Brain. 2009 May;132(Pt 5):1355-65. doi: 10.1093/brain/awp062. Epub 2009 Mar 31.

Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease.

Jack CR Jr, Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, Shiung MM, Gunter JL, Boeve BF, Kemp BJ, Weiner M, Petersen RC; Alzheimer's Disease Neuroimaging Initiative.

Collaborators (206)

Weiner M, Thal L, Weiner M, Thal L, Petersen R, Jack CR Jr, Jagust W, Trojanowki J, Toga AW, Beckett L, Green RC, Gamst A, Potter WZ, Green RC, Montine T, Petersen R, Thal L, Jack CR Jr, Anders D, Bernstein M, Felmlee J, Fox N, Thompson P, Schuff N, Alexander G, Jagust W, Bandy D, Koeppe RA, Foster N, Reiman EM, Chen K, Trojanowki J, Shaw L, Lee VM, Korecka M, Toga AW, Crawford K, Neu S, Beckett L, Harvey D, Gamst A, Kornak J, Kachaturian Z, Frank R, Snyder PJ, Molchan S, Kaye J, Vorobik R, Quinn J, Schneider L, Pawluczyk S, Spann B, Fleisher AS, Vanderswag H, Heidebrink JL, Lord JL, Petersen R, Johnson K, Doody RS, Villanueva-Meyer J, Chowdhury M, Stern Y, Honig LS, Bell KL, Morris JC, Mintun MA, Schneider S, Marson D, Griffith R, Badger B, Grossman H, Tang C, Stern J, deToledo-Morrell L, Shah RC, Bach J, Duara R, Isaacson R, Strauman S, Albert MS, Pedroso J, Toroney J, Rusinek H, de Leon MJ, De Santi SM, Doraiswamy PM, Petrella JR, Aiello M, Clark CM, Pham C, Nunez J, Smith CD, Given CA 2nd, Hardy P, DeKosky ST, Oakley M, Simpson DM, Ismail MS, Porsteinsson A, McCallum C, Cramer SC, Mulnard RA, McAdams-Ortiz C, Diaz-Arrastia R, Martin-Cook K, DeVous M, Levey AI, Lah JJ, Cellar JS, Burns JM, Anderson HS, Laubinger MM, Bartzokis G, Silverman DH, Lu PH, Fletcher R, Parfitt F, Johnson H, Farlow M, Herring S, Hake AM, van Dyck CH, MacAvoy MG, Bifano LA, Chertkow H, Bergman H, Hosein C, Black S, Graham S, Caldwell C, Feldman H, Assaly M, Hsiung GY, Kertesz A, Rogers J, Trost D, Bernick C, Gitelman D, Johnson N, Mesulam M, Sadowsky C, Villena T, Mesner S, Aisen PS, Johnson KB, Behan KE, Sperling RA, Rentz DM, Johnson KA, Rosen A, Tinklenberg J, Ashford W, Sabbagh M, Connor D, Obradov S, Green RC, Killiany R, Norbash A, Obisesan TO, Jayam-Trouth A, Wang P, Auchus AP, Huang J, Friedland RP, DeCarli C, Fletcher E, Carmichael O, Kittur S, Mirje S, Johnson SC, Borrie M, Lee TY, Asthana S, Carlsson CM, Potkin SG, Highum D, Preda A, Nguyen D, Tariot PN, Reiman EM, Hendin BA, Scharre DW, Kataki M, Beversdorf DQ, Zimmerman EA, Celmins D, Brown AD, Gandy S, Marenberg ME, Rovner BW, Pearlson G, Blank K, Anderson K, Saykin AJ, Santulli RB, Pare N, Williamson JD, Sink KM, Potter H, Raj BA, Giordano A, Ott BR, Wu CK, Cohen R, Wilks KL, Safirstein BE.

Source

Clifford R. Jack, Mayo Clinic, Diagnostic Radiology, 200 First Street SW, Rochester, MN 55905, USA. jack.clifford@mayo.edu.

Abstract

The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial (11)C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources--ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm(3) by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm(3)/year) < amnestic mild cognitive impairment (2.5 cm(3)/year) < Alzheimer's disease (7.7 cm(3)/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = -0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =-0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =-0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimer's disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.