals in the striatum is so marked that the patient will experience parkinsonian motor symptoms and signs.