Neurobiology of AgingThe microvascular frontal-subcortical syndrome of aging
Introduction
The process of human aging often results in changes within motor and cognitive systems that are sufficiently characteristic; they might arguably be described as “phenotypic.” For example, motor and cognitive slowing leads to age-related differences in reaction times, gait speed, and “fluid” intelligence [9], [48], [106]. It is not surprising that these are key features of geriatric syndromes that include falls, cognitive impairment, and depression. We believe considerable evidence to date suggests that pathophysiologic processes of the human frontal lobes and their subcortical connections may in part account for the “phenotypic” changes and syndromes that occur with aging. The frontal-subcortical model is helpful in understanding why geriatric syndromes often coexist within an individual patient.
Cognitive neuroscientists were among the first to speculate on a relationship between the frontal lobes and clinical features of aging. One popular theory of cognitive aging attempts to understand age-related cognitive decline in terms of frontal lobe impairment [130]. Compared with young adults, elderly persons often show relative deficits in abstract reasoning, problem solving, psychomotor speed, and memory retrieval, with little evidence for change in linguistic abilities or general knowledge [78]. Many studies demonstrate age-related declines in working memory, memory retrieval, loss of inhibitory control, and alterations in complex attention [2], [51], [68], [87]. A feature common to these cognitive processes is their apparent localization within an extensive network of prefrontal neural pathways, which connect to both subcortical and posterior parietal regions [61], [71].
We argue that frontal-subcortical dysfunction may result from a combination of age-dependent neuronal changes that are often exacerbated by microangiopathic vascular damage, which develops as elderly persons progressively accumulate cardiovascular risk factors. The link between microangiopathic vascular damage and several geriatric syndromes will be explored. We hope this model provides a foundation for further multidisciplinary research into the pathophysiologic mechanisms, prevention, and potential treatment for several conditions associated with aging (Fig. 1).
Section snippets
The microvascular frontal-subcortical syndrome of aging
Evidence for small-vessel subcortical ischemic cerebrovascular disease is extremely common among otherwise neurologically normal elderly patients. The usual findings include radiographic changes in the subcortical white matter and deep gray nuclei. For consistency and clarity, we collectively refer to the combination of these lesions as subcortical ischemic microangiopathy (SCIM). Small-vessel vascular lesions that comprise SCIM are perhaps the most significant cause for frontal-subcortical
Evidence for age-related frontal-subcortical dysfunction
Frontal-subcortical structures are highly vulnerable to the process of aging, yet drawing firm conclusions about what is “normal” and what represents neurodegenerative or cerebrovascular disease remains difficult. Because of the cross-sectional design of most studies on aging, investigators are frequently unable to determine whether aging per se, or simply intergenerational variation in factors such as nutrition, education, or prevalent disease are responsible for observed differences in brain
Subcortical ischemic microangiopathy: the most common cause of frontal-subcortical dysfunction in aging?
Vascular disease may be the most common pathway to frontal-subcortical dysfunction in aging. The sheer volume of the frontal lobes, nearly 30% of total cerebral volume, suggests that vascular lesions are likely to affect the integrity of frontal-subcortical circuits. Much of this tissue lies at the boundaries of large vessel perfusion territories and represents the “watershed” regions of cerebral circulation.
Clinical implications of SCIM for the geriatric patient
It is clear that the small and often occult cerebrovascular lesions that we define as SCIM are not clinically “silent” as once believed. This is particularly true given that these lesions appear frequently associated with the common functional problems that characterize the phenotype of aging. The link to each of these functional problems is discussed below.
Areas for future research and present opportunities
We have presented substantial evidence for an association between age-related frontal-subcortical changes, ischemic microangiopathy, and several geriatric syndromes. Yet, despite this, it remains difficult to predict which individual patients will ultimately develop these syndromes. There are reports of patients with extensive white matter changes who seem to display no adverse effects [32]. It has been suggested that white matter lesions detected by computerized tomography, which is less
Conclusion
As we have shown, many phenotypic features of aging may be related to frontal- subcortical dysfunction. Features of the common geriatric syndromes that lead to disability may in fact be related to the influence these circuits have over cognitive, motor, affective, and urinary function. Aging itself seems to preferentially involve frontal-subcortical regions. In addition, subcortical ischemic microangiopathy is exceedingly common among older individuals and has its greatest impact on these same
Acknowledgments
This work was supported by grants AG04390 and AG05134 from the National Institutes of Health, Bethesda, MD, and a Hartford Foundation Center of Excellence in Geriatric Medicine grant to Harvard Medical School, Boston, MA. LCDR Pugh was also supported by the U.S. Navy, Naval School of Health Sciences, Bethesda, MD
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- 1
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government.
- 2
Dr. Lipsitz holds the Irving and Edith S. Usen and Family Chair in Geriatric Medicine at the Hebrew Rehabilitation Center for Aged, Boston, MA.