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: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Its characteristic neuropathological features encompass the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies and Lewy neurites. These are intraneuronal and intraneuritic proteinaceous insoluble aggregates whose main constituent is the synaptic protein α-synuclein. Compelling lines of evidence indicate that mitochondrial dysfunction and α-synuclein synaptic deposition may play a primary role in the onset of this disorder. However, it is not yet clear which of these events may come first in the sequel of processes leading to neurodegeneration. Here, we reviewed data supporting either that α-synuclein synaptic deposition precedes and indirectly triggers mitochondrial damage or that mitochondrial deficits lead to neuronal dysfunction and α-synuclein synaptic accumulation. The present overview shows that it is still difficult to establish the exact temporal sequence and contribution of these events to PD.Parkinson's Disease 01/2015; 2015:1-10. DOI:10.1155/2015/108029 · 2.10 Impact Factor
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ABSTRACT: Resting-state functional magnetic resonance imaging (RS-fMRI) has been considered for development as a biomarker and analytical tool for evaluation of Parkinson's disease (PD). Here we utilized analysis of the amplitude of low-frequency ﬂuctuations (ALFF) to determine changes in intrinsic neural oscillations in 72 patients with PD. Two different frequency bands (slow-5: 0.01-0.027Hz; slow-4: 0.027-0.073Hz) were analyzed. In the slow-5 band, PD patients compared with controls had increased ALFF values mainly in the caudate and several temporal regions, as well as decreased ALFF values in the cerebellum and the parieto-temporo-occipital cortex. Additionally, in the slow-4 band, PD patients relative to controls exhibited reduced ALFF value in the thalamus, cerebellum, and several occipital regions. Together, our data demonstrate that PD patients have widespread abnormal intrinsic neural oscillations in the corticostriatal network in line with the pathophysiology of PD, and further suggest the abnormalities are dependent on speciﬁc frequency bands. Thus, frequency domain analyses of resting state BOLD signals may provide a useful means to study the pathophysiology of PD and the physiology of the brain's dopaminergic pathways.Behavioural brain research 05/2013; 252. DOI:10.1016/j.bbr.2013.05.039 · 3.39 Impact Factor
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ABSTRACT: Patients with Parkinson's disease suffer from significant motor impairments and accompanying cognitive and affective dysfunction due to progressive disturbances of basal ganglia-cortical gating loops. Parkinson's disease has a long presymptomatic stage, which indicates a substantial capacity of the human brain to compensate for dopaminergic nerve degeneration before clinical manifestation of the disease. Neuroimaging studies provide evidence that increased motor-related cortical activity can compensate for progressive dopaminergic nerve degeneration in carriers of a single mutant Parkin or PINK1 gene, who show a mild but significant reduction of dopamine metabolism in the basal ganglia in the complete absence of clinical motor signs. However, it is currently unknown whether similar compensatory mechanisms are effective in non-motor basal ganglia-cortical gating loops. Here, we ask whether asymptomatic Parkin mutation carriers show altered patterns of brain activity during processing of facial gestures, and whether this might compensate for latent facial emotion recognition deficits. Current theories in social neuroscience assume that execution and perception of facial gestures are linked by a special class of visuomotor neurons ('mirror neurons') in the ventrolateral premotor cortex/pars opercularis of the inferior frontal gyrus (Brodmann area 44/6). We hypothesized that asymptomatic Parkin mutation carriers would show increased activity in this area during processing of affective facial gestures, replicating the compensatory motor effects that have previously been observed in these individuals. Additionally, Parkin mutation carriers might show altered activity in other basal ganglia-cortical gating loops. Eight asymptomatic heterozygous Parkin mutation carriers and eight matched controls underwent functional magnetic resonance imaging and a subsequent facial emotion recognition task. As predicted, Parkin mutation carriers showed significantly stronger activity in the right ventrolateral premotor cortex during execution and perception of affective facial gestures than healthy controls. Furthermore, Parkin mutation carriers showed a slightly reduced ability to recognize facial emotions that was least severe in individuals who showed the strongest increase of ventrolateral premotor activity. In addition, Parkin mutation carriers showed a significantly weaker than normal increase of activity in the left lateral orbitofrontal cortex (inferior frontal gyrus pars orbitalis, Brodmann area 47), which was unrelated to facial emotion recognition ability. These findings are consistent with the hypothesis that compensatory activity in the ventrolateral premotor cortex during processing of affective facial gestures can reduce impairments in facial emotion recognition in subclinical Parkin mutation carriers. A breakdown of this compensatory mechanism might lead to the impairment of facial expressivity and facial emotion recognition observed in manifest Parkinson's disease.Brain 03/2012; 135(Pt 4):1128-40. DOI:10.1093/brain/aws040 · 10.23 Impact Factor