PiB-PET image analysis

Although visual reading of PiB images seems more accurate than that of FDG for identification of AD, better accuracy is obtained using a quantitative approach without requiring the expertise of readers. PiB binding to Aβ plaque in the gray matter is specific and reversible, whereas PiB binding in the white matter is nonspecific and nonsaturable. The relatively slow kinetics of PiB makes the specific PiB uptake in the gray matter prominent at later time points, which may impede the quantification of Aβ deposits because of the short half-life of ¹¹ C-labeled tracer. To overcome this drawback in quantification, three-dimensional dynamic sampling of emission data for the whole brain is desirable, lasting 70 to 90 minutes after tracer injection. Application of the linear models developed by Logan to these sampling data has become a standard calculation method for robust quantification in PiB studies ( Fig. 1 ). Logan analysis is used to calculate the distribution volume of ligand tracers that have reversible binding kinetics. The choice of cerebellar cortex as a reference region that has no specific PiB deposition enables calculation of a distribution volume ratio (DVR) without arterial plasma data sampling as a slope of a graphical plot. The DVR equals binding potential + 1. The pons can also be chosen as a reference area. On the other hand, the standardized uptake value ratio (SUVR) has been proposed as a more feasible semiquantitative analysis than DVR ( Fig. 2 ). SUVR is calculated by computing the region/cerebellum ratio at later time points. The optimal time range was studied by McNamee and colleagues ; their suggestion was to use a 40- to 60-minute period in studies limited by low injected dose, or a 50- to 70-minute period because of greater measurement stability, especially for longitudinal multisite studies ( Fig. 3 ). The advantages of the SUVR approach are large effect sizes for AD and control group differences, and the possibility of obtaining the required data from a single short scan of 20 minutes. The disadvantages of this approach are the lower test-retest variability compared with the DVR approach and the potential for time-varying outcomes. It also has the inherent bias of a tendency to overestimate PiB deposition. The use of a standardized volume-of-interest template with spatially normalized PiB images to the same standardized space has been proposed as an automated voxel-based method for PiB deposition analysis.

Typical time-activity curves from dynamic PiB-PET studies from a patient with AD ( A ) and graphical analysis using a Logan plot ( B ). Using cerebellar cortex as input, the DVR in the posterior cingulate cortex is determined as a slope of a graphical plot without arterial plasma data sampling.

Comparison of SUVR and DVR images. DVR provides better image quality than SUVR. A longer period of approximately 70 minutes is required for data acquisition for DVR compared with 20 minutes for SUVR.

SUVR images for the periods 0 to 25 minutes, 25 to 50 minutes, and 50 to 70 minutes for a control subject and a patient with AD. Note temporal changes in PiB distribution. The main factors determining PiB distribution changed from perfusion in an early phase to deposition in Aβ in a late phase. A control individual shows no accumulation in cerebral cortex but nonspecific accumulation in white matter in the late phase (PiB-negative). A patient with AD shows prominent PiB accumulation in the entire cerebral cortex except for occipital cortex and striatum in the late phase (PiB-positive). The cerebellar cortex shows very low accumulation in the late phase.

Regions that share a border with lower-binding or higher-binding structures are susceptible to partial volume effects because of a blurring caused by the low resolution of PET. Because gray matter, white matter, and cerebrospinal fluid (CSF) have different PiB uptake patterns, all gray matter boarders undergo partial volume effects. Atrophy of a region that increases the amount of neighboring CSF accentuates these partial volume effects. Applying partial volume correction to PiB-PET has been expected to increase the PiB deposition in atrophied gray matter and lead to more accurate quantification. Partial volume correction is usually performed using segmented gray matter from three-dimensional MR imaging coregistered to PiB images.

PiB-PET in normal controls

Several autopsy studies have reported that significant Aβ deposits can be found post mortem in more than 30% of cognitively normal older individuals and that the extent of Aβ pathology may be indistinguishable from that found in AD. In accordance with these autopsy results, several PiB-PET studies have consistently detected increased PiB binding in a subset of normal older volunteers ( Fig. 4 ), with the proportion of PiB-positive cases ranging from 10% to 30% depending on the age of the cohort and the threshold for defining PiB positivity. In contrast, increased binding has not been reported in young normal controls. Several studies suggest preferential PiB deposition in the prefrontal cortex and posterior cingulate/precuneus similar to the regions of earliest Aβ deposition noted in autopsy studies. Some older controls show a distribution pattern of PiB binding that is essentially indistinguishable from that seen in AD. The high rate of PiB positivity in normal controls suggests that a positive PiB scan cannot be interpreted without a careful clinical evaluation and emphasizes that amyloid imaging alone must not serve as a surrogate for a clinical diagnosis of AD.

Fluorodeoxyglucose and PiB-PET images in normal controls, MCI, patients without AD, and patients with AD. Both PiB-negative and PiB-positive findings are shown in normal controls and patients with MCI. PiB is useful for differentiating patients with and without AD.

The most important risk factors for AD are age, family history, and heredity. The relationship between these risk factors and PiB deposition has been investigated using a voxel-based statistical analysis. Advancing age increases PiB-positive frequency in normal controls: 18% in those aged 60 to 69 years, rising to 65% in those older than 80 years. The prevalence of Aβ deposition, as detected post mortem in cognitively normal subjects, exponentially increases with advancing age. The prevalence of PiB-positive normal controls increases with advancing age in a similar exponential fashion but precedes the postmortem study by 10 to 15 years. Aβ deposition seems almost inevitable with advancing age. A recent study shows that normal controls with a parent affected by late-onset AD have increased PiB deposition in brain regions typically affected in patients with clinical AD compared with normal controls with no family history. In addition, significant parent-of-origin effects on Aβ deposition were found. Normal controls with mothers affected by late-onset AD show increased and more widespread PiB deposition than those with affected fathers. Another recent study showed that PiB deposition in normal controls correlates with apolipoprotein E (APOE) ε4 gene dose, which is the best known genetic risk factor for AD. The APOE4 allele increases the risk of the disease by 3 times in heterozygous individuals and 15 times in homozygotes. Emerging evidence suggests there may be other risk factors for AD. Epidemiologic studies suggest that cardiovascular risk factors such as increased blood pressure in midlife are associated with increased risk of AD in late life. Langbaum and colleagues revealed that systolic blood pressure and pulse pressure were both positively correlated with PiB depositions. These preliminary findings provide additional evidence that higher BP, which is likely to reflect arterial stiffness during late midlife, may be associated with increased risk of presymptomatic AD. There is some evidence that only angiotensin receptor blockers and angiotensin-converting enzyme inhibitors, and not other blood-pressure–lowering medications, are associated with reduced risk of AD. Antihypertensive treatments may protect against AD neuropathology, potentially by reducing vascular and arterial stiffness, thereby increasing blood flow to the brain and aiding in the removal of Aβ.

A major unresolved issue in AD research is whether cognitively normal people with amyloid deposition are on a trajectory toward AD, or whether the disease is benign in these individuals. Cross-sectional studies evaluating the influence of PiB binding on brain structure and cognition in older control individuals have yielded seemingly conflicting results. When individuals are dichotomized into PiB-positive and PiB-negative groups, most studies have not found significant differences in cognitive performance, with the exception of a study that found lower episodic memory scores in the PiB-positive group. In contrast, most studies that evaluated PiB deposition as a continuous variable have found significant negative correlations between PiB uptake and episodic memory scores. Mormino and colleagues revealed significant correlations between PiB deposition and episodic memory, PiB deposition and hippocampal volume, as well as hippocampal volume and episodic memory. This observation suggests that declining episodic memory in older individuals may be caused by Aβ-induced hippocampal atrophy. Becker and colleagues found the significant Aβ-associated cortical thinning particularly in parietal and posterior cingulate regions extending into the precuneus in a pattern consistent with early AD among nondemented older individuals. This finding suggests that Aβ-associated neurodegeneration is manifest as cortical thinning in regions vulnerable to early Aβ deposition. Oh and colleagues found that gray matter volume in the left inferior frontal cortex was negatively associated with amyloid deposition across all participants of nondemented older controls, whereas reduced gray matter volume was shown in the posterior cingulate among older controls with high amyloid deposition. This reduction of gray matter volume in the left inferior frontal cortex was associated with poorer working memory performance. The pattern of Aβ deposition as detected by PiB-PET shows substantial spatial overlap with the default mode network comprising a group of brain regions that typically deactivate during externally driven cognitive tasks. Functional connectivity in the default mode network is altered with increasing levels of PiB uptake. These findings highlight structural and cognitive changes in association with the level of Aβ deposition in cognitively intact normal elderly individuals.

Longitudinal studies evaluating the relationship between PiB deposition and cognitive decline or brain atrophy have also yielded conflicting results. Dricoll and colleagues examined associations between PiB deposition and brain volume changes in the preceding years in 57 nondemented individuals. Despite significant longitudinal decline in the volumes of all the regions investigated, no associations were detected between PiB deposition and regional brain volume decline trajectories in the preceding year, nor did the regional volume trajectories differ between those with highest and lowest Aβ burden. These findings suggest that Aβ load does not seem to affect brain volume changes in individuals without dementia. These investigators’ observations are in agreement with existing reports on PiB deposition and brain volume loss. Jack and colleagues investigated MR imaging and PiB studies at 2 time points, approximately 1 year apart, to gain insight into the sequence of pathologic events in AD. These investigators reported a dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life over 1 year of follow-up. Amyloid deposition proceeded at a constant low rate irrespective of clinical status, whereas neurodegeneration accelerated in association with clinical symptoms. These findings suggest that in nondemented elderly individuals, amyloid accumulation does not affect the rate of brain atrophy beyond that already observed as a part of the normal aging process. On the contrary, Villemagne and colleagues reported that normal controls who progressed to MCI or AD over 38 months had significantly lower memory scores, higher baseline, and greater increase of PiB deposition than those normal controls who did not progress. Sojkova and colleagues also found that longitudinal increases in Aβ deposition varied among individuals. This variability in the annual rate of change was affected by PiB deposition at the initial PET study, and increases were greater in nondemented older adults with an increased Aβ level compared with a minimal Aβ level at the initial evaluation. Furthermore a longitudinal cohort study was performed to determine whether preclinical AD, as detected by PiB-PET in cognitively normal older adults, is associated with a risk of symptomatic AD. Twenty-three of 159 participants with a clinical dementia rating (CDR) of 0 progressed to CDR 0.5 at follow-up assessment. More increased PiB deposition highly predicted progression to CDR 0.5, with a hazard ratio of 4.85. These findings suggest that PiB deposition is not benign, because it is associated with progression to symptomatic AD.