2006 overview: Highlights from Parkinson's research

Highlights 2006

There were no break-throughs in the field of Parkinson disease in year 2006, yet there were several significant results with regard to clinical practice and understanding of disease pathophysiology. The highlights, most of which have been described during the year, are excerpted below.

Deep-brain stimulation of subthalamic nucleus has been an increasingly popular treatment approach with dramatic results in short-term, the question has been open how long the beneficial effects would last and if there would be any long-term safety issues. These issues were addressed in a new study (ref. 1).

In 37 consecutive PD patients treated with bilateral STN stimulation, 5 years after surgery UPDRS ADL Score was improved during stimulation of the STN by 40% ("off" drug) and 60% ("on" drug). UPDRS Motor Score was improved by 54% ("off" drug) and 73% ("on" drug). The severity of levodopa related motor complications was decreased by 67% and the levodopa daily doses were reduced by 58%.

The Mattis Dementia Rating Scale score remained unchanged, but the cognitive performance declined significantly. The authors concluded that despite moderate motor and cognitive decline over time, which they interpreted to be probably due to disease progression, the marked improvement in motor function observed after surgery was sustained for 5 years. Thus, this method remains as a powerfull tool in the treatment of PD patients with motor complications, one should, however, be aware of possible persistent behavioral problems.

Dopaminergic cell transplantation in patients with PD had fallen in disfavor after disappointing results and uncontrollable dyskinesias were reported in patients with transplantation of fetal dopaminergic cells. It remained open if transplantation of other types of cells may provide better results. In a small, open-label study the efficacy and safety of human retinal pigment epithelial cells, which  produce levodopa, were investigated (ref. 2).

Six patients with advanced PD received intrastriatal implantation of approximately 325,000 RPE cells on microcarriers, into the putamen contralateral to the more symptomatic side. At 12 months after the implantation there was an average improvement of 48% in the UPDRS motor score in the off-state, which was sustained through 24 months. Improvements were also seen in a number of secondary measures.

Importantly, no off-state dyskinesias were observed. These results were encouraging, but before this method is accepted as a new way of dopaminergic cell transplantation, results from larger controlled studies must be awaited.

PD has long been conceived to be a purely motor disorder. Cognitive dysfunction already in non-demented patients, however, has been increasingly more recognized and it was suggested that visual dysfunction may be one of the earliest ones. This was confirmed in a prospective study in a sizable population (ref. 3). Patients with PD scored significantly worse on all tests of vision and cognition compared to normal elderly persons.

Impairments in visual attention and spatial perception predicted worse cognitive function. Worse performances on tests of visual speed of processing and attention, spatial and motion perception, visual construction, and executive functions correlated with measures of postural instability and gait difficulty as measured with UPDRS.

Novel strategies in early phases of drug development are necessary, especially to predict the potential value of treatment strategies which can only be properly assessed in large samples and over a long durations, such as disease modifying agents for PD. Futility designs, a type of Phase II clinical trials intended to eliminate substances that show low potential for further development that can serve this purpose: those substances which do not perform better than a pre-determined futility threshold are rejected as futile.

Creatine and minocycline, which were previously prioritized for clinical testing in PD based on a systematic review of potentially neuroprotective compounds, were tested in a study with futility design involving 200 patients. Both compounds were found to be "non-futile" (ref. 4). Based on these reults a larger trial with creatine has been initiated and is still ongoing.

Unlike promising results with retinal dopaminergic cell transplantation, disappointing results were reported with another interventional treatment approach, which was reported to be promising in earlier smaller studies. Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic effects on midbrain dopaminergic neurons. In a randomized, placebo controlled trial 34 patients with advanced PD were randomized to receive either bilateral continous intraputaminal infusion of GDNF (liatermin) or placebo (ref. 5).

At 6 months, mean percentage changes in the primary end-point, UPDRS motor score during "off" phase, as well as secondary end-points, did not show any significant difference between active and placebo groups. Neutralizing anti-liatermin antibodies were detected in three patients. This study was another example of disparate outcomes between open-label and double-blind, randomized, controlled surgical studies and demonstrated once more the necessity of controlled studies, also for surgical interventions, however difficult they may be to conduct.

The effects of DBS on functional activation of motor cortex and related cortical areas have not been well understood. The effects of therapeutic unilateral DBS of the STN was assessed in an experimental study involving 6 patients (ref. 6). During movement execution effective DBS caused an increase of activation in the supplementary motor area (SMA), superior parietal cortex, and cerebellum towards a normal pattern.

At rest, effective stimulation reduced overactivity of SMA. Therapeutic stimulation also induced reduction of movement related "overactivity" compared with healthy subjects in prefrontal, temporal lobe, and basal ganglia circuits, consistent with the notion that many areas are recruited associated with reductions of activity in primary motor cortex, SMA and basal ganglia.

It was concluded that effective subthalamic nucleus stimulation leads to task-specific modifications with appropriate recruitment of motor areas as well as wide-spread, nonspecific reductions of compensatory or competing cortical activity, normalizing the disruptive pattern of activity.

In patients who develop Parkinsonism under neuroleptic treatment, it can be difficult to judge if symptoms are due to dopamine receptor blockade alone or combined with a co-existent nigrostriatal dysfunction. It has been reported that imaging of dopamin transporter (DaT) receptors using (123I)-FP/CIT SPECT helps to differentiate between pre-synaptic versus post-synaptic dysfunction in nigrostriatal dopaminergic transmission.

This was further investigated in a cross-sectional study involving 20 patients in whom parkinsonian symptoms developed during treatment with neuroleptcis (ref. 7). Eleven patients showed significantly diminished striatal binding, suggesting degeneration of the nigrostriatal system, particularly in the caudate and putamen. There were no differences in clinical features between patients with normal and abnormal scans, including asymmetric tremor.

These results indicate that DIP is clinically indistinguishable from PD, it should not be taken as granted that parkinsonism developing under neuroleptic treatment is always drug-induced and brain imaging with FP-CIT may help to discriminate.
 
REM-sleep behaviour disorder (RBD) is characterized by dream-enacting behaviours such as shouting and punching, usually related to scary or unpleasent dreams. Although RBD can be idiopathic, it has been suggested that RBD may also be the initial manifestation of neurodegenerative diseases, basically those associated with synuclein pathology. The frequency and nature of neurological disorders developing in patients diagnosed to have idiopathic RBD was evalauted in a further study (ref. 8).

Fourty-four consecutive patients with at least 2 years of clinical follow-up after a diagnosis of idiopathic RBD were retrospectively assessed. Twenty (45%) patients developed a neurological disorder after a mean of 11.5 (range 6-23) years from the reported onset of RBD. Emerging disorders included PD in nine patients, DLB in six, MSA in one, and MCI in four. This study confirmed that RBD often antedates the development of a neurodegenerative disorder and  follow-up of patients with idiopathic RBD could enable early detection of such diseases.

Apathy has been reported to be frequent in PD, more so when cognitive impairment is present. At times it is difficult to differentiate apathy from lack of motivation due to depression, and the true extent of apathy in PD has not been studied using appropriate scales and a disease control group. This was achieved in a study in 80 consecutive PD patients and 20 patients with dystonia (ref. 9).

Validated scales were used to assess apathy, depression and correlation thereof. There was a significantly higher severity and frequency of apathy in PD (frequency 51%) than in dystonia (frequency 20%). When those patients with a diagnosis of depression were excluded, apathy in the absence of depression was still frequent in PD, and did not occur in dystonia (PD 28.8%, dystonia 0%). It was concluded that apathy may be a core feature of PD occuring in the absence of depression, possibly due to impairment in dopaminergic modulation of frontal-subcortical circuits subserving motivation.

As for apathy, excessive daytime sleepiness is frequently observed in patients with PD, this phenomenon has been blamed on drugs, especially on dopaminergic agonists, whereas others put the blame on the disease process itself. Associated demographic features, clinical correlates and the development of excessive daytime sleepiness (EDS) were evaluated over an 8 year period in patients in a cohort of 232 patients with PD (ref. 10).

Frequency of EDS increased from 5.6% at baseline to 22.5% after 4 and to 40.8 after 8 years, with an 8-year prevalence of 54.2%. In the logistic regression model, EDS was related to age, gender, and use of dopaminergic agonists. In those who never used dopamine agonists hypersomnia was associated with the Hoehn and Yahr stage only. It was thus concluded that EDS is a frequent and persistent feature in PD, the findings indicate a role for age, disease related disturbances of sleep-wake regulation as well as treatment with dopamine agonists.

Although epidemiological data suggest a role for genetics also in sporadic PD, few genetic variants have been unequivocally linked to it. Genome-wide screens can be a suitable method to identify common genotypic variants which may be associated with sporadic PD. A new study attempted to identify any common genetic variability exerting a large effect in risk for PD in a population cohort (ref. 11).

A genome-wide, single-nucleotide-polymorphism (SNP) genotyping was performed in 267 patients with PD and 270 neurologically normal controls. Genotype and allele association tests were performed comparing the patient population with normals. The results did not identify any significant differences between patients and controls. In a previous  genome-wide screening 13 SNPs were found to be associated with increased risk for PD. These results met with justified excitement, unfortunately these associatons could not be confirmed in this study.

The year ended with reporting of an important study, albeit the results were negative. TCH 346, a potent anti-apoptotic agent, that protects against loss of dopaminergic neurons in laboratory models was tested in patients with early untreated PD, as a potential neuroprotective drug (ref. 12). Three different doses of TCH were tested against placebo in 301 patients treated for 12-18 months.

Unfortunately, the primary outcome (time to development of a disability requiring dopaminergic treatment) as well as secondary measures (annual rate of change in UPDRS and PDQ-39, a mesure of quality of life) did not show any difference between treated and untreated groups. This was another example of discrepancy between strongly positive preclinical findings as opposed to negative clinical results.

References

1. Schupbach WM, Chastan N, Welter ML, Houeto JL, Mesnage V, Bonnet AM, et al. Stimulation of the subthalamic nucleus in Parkinson's disease: a 5 year follow up. Journal of Neurology, Neurosurgery and Psychiatry 2005;76 (12); 1640-1644

2. Stover NP, Bakay RA, Subramanian T, Raiser CD, Cornfeldt ML, Schweikert AW, et al. Intrastriatal implantation of human retinal pigment epithelial cells attached to microcarriers in advanced Parkinson disease. Archives of Neurology 2005; 62 (12); 1833-1837

3. Uc EY, Rizzo M, Anderson SW, Qian S, Rodnitzky RL, Dawson JD. Visual dysfunction in Parkinson disease without dementia. Neurology 2005; 65 (12); 1907-1913. [Epub 2005 Nov 9]

4. NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 2006; 66 (5); 664-671. [Epub 2006 Feb 15]

5. Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Annals of Neurology 2006; 59 (3); 459-466

6. Grafton ST, Turner RS, Desmurget M, Bakay R, Delong M, Vitek J, et al. Normalizing motor-related brain activity: subthalamic nucleus stimulation in Parkinson disease. Neurology 2006; 66 (8); 1192-1199

7. Lorberboym M, Treves TA, Melamed E, Lampl Y, Hellmann M, Djaldetti R. [123I]-FP/CIT SPECT imaging for distinguishing drug-induced parkinsonism from Parkinson's disease. Movement Disorders 2006; 21 (4); 510-514

8. Iranzo A, Molinuevo JL, Santamaria J, Serradell M, Marti MJ, Valldeoriola F, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurology 2006; 5 (7); 572-577

9. Kirsch-Darrow L, Fernandez HH, Marsiske M, Okun MS, Bowers D. Dissociating apathy and depression in Parkinson disease. Neurology 2006; 67 (1); 33-38

10. Gjerstad MD, Alves G, Wentzel-Larsen T, Aarsland D, Larsen JP. Excessive daytime sleepiness in Parkinson disease: is it the drugs or the disease/a>? Neurology 2006; 67 (5); 853-858

11. Fung HC, Scholz S, Matarin M, Simon-Sanchez J, Hernandez D, Britton A, et al. Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurology 2006; 5 (11); 911-916

12. Olanow CW, Schapira AH, LeWitt PA, Kieburtz K, Sauer D, Olivieri G, Pohlmann H, et al. TCH346 as a neuroprotective drug in Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurology 2006; 5 (12); 1013-1020