Neuroinflammatory glial response may contribute to degenerative processes in Parkinson's disease (PD). To investigate changes in microglial activity associated with changes in the presynaptic dopamine transporter density in the PD brain in vivo, we studied 10 early-stage drug-naive PD patients twice using positron emission tomography with a radiotracer for activated microglia [(11)C](R)-PK11195 and a dopamine transporter marker [(11)C]CFT. Quantitative levels of binding potentials (BPs) of [(11)C](R)-PK11195 and [(11)C]CFT in the nigrostriatal pathway were estimated by compartment analyses. The levels of [(11)C](R)-PK11195 BP in the midbrain contralateral to the clinically affected side were significantly higher in PD than that in 10 age-matched healthy subjects. The midbrain [(11)C](R)-PK11195 BP levels significantly correlated inversely with [(11)C]CFT BP in the putamen and correlated positively with the motor severity assessed by the Unified Parkinson's Disease Rating Scale in PD. In healthy subjects, the [(11)C](R)-PK11195 BP in the thalamus and midbrain showed an age-dependent increase. In vivo demonstration of parallel changes in microglial activation and corresponding dopaminergic terminal loss in the affected nigrostriatal pathway in early PD supports that neuroinflammatory responses by intrinsic microglia contribute significantly to the progressive degeneration process of the disease and suggests the importance of early therapeutic intervention with neuroprotective drugs.
"Enteric α-synuclein aggregates are described with local inflammation in the gut, both clinical and experimental colitis (Grathwohl et al. 2013). In early PD, inflammation, measured by imaging microglial activation , in the affected nigrostriatal pathway accompanies loss of presynaptic dopamine transporter (Ouchi et al. 2005) and becomes more widespread on follow-up (Ouchi et al. 2009). Central neuro-inflammation may have peripheral mediators (see 'Influence of immuno-inflammatory milieu'). "
[Show abstract][Hide abstract] ABSTRACT: We seek an aetiopathogenic model for the spectrum of Parkinson's disease (PD), functional bowel disease, depression and cognitive impairment. The adopted concept is that systemic immuno-inflammatory processes mediate neuro-inflammation. The model would be based on phenotype, exposome (including gastrointestinal microbiome), milieu (immuno-inflammatory and metabolome), human genetics and their interactions. It would enable a patient's position, to be understood in terms of drivers, perpetuators and mediators, and a future position, with and without intervention, predicted. Even the cardinal facets of PD may have different drivers: halting one may allow escape down subordinate pathways. Peptic ulceration is prodromal to PD. In our randomised placebo-controlled trial, hypokinesia improved over the year following biopsy-proven Helicobacter pylori eradication and rigidity worsened. This was independent of any (stable, long t½) antiparkinsonian medication. There are pointers to an autoimmune process: for example, surveillance-confirmed hypokinesia effect was indication specific. During surveillance, successive antimicrobial courses, other than for Helicobacter, were associated with cumulative increase in rigidity. Exhibiting laxatives appeared to stem the overall temporal increase, despite antiparkinsonian medication, in rigidity. Thus, intestinal dysbiosis may be a major source of bystander neuronal damage. There are biological gradients of objective measures of PD facets on circulating inflammatory markers and leucocyte subset counts. Moreover, lactulose hydrogen breath test positivity for small-intestinal bacterial overgrowth (present in two thirds of PD patients) is associated with the same subsets: higher natural killer and total CD4+ counts and lower neutrophils. With greater aetiopathogenic understanding, relatively low cost and on-the-shelf medication could have a major impact. A new generation of animal models, based on the gut microbiome, is envisaged.
Journal of NeuroVirology 06/2015; DOI:10.1007/s13365-015-0357-8 · 2.60 Impact Factor
"These lines of evidence hint that synaptic í µí»¼-synuclein pathology could initiate and determine the onset of motor symptoms in PD. Indeed, clinical manifestations of the disease appear when dopamine levels in the striatum are reduced to 80% of normal levels, as measured by a decrease in [ 18 F] fluoro-DOPA PET binding, a consequence of dopamine neuron loss in substantia nigra   . Of note, this initial symptomatic phase is characterized by a significant worsening of putaminal presynaptic deficiency, with a marked reduction in dopamine presynaptic storage, transporter binding , and release  . "
[Show abstract][Hide abstract] 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.
"It has in fact long been recognized that PD brains are characterized by the presence of a microglial reaction (McGeer et al., 1988; McGeer and McGeer, 2004) which increases with disease duration (Croisier et al., 2005). Positron emission tomography studies have similarly reported increased microglial responses in early stages of the disease, correlating with severity of motor impairments (Ouchi et al., 2005). More targeted studies have revealed a possible role for toll-like receptors (TLRs) in the pathological processes underlying neurodegenerative disorders, including PD (Panaro et al., 2008; Ros-Bernal et al., 2011; Cote et al., 2011; Drouin-Ouellet et al., 2011; Drouin-Ouellet and Cicchetti, 2012; Kim et al., 2013;) For example, Syn can act as a DAMP for TLR2 (Kim et al., 2013) while TLR4 activation promotes microglial Syn clearance in synucleinopathies (Stefanova et al., 2011). "
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