Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals

Kall, Laura M. van Der; Truong, T.H.; Burnham, Samantha; Doré, Vincent; Mulligan, Rachel; Bozinovski, Svetlana; Lamb, Fiona; Bourgeat, Pierrick; Fripp, Jürgen; Schultz, Stephanie A.; Lim, Yen Ying; Laws, Simon M.; Ames, David; Fowler, Christopher; Martins, Ralph N.; Salvado, Olivier; Robertson, Joanne; Maruff, Paul; Masters, Colin L.; Villemagne, Victor L.; Rowe, Christopher C.

doi:10.1212/wnl.0000000000011222

Cited by 45 publications

(55 citation statements)

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“…This finding is consistent with the 50 CL threshold we found in our post-mortem study for the presence of Alzheimer's Disease Neuropathic Change (ADNC) sufficient to meet the criteria for Alzheimer's disease [25]. It is also consistent with our previous finding that an Aβ level of greater than 50 CL is required to see a substantial increase in the risk of developing mild cognitive decline over 5-year follow-up in cognitively unimpaired participants in the AIBL study [33]. The increase of prevalence in our model shows that in a few individuals, tau deposits are detectable when sparse Aβ-amyloid is present, while for the vast majority, tau scans are only positive when amyloidosis is well-established.…”

Section: Discussionsupporting

confidence: 92%

Relationship between amyloid and tau levels and its impact on tau spreading

Doré

Krishnadas

Bourgeat

et al. 2021

Alzheimer's & Dementia

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Background Previous studies have shown that Aß‐amyloid (Aß) likely promotes tau to spread beyond the medial temporal lobe. However, the Aß levels necessary for tau to spread in the neocortex is still unclear. Method 466 participants underwent tau imaging with [18F]MK6420 and Aß imaging with [18F]NAV4694 (Fig. 1). Aß scans were quantified on the Centiloid (CL) scale with a cut‐off of 25CL for abnormal levels of Aß (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus and parahippocampus) using the cerebellar cortex as reference region. Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A‐ subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined. Result The plots of prevalence of T+ (Fig. 2) show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aß level between 10‐40 CL reaching 23% in Me, 15% in Te and 11% in R. Between 40‐70 CL, the prevalence of T+ subjects per CL increased four‐fold faster and at 70 CL was 64% in Me, 51% in Te and 37% in R. In cognitively unimpaired (Fig. 3), there were no T+ in R below 50 CL. The highest prevalence of T+ was found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL. Conclusion Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aß levels below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aß levels are required before neocortical tau becomes detectable.

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Section: Discussionsupporting

confidence: 92%

Relationship between amyloid and tau levels and its impact on tau spreading

Doré

Krishnadas

Bourgeat

et al. 2021

Alzheimer's & Dementia

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“…It is also consistent with our previous finding that an Aβ level of greater than 50 CL is required to see a substantial increase in the risk of developing mild cognitive decline over 5-year follow-up in cognitively Fig. 5 Scatter plot of tau SUVR in the Me (left) and Te (middle) and R (right) ROI versus age at tau scan in 2 different colour-coded clinical diagnostic groups (cognitively unimpaired (CU) and cognitively impaired (CI)), with light colours used to identify A-subjects unimpaired participants in the AIBL study [33]. The increase of prevalence in our model shows that in a few individuals, tau deposits are detectable when sparse Aβ-amyloid is present, while for the vast majority, tau scans are only positive when amyloidosis is well-established.…”

Section: Discussionmentioning

confidence: 99%

Relationship between amyloid and tau levels and its impact on tau spreading

Doré

Krishnadas

Bourgeat

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose Previous studies have shown that Aβ-amyloid (Aβ) likely promotes tau to spread beyond the medial temporal lobe. However, the Aβ levels necessary for tau to spread in the neocortex is still unclear. Methods Four hundred sixty-six participants underwent tau imaging with [18F]MK6420 and Aβ imaging with [18F]NAV4694. Aβ scans were quantified on the Centiloid (CL) scale with a cut-off of 25 CL for abnormal levels of Aβ (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus, and parahippocampus). Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A- subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined. Results The plots of prevalence of T+ show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aβ level between 10 and 40 CL reaching 23% in Me, 15% in Te, and 11% in R. Between 40 and 70 CL, the prevalence of T+ subjects per CL increased fourfold faster and at 70 CL was 64% in Me, 51% in Te, and 37% in R. In cognitively unimpaired, there were no T+ in R below 50 CL. The highest prevalence of T+ were found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL. Conclusion Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aβ below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aβ levels are required before abnormal neocortical tau becomes detectable.

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“…The CL threshold for visual inspection of [ 18 F]flutemetamol was shown to be approximately 40 units in a clinical study with MCI subjects [20]. In relation to predicting cognitive decline, the AIBL team followed a healthy volunteer cohort and found increasing CLs from 25 to over 100 corresponded to a ten-fold increased risk of progression to MCI over a 5-year observation period [25]. The St Luc team had an equally long follow-up period of 6 years with a CL level of 26 optimally predicting progression to dementia from earlier clinical stages [20].…”

Section: Generic Discussion On the Use Of Quantitative Methods In Amyloid Imagingmentioning

confidence: 99%

A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [18F]flutemetamol amyloid PET images

Bucci

Savitcheva

Farrar³

et al. 2021

Eur J Nucl Med Mol Imaging

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Background [18F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases. Methods A total of 2770 [18F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [18F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer’s disease (AD) and other diagnoses (OD). Results Weighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region. Conclusions Quantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.

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Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals

Cited by 45 publications

References 41 publications

Relationship between amyloid and tau levels and its impact on tau spreading

Relationship between amyloid and tau levels and its impact on tau spreading

Relationship between amyloid and tau levels and its impact on tau spreading

A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [18F]flutemetamol amyloid PET images

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