Elsevier

Neurobiology of Aging

Volume 23, Issue 3, May–June 2002, Pages 421-431
Neurobiology of Aging

Neurobiology of Aging
The microvascular frontal-subcortical syndrome of aging

https://doi.org/10.1016/S0197-4580(01)00319-0Get rights and content

Abstract

Many features of aging suggest dysfunction in both frontal and subcortical regions. Connections between the two areas form a series of pathways that critically influence various aspects of cognition, motor control, affect, and as recently discovered, normal urinary function. Age-related changes in the structure and integrity of these circuits may be associated with cognitive impairment, mood disorders, loss of balance, falls, and urinary dysfunction. In addition, cardiovascular risk factors in elderly people are associated with the development of cerebral microangiopathic changes in both the periventricular white matter and basal ganglia. These lesions are common, usually unsuspected, and were previously believed to be clinically innocuous. However, increasing evidence supports a role for these lesions as a cause for both dysfunction in frontal-subcortical systems, and many clinical features of aging that account for substantial disability. Because this form of cerebrovascular disease is potentially preventable, interventions that address risk factors for the development of cerebral microangiopathy may go a long way in preventing disability for the next generation of elderly persons.

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

References (133)

  • M.A. Petty et al.

    White matter ischaemia

    Brain Res Brain Res Rev

    (1999)
  • N. Raz et al.

    Age, gender, and hemispheric differences in human striatuma quantitative review, and new data from in vivo MRI morphometry

    Neurobiol Learn Mem

    (1995)
  • N.M. Resnick

    Urinary incontinence

    Lancet

    (1995)
  • M.A. Rogers et al.

    Frontostriatal deficits in unipolar major depression

    Brain Research Bulletin

    (1998)
  • G.S. Alexopoulos et al.

    ‘Vascular depression’ hypothesis

    Arch Gen Psychiatry

    (1997)
  • P. Andres et al.

    Age-related differences in supervisory attentional system functions

    J Gerontol B Psychol Sci Soc Sci

    (2000)
  • B.S. Athwal et al.

    Brain responses to changes in bladder volume and urge to void in healthy men

    Brain

    (2001)
  • J.C. Baron et al.

    Effects of thalamic stroke on energy metabolism of the cerebral cortex. A positron tomography study in man

    Brain

    (1986)
  • D.A. Bennett et al.

    Prevalence of parkinsonian signs and associated mortality in a community population of older people

    N Engl J Med

    (1996)
  • B.F. Blok et al.

    The central control of micturition and continence: implications for urology

    BJU Int

    (1999)
  • B.F. Blok et al.

    A PET study on brain control of micturition in humans

    Brain

    (1997)
  • R.W. Bohannon

    Comfortable and maximum walking speed of adults aged 20–79 yearsreference values and determinants

    Age Ageing

    (1997)
  • K.B. Boone et al.

    Neuropsychological correlates of white-matter lesions in healthy elderly subjects. A threshold effect

    Arch Neurol

    (1992)
  • J.S. Brown et al.

    Urinary incontinencedoes it increase risk for falls and fractures? Study of Osteoporotic Fractures Research Group

    J Am Geriatr Soc

    (2000)
  • R.N. Bryan et al.

    Prevalence and anatomic characteristics of infarct-like lesions on MR images of middle-aged adultsthe atherosclerosis risk in communities study

    AJNR Am J Neuroradiol

    (1999)
  • D.A. Cahn-Weiner et al.

    Prediction of functional status from neuropsychological tests in community-dwelling elderly individuals

    Clin Neuropsychol

    (2000)
  • R. Camicioli et al.

    Motor slowing precedes cognitive impairment in the oldest old

    Neurology

    (1998)
  • R. Camicioli et al.

    Age-related brain changes associated with motor function in healthy older people

    J Am Geriatr Soc

    (1999)
  • D. Carmelli et al.

    Midlife cardiovascular risk factors and brain morphology in identical older male twins

    Neurology

    (1999)
  • J.L. Cummings

    Anatomic and behavioral aspects of frontal-subcortical circuits

    Ann N Y Acad Sci

    (1995)
  • J.L. Cummings

    Vascular subcortical dementiasclinical aspects

    Dementia

    (1994)
  • J.L. Cummings

    Frontal-subcortical circuits, and human behavior

    Arch Neurol

    (1993)
  • J.C. de Groot et al.

    Cerebral white matter lesions and depressive symptoms in elderly adults

    Arch Gen Psychiatry

    (2000)
  • J.C. de Groot et al.

    Cerebral white matter lesions and cognitive functionthe Rotterdam Scan Study

    Ann Neurol

    (2000)
  • F.E. de Leeuw et al.

    Prevalence of cerebral white matter lesions in elderly peoplea population based magnetic resonance imaging study. The Rotterdam Scan Study

    J Neurol Neurosurg Psychiatry

    (2001)
  • F.E. de Leeuw et al.

    Aortic atherosclerosis at middle age predicts cerebral white matter lesions in the elderly

    Stroke

    (2000)
  • S. De Santi et al.

    Age-related changes in brainII

    Positron emission tomography of frontal and temporal lobe glucose metabolism in normal subjects. Psychiatr Q

    (1995)
  • B. Dubois et al.

    Cognitive deficits in Parkinson’s disease

    Journal of Neurology

    (1997)
  • B. Dubois et al.

    The FABa Frontal Assessment Battery at bedside

    Neurology

    (2000)
  • L.M. Duke et al.

    Executive control functions in degenerative dementiasa comparative review

    Neuropsychol Rev

    (2000)
  • P.K. Elias et al.

    NIDDM, and blood pressure as risk factors for poor cognitive performance. The Framingham Study

    Diabetes Care

    (1997)
  • K. Fassbender et al.

    Homocysteine in cerebral macroangiography and microangiopathy

    Lancet

    (1999)
  • F. Fazekas et al.

    Pathophysiologic mechanisms in the development of age-related white matter changes of the brain

    Dement Geriatr Cogn Disord

    (1998)
  • G. Fein et al.

    Preservation of normal cognitive functioning in elderly subjects with extensive white-matter lesions of long duration

    Arch Gen Psychiatry

    (1990)
  • C.M. Filley

    The behavioral neurology of cerebral white matter

    Neurology

    (1998)
  • C.M. Fisher

    Lacunessmall, deep cerebral infarcts

    Neurology

    (1998)
  • B.S. Fogel

    The significance of frontal system disorders for medical practice and health policy

    J Neuropsychiatry Clin Neurosci

    (1994)
  • L. Fratiglioni et al.

    Worldwide prevalence and incidence of dementia

    Drugs Aging

    (1999)
  • T. Fujikawa et al.

    Incidence of silent cerebral infarction in patients with major depression

    Stroke

    (1993)
  • I.B. Goldstein et al.

    Relationship between blood pressure and subcortical lesions in healthy elderly people

    Stroke

    (1998)
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    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.

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    Dr. Lipsitz holds the Irving and Edith S. Usen and Family Chair in Geriatric Medicine at the Hebrew Rehabilitation Center for Aged, Boston, MA.

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