Parkinson’s disease: recent advances
- First Online:
- Cite this article as:
- Katzenschlager, R. J Neurol (2014) 261: 1031. doi:10.1007/s00415-014-7308-9
- 1k Views
While a curative treatment for Parkinson’s disease remains elusive, our understanding of disease mechanisms as well as preclinical and pre-motor early manifestations has improved greatly over the past years. An agent with proven disease modifying properties has not yet been identified but symptomatic treatment options for affected patients have improved. For patients with motor complications, this includes invasive approaches such as deep brain stimulation and continuous device-aided drug delivery. The many facets of non-motor problems patients are faced with have finally been fully recognized and have become the target of treatment trials, as have been non-pharmacological approaches.
KeywordsParkinson’s diseaseSymptomatic treatmentDisease mechanism
This article continues a series of updates on neurological conditions published in the Journal of Neurology which are based on selected recent publications, and focuses on new developments in Parkinson’s disease (PD). Our understanding of disease mechanisms underlying this progressive neurodegenerative disorder has improved in the past few years, as have symptomatic treatment options. Research efforts increasingly target pre-motor manifestations as well as the management of non-motor problems.
An increasing body of evidence is pointing toward prion-like mechanisms as potentially underlying the spread of the neurodegenerative process by seeding abnormally folded proteins. Fibrils derived from recombinant alpha-synuclein have been shown to enter neurons and to induce the recruitment of soluble endogenous alpha-synuclein into Lewy body-like inclusion bodies, resulting in neuronal death . Further studies have recently supported the pathogenicity of alpha-synuclein: Nigral Lewy body-enriched fractions containing alpha-synuclein were purified from post-mortem brains of PD patients and inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys . In contrast to control animals, which had received non-Lewy body alpha-synuclein from the same patients, Lewy body-derived human alpha-synuclein was internalised within host neurons, accumulated within nigral neurons, and spread to interconnected areas. This triggered the pathological conversion of endogenous alpha-synuclein and subsequent progressive nigrostriatal neurodegeneration. The spread of pathological alpha-synuclein therefore appears to play an important role in the progression of PD, and Lewy bodies likely represent a protective mechanism. This hypothesis is supported further by evidence from animal models of multiple system atrophy (MSA), pointing toward a similar mechanism .
Biomarkers, risk factors and pre-motor manifestations
Clinical diagnostic criteria and biomarkers
The clinical diagnostic criteria for PD are currently being re-evaluated in view of the heterogeneity of the genetic and molecular changes, the variability of the clinical features and disease courses as well as the long period of time, termed pre-motor, in which a number of non-motor symptoms occur . With the advances in the field of genetics, it appears likely that in the future, PD will be considered to be several diseases with similar and overlapping clinical phenotypes . While the disease can be attributed to a single genetic cause in only a small percentage of patients at present, the contribution of a genetic predisposition is being explored further . No definite biomarker has been established, but this will become increasingly important as the field of research into disease-modifying strategies develops, and in particular once effective disease modifying drugs become available. An example of a potential biomarker is the recent finding of low concentrations of Aβ and P-tau in the cerebrospinal fluid (CSF) of patients with very early PD .
In a retrospective study, 4,634 patients with depression and 18,544 matched control patients were observed for a maximum of 10 years to determine the rates of new-onset PD, and to identify the predictors of PD. During the 10-year follow-up period, 66 patients with depression (1.42 %) and 97 control patients (0.52 %) were diagnosed with PD. After adjusting for age and sex, patients with depression were 3.24 times more likely to develop PD (95 % CI 2.36–4.44, p < 0.001) than controls .
Idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD)
Idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) is a parasomnia characterised by dream-enacting behaviours such as talking, screaming, thrashing, and falling out of bed, which are due to a loss of the physiological atonia (loss of muscle tone) during REM sleep. Several prospective reports had strongly suggested that many patients with IRBD go on to develop a neurodegenerative disorder over time. Long-term follow-up data from a cohort of IRBD patients have recently been published . Of the 44 participants from the original cohort, 36 (82 %) had developed a defined neurodegenerative syndrome by the 14-year assessment (16 patients were diagnosed with PD, 14 with dementia with Lewy bodies (DLB), one with multiple system atrophy, and five with mild cognitive impairment). The rates of survival without neurological disease from the time of the diagnosis of IRBD were: 65.2 % at 5 years, 26.6 % at 10 years, and 7.5 % at 14 years. All four remaining patients free from neurological disease had decreased striatal dopamine transporter tracer uptake, one had substantia nigra hyperechogenicity, and two had impaired olfaction. In three patients, the clinical diagnoses of PD and DLB were confirmed by neuropathological examination. Neuronal loss and Lewy pathology were found in the brainstem nuclei that regulate REM sleep atonia. The findings indicate that IRBD is either a risk factor, or more likely, a prodromal phase of a Lewy body disorder, making it highly suited for inclusion in screening batteries to test disease-modifying strategies.
Following the delayed-start trial of the MAO-B inhibitor rasagiline in de novo PD patients, which had suggested a potential disease modifying effect for the 1 mg dose , no further clinical studies of disease modification have as yet shown encouraging results. The dopamine agonist pramipexole was also investigated in a delayed-start design trial including 535 patients with early PD, at a dose of 1.5 mg daily (PROUD Study; ). Patients were randomised to receiving pramipexole immediately or with a 9-month delay (6 months if deemed clinically necessary). No significant differences between early and delayed pramipexole were found in the primary outcome, the total score on the unified PD rating scale (UPDRS), or in the imaging outcome, dopamine transporter SPECT.
Dopaminergic replacement therapies significantly improve motor function in most patients with PD. However, long-term levodopa therapy is frequently associated with troublesome motor fluctuations and drug-induced involuntary movements (dyskinesias).
Deep brain stimulation
High-frequency stimulation of the subthalamic nucleus or globus pallidus (deep brain stimulation, DBS) greatly improves parkinsonian motor problems and allows a substantial reduction in oral medication. Robust evidence exists for beneficial effects of DBS on refractory motor fluctuations and dyskinesias. A multi-centre study (EARLY-STIM) was set up to determine whether DBS would lead to greater benefits if performed at an earlier stage of the illness, while psychosocial factors are still largely intact . In this study, 251 patients with onset of motor complications within the previous 3 years (mean age, 52 years; mean disease duration, 7.5 years) were randomised to DBS versus strictly standardised best medical treatment. Blinded assessments were carried out, but patients were unblinded. At 2 years, significantly greater improvements were found in the primary outcome measure, quality of life, assessed by PDQ-39 (−7.8 points in the DBS arm versus +0.2 points in the medical arm, p < 0.002), and in the secondary outcomes of motor disability, activities of daily living, motor complications, and time with good mobility and no dyskinesias. Serious adverse events related to surgical implantation or to the device occurred in 17.7 %. Suicides occurred in both arms (two on DBS, one on medical treatment). The authors concluded from the findings on motor function and quality of life that DBS should routinely be considered earlier than it is now, where it is often offered to patients after prolonged attempts to adjust oral medication and after irreversible changes in the patients’ professional and personal lives have occurred. While the EARLY-STIM study certainly contributes to the basis on which treatment choices will be discussed with patients in the future, it should be kept in mind that—as with all carefully designed and performed randomised-controlled studies, but particularly so in the case of this surgical study—the patients entered into this trial do not necessarily reflect the general population of patients with refractory motor complications, who often would not have fulfilled the inclusion criteria due to, e.g., age, comorbid conditions, concomitant medication, or cognitive function. The relatively high suicide rate (compared to the low background rate in PD) also suggests possible differences in the personalities or in expectations between patients who would normally be offered DBS and those selected for EARLY-STIM . In addition, while performing double-blind trials involving surgery poses logistical and ethical difficulties, the fact that this study was not blinded (although the assessments were carried out by blinded raters) also detracts from the generalisability of the findings.
Continuous drug delivery
Although our understanding of the mechanisms underlying motor complications remains incomplete, discontinuous drug delivery is thought to be involved. While striatal dopamine release is relatively stable under physiological conditions, substitution with a short half-life drug such as levodopa is associated with oscillating dopamine concentrations that are believed to induce maladaptive changes in basal ganglia motor circuits. Several uncontrolled studies had suggested that switching patients with refractory motor complications from oral to continuous treatment might improve motor fluctuations and possibly also dyskinesias. The first randomised, placebo-controlled study of continuous pump delivery of a dopaminergic drug in this clinical scenario was published recently . In this 12-week study, all 71 patients underwent gastrostomy and were randomised to intrajejunal or oral immediate-release levodopa in a double-dummy design. The degree of improvement with intrajejunal levodopa [1.91 h less OFF time per day than with oral levodopa (95 % CI −3.05 to −0.76, p = 0.0015)] is smaller than previously reported in uncontrolled studies, but the results very likely reflect true superiority of continuous intraintestinal delivery of levodopa. The magnitude of decrease in OFF-time from baseline (−4 h) exceeds that reported for any agent tested so far; moreover, quality of life improved significantly. The conclusions on dyskinesia that can be drawn from the study are less firm. Included patients had relatively little baseline dyskinesia and there was little change in both arms. Moreover, no measure of dyskinesia severity was employed. Even so, the findings strongly suggest a clinical benefit, as there was a significantly greater increase in ON time without troublesome or without any dyskinesia in the infusion group. The impressive symptomatic effects that can be achieved with intrajejunal levodopa come at a price, however . This procedure is associated with risks and requires the insertion of a percutaneous gastrojejunostomy tube. In the placebo-controlled study, 97 % of patients experienced at least one adverse event, and in 89 %, a complication related to the device occurred. Three patients discontinued due to adverse events; in one case this was peritonitis. While most adverse events were mild or moderate and resolved, the risk of surgical and device-related complications must be taken seriously. In addition, several reports have linked levodopa exposure to peripheral neuropathy , and weight loss and possible malabsorption have also been observed. This highly effective but invasive treatment should only be used in the setting of expert movement disorder centres closely collaborating with gastroenterology units.
The relative efficacy and safety of the three currently available device-aided and invasive treatments for motor complications in PD, DBS, intrajejunal levodopa and subcutaneous infusion of the dopamine agonist apomorphine have not been investigated in randomised studies. While level 1 evidence is now available for DBS and for intrajejunal levodopa, a randomised, placebo-controlled study of apomorphine infusion is currently underway.
The impact of non-motor problems that PD patients face has finally been fully recognised over the past years . These include neuropsychiatric and dysautonomic problems, pain and non-motor fluctuations.
Depression has been shown to have an important impact on quality of life in PD patients. To evaluate the efficacy of a selective serotonin reuptake inhibitor and a serotonin and norepinephrine reuptake inhibitor, 115 patients were randomised to paroxetine (at a maximum dose 40 mg per day), venlafaxine (maximum 225 mg) or placebo . Patients met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression. The primary outcome measure was change in the Hamilton Rating Scale for Depression from baseline to week 12. Treatment effects (relative to placebo) were 6.2 points (97.5 % CI 2.2–10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5 % CI 0.1–8.4, p = 0.02) in the venlafaxine group. No changes were seen in motor function. This study provides evidence for efficacy and safety for drugs from two classes that are frequently used in clinical practice for depression associated with PD and for which high level evidence had previously been missing.
Among the many non-motor problems affecting patients with PD, psychosis is particularly relevant, as it represents a great burden to caregivers and increases the risk that a patient can no longer be looked after at home, but will move to a nursing home. While the cholinesterase inhibitor rivastigmine may relieve psychotic symptoms in PD patients, (Emre 2004) it is not licensed for this indication, and neuroleptics often become necessary. Among the available antipsychotics, only clozapin has been classified as being effective in PD patients ; however, specialised monitoring is required due to the risk of agranulocytosis. Quetiapine, which is used more commonly in clinical practice, as it does not carry this risk, does not have evidence for efficacy in PD-related psychosis. All classical neuroleptics, but also olanzapine and several other atypical neuroleptics, have been shown to lead to considerable motor worsening in PD patients. Therefore, there is an urgent clinical need for additional therapeutic options for psychosis in PD. Pimavanserin is a selective serotonin 5-HT2A inverse agonist and was investigated at a dose of 40 mg per day in a 6-week, randomised, double-blind, placebo-controlled study in 199 PD patients with psychosis . The design included a 2-week lead-in phase to limit the placebo response, which has been shown to be high in PD. The primary outcome was antipsychotic benefit as assessed by independent raters with the PD-adapted scale for assessment of positive symptoms (SAPS-PD). Pimavanserin was associated with a −5.8 decrease in SAPS-PD scores compared with −2.7 for placebo (95 % CI for difference −4.9 to −1.2, p = 0.001). Pimavanserin was well tolerated without significant safety concerns or worsening of motor function. With this potentially improved safety profile compared to other neuroleptics, pimavanserin might turn out to be useful for the treatment of patients with PD and psychosis. In fact, it might help prevent progression to more severe forms of psychosis, as use of neuroleptics has been linked to less progression in the severity of neuropsychiatric problems in PD .
Physical therapy in PD
The area of non-pharmacological interventions for motor problems in PD has been recognised as potentially important, and these approaches are now being investigated in randomised trials. While many of the reports of various interventions have methodological limitations, including a lack of blinding, physical therapy as a whole was classified as likely efficacious by the Evidence Based Medicine Task Force of the International Parkinson and Movement Disorder Society .
The therapeutic methods investigated vary widely and have included a type of physiotherapy termed “BIG”, which is based on the principles of Lee Silverman voice training and focuses on high amplitude movements . Other randomised trials have investigated, among other approaches, dancing, tai chi, qigong, treadmill training, and acoustic cueing , and an increasing number of reports has been published more recently [2, 9, 22]. While methodological issues remain, these studies largely confirm the overall encouraging results for physical therapy in patients with PD.
PD remains a relentlessly progressive neurodegenerative disorder, with patients increasingly troubled by motor and non-motor problems as the disease progresses. The search for an intervention that may slow or halt this process is therefore of utmost importance. This goal has remained elusive, but a number of pharmacological and non-pharmacological treatments that have been reported or investigated in recent years have helped to improve patients’ quality of life.
In addition, very early diagnosis has improved. Screening batteries involving a number of risk factors and early non-motor signs have been identified, and potential biomarkers are being explored. All of these will become particularly important once a strategy with disease-modifying properties becomes available.
Conflicts of interest