Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions

Objective: The objective of this study was to define whether vascular risk factors interact with β-amyloid (Aβ) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD). Methods: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aβ was assessed using [11C]Pittsburgh compound B–PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index. Results: Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aβ. These frontotemporal regions are also affected in individuals with Aβ deposition, but the latter show additional thinning in parietal cortices. Aβ and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aβ has its greatest effect. In this way, the negative effect of Aβ in posterior regions is increased by the presence of vascular risk. Conclusion: Aβ and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD.

[1]  Evan Fletcher,et al.  Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study , 2012, The Lancet Neurology.

[2]  A. Fleisher,et al.  Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons , 2012, Neurobiology of Aging.

[3]  G. Alexander,et al.  Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer's Disease Treatment Studies. , 2002, The American journal of psychiatry.

[4]  U. Yoon,et al.  Cortical thinning in subcortical vascular dementia with negative 11C-PiB PET. , 2012, Journal of Alzheimer's disease : JAD.

[5]  Richard J. Caselli,et al.  Higher serum total cholesterol levels in late middle age are associated with glucose hypometabolism in brain regions affected by Alzheimer's disease and normal aging , 2010, NeuroImage.

[6]  J. Morris,et al.  The Cortical Signature of Alzheimer's Disease: Regionally Specific Cortical Thinning Relates to Symptom Severity in Very Mild to Mild AD Dementia and is Detectable in Asymptomatic Amyloid-Positive Individuals , 2008, Cerebral cortex.

[7]  Bruce Fischl,et al.  Thickness of the human cerebral cortex is associated with metrics of cerebrovascular health in a normative sample of community dwelling older adults , 2011, NeuroImage.

[8]  Wendy J Mack,et al.  Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review , 2011, Alzheimer's Research & Therapy.

[9]  Sterling C. Johnson,et al.  Low HDL Cholesterol is Associated with Lower Gray Matter Volume in Cognitively Healthy Adults , 2010, Front. Ag. Neurosci..

[10]  Denise C. Park,et al.  Risk factors for β-amyloid deposition in healthy aging: vascular and genetic effects. , 2013, JAMA neurology.

[11]  Albert Hofman,et al.  Serum lipids and hippocampal volume: The link to Alzheimer's disease? , 2005, Annals of neurology.

[12]  Anders M. Dale,et al.  Cortical Surface-Based Analysis I. Segmentation and Surface Reconstruction , 1999, NeuroImage.

[13]  M. Saemann,et al.  Inflammation alters HDL composition and function: implications for HDL-raising therapies. , 2013, Pharmacology & therapeutics.

[14]  L. Launer,et al.  Microinfarcts, brain atrophy, and cognitive function: The Honolulu Asia Aging Study Autopsy Study , 2011, Annals of neurology.

[15]  P. D'Amore,et al.  The role of hypoxia in vascular injury and repair. , 2008, Annual review of pathology.

[16]  J. Schneider,et al.  Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology , 2004, Neurology.

[17]  J. Kaye,et al.  Dyslipidemia and Blood-Brain Barrier Integrity in Alzheimer's Disease , 2012, Current gerontology and geriatrics research.

[18]  Cindee M. Madison,et al.  Cortical thickness mediates the effect of β-amyloid on episodic memory , 2014, Neurology.

[19]  C. Jack,et al.  Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade , 2010, The Lancet Neurology.

[20]  R. Killiany,et al.  Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults , 2011, Neurology.

[21]  W. Jagust,et al.  Coronary risk correlates with cerebral amyloid deposition , 2012, Neurobiology of Aging.

[22]  Nick C Fox,et al.  Clinical and biomarker changes in dominantly inherited Alzheimer's disease. , 2012, The New England journal of medicine.

[23]  D. Levy,et al.  Prediction of coronary heart disease using risk factor categories. , 1998, Circulation.

[24]  Jong Hun Kim,et al.  Cardiovascular Risk Factors Cause Cortical Thinning in Cognitively Impaired Patients: Relationships Among Cardiovascular Risk Factors, White Matter Hyperintensities, and Cortical Atrophy , 2012, Alzheimer disease and associated disorders.

[25]  R. Akinyemi,et al.  Does vascular pathology contribute to Alzheimer changes? , 2012, Journal of the Neurological Sciences.

[26]  C. Jack,et al.  An operational approach to National Institute on Aging–Alzheimer's Association criteria for preclinical Alzheimer disease , 2012, Annals of neurology.

[27]  J. Farmer,et al.  High-Density Lipoprotein and Atherosclerosis: The Role of Antioxidant Activity , 2012, Current Atherosclerosis Reports.

[28]  C. DeCarli,et al.  Associations between serum cholesterol levels and cerebral amyloidosis. , 2014, JAMA neurology.

[29]  Thomas E. Nichols,et al.  Validating cluster size inference: random field and permutation methods , 2003, NeuroImage.

[30]  W. Markesbery,et al.  AD brain pathology: Vascular origins? Results from the HAAS autopsy study , 2008, Neurobiology of Aging.

[31]  Cindee M. Madison,et al.  Cerebrovascular disease, beta-amyloid, and cognition in aging , 2012, Neurobiology of Aging.

[32]  J. C. de la Torre.  Cardiovascular Risk Factors Promote Brain Hypoperfusion Leading to Cognitive Decline and Dementia , 2012, Cardiovascular psychiatry and neurology.

[33]  J. C. Torre.  Cardiovascular Risk Factors Promote Brain Hypoperfusion Leading to Cognitive Decline and Dementia , 2012 .

[34]  A. Mokdad,et al.  The distribution of 10-Year risk for coronary heart disease among US adults: findings from the National Health and Nutrition Examination Survey III. , 2004, Journal of the American College of Cardiology.

[35]  Elizabeth C Mormino,et al.  Not quite PIB-positive, not quite PIB-negative: Slight PIB elevations in elderly normal control subjects are biologically relevant , 2012, NeuroImage.

[36]  R. Buckner.  Memory and Executive Function in Aging and AD Multiple Factors that Cause Decline and Reserve Factors that Compensate , 2004, Neuron.

[37]  Owen Carmichael,et al.  Associations Among Vascular Risk Factors, Carotid Atherosclerosis, and Cortical Volume and Thickness in Older Adults , 2012, Stroke.