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 11C 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 cm3 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 cm3/year) <  amnestic mild cognitive impairment (2.5 cm3/year) <  Alzheimer's disease (7.7 cm3/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.

To date, most diagnostic imaging comparisons between amyloid labelling ligands and other imaging modalities have been between the use of amyloid labelling ligand (11)C Pittsburgh Compound B (PiB) and FDG-PET. Our objectives were to compare cognitive performance and diagnostic group-wise discrimination between cognitively normal, amnestic mild cognitive impairment (MCI) and Alzheimer's disease subjects with MRI-based measures of hippocampal volume and PiB retention, and secondly to evaluate the topographic distribution of PiB retention and grey matter loss using 3D voxel-wise methods. Twenty cognitively normal, 17 amnestic MCI and 8 probable Alzheimer's disease subjects were imaged with both MRI and PiB. PiB retention was quantified as the ratio of uptake in cortical to cerebellar regions of interest (ROIs) 40-60 min post-injection. A global cortical PiB retention summary measure was derived from six cortical ROIs. Statistical parametric mapping (SPM) and voxel-based morphometry (VBM) were used to evaluate PiB retention and grey matter loss on a 3D voxel-wise basis. Alzheimer's disease subjects had high global cortical PiB retention and low hippocampal volume; most cognitively normal subjects had low PiB retention and high hippocampal volume; and on average amnestic MCI subjects were intermediate on both PiB and hippocampal volume. A target-to-cerebellar ratio of 1.5 was used to designate subjects with high or low PiB cortical retention. All Alzheimer's disease subjects fell above this ratio, as did 6 out of 20 cognitively normal subjects and 9 out of 17 MCI subjects, indicating bi-modal PiB retention in the latter two groups. Interestingly, we found no consistent differences in learning and memory performance between high versus low PiB cognitively normal or amnestic MCI subjects. The SPM/VBM voxel-wise comparisons of Alzheimer's disease versus cognitively normal subjects provided complementary information in that clear and meaningful similarities and differences in topographical distribution of amyloid deposition and grey matter loss were shown. The frontal lobes had high PiB retention with little grey matter loss, anteromedial temporal areas had low PiB retention with significant grey matter loss, whereas lateral temporoparietal association cortex displayed both significant PiB retention and grey matter loss. A voxel-wise SPM conjunction analysis revealed that subjects with high PiB retention shared a common PiB retention topographical pattern regardless of clinical category, and this matched that of amyloid plaque distribution from autopsy studies of Alzheimer's disease. Both global cortical PiB retention and hippocampal volumes demonstrated significant correlation in the expected direction with cognitive testing performance; however, correlations were stronger with MRI than PiB. Pair-wise inter-group diagnostic separation was significant for all group-wise pairs for both PiB and hippocampal volume with the exception of the comparison of cognitively normal versus amnestic MCI, which was not significant for PiB...

Objectives-To correlate different methods of measuring rates of brain atrophy from serial MRI with corresponding clinical change in normal elderly subjects, patients with mild cognitive impairment (MCI), and probable Alzheimer's disease (AD).Methods-One-hundred sixty subjects were recruited from the Mayo Clinic AD Research Center and AD Patient Registry studies. At baseline 55 subjects were cognitively normal, 41 met criteria for MCI, and 64 met criteria for AD. Each subject went under an MRI examination of the brain at the time of the baseline clinical assessment and then again at the time of a follow-up clinical assessment, 1-5 years later. The annualized changes in volume of four structures were measured from the serial MRI studies -hippocampus, entorhinal cortex, whole brain, and ventricle. Rates of change on several cognitive tests/rating scales were also assessed. Subjects who were classified as normal or MCI at baseline could either remain stable or could convert to a lower functioning group. AD subjects were dichotomized into slow versus fast progressors.Results-All four atrophy rates were greater among normal subjects who converted to MCI or AD than those who remained stable; greater among MCI subjects who converted to AD than those who remained stable, and greater among fast than slow AD progressors. In general, atrophy on MRI was detected more consistently than decline on specific cognitive tests/rating scales._ With one exception, no differences were found among the four MRI rate measures in the strength of the correlation with clinical deterioration at different stages of the disease.Conclusions-These data support the use of rates of change from serial MR imaging studies in addition to standard clinical/psychometric measures as surrogate markers of disease progression in AD. Estimated sample sizes required to power a therapeutic trial in MCI were an order of magnitude less for MRI than for change measures based cognitive tests/rating scales.Psychometric tests and severity rating scales are the de facto gold standard for assessing disease progression in Alzheimer's disease (AD). Change measures from serial imaging studies have been proposed as an adjunctive surrogate marker of disease progression in AD with the expectation that imaging may provide better sensitivity and precision than standard clinical and psychometric measures(1-4). Various serial imaging approaches have been proposed including different structural magnetic resonance imaging (MRI) atrophy rate measures and also serial measures of glucose metabolism with positron emission tomography (PET). NIH Public Access Author ManuscriptNeurology. Author manuscript; available in PMC 2009 August 21. Published in final edited form as:Neurology. 2004 February 24; 62(4): 591-600. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 5-9) The fact that different serial imaging approaches have been proposed for largely the same objective raises obvious questions. Which imaging approach is best? Do some imaging measures of p...

Objective-To test the hypothesis that the atrophy rate measured from serial magnetic resonance imaging (MRI) studies is associated with time to subsequent clinical conversion to a more impaired state in both cognitively normal elderly subjects and in subjects with amnestic mild cognitive impairment (MCI).Methods-Ninety one normal elderly and 72 patients with amnestic MCI were identified from the Mayo Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry who met inclusion criteria. Atrophy rates of four different brain structures -hippocampus, entorhinal cortex, whole brain, and ventricle -were measured from a pair of MRI studies separated by one to two years. The time of the second scan marked the beginning of the clinical observation period.Results-During follow-up, 13 normal patients converted to MCI or AD while 39 MCI subjects converted to AD. Among those normal at baseline, only larger ventricular annual percent volume change (APC) was associated with a higher risk of conversion (hazard ratio for a 1-SD increase 1.9, p = 0.03). Among MCI subjects both greater ventricular volume APC (hazard ratio for a 1-SD increase 1.7, p<0.001) and greater whole brain APC (hazard ratio for a 1-SD increase 1.4, p = 0.007) increased the risk of conversion to AD. Both ventricular APC (hazard ratio for a 1-SD increase 1.32, p = 0.009) and whole brain APC (hazard ratio for a 1-SD increase1.59, p = 0.001) provided additional predictive information to covariate-adjusted cross-sectional hippocampal volume at baseline about the risk of converting from MCI to AD.Discussion-Higher whole brain and ventricle atrophy rates 1-2 years prior to baseline are associated with an increased hazard of conversion to a more impaired state. Combining a measure of hippocampal volume at baseline with a measure of either whole brain or ventricle atrophy rates from serial MRI scans provides complimentary predictive information about the hazard of subsequent conversion from MCI to AD. However, overlap among those who did versus those who did not convert indicate that these measures are unlikely to provide absolute prognostic information for individual patients.Imaging is increasingly recognized as a potentially useful way to measure disease progression as well as disease severity in Alzheimer's disease (AD). Much of the effort in imaging research in AD is centered on validating various imaging measures as biomarkers of disease stage and progression. Acceptance of imaging as a valid biomarker of AD requires convergence of information from multiple types of studies, from multiple research groups, and in a variety of longitudinal studies in which a single imaging measurement is used to predict subsequent clinical course; and, longitudinal studies in which an imaging study and a clinical assessment are coupled at two or more time points and the rate of change in imaging is correlated with contemporaneous assessments of clinical change. A fourth type of study design is the one employed in this paper and described below.In the pr...