Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity.
ABSTRACT The investigation of disease progression provides important information on the dynamics of cell death in Parkinson disease (PD).
To determine the progression of dopaminergic impairment in PD with the use of positron emission tomography (PET).
Longitudinal prospective cohort study with a follow-up period of 64.5 +/- 22.6 months (mean +/- SD).
A consecutive sample of patients with PD (N = 31; age at symptom onset, 53.6 +/- 11.3 years) with a wide range of symptom duration and severity at the time of study entry.
Investigation by serial fluorodopa F 18 ([(18)F]fluorodopa) PET as a marker for striatal dopaminergic function.
Changes in caudate and putaminal [(18)F]fluorodopa influx constant (K(i)) values.
In patients with PD, the decline rate of putaminal [(18)F]fluorodopa K(i) correlated inversely with disease duration before study inclusion (r = -0.46, P = .01) and positively with baseline K(i) values (r = 0.44, P = .01), indicating a negative exponential loss of dopamine neurons. Annual disease progression rates ranged from 4.4% in the caudate nucleus to 6.3% in the putamen. A mean preclinical period of 5.6 +/- 3.2 years was calculated with symptom onset at a putaminal K(i) threshold of 69% from controls. Assuming nonlinear progression kinetics, the required sample size to prove neuroprotection with the use of [(18)F]fluorodopa PET was found to increase strongly with the preceding symptom duration of study subjects.
These data suggest that the neurodegenerative process in PD follows a negative exponential course and slows down with increasing symptom duration, contradicting the long-latency hypothesis of PD.
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ABSTRACT: Positron emission tomography (PET) studies on presynaptic dopaminergic function can reveal hypofunction in early Parkinson's disease (PD) which may help in the early diagnosis especially in patients with mild symptoms. This hypofunction can be detected with fluorodopa (reflecting mainly aromatic amino acid decarboxylase activity of nigrostriatal terminals) or dopamine transporter ligands. These studies can also help to distinguish PD from essential tremor. However, investigations of presynaptic dopaminergic function are not useful in the differential diagnosis of parkinsonian syndromes. PET ligands, such as fluorodeoxyglucose (reflecting glucose metabolism) and dopamine receptor ligands, reflecting striatal neuronal function are better in this respect. Cardiac sympathetic function studies represent a new and interesting approach to improve differential diagnosis of parkinsonian syndromes but more studies are needed in larger patient populations with longer follow-up to evaluate the usefulness of these investigations. Multitracer approach combining ligands reflecting different aspects of dopaminergic neurotransmission and other physiological function will increase differential diagnostic accuracy.Journal of movement disorders. 10/2009; 2(2):53-57.
Article: Recent important trials of pharmacotherapy in Parkinson’s diseaseFAHN S, OAKES D, SHOULSON I et al.: Levodopa and the progression of Parkinson’s disease. N. Engl. J. Med. (2004) 351:2498-2508  and EMRE M, AARSLAND D, ALBANESE A et al.: Rivastigmine for dementia associated with Parkinson’s disease. N. Engl. J. Med. (2004) 351:2509-2518 .[Show abstract] [Hide abstract]
ABSTRACT: Parkinson’s disease (PD) affects ~ 1% of individuals > 60 years. Of these PD patients 40% suffer dementia in later life. Levodopa is commonly used in the treatment of PD. Experimental evidence suggests that the dopamine synthesised from levodopa may contribute to the further degeneration of dopaminergic neurons. The results of the clinical outcome part of the Earlier Versus Later Levodopa Therapy in PD study suggest that levodopa slows the progression of PD. In contrast, the single photon emission-computed tomography imaging substudy was not conclusive but suggested that levodopa hastened the progression of PD. Thus, further studies of the effects of levodopa on the progression of PD are needed before it can be proved that levodopa does not have a detrimental effect on dopaminergic neurons. In a clinical trial of the anticholinesterase rivastigmine, a small improvement was observed in some patients suffering from dementia associated with PD. This small benefit has to be balanced against cholinergic side effects and a possible loss of efficacy of antimuscarinic agents used for motor control in PD.Expert Opinion on Pharmacotherapy 06/2005; 6(6). · 2.86 Impact Factor
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ABSTRACT: To gain a better understanding of the significance of α-synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α-synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α-synuclein pathological conditions are related to clinical measures of disease progression. Post-mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age-matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α-synuclein aggregates. The progression from Braak α-synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α-synuclein stages but did not vary across consecutive Braak α-synuclein stages. We observed a negative correlation between neuronal density and local α-synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = −0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α-synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α-synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease. © 2014 International Parkinson and Movement Disorder SocietyMovement Disorders 07/2014; · 5.63 Impact Factor