Association of cerebrovascular reactivity and Alzheimer pathologic markers with cognitive performance

Objective To determine whether MRI-based cerebrovascular reactivity (CVR) can predict cognitive performance independently of Alzheimer pathologic markers, we studied the relationship between cognition, CVR, and CSF-derived β-amyloid42 (Aβ42) and tau in a group of elderly individuals with mixed Alzheimer and vascular cognitive impairment and dementia. Methods This was a cross-sectional study of 72 participants 69 ± 8 years of age consisting of individuals with normal cognition (n = 28) and cognitive impairment (n = 44) (including 36 with mild cognitive impairment [MCI] and 8 with mild dementia). CVR was measured with hypercapnia-MRI. Whole-brain CVR (percent blood oxygen level–dependent per 1 mm Hg Etco2) was used to estimate vasodilatory capacity. Montreal Cognitive Assessment (MoCA) scores, cognitive domains scores, and a global composite cognitive score were obtained. AD biomarkers included CSF assays of Aβ42 and tau. Results Whole-brain CVR was lower in the impaired (mean ± SE, 0.132 ± 0.006%/mm Hg) compared to the normal (0.151 ± 0.007%/mm Hg) group (β = −0.02%/mm Hg; 95% confidence interval [CI] −0.038 to −0.001). After adjustment for CSF Aβ42 and tau, higher whole-brain CVR was associated with better performance on the MoCA (β = 29.64, 95% CI 9.94–49.34) and with a global composite cognitive score (β = 4.32, 95% CI 0.05–8.58). When the CVR marker was compared with the Fazekas score based on white matter hyperintensities and vascular risk-score in a single regression model predicting the MoCA score, only CVR revealed a significant effect (β = 28.09, 95% CI 6.14–50.04), while the other 2 measures were not significant. Conclusions CVR was significantly associated with cognitive performance independently of AD pathology. Whole-brain CVR may be a useful biomarker for evaluating cognitive impairment related to vascular disease in older individuals. Classification of evidence This study provides Class II evidence that CVR was significantly associated with cognitive performance independent of AD pathology.

[1]  Kevin Murphy,et al.  Reliable quantification of BOLD fMRI cerebrovascular reactivity despite poor breath-hold performance☆ , 2013, NeuroImage.

[2]  A. Alavi,et al.  MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. , 1987, AJR. American journal of roentgenology.

[3]  Rong Zhang,et al.  Reduced global brain metabolism but maintained vascular function in amnestic mild cognitive impairment , 2017, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[4]  S. Pereson,et al.  From innotest to the fully automated chemiluminescent b-amyloid(1-42) and total tau assays on the LUMIPULSE® G instrument series: Taking quantification of Alzheimer’s disease CSF biomarkers to the next level , 2015, Alzheimer's & Dementia.

[5]  M. O’Sullivan,et al.  Impact of MRI markers in subcortical vascular dementia: A multi-modal analysis in CADASIL , 2010, Neurobiology of Aging.

[6]  H. Brodaty,et al.  The neuropsychological profile of vascular cognitive impairment in stroke and TIA patients , 2004, Neurology.

[7]  Jinsoo Uh,et al.  Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer's disease , 2012, Neurobiology of Aging.

[8]  Denise C. Park,et al.  Alterations in cerebral metabolic rate and blood supply across the adult lifespan. , 2011, Cerebral cortex.

[9]  Manus J. Donahue,et al.  Neuroimaging of vascular reserve in patients with cerebrovascular diseases , 2017, NeuroImage.

[10]  Xi Chen,et al.  Age-related changes in cerebrovascular reactivity and their relationship to cognition: A four-year longitudinal study , 2018, NeuroImage.

[11]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[12]  David A. Bennett,et al.  Mixed brain pathologies account for most dementia cases in community-dwelling older persons , 2007, Neurology.

[13]  P. Scheltens,et al.  Measuring progression of cerebral white matter lesions on MRI , 2004, Neurology.

[14]  Clifford R Jack,et al.  Vascular imaging abnormalities and cognition: mediation by cortical volume in nondemented individuals: atherosclerosis risk in communities-neurocognitive study. , 2015, Stroke.

[15]  R. von Kummer,et al.  Imaging of cerebral blood flow-to-volume distribution using SPECT. , 1986, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  J. Orgogozo,et al.  Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia , 2004, Journal of the Neurological Sciences.

[17]  B. Reisberg,et al.  Vascular cognitive impairment , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[18]  Keith A. Johnson,et al.  Interactive Associations of Vascular Risk and &bgr;-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals: Findings From the Harvard Aging Brain Study , 2018, JAMA Neurology.

[19]  M. Dichgans,et al.  Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging , 2013, The Lancet Neurology.

[20]  Deborah A. Levine,et al.  Trajectory of Cognitive Decline After Incident Stroke. , 2015, JAMA.

[21]  Sven Haller,et al.  Altered cerebrovascular reactivity velocity in mild cognitive impairment and Alzheimer's disease , 2015, Neurobiology of Aging.

[22]  D. Birkett.  Cerebrovascular responsiveness to hypercapnia in Alzheimer's dementia and vascular dementia of the Binswanger type. , 1992, Stroke.

[23]  E. Rüther,et al.  Cerebrovascular reactivity to acetazolamide in (senile) dementia of Alzheimer's type: relationship to disease severity. , 1995, Dementia.

[24]  David J Mikulis,et al.  Mapping Cerebrovascular Reactivity Using Blood Oxygen Level-Dependent MRI in Patients With Arterial Steno-occlusive Disease: Comparison With Arterial Spin Labeling MRI , 2008, Stroke.

[25]  Arthur W. Toga,et al.  Brain imaging of neurovascular dysfunction in Alzheimer’s disease , 2016, Acta Neuropathologica.

[26]  Yoko Mochizuki,et al.  Regional differences in cerebrovascular reactivity to acetazolamide in Alzheimer's disease , 1999, Journal of Clinical Neuroscience.

[27]  Peiying Liu,et al.  Cerebrovascular reactivity (CVR) MRI with CO2 challenge: A technical review , 2019, NeuroImage.

[28]  D. Bennett,et al.  Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology , 2018, Neurology.

[29]  J. Jean Chen,et al.  Quantitative mapping of cerebrovascular reactivity using resting-state BOLD fMRI: Validation in healthy adults , 2016, NeuroImage.

[30]  Nick C Fox,et al.  The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[31]  Rachel L. Mistur,et al.  Framingham Cardiovascular Risk Profile Correlates with Impaired Hippocampal and Cortical Vasoreactivity to Hypercapnia , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[32]  A. Hofman,et al.  Periventricular cerebral white matter lesions predict rate of cognitive decline , 2002, Annals of neurology.

[33]  Peiying Liu,et al.  MRI Mapping of Cerebrovascular Reactivity via Gas Inhalation Challenges , 2014, Journal of visualized experiments : JoVE.

[34]  F. de Leeuw,et al.  A Novel Imaging Marker for Small Vessel Disease Based on Skeletonization of White Matter Tracts and Diffusion Histograms , 2016, Annals of neurology.

[35]  David M. Rissin,et al.  COMPARISON OF TWO PLATFORMS QUANTITATING FG/ML NEUROLOGICAL BIOMARKERS USING SINGLE MOLECULE ARRAYS AND DIGITAL ELISA: THE BENCHTOP READER SR-X™ AND THE FULLY AUTOMATED ANALYZER HD-1™ , 2018, Alzheimer's & Dementia.

[36]  Martijn Froeling,et al.  Investigating the non-linearity of the BOLD cerebrovascular reactivity response to targeted hypo/hypercapnia at 7T , 2014, NeuroImage.

[37]  F. Sakai,et al.  Noninvasive regional cerebral blood flow measurements in dementia. , 1980, Archives of neurology.

[38]  M. Sano,et al.  Association of the Haptoglobin Gene Polymorphism With Cognitive Function and Decline in Elderly African American Adults With Type 2 Diabetes , 2018, JAMA network open.

[39]  M. Wintermark,et al.  Consensus statement on current and emerging methods for the diagnosis and evaluation of cerebrovascular disease , 2017, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[40]  W. Jagust,et al.  Clinical Studies of Cerebral Blood Flow in Alzheimer's Disease , 1997, Annals of the New York Academy of Sciences.

[41]  Fabrizio Vernieri,et al.  Cerebrovascular Reactivity and Cognitive Decline in Patients With Alzheimer Disease , 2006, Stroke.

[42]  M. Fujishima,et al.  Cerebrovascular Responsiveness to Hypercapnia in Alzheimer's Dementia and Vascular Dementia of the Binswanger Type , 1992, Stroke.

[43]  Peiying Liu,et al.  Cerebrovascular Reactivity in the Brain White Matter: Magnitude, Temporal Characteristics, and Age Effects , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[44]  A. Rahmim,et al.  Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition , 2017, JAMA.

[45]  Jan Warnking,et al.  Impaired cerebral vasoreactivity to CO2 in Alzheimer's disease using BOLD fMRI , 2011, NeuroImage.

[46]  Jeffrey N. Browndyke,et al.  The neuropsychological profile of vascular cognitive impairment--no dementia: comparisons to patients at risk for cerebrovascular disease and vascular dementia. , 2004, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.

[47]  H. Chui,et al.  Recognition memory and verbal fluency differentiate probable Alzheimer disease from subcortical ischemic vascular dementia. , 2001, Archives of neurology.

[48]  Guanghua Xiao,et al.  On the assessment of cerebrovascular reactivity using hypercapnia BOLD MRI , 2009, NMR in biomedicine.

[49]  Hanli Liu,et al.  On the optimization of imaging protocol for the mapping of cerebrovascular reactivity , 2016, Journal of magnetic resonance imaging : JMRI.

[50]  M. Strother,et al.  Relationships between hypercarbic reactivity, cerebral blood flow, and arterial circulation times in patients with moyamoya disease , 2013, Journal of magnetic resonance imaging : JMRI.

[51]  M. Weiner,et al.  The effect of acetazolamide on regional cerebral blood flow in patients with Alzheimer's disease or stroke as measured by single-photon emission computed tomography. , 1989, Investigative radiology.

[52]  O Salonen,et al.  Cognitive profile of subcortical ischaemic vascular disease , 2005, Journal of Neurology, Neurosurgery & Psychiatry.