1. “ La medicina nucleare nella diagnosi delle demenze: dalla ricerca alla pratica clinica” Susanna Nuvoli Medicina Nucleare Università degli studi di Sassari [email_address]
3. L’imaging Medico Nucleare, è un mezzo a cui si fa ricorso sempre più di frequente, sia nella ricerca che nella pratica clinica, per la sua peculiare e pressoché esclusiva capacità di valutare nel vivente anomalie funzionali, cellulari e biochimiche finora solo supposte o evidenziate esclusivamente al tavolo autoptico. ?
4. Isolation and partial characterization of neurofibrillary tangles and amyloid plaque core in Alzheimer's disease: immunohistological studies. Gorevic PD , Goñi F , Pons-Estel B , Alvarez F , Peress NS , Frangione B . J Neuropathol Exp Neurol. 1986 Nov; 45(6):647-64. Alzheimer's disease: the amyloid cascade hypothesis. Hardy JA , Higgins GA . Science. 1992 Apr 10;256(5054):184-5. Über eine eigenartige Erkrankung der Hirnrinde (a proposito di una rara malattia della corteccia cerebrale) Alzheimer A. Allg Z Psychiat (1907) 64:146–148
5. PET imaging of amyloid in Alzheimer's disease Nordberg A. Lancet Neurol. 2004 Sep;3(9):519-27 In-vivo measurement of activated microglia in dementia A.Cagnin, D.J.Brooks, A.M. Kennedy, R.N. Gunn, R. Myers, F.E. Turkheimer, T. Jones, R. B. Banati Lancet 2001 ; 358: 461–67
6. Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study P. Edison, H. A. Archer, A. Gerhard, R. Hinz, N. Pavese, F. E. Turkheimer, A. Hammers, Y. F. Tai, N.Fox, A. Kennedy,M. Rossor, D. J. Brooks Neurobiology of Disease 32 (2008) 412–419 In the future, the combined use of amyloid andmicroglial imaging should allow us to determine whether anti amyloid strategies clear plaques and exert their therapeutic effects via stimulating or suppressing glial activation. Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer's disease. Kadir A, Marutle A, Gonzalez D, Schöll M, Almkvist O, Mousavi M, Mustafiz T, Darreh-Shori T, Nennesmo I, Nordberg A. Brain. 2011 Jan;134(Pt 1):301-17 11C-PIB PET scan at age 56, MMSE score 21/30 11C-PIB PET scan at age 58, MMSE score 13/30
7. Faraci FM, Circ Res. 1993 Yang ST, Neuroreport. 1998 Brenman JE Cell. 1996 Devous M D Eur J Nucl Med 2002 Irreversibile Reversibile Regioni ippocampali in AD (atrofia)
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9. Neuropsychophysiological findings in a case of long-standing overt ventriculomegaly (LOVA) E D.G. Canu……., S. Nuvoli, I. Aiello. N euroscience Letters 385 (2005) 24–29 The level of adaptation to which human brain can reach under chronic mechanic stress conditions. The striking poor cerebral parenchyma representation and the relatively spared language and praxic abilities account for a functional reorganization of residual structures due to the neural plasticity . 59-year-old man with congenital hydrocephalus complaining of persistent gait impairment. Neurological examination showed a mild paraparesis, severe higher cortical function impairment but relatively sparing of daily living activity. remarkable ventriculomegaly compressing the brain cortex but sparing the cerebellum and the brainstem. diffuse decrease of brain perfusion. A relatively hypoperfusion was seen in the left temporal and parieto-occipital areas (A). A normal pattern of perfusion was evident in both cerebellar lobes (B).
10. PET (Positron Emission Tomography) SPECT (Single Photon Emission Computed Tomography) APPARECCHIATURE Sistemi Ibridi: SPECT/TC o PET/TC
11. dalla ricerca……….. PET (Positron Emission Tomography) ………………… alla pratica clinica SPECT (Single Photon Emission Computed Tomography) risoluzione spaziale: maggiore per la PET 4-5 mm vs la SPECT 7-8 mm costi : maggiori per la PET vs la SPECT
12. Radiofarmaci: dalla ricerca PET…….. Radiofarmaci: ….alla pratica clinica SPECT Imaging Funzionale : 99mTc HMPAO (flusso cerebrale regionale) Imaging Biomolecolare: 123I-DaTSCAN (123I IOFLUPANO) -> target: trasportatori della dopamina nelle terminazioni pre-sinaptiche delle fibre nigro-striatale. 123I-IBZM -> target: recettori post-sinaptici striatali D2 Sintesi della dopamina Siti del reuptake della DA Recettori D1 della DA Recettori D2 della DA Monoamine transporter 18 F- fluoro dopa 11 C- beta-CIT 11 C-SCH-23390 11 C-raclopride 11 C-DTBZ dopamina recettori 5HT 1A recettori 5HT 2A 18 F- MPPF 18 F-altaserin serotonina attività della acetilcolinesterasi attività della acetilcolinesterasi attività della butircolinesterasi recettori nicotinici recettori muscarinici 11 C- PMP 11 C-MP4A 11 C-methyl-4-piperidinyl-butyrare 11 C- nicotine 11 C- benztropine acetilcolina Neurotrasmettitori Flusso ematico cerebrale Flusso ematico cerebrale Metabolismo del glucosio 11 C- butanolo 11 O- H2O 18 FDG Funzione valutazione radiofarmaco Parametro Radiofarmaci PET per la valutazione funzionale e dei neurotrasmettitori nelle demenze 11 C-DED Astrociti 11 C-DAA-1106…. microglia 18 F-FDDNP Proteina tau 18 F-FDNP 11 C-PIB 18 FBAY-94-9172 18 F-AV-45…… amiloide Radiofarmaco Parametro Radiofarmaci PET utilizzati per la studio dei biomarker delle demenze
13. Informazioni Fisiopatologia del sistema a sua volta espressione delle variazioni della struttura bio-molecolare delle cellule nervose Imaging Funzionale PET SPECT
14. Informazioni eziopatogenesi (sede del sistema colpito, gravità, estensione) conseguenti alterazioni bio-chimiche indotte dalla patologia PET SPECT Imaging biomolecolare 18F DOPA normale PD 123IDaTSCAN PD MSA 123I IBZM
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16. NEUROGAM Analisi Semiquantitativa delle Immagini funzionali …… ..applying the Talaraich technique (NEUROGAM, SEGAMI Corporation) which renders the single brain volume into a normalized one and allows a voxel by voxel comparative analysis with a normal age matched control group; quantitative analysis, expressed as Standard Deviation (SD) below the normal mean for age group…… (Nuvoli S. 2008)
17. Valutazione semiquantitativa della captazione specifica nei nuclei della base: metodi 3D ? neurotrans3D Binding Potentials Patologico Non patologico 123I DaTSCAN: sezioni transassiali 123I DaTSCAN: sezioni transassiali ?
19. FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer’s disease Norman L. Foster, Brain (2007), 130, 2616-2635 Michael D. Devous Sr Eur J Nucl Med (2002) 29:1685–1687. Functional brain imaging in the dementias: role in early detection, differential diagnosis,and longitudinal studies Numerous studies using SPET and PET have consistently demonstrated temporoparietal hypoperfusion or hypometabolism in patients with AD, as well as posterior cingulate pathology Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer's disease K. M. Bradley Brain (2002), 125, 1772±1781 The time course of these perfusion defects appears relatively long, suggesting that perfusion changes may have scope to be a diagnostic aid in staging Alzheimer's disease in life. The reduction in anterior medial temporal lobe perfusion may have future relevance on modern high resolution SPET and PET systems
20. Evaluating Early Dementia With and Without Assessment of Regional Cerebral Metabolism by PET: A Comparison of Predicted Costs and Benefits Daniel H.S. Silverman THE JOURNAL OF NUCLEAR MEDICINE • Vol. 43 • No. 2 • February 2002 Appropriate use of PET for evaluating early dementia in geriatric patients can add valuable information to the clinical work-up, without adding to the overall costs of evaluation and management, resulting in a greater number of patients being accurately diagnosed for the same level of financial expenditure. Thus, the opportunity exists for diminishing the morbidity of dementia economically, with earlier institution of more appropriate management in evaluated patients. Cost-effectiveness of 18F-fluorodeoxyglucose positron emission tomography in the assessment of early dementia from a Belgian and European perspective G. Moulin-Romseea, A. Maesa, D. Silvermanb, L. Mortelmansa and K. Van Laerea European Journal of Neurology 2005, 12: 254–263
21. S L PIMLOTT The British Journal of Radiology, 80 (2007), S153–S159 99mTc HM PAO perfusion SPECT Analoghi risultati in termini di accuratezza diagnostica (<risoluzione) MAGGIORE DIFFUSIONE COSTI MINORI Studio del flusso cerebrale regionale (99mTc HMPAO SPECT) METODICA DI RIFERIMENTO Mielke R. Eur J Nucl Med 1994
22. 99mTc HM PAO perfusion SPECT Demenza di Alzheimer Ipoperfusione temporo-parietale posteriore posteriore anteriore Lat sinistra Lat destra MTV soglia 67%
26. dalla ricerca ……………..alla pratica clinica Lewy Body Dementia (LBD) Degenerazione corticale Degenerazione del sistema extrapiramidale Degenerazione del sistema noradrenergico
28. Sens: 77.7% Spec: 90.4% PPV: 82.4% NPV: 87.5% Acc: 85.7% Degenerazione corticale Degenerazione del sistema extrapiramidale (come nella malattia di Parkinson) Degenerazione del sistema noradrenergico 123I DaTSCAN
29. 123I-Ioflupane SPECT qualitative and quantitative analysis by 3D attenuation/partial volume effect correction in Cognitive Disorders differential diagnosis S. Nuvoli, A. Nieddu, A. Rotondo, R. Salvo, F. Chessa, A. Spanu, G. Madeddu Quarterly J of nuclear medicine and molecular imaging: 55 (1) aprile 2011 Our data confirm that 123I-Ioflupane SPECT and Consensus Criteria combined use has higher reliability in supporting differential diagnosis of cognitive disorders especially in discriminating LBD from non LBD (AD/DV). Furthermore, in our doubtful early stage cases QL performance was improved by 3D QN method with BP calculation thus suggesting its use in unclear qualitative 123I-Ioflupane SPECT results. 98 pts con RMN/TC non significativa Consortium on LBD international Workshop Criteria;1996 e 2005 Pathological DaTSCAN 21/98 Normal DaTSCAN 77/98 LBD Non LBD
30. RMN: ndr Lewy body Dementia 123I DaTSCAN SPECT captazione ridotta RMN: aree ischemiche aspecifiche Non Lewy body Dementia (Alzheimer dementia) 123I DaTSCAN normale distribuzione
31. Degenerazione corticale (come nella demenza di Alzheimer) Degenerazione del sistema extrapiramidale Degenerazione del sistema noradrenergico Ipoperfusione temporo- occipitale Posteriore Anteriore Laterale sn Laterale dx MTV: soglia 67% 99m Tc HM-PAO SPECT 99m Tc HM-PAO SPECT Valutazione qualitativa: sezioni transassiali
32. Degenerazione corticale Degenerazione del sistema extrapiramidale Degenerazione del sistema noradrenergico (come nella malattia di Parkinson) Scintigrafia cardica con 123 I Meta-Iodo-Benzil-Guanidina (MIBG) per lo studio dell’innervazione parasimpatica postgangliare del cuore Non Lewy body Dementia Lewy body Dementia
35. MCI early stage of AD? dalla ricerca ……………..alla pratica clinica Mild Cognitive Impairment (MCI)
36. MCI: 18 FDG PET A critical discussion of the role of neuroimaging in mild cognitive impairment WOLF H et al: Acta Neurologica Scandinavica Supp 2003, vol. 107 52-76 Accuratezza diagnostica 81% SPECT/PET
37. SPECT Perfusion Differences In Mild Cognitive Impairment Johnson K A et al J Neurol Neurosurg Psyc. 2006 105 non-demented elderly subjects with mild cognitive impairment (MCI), using 99mTc-HMPAO. five-year Clinical follow-up : Riduzione della perfusione temporo-parietale, del giro posteriore del cingolo e dell’ippocampo correla con un alto rischio di progressione verso la malattia di Azheimer e consente di individuare i soggetti converter vs non converter e normali di controllo. These results suggest that clinical heterogeneity in MCI is reflected in SPECT perfusion differences, and that the pattern of perfusion abnormalities evolves with increasing clinical severity
38. Conclusions: 99mTc HMPAO SPECT may be a useful complementary tool to NT, in particular DemTect, to identify and monitor MCI and to early ascertain its progression to D. Moreover, in our study, SPECT proved more sensitive than NT also preceding MCI diagnosis in some cases. Statistical Quantitative Analysis of 99mTc HM-PAO Brain SPECT in Amnestic Mild Cognitive Impairment (aMCI) and Alzheimer Dementia (AD) S. Nuvoli , M.R. Piras, C. Bagella, R. Cherchi, A. Spanu, G. Madeddu Quarterly J of nuclear medicine and molecular imaging: 55 (1) aprile 2011 . In particular the findings of hypoperfusion areas in limbic regions could suggest a closer follow up in these cases who can present high risk of AD .
39. MV ♀ aa 72 1° osservazione: giugno 2007 : sospetto MCI amnesico (TC: ndr; MMSE 26.4/30; DemTect: 10/18)
40.
41. dalla ricerca ……………..alla pratica clinica ? …… Come faceva un medico di fronte a quel relitto piangente a sapere che normalmente mia madre era una donna affettuosa, spiritosa e piena di vita? Papà invece lo sapeva eccome e non aveva dubbi che, quando si fosse risvegliata dall’incubo, lui doveva essere li ad accoglierla e ad assicurarle che aveva ritrovato se stessa…… PROSSIMA FRONTIERA…. Ricerca Pratica clinica
2) Nitric oxide mediates vasodilatation in response to activation of N methyl-D-aspartate receptors in brain. FM Faraci and KR Breese Circ. Res. 1993;72;476-480 3) Nitric oxide of neuronal origin mediates NMDA-induced cerebral hyperemia in rats. Shuh-Tsong YangCA and Hsi-Hsien Chang NeuroReport 9 , 415–418 (1998) 4) Interaction of nitric oxidate synthase with the postsynaptic density protein PSD95 and alfa1syntrophin mediated by PDZ Domains. Brenman JE, Chaos DS, Gee SH, Mc Gee AW, Craven SE, Santillano DR, Wu Z, Huanf F, Xia H, Peters MF, Froener SC, Bredt DS. Cell 1996Mar 8; 84(5) 757-67 5) Functional brain imaging in the dementias: role in early detection, differential diagnosis, and longitudinal studies Michael D. Devous Sr. Eur J Nucl Med (2002) 29:1685–1687
1) Lionel Feuillet, Henry Dufour, Jean Pelletier: Brain of a white-collar worker Lancet 2007; 370: 262
6) U.P. Guerra, F. Nobili: SPECT e PET in neurologia, Patron editore 2006
6) U.P. Guerra, F. Nobili: SPECT e PET in neurologia, Patron editore 2006 7) E.M. Covell, A.A. Diano: Malattia di Parkinson e Parkinsonismi: diagnostica neuroradiologica e medico nucleare; Loghia Editrice 2006
10) Nuvoli S, Nieddu A, Rotondo A, Salvo R, Rubattu E, Chessa F, Spanu A, Madeddu G. 99mTc HMPAO Brain SPECT statistical quantitative analysis in Alzheimer’s disease and Lewy body dementia. Eur J Nucl Med Mol Imaging 2008
7) E.M. Covell, A.A. Diano: Malattia di Parkinson e Parkinsonismi: diagnostica neuroradiologica e medico nucleare; Loghia Editrice 2006
14) Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer's disease K. M. Bradley Brain (2002), 125, 1772±1781
15) Evaluating Early Dementia With and Without Assessment of Regional Cerebral Metabolism by PET: A Comparison of Predicted Costs and Benefits. Daniel H.S. Silverman THE JOURNAL OF NUCLEAR MEDICINE • Vol. 43 • No. 2 • February 2002
17) SPECT imaging in dementia. S L PIMLOTT, K P EBMEIER . The British Journal of Radiology, 80 (2007), S153–S159
23) A critical discussion of the role of neuroimaging in mild cognitive impairment Wolf H, Jelic V, Gertz HJ, Nordberg A, Julin P, Wahlund LO. Acta Neurol Scand Suppl. 2003;179:52-76
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