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

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.

Figure 1

Baseline global cortical PIB ratio and baseline ventricular volume by clinical diagnosis. Global PIB represents a weighted average of the pre-frontal, temporal, parietal, cingulate precuneus, anterior cingulate and orbito frontal regions normalized to cerebellar retention. Baseline ventricular volume is expressed as a percentage of TIV in each subject. Boxes represent the 25th, 50th and 75th percentiles of the data. Individual points have been randomly shifted along the horizontal axis to reduce overlap.

Figure 2

Annual change in global PIB ratio and ventricular volume by clinical diagnosis. Mayo and ADNI subjects have been combined. Boxes represent the 25th, 50th and 75th percentiles of the data. Individual points have been randomly shifted along the horizontal axis to reduce overlap. PIB positive subjects (baseline global cortical PIB ≥1.5) are represented with triangles and PIB negative subjects (baseline global cortical PIB <1.5) are represented with circles.

Figure 3

Proposed model relating imaging, pathology and clinical presentation over an individual's adult lifetime. The lifetime clinical course of the disease is divided into pre-symptomatic, prodromal and dementia phases. Neurodegeneration, detected by MRI, is indicated by a dashed line. Cognitive function is indicated by a dot-dash line. Amyloid deposition, detected by PIB, is indicated by a solid line late in life (i.e. that portion of the disease for which we have data). The time course of amyloid deposition early in life is represented as two possible theoretical trajectories (dotted lines), reflecting uncertainty about the time course of early PIB deposition.