Memory after silent stroke
Hippocampus and infarcts both matter
S. Blum, MD, PhD
J.A. Luchsinger, MD,
J.J. Manly, PhD
N. Schupf, PhD
Y. Stern, PhD
T.R. Brown, PhD
C. DeCarli, MD
S.A. Small, MD
R. Mayeux, MD
A.M. Brickman, PhD
Objective: Memory decline commonly occurs among elderly individuals. This observation is often
attributed to early neurodegenerative changes in the hippocampus and related brain regions.
However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and
age-associated memory decline remains unclear.
Methods: We studied 658 elderly participants without dementia from a prospective, community-
based study on aging and dementia who received high-resolution structural MRI. Cortical and
subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated
following standard protocols. Summary scores reflecting performance on tasks of memory, lan-
guage, processing speed, and visuospatial function were derived from a comprehensive neuro-
psychological battery. We used multiple regression analyses to relate cortical and subcortical
infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains
of memory, language, processing speed, and visuospatial ability.
Results: Presence of brain infarcts was associated with a smaller hippocampus. Smaller hip-
pocampus volume was associated with poorer memory specifically. Brain infarcts were associ-
ated with poorer memory and cognitive performance in all other domains, which was independent
of hippocampus volume.
Conclusions: Both hippocampal volume and brain infarcts independently contribute to memory
performance in elderly individuals without dementia. Given that age-associated neurodegenera-
tive conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these
findings have clinical implications for prevention and for identification of pathogenic factors asso-
ciated with disease symptomatology. Neurology®2012;78:38–46
AD ? Alzheimer disease; FLAIR ? fluid-attenuated inversion recovery; FOV ? field of view; MCI ? mild cognitive impairment;
PCA ? posterior cerebral artery; SRT ? Selective Reminding Test; TE ? echo time; TI ? inversion time; TR ? repetition time.
Memory decline is frequent among the elderly and it is most often attributed to dysfunction
and atrophy of the hippocampus and related mesial temporal lobe structures.1–3Subclinical
brain infarcts are present in about one-third of older adults, and are associated with a 2-fold risk
of dementia and a steeper decline in age-associated cognitive function.4–6However, the effects
of subclinical brain infarcts on hippocampal integrity and age-related memory decline are not
Memory deficits have been described following brain infarcts. Cortical infarcts can result in
diverse deficits depending on size and location of lesion and can produce cognitive decline in
multiple domains, including perceptual speed and memory.7,8Subcortical infarcts can result
in executive dysfunction,9although strategic thalamic or limbic system infarcts can result in
memory loss.10,11Clinically, it can be difficult to differentiate between cognitive decline due to
From the Gertrude H. Sergievsky Center (S.B., J.J.M., N.S., Y.S., S.A.S., R.M., A.M.B.), Department of Neurology (S.B., J.J.M., Y.S., S.A.S., R.M.,
A.M.B.), Department of Medicine (J.A.L.), Taub Institute for Research on Alzheimer’s Disease and the Aging Brain (J.J.M., N.S., Y.S., S.A.S., R.M.,
A.M.B.), and Department of Psychiatry (N.S., Y.S., R.M.), College of Physicians and Surgeons, and Department of Epidemiology, Mailman School
of Public Health (N.S., R.M.), Columbia University, New York, NY; Department of Radiology and Radiological Science (T.R.B.), Medical
University of South Carolina, Charleston; and Department of Neurology (C.D.), University of California at Davis, Sacramento.
Study funding: Supported by the NIH (AG037212, AG007232, AG029949, AG034189) and the Charles and Ann Lee Saunders Fellowship.
Disclosure: Author disclosures are provided at the end of the article.
Correspondence & reprint
Copyright © 2012 by AAN Enterprises, Inc.
ischemic brain injury vs incipient Alzheimer
disease (AD). By the time significant memory
decline and dementia are present, pathologic
evaluations reveal mixed pathology in over
50% of cases.11Despite the heterogeneous
profile of deficits seen after clinical strokes,
silent infarcts are thought to affect primarily
the cognitive domains of processing speed and
executive function.5Although memory defi-
cits may be a downstream consequence of
poor learning efficiency secondary to the
speed/executive dysfunction, the memory def-
icits seen in elderly people with silent brain
infarcts are typically not attributed to infarcts
alone but rather to hippocampal atrophy,12
which is considered a marker of AD.13Mem-
ory function is dependent on the hippocam-
pus, but also on the complex network of its
input and output pathways required for ap-
propriate information processing.14The pres-
ence of infarcts likely has a negative effect on
information flow due to structural distur-
bance in cortex and white matter, and may
also negatively impact hippocampal func-
tion or structure due to the fact that the
hippocampus is very sensitive to ischemia.15,16
There are few studies examining the impact
of brain infarcts and hippocampal volume
simultaneously in relation to memory per-
formance. Thus, it remains unclear whether
infarcts and hippocampus atrophy are re-
lated, and contribute to memory decline
We hypothesized that brain infarcts and
diminished hippocampus volume are each
independently associated with poorer mem-
ory, reflecting the important contribution
of both the integrity of the hippocampus
proper as well as the more diffuse brain net-
works that are a part of hippocampal projec-
tion system. In addition, we hypothesized
that brain infarcts and hippocampus vol-
ume are associated with a unique profile of
METHODS Participants. Participants came from a
community-based prospective cohort study of aging and demen-
tia in adults age 65 and older residing in northern Manhattan
(Washington Heights-Inwood Columbia Aging Project).17Be-
ginning in 2004, participants who did not have dementia at their
previous follow-up visit were invited to participate in a neuroim-
aging study.18Of these 1,841 participants, 769 (41.8%) under-
went MRI. Frequencies and reasons why participants did not
undergo imaging were reported elsewhere.18
Standard protocol approvals and patient consents. All
procedures were approved by a local Institutional Review Board.
Written informed consent was obtained from all participants.
Neuropsychological assessment. Participants were admin-
istered a neuropsychological battery comprising 15 standardized
tests.19Composite scores were developed using factor analysis,
which identified factors of memory, language, processing speed,
and visuospatial ability.20,21Based on factor loadings, summary
variables reflecting performances in specific domains were de-
rived as composite z scores: 1) memory: Selective Reminding
Test (SRT)22: total recall, delayed recall, and delayed recogni-
tion; 2) language: Boston Naming Test25, Letter Fluency Test;
Category Fluency test; Wechsler Adult Intelligence Scale–R
Similarities subtest26; and Boston Diagnostic Aphasia Examina-
tion Repetition and Comprehension subtests25; 3) executive
functioning/processing speed: Color Trails 1 and Color Trails
227; 4) visuospatial ability: Benton Visual Retention Test recog-
nition and matching variables,28Rosen Drawing Test29, and
Identities and Oddities subtest.26In secondary analyses, we con-
sidered specific aspects of the SRT, including learning, long-
term recall (i.e., number of words recalled on consecutive trials
without selective reminding), delayed free recall, and delayed
MRI. Image acquisition was performed on a 1.5 Tesla scanner
(Philips Intera) at Columbia University. The following images
were acquired axially: T2-weighted fluid-attenuated inversion re-
covery (FLAIR) images (repetition time [TR]: 11,000 msec;
echo time [TE]: 144.0 msec; inversion time [TI]: 2,800 msec;
field of view [FOV]: 25 cm; 256 ? 192 pixel matrix, 3 mm
section thickness); proton density/T2-weighted double-echo
(TR: 2,675 msec; TE: 12/92 msec; FOV: 220 cm; 256 ? 192
pixel matrix, 4 mm section thickness); T1-weighted (TR: 20
msec; TE: 2.1 msec; FOV: 240 cm; 256 ? 160 pixel matrix, 1.3
mm section thickness).
Relative brain volume. Images were transferred to the Imag-
ing of Dementia and Aging Laboratory at the University of Cal-
ifornia, Davis, for morphometric analysis. Total brain and
cranial volumes were derived manually on FLAIR images as pre-
viously described.18,23Relative brain volume was the ratio of total
brain volume to intracranial volume.
Hippocampal volume. The T1-weighted images were reori-
ented in the coronal plane perpendicular to the long axis of the
left hippocampus.18Borders of the hippocampus were traced
manually with simultaneous monitoring in the sagittal and axial
views.18Intrarater reliability in the right and left hippocampi was
good (intraclass correlation coefficient 0.98 and 0.96). We ex-
amined total relative hippocampal volume (i.e., total hippocam-
Brain infarct assessment on MRI. Lesions 3 mm or larger
qualified for consideration as brain infarcts. Signal void seen
on the T2-weighted images was interpreted to indicate a ves-
sel. Other necessary characteristics included CSF density on
the T1-weighted image and separation from the circle of Wil-
lis vessels and perivascular spaces. Previously published reli-
ability estimates among raters have been good.24Cortical
infarcts were defined as those in the frontal, parietal, tempo-
ral, and occipital cortices, and those in the extreme capsule (as
defined in our sample, this region falls adjacent to or overlap-
ping with insular cortex). Subcortical infarcts were defined as
Neurology 78January 3, 2012
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infarcts and hippocampal atrophy in subcortical ischaemic
vascular dementia. Neurol Sci 2004;25:192–197.
Fein G, Di Sclafani V, Tanabe J, et al. Hippocampal and
cortical atrophy predict dementia in subcortical ischemic
vascular disease. Neurology 2000;55:1626–1635.
Jellinger KA. The pathology of ischemic-vascular demen-
tia: an update. J Neurol Sci 2002;203–204:153–157.
Snowdon DA, Greiner LH, Mortimer JA, Riley KP,
Greiner PA, Markesbery WR. Brain infarction and the
clinical expression of Alzheimer disease: The Nun Study.
Jagust WJ, Zheng L, Harvey DJ, et al. Neuropathological
basis of magnetic resonance images in aging and dementia.
Ann Neurol 2008;63:72–80.
35. Chui HC, Zarow C, Mack WJ, et al. Cognitive impact of
subcortical vascular and Alzheimer’s disease pathology.
Ann Neurol 2006;60:677–687.
Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S,
Mayeux R. Aggregation of vascular risk factors and risk
of incident Alzheimer disease. Neurology 2005;65:545–
Honig LS, Tang MX, Albert S, et al. Stroke and the risk of
Alzheimer disease. Arch Neurol 2003;60:1707–1712.
Desikan RS, Sabuncu MR, Schmansky NJ, et al. Selective
disruption of the cerebral neocortex in Alzheimer’s disease.
PLoS One 2010;5:e12853.
Reitz C, Schupf N, Luchsinger JA, et al. Validity of self-
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Editor’s Note to Authors and Readers: Levels of Evidence coming to Neurology®
Effective January 15, 2009, authors submitting Articles or Clinical/Scientific Notes to Neurology®that report on clinical
therapeutic studies must state the study type, the primary research question(s), and the classification of level of evidence assigned
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articles and the editorial on the use of classification of levels of evidence published in Neurology.1-3
1. French J, Gronseth G. Lost in a jungle of evidence: we need a compass. Neurology 2008;71:1634–1638.
2. Gronseth G, French J. Practice parameters and technology assessments: what they are, what they are not, and why you should care. Neurology
3. Gross RA, Johnston KC. Levels of evidence: taking Neurology®to the next level. Neurology 2009;72:8–10.
Neurology 78 January 3, 2012