The pathology roadmap in Parkinson disease

Surmeier, D. James; Sulzer, David

doi:10.4161/pri.23582

Cited by 60 publications

(68 citation statements)

References 119 publications

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“…Several other regions have been reported to have neuronal loss in PD, many in single studies. These include for example the hypothalamus, the intralaminar nuclei of the thalamus and possibly the nucleus basalis of Meynert, and DA neurons of the retina (Surmeier and Sulzer, 2013). …”

Section: Role Of Da Oxidation In Neurodegenerative Processes Of Pdmentioning

confidence: 99%

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

Zucca

Segura‐Aguilar

Ferrari

et al. 2017

Progress in Neurobiology

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532

482

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There are several interrelated mechanisms involving iron, dopamine, and neuromelanin in neurons. Neuromelanin accumulates during aging and is the catecholamine-derived pigment of the dopamine neurons of the substantia nigra and norepinephrine neurons of the locus coeruleus, the two neuronal populations most targeted in Parkinson’s disease. Many cellular redox reactions rely on iron, however an altered distribution of reactive iron is cytotoxic. In fact, increased levels of iron in the brain of Parkinson’s disease patients are present. Dopamine accumulation can induce neuronal death; however, excess dopamine can be removed by converting it into a stable compound like neuromelanin, and this process rescues the cell. Interestingly, the main iron compound in dopamine and norepinephrine neurons is the neuromelanin-iron complex, since neuromelanin is an effective metal chelator. Neuromelanin serves to trap iron and provide neuronal protection from oxidative stress. This equilibrium between iron, dopamine, and neuromelanin is crucial for cell homeostasis and in some cellular circumstances can be disrupted. Indeed, when neuromelanin-containing organelles accumulate high load of toxins and iron during aging a neurodegenerative process can be triggered. In addition, neuromelanin released by degenerating neurons activates microglia and the latter cause neurons death with further release of neuromelanin, then starting a self-propelling mechanism of neuroinflammation and neurodegeneration. Considering the above issues, age-related accumulation of neuromelanin in dopamine neurons shows an interesting link between aging and neurodegeneration.

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Section: Role Of Da Oxidation In Neurodegenerative Processes Of Pdmentioning

confidence: 99%

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

Zucca

Segura‐Aguilar

Ferrari

et al. 2017

Progress in Neurobiology

Self Cite

532

482

View full text Add to dashboard Cite

show abstract

“…A better understanding of the biochemical and cellular pathways that lead to neurodegeneration may also open up new imaging targets to facilitate early detection and disease staging (e.g. NO and glial activation (Bortolanza et al, 2015); axonal degeneration (Burke & O’Malley, 2013); prion-like mechanisms (Goedert et al, 2013; Surmeier & Sulzer, 2013). …”

Section: Overall Summary and Future Directionsmentioning

confidence: 99%

Neuroimaging of Parkinson's disease: Expanding views

Weingarten

Sundman

Hickey

et al. 2015

Neuroscience & Biobehavioral Reviews

137

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Advances in molecular and structural and functional neuroimaging are rapidly expanding the complexity of neurobiological understanding of Parkinson’s disease (PD). This review article begins with an introduction to PD neurobiology as a foundation for interpreting neuroimaging findings that may further lead to more integrated and comprehensive understanding of PD. Diverse areas of PD neuroimaging are then reviewed and summarized, including positron emission tomography, single photon emission computed tomography, magnetic resonance spectroscopy and imaging, transcranial sonography, magnetoencephalography, and multimodal imaging, with focus on human studies published over the last five years. These included studies on differential diagnosis, co-morbidity, genetic and prodromal PD, and treatments from L-DOPA to brain stimulation approaches, transplantation and gene therapies. Overall, neuroimaging has shown that PD is a neurodegenerative disorder involving many neurotransmitters, brain regions, structural and functional connections, and neurocognitive systems. A broad neurobiological understanding of PD will be essential for translational efforts to develop better treatments and preventive strategies. Many questions remain and we conclude with some suggestions for future directions of neuroimaging of PD.

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“…In addition, post mortem studies revealed variable levels of dopaminergic neural loss in ventral tegmental area (VTA) (Alberico et al, 2015, Surmeier and Sulzer, 2013). This system, however, has been associated to a series of psychopathological states, which often occur in PD and may precede motor disturbances by many years (Gustafsson et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease

Caminiti¹,

Presotto²,

Baroncini³

et al. 2017

NeuroImage: Clinical

101

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A progressive loss of dopamine neurons in the substantia nigra (SN) is considered the main feature of idiopathic Parkinson's disease (PD). Recent neuropathological evidence however suggests that the axons of the nigrostriatal dopaminergic system are the earliest target of α-synuclein accumulation in PD, thus the principal site for vulnerability. Whether this applies to in vivo PD, and also to the mesolimbic system has not been investigated yet.We used [11C]FeCIT PET to measure presynaptic dopamine transporter (DAT) activity in both nigrostriatal and mesolimbic systems, in 36 early PD patients (mean disease duration in months ± SD 21.8 ± 10.7) and 14 healthy controls similar for age. We also performed anatomically-driven partial correlation analysis to evaluate possible changes in the connectivity within both the dopamine networks at an early clinical phase.In the nigrostriatal system, we found a severe DAT reduction in the afferents to the dorsal putamen (DPU) (η2 = 0.84), whereas the SN was the less affected region (η2 = 0.31). DAT activity in the ventral tegmental area (VTA) and the ventral striatum (VST) were also reduced in the patient group, but to a lesser degree (VST η2 = 0.71 and VTA η2 = 0.31). In the PD patients compared to the controls, there was a marked decrease in dopamine network connectivity between SN and DPU nodes, supporting the significant derangement in the nigrostriatal pathway.These results suggest that neurodegeneration in the dopamine pathways is initially more prominent in the afferent axons and more severe in the nigrostriatal system. Considering PD as a disconnection syndrome starting from the axons, it would justify neuroprotective interventions even if patients have already manifested clinical symptoms.

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The pathology roadmap in Parkinson disease

Cited by 60 publications

References 119 publications

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

Neuroimaging of Parkinson's disease: Expanding views

Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease

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