Abnormal Amyloid Load in Mild Cognitive Impairment: The Effect of Reducing the PiB‐PET Threshold

Abstract

BACKGROUND AND PURPOSE:In vivo detection of β-amyloid (Aβ) plaques in Alzheimer's disease (AD) is now possible with 11 C-PiB positron emission tomography (PET). Conventionally, a cortical:cerebellar PiB uptake ratio threshold of 1.4-1.5 has been used to categorize at-risk subjects as "amyloid-positive" and "amyloid-negative." It has been suggested that this threshold is too conservative and may miss early amyloid pathology. We investigated the relationship between conventional and lower baseline 11 C-PiB PET thresholds for raised amyloid load and the subsequent clinical and radiological progression of mild cognitive impairment (MCI) cases longitudinally. METHODS: We serially determined the cortical amyloid load with 11 C-PiB PET of 44 MCI subjects over 2 years and compared findings with those for 12 healthy controls (HC) and 5 AD cases. RESULTS:Twenty-four subjects were classified as normal at baseline with mean cortical PiB standard uptake value ratios (SUVR) between 1.2 and 1.5. Their cognitive status remained stable over time. Three of these cases increased their amyloid load above a threshold of 1.5 over 2 years. Twenty-seven "raised amyloid" MCI cases with baseline cortical SUVRs above 1.5, showed deteriorating cognition. Note that 50% of these cases converted clinically to AD during the follow-up period. CONCLUSION: Use of a PiB SUVR threshold of >1.5 for raised amyloid missed 14.3% of MCI cases who likely had Thal stage 1 or 2 pathology and showed a progressive amyloid increase over 2 years. Lowering the threshold for abnormality to 1.3 abolished all false negatives but resulted in 75% of HCs being falsely diagnosed as raised amyloid subjects.

The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer’s disease: a longitudinal PET study

“…This suggests that these low PiB MCI cases may initially have had early Thal phase 1 or 2 levels of Aβ present below our 1.5 SUVR threshold of abnormality and progressed over the 2 years associated with increased levels of inflammation-see Fig. 3 [31,33,34]. The 8 low PiB MCI cases which remained stable over 2 years showed no association between levels of PiB and PK11195 uptake and are unlikely to have Alzheimer's disease.…”

“…Our MCI cohort showed a bimodal distribution, with a clear separation of high and low PiB uptake clusters at a baseline composite cortical:cerebellar PiB SUVR of 1.5 [31].…”

“…2a. In this low-PiB MCI group, 7 of the 15 subjects showed increasing cortical PiB SUVR values at a 2-year follow-up, and three SUVRs now exceeding the 1.5 threshold for raised amyloid and so had formally converted to pAD [31]. When examining the positive correlation between PiB and PK11195 uptake in those 7 subjects with rising PiB uptake (Fig.…”

Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment

“…was not sensitive to MCI patients in Thal Phase 1 or 2, and just lowering this value by 0.2 led to approximately 75% of healthy control subjects being classified as having significant brain amyloidosis (Ismail et al, 2019).…”

Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-β plaques in Alzheimer’s disease

“…Regarding imaging biomarkers, the latest concept is a "research framework" which combines Aβ and tau measures with measures of neurodegeneration [20] to assign subjects and patients into groups by biomarker status. However, relevant thresholds of amyloid PET signal for normality and abnormality remain to be determined [19,39] and require further research of amyloid PET imaging and other biomarkers such as cerebral spinal fluid (CSF) measures in relation to underlying pathology.…”