2005 overview: Highlights from Parkinson's research

The year 2004 ended with the publication of two significant papers related to the treatment of Parkinson’s disease (PD), which constituted the topic of the first two reviews in this year’s commented articles . Other highlights from this year are described below.

Rivastigmine

The first large randomized controlled trial in PD dementia with a cholinesterase inhibitor, rivastigmine revealed that the both primary and all secondary efficacy parameters showed significant benefits in favour of rivastigmine. The most frequent adverse events were nausea and vomiting, worsening of tremor was reported in 10% of the patients, it was, however, rarely a cause of discontinuation.

This study was important because it demonstrated for the first time in a large, controlled, prospective study that cholinergic stimulation with a ChE-I can provide benefits in all symptom domains of dementia associated with PD, a condition for which there has been no specific treatment available (ref. 1).

Gold Standard

The gold standard in the treatment of PD, L-dopa, has been used for decades without having a properly designed large enough, long-term efficacy study. This gap was filled with the ELLDOPA trial which was conducted also amidst the concerns that L-dopa could be toxic. The results revealed a clear-cut dose-response.

Clinical measures suggested that benefits of L-dopa were still detectable two weeks after discontinuation, suggesting that L-dopa is not toxic and may be protective, whereas the imaging results suggested that L-dopa was associated with a reduction in the number of dopamine transporter sites, a measure of presynaptic dopaminergic terminals, which stood in contradiction with the clinical measures. Thus the issue on potential beneficial or hazardous effects of long-term L-dopa remained unresolved (ref. 2).  

Glial cell line-derived neurotrophic factor

The long-term results of a small, open study in five patients published earlier this year suggested that intraputaminal infusion of glial cell line-derived neurotrophic factor continued to improve off-medication motor and ADL subscores of UPDRS over 2 years (ref. 3). It was announced subsequently, however, that the randomized, controlled study with glial cell line-derived neurotrophic factor (GDNF) in PD has been discontinued, the results for this study await publication.

Surgical treatment

Two papers also published earlier this year extended our knowledge on surgical treatment of PD. In the first paper it was reported that stimulation of either the internal globus pallidus (Gpi) or subthalamic nucleus (STN) improved features of advanced PD, it was concluded that it would be premature to exclude GPi as an appropriate target for deep brain stimulation (DBS) in patients with advanced disease (ref. 4).

Another study on DBS demonstrated that motor symptoms greatly improved by bilateral STN stimulation even in patients with previous thalamic surgery, and STN stimulation was more effective than ventral intermediate thalamic nucleus (VIM) stimulation in tremor dominant parkinsonian patients (ref. 5).

Rasagiline

Rasagiline, a novel, selective and irreversible MAO-B inhibitor has been previously reported to be effective in the treatment of de novo patients with Parkinson disease. The results of two large randomised clinical trials (RCT) published this year extended the knowledge base on rasagiline.

The PRESTO trial revealed that rasagiline was effective in reducing off time in patients with motor fluctuations, despite optimized levodopa treatment. The efficacy of rasagiline in fluctuating patients as compared to COMT inhibitor entacapone, another treatment strategy to increase the efficiency of dopaminergic treatment, was reported in the LARGO study which revealed that rasagiline 1 mg, once daily reduced mean daily off-time and improved symptoms of PD in levodopa-treated patients with motor fluctuations, with an effect size similar to that of entacapone (ref. 6; ref. 7).

Cigarette smoking

The inverse relation between cigarette smoking and the risk of PD is one of the most robust epidemiological associations known for PD. Two more studies published this year further confirmed and extended this association.

In the first study patients with high exposure to pesticides and thus theoretically at increased risk to develop PD also seemed to demonstrate the inverse association. In other words if smoking is indeed protective it seemed to do so also in this high risk population.

The second study took the siblings of patients as controls, thus reducing the effect of confounding due to potential ethnic variability and resulting genetic variation in control groups.

The results confirmed the inverse association between cigarette smoking and the risk of PD, the mechanism of this effect, however, still remains elusive (ref. 8; ref. 9).

Driving performance

Impaired driving performance and an increased accident risk have been reported for patients with PD. Although a control group of age-matched healthy individuals was missing, a study published this year also revealed a substantial risk of driving accidents and demonstrated that in addition to motor disability daytime sleepiness and falling asleep at the wheel are significantly correlated with increased risk of accidents.

The results suggest that it is important for physicians to inquire with their patients and their families for the presence of daytime sleepiness and sleep attacks (ref. 10).

Pathological staging

Braak and his co-workers had previously proposed a pathological staging for sporadic Parkinson disease, similar to that used for pathological staging of Alzheimer disease. This year they reported the association between cognitive status and the neuropathological staging of sporadic PD.

They concluded that the risk of developing dementia increases with disease progression, in some individuals, however, cognitive decline can develop in the presence of mild PD-related cortical pathology and, conversely, widespread cortical lesions do not necessarily lead to cognitive decline (ref. 11).

Nutrition

The role of nutrition in neurodegenerative diseases, particularly of certain nutrients, such as vitamins and fatty acids, has always been a hot topic. The association between dietary fatty acids and the risk of PD was investigated in the large, prospective, population-based Rotterdam Study covering 5,289 subjects.

After a mean follow-up of 6 years, 51 subjects were diagnosed with incident PD, the intake of total fat, monounsaturated fatty acids, and polyunsaturated fatty acids were significantly associated with a lower risk of PD, no associations were found for dietary saturated fat, cholesterol, or trans-fat. The authors suggested that high intake of unsaturated fatty acids might protect against Parkinson disease (ref. 12).

Levodopa

Levodopa still remains to be the most effective medication in the treatment of PD, its long-term motor complications, however, still remain as a concern. The role of non-physiological, pulsatile stimulation of striatal dopaminergic receptors and the subsequent involvement of downstream, non-dopaminergic mechanisms in the development of these complications have been hypothesized, including an involvement of 5-HT1A autoreceptors.

It was also suggested that the inhibition of striatal serotonergic neuron firing by stimulation of their autoreceptors may result in maintaining a more physiological intrasynaptic dopamine concentration. These assumptions seem to have gained some support from a small, but carefully conducted proof-of-concept study.

The results of this study demonstrated that sarizotan, a selective 5HT1A agonist, co-administered with L-dopa, reduced dyskinesias and prolonged the duration of action of L-dopa without reducing its anti-parkinsonian efficacy (ref. 13).

LRKK2 mutations

Mutations in the LRRK2 gene, encoding the protein called dardarin, were the latest added in the list of inherited PD. Some families with LRKK2 mutations have been reported to include patients with highly variable clinical and pathological features, raising the possibility that these mutations may be found in other diseases.

A recent study investigated the presence of the most common mutation of LRKK2 gene in a series of patients with PD, Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), frontotemporal dementia (FTD) and normal controls.

The mutation was found only in PD patients or their relatives, but not in those with other neurodegenerative diseases (ref. 14).

Deep brain stimulation

This review on the highlights of the year ends with two recent publications. The findings from the first study suggest that deep brain stimulation of the subthalamic nucleus does not slow progression of PD, and thus does not support the hypothesis that suppression of glutamate excitotoxicity by DBS of STN might reduce nigral cell death.

This study conducted in 30 patients who received bilateral deep brain stimulation of STN revealed that after 16 months treatment there was 9.5-12.9% annual decline of the radiotracer signal as measured by PET scan, despite 52% improvement in the off-medication UPDRS scores, which was maintained over 16 months.

The disease progression rate was comparable to that reported in previous studies on medically treated patients. Thus the data from this study suggest that DBS masks rather than preventing clinical progression of PD (ref. 15).

Visual hallucinations

Visual hallucinations (VH) frequently occur in patients with idiopathic Parkinson’s disease, this has been thought to be largely related to antiparkinsonian medication. The relationship between pathological diagnosis of a bradykinetic-rigid syndrome and visual hallucinations    was investigated in 788 cases with parkinsonism in their life-time.

VH occurred in 50% of patients with PD, 73% with DLB, but only in 7% with non-Lewy-body parkinsonism such as PSP and MSA. In patients with PD, the onset of VH typically occurred in the second half of the disease course, and the time to onset of VH was only weakly correlated with use of selegiline and ergot dopamine agonists, but not correlated with use of levodopa, amantadine, or anticholinergic drugs.

These results suggest that VH may be an integral part of the Lewy body disease pathology. The authors suggested that the presence of VH is helpful in the differentiation of PD from other non-Lewy-body causes of parkinsonism and proposed that VH be added to the operational clinical criteria for the diagnosis of PD, as a supportive criterion (ref. 16).

References

1. Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson's disease. New England Journal of Medicine 2004; 351 (24); 2509-2518 (Free full text article)

2. Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. New England Journal of Medicine 2004; 351 (24); 2498-2508 (Free full text article)

3. Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P and Gill SS. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Annals of Neurology 2005; 57 (2); 298-302

4. Anderson VC, Burchiel KJ, Hogarth P, Favre J and Hammerstad JP. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Archives of Neurology 2005; 62 (4); 554-560

5. Fraix V, Pollak P, Moro E, Chabardes S, Xie J, et al. Subthalamic nucleus stimulation in tremor dominant parkinsonian patients with previous thalamic surgery. Journal of Neurology Neurosurger and Psychiatry 2005; 76 (2); 246-248 

6. Parkinson Study Group. A randomized, placebo controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations. The PRESTO study. Archives of Neurology 2005; 62 (2); 241-248

7. Rascol O, Brooks DJ, Melamed E, et al. for the LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting Effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomized, double-blind, parallel group trial. Lancet 2005; 365 (9463); 947-54

8. Galanaud JP, Elbaz A, Clavel J, Vidal J-S, Correze J-R, et al. Cigarette smoking and Parkinson’s disease: a case-control study in a population characterized by a high prevalence of pesticide exposure. Movement Disorders 2005; 20 (2); 181-189

9. Scott WK, Zhang F, Stajich JM, Scott BL, Stacy MA and Vance JM. Family-based case-control study of cigarette smoking and Parkinson disease. Neurology 2005; 64 (3); 442-447

10. Meindorfner C, Körner Y, Möller JK, Stiasny-Kolster K, Oertel WH and Krüger HP. Driving in Parkinson’s disease: mobility, accidents, and sudden onset of sleep at the wheel. Movement Disorders 2005; 20 (7); 832-842

11. Braak H, Rüb U, Jansen Steur EN, Del Tredici K, de Vos RA. Cognitive status correlates with nueropathologic stage in Parkinson disease. Neurology 2005; 64 (8); 1404-1410

12. De Lau LML, Bornebroek M, Witteman JCM, Hofman A, Koudstaal PJ and Breteler M. Dietary fatty acids and the risk of Parkinson disease. The Rotterdam study. Neurology 2005; 64 (12); 2040-2045

13. Bara-Jimenez W, Bibbiani F, Morris MJ, Dimitrova T, et al. Effects of serotonin 5-HT1A agonist in advanced Parkinson’s disease. Movement Disorders 2005; 20 (8); 932-936

14. Hernandez D, Ruiz CP, Crawley A, et al. The dardarin G2019S mutation is a common cause of Parkinson’s disease, but not other neurodegenerative diseases. Neuroscience Letters 2005; 389; 137-139

15. Hilker R, Portman AT, Voges J, et al. Disease progression continues in patients with advanced Parkinson’s disease and effective subtahalamic nucleus stimulation. Journal of Neurology Neurosurgery and Psychiatry 2005; 76 (9); 1217-1221

16. Williams DR and Lees AJ. Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. Lancet Neurology 2005; 4 (10); 605-610