Amyloid deposition detected with florbetapir F 18 (18F-AV-45) is related to lower episodic memory performance in clinically normal older individuals

Sperling, Reisa A.; Johnson, Keith A.; Doraiswamy, P. Murali; Reiman, Eric M.; Fleisher, Adam; Sabbagh, Marwan N.; Sadowsky, Carl; Carpenter, Alan; Davis, Mat D.; Lu, Ming; Flitter, Matthew; Joshi, Abhinay D.; Clark, Christopher M.; Grundman, Michael; Mintun, Mark A.; Skovronsky, Daniel; Pontecorvo, Michael J.

doi:10.1016/j.neurobiolaging.2012.06.014

Cited by 119 publications

(96 citation statements)

References 48 publications

(75 reference statements)

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“…Our findings have also confirmed the selective impairment of cognitive domains involved in the amyloid-cognition relationship. Episodic memory decline associated with amyloid burden appears earlier than other cognitive domain declines, 12,20,23 and cognitive declines in global cognition and working memory occur in symptomatic stages. 17,19,23 In our current findings examining s-MCs, amyloid PET was associated with cross-sectional deficits but not longitudinal declines in episodic memory, a finding at odds with some studies of late-onset symptomatic AD.…”

Section: Discussionmentioning

confidence: 95%

“…Most prior studies of cognitively healthy older people demonstrated episodic memory decline associated with amyloid burden in the brain 7,[10][11][12][13]15,18,20,21,23 earlier than other cognitive domain declines. 12,20,23 A meta-analysis including 16 independent cohorts (maximum of 1,278 participants) assessed the amyloid-cognition relationship in cognitively normal adults, and the results also showed that only episodic memory had a modest but significant negative relationship to amyloid burden detected by PiB-PET in presymptomatic AD. 39 Similar to these results found in sporadic AD, our results in ADAD showed that cerebral amyloidosis predicted episodic memory decline over time in presymptomatic ADAD.…”

Section: Discussionmentioning

confidence: 97%

“…[3][4][5][6] Studies using amyloid PET in cognitively normal elderly individuals and individuals with mild cognitive impairment (MCI) and AD dementia have found significant relationships between cognitive deficits and increased brain fibrillar amyloid using both cross-sectional [7][8][9][10][11][12] and longitudinal data [13][14][15][16][17][18][19][20][21][22][23] ; however, other studies have not shown amyloid and cognitive correlations. [24][25][26] In autosomal dominant AD (ADAD), brain amyloid deposition is known to occur 15 years or more before the onset of clinical symptoms, 27,28 and estimated years from expected symptom onset (EYO) calculated from family history data can provide an objective biomarkerindependent estimate of an individual's relative point in the disease process.…”

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Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

et al. 2015

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Objective: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD).Methods: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years 6 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE e4 allelic status, and education.Results: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination.Conclusions: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials. b-Amyloid (Ab) is thought to be an initiating factor in the pathophysiologic process of Alzheimer disease (AD).1,2 However, the relationship between cognition, brain Ab burden, and the future development of dementia is still unclear.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 97%

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Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

et al. 2015

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“…In addition, discrepant data exist regarding the relationships between amyloidosis or neurodegeneration and cognitive decline in preclinical AD. 3,5 Neurodegeneration can be measured using the hippocampal volume or cortical thickness within the topography affected by AD (i.e., "AD signature"). 6,7 The AD signature has been shown to predict prognosis in individuals without dementia, 8 although an important gap remains.…”

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confidence: 99%

Spatially distinct atrophy is linked to β-amyloid and tau in preclinical Alzheimer disease

et al. 2015

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Objectives: To determine whether an MRI-based Alzheimer disease (AD) signature biomarker can detect tau-related neurodegeneration in preclinical AD, and to assess whether AD signature cortical thinning is associated with cognitive changes in cognitively normal (CN) older individuals. Methods:In a large cohort of CN individuals (n 5 188), we measured the hippocampal volume and cortical thickness within independently defined AD signature regions. We cross-sectionally assessed the associations between AD signature cortical thinning or hippocampal atrophy with CSF biomarkers of tau (increased tau) and b-amyloid (Ab) (decreased Ab42). We also examined the impact of AD signature cortical thinning or other biomarker changes (i.e., hippocampal atrophy, reduced CSF Ab42, or increased CSF tau) on cognitive performance in CN individuals.Results: Elevated CSF tau was associated with AD signature cortical thinning but not hippocampal atrophy. In contrast, decreased CSF Ab42 was associated with hippocampal loss but not AD signature cortical thinning. In addition, AD signature cortical thinning was associated with lower visuospatial performance. Reduced CSF Ab42 was related to poorer performance on episodic memory. Isolated amyloidosis is the earliest stage of preclinical Alzheimer disease (AD), followed by neurodegeneration and then subtle cognitive decline. Conclusions:1 However, recent work has observed that some cognitively normal (CN) individuals have neurodegeneration (e.g., AD-like brain atrophy on structural MRI) independent of amyloidosis.2-4 These observations motivate the investigation of tau-related neurodegenerative process in preclinical AD. In addition, discrepant data exist regarding the relationships between amyloidosis or neurodegeneration and cognitive decline in preclinical AD. 3,5 Neurodegeneration can be measured using the hippocampal volume or cortical thickness within the topography affected by AD (i.e., "AD signature").6,7 The AD signature has been shown to predict prognosis in individuals without dementia, 8 although an important gap remains. Specifically, the AD topography has been derived primarily as a function of clinical assessment and not biomarkers. Many supposed CN older persons may have biomarker evidence of AD pathology.9 Some individuals with clinically defined AD do not have biomarker evidence of AD pathology. 10 Here, we refined the AD signature using a cohort of clinical and biomarker-confirmed CN and symptomatic AD individuals. In a separate group of CN individuals (n 5 188), we investigated whether abnormal CSF biomarker of tau pathology was associated with

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“…1,2 CN subjects [3][4][5] and subjects with MCI 6,7 who are amyloid-positive experience greater cognitive decline than amyloid-negative individuals. Amyloid positivity must therefore be recognized as a pathologic state.…”

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Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity

et al. 2013

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Objective: To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity.Methods: Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n 5 207). Twelve subjects with Alzheimer disease dementia were included for comparison.Results: Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline. Conclusions:The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both "amyloid-first" and "neurodegeneration-first" biomarker profile pathways to preclinical AD exist. Amyloid positivity is associated with higher rates of brain atrophy in cognitively normal (CN) subjects and subjects with mild cognitive impairment (MCI).1,2 CN subjects 3-5 and subjects with MCI 6,7 who are amyloid-positive experience greater cognitive decline than amyloid-negative individuals. Amyloid positivity must therefore be recognized as a pathologic state.Like any quantitative biomarker, amyloid PET values exist on a continuous scale. However, defining incident amyloid positivity requires that a precise normal/abnormal threshold be adopted. Categorizing individual subjects as amyloid-positive or -negative is required to implement new diagnostic criteria for preclinical Alzheimer disease (AD) and to integrate amyloid biomarkers into the new diagnostic criteria for MCI and AD dementia. 8,9 A precise normal/abnormal threshold is also required to define eligibility for some antiamyloid therapeutic trials. 10A popular model of the temporal evolution of AD biomarkers 11,12 proposes that amyloid biomarkers are the first to become abnormal in the pathophysiologic cascade and do so while subjects are still considered CN via neuropsychological and clinical criteria. Thus, characterization of incident amyloid PET positivity should focus on subjects who are CN at baseline. The state of amyloid positivity is clinically important as this defines preclinical AD.9 Ther...

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Amyloid deposition detected with florbetapir F 18 (18F-AV-45) is related to lower episodic memory performance in clinically normal older individuals

Cited by 119 publications

References 48 publications

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

Spatially distinct atrophy is linked to β-amyloid and tau in preclinical Alzheimer disease

Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity

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