Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012775
Author(s):  
Suzanne Schindler ◽  
Yan Li ◽  
Virginia D. Buckles ◽  
Brian Andrew Gordon ◽  
Tammie L.S. Benzinger ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Symptom Onset ◽  
Standardized Uptake Value ◽  
Tipping Point ◽  
Pet Scan ◽  
Amyloid Pet ◽  
Amyloid Burden ◽  
Cognitively Normal ◽  
Amyloid Accumulation ◽  
Dementia Syndrome

Objective:To predict when cognitively normal individuals with brain amyloidosis will develop symptoms of Alzheimer disease (AD).Methods:Brain amyloid burden was measured by amyloid PET with Pittsburgh compound B. The mean cortical standardized uptake value ratio (SUVR) was transformed into a timescale using longitudinal data.Results:Amyloid accumulation was evaluated in 236 individuals who underwent more than one amyloid PET scan. The average age was 66.5 ± 9.2 years and twelve individuals (5%) had cognitive impairment at their baseline amyloid PET scan. A tipping point in amyloid accumulation was identified at a low level of amyloid burden (SUVR 1.2), after which nearly all individuals accumulated amyloid at a relatively consistent rate until reaching a high level of amyloid burden (SUVR 3.0). The average time between levels of amyloid burden was used to estimate the age at which an individual reached SUVR 1.2. Longitudinal clinical diagnoses for 180 individuals were aligned by the estimated age at SUVR 1.2. In the twenty-two individuals who progressed from cognitively normal to a typical AD dementia syndrome, the estimated age at which an individual reached SUVR 1.2 predicted the age at symptom onset (R2=0.54, p<0.0001, root mean square error (RMSE) 4.5 years); the model was more accurate after exclusion of three likely misdiagnoses (R2=0.84, p<0.0001, RMSE of 2.8 years).Conclusions:The age of symptom onset in sporadic AD is strongly correlated with the age that an individual reaches a tipping point in amyloid accumulation.

scholarly journals Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jason Hassenstab ◽  
Jessica Nicosia ◽  
Megan LaRose ◽  
Andrew J. Aschenbrenner ◽  
Brian A. Gordon ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Multiple Regression ◽  
Cortical Thickness ◽  
Symptom Onset ◽  
Alternative Assessment ◽  
Amyloid Pet ◽  
Cognitively Normal ◽  
Long Form ◽  
Neuroimaging Biomarkers ◽  
Tau Pet

Abstract Background Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a “sampling” of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers. Methods Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer’s Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness. Results Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong’s test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = − 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15–0.16, ps < 0.007). Conclusions Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset.

scholarly journals Association of APOE4 and clinical variability in Alzheimer disease with the pattern of tau- and amyloid-PET

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011270
Author(s):  
Renaud La Joie ◽  
Adrienne V. Visani ◽  
Orit H. Lesman-Segev ◽  
Suzanne L. Baker ◽  
Lauren Edwards ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Linear Models ◽  
Rating Scale ◽  
Standardized Uptake Value ◽  
Cortical Atrophy ◽  
Amyloid Pet ◽  
Clinical Dementia Rating ◽  
Clinical Variables ◽  
Β Amyloid

ObjectiveTo assess whether Alzheimer disease (AD) clinical presentation and APOE4 relate to the burden and topography of β-amyloid and tau pathologies using in vivo PET imaging.MethodsWe studied 119 β-amyloid-positive symptomatic patients aged 48–95 years, including 29 patients with logopenic variant primary progressive aphasia (lvPPA) and 21 with Posterior Cortical Atrophy (PCA). PIB- (β-amyloid) and Flortaucipir (tau)-PET standardized uptake value ratio (SUVR) images were created. General linear models assessed relationships between demographic/clinical variables (phenotype, age), APOE4, and PET (including global cortical and voxelwise SUVR values) while controlling for disease severity using the clinical dementia rating scale sum of boxes.ResultsPIB-PET binding showed a widespread cortical distribution with subtle differences across phenotypes and was unrelated to demographic/clinical variables or APOE4. Flortaucipir-PET was commonly elevated in temporo-parietal regions, but showed marked phenotype-associated differences, with higher binding observed in occipito-parietal areas for PCA, in left temporal and inferior frontal for lvPPA, and in medial temporal areas for other patients with AD. Cortical Flortaucipir-PET binding was higher in younger patients across phenotypes (r = −0.63, 95%CI [−0.72, −0.50)]), especially in parietal and dorsal prefrontal cortices. The presence of APOE4 was associated with a focal medial temporal Flortaucipir-SUVR increase, controlling for all other variables (entorhinal: + 0.310 SUVR 95%CI [0.091, 0.530]).ConclusionsClinical phenotypes are associated with differential patterns of tau but not amyloid pathology. Older age and APOE4 are not only risk factors for AD but also seem to affect disease expression by promoting a more MTL-predominant pattern of tau pathology.

scholarly journals The presubiculum links incipient amyloid and tau pathology to memory function in older persons

Neurology ◽  
2020 ◽  
Vol 94 (18) ◽  
pp. e1916-e1928
Author(s):  
Heidi I.L. Jacobs ◽  
Jean C. Augustinack ◽  
Aaron P. Schultz ◽  
Bernard J. Hanseeuw ◽  
Joseph Locascio ◽  
...  
Keyword(s):  
Memory Performance ◽  
Memory Function ◽  
Hippocampal Volume ◽  
Cognitive Testing ◽  
Pet Scan ◽  
Aging Brain ◽  
Amyloid Pet ◽  
Older Individuals ◽  
Amyloid Burden ◽  
Tau Pathology

ObjectiveTo identify the hippocampal subregions linking initial amyloid and tau pathology to memory performance in clinically normal older individuals, reflecting preclinical Alzheimer disease (AD).MethodsA total of 127 individuals from the Harvard Aging Brain Study (mean age 76.22 ± 6.42 years, 68 women [53.5%]) with a Clinical Dementia Rating score of 0, a flortaucipir tau-PET scan, a Pittsburgh compound B amyloid-PET scan, a structural MRI scan, and cognitive testing were included. From these images, we calculated neocortical, hippocampal, and entorhinal amyloid pathology; entorhinal and hippocampal tau pathology; and the volumes of 6 hippocampal subregions and total hippocampal volume. Memory was assessed with the selective reminding test. Mediation and moderation analyses modeled associations between regional markers and memory. Analyses included covariates for age, sex, and education.ResultsNeocortical amyloid, entorhinal tau, and presubiculum volume univariately associated with memory performance. The relationship between neocortical amyloid and memory was mediated by entorhinal tau and presubiculum volume, which was modified by hippocampal amyloid burden. With other biomarkers held constant, presubiculum volume was the only marker predicting memory performance in the total sample and in individuals with elevated hippocampal amyloid burden.ConclusionsThe presubiculum captures unique AD-related biological variation that is not reflected in total hippocampal volume. Presubiculum volume may be a promising marker of imminent memory problems and can contribute to understanding the interaction between incipient AD-related pathologies and memory performance. The modulation by hippocampal amyloid suggests that amyloid is a necessary, but not sufficient, process to drive neurodegeneration in memory-related regions.

scholarly journals Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease

Neurology ◽  
2018 ◽  
Vol 91 (9) ◽  
pp. e859-e866 ◽  
Author(s):  
Andrew J. Aschenbrenner ◽  
Brian A. Gordon ◽  
Tammie L.S. Benzinger ◽  
John C. Morris ◽  
Jason J. Hassenstab
Keyword(s):  
Alzheimer Disease ◽  
Executive Functioning ◽  
Episodic Memory ◽  
Cognitive Decline ◽  
Hippocampal Volume ◽  
Cognitive Change ◽  
Pet Scan ◽  
Cognitive Domain ◽  
Amyloid Pet ◽  
Tau Pet

ObjectiveTo examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline.MethodsA total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir (18F-AV-1451) tau PET scan, a florbetapir (18F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed.ResultsResults from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the largest negative influence on tests of episodic memory and executive functioning.ConclusionsTogether, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression.

scholarly journals Brain amyloid in virally suppressed HIV-associated neurocognitive disorder

2020 ◽  
Vol 7 (4) ◽  
pp. e739 ◽  
Author(s):  
Gemma C. Howdle ◽  
Yann Quidé ◽  
Mustafa S. Kassem ◽  
Kate Johnson ◽  
Caroline D. Rae ◽  
...  
Keyword(s):  
Standardized Uptake Value ◽  
Amyloid Deposition ◽  
Imaging Biomarkers ◽  
Csf Biomarkers ◽  
Neurocognitive Disorder ◽  
Amyloid Burden ◽  
Cognitively Normal ◽  
Individual Level ◽  
Hiv Associated Neurocognitive Disorder ◽  
The Individual

ObjectiveTo determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition.MethodsA total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46–68 years, underwent 11C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal individuals (aged 60–74 years), 7 individuals with mild cognitive impairment (MCI) (aged 64–71 years), and 11 individuals with Alzheimer disease (AD) (aged 55–74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV sample. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV sample, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8–10 years of long-term health outcomes in 100%.ResultsHAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD–like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8–9 years after the study PET, then progression to severe dementia within 2–3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas.ConclusionsRelative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur.

scholarly journals Blunted cerebrovascular response is associated with elevated beta-amyloid

2017 ◽  
Vol 39 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Jason-Flor V Sisante ◽  
Eric D Vidoni ◽  
Kiersten Kirkendoll ◽  
Jaimie Ward ◽  
Yumei Liu ◽  
...  
Keyword(s):  
Processing Speed ◽  
Beta Amyloid ◽  
Moderate Intensity ◽  
Artery Blood Flow ◽  
Amyloid Burden ◽  
Moderate Intensity Exercise ◽  
Velocity Change ◽  
Cognitively Normal ◽  
Positron Emission ◽  
Amyloid Accumulation

The goal of this study was to explore the association of beta-amyloid accumulation and cerebrovascular response (CVR) in cognitively normal older adults. Beta-amyloid accumulation was characterized with [18F] Florbetapir positron emission tomography scans. CVR was calculated as middle cerebral artery blood flow velocity change from rest to moderate intensity exercise. We found that individuals with elevated beta-amyloid aggregation had a blunted CVR ( n = 25, age 70.1 ± 4.8; 3.3 ± 3.7 cm/s) compared to non-elevated individuals ( n = 45, age 72.0 ± 4.9; 7.2 ± 5.0 cm/s, p < 0.001). Further, greater beta-amyloid burden was linearly associated with less CVR across all participants (b = −11.7, p < 0.001). Greater CVR and less beta-amyloid burden were associated with processing speed ( p < 0.05). This study is the first to show that CVR from rest to exercise is blunted across increased global beta-amyloid burden.

scholarly journals Sequence of Alzheimer disease biomarker changes in cognitively normal adults

Neurology ◽  
2020 ◽  
Vol 95 (23) ◽  
pp. e3104-e3116
Author(s):  
Jingqin Luo ◽  
Folasade Agboola ◽  
Elizabeth Grant ◽  
Colin L. Masters ◽  
Marilyn S. Albert ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Change Point ◽  
Standardized Uptake Value ◽  
Brain Structures ◽  
Hippocampal Volume ◽  
Cognitive Outcomes ◽  
Cross Sectional ◽  
Cognitively Normal ◽  
Preclinical Ad ◽  
Normal Individuals

ObjectiveTo determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals.MethodsCross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [11C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers.ResultsAccelerated changes in CSF Aβ1-42 (Aβ42) occurred at 48.28 years of age and in Aβ42/Aβ40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ42 and Aβ42/Aβ40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other.ConclusionsOur findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.

scholarly journals Early detection of amyloid load using 18F-florbetaben PET

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Santiago Bullich ◽  
Núria Roé-Vellvé ◽  
Marta Marquié ◽  
Susan M. Landau ◽  
Henryk Barthel ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Subjective Cognitive Decline ◽  
Amyloid Pet ◽  
Gray Zone ◽  
Amyloid Burden ◽  
Link Type ◽  
Amyloid Accumulation ◽  
Amyloid Load ◽  
Study Population ◽  
Over Time

Abstract Background A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov (NCT00928304, NCT00750282, NCT01138111, NCT02854033) and EudraCT (2014-000798-38).

[P4-218]: YEARS TO PARENTAL SYMPTOM ONSET PREDICTS AMYLOID BURDEN IN HEALTHY ELDERLY WITH A PARENTAL HISTORY OF SPORADIC ALZHEIMER DISEASE

2017 ◽  
Vol 13 (7S_Part_28) ◽  
pp. P1352-P1352
Author(s):  
Sylvia Villeneuve ◽  
Jacob W. Vogel ◽  
Julie Gonneaud ◽  
Alexa Pichet Binette ◽  
Pedro Rosa-Neto ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Symptom Onset ◽  
Amyloid Burden ◽  
Parental History ◽  
Healthy Elderly ◽  
History Of ◽  
Sporadic Alzheimer Disease
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