Neuroimaging correlates with neuropathologic schemes in neurodegenerative disease

Abstract

Introduction: Neuroimaging biomarkers are important for early diagnosis of Alzheimer's disease, and comparing multimodality neuroimaging to autopsy data is essential.

Methods: We compared the pathologic findings from a prospective autopsy cohort (n = 100) to Pittsburgh compound B PET (PiB-PET), ¹⁸F-fluorodeoxyglucose PET (FDG-PET), and MRI. Correlations between neuroimaging biomarkers and neuropathologic schemes were assessed.

Results: PiB-PET showed strong correlations with Thal amyloid phase and Consortium to Establish a Registry for Alzheimer's Disease score and categorized 44% of Thal phase 1 participants as positive. FDG-PET and MRI correlated modestly with Braak tangle stage in Alzheimer's type pathology. A subset of participants with "none" or "sparse" neuritic plaque scores had elevated PiB-PET signal due to diffuse amyloid plaque. Participants with findings characterized as "suspected non-Alzheimer's pathophysiology" represented 15% of the group.

Discussion: PiB-PET is associated with Alzheimer's disease, neuritic plaques, and diffuse plaques. FDG-PET and MRI have modest correlation with neuropathologic schemes. Participants with findings characterized as suspected non-Alzheimer's pathophysiology most commonly had primary age-related tauopathy.

Keywords: Alzheimer's disease; Amyloid; Amyloid-PET; Autopsy; Braak tangle stage; CERAD; Dementia; MRI; Mild cognitive impairment; Neurodegeneration; SNAP; Tau-PET; Thal amyloid stage.

Figure 1.. PiB-PET SUVr and Amyloid Neuropathologic Measures.

Relationships between PiB-PET and Thal amyloid phase (A), neuritic plaque score (B) and diffuse plaque score (C) are shown. PiB-PET SUVr is based on the crus reference region with GM segmentation and partial volume correction (crus, GM, PVCY). Spearman rank correlation rho (p-value) between different PiB-PET analysis methods and pathology score are shown (D). Call out boxes in the panels A and B show subcategorizations for diffuse plaque scores in colors and in the panel C show SUVr for “sparse” neuritic plaques score (green) or “none” neuritic plaques score (purple). Dotted line on the “x”axis represents the PiB cutoff of 1.47. Squares indicate 3-5 years from imaging to autopsy. PiB-PET correlations with Thal amyloid phase was not statistically different with the various methods of PiB-PET quantitative analysis (Choi’s test comparing analytic methods; p-value range: 0.08 to 0.3) (D, Appendix Figure C1). PiB-PET and neuritic plaque scores also correlated strongly regardless of the method of PiB-PET quantitative analysis with Spearman’s rho ranging from 0.68 to 0.71 (Choi’s test comparing analytic methods, p-value 0.09 to 0.6; D, Appendix Figure C2). Correlations of diffuse plaques with PiB-PET were high and indistinguishable for the various methods of quantitative analyses (C) with rho ranging from 0.77 to 0.78 (Choi’s test comparing analytic methods, p-value 0.29 to 0.97; Appendix Figure C3).

Figure 2:. PiB-PET, FDG-PET and MRI by Primary Neuropathologic Diagnoses.

Imaging modality findings are shown vs. neuropathologic diagnosis. Subgroups noted in the call-out box show additional secondary neuropathologic diagnoses of AD (triangle), PA (X), and PART (square). Dotted line on the “x” axes represents the imaging modality cut points. All modalities are abnormal in most of the cohort. This represents the high sensitivity of the tests with limited specificity in the AD centric quantitation methods.

Figure 3:. FDG-PET correlation with Neuropathologic Measures in the AD spectrum.

FDG-PET by Thal amyloid phase (A) and by Braak neurofibrillary tangle stage (B). In the AD spectrum, FDG-PET association with Thal amyloid phase is poor. Most participants have an SUVr below the FDG cutoff even for low Thal amyloid phase and Braak stage demonstrating nonspecificity and a probable influence in the regions from multiple neurodegenerative diseases. FDG-PET identified 45/48 (96%) participants as abnormal among Braak neurofibrillary tangle stage stages III or greater in the AD spectrum and 21/25 (84%) in the entire cohort (Appendix Figure C4) with a Braak neurofibrillary tangle stage of 2 or less as abnormal. The correlations were larger (better) when only those in the AD disease spectrum (AD, pathological aging, or senile change) were included vs. participants with non-AD pathologic diagnoses (rho = −0.61 and −0.13, respectively; Fisher’s r-to-z transformation p=0.005).

Figure 4.. MRI correlation with Neuropathologic Measures in the AD spectrum.

MRI by Thal amyloid phase (A) and by Braak neurofibrillary tangle stage (B) with both AD signature ROI and hippocampal volume assessments. Call out boxes in panels show subcategorizations for disease groups. Dotted line on the “x” axes represents the MRI AD signature cutoff of 3.50mm. In the AD spectrum, MRI association with Thal amyloid phase is poor by either quantitation method. The MRI AD signature thickness cut point of < 3.5 identified 44/48 (92%) participants with a Braak neurofibrillary tangle stage of III or greater in the AD spectrum as abnormal and 19/25 (76%) in the entire cohort (Appendix Figure C5) with a Braak neurofibrillary tangle stage of 2 or less as abnormal. Among the 3 diagnostic groups in the AD neuropathologic spectrum, AD (triangles, n=42, 2.82mm) and SC (diamonds, n=2, 2.75mm) had the thinnest mean AD signature. Hippocampal volume correlation with Braak was no better than MRI AD signature thickness.

Figure 5.. Examples of inconsistent findings.

Amyloid negative and Thal amyloid phase 3-5 participants (A-D) and participants with elevated amyloid but Thal amyloid phase 0 and/or no neuritic plaque (E-I) are shown. Clinical diagnosis at the time of scanning, neuropathologic data and PiB-PET, FDG-PET, and MRI images (with their respective quantitative and visual findings) are shown for each participant. For A, left sided atrophy and hypometabolism on FDG corresponded to the FTLD diagnosis. Visual assessment showed asymmetrically increased PiB-PET signal (arrow) in the left temporal lobe in B and in the right hemisphere in C (arrow). For B, focally positive temporal PiB-PET signal may have been averaged out in the metaROI but could be consistent with moderate plaque. FDG and MRI were contradictory for abnormality suggesting borderline changes that may be consistent with early pathologic aging changes in these two. For C, diffuse, mild PiB-PET signal, greater on the right, was seen that may have been caused mainly by diffuse plaques. The FDG-PET findings in this case were consistent with LBD (MRI was negative). For D, only MRI was abnormal (AD sig only) in this participant with a neuropathology diagnosis of AD, yet cognitively unimpaired at the time of the scans, suggesting rapid onset of AD. Visual assessment showed preserved contrast between white matter and grey matter suggesting a negative PiB-PET (arrows) in E and F and was consistent with neuropathology that showed no neuritic plaques or diffuse plaques. The white matter signal is high in E and F suggesting possible “bleed-in” of white matter signal. By using Ab antibodies, a Thal 1 phase was assigned to E. Both FDG (but only on SUVr) and MRI measurements were positive (E), suggesting non-specific atrophy changes. In F, FDG findings reflected LBD while the MRI showed generalized cerebral atrophy. In G and H (no neuritic plaques) SUVr and visual PiB-PET assessment was positive (arrows). Diffuse plaques may have caused the elevated SUVr and visual findings (as typically seen in LBD (G)). Both FDG and MRI measurements were also positive in G and H. FDG-PET in G showed occipital hypometabolism (arrow) suggesting LBD. The MRI findings in H showed moderate diffuse cerebral atrophy and white matter infarcts (arrow). In I, increased PiB-PET retention in the right frontal lobe seen visually (arrow) correlated with focal amyloid on neuropathology. The FDG-PET SUVr was positive but the visual interpretation was negative and the MRI showed moderate diffuse cortical atrophy with a small right hippocampus.