Dopamine; Dopamine Plasma Membrane Transport Proteins; Tropanes; 2-carbomethoxy-8-(3-fluoropropyl)-3-(4-iodophenyl)tropane; Humans; Male; Female; Aged; Brain/metabolism; Brain/diagnostic imaging; Tomography, Emission-Computed, Single-Photon/methods; Dopamine Plasma Membrane Transport Proteins/metabolism; Aged, 80 and over; Cognitive Dysfunction/metabolism; Middle Aged; Neural Pathways/metabolism; Alzheimer Disease/metabolism; Alzheimer Disease/diagnostic imaging; Dopamine/metabolism; Alzheimer Disease; Brain; Cognitive Dysfunction; Neural Pathways; Tomography, Emission-Computed, Single-Photon; Molecular Biology; Cellular and Molecular Neuroscience; Psychiatry and Mental Health
Abstract :
[en] Both post-mortem and in vivo data argue for dopamine dysfunction in patients with Alzheimer's Disease (AD). However, the timing and regional progression of dopaminergic systems alterations in AD are still debated. The aim of the study was to investigate in vivo the pattern of dopaminergic changes and connectivity using DAT-SPECT imaging in patients across the AD spectrum. Fifty-nine AD patients (n = 21 AD-MCI; n = 38 AD-DEM) and a control group (CG) of n = 45 age- and sex-matched individuals entered the study and underwent 123I-FP-CIT dopaminergic imaging. The occipital binding was used as reference region to obtain single-subject binding in different brain regions. Between-group differences in 123I-FP-CIT binding in both mesolimbic and nigrostriatal dopaminergic pathways were assessed using an ANCOVA test, adjusting for the effect of center of imaging acquisition, age, and sex. Regions resulting from the voxel-wise direct comparison between AD-MCI and AD-DEM were considered as a seed of interest for a voxel-wise interregional correlation analysis. Both AD-MCI and AD-DEM patients showed dopaminergic depletion within the basal ganglia, whereas cortico-limbic regions (namely hippocampus, amygdala, anterior and middle cingulate, frontal cortex and thalamus) resulted impaired only in the dementia phase. The brain voxel-wise interregional correlation analysis showed a progressive pattern of disruption of caudate/thalamus dopaminergic connectivity to hippocampus and amygdala from AD-MCI to AD-DEM stages. This study indicates basal ganglia dopaminergic alterations and connectivity disruption in the nigrostriatal and mesolimbic systems already in early stage AD, extending to several cortico-limbic regions in dementia phases.
Disciplines :
Neurology
Author, co-author :
Pilotto, Andrea ; Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy. pilottoandreae@gmail.com ; Laboratory of Digital Neurology and Biosensors, University of Brescia, Brescia, Italy. pilottoandreae@gmail.com ; Neurology Unit, Department of continuity of care and frailty, ASST Spedali Civili Brescia Hospital, Brescia, Italy. pilottoandreae@gmail.com ; Neurobiorepository and Laboratory of advanced biological markers, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy. pilottoandreae@gmail.com
Galli, Alice; Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy ; Laboratory of Digital Neurology and Biosensors, University of Brescia, Brescia, Italy
Sala, Arianna ; Université de Liège - ULiège > Département des sciences cliniques
Caminiti, Silvia Paola; Department of Brain and Behavioral Sciences- Univeristy of Pavia, Pavia, Italy
Presotto, Luca; Department of Physics "G. Occhialini", University of Milano-Bicocca, Milan, Italy
Liguori, Claudio; Neurophysiology Unit, Sleep and Epilepsy Center- University of Rome Tor Vergata, Rome, Italy
Mercuri, Nicola Biagio ; Neurophysiology Unit, Sleep and Epilepsy Center- University of Rome Tor Vergata, Rome, Italy
Garibotto, Valentina ; Department of Radiology and Medical Informatics- Geneva University Hospital, Geneva, Switzerland
Frisoni, Giovanni; Department of Psychiatry- Geneva University Hospital, Geneva, Switzerland
Chiaravalloti, Agostino; Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
Schillaci, Orazio; Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
D'Amelio, Marcello ; Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Rome, Italy ; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
Paghera, Barbara; Nuclear Medicine Unit- University of Brescia, Brescia, Italy
Lucchini, Silvia; Nuclear Medicine Unit- University of Brescia, Brescia, Italy
Bertagna, Francesco; Nuclear Medicine Unit- University of Brescia, Brescia, Italy
Perani, Daniela; University Vita-Salute San Raffaele, IRCCS San Raffaele Hospital, Milan, Italy
Padovani, Alessandro ; Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy ; Laboratory of Digital Neurology and Biosensors, University of Brescia, Brescia, Italy ; Neurology Unit, Department of continuity of care and frailty, ASST Spedali Civili Brescia Hospital, Brescia, Italy ; Brain Health Center, University of Brescia, Brescia, Italy
Ministero della Salute MIUR - Ministero dell'Istruzione, dell'Università e della Ricerca
Funding text :
We thank the participants in this study for their time and willingness to contribute this research. The study was partially supported by the Italian Ministry of Health with the grant RF-2018-12366209 and by #NEXTGENERATIONEU (NGEU) funded by the Ministry of University and Research (MIUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) \u2013 a multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022) to Silvia Paola Caminiti, Nicola Biagio Mercuri and Claudio Liguori; by the American Alzheimer\u2019s Association (AARG-21-851219) and by Fondazione Roma (Rome, Italy) to Marcello D\u2019Amelio.
J.J. Palop L. Mucke Amyloid-β–induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks Nat Neurosci 13 812 8 1:CAS:528:DC%2BC3cXnvFSgtr0%3D 20581818 3072750
R.D. Rudelli M.W. Ambler H.M. Wisniewski Morphology and distribution of Alzheimer neuritic (senile) and amyloid plaques in striatum and diencephalon Acta Neuropathol 64 273 81 1:STN:280:DyaL2M%2FmvVKisA%3D%3D 6542292
J. Attems D.R. Thal K.A. Jellinger The relationship between subcortical tau pathology and Alzheimer’s disease Biochem Soc Trans 40 711 5 1:CAS:528:DC%2BC38XhtVOjtrfO 22817721
L. Trillo D. Das W. Hsieh B. Medina S. Moghadam B. Lin et al. Ascending monoaminergic systems alterations in Alzheimer’s disease. Translating basic science into clinical care Neurosci Biobehav Rev 37 1363 79 1:CAS:528:DC%2BC3sXhsFGjsLfO 23707776
O.L. Lopez S.R. Wisnieski J.T. Becker F. Boiler S.T. DeKosky Extrapyramidal signs in patients with probable Alzheimer disease Arch Neurol 54 969 75 1:STN:280:DyaK2svhtFymug%3D%3D 9267971
J.O. Rinne E. Säkö L. Paljärvi P.K. Mölsä U.K. Rinne Brain dopamine D-2 receptors in senile dementia J Neural Transm 65 51 62 1:STN:280:DyaL287ntVCluw%3D%3D 2870131
J.N. Joyce G. Smutzer C.J. Whitty A. Myers M.J. Bannon Differential modification of dopamine transporter and tyrosine hydroxylase mRNAs in midbrain of subjects with Parkinson’s, Alzheimer’s with parkinsonism, and Alzheimer’s disease Mov Disord 12 885 97 1:STN:280:DyaK1c%2FmtFKjuw%3D%3D 9399211
W.R. Gibb C.Q. Mountjoy D.M. Mann A.J. Lees The substantia nigra and ventral tegmental area in Alzheimer’s disease and Down’s syndrome J Neurol Neurosurg Psychiatry 52 193 200 1:STN:280:DyaL1M7pvFSjsw%3D%3D 2539435 1032505
N. Kemppainen M. Laine M.P. Laakso V. Kaasinen K. Någren T. Vahlberg et al. Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer’s disease Eur J Neurosci 18 149 54 1:STN:280:DC%2BD3szntlCrsQ%3D%3D 12859348
R. Cortés A. Probst J. Palacios Decreased densities of dopamine D1 receptors in the putamen and hippocampus in senile dementia of the Alzheimer type Brain Res 475 164 7 2975188
M. Pievani M. Bocchetta M. Boccardi E. Cavedo M. Bonetti P.M. Thompson et al. Striatal morphology in early-onset and late-onset Alzheimer’s disease: a preliminary study Neurobiol Aging 34 1728 39 1:CAS:528:DC%2BC3sXisleht7w%3D 23428181
A. Sala S.P. Caminiti L. Presotto A. Pilotto C. Liguori A. Chiaravalloti et al. In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases Alzheimers Res Ther 13 1 12
G. Pizzolato F. Chierichetti M. Fabbri A. Cagnin M. Dam G. Ferlin et al. Reduced striatal dopamine receptors in Alzheimer’s disease: Single photon emission tomography study with the D sub 2 tracer [sup 123 I]-IBZM Neurology 47 1065 8 1:STN:280:DyaK2s%2FhtVOisQ%3D%3D 8857746
G. Koch F. Di Lorenzo S. Bonnì V. Giacobbe M. Bozzali C. Caltagirone et al. Dopaminergic modulation of cortical plasticity in Alzheimer’s disease patients Neuropsychopharmacology 39 2654 61 1:CAS:528:DC%2BC2cXhtVagsbfL 24859851 4207345
G. Koch C. Motta S. Bonnì M.C. Pellicciari S. Picazio E.P. Casula et al. Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease: A Randomized Clinical Trial JAMA Netw Open 3 e2010372 e2010372 32667654 7364345
C.R. Jack D.A. Bennett K. Blennow M.C. Carrillo B. Dunn S.B. Haeberlein et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease Alzheimer’s Dement 14 535 62
M. Boccardi D. Altomare C. Ferrari C. Festari U.P. Guerra B. Paghera et al. Assessment of the incremental diagnostic value of florbetapir F 18 imaging in patients with cognitive impairment: the incremental diagnostic value of amyloid PET with [18F]-florbetapir (INDIA-FBP) study JAMA Neurol 73 1417 24 27802513
A. Pilotto F. Schiano di Cola E. Premi R. Grasso R. Turrone S. Gipponi et al. Extrastriatal dopaminergic and serotonergic pathways in Parkinson’s disease and in dementia with Lewy bodies: a 123 I-FP-CIT SPECT study Eur J Nucl Med Mol Imaging 46 1642 51 1:CAS:528:DC%2BC1MXhtFert7jF 31098748
S.P. Caminiti A. Pilotto E. Premi A. Galli E. Ferrari S. Gipponi et al. Dopaminergic connectivity reconfiguration in the dementia with Lewy bodies continuum Parkinsonism Relat Disord 108 105288 1:CAS:528:DC%2BB3sXitFKqtrk%3D 36724569
S. Morbelli G. Esposito J. Arbizu H. Barthel R. Boellaard N.I. Bohnen et al. EANM practice guideline/SNMMI procedure standard for dopaminergic imaging in Parkinsonian syndromes 1.0 Eur J Nucl Med Mol Imaging 47 1885 912 32388612 7300075
J. Darcourt J. Booij K. Tatsch A. Varrone T. Vander Borght Ö.L. Kapucu et al. EANM procedure guidelines for brain neurotransmission SPECT using 123 I-labelled dopamine transporter ligands, version 2 Eur J Nucl Med Mol Imaging 37 443 50 1:CAS:528:DC%2BC3cXhsVyitr0%3D 19838702
L. Iaccarino A. Sala S.P. Caminiti L. Presotto D. Perani Initiative ADN In vivo MRI structural and PET metabolic connectivity study of dopamine pathways in Alzheimer’s disease J Alzheimer’s Dis 75 1003 16
N. Tzourio-Mazoyer B. Landeau D. Papathanassiou F. Crivello O. Etard N. Delcroix et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain Neuroimage 15 273 89 1:STN:280:DC%2BD38%2FltFCntw%3D%3D 11771995
T. Shigekiyo S. Arawaka Laterality of specific binding ratios on DAT-SPECT for differential diagnosis of degenerative parkinsonian syndromes Sci Rep 10 1:CAS:528:DC%2BB3cXhvFOhsL3E 32978422 7519659 15761
G.M. McKhann D.S. Knopman H. Chertkow B.T. Hyman C.R. Jack Jr C.H. Kawas et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease Alzheimer’s Dementia 7 263 9 21514250
A. Nobili E.C. Latagliata M.T. Viscomi V. Cavallucci D. Cutuli G. Giacovazzo et al. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease Nat Commun 8 1:CAS:528:DC%2BC2sXls1Khtbo%3D 28367951 5382255 14727
P. Moreno-Castilla L.F. Rodriguez-Duran K. Guzman-Ramos A. Barcenas-Femat M.L. Escobar F. Bermudez-Rattoni Dopaminergic neurotransmission dysfunction induced by amyloid-β transforms cortical long-term potentiation into long-term depression and produces memory impairment Neurobiol Aging 41 187 99 1:CAS:528:DC%2BC28XksFGqtbY%3D 27103531
L. Frings S. Hellwig T.S. Spehl T. Bormann R. Buchert W. Vach et al. Asymmetries of amyloid-β burden and neuronal dysfunction are positively correlated in Alzheimer’s disease Brain 138 3089 99 26280595
A. Pilotto M. Bongianni C. Tirloni A. Galli A. Padovani G. Zanusso CSF alpha‐synuclein aggregates by seed amplification and clinical presentation of AD Alzheimer’s Dement 19 3754 9 1:CAS:528:DC%2BB3sXovVGms7k%3D
L. Nyberg N. Karalija A. Salami M. Andersson A. Wåhlin N. Kaboovand et al. Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory Proc Natl Acad Sci 113 7918 23 1:CAS:528:DC%2BC28XhtFentrnM 27339132 4948341
R.L. Buckner Memory and executive function in aging and AD: multiple factors that cause decline and reserve factors that compensate Neuron 44 195 208 1:CAS:528:DC%2BD2cXovVOks7w%3D 15450170
S. Delli Pizzi R. Franciotti J.-P. Taylor A. Thomas A. Tartaro M. Onofrj et al. Thalamic involvement in fluctuating cognition in dementia with Lewy bodies: magnetic resonance evidences Cereb Cortex 25 3682 9 25260701
S.J. Kish K. Shannak O. Hornykiewicz Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease N Engl J Med 318 876 80 1:STN:280:DyaL1c7nsV2jtg%3D%3D 3352672
M.C. Masters J.C. Morris C.M. Roe Noncognitive” symptoms of early Alzheimer disease: a longitudinal analysis Neurology 84 617 22 1:CAS:528:DC%2BC2MXislSgsbw%3D 25589671 4335988
P. Krashia E. Spoleti M. D’Amelio The VTA dopaminergic system as diagnostic and therapeutical target for Alzheimer’s disease Front Psychiatry 13 1039725 36325523 9618946
N. Udo N. Hashimoto T. Toyonaga T. Isoyama Y. Oyanagi H. Narita et al. Apathy in Alzheimer’s disease correlates with the dopamine transporter level in the caudate nuclei Dement Geriatr Cogn Dis Extra 10 86 93 33082772 7548940
R.A. Mitchell N. Herrmann K.L. Lanctôt The role of dopamine in symptoms and treatment of apathy in Alzheimer’s disease CNS Neurosci Ther 17 411 27 1:CAS:528:DC%2BC3MXhtlOntL%2FO 20560994
J.A. Grahn J.A. Parkinson A.M. Owen The cognitive functions of the caudate nucleus Prog Neurobiol 86 141 55 18824075
F. Clément S. Gauthier S. Belleville Executive functions in mild cognitive impairment: emergence and breakdown of neural plasticity Cortex 49 1268 79 22841389
R. Manca J.M. Valera-Bermejo A. Venneri Initiative ADN Accelerated atrophy in dopaminergic targets and medial temporo-parietal regions precedes the onset of delusions in patients with Alzheimer’s disease Eur Arch Psychiatry Clin Neurosci 273 229 41 35554669
A. Venneri M. De Marco Reduced monoaminergic nuclei MRI signal detectable in pre-symptomatic older adults with future memory decline Sci Rep 10 1:CAS:528:DC%2BB3cXit1Orur7O 33127923 7603335 18707
L. Serra M. D’Amelio S. Esposito C. Di Domenico G. Koch C. Marra et al. Ventral tegmental area disconnection contributes two years early to correctly classify patients converted to Alzheimer’s disease: implications for treatment J Alzheimer’s Dis 82 985 1000 1:CAS:528:DC%2BB3MXhs12itrzL
J.I. Broussard K. Yang A.T. Levine T. Tsetsenis D. Jenson F. Cao et al. Dopamine regulates aversive contextual learning and associated in vivo synaptic plasticity in the hippocampus Cell Rep 14 1930 9 1:CAS:528:DC%2BC28XivFOqtb4%3D 26904943 4772154
J.I. Rossato L.R.M. Bevilaqua I. Izquierdo J.H. Medina M. Cammarota Dopamine controls persistence of long-term memory storage Science 325 1017 20 1:CAS:528:DC%2BD1MXhtValsrrL 19696353
A. Cordella P. Krashia A. Nobili A. Pignataro L. La Barbera M.T. Viscomi et al. Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer’s disease Neurobiol Dis 116 142 54 1:CAS:528:DC%2BC1cXhtVOjurbO 29778899
L. La Barbera F. Vedele A. Nobili P. Krashia E. Spoleti E.C. Latagliata et al. Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s disease Prog Neurobiol 202 102031 33684513
Y. Gloria K. Ceyzériat S. Tsartsalis P. Millet B.B. Tournier Dopaminergic dysfunction in the 3xTg-AD mice model of Alzheimer’s disease Sci Rep 11 1:CAS:528:DC%2BB3MXitFGqt7rK 34593951 8484608 19412
V. Vorobyov B. Bakharev N. Medvinskaya I. Nesterova A. Samokhin A. Deev et al. Loss of midbrain dopamine neurons and altered apomorphine EEG effects in the 5xFAD mouse model of Alzheimer’s disease J Alzheimer’s Dis 70 241 56 1:CAS:528:DC%2BC1MXhtlamsbvK
W.H. Jung J.H. Jang J.W. Park E. Kim E.-H. Goo O.-S. Im et al. Unravelling the intrinsic functional organization of the human striatum: a parcellation and connectivity study based on resting-state FMRI PLoS One 9 e106768 25203441 4159235
