In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults

Roussotte, Florence F.; Siddarth, Prabha; Merrill, David A.; Narr, Katherine L.; Ercoli, Linda M.; Martinez, Jacqueline; Emerson, Natacha D.; Barrio, Jorge R.; Small, Gary W.

doi:10.1016/j.jagp.2017.09.001

Title: In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults

Abstract

OBJECTIVE Growing evidence supports an association among increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. METHODS Positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden. A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. RESULTS Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (η2 = 0.06). However, this relationship was no longer significant after introducing FDDNP-PET binding as an additional covariate in the statistical models. In vivo plaque and tangle burden accounted for over 30% of the observed association between higher DBP andmore »« less

Authors:

Roussotte, Florence F. ^[1]; Siddarth, Prabha ^[1]; Merrill, David A. ^[1]; Narr, Katherine L. ^[1]; Ercoli, Linda M. ^[1]; Martinez, Jacqueline ^[1]; Emerson, Natacha D. ^[1]; Barrio, Jorge R. ^[1]; Small, Gary W. ^[1]

Univ. of California, Los Angeles, CA (United States)

Publication Date:: Fri Sep 15 00:00:00 EDT 2017

Research Org.:: Univ. of California, Los Angeles, CA (United States)

Sponsoring Org.:: USDOE

OSTI Identifier:: 1511835

Alternate Identifier(s):: OSTI ID: 1549967

Grant/Contract Number:: FC03-87ER60615; FC03-87-ER60615

Resource Type:: Accepted Manuscript

Journal Name:: The American Journal of Geriatric Psychiatry

Additional Journal Information:: Journal Volume: 26; Journal Issue: 1; Journal ID: ISSN 1064-7481

Publisher:: American Association for Geriatric Psychiatry - Elsevier

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; FDDNP-PET; age-related cognitive decline; diastolic blood pressure; plaques; tangles

Citation Formats


                    Roussotte, Florence F., Siddarth, Prabha, Merrill, David A., Narr, Katherine L., Ercoli, Linda M., Martinez, Jacqueline, Emerson, Natacha D., Barrio, Jorge R., and Small, Gary W. In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults.  United States: N. p., 2017. 
Web.  doi:10.1016/j.jagp.2017.09.001.

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                    Roussotte, Florence F., Siddarth, Prabha, Merrill, David A., Narr, Katherine L., Ercoli, Linda M., Martinez, Jacqueline, Emerson, Natacha D., Barrio, Jorge R., & Small, Gary W. In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults.  United States.  https://doi.org/10.1016/j.jagp.2017.09.001

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                    Roussotte, Florence F., Siddarth, Prabha, Merrill, David A., Narr, Katherine L., Ercoli, Linda M., Martinez, Jacqueline, Emerson, Natacha D., Barrio, Jorge R., and Small, Gary W. Fri .  
"In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults".  United States.  https://doi.org/10.1016/j.jagp.2017.09.001.  https://www.osti.gov/servlets/purl/1511835.

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@article{osti_1511835,

  title        = {In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults},

  author       = {Roussotte, Florence F. and Siddarth, Prabha and Merrill, David A. and Narr, Katherine L. and Ercoli, Linda M. and Martinez, Jacqueline and Emerson, Natacha D. and Barrio, Jorge R. and Small, Gary W.},

  abstractNote = {OBJECTIVE Growing evidence supports an association among increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. METHODS Positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden. A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. RESULTS Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (η2 = 0.06). However, this relationship was no longer significant after introducing FDDNP-PET binding as an additional covariate in the statistical models. In vivo plaque and tangle burden accounted for over 30% of the observed association between higher DBP and poorer cognitive performance. CONCLUSIONS By indicating a mediation of the relationship between DBP and cognitive functioning by FDDNP-PET binding, this study advances our understanding of some potential predictors of cognitive decline in non-demented adults, and underscores the importance of devising early multimodal interventions to more effectively combat degenerative brain disorders.},

  doi          = {10.1016/j.jagp.2017.09.001},

  journal      = {The American Journal of Geriatric Psychiatry},

  number       = 1,

  volume       = 26,

  place        = {United States},

  year         = {Fri Sep 15 00:00:00 EDT 2017},

  month        = {Fri Sep 15 00:00:00 EDT 2017}

}

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Figure 1: Global FDDNP-PET binding mediates the association between diastolic blood pressures and cognitive functioning

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https://doi.org/10.1093/brain/awn016

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Evidence for a major gene influencing 7-year increases in diastolic blood pressure with age

Journal Article Cheng, Li Shu-Chuan ; Carmelli, D ; Hunt, S C - American Journal of Human Genetics

The contribution of genetic factors to blood pressure levels is well established. The contribution of genes to the longitudinal change in blood pressure has been less well studied, because of the lack of longitudinal family data. The present study investigated a possible major-gene effect on the observed increase with age in diastolic blood pressure (DBP) levels. Subjects included 965 unmedicated adults (age {ge}18 years) in 73 pedigrees collected in Utah as part of a longitudinal cardiovascular family study. Segregation analysis of DBP change over 7.2 years of follow-up identified a recessive major-gene effect with a gene frequency of p =more »« less

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Title: In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults

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The overlap between vascular disease and Alzheimer’s disease - lessons from pathology journal, November 2014

Neuropathological stageing of Alzheimer-related changes journal, September 1991

Tangles and plaques in nondemented aging and ?preclinical? Alzheimer's disease journal, March 1999

Localization of Neurofibrillary Tangles and Beta-Amyloid Plaques in the Brains of Living Patients With Alzheimer Disease journal, January 2002

Postmortem 3-D Brain Hemisphere Cortical Tau and Amyloid-β Pathology Mapping and Quantification as a Validation Method of Neuropathology Imaging journal, June 2013

Effects of White Matter Lesions and Lacunes on Cortical Function journal, October 2004

Small Vessel Disease and General Cognitive Function in Nondisabled Elderly: The LADIS Study journal, October 2005

Cerebral Amyloid Angiopathy Is Associated With Executive Dysfunction and Mild Cognitive Impairment journal, August 2016

Synergistic Effects of Ischemia and β-Amyloid Burden on Cognitive Decline in Patients With Subcortical Vascular Mild Cognitive Impairment journal, April 2014

Diabetes, related conditions, and dementia journal, December 2010

Smoking as a Risk Factor for Dementia and Cognitive Decline: A Meta-Analysis of Prospective Studies journal, June 2007

Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID) journal, May 2016

Relation of Blood Pressure to Cognitive Function in the Elderly journal, December 1991

Can the blood pressure predict cognitive task performance in a healthy population sample? journal, January 1997

Changes in metabolic risk factors over 10 years and their associations with late‐life cognitive performance: The Multi‐Ethnic Study of Atherosclerosis journal, January 2017

Hypertension and Its Role in Cognitive Function: Current Evidence and Challenges for the Future journal, November 2015

PET of Brain Amyloid and Tau in Mild Cognitive Impairment journal, December 2006

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints journal, September 2016

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families journal, August 1993

High-Yield, Automated Radiosynthesis of 2-(1-{6-[(2-[18F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP) Ready for Animal or Human Administration journal, October 2006

Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data journal, September 1996

Serotonin 1A receptors in the living brain of Alzheimer's disease patients journal, January 2006

A Simulation Study of Mediated Effect Measures journal, January 1995

The Decomposition of Effects in Path Analysis journal, February 1975

Monotonicity of effect sizes: Questioning kappa-squared as mediation effect size measure. journal, January 2015

The role of blood pressure in cognitive impairment in an elderly population journal, January 1997

Hypertension and Cognitive Impairment: Kahrizak Elderly Study journal, December 2011

Effect of Blood Pressure on Cognitive Functions in Elderly Persons journal, November 2004

Total Plasma Homocysteine, Age, Systolic Blood Pressure, and Cognitive Performance in Older People journal, December 2002

The relationship between blood pressure and cognitive function journal, October 2010

Midlife Hypertensive Status and Cognitive Function 20 Years Later: The S outhall and B rent Revisited Study journal, August 2013

Midlife Hypertension and 20-Year Cognitive Change: The Atherosclerosis Risk in Communities Neurocognitive Study journal, October 2014

Increased incidence of neurofibrillary tangles (NFT) in non-demented individuals with hypertension journal, August 1995

Cardiovascular risk factors, cortisol, and amyloid-β deposition in Alzheimer's Disease Neuroimaging Initiative journal, November 2012

Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons journal, April 2012

Blood Amyloid Beta Levels in Healthy, Mild Cognitive Impairment and Alzheimer’s Disease Individuals: Replication of Diastolic Blood Pressure Correlations and Analysis of Critical Covariates journal, November 2013

Pulse wave velocity is associated with -amyloid deposition in the brains of very elderly adults journal, October 2013

Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults journal, May 2014

Midlife Blood Pressure, Plasma β-Amyloid, and the Risk for Alzheimer Disease: The Honolulu Asia Aging Study journal, April 2012

Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders journal, November 2011

Can the Treatment of Hypertension in the Middle-Aged Prevent Dementia in the Elderly? journal, April 2016

Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons journal, February 2009

Risk Factors for β-Amyloid Deposition in Healthy Aging: Vascular and Genetic Effects journal, May 2013

Rapid Buildup of Brain White Matter Hyperintensities Over 4 Years Linked to Ambulatory Blood Pressure, Mobility, Cognition, and Depression in Old Persons journal, June 2013

Effects of White Matter Lesions and Lacunes on Cortical Function journal, October 2004

Reliability of drawing regions of interest for positron emission tomographic data journal, November 1992

Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID) journal, May 2016

Hypertension and Cognitive Impairment: Kahrizak Elderly Study journal, December 2011

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints journal, September 2016

Cardiovascular risk factors, cortisol, and amyloid-β deposition in Alzheimer's Disease Neuroimaging Initiative journal, November 2012

Diabetes, related conditions, and dementia journal, December 2010

Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders journal, November 2011

Total Plasma Homocysteine, Age, Systolic Blood Pressure, and Cognitive Performance in Older People journal, December 2002

Effect of Blood Pressure on Cognitive Functions in Elderly Persons journal, November 2004

Relation of Blood Pressure to Cognitive Function in the Elderly journal, December 1991

Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data journal, September 1996

The overlap between vascular disease and Alzheimer’s disease - lessons from pathology journal, November 2014

A Simulation Study of Mediated Effect Measures journal, January 1995

Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons journal, February 2009

Association of higher diastolic blood pressure levels with cognitive impairment journal, August 2009

Association of Blood Pressure and Arterial Stiffness With Cognition in 2 Population‐Based Child and Adult Cohorts journal, November 2018

Differential Associations of Diastolic and Systolic Pressures With Cerebral Measures in Older Individuals With Mild Cognitive Impairment journal, July 2018

The overlap between vascular disease and Alzheimer’s disease - lessons from pathology
journal, November 2014

Neuropathological stageing of Alzheimer-related changes
journal, September 1991

Tangles and plaques in nondemented aging and ?preclinical? Alzheimer's disease
journal, March 1999

Localization of Neurofibrillary Tangles and Beta-Amyloid Plaques in the Brains of Living Patients With Alzheimer Disease
journal, January 2002

Postmortem 3-D Brain Hemisphere Cortical Tau and Amyloid-β Pathology Mapping and Quantification as a Validation Method of Neuropathology Imaging
journal, June 2013

Effects of White Matter Lesions and Lacunes on Cortical Function
journal, October 2004

Small Vessel Disease and General Cognitive Function in Nondisabled Elderly: The LADIS Study
journal, October 2005

Cerebral Amyloid Angiopathy Is Associated With Executive Dysfunction and Mild Cognitive Impairment
journal, August 2016

Synergistic Effects of Ischemia and β-Amyloid Burden on Cognitive Decline in Patients With Subcortical Vascular Mild Cognitive Impairment
journal, April 2014

Diabetes, related conditions, and dementia
journal, December 2010

Smoking as a Risk Factor for Dementia and Cognitive Decline: A Meta-Analysis of Prospective Studies
journal, June 2007

Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)
journal, May 2016

Relation of Blood Pressure to Cognitive Function in the Elderly
journal, December 1991

Can the blood pressure predict cognitive task performance in a healthy population sample?
journal, January 1997

Changes in metabolic risk factors over 10 years and their associations with late‐life cognitive performance: The Multi‐Ethnic Study of Atherosclerosis
journal, January 2017

Hypertension and Its Role in Cognitive Function: Current Evidence and Challenges for the Future
journal, November 2015

PET of Brain Amyloid and Tau in Mild Cognitive Impairment
journal, December 2006

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints
journal, September 2016

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
journal, August 1993

High-Yield, Automated Radiosynthesis of 2-(1-{6-[(2-[18F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP) Ready for Animal or Human Administration
journal, October 2006

Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data
journal, September 1996

Serotonin 1A receptors in the living brain of Alzheimer's disease patients
journal, January 2006

A Simulation Study of Mediated Effect Measures
journal, January 1995

The Decomposition of Effects in Path Analysis
journal, February 1975

Monotonicity of effect sizes: Questioning kappa-squared as mediation effect size measure.
journal, January 2015

The role of blood pressure in cognitive impairment in an elderly population
journal, January 1997

Hypertension and Cognitive Impairment: Kahrizak Elderly Study
journal, December 2011

Effect of Blood Pressure on Cognitive Functions in Elderly Persons
journal, November 2004

Total Plasma Homocysteine, Age, Systolic Blood Pressure, and Cognitive Performance in Older People
journal, December 2002

The relationship between blood pressure and cognitive function
journal, October 2010

Midlife Hypertensive Status and Cognitive Function 20 Years Later: The S outhall and B rent Revisited Study
journal, August 2013

Midlife Hypertension and 20-Year Cognitive Change: The Atherosclerosis Risk in Communities Neurocognitive Study
journal, October 2014

Increased incidence of neurofibrillary tangles (NFT) in non-demented individuals with hypertension
journal, August 1995

Cardiovascular risk factors, cortisol, and amyloid-β deposition in Alzheimer's Disease Neuroimaging Initiative
journal, November 2012

Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons
journal, April 2012

Blood Amyloid Beta Levels in Healthy, Mild Cognitive Impairment and Alzheimer’s Disease Individuals: Replication of Diastolic Blood Pressure Correlations and Analysis of Critical Covariates
journal, November 2013

Pulse wave velocity is associated with -amyloid deposition in the brains of very elderly adults
journal, October 2013

Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults
journal, May 2014

Midlife Blood Pressure, Plasma β-Amyloid, and the Risk for Alzheimer Disease: The Honolulu Asia Aging Study
journal, April 2012

Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders
journal, November 2011

Can the Treatment of Hypertension in the Middle-Aged Prevent Dementia in the Elderly?
journal, April 2016

Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons
journal, February 2009

Risk Factors for β-Amyloid Deposition in Healthy Aging: Vascular and Genetic Effects
journal, May 2013

Rapid Buildup of Brain White Matter Hyperintensities Over 4 Years Linked to Ambulatory Blood Pressure, Mobility, Cognition, and Depression in Old Persons
journal, June 2013

Effects of White Matter Lesions and Lacunes on Cortical Function
journal, October 2004

Reliability of drawing regions of interest for positron emission tomographic data
journal, November 1992

Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)
journal, May 2016

Hypertension and Cognitive Impairment: Kahrizak Elderly Study
journal, December 2011

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints
journal, September 2016

Cardiovascular risk factors, cortisol, and amyloid-β deposition in Alzheimer's Disease Neuroimaging Initiative
journal, November 2012

Diabetes, related conditions, and dementia
journal, December 2010

Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders
journal, November 2011

Total Plasma Homocysteine, Age, Systolic Blood Pressure, and Cognitive Performance in Older People
journal, December 2002

Effect of Blood Pressure on Cognitive Functions in Elderly Persons
journal, November 2004

Relation of Blood Pressure to Cognitive Function in the Elderly
journal, December 1991

Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data
journal, September 1996

The overlap between vascular disease and Alzheimer’s disease - lessons from pathology
journal, November 2014

A Simulation Study of Mediated Effect Measures
journal, January 1995

Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons
journal, February 2009

Association of higher diastolic blood pressure levels with cognitive impairment
journal, August 2009

Association of Blood Pressure and Arterial Stiffness With Cognition in 2 Population‐Based Child and Adult Cohorts
journal, November 2018

Differential Associations of Diastolic and Systolic Pressures With Cerebral Measures in Older Individuals With Mild Cognitive Impairment
journal, July 2018