Elsevier

NeuroImage

Volume 55, Issue 2, 15 March 2011, Pages 468-478
NeuroImage

Age-associated reductions in cerebral blood flow are independent from regional atrophy

https://doi.org/10.1016/j.neuroimage.2010.12.032Get rights and content

Abstract

Prior studies have demonstrated decreasing cerebral blood flow (CBF) in normal aging, but the full spatial pattern and potential mechanism of changes in CBF remain to be elucidated. Specifically, existing data have not been entirely consistent regarding the spatial distribution of such changes, potentially a result of neglecting the effect of age-related tissue atrophy in CBF measurements. In this work, we use pulsed arterial-spin labelling to quantify regional CBF in 86 cognitively and physically healthy adults, aged 23 to 88 years. Surface-based analyses were utilized to map regional decline in CBF and cortical thickness with advancing age, and to examine the spatial associations and dissociations between these metrics. Our results demonstrate regionally selective age-related reductions in cortical perfusion, involving the superior-frontal, orbito-frontal, superior-parietal, middle-inferior temporal, insular, precuneus, supramarginal, lateral-occipital and cingulate regions, while subcortical CBF was relatively preserved in aging. Regional effects of age on CBF differed from that of grey-matter atrophy. In addition, the pattern of CBF associations with age displays an interesting similarity with the default-mode network. These findings demonstrate the dissociation between regional CBF and structural alterations specific to normal aging, and augment our understanding of mechanisms of pathology in older adults.

Research Highlights

► First study to map quantitative CBF in normal aging using pulsed arterial-spin labelling. ► First study to probe spatial link between CBF and atrophy in normal aging using surface-based analysis. ► Grey matter CBF was regional reduced in aging primarily in the cortex. ► CBF reductions were not strongly associated with grey-matter atrophy. ► Perfusion and structural imaging provide distinct pictures of neuronal health.

Introduction

Continuous and sufficient cerebral blood flow (CBF) is vital to neural function; thus, cerebral perfusion, typically quantified by measuring the volume of blood passing through the microvascular network in a given volume of tissue over a certain duration, is a key indicator of cerebral health. It has long been established that CBF is normally coupled to cerebral oxygen (CMRO2) and glucose consumption in steady state (Hoge et al., 1999, Sokoloff et al., 1977). Disruption of this system may suggest compromised vascular function and/or abnormal metabolism. It is therefore not surprising that reduced CBF and disrupted neurovascular coupling are associated with numerous pathological conditions, such as hypertension, ischemic stroke, and Alzheimer's disease (Girouard and Iadecola, 2006, Gsell et al., 2000). However, it is not fully understood if changes in CBF arise in normal aging, and whether such changes are associated with the well described tissue atrophy in older adults.

The brain undergoes a wide array of anatomical and functional changes in normal aging (Morrison and Hof, 1997), associated with an increasing risk of age-related neurovascular diseases that compromise the functional integrity of the neurological system. A number of epidemiological (Aguero-Torres et al., 2006, Breteler, 2000, Ruitenberg et al., 2005), pharmacotherapeutic (Duron and Hanon, 2010, Forette et al., 2002, Tzourio et al., 2003), and neuroimaging studies (Alsop et al., 2008, Dai et al., 2008c, Dai et al., 2009, Uh et al., 2010) suggest vascular contributions to Alzheimer's disease (AD) and other dementia (Bell and Zlokovic, 2009, Caroli et al., 2007, de la Torre, 2005, Dickstein et al., 2010, Helzner et al., 2009, Ruitenberg et al., 2005, Sachdev et al., 1999, Zlokovic, 2005). Thus, understanding changes in blood flow in cognitively healthy older adults is an important step towards differentiating normal from abnormal alterations in physiology (Elias et al., 1995, Farmer et al., 1990, Nagata et al., 2000, Skoog et al., 1996). Regional hypoperfusion has been found to be associated with amyloid accumulation (Driscoll et al., 2010, Sojkova et al., 2008) as well as cognitive deficits (Alves and Busatto, 2006). The reported links between perfusion reduction, neuronal damage and structural deterioration (Fierstra et al., 2010, Tohgi et al., 1998) beg the question of how aging-associated CBF reductions relate to the wide-spread cerebral atrophy (Akiyama et al., 1997, Buckner et al., 2004, Raz et al., 1997, Salat et al., 2004), and more critically, which changes are not secondary to normal aging but may instead indicate impending pathology. Invaluable clues can be gleaned by integrating quantitative perfusion and anatomical imaging.

Perfusion imaging has conventionally been performed using positron-emission tomography (PET) (Beason-Held et al., 2009, Meltzer et al., 2000, Pantano et al., 1984), single-photon emission computed tomography (SPECT) (Alves and Busatto, 2006, Inoue et al., 2005, Yang et al., 2002), X-ray computed tomography (CT) (Akiyama et al., 1997, Meyer et al., 1994) and contrast-enhanced MRI (Helenius et al., 2003). Arterial-spin labelling (ASL) (Detre et al., 1998a, Detre et al., 1998b, Oguz et al., 2003, Parkes et al., 2004, Williams et al., 1992, Wong et al., 1997) is a relatively novel and minimally invasive perfusion methodology requiring no exogenous tracers, and continuous ASL (CASL) (Detre et al., 1992, Detre et al., 1994, Detre et al., 1998a, Detre et al., 1998b) as well as the more novel pseudo-continuous ASL (Dai et al., 2008b, Silva and Kim, 1999) have recently found application in clinical populations (Alsop et al., 2008, Alsop et al., 2010, Detre et al., 1998a, Detre et al., 1998b, Xu et al., 2010). However, regional CBF changes in cognitively healthy adults specific to the full adult life-span remains to be clarified. In this work, we examine the effects of normal adult aging on CBF using advanced anatomical models and morphological procedures which permitted the assessment of regional alterations in cortical and subcortical tissue. We used pulsed ASL in conjunction with high-resolution structural MRI to evaluate regional cortical and subcortical resting CBF measures in cognitively healthy older adults. Unique to this study is the mapping of MRI measurements of age-associations in CBF in relation to regional brain atrophy in a cortical surface-oriented manner. This procedure permitted detailed examination of the association between age-related changes in CBF and tissue volume, as well as the reduction of the potential influence of partial volume contamination on the CBF values. We found that reductions in CBF were independent of concurrent age-related tissue volume reduction, as perfusion can remain unaltered in regions of significant tissue atrophy. This apparent “dissociation” suggests that tissue shrinkage and hypoperfusion may not take place concurrently. Our findings underscore the importance of perfusion and structural measures as individually unique metrics of neurological changes in aging.

Section snippets

Participants

This study involved 86 cognitively healthy participants, (38 men/48 women), aged from 22.9 to 88.2 years. These were subdivided into young (YA, age < 40), middle-aged (MA, 40  age < 60) and older (OA, age  60) adult groups. Younger adults were recruited through the MGH and local community, and older adults were recruited through the Harvard Cooperative Program on Aging (http://www.hebrewrehab.org/home_institute.cfm?id=90) and the Nurses' Health Study (http://www.channing.harvard.edu/nhs/) at Harvard

Effect of age on global CBF

The mean CBF value across the entire cortical grey matter volume was 52.6 ± 9.3, 52.0 ± 10.7, and 42.7 ± 8.8 ml/100 g/min in the young (YA), middle-aged (MA) and older (OA) adult groups, respectively. No significant difference was found between the YA and MA, but these latter were both found to differ from the OA group. The mean subcortical CBF, taken across the amygdala, accumbens, caudate, globus pallidus, putamen and thalamus, was 40.5 ± 7.6, 41.7 ± 7.1, and 39.5 ± 6.2 ml/100 g/min, respectively. One-tailed

Discussion

This study investigated the relationship between cerebral perfusion and aging. Reproducibility associated with pulsed ASL CBF measurements is in agreement with previous findings (Jiang et al., 2010, Parkes et al., 2004). We demonstrated substantial spatial non-uniformity in CBF cortically and subcortically, independent of age. Significant age-associated regional CBF reduction was widely observed throughout the cortex. Importantly, these reductions were not closely associated with age-related

Acknowledgments

This research was supported by NIH grants K01AG024898, R01NR010827, NS042861, and P41RR14075, as well as the Canadian Institutes of Health Research (CIHR) and the Athinoula A. Martinos Center for Biomedical Imaging. We also thank Dr. Doug Greve for his input on multi-modal image registration, and Mr. Robert McInnis for help with cognitive testing.

References (128)

  • M.F. Folstein et al.

    “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician

    Journal of Psychiatric Research

    (1975)
  • C.R. Genovese et al.

    Thresholding of statistical maps in functional neuroimaging using the false discovery rate

    Neuroimage

    (2002)
  • W. Gsell et al.

    The use of cerebral blood flow as an index of neuronal activity in functional neuroimaging: experimental and pathophysiological considerations

    Journal of Chemical Neuroanatomy

    (2000)
  • S. Hayasaka et al.

    A non-parametric approach for co-analysis of multi-modal brain imaging data: application to Alzheimer's disease

    Neuroimage

    (2006)
  • S. Heo et al.

    Resting hippocampal blood flow, spatial memory and aging

    Brain Research

    (2010)
  • L. Jiang et al.

    Reliability and reproducibility of perfusion MRI in cognitively normal subjects

    Magnetic Resonance Imaging

    (2010)
  • R.C. Koehler et al.

    Astrocytes and the regulation of cerebral blood flow

    Trends in Neurosciences

    (2009)
  • J.S. Meyer et al.

    CT changes associated with normal aging of the human brain

    Journal of the Neurological Sciences

    (1994)
  • K. Obara et al.

    Cognitive declines correlate with decreased cortical volume and perfusion in dementia of Alzheimer type

    Journal of the Neurological Sciences

    (1994)
  • M.E. Raichle et al.

    A default mode of brain function: a brief history of an evolving idea

    Neuroimage

    (2007)
  • N. Schuff et al.

    Cerebral blood flow in ischemic vascular dementia and Alzheimer's disease, measured by arterial spin-labeling magnetic resonance imaging

    Alzheimer's & Dementia

    (2009)
  • F. Segonne et al.

    A hybrid approach to the skull stripping problem in MRI

    Neuroimage

    (2004)
  • H. Aguero-Torres et al.

    Rethinking the dementia diagnoses in a population-based study: what is Alzheimer's disease and what is vascular dementia? A study from the Kungsholmen project

    Dementia and Geriatric Cognitive Disorders

    (2006)
  • D.C. Alsop et al.

    Arterial spin labeling blood flow MRI: its role in the early characterization of Alzheimer's disease

    Journal of Alzheimer's Disease

    (2010)
  • T.C. Alves et al.

    Regional cerebral blood flow reductions, heart failure and Alzheimer's disease

    Neurological Research

    (2006)
  • I. Asllani et al.

    Regression algorithm correcting for partial volume effects in arterial spin labeling MRI

    Magnetic Resonance in Medicine

    (2008)
  • L.R. Barnden et al.

    Age related preservation and loss in optimized brain SPECT

    Nuclear Medicine Communications

    (2005)
  • L.L. Beason-Held et al.

    Stability of default-mode network activity in the aging brain

    Brain Imaging Behav

    (2009)
  • R.D. Bell et al.

    Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease

    Acta Neuropathologica

    (2009)
  • R.L. Buckner et al.

    Molecular, structural, and functional characterizatioin of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory

    Neurobiology of Aging

    (2005)
  • P.C. Buijs et al.

    Effect of age on cerebral blood flow: measurement with ungated two-dimensional phase-contrast MR angiography in 250 adults

    Radiology

    (1998)
  • S. Burgmans et al.

    The posterior parahippocampal gyrus is preferentially affected in age-related memory decline

    Neurobiology of Aging (Electronic publication ahead of print)

    (2009)
  • A. Burns et al.

    Association of age with regional cerebral oxygen utilization: a positron emission tomography study

    Brain

    (1992)
  • R.B. Buxton et al.

    A general kinetic model for quantitative perfusion imaging with arterial spin labeling

    Magnetic Resonance in Medicine

    (1998)
  • F. Calamante et al.

    Measuring cerebral blood flow using magnetic resonance imaging techniques

    Journal of Cerebral Blood Flow and Metabolism

    (1999)
  • A. Caroli et al.

    Cerebral perfusion correlates of conversion to Alzheimer's disease in amnestic mild cognitive impairment

    Journal of Neurology

    (2007)
  • J.J. Chen et al.

    The advantages of frequency domain modeling in DSC MR CBF quantification

    Magnetic Resonance in Medicine

    (2005)
  • J.J. Chen et al.

    Partial-volume effects in DSC MR perfusion quantification

    Journal of Magnetic Resonance Imaging

    (2005)
  • W. Dai et al.

    Effects of image normalization on the statistical analysis of perfusion MRI in elderly adults

    Journal of Magnetic Resonance Imaging

    (2008)
  • W. Dai et al.

    Continuous flow-driven inversion for arterial spin labeling using pulsed radio frequency and gradient fields

    Magnetic Resonance in Medicine

    (2008)
  • W. Dai et al.

    Abnormal regional cerebral blood flow in cognitively normal elderly subjects with hypertension

    Stroke

    (2008)
  • W. Dai et al.

    Mild cognitive impairment and alzheimer disease: patterns of altered cerebral blood flow at MR imaging

    Radiology

    (2009)
  • J.C. de la Torre

    Is Alzheimer's disease preceded by neurodegeneration or cerebral hypoperfusion?

    Annals of Neurology

    (2005)
  • J.A. Detre et al.

    Cerebravascular Reserve Testing Using Perfusion MRI with Arterial Spin Labeling in Normal Subjects and Patients with Cerebrovascualr Disease

    (1998)
  • J.A. Detre et al.

    Noninvasive MRI evaluation of cerebral blood flow in cerebrovascular disease

    Neurology

    (1998)
  • J.A. Detre et al.

    Perfusion imaging. Magnetic Resonance in Medicine

    (1992)
  • J.A. Detre et al.

    Tissue specific perfusion imaging using arterial spin labeling

    NMR in Biomedicine

    (1994)
  • D.L. Dickstein et al.

    Role of vascular risk factors and vascular dysfunction in Alzheimer's disease

    The Mount Sinai Journal of Medicine

    (2010)
  • I. Driscoll et al.

    Lack of association between 11C-PiB and longitudinal brain atrophy in non-demented older individuals

    Neurobiology of Aging

    (2010)
  • E. Duron et al.

    Antihypertensive treatments, cognitive decline, and dementia

    Journal of Alzheimer's Disease

    (2010)
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