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Abstract: The early motor manifestations of Parkinson’s disease (PD) reflect degeneration of nigrostriatal dopamine neurons projecting to the caudal putamen. However, extrastriatal dopamine and other monoamine systems are also involved, particularly in later disease. We used 18F-dopa PET in a cross-sectional study to characterize extrastriatal monoamine neuronal dysfunction in PD. 16 Controls and 41 patients underwent investigation. We found that 18F-dopa uptake was decreased in cortical motor areas, particularly the motor cortex, even in early disease. Frontal association areas were also affected in later disease but limbic areas were spared except for hypothalamus. The substantia nigra, midbrain raphe and locus coeruleus showed normal or increased 18F-dopa uptake until PD was advanced, indicating compensatory responses in intact monoamine neuron perikarya. The red nucleus, subthalamus, ventral thalamus and pineal gland were also eventually involved. These findings provide a further basis for understanding the complex pathophysiology of PD in vivo and complement pathological studies. [Copyright &y& Elsevier]

Abstract: Post-mortem studies of multiple system atrophy (MSA) patients have shown widespread subcortical neurodegeneration. In this study, we have used 18F-dopa PET, a marker of monoaminergic nerve terminal function, to explore in vivo changes in striatal and extrastriatal dopamine, noradrenaline, and serotonin transmission for a cohort of patients with MSA with predominant parkinsonism. Fourteen patients with MSA, ten patients with idiopathic Parkinson''s disease (PD) matched for disease duration, and ten healthy controls were studied with 18F-dopa PET. Regions of interest (ROIs) were placed to sample 18F-dopa uptake in thirteen structures and mean activity was compared between groups. The MSA patients showed significantly decreased 18F-dopa uptake in putamen, caudate nucleus, ventral striatum, globus pallidus externa and red nucleus compared to controls, whereas PD patients only had decreased 18F-dopa uptake in putamen, caudate nucleus, and ventral striatum. MSA cases with orthostatic hypotension had lower 18F-dopa uptake in the locus coeruleus than patients without this symptom. In conclusion, 18F-dopa PET showed more widespread basal ganglia dysfunction in MSA than in PD with similar disease duration, and extrastriatal loss of monoaminergic innervation could be detected in the red nucleus and locus coeruleus. In contrast to PD, there was no evidence of early compensatory increases in regional 18F-dopa uptake. [Copyright &y& Elsevier]

Abstract: Thirty Parkinson''s disease (PD) patients were divided into three equal groups according to their disease duration while 10 normal healthy volunteers matched for age and sex served as a control group. Striatal and extrastriatal serotonergic function was studied with 11C-DASB PET, a marker of serotonin transporter availability. 11C-DASB binding was correlated with disease disability and exposure to dopaminergic therapy. We found significant 11C-DASB binding reductions in striatal, brainstem, and cortical regions in PD but no correlations were evident between 11C-DASB binding and UPDRS scores, Hoehn &Yahr staging, disease duration and level of exposure to dopaminergic therapy. Our results suggest that progressive non-linear serotonergic dysfunction occurs in PD but it does not determine levels of disability. Additionally, chronic exposure to dopaminergic therapy does not appear to influence SERT binding. [Copyright &y& Elsevier]

Abstract: Idiopathic Parkinson''s disease (PD) is a neurodegenerative disorder associated with akinesia, tremor and rigidity. While the characteristic Lewy body pathology targets pigmented and other brainstem nuclei at post-mortem, activated microglia are found in both subcortical and cortical areas. [11C](R)-PK11195 is a positron emission tomography (PET) marker of peripheral benzodiazepine sites (PBBS), which are selectively expressed by activated microglia. We examined 18 PD patients clinically and with [11C](R)-PK11195 and [18F]-dopa PET. Compared to 11 normal controls, the PD patients showed significantly increased mean levels of [11C](R)-PK11195 binding in the pons, basal ganglia and frontal and temporal cortical regions. Eight PD patients were examined longitudinally, and their [11C](R)-PK11195 signal remained stable over 2 years. Levels of microglial activation did not correlate with clinical severity or putamen [18F]-dopa uptake. Our in vivo findings confirm that widespread microglial activation is associated with the pathological process in PD. The absence of significant longitudinal changes suggests that microglia are activated early in the disease process, and levels then remain relatively static, possibly driving the disease via cytokine release. [Copyright &y& Elsevier]

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had 11C-methylreboxetine(11C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11C-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for 11C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined. Tremor positive PD patients had a significantly higher mean 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-MeNER DVR across all regions compared to HC. While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype. • Noradrenaline is associated with rest tremor in Parkinson's disease. • Noradrenaline is preserved in tremor predominant Parkinson's Disease. • Patients without tremor show loss of noradrenaline in locus coeruleus and thalamus. [ABSTRACT FROM AUTHOR]

Alpha-synuclein (a-syn) can aggregate and form toxic oligomers and insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal Lewy bodies are a major pathological characteristic of Parkinson's disease (PD). These fibrillar structures can act as seeds and accelerate the aggregation of monomeric a-syn. Indeed, recent studies show that injection of preformed a-syn fibrils (PFF) into the rodent brain can induce aggregation of the endogenous monomeric a-syn resulting in neuronal dysfunction and eventual cell death. We injected 8 μg of murine a-syn PFF, or soluble monomeric a-syn into the right striatum of rats. The animals were monitored behaviourally using the cylinder test, which measures paw asymmetry, and the corridor task that measures lateralized sensorimotor response to sugar treats. In vivo PET imaging was performed after 6, 13 and 22 weeks using [11C]DTBZ, a marker of the vesicular monoamine 2 transporter (VMAT2), and after 15 and 22 weeks using [11C]UCB-J, a marker of synaptic SV2A protein in nerve terminals. Histology was performed at the three time points using antibodies against dopaminergic markers, aggregated a-syn, and MHCII to evaluate the immune response. While the a-syn PFF injection caused only mild behavioural changes, [11C]DTBZ PET showed a significant and progressive decrease of VMAT2 binding in the ipsilateral striatum. This was accompanied by a small progressive decrease in [11C]UCB-J binding in the same area. In addition, our histological analysis revealed a gradual spread of misfolded a-syn pathology in areas anatomically connected to striatum that became bilateral with time. The striatal a-syn PFF injection resulted in a progressive unilateral degeneration of dopamine terminals, and an early and sustained presence of MHCII positive ramified microglia in the ipsilateral striatum and substantia nigra. Our study shows that striatal injections of a-syn fibrils induce progressive pathological synaptic dysfunction prior to cell death that can be detected in vivo with PET. We confirm that intrastriatal injection of a-syn PFFs provides a model of progressive a-syn pathology with loss of dopaminergic and synaptic function accompanied by neuroinflammation, as found in human PD. • Intrastriatal α-Synuclein fibrils induce nigrostriatal degeneration. • α-Synuclein pathology induced early and sustained MHCII expression. • α-Synuclein fibrils injection results in hyperactivity and mild sensorimotor defects. • rats with α-Synuclein pathology show progressive decrease in [11C]DTBZ PET striatal binding. • α-Synuclein pathology induced decreased synaptic density measured by [11C]UCB-J PET. [ABSTRACT FROM AUTHOR]