Amyloid involvement in subcortical regions predicts cognitive decline

Cho, Soo Hyun; Shin, Jeong-Hyeon; Park, Seongbeom; Kim, Hee Jin; Kim, Si Eun; Kim, Seungjoo; Kim, Yeshin; Lee, Jin San; Na, Duk L.; Lockhart, Samuel N.; Rabinovici, Gil D.; Seong, Joon‐Kyung; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1007/s00259-018-4081-5

Cited by 36 publications

(43 citation statements)

References 29 publications

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“…Importantly, increasing amyloid stages were also associated with lower memory scores among cognitively normal individuals, thus indicating the potential of this method for estimating risk of disease progression towards clinically relevant stages during the preclinical phase of AD. Recent studies of the topography of amyloid progression suggest that amyloid spread to subcortical regions is associated with higher risk of cognitive decline among nondemented individuals (Cho et al, 2018;Hanseeuw et al, 2018). Hanseeuw et al (2018)…”

Section: Discussionmentioning

confidence: 99%

“…Amyloid imaging with positron emission tomography (PET) has become an important diagnostic tool for AD (Villemagne et al, 2011), displaying high sensitivity and specificity by comparison with neuropathological findings (Clark et al, 2012;Sabri, Seibyl, Rowe, & Barthel, 2015;Villeneuve et al, 2015). Recent amyloid PET studies have attempted to characterize and stage the regional amyloid pathology spread in-vivo, either using an a priori distinction between early neocortical and later subcortical amyloid deposition (Cho et al, 2018;Hanseeuw et al, 2018;Thal et al, 2018) or more comprehensive data-driven models including regional deposition differences within both cortical and subcortical areas (Cho et al, 2016;Grothe et al, 2017;Sakr et al, 2019). In our previous work (Grothe et al, 2017) we have developed an in-vivo staging model that adopts a commonly used analytic approach for determining regional staging schemes in neuropathological studies (Braak & Braak, 1991;Josephs et al, 2016;Thal et al, 2002) and is based on the frequency of regionally measured uptake positivity in cognitively normal older participants.…”

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confidence: 99%

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Longitudinal validity of PET‐based staging of regional amyloid deposition

Jelistratova

Teipel

Grothe

2020

Human Brain Mapping

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Positron emission tomography (PET)‐based staging of regional amyloid deposition has recently emerged as a promising tool for sensitive detection and stratification of pathology progression in Alzheimer's Disease (AD). Here we present an updated methodological framework for PET‐based amyloid staging using region–specific amyloid‐positivity thresholds and assess its longitudinal validity using serial PET acquisitions. We defined region‐specific thresholds of amyloid‐positivity based on Florbetapir‐PET data of 13 young healthy individuals (age ≤ 45y), applied these thresholds to Florbetapir‐PET data of 179 cognitively normal older individuals to estimate a regional amyloid staging model, and tested this model in a larger sample of patients with mild cognitive impairment (N = 403) and AD dementia (N = 85). 2‐year follow‐up Florbetapir‐PET scans from a subset of this sample (N = 436) were used to assess the longitudinal validity of the cross‐sectional model based on individual stage transitions and data‐driven longitudinal trajectory modeling. Results show a remarkable congruence between cross‐sectionally estimated and longitudinally modeled trajectories of amyloid accumulation, beginning in anterior temporal areas, followed by frontal and medial parietal areas, the remaining associative neocortex, and finally primary sensory‐motor areas and subcortical regions. Over 98% of individual amyloid deposition profiles and longitudinal stage transitions adhered to this staging scheme of regional pathology progression, which was further supported by corresponding changes in cerebrospinal fluid biomarkers. In conclusion, we provide a methodological refinement and longitudinal validation of PET‐based staging of regional amyloid accumulation, which may help improving early detection and in‐vivo stratification of pathologic disease progression in AD.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Longitudinal validity of PET‐based staging of regional amyloid deposition

Jelistratova

Teipel

Grothe

2020

Human Brain Mapping

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“…Also, in contrast with global cortical Aβ values, subcortical Aβ predicted cognitive decline with better accuracy than cortical Aβ , suggesting that the use of global or cortical PiB retention values in cognitively normal individuals may overshadow some structural changes associated with accumulation of Aβ in subcortical structures. Therefore, our findings underline the importance of investigating the impact of Aβ accumulation in subcortical structures, especially since subcortical Aβ was shown to be associated with worse clinical outcomes (Beach et al, 2012;Cho et al, 2018;Hanseeuw, Jonas, et al, 2018), including steeper cognitive decline and functional and structural abnormalities such as hippocampal atrophy (Cho et al, 2018). It is important to precise that our findings do not propose that Aβ accumulates preferentially in subcortical structures compared to the cortex but that its accumulation in subcortical structures allows revealing morphological changes in individuals still free of cognitive impairment.…”

Section: Discussionmentioning

confidence: 70%

“…Similarly to previous studies (Cho et al, ; Hanseeuw, Betensky, et al, ), every participant was classified according to a staging of cerebral Aβ based on the PiB retention values derived from the cortex and the subcortical regions in which Aβ‐associated surface effects were identified. First, we identified cutoff scores in order to classify every participant as Aβ‐positive or Aβ‐negative in terms of their cortical PiB uptake.…”

Section: Methodsmentioning

confidence: 99%

“…Despite some evidence showing that cortical Aβ associates with cognitive decline and hippocampal atrophy in cognitively normal individuals (Andrews et al, ; Villemagne et al, ), several authors have used approaches based on regional PiB retention by using regions that are more vulnerable to Aβ (Seo et al, ; Villeneuve et al, ). In this line of thought, regional PiB retention in subcortical structures appears as a promising candidate for improving the prediction of cognitive impairment and cognitive decline (Cho et al, ). Moreover, a recent PET staging of amyloidosis showed that high Aβ in the striatum predicted hippocampal atrophy and cognitive impairment better than cortical Aβ (Hanseeuw, Betensky, et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Subcortical amyloid load is associated with shape and volume in cognitively normal individuals

Rahayel

Bocti

Dupont

et al. 2019

Human Brain Mapping

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Amyloid‐beta (Aβ) deposition is one of the main hallmarks of Alzheimer's disease. The study assessed the associations between cortical and subcortical 11C‐Pittsburgh Compound B (PiB) retention, namely, in the hippocampus, amygdala, putamen, caudate, pallidum, and thalamus, and subcortical morphology in cognitively normal individuals. We recruited 104 cognitive normal individuals who underwent extensive neuropsychological assessment, PiB–positron emission tomography (PET) scan, and 3‐T magnetic resonance imaging (MRI) acquisition of T1‐weighted images. Global, cortical, and subcortical regional PiB retention values were derived from each scan and subcortical morphology analyses were performed to investigate vertex‐wise local surface and global volumes, including the hippocampal subfields volumes. We found that subcortical regional Aβ was associated with the surface of the hippocampus, thalamus, and pallidum, with changes being due to volume and shape. Hippocampal Aβ was marginally associated with volume of the whole hippocampus as well as with the CA1 subfield, subiculum, and molecular layer. Participants showing higher subcortical Aβ also showed worse cognitive performance and smaller hippocampal volumes. In contrast, global and cortical PiB uptake did not associate with any subcortical metrics. This study shows that subcortical Aβ is associated with subcortical surface morphology in cognitively normal individuals. This study highlights the importance of quantifying subcortical regional PiB retention values in these individuals.

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Association of PET‐based stages of amyloid deposition with neuropathological markers of Aβ pathology

Teipel

Temp

Levin

et al. 2020

Ann Clin Transl Neurol

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Objective To determine if PET‐based stages of regional amyloid deposition are associated with neuropathological phases of Aβ pathology. Methods We applied data‐driven regional frequency‐based and a‐priori striatum‐based PET staging approaches to ante‐mortem 18F‐Florbetapir‐PET scans of 30 cases from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort, and used Bayesian regression analysis to study the associations of these in vivo amyloid stages with neuropathological Thal phases of regional Aβ plaque distribution and with semi‐quantitative ratings of neocortical and striatal plaque densities. Results Bayesian regression revealed extreme evidence for an association of both PET‐based staging approaches with Thal phases, and these associations were about 44 times more likely for frequency‐based stages and 89 times more likely for striatum‐based stages than for global cortical 18F‐Florbetapir‐PET signal. Early (i.e., neocortical‐only) PET‐based amyloid stages also predicted the absence of striatal/diencephalic cored plaques. Receiver operating characteristics curves revealed highly accurate discrimination between low/high Thal phases and the presence/absence of regional plaques. The median areas under the curve were 0.99 for frequency‐based staging (95% credibility interval 0.97–1.00), 0.93 for striatum‐based staging (0.83–1.00), and 0.87 for global 18F‐Florbetapir‐PET signal (0.72–0.98). Interpretation Our data indicate that both regional frequency‐ and striatum‐based amyloid‐PET staging approaches were superior to standard global amyloid‐PET signal for differentiating between low and high degrees of regional amyloid pathology spread. Despite this, we found no evidence for the ability of either staging scheme to differentiate between low and moderate degrees of amyloid pathology which may be particularly relevant for early, preclinical stages of Alzheimer’s disease.

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Amyloid involvement in subcortical regions predicts cognitive decline

Cited by 36 publications

References 29 publications

Longitudinal validity of PET‐based staging of regional amyloid deposition

Longitudinal validity of PET‐based staging of regional amyloid deposition

Subcortical amyloid load is associated with shape and volume in cognitively normal individuals

Association of PET‐based stages of amyloid deposition with neuropathological markers of Aβ pathology

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