Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study

Heather Wilson; George Dervenoulas; Gennaro Pagano; Christos Koros; Tayyabah Yousaf; Marina Picillo; Sotirios Polychronis; Athina Simitsi; Beniamino Giordano; Zachary Chappell; Benjamin Corcoran; Maria Stamelou; Roger N Gunn; Maria Teresa Pellecchia; Eugenii A Rabiner; Paolo Barone; Leonidas Stefanis; Marios Politis

doi:10.1016/S1474-4422(19)30140-1

Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study

Heather Wilson, George Dervenoulas, Gennaro Pagano, Christos Koros, Tayyabah Yousaf, Marina Picillo, Sotirios Polychronis, Athina Simitsi, Beniamino Giordano, Zachary Chappell, Benjamin Corcoran, Maria Stamelou, Roger N Gunn, Maria Teresa Pellecchia, Eugenii A Rabiner, Paolo Barone, Leonidas Stefanis, Marios Politis

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Abstract

Summary Background Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden. Methods In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [11C]DASB PET non-displaceable binding to quantify serotonin transporter density. We constructed brain topographic maps reflecting Braak stages 1–6 and used these as seed maps to calculate [11C]DASB non-displaceable binding potential in our cohort of A53T SNCA carriers. Additionally, all participants underwent a battery of clinical assessments to determine motor and non-motor symptoms and cognitive status, and [123I]FP-CIT single-photon emission CT (SPECT) to assess striatal dopamine transporter binding and MRI for volumetric analyses to assess whether pathology is associated with measures of Parkinson's disease burden. Findings Between Sept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthy controls, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of 14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed to have Parkinson's disease, and the absence of motor symptoms was confirmed in seven (50%) A53T SCNA carriers (ie, premotor), in whom [123I]FP-CIT SPECT confirmed the absence of striatal dopaminergic deficits. Compared with healthy controls, premotor A53T SNCA carriers showed loss of [11C]DASB non-displaceable binding potential in the ventral (p

Original language	English
Pages (from-to)	748-759
Number of pages	12
Journal	Lancet neurology
Volume	18
Issue number	8
Early online date	19 Jun 2019
DOIs	https://doi.org/10.1016/S1474-4422(19)30140-1
Publication status	Published - 1 Aug 2019

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10.1016/S1474-4422(19)30140-1

Serotonergic pathology_WILSON_Accepted3April2019_GREEN AAMAccepted author manuscript, 269 KBLicence: CC BY-NC-ND

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Wilson, H., Dervenoulas, G., Pagano, G., Koros, C., Yousaf, T., Picillo, M., Polychronis, S., Simitsi, A., Giordano, B., Chappell, Z., Corcoran, B., Stamelou, M., Gunn, R. N., Pellecchia, M. T., Rabiner, E. A., Barone, P., Stefanis, L., & Politis, M. (2019). Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study. Lancet neurology, 18(8), 748-759. https://doi.org/10.1016/S1474-4422(19)30140-1

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abstract = "Summary Background Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden. Methods In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [11C]DASB PET non-displaceable binding to quantify serotonin transporter density. We constructed brain topographic maps reflecting Braak stages 1–6 and used these as seed maps to calculate [11C]DASB non-displaceable binding potential in our cohort of A53T SNCA carriers. Additionally, all participants underwent a battery of clinical assessments to determine motor and non-motor symptoms and cognitive status, and [123I]FP-CIT single-photon emission CT (SPECT) to assess striatal dopamine transporter binding and MRI for volumetric analyses to assess whether pathology is associated with measures of Parkinson's disease burden. Findings Between Sept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthy controls, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of 14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed to have Parkinson's disease, and the absence of motor symptoms was confirmed in seven (50%) A53T SCNA carriers (ie, premotor), in whom [123I]FP-CIT SPECT confirmed the absence of striatal dopaminergic deficits. Compared with healthy controls, premotor A53T SNCA carriers showed loss of [11C]DASB non-displaceable binding potential in the ventral (p",

author = "Heather Wilson and George Dervenoulas and Gennaro Pagano and Christos Koros and Tayyabah Yousaf and Marina Picillo and Sotirios Polychronis and Athina Simitsi and Beniamino Giordano and Zachary Chappell and Benjamin Corcoran and Maria Stamelou and Gunn, {Roger N} and Pellecchia, {Maria Teresa} and Rabiner, {Eugenii A} and Paolo Barone and Leonidas Stefanis and Marios Politis",

year = "2019",

month = aug,

day = "1",

doi = "10.1016/S1474-4422(19)30140-1",

language = "English",

volume = "18",

pages = "748--759",

journal = "Lancet neurology",

issn = "1474-4422",

publisher = "Elsevier",

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Wilson, H , Dervenoulas, G , Pagano, G, Koros, C, Yousaf, T, Picillo, M, Polychronis, S, Simitsi, A, Giordano, B, Chappell, Z, Corcoran, B, Stamelou, M, Gunn, RN, Pellecchia, MT, Rabiner, EA, Barone, P, Stefanis, L & Politis, M 2019, 'Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study', Lancet neurology, vol. 18, no. 8, pp. 748-759. https://doi.org/10.1016/S1474-4422(19)30140-1

TY - JOUR

T1 - Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study

AU - Wilson, Heather

AU - Dervenoulas, George

AU - Pagano, Gennaro

AU - Koros, Christos

AU - Yousaf, Tayyabah

AU - Picillo, Marina

AU - Polychronis, Sotirios

AU - Simitsi, Athina

AU - Giordano, Beniamino

AU - Chappell, Zachary

AU - Corcoran, Benjamin

AU - Stamelou, Maria

AU - Gunn, Roger N

AU - Pellecchia, Maria Teresa

AU - Rabiner, Eugenii A

AU - Barone, Paolo

AU - Stefanis, Leonidas

AU - Politis, Marios

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Summary Background Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden. Methods In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [11C]DASB PET non-displaceable binding to quantify serotonin transporter density. We constructed brain topographic maps reflecting Braak stages 1–6 and used these as seed maps to calculate [11C]DASB non-displaceable binding potential in our cohort of A53T SNCA carriers. Additionally, all participants underwent a battery of clinical assessments to determine motor and non-motor symptoms and cognitive status, and [123I]FP-CIT single-photon emission CT (SPECT) to assess striatal dopamine transporter binding and MRI for volumetric analyses to assess whether pathology is associated with measures of Parkinson's disease burden. Findings Between Sept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthy controls, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of 14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed to have Parkinson's disease, and the absence of motor symptoms was confirmed in seven (50%) A53T SCNA carriers (ie, premotor), in whom [123I]FP-CIT SPECT confirmed the absence of striatal dopaminergic deficits. Compared with healthy controls, premotor A53T SNCA carriers showed loss of [11C]DASB non-displaceable binding potential in the ventral (p

AB - Summary Background Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden. Methods In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [11C]DASB PET non-displaceable binding to quantify serotonin transporter density. We constructed brain topographic maps reflecting Braak stages 1–6 and used these as seed maps to calculate [11C]DASB non-displaceable binding potential in our cohort of A53T SNCA carriers. Additionally, all participants underwent a battery of clinical assessments to determine motor and non-motor symptoms and cognitive status, and [123I]FP-CIT single-photon emission CT (SPECT) to assess striatal dopamine transporter binding and MRI for volumetric analyses to assess whether pathology is associated with measures of Parkinson's disease burden. Findings Between Sept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthy controls, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of 14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed to have Parkinson's disease, and the absence of motor symptoms was confirmed in seven (50%) A53T SCNA carriers (ie, premotor), in whom [123I]FP-CIT SPECT confirmed the absence of striatal dopaminergic deficits. Compared with healthy controls, premotor A53T SNCA carriers showed loss of [11C]DASB non-displaceable binding potential in the ventral (p

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DO - 10.1016/S1474-4422(19)30140-1

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Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study

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