 |
|
Age-Related Memory Decline
Current Concepts and Future Directions
Scott A. Small, MD
Arch Neurol. 2001;58:360-364.
ABSTRACT
The effect of age on memory and the brain has been the focus of many
studies. Results have identified critical questions that need to be addressed
to further our understanding of age-related memory decline: Is cognitive decline
diffuse or selective? Where does memory decline localize to anatomically?
Does decline represent an abnormal state? What are the causes of memory decline?
What level of analysis is needed to investigate age-related cortical changes?
These questions are reviewed herein, and attempts at early answers are discussed.
INTRODUCTION
The neuroscience community has increasingly focused on age-related changes
in higher cortical function. The drive behind this interest extends beyond
the influence aging baby boomers have on policy-makers or arouse in the pharmacological
industry. Bench researchers have come to appreciate that age-related memory
decline offers insight into the neurobiological underpinnings of normal mnemonic
function. Clinical investigators, emboldened by successes in diagnosing neurological
diseases with high morbidity, have been inclined to tackle subtle entities
such as mild memory deficits.
Beyond expanding our knowledge base, the accumulation of new findings
has served to identify important questions critical in understanding age-related
changes in higher cortical function. These questions, and attempts at providing
answers, are reviewed herein.
IS COGNITIVE DECLINE DIFFUSE OR SELECTIVE?
Do age-related changes occur equally across all cognitive domains, or
is memory function uniquely sensitive to the effects of aging? Age-related
processes, some which underlie cognitive decline, do not target cortical regions
equally. Insofar as different cognitive domains involve independent cortical
topographies, a starting assumption is that the effect of aging will not be
cognitively diffuse.
Neuropsychologic studies1, 2, 3, 4, 5, 6
have attempted to address this question using cross-sectional or longitudinal
designs. Both approaches, however, have inherent limitations. Cross-sectional
findings are limited by the sensitivity of cognitive tests to demographic
differences.7 Although an attempt can be made
to control for some differences among cohorts of varying ages, the effect
of generational differences—such as unequal levels of education and
exposure to different environmental stimuli—cannot be accounted for.
This cohort effect is most effectively addressed by following up a group of
subjects prospectively and observing how performance changes with time. Administering
a cognitive test repeatedly, however, results in improving performance,8 and this learning effect can obscure an underlying
cognitive decline. Furthermore, longitudinal effects often necessitate long
follow-up, which results in greater subject attrition, and this could minimize
the change over time because attrition might occur differentially among subjects
with greater cognitive decline.9
Thus, cross-sectional studies may overestimate cognitive decline because
of the cohort effect, whereas longitudinal studies may underestimate decline
because of the learning effect—or if the learning effect is controlled,
then because of selective subject attrition.
Recent studies9, 10 have
addressed these limitations by using a mixed experimental design. By following
separate cohorts prospectively, a cross-sectional x longitudinal analysis
can be performed that controls for the limitations of each. Results of these
studies show that across cognitive domains, memory performance undergoes conspicuous
decline with increasing age. Future studies using complicated designs are
needed to further establish the precise profile of age-related cognitive decline
and to determine which aspects of cognition are preserved throughout the life
span.
WHERE DOES MEMORY DECLINE LOCALIZE TO ANATOMICALLY?
One of the fundamental findings to emerge from cognitive science in
the past half century is that memory is a fractionated process and that memory
subtypes localize to different anatomical sites.11
Aging has a salient effect on declarative memories—conscious, explicit
recollections of episodes and events, as well as semantic information. Although
the neuroanatomic mapping of any complex cognitive function oversimplifies,
the basic scheme of declarative memory is illustrated in Figure 1. The long-term storage of memory resides in the same associational
neocortical sites accessed during perception and activated during memory acquisition.12 The consolidation of long-term memories requires
an interplay between the neocortical sites and components of the medial temporal
lobes, including the hippocampus. This consolidation phase likely lasts weeks
to months, and maybe longer.13 Finally, a successful
memory system requires the ability to retrieve information on demand, and
retrieval strategies involve the prefrontal cortices.14
|
|
|
|
Figure 1. The gross anatomy of memory. A
simplified memory circuit includes the posterior associational neocortex,
where memories are stored (dashed-line rectangle); the medial temporal lobe
(oval), which consolidates memory storage; and the prefrontal cortex, which
facilitates memory retrieval (solid-line rectangle). Pathological processes
can selectively target different brain areas.
|
|
|
Where does memory decline localize to within this functional circuit?
Neuropsychologic, physiological,15 and brain
imaging16, 17, 18 studies
suggest that the prefrontal cortex and the medial temporal lobes are most
sensitive to age-related changes. Nevertheless, it remains undetermined whether
all causes of memory decline spare the posterior associational neocortices.
DOES MEMORY DECLINE REPRESENT AN ABNORMAL STATE?
Since first addressed by Kral19 in the
late 1950s, numerous studies2, 3, 4, 10, 20, 21, 22
have documented poorer memory performance in older compared with younger age
groups. Although the exact prevalence is uncertain, most agree that memory
decline occurs in more than 40% of individuals older than 60 years.23 Despite this high prevalence, or perhaps because
of it, there is continued debate about whether memory decline in otherwise
healthy older people should be considered a clinical entity. In other words,
does it reflect an abnormal state?
Statistical definitions of normality can be used to address this issue.
If memory decline is a normal occurrence with age, distribution curves of
memory scores in old and young age groups should have similar variance, with
a leftward shift in the mean for the older age group. However, if memory decline
is not normal, the distribution curve of the old age group should have increased
variance, and might show bimodality, compared with the young age group. Studies24 with humans and animals have shown that the variance
of memory performance in aging samples increases with age, and some studies
have found clear bimodal distributions. These findings suggest that memory
decline is not inevitable with increasing age and therefore should be considered
a clinical entity.
A more ecological approach to defining abnormal memory decline has less
to do with population statistics and more to do with whether the decline has
a negative impact on functional ability. The number and proportion of aging
individuals in the population is increasing. These aging individuals expect
to lead intellectually challenging lives in an environment rich with information
and reliant on rapidly changing technologies. The ability to negotiate this
environment depends on cognitive skills that include the specific types of
memory systems most vulnerable to age-associated changes. Memory decline interferes
with an aging individual's activities of daily living, without necessarily
progressing to amnesia or extending into dementia.25, 26, 27
Thus, even if memory decline were quantitatively normal, it would still qualify
as an entity that warrants clinical attention.
WHAT ARE THE CAUSES OF MEMORY DECLINE?
Nondegenerative disorders causing dementia—metabolic, toxic, infectious,
and structural—can present with isolated memory deficits,28, 29, 30
but such causes account for only a small percentage of elderly people with
isolated cognitive decline.
Because Alzheimer disease (AD) is relatively common in individuals older
than 65 years, and because AD pathological processes target the hippocampal
formation early in its course,31 early AD is
a major contributor to memory decline in otherwise healthy and nondemented
older people.32, 33 Still, not
every older individual with memory deficits progresses to AD dementia,32, 33 and there is evidence from postmortem
studies supporting other—non-AD—causes of memory decline. These
studies34, 35 have shown that among
brains free of AD pathology, cell loss occurs in select subfields of the hippocampal
formation in an age-dependent fashion.
Indirect support of non-AD causes of memory decline is provided by animal
studies24, 36: all nonhuman mammalian
species demonstrate some form of hippocampal-based memory decline with age.
None develop the pathognomic features associated with AD, and the memory decline
therefore is caused by non-AD processes. It is unlikely that a non-AD process
pervasive across all mammalian species would spare our own.
The exact cause of non-AD memory decline is still a matter of debate
and is the focus of ongoing investigations. As shown in Figure 2, likely causes include age-related changes in adrenal and
gestational hormonal levels,37, 45, 46, 47, 48
changes in cerebrovascular supply,49 and age-related
accrual of oxidative stress.50 Non-AD memory
decline does not necessarily have to be a secondary effect of these processes;
rather, it might reflect time-dependent alterations inherent to particular
sets of neuronal populations.51, 52, 53
|
|
|
|
Figure 2. The microanatomy of memory illustrated
with the hippocampal formation. The general locales of the hippocampal subregions
are shown on a transverse hippocampal slice. The subregions are interconnected
to form a circuit engaged during memory function. The subregions are composed
of unique populations of neurons and are differentially sensitive to physiological
processes.
|
|
|
There is indirect evidence suggesting that age-related memory decline
might have a genetic component. Twin studies54
show an association between genes and cognition—including language,
visuospatial ability, and memory function. Memory function is unique, however,
because its genetic association seems to increase in an age-related fashion.55 A gene, or a set of genes, that increases the vulnerability
of strategic brain regions, such as the hippocampal formation, to age-related
injury might account for this intriguing finding. Although all individuals
in a population might be equally exposed to pathological processes that target
the hippocampal formation, individuals expressing the "vulnerability" gene
would be at greater risk to sustain hippocampal lesions as they age. With
time, therefore, this subpopulation would be more likely to undergo memory
decline, and in late life those with and without the gene would segregate
along memory performance scores. There are, in fact, genes that might act
in this manner. The APOE gene is one candidate because
it is expressed with relative selectivity in hippocampal neurons,56 its products are involved in mechanisms of neuronal
repair,57 and its expression is up-regulated
in the setting of hippocampal injury.58 Consistent
with this, the APOE4 genotype is associated not only
with AD but also with cognitive deficits associated with head trauma,59 open heart surgery,60
mesiotemporal sclerosis,61 and stroke.62
FUTURE INVESTIGATIONS OF MEMORY DECLINE
What variable should be measured in assessing cortical abnormalities
associated with memory decline? An important observation to emerge from recent
studies63 is that age-related memory decline
need not be associated with clear structural lesions. This corresponds to
the fact that many age-related processes result in physiological dysfunction64 and not neuronal loss. Some processes that do ultimately
manifest in tissue damage, such as AD pathology, often have a prodromal stage
during which neuronal dysfunction occurs in the absence of cell death. Thus,
techniques that assess neuronal physiological dysfunction independent of structure
are best suited to detect and localize brain regions associated with age-related
memory decline. Neuropsychologic testing, electrical recording (electroencephalogram
and evoked potentials), and functional imaging (single photon emission computed
tomography, positron emission tomography, functional magnetic resonance imaging,
and magnetoencephalography) can accomplish this goal at a gross anatomical
level.
What is the optimal spatial resolution for evaluating physiological
dysfunction? Brain regions incorporate separate but interconnected neuronal
populations, which serve as the basic computational units of the brain. Neurons
within a same population have unique molecular phenotypes, which makes them
differentially vulnerable to pathological processes. The hippocampal formation
offers a good example of this point. The hippocampal formation is composed
of separate subregions—the entorhinal cortex, the dentate gyrus, the
CA subfields, and the subiculum. Neurons within each subregion have unique
biophysical properties, receptor profiles, and intracellular environments.
These differences can account for why pathological processes vary in their
proclivity at targeting different subregions (Figure 2).
Because hippocampal subregions are interconnected to form a circuit,
a lesion at any subregion may be equipotent in disrupting the global hippocampal
network. Thus, techniques that measure global hippocampal function—such
as neuropsychologic testing and most functional imaging modalities—cannot
resolve lesions to different subregions and have difficulty in honing a differential
diagnosis among multiple causes of memory decline. An example of this diagnostic
ambiguity is provided by the current clinical goal of detecting AD in its
earliest stages, when it primarily affects the hippocampal formation and presents
with isolated memory impairment. Measures of global hippocampal function will
be sensitive in detecting early AD. However, a global measurement will not
be specific in dissociating early AD from other age-related processes that
disrupt hippocampal function.
An optimum technique for evaluating the neuroanatomic characteristics
of memory decline, therefore, is sensitive to neuronal physiological processes
and has sufficient spatial resolution to differentially evaluate neuronal
populations.
Among the techniques that evaluate brain function in humans, functional
magnetic resonance imaging provides the best spatial resolution, and a few
studies have used this technique to evaluate select subregions. Nevertheless,
most functional magnetic resonance imaging protocols have difficulty resolving
all hippocampal subregions.65 Because neuronal
populations are usually a few millimeters in dimension, the ideal technique
for localizing memory decline will be one that can assess neuronal function
at the submillimeter range. This is the goal of the next generation of imaging
techniques.66
CONCLUSIONS
There is little question that memory declines with age. Although there
is continued debate as to whether memory decline is normal, epidemiological
data suggest that components of memory decline are not inevitable and, at
the very least, that memory decline impacts day-to-day function.
Numerous physiological processes change in an age-dependent manner,
changes that target brain regions involved in memory function. Organizing
these causes according to functional neuroanatomic characteristics provides
an effective classification scheme for age-related memory decline. Currently
available techniques that assess brain function can localize memory decline
at the gross anatomical level. Newer techniques are required to localize memory
decline to specific neuronal populations within a brain region.
Identifying the source of memory decline at the level of a neuronal
population will offer a more precise nosologic classification of memory decline
and will aid in developing effective treatments.
AUTHOR INFORMATION
Accepted for publication May 9, 2000.
This study was supported by federal grants AG08702 and AG00949 from
the National Institute on Aging.
I thank John C. M. Brust, MD, for his critical review of the manuscript.
From the Division of Neurobehavior of the Department of Neurology and
the Taub Institute for Research on Alzheimer's Disease and the Aging Brain,
Columbia University College of Physicians and Surgeons, New York, NY.
Reprints: Scott A. Small, MD, Columbia University College of Physicians
and Surgeons, 630 W 168 St, PH #19, New York, NY 10032.
REFERENCES
| |
1. Craik F, McDowd J. Age differences in recall and recognition. J Exp Psychol Learn Mem Cogn. 1987;13:474-479.
FULL TEXT
|
ISI
2. Petersen RC, Smith G, Kokmen E, Ivnik RJ, Tangalos EG. Memory function in normal aging. Neurology. 1992;42:396-401.
FREE FULL TEXT
3. Youngjohn JR, Crook III TH. Learning, forgetting, and retrieval of everyday material across the
adult life span. J Clin Exp Neuropsychol. 1993;15:447-460.
ISI
| PUBMED
4. Mitrushina M, Satz P. Changes in cognitive functioning associated with normal aging. Arch Clin Neuropsychol. 1991;6:49-60.
5. Hultsch DF, Hertzog C, Small BJ, McDonald-Miszczak L, Dixon RA. Short-term longitudinal change in cognitive performance in later life. Psychol Aging. 1992;7:571-584.
FULL TEXT
|
ISI
| PUBMED
6. Flicker C, Ferris SH, Reisberg B. Mild cognitive impairment in the elderly: predictors of dementia. Neurology. 1991;41:1006-1009.
FREE FULL TEXT
7. Loring DW, Papanicolaou AC. Memory assessment in neuropsychology: theoretical considerations and
practical utility. J Clin Exp Neuropsychol. 1987;9:340-358.
ISI
| PUBMED
8. Schaie KW. The course of adult intellectual development. Am Psychol. 1994;49:304-313.
FULL TEXT
| PUBMED
9. Zelinski EM, Burnight KP. Sixteen-year longitudinal and time lag changes in memory and cognition
in older adults. Psychol Aging. 1997;12:503-513.
FULL TEXT
|
ISI
| PUBMED
10. Small SA, Stern Y, Tang M, Mayeux R. Selective decline in memory function among healthy elderly. Neurology. 1999;52:1392-1396.
FREE FULL TEXT
11. Squire LR, Zola SM. Structure and function of declarative and nondeclarative memory systems. Proc Natl Acad Sci U S A. 1996;93:13515-13522.
FREE FULL TEXT
12. Zola-Morgan S, Squire LR. Neuroanatomy of memory. Annu Rev Neurosci. 1993;16:547-563.
ISI
| PUBMED
13. Rempel-Clower NL, Zola SM, Squire LR, Amaral DG. Three cases of enduring memory impairment after bilateral damage limited
to the hippocampal formation. J Neurosci. 1996;16:5233-5255.
FREE FULL TEXT
14. Ungerleider LG. Functional brain imaging studies of cortical mechanisms for memory. Science. 1995;270:769-775.
FREE FULL TEXT
15. Peters A, Sethares C, Moss MB. The effects of aging on layer 1 in area 46 of prefrontal cortex in
the rhesus monkey. Cereb Cortex. 1998;8:671-684.
FREE FULL TEXT
16. Esposito G, Kirkby BS, Van Horn JD, Ellmore TM, Berman KF. Context-dependent, neural system-specific neurophysiological concomitants
of ageing: mapping PET correlates during cognitive activation. Brain. 1999;122:963-979.
FREE FULL TEXT
17. Grady CL, McIntosh AR, Horwitz B, et al. Age-related reductions in human recognition memory due to impaired
encoding. Science. 1995;269:218-221.
FREE FULL TEXT
18. Small SA, Perera GM, De LaPaz R, Mayeux R, Stern Y. Differential regional dysfunction of the hippocampal formation among
elderly with memory decline and Alzheimer's disease. Ann Neurol. 1999;45:466-472.
FULL TEXT
|
ISI
| PUBMED
19. Kral VA. Neuro-psychiatric observations in an old peoples home: studies of memory
dysfunction in senescence. J Gerontol. 1958;13:169-176.
ISI
| PUBMED
20. Craik FIM, McDowd JM. Age differences in recall and recognition. J Exp Psychol Learn Mem Cogn. 1987;13:474-479.
21. Zelinski EM, Gilewski MJ, Schaie KW. Individual differences in cross-sectional and 3-year longitudinal memory
performance across the adult life span. Psychol Aging. 1993;8:176-186.
FULL TEXT
|
ISI
| PUBMED
22. Rubin EH, Storandt M, Miller JP, et al. A prospective study of cognitive function and onset of dementia in
cognitively healthy elders. Arch Neurol. 1998;55:395-401.
FREE FULL TEXT
23. Hanninen T, Koivisto K, Reinikainen KJ, et al. Prevalence of ageing-associated cognitive decline in an elderly population. Age Ageing. 1996;25:201-205.
FREE FULL TEXT
24. Rapp PR, Amaral DG. Individual differences in the cognitive and neurobiological consequences
of normal aging. Trends Neurosci. 1992;15:340-345.
FULL TEXT
|
ISI
| PUBMED
25. Diehl M, Willis SL, Schaie KW, et al. Everyday problem solving in older adults: observational assessment
and cognitive correlates. Psychol Aging. 1995;10:478-491.
FULL TEXT
|
ISI
| PUBMED
26. Hultsch DF, Hammer M, Small BJ. Age differences in cognitive performance in later life: relationships
to self-reported health and activity life style. J Gerontol. 1993;48:P1-P11.
27. Albert SA, Michaels K, Padilla M, et al. Functional significance of mild cognitive impairment in elderly patients
without a dementia diagnosis. Am J Geriatr Psychiatry. 1999;7:213-220.
FREE FULL TEXT
28. Baldini IM, Vita A, Mauri MC, et al. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997;21:925-935.
FULL TEXT
| PUBMED
29. Heishman SJ, Arasteh K, Stitzer ML. Comparative effects of alcohol and marijuana on mood, memory, and performance. Pharmacol Biochem Behav. 1997;58:93-101.
FULL TEXT
|
ISI
| PUBMED
30. Wahlin A, Hill RD, Winblad B, Backman L. Effects of serum vitamin B12 and folate status on episodic memory performance
in very old age: a population-based study. Psychol Aging. 1996;11:487-496.
FULL TEXT
|
ISI
| PUBMED
31. Braak H, Braak E. Evolution of the neuropathology of Alzheimer's disease. Acta Neurol Scand Suppl. 1996;165:3-12.
PUBMED
32. Masur DM, Sliwinski M, Lipton RB, Blau AD, Crystal HA. Neuropsychological prediction of dementia and the absence of dementia
in healthy elderly persons [see comments]. Neurology. 1994;44:1427-1432.
FREE FULL TEXT
33. Jacobs DM, Sano M, Dooneief G, Marder K, Bell KL, Stern Y. Neuropsychological detection and characterization of preclinical Alzheimer's
disease [comment]. Neurology. 1995;45:957-962.
ABSTRACT
34. Simic G, Kostovic I, Winblad B, Bogdanovic N. Volume and number of neurons of the human hippocampal formation in
normal aging and Alzheimer's disease. J Comp Neurol. 1997;379:482-494.
FULL TEXT
|
ISI
| PUBMED
35. West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing
and Alzheimer's disease. Lancet. 1994;344:769-772.
FULL TEXT
|
ISI
| PUBMED
36. Barnes CA. Normal aging: regionally specific changes in hippocampal synaptic transmission. Trends Neurosci. 1994;17:13-18.
FULL TEXT
|
ISI
| PUBMED
37. Lupien SJ, de Leon M, de Santi S, et al. Cortisol levels during human aging predict hippocampal atrophy and
memory deficits [see comments]. Nat Neurosci. 1998;1:69-73. [published correction appears in Nat Neurosci. 1998;1:329].
38. Woolley CS. Effects of estrogen in the CNS. Curr Opin Neurobiol. 1999;9:349-354.
FULL TEXT
|
ISI
| PUBMED
39. Haas HL, Felix D, Celio MR, Inagami T. Angiotensin II in the hippocampus: a histochemical and electrophysiological
study. Experientia. 1980;36:1394-1395.
FULL TEXT
|
