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

Abstract 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 [(11)C]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) (η(2) = 0.84), whereas the SN was the less affected region (η(2) = 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 η(2) = 0.71 and VTA η(2) = 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.
PMID
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Authors

Mayor MeshTerms
Keywords

AI, asymmetry index

Axonal damage

DCA, dorsal caudate

DPU, dorsal putamen

Dopamine transporter

Molecular connectivity

Parkinson's disease

Positron emission tomography

SN, substantia nigra

SUVr, standardized uptake value ratio

VST, ventral striatum

VTA, ventral tegmental area

cAS, clinical asymmetry

Journal Title neuroimage. clinical
Publication Year Start




PMID- 28409113
OWN - NLM
STAT- MEDLINE
DA  - 20170414
DCOM- 20170420
LR  - 20170420
IS  - 2213-1582 (Electronic)
IS  - 2213-1582 (Linking)
VI  - 14
DP  - 2017
TI  - Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine
      pathways in early Parkinson's disease.
PG  - 734-740
LID - 10.1016/j.nicl.2017.03.011 [doi]
AB  - 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 alpha-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) (eta2 = 0.84), whereas the SN was the less affected region
      (eta2 = 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 eta2 = 0.71 and VTA eta2 = 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.
FAU - Caminiti, Silvia Paola
AU  - Caminiti SP
AD  - Vita-Salute San Raffaele University, Via Olgettina, 58, 20132 Milan, Italy.
AD  - Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina, 58,
      20132 Milan, Italy.
FAU - Presotto, Luca
AU  - Presotto L
AD  - Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina, 58,
      20132 Milan, Italy.
FAU - Baroncini, Damiano
AU  - Baroncini D
AD  - Department of Neurology, San Raffaele Hospital, Via Olgettina, 60, 20132 Milan,
      Italy.
FAU - Garibotto, Valentina
AU  - Garibotto V
AD  - Department of Medical Imaging, Geneva University, Geneva University Hospitals,
      Geneva, Switzerland.
FAU - Moresco, Rosa Maria
AU  - Moresco RM
AD  - IBFM-CNR, Segrate, Italy, Tecnomed Foundation, Department of Health Sciences,
      University of Milan-Bicocca, Monza, Italy.
FAU - Gianolli, Luigi
AU  - Gianolli L
AD  - Nuclear Medicine Unit, San Raffaele Hospital, Via Olgettina, 60, 20132 Milan,
      Italy.
FAU - Volonte, Maria Antonietta
AU  - Volonte MA
AD  - Department of Neurology, San Raffaele Hospital, Via Olgettina, 60, 20132 Milan,
      Italy.
FAU - Antonini, Angelo
AU  - Antonini A
AD  - Parkinson's Disease and Movement Disorders Unit, I.R.C.C.S Hospital San Camillo, 
      Via Alberoni 70, 30126 Venice, Italy.
AD  - Department of Neurosciences (DNS), University of Padua, Via Giustiniani 5, 35128 
      Padova, Italy.
FAU - Perani, Daniela
AU  - Perani D
AD  - Vita-Salute San Raffaele University, Via Olgettina, 58, 20132 Milan, Italy.
AD  - Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina, 58,
      20132 Milan, Italy.
AD  - Nuclear Medicine Unit, San Raffaele Hospital, Via Olgettina, 60, 20132 Milan,
      Italy.
LA  - eng
PT  - Journal Article
DEP - 20170327
PL  - Netherlands
TA  - Neuroimage Clin
JT  - NeuroImage. Clinical
JID - 101597070
RN  - 0 (Dopamine Plasma Membrane Transport Proteins)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Aged
MH  - Axons/metabolism/*pathology
MH  - Brain Injuries/diagnostic imaging/etiology/*pathology
MH  - Corpus Striatum/*diagnostic imaging
MH  - Dopamine/*metabolism
MH  - Dopamine Plasma Membrane Transport Proteins/metabolism
MH  - Female
MH  - Humans
MH  - Image Interpretation, Computer-Assisted
MH  - Limbic System/*diagnostic imaging
MH  - Male
MH  - Middle Aged
MH  - Parkinson Disease/complications/diagnostic imaging
MH  - Positron-Emission Tomography
MH  - Retrospective Studies
MH  - Substantia Nigra/*diagnostic imaging
PMC - PMC5379906
OTO - NOTNLM
OT  - AI, asymmetry index
OT  - Axonal damage
OT  - DCA, dorsal caudate
OT  - DPU, dorsal putamen
OT  - Dopamine transporter
OT  - Molecular connectivity
OT  - Parkinson's disease
OT  - Positron emission tomography
OT  - SN, substantia nigra
OT  - SUVr, standardized uptake value ratio
OT  - VST, ventral striatum
OT  - VTA, ventral tegmental area
OT  - cAS, clinical asymmetry
EDAT- 2017/04/15 06:00
MHDA- 2017/04/21 06:00
CRDT- 2017/04/15 06:00
PHST- 2016/10/20 [received]
PHST- 2017/03/13 [revised]
PHST- 2017/03/24 [accepted]
AID - 10.1016/j.nicl.2017.03.011 [doi]
AID - S2213-1582(17)30071-2 [pii]
PST - epublish
SO  - Neuroimage Clin. 2017 Mar 27;14:734-740. doi: 10.1016/j.nicl.2017.03.011.
      eCollection 2017.

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