Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees

Abstract

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

Figure 1.

PiB–PET and MRI images from sporadic AD and two older controls. Transaxial PiB–PET SUVRpons images (40–60 min) from a mild AD patient (77 years old; MMSE of 27), a normal elderly control (NC⁻: 72 years old; MMSE of 30), an elderly PiB-positive normal control (NC⁺) at baseline (MMSE of 30) and 2 years later (MMSE of 29), along with the MRI of the NC⁺ subject. The age of the NC⁺ subject was in the mid-70s and is not specified for reasons of confidentiality and blinding. A tracing of the location of the striatum from each subject's MRI scan is superimposed on the respective PiB image, but only the MRI for the NC⁺ subject is shown (far right).

Figure 2.

PS1C410Y mutation carriers: PiB–PET and MRI images. Transaxial PiB–PET SUVRpons images from five cousins who carry the PS1C410Y mutation and a cousin without the mutation, CY-C(35). All are cognitively normal. The top row shows the MRI and PiB–PET scan of CY1(35) and the PiB–PET of the noncarrier cousin. The middle row shows the two other PS1C410Y carrier cousins studied in Pittsburgh. The bottom row shows two PS1C410Y carrier sibs (cousins of the Pittsburgh subjects) that were imaged at MGH (averaged over 20–60 min to facilitate comparison with the Pittsburgh images; see Materials and Methods). A tracing of the location of the striatum from each Pittsburgh subject's MRI scan is superimposed on the respective PiB image, but only the MRI for the CY1(35) subject is shown (top left).

Figure 3.

Detailed regional distribution of striatal PiB retention in a PS1C410Y mutation carrier and a subject with sporadic AD. Areas with high levels of PiB retention (SUVRpons >1.3) are superimposed over coronal, sagittal and transaxial MR images. The corresponding unobstructed MR images are shown to the right of each PiB overlay to aid in anatomical definition. PiB retention in an asymptomatic PS1 mutation carrier, CY2(37), is shown in the left six columns and that in a mild, sporadic AD subject (MMSE of 25) is shown on the right. Every other slice (2.4 mm) in the coronal, sagittal, and transaxial planes is shown through the entire distribution of PiB retention in the striatum. Full sagittal and transaxial slices are included at the bottom to show the marked striatal focality in the PS1 mutation carrier compared with the extensive cortical involvement in the sporadic AD subject.

Figure 4.

PS1A426P mutation carriers: PiB–PET and MRI images. Transaxial PiB–PET SUVRpons images (40–60′) from five siblings who carry the PS1A426P mutation and a sibling without the mutation [AP-C(47)] are shown. The clinical diagnoses of the mutation carriers are noted. The MRI of the AP1(35) MCI subject is shown as an example. A tracing of the location of the striatum from each subject's MRI scan is superimposed on the respective PiB image, but only the MRI for the AP1(35) MCI subject is shown (top left).

Figure 5.

Quantitative assessment of PiB retention in controls, AD subjects, and PS1 mutation carriers. Rectangles show the range of PiB retention for cognitively normal controls (red), AD subjects (blue), and PS1 mutation carriers (white). The young control (ages of 39–48 years) range is shown as a darker red box behind the full control range. PiB retention in individual subjects are shown within each rectangle for controls (red diamonds), AD subjects (blue triangles), and PS1 mutation carriers with normal cognition (white diamonds studied at Pittsburgh; black diamonds studied at MGH), mutation carriers with MCI (white circles), and mutation carriers with AD (white triangles). The filled red diamond represents NC⁺ from Figure 1 (shown for comparison but not included in the statistical analysis). PiB retention is expressed as the SUVR with pons as a reference averaged over 40–60 min after injection of PiB for all data. The means ± SD are shown with error bars within each rectangle. p values for the difference between controls and PS1 mutation carriers are indicated in red along the bottom, and p values comparing PS1 mutation carriers with AD patients are indicated in blue along the top (ns, not significant; *p < 0.005, **p < 0.00005, ***p < 0.0000005). Brain areas included were the frontal cortex (FRC), precuneus (PRC), parietal cortex (PAR), anterior–ventral striatum (AVS), occipital cortex (OCC), mesial temporal cortex (MTC), thalamus (THL), and cerebellum (CER).

Figure 6.

Plaque deposits in the striatum and adjacent neocortex from one parent of a PS1C410Y mutation carrier. Paired photomicrographs of striatal and cortical regions are shown from three representative tissue sections processed for immunohistochemistry with 10D5 anti-Aβ antibody (A, D) or 6-CN-PiB (B, E) and X-34 (C, F) histochemistry. Plaques are abundant and densely distributed throughout the striatum (A–C). In cortical gray matter (D–F; pial surface toward the top), plaques are also present but at much lower densities. Scale bar, 200 μm.