Gender differences in Parkinson’s disease: focus on plasma alpha-synuclein

Caranci, Giovanni; Rivabene, Roberto; Traficante, Anna; Riozzi, Barbara; Castellano, Anna Elisa; Ruggieri, Stefano; Vanacore, Nicola; Confaloni, Annamaria

doi:10.1007/s00702-013-0972-6

Cited by 43 publications

(33 citation statements)

References 26 publications

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“…Oligomeric alpha‐synuclein was not detected in the plasma, but we detected a significant effect on total alpha‐synuclein levels with lower single doses (150 and 200 mg) of Nilotinib. Nilotinib significantly reduced the concentration of alpha‐synuclein that is elevated in the blood of PD patients . These results are consistent with our previous findings that demonstrated Nilotinib effects on lowering blood alpha‐synuclein in mice .…”

Section: Discussionsupporting

confidence: 92%

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pagán

Hebron

Wilmarth

et al. 2019

Pharmacology Res & Perspec

111

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Nilotinib is a broad‐based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c‐Abl) and discoidin domain receptors ( DDR 1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha‐synuclein and attenuates inflammation in models of Parkinson's disease ( PD ). We previously showed that Nilotinib penetrates the blood‐brain barrier ( BBB ) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies ( DLB ). We performed a physiologically based population pharmacokinetic/pharmacodynamic (pop PK / PD ) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open‐label random single dose ( RSD ) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid ( CSF ) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose‐independent manner and 200 mg Nilotinib increases the level of 3,4‐Dihydroxyphenylacetic acid ( DOPAC ) and homovanillic acid ( HVA ), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha‐synuclein and appears to reduce CSF oligomeric: total alpha‐synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells ( TREM )‐2, suggesting an anti‐inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha‐synuclein.

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Section: Discussionsupporting

confidence: 92%

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pagán

Hebron

Wilmarth

et al. 2019

Pharmacology Res & Perspec

111

View full text Add to dashboard Cite

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“…The genes involved in the pathogenesis of PD including α-synuclein and PINK-1 are shown to be overexpressed in male, while the genes responsible for the neuronal maturation and signal transduction are overexpressed in female [11, 39]. Recent study measured higher level of α-synuclein in plasma of male PD than female PD [12]. Further, they observed that increased plasma α-synuclein level correlates with cognitive impairment, hallucinations, psychosis, apathy and sleep disorders in PD patients [12].…”

Section: Discussionmentioning

confidence: 99%

“…Recent study measured higher level of α-synuclein in plasma of male PD than female PD [12]. Further, they observed that increased plasma α-synuclein level correlates with cognitive impairment, hallucinations, psychosis, apathy and sleep disorders in PD patients [12]. We suggest that higher expression of genes involved in PD pathogenesis in male and neuroprotective effects of sex hormones in female might be a possible explanation for the lower cortical thickness in male PD than female PD.…”

Section: Discussionmentioning

confidence: 99%

Gender-based analysis of cortical thickness and structural connectivity in Parkinson’s disease

et al. 2016

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Parkinson’s disease (PD) is a progressive neurological disorder and appears to have gender-specific symptoms. Studies have observed a higher frequency for development of PD in male than in female. In the current study, we evaluated the gender-based changes in cortical thickness and structural connectivity in PD patients. With informed consent, 64 PD (43 males and 21 females) patients, and 46 (12 males and 34 females) age-matched controls underwent clinical assessment including MiniMental State Examination (MMSE) and magnetic resonance imaging on a 1.5 Tesla clinical MR scanner. Whole brain high-resolution T1-weighted images were acquired from all subjects and used to measure cortical thickness and structural network connectivity. No significant difference in MMSE score was observed between male and female both in control and PD subjects. Male PD patients showed significantly reduced cortical thickness in multiple brain regions including frontal, parietal, temporal, and occipital lobes as compared with those in female PD patients. The graph theory-based network analysis depicted lower connection strengths, lower clustering coefficients, and altered network hubs in PD male than in PD female. Male-specific cortical thickness changes and altered connectivity in PD patients may derive from behavioral, physiological, environmental, and genetical differences between male and female, and may have significant implications in diagnosing and treating PD among genders.

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“…This is pronounced in western countries where men are approximately 1.5 times more likely to develop PD than women 2, 3, 4, 5, 6, 7, 8. Sex differences may be attributable to genetics, sexual brain dimorphism, hormonal, and immunological factors, environmental exposures, referral bias, treatment differences, or a combination of these.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Luciano

Wang

Ortega

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD).Methods530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women.Results Among IPD: men had higher levodopa equivalency dose (LED), worse activities of daily living and motoric severity but lower complications of therapy (UPDRS‐IV). IPD women had higher olfaction and thermoregulatory scores and were more likely to report family history of PD. Among LRRK2 PD: Male predominance was not observed among G2019S LRRK2 cases. Women had worse UPDRS‐IV but better olfaction. Among same sex:LRRK2 men and women had better olfaction than IPD counterparts. LRRK2 men demonstrated lower motor and higher cognitive, RBD and thermoregulation scores than IPD men and LRRK2 women had greater UDPRS‐IV and rates of dyskinesia.InterpretationThere were clinical differences between sexes with a more severe phenotype in IPD men and more complications of therapy in women. The more severe male phenotype was moderated by LRRK2, with LRRK2 men and women showing less diversity of phenotype. Our study supports that both genetics and sex drive phenotype, and thus trials in LRRK2 and IPD should consider gender stratification in design or analysis.

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Gender differences in Parkinson’s disease: focus on plasma alpha-synuclein

Cited by 43 publications

References 26 publications

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Gender-based analysis of cortical thickness and structural connectivity in Parkinson’s disease

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

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