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