Neuroprotection and Natural History in Parkinson's Plus Syndromes (NNIPPS)

• functional measures (UPDRS, Parkinson's Plus Scale)
• Change in MRI abnormalities
• Cognitive changes

NNIPPS is a clinical trial of riluzole (a drug previously shown to slow down the rate of progression og amyotrophic lateral sclerosis-ALS; Lou Gehrig's disease) involving nearly 800 people diagnosed with the 'parkinson plus' syndromes of multiple system atrophy (MSA) and progressive supranuclear plasy (PSP). In addition to showing whether riluzole is helpful in MSA and PSP, NNIPPS will improve criteria for making an accurate and early diagnosis, for assessing the rate of progression, and will advance understanding of the biology of these disabling and progressive neurodegenerative diseases.

Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) often present as akinetic-rigid syndromes and in the early stages are difficult to differentiate in the clinic. Current Consensus Diagnostic Criteria based on retrospective studies have high specificity but low sensitivity. The NNIPPS study is an EU-funded multinational (France, UK, Germany) multi-centre academic-led project with four main aims. The first aim is to test the hypothesis that riluzole, which may have generic neuroprotective properties, reduces the risk of death and improves function and quality of life (QL) in patients with MSA and PSP- ‘parkinson’s plus syndromes’. The second aim is to identify prognostic factors for survival and functional deterioration, and to develop and validate functional rating scales prospectively. The third aim is to investigate MRI, cognitive, pathological and genetic aspects of these disorders in relation to disease progression and pathogenesis. The fourth aim is to understand the impact of these diseases on the QL of patients and carers and to identify the health costs of treatment.

The study is designed as a randomised, stratified, controlled trial of the efficacy and safety of riluzole (up to 200mg daily) versus placebo in MSA and PSP. The primary outcome measure is survival at 36 months. Power calculations suggested that we would need to recruit ~400 patients into each stratum (MSA, PSP) in order to detect a reduction in the relative risk (RR) of death at 36 months with 80% power and two-sided a=0.05. Using modified consensus criteria (to provide greater sensitivity) we recruited 766 patients (363 PSP, 404 MSA) over 2 years (1999-2001). The first patients recruited are about to enter the open-label study. The final analysis of the primary efficacy measure is planned for December 2005. Secondary outcome measures include safety, rate of change in UPDRS and other rating scales including a parkinson’s plus symtoms rating scale (PPSS), changes in cognitive function assessed using the Mattis Dementia Rating Scale, the Frontal Assessment Battery, The Bushke Selective Reminding Test, The Neuropsychiatric Inventory, and other tests of memory and executive function. QL and Health economic data is collected using the SF36 and a Client Service Receipt Inventory (CSRI). Assessments are made at 6 monthly intervals. Standardised MRI has been acquired in ~70% of cases at entry and will be repeated at 36 months where possible. DNA has been collected from ~75% of cases. 100 brains have been donated and are being analysed using a standardised protocol.

• Multiple System Atrophy
• Progressive Supranuclear Palsy

• Payan CA, Viallet F, Landwehrmeyer BG, Bonnet AM, Borg M, Durif F, Lacomblez L, Bloch F, Verny M, Fermanian J, Agid Y, Ludolph AC, Leigh PN, Bensimon G; NNIPPS Study Group. Disease severity and progression in progressive supranuclear palsy and multiple system atrophy: validation of the NNIPPS--Parkinson Plus Scale. PLoS One. 2011;6(8):e22293. Epub 2011 Aug 4.
• Rolland Y, Vérin M, Payan CA, Duchesne S, Kraft E, Hauser TK, Jarosz J, Deasy N, Defevbre L, Delmaire C, Dormont D, Ludolph AC, Bensimon G, Leigh PN; NNIPPS Study Group. A new MRI rating scale for progressive supranuclear palsy and multiple system atrophy: validity and reliability. J Neurol Neurosurg Psychiatry. 2011 Sep;82(9):1025-32. Epub 2011 Mar 8.
• Al-Chalabi A, Dürr A, Wood NW, Parkinson MH, Camuzat A, Hulot JS, Morrison KE, Renton A, Sussmuth SD, Landwehrmeyer BG, Ludolph A, Agid Y, Brice A, Leigh PN, Bensimon G; NNIPPS Genetic Study Group. Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy. PLoS One. 2009 Sep 22;4(9):e7114.
• Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN; NNIPPS Study Group. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain. 2009 Jan;132(Pt 1):156-71. Epub 2008 Nov 23.

Inclusion Criteria:

• akinetic rigid syndrome plus clinical criteria for MSA or PSP

Exclusion Criteria:

• Idiopathic Parkinson's disease
• Other neurological or serious medical disorders
• Unable to give informed consent
• dementia
• liver damage
• women of child bearing age unable to use effective method of contraception

• Assistance Publique - Hôpitaux de Paris
• University of Ulm
• Aventis Pharmaceuticals