Cerebrospinal fluid biomarkers in Parkinson disease

Parnetti, Lucilla; Castrioto, Anna; Chiasserini, Davide; Persichetti, Emanuele; Tambasco, Nicola; El-Agnaf, Omar Ali; Calabresi, Paolo

doi:10.1038/nrneurol.2013.10

Cited by 185 publications

(141 citation statements)

References 124 publications

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“…Most studies of CSF A β species in PD have reported slight reductions 14, 15. We and others have found a correlation between CSF A β 42 levels and memory performance in PD,15, 16 also in subjects with normal CSF A β 42 levels (thus without evidence for amyloid plaques) 15, 17.…”

Section: Introductionmentioning

confidence: 49%

Impaired synaptic function is linked to cognition in Parkinson's disease

Selnes

Stav

Johansen

et al. 2017

Ann Clin Transl Neurol

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ObjectiveCognitive impairment is frequent in Parkinson's disease, but the underlying mechanisms are insufficiently understood. Because cortical metabolism is reduced in Parkinson's disease and closely associated with cognitive impairment, and CSF amyloid‐β species are reduced and correlate with neuropsychological performance in Parkinson's disease, and amyloid‐β release to interstitial fluid may be related to synaptic activity; we hypothesize that synapse dysfunction links cortical hypometabolism, reduced CSF amyloid‐β, and presynaptic deposits of α‐synuclein. We expect a correlation between hypometabolism, CSF amyloid‐β, and the synapse related‐markers CSF neurogranin and α‐synuclein.MethodsThirty patients with mild‐to‐moderate Parkinson's disease and 26 healthy controls underwent a clinical assessment, lumbar puncture, MRI, 18F‐fludeoxyglucose‐PET, and a neuropsychological test battery (repeated for the patients after 2 years).ResultsAll subjects had CSF amyloid‐β 1‐42 within normal range. In Parkinson's disease, we found strong significant correlations between cortical glucose metabolism, CSF Aβ, α‐synuclein, and neurogranin. All PET CSF biomarker‐based cortical clusters correlated strongly with cognitive parameters. CSF neurogranin levels were significantly lower in mild‐to‐moderate Parkinson's disease compared to controls, correlated with amyloid‐β and α‐synuclein, and with motor stage. There was little change in cognition after 2 years, but the cognitive tests that were significantly different, were also significantly associated with cortical metabolism. No such correlations were found in the control group.Interpretation CSF Aβ, α‐synuclein, and neurogranin concentrations are related to cortical metabolism and cognitive decline. Synaptic dysfunction due to Aβ and α‐synuclein dysmetabolism may be central in the evolution of cognitive impairment in Parkinson's disease.

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Section: Introductionmentioning

confidence: 49%

Impaired synaptic function is linked to cognition in Parkinson's disease

Selnes

Stav

Johansen

et al. 2017

Ann Clin Transl Neurol

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“…27 We previously demonstrated that actin is a target for intracellular Syn, and that wt and A30P-mutated Syn differentially modulate actin dynamics. 13 Here, we provide evidences that the extracellular accumulation of either wt or A30P Syn correlates with an unbalance of actin turnover, resulting in microfilament stabilization.…”

Section: Discussionmentioning

confidence: 99%

GRP78 clustering at the cell surface of neurons transduces the action of exogenous alpha-synuclein

et al. 2014

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Mutation or multiplication of the alpha-synuclein (Syn)-encoding gene is frequent cause of early onset Parkinson's disease (PD). Recent evidences point to the pathogenic role of excess Syn also in sporadic PD. Syn is a cytosolic protein, which has been shown to be released from neurons. Here we provide evidence that extracellular Syn induces an increase in surface-exposed glucose-related protein of 78 kDa (GRP78), which becomes clustered in microdomains of the neuronal plasma membrane. Upon interacting with Syn, GRP78 activates a signaling cascade leading to cofilin 1 inactivation and stabilization of microfilaments, thus affecting morphology and dynamics of actin cytoskeleton in cultured neurons. Downregulation of GRP78 abolishes the activity of exogenous Syn, indicating that it is the primary target of Syn. Inactivation of cofilin 1 and stabilization of actin cytoskeleton are present also in fibroblasts derived from genetic PD patients, which show a dramatic increase in stress fibers. Similar changes are displayed by control cells incubated with the medium of PD fibroblasts, only when Syn is present. The accumulation of Syn in the extracellular milieu, its interaction with the plasma membrane and Syn-driven clustering of GRP78 appear, therefore, responsible for the dysregulation of actin turnover, leading to early deficits in synaptic function that precede neurodegeneration.

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“…α-Synuclein is the main component of Lewy bodies, the hallmark of Parkinson's disease, and elevated wild-type α-synuclein levels and polymorphisms of the α-synuclein gene are known to be closely linked to the severity and risk of developing Parkinson's disease (Parnetti et al, 2013). Furthermore, a physical interaction between PLD2 and α-synuclein reported in vivo can inhibit PLD2 activity (Jenco et al, 1998).…”

Section: Notementioning

confidence: 99%