 |
|
Clinical and Neuropathological Characteristics of Hippocampal Sclerosis
A Community-Based Study
James B. Leverenz, MD;
Christina M. Agustin, BS;
Debby Tsuang, MD;
Elaine R. Peskind, MD;
Steven D. Edland, PhD;
David Nochlin, MD;
Lillian DiGiacomo, BS;
James D. Bowen, MD;
Wayne C. McCormick, MD;
Linda Teri, PhD;
Murray A. Raskind, MD;
Walter A. Kukull, PhD;
Eric B. Larson, MD, MPH
Arch Neurol. 2002;59:1099-1106.
ABSTRACT
| |
Background Hippocampal sclerosis (HS) is a neuropathologic finding characterized
by neuronal loss and gliosis in the CA-1 and subiculum of the hippocampus.
Previous studies of HS have shown that this is a common postmortem finding
in elderly subjects with dementia. However, these studies were from selected
samples and therefore are not necessarily representative of patients seen
in the general medical community.
Objectives To examine the clinical and pathologic characteristics of HS in a community-based
case series of dementia and to compare these characteristics with those observed
in subjects with Alzheimer disease (AD) from the same study sample.
Methods One hundred thirty-four autopsy cases were available from a community-based
registry of dementia. Sixteen cases (12%) had a postmortem diagnosis of HS.
Thirty-two comparison control cases with a neuropathologic diagnosis of AD
were selected from the same files. Each case of HS was reviewed for HS neuropathologic
features, including severity, distribution, and additional pathologic processes.
Blinded review of clinical characteristics for the HS and control groups was
performed to assess risk factors.
Results There was a wide range of severity and distribution of HS lesions between
cases and substantial variability in lesion severity and age within individual
cases. Serial neuropsychologic and behavioral assessments revealed similar
clinical features and rates of dementia progression between HS and AD groups.
Of all neuropsychologic tests performed at enrollment, only enhanced performance
on Trails A differentiated the HS from the AD group (64 seconds, 0 errors
vs 114 seconds, 0.6 errors; P .05). The number
of AD cases with at least 1 apolipoprotein  4 allele was significantly
greater than the HS cases (61% vs 31%;  2 = 3.81, P.05). Although medical record review indicated higher frequencies
of clinical stroke and neuroradiologic white matter abnormalities in the HS
group, risk factors for vascular disease and neuropathologic evidence of cerebrovascular
disease did not differ between the groups.
Conclusions Our results suggest that HS is a frequent pathologic finding in community-based
dementia. Individuals with HS have similar initial symptoms and rates of dementia
progression to those with AD and therefore are frequently misclassified as
having AD. Our clinical and pathologic findings suggest that HS has characteristics
of a progressive disorder although the underlying cause remains elusive.
INTRODUCTION
DEMENTING DISORDERS are a major source of disability in elderly persons
and are of increasing public health concern as the number of elderly persons
in our society increases. While Alzheimer disease (AD) remains the most common
cause of dementia in elderly persons, other disorders, such as Lewy body dementias,
may be causal as well. Recently, several studies have suggested that hippocampal
sclerosis (HS), a pathologically diagnosed entity in which there is severe
neuronal loss and gliosis in the CA-1 and subiculum region of the hippocampus,
may also be an important cause of non-AD dementias.1-6
While some of these studies have found that up to 17% of individuals with
dementia have HS, others have suggested that HS may be a rare cause of dementia.
The clinical signs and symptoms of HS are generally quite similar to
those seen in AD, with recent memory loss being prominent. There is evidence
that, similar to AD, dementia in HS may progress over time.1-4,7-8
However, behavioral disturbances and subtle neuropsychologic deficits may
differentiate these patients from those with AD.2, 7-11
Pathologically, HS is generally defined by the severe loss of neurons and
concomitant gliosis in the CA-1 and subiculum region, with relative sparing
of other hippocampal fields. However, there is some suggestion that other
hippocampal fields, medial temporal structures, and even cortical and subcortical
structures may also be involved.1-2,4, 9-11
Previous published studies of HS have been performed in selected research
samples, such as cases from Alzheimer disease research centers. There is a
possible selection bias in such samples that could be important in the interpretation
of demographic and clinical characteristics.12-13
We previously examined a community-based case series of autopsies of incident
cases of dementia.14 From this investigation,
16 cases had a pathologic diagnosis of HS. Our current study compares the
demographic, genetic, and clinical characteristics of these cases with a group
of AD cases from that same study sample. We also examined in detail the distribution
and severity of the pathologic findings in HS within the medial temporal lobe.
By examining cases of HS selected from this community-based case series, we
hope to provide a more accurate picture of the clinical and neuropathologic
characteristics of HS and begin to identify potential risk factors for this
disorder.
SUBJECTS AND METHODS
SUBJECTS
The University of Washington–Group Health Cooperative Alzheimer's
Disease Patient Registry (ADPR) is a population-based registry of incident
dementia cases in a Puget Sound–area health maintenance organization
with 350 000 members in Washington State. The ADPR case–finding
strategy has been described in detail elsewhere.15-17
Patients with new symptoms of possible dementia (based on surveillance of
computed tomography logs, computerized hospital admission and discharge records,
clinic registration lists, and primary care physician referrals) underwent
a complete standardized diagnostic workup, including (1) medical history;
(2) physical, neurologic, and neuropsychologic examinations; (3) laboratory
testing; and (4) brain computed tomographic imaging. All subjects gave informed
consent according to guidelines approved by the human subjects review committee
at the University of Washington (Seattle) and Group Health Cooperative. When
the workup was completed, the physicians and psychologists reviewed the results
and arrived at a consensus diagnosis for each case based on criteria of the
National Institute of Neurologic and Communicative Disorders and Stroke–Alzheimer
Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.18-19 Patients in the
ADPR received annual follow-up with interim history, neuropsychologic testing,
and additional physical and neurologic examinations if indicated by a change
in clinical symptoms.
A total of 1028 patients were enrolled in the ADPR from 1987 to 1996.
Of these, 970 individuals came to the evaluation, with 77% meeting NINCDS-ADRDA
diagnostic criteria for any dementia and 58% with probable or possible AD.
From this group, 425 deaths occurred and autopsies were performed on 134 cases.
A recent comparison of autopsied and nonautopsied cases from this sample found
similar age and sex distribution between the 2 groups as well as similar dementia
severity at initial evaluation and at last evaluation. However, there was
a higher frequency of clinically diagnosed vascular disease and minorities
in the nonautopsied vs autopsied groups (19% vs 8% diagnosed vascular dementia
and 13% vs 5% minorities, respectively; P.05).20
NEUROPATHOLOGIC EVALUATION
Neuropathologic evaluation was performed at the University of Washington
Medical Center by neuropathologists (J.B.L., D.N.) from the department of
pathology and the Alzheimer's Disease Research Center. Neuropathologic examinations
focused on the cingulate gyrus, superior and middle frontal gyri, medial orbital
cortex, superior, middle, and inferior temporal gyri, inferior parietal lobule,
medial occipital cortex, hippocampus, amygdala, entorhinal cortex, parahippocampal
gyrus, hypothalamus, mamillary bodies, thalamus, midbrain, pons, medulla,
and cerebellum. When possible, multiple anterior to posterior blocks of the
medial temporal lobe were taken from both the left and right hemispheres.
Standard tissue stain consisted of hematoxylin-eosin (H&E), thioflavin
S, and the modified Bielschowsky silver methods, on 8-µm-thick paraffin-embedded
sections. Neuropathologic results from this sample have been previously described.14
Individuals with HS were identified from a review of all 134 ADPR cases
that were autopsied. Hematoxylin-eosin–stained sections of the available
hippocampal blocks were examined for evidence of HS (severe neuronal loss
with gliosis in the CA-1 of the hippocampus and/or subiculum with relative
sparing of the CA-2/3 region).2 All hippocampal
sections from both hemispheres were assessed semiquantitatively for severity
of pathologic findings (absent, mild, moderate, or severe; 0 to +++). The
distribution of the pathologic evidence was defined, for each hemisphere,
as "diffuse" if present at all hippocampal levels or "patchy" if restricted
to less than all levels. Subicular involvement was also noted. The cases were
staged for neurofibrillary tangle and senile plaque pathologic changes.21 The presence of neuropathologic AD, using the Consortium
to Establish a Registry for Alzheimer Disease (CERAD) criteria, was noted
for all HS cases (criteria were chosen for the neuropathologic AD diagnosis
on study inception).22 Braak stages were established
in the HS cases after review of sections stained by the modified Bielschowsky
method. Although severe pathologic findings in AD can be associated with CA-1
neuronal loss, only 1 case (9) was at a Braak stage that might have been associated
with severe CA-1 neuronal loss.21 In this and
the other HS cases with neuropathologic diagnoses of AD, HS was associated
with a CA-1 neuronal loss out of proportion to the severity of the AD pathologic
change, significant subicular neuronal loss, and a virtual absence of either
intraneuronal or extracellular ("ghost") neurofibrillary tangles within the
affected CA-1 regions.
For each HS case, we selected 2 pathologically confirmed AD cases from
the same ADPR autopsy sample based on a comparable date of autopsy. Age and
sex were not matched so that relationships of these variables to HS could
be explored.
MEDICAL RECORD REVIEW
Two investigators (D.T. and E.P.) examined the medical records of all
48 cases (16 HS and 32 AD comparison cases). These investigators were blinded
to the neuropathologic diagnoses. Clinical information was classified into
the following categories: neurologic (head trauma, seizures, parkinsonism,
falls), cerebrovascular (cerebrovascular accident by clinical history, cerebrovascular
and/or white matter changes by brain imaging [based on official radiology
report]), cardiovascular (myocardial infarction, congestive heart failure,
cardiomegaly by chest x-ray, hypertension, arrhythmias, syncope, high cholesterol
or other lipids, smoking), endocrine (hypothyroidism, diabetes), pulmonary
(chronic obstructive pulmonary disease, sleep apnea) and miscellaneous (height,
weight, alcohol abuse). Behavioral symptoms were also assessed based on the
major categories of the Neuropsychiatric Inventory (delusions, hallucinations,
agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference,
disinhibition, irritability/lability, aberrant motor behavior).23
In cases where there was disagreement, consensus was established by discussion
between the 2 raters.
NEUROPSYCHOLOGIC TESTING
Neuropsychologic data from the initial study visit for 11 pure HS cases
(without concomitant CERAD-based neuropathologic AD) and their matched AD
cases were examined. These data included baseline Folstein Mini-Mental State
Examination (MMSE),24 Trails A Time and Errors
(there was insufficient Trails B data points for analysis),25
Wechsler Adult Intelligence Scale–Revised Block Design,26
Wechsler Memory Scale (Logical Memory Immediate and Delayed),27
and the Conceptualization and Construction subscales of the Coblentz Dementia
Rating Scale.28 Previous studies in HS had
suggested that these tests might differentiate HS from other dementias.2, 8, 11 First and last MMSE
scores were also used to assess the rate of cognitive decline.
APOE GENOTYPING
The APOE genotype was obtained from either blood samples or paraffin-embedded
tissue. For blood, the genotyping was performed using the dot blot method29 and replicated using a restriction enzyme digest
method.30 The 2 methods yielded the same APOE
genotype on all cases. In paraffin-embedded tissue, DNA was extracted, amplified
by the polymerase chain reaction, and genotyped using a restriction enzyme
digest method.30-31 The reliability
of the paraffin method has been previously demonstrated.32
The APOE genotype was available for 15 HS and 31 AD cases.
STATISTICAL ANALYSIS
The 2-sample t test was used to compare continuous
variables (ie, age, duration of illness). When distribution assumptions of
the 2-sample t test were not met, distributions were
compared by the rank sum test. The Cochran-Mantel-Haenszel 2
statistic for stratified data was used to compare categorical variables (ie,
presence of systemic vascular disease, stroke history, behavioral disturbances).
The rate of progression of cognitive decline was determined using the first
and last MMSE scores, adjusting for the number of months elapsed between the
2 examinations.
RESULTS
DEMOGRAPHICS
Patient characteristics are presented in Table 1. Mean ± SD age of dementia onset did not significantly
differ between the HS and AD groups (79.8 ± 1.4 years vs 77.3 ±
1.4 years; t = 1.10, P =
.28). Mean ± SD age at death (84.8 ± 1.2 years vs 83.2 ±
1.5 years; t = 0.74, P =
.46) and duration of illness were also similar in the HS and comparison AD
groups (5.1 ± 0.7 vs 5.9 ± 0.5 years; t
= 0.92, P = .36). There was a trend for a preponderance
of men in the HS group (10 men [63%] and 6 women vs 11 men [34%] and 21 women; 2 = 3.43, P = .06). Height, weight, and height-weight
ratios were the same for both groups (data not shown).
|
|
|
|
Table 1. Demographic and Clinical Characteristics of Subjects With
Hippocampal Sclerosis and Alzheimer Disease*
|
|
|
CLINICAL CHARACTERISTICS
There was an increase in clinical history of stroke in the HS cases
(9 [56%] of 16 vs 8 [25%] of 32; 2 = 4.55, P.05). There also was a trend toward greater frequency of white
matter changes on computed tomographic scans in the HS group (4 [25%] of 16
vs 2 [6%] of 32; 2 = 3.43, P = .06).
In contrast, the HS group had a lower frequency of electrocardiogram abnormalities
(2 [13%] of 16 vs 14 [44%] of 32; 2 = 4.69, P.05) and diabetes mellitus (0 of 16 vs 7 [22%] of 32; 2 = 4.10, P.05). The frequencies of the
remainder of the clinical characteristics outlined in the "Methods" section
did not differ between HS and comparison AD groups.
Behavioral disturbances were common in both the HS and AD groups. The
frequency of the subtypes of behavior disturbances were remarkably similar
except for apathy/indifference, which was more frequent in the AD group but
did not reach statistical significance (2 = 2.59, P = .11).
NEUROPSYCHOLOGIC CHARACTERISTICS
Enrollment visit MMSE scores were available for all HS and comparison
AD cases and a follow-up MMSE was available for 13 HS and 18 AD cases. Mini-Mental
State Examination scores did not differ between subjects with HS and AD for
either the initial visit (mean ± SD, 20.1 ± 1.6 vs 19.0 ±
1.3; t = 0.50, P = .62)
or the last visit (10.4 ± 2.5 vs 11.6 ± 2.1; t = 0.36, P = .72). The rate of change in
MMSE score did not differ significantly between HS and AD groups (mean ±
SD, -0.39 ± 0.6 vs -0.30 ± 0.8 points per month; t = 0.78, P = .44).
At enrollment, the AD comparison group performed worse on Trails A time
to completion (mean ± SD, 114 ± 19 seconds vs 64 ± 11
seconds; t = 2.30, P = .05)
and number of errors (0.6 ± 0.2 errors vs 0 errors; Wilcoxon rank sum P = .09) than the HS group. There were insufficient data
points to compare performances on Trails B. The performances on Boston Naming,
Wechsler Adult Intelligence Scale–Revised Block Design, Logical Memory
(Immediate and Delayed), Coblentz Construction, and Conceptualization were
not significantly different between the HS and comparison AD groups.
GENETICS
The frequency of APOE 4–positive cases was significantly
greater in the AD comparison group (19 [61%] of 31) than in the HS group (5
[31%] of 16; 2 = 3.81, P.05).
The 5 cases with concomitant neuropathologic AD and HS were more frequently
APOE 4 positive than the cases with HS alone (3 [60%] of 5 vs 2 [18%]
of 11). One HS case was homozygous for APOE 4. Interestingly, this patient
did not manifest significant neuropathologic changes of AD (case 14, Braak
stage II A).
NEUROPATHOLOGIC CHARACTERISTICS
A detailed neuropathologic characterization of the 16 cases of HS is
presented in Table 2. Thirteen
of 16 HS cases had hippocampal sections available from both the right and
left hemispheres, and in all cases, at least 2 anterior to posterior levels
of the hippocampus were available. Hippocampal sclerosis was frequently more
severe on 1 side, and within the same side it was often patchy (Table 1 and Figure 1).
This included marked differences in severity of gliosis between affected and
unaffected regions (Figure 1B and
D). Also notable was evidence of acute and chronic gliosis within the HS lesions
of the same patient (Figure 2).
Subicular neuronal loss and gliosis usually coexisted with HS pathologic change
in CA-1, although there were 3 cases (cases 2, 3, and 12) with CA-1 involvement
without subicular changes, at the same level, and 1 case (case 14) with subicular
neuronal loss and gliosis without CA-1 change (although there was CA-1 involvement
in the contralateral hippocampus). In 3 cases (cases 1, 4, and 15), neuronal
loss and gliosis extended into the parahippocampal and inferior temporal gyri.
This latter change was always associated with severe neuronal loss in the
CA-1 and subiculum. Occasionally, there also appeared to be an extension of
neuronal loss into the CA-2 regions (Figure
1A). Using CERAD criteria for probable or definite AD,22
significant pathologic changes of AD was observed in 5 HS cases. One of these
cases (case 2, Braak stage II-B) did not fulfill the more recently described
Reagan criteria33 because of insufficient neurofibrillary
tangle pathologic findings. Despite the clinical evidence on medical record
review of increased stroke in the HS cases, there was no difference in the
frequency of pathologic stroke between the HS and AD cases.
|
|
|
|
Table 2. Neuropathological Features of Hippocampal Sclerosis Cases*
|
|
|
|
|
|
|
Figure 1. Left (A) and right (B) mid-hippocampal
sections from case 5 demonstrating substantial loss of neurons and contraction
of the pyramidal layer in CA-1 of the right hippocampus. Arrows indicate the
transition of CA-1/CA-2 (thionin). Note the preservation of CA-1 neurons in
the left hippocampus. Glial fibrillary acid protein immunostaining demonstrates
significant gliosis in CA-1 of the right (D), but not the left (C), hippocampus.
|
|
|
|
|
|
|
Figure 2. Gliosis within individual cases
demonstrated acutely reactive gemistocytic glia in some regions of the CA-1
(A, arrows) and chronic gliosis within other regions of CA-1 (B) in the same
hippocampal sclerosis case (case 7).
|
|
|
PURE HS AND HS WITH AND WITHOUT SIGNIFICANT PATHOLOGIC FINDINGS IN
AD
Frequency of HS in our study sample was 16 (12%) of 134 using the criteria
outlined in the "Subjects and Methods" section. We found that only 3 (2%)
of 134 of our sample had HS, using the significantly more restrictive criteria
for pure HS (severe neuronal loss in CA-1, Braak stage II or lower, and/or
other neuropathologic explanation for dementia1).
If HS cases diagnosed neuropathologically as having AD (based on CERAD criteria22) were eliminated, HS frequency was 11 (8%) of 134.
Analysis of demographic, clinical, neuropsychologic, and genetic data after
elimination of these 5 HS cases with concomitant AD did not reveal any additional
significant differences between our HS and AD comparison groups.
COMMENT
This is the first study, to our knowledge, to describe HS in a community-based
case series of dementia. Our sample provides a more representative picture
of the clinical, pathologic, and genetic characteristics of HS as it exists
in the general medical community. Consistent with studies in more selected
samples,3-6,34
we found that more than 10% of individuals with dementia in the study population
had HS. Using the more restrictive criteria for pure HS reported by Ala et
al,1 we found a much lower frequency (2%),
although modestly higher than that reported by 2 other groups1, 6
using more selected samples (0.4% and 0.5%, respectively).
Demographic and clinical features of our HS group, including age of
onset, age at death, and duration of illness, were very similar to the AD
comparison group. Similar to Dickson et al,4
our HS cases were in their 80s on average (mean age at death, 84.8 years),
although, as emphasized by others,1-2
this disorder can occur in younger individuals (the youngest age at onset
in our sample was 66 years).
Previous reports of an association between antemortem hypoxia or hypotension
and isolated neuronal loss in the hippocampal CA-1 region have suggested a
pathophysiologic connection between HS and vascular disease.35-36
In more recent case series, it has been unclear if there is an increased frequency
of vascular risk factors in HS.1-5
Although a clinical history of stroke and the presence of white matter changes
on neuroimaging were increased in our HS group, neuropathologic evidence for
stroke was not more abundant in the HS cases. In addition, we did not find
an increase in history of cardiovascular or pulmonary disease, or vascular
risk factors, such as diabetes mellitus or smoking, in HS cases. The link
between vascular disease and HS remains uncertain.
We are aware that epilepsy is a risk factor for HS in individuals with
recurrent seizures.37-38 In addition,
although seizure-associated HS is not clinically characterized by a progressive
AD-like dementia, the pathologic picture could look quite similar (at least
within the hippocampal formation). Therefore, we specifically addressed seizure
history in our HS and comparison cases, and found that there was no evidence
of an increased frequency of seizure history in our HS group.
The severity of dementia was very similar for the HS and AD comparison
groups. Consistent with Corey-Bloom et al2
and Crystal et al,3 we found that the neuropsychologic
profiles and rates of cognitive decline did not substantially differ between
HS and AD. In contrast, Zabar et al8 reported
a slower rate of cognitive decline in patients with HS. However, their HS
group had higher levels of cognitive functioning at the initial visit compared
with their AD comparison group, which may have accounted for these differences.39 As expected, the memory dysfunction in HS was very
similar to that observed in our AD cases and is presumably related to the
medial temporal lobe involvement. The frequency of behavioral disturbance
and language dysfunction was again similar in the HS and AD comparison groups,
supporting the hypothesis that the pathologic findings in HS may be more widespread
than the medial temporal lobe.1-3
We found that the only neuropsychologic test result that distinguished HS
from AD was a significantly better performance on Trails A on the initial
visit. Corey-Bloom et al2 found a similar trend
for enhanced performance on Trails A in HS patients. Impairment on Trails
A is a sensitive indicator of early AD.40 It
is possible that in the early stages of HS, the pathologic evidence is relatively
restricted to the temporal lobes, while in AD, earlier frontal lobe involvement
is associated with poor performance on Trails A. Hippocampal sclerosis should
be considered in the differential diagnosis of patients with a mild to moderate
AD-like dementia and good Trails A performance.
Demographic features, putative risk factors (except for APOE genotype),
and clinical symptoms, including rate of dementia progression of the HS group,
were very similar to those in the AD comparison group. Because of these similarities,
it is not surprising that dementia secondary to HS has frequently been clinically
misclassified as AD antemortem. In our sample of HS, 8 of 11 pure HS cases
were clinically diagnosed as probable AD, and in at least 2 other studies,
most HS cases had been clinically diagnosed as possible or probable AD.1-2
The association between the APOE 4 allele and AD is well established.41-42 In our study groups, there were more
APOE–4 positive cases in the AD comparison group than in the HS
group. Even within the HS group, those cases without concomitant AD had a
very low frequency of the APOE 4 allele (18%). Interestingly, it is
worth noting that 1 HS case with very mild pathologic consequences of AD (case
14, Braak stage II A) was homozygous for the APOE 4 allele. Thus, for
the individual patient, APOE genotyping results must be interpreted with caution.
The neuropathologic features of HS observed in our sample, neuronal
loss and gliosis in the CA-1 and subiculum with occasional extension into
the parahippocampal and inferior temporal gyri, were generally consistent
with other reports.2, 4-5,7
However, we examined both the left and right hippocampi and multiple rostral
to caudal sections for each hippocampal side in most of our cases, which revealed
more patchy pathologic change of HS than previously reported. Surprisingly,
there was evidence of unilateral involvement in 4 cases. In addition, there
was evidence of differentially aged lesions within the same case. This latter
finding is consistent with a progressive neurodegenerative process. In the
most severely affected cases, the neuronal loss and gliosis extended into
the parahippocampal and temporal cortical regions. Corey-Bloom et al2 found evidence of pathologic change in the frontal
cortex and have suggested that extension of the HS pathologic process beyond
the medial temporal lobe may account for the development of cortical dysfunction
on neuropsychologic testing. These findings in HS suggest a progressive process
with increasing involvement of medial temporal lobe structures and extension
to other cortical regions with the development of other broader clinical symptoms.
The pathogenesis of HS remains unclear. One hypothesis suggests that
HS is related to vascular disease. However, the inconsistent association of
vascular risk factors with HS suggests that alternative processes should be
considered. The progressive clinical and pathologic picture observed in our
HS cases suggests a possible neurodegenerative process. Two recent studies
have suggested that HS has similarities to frontotemporal dementia (FTD),1, 3 in particular, the subtype originally
described as "dementia lacking distinctive histopathology."43
However, as pointed out by other authors, the late age of onset for most HS
cases would argue against this latter hypothesis.
Since HS is rarely observed in elderly persons who do not have dementia,3 our results suggest that HS is commonly associated
with dementia in the general medical community. It is a difficult group of
patients to study clinically because of its similarities to AD in presentation
and progression. Subtle neuropsychologic differences, such as performance
on Trails A, may be important in identifying patients with this disorder.
The etiology of and risk factors for this disorder remain speculative, although
both vascular and neurodegenerative processes are hypothesized to play a role.
Pathologic study of HS should include additional examination of regions outside
of the medial temporal lobe to better understand the full extent of the pathologic
process. Further pathophysiologic investigation of this important cause of
dementia in elderly persons is needed.
AUTHOR INFORMATION
Accepted for publication March 25, 2002.
This study was supported by grants UO1AG06781, RO1AG10845, AG05136,
and AG06781 from the National Institute on Aging, Washington, DC, and the
Department of Veterans Affairs, Washington, DC.
Author contributions: Study concept and design (Drs Leverenz, Peskind, Teri, Raskind, Kukull, and Larson);
acquisition of data (Dr Leverenz, Tsuang, Peskind, Edland,
Nochlin, Bowen, Teri, and Larson, and Mss Agustin and DiGiacomo); analysis
and interpretation of data (Drs Leverenz, Tsuang, Peskind,
Edland, McCormick, and Kukull, and Ms DiGiacomo); drafting of the manuscript (Drs Leverenz and Dr Teri, and Mss Agustin and DiGiacomo);
critical revision of the manuscript for important intellectual content (Drs Leverenz, Tsuang, Peskind, Edland, Nochlin, Bowen, McCormick,
Teri, Raskind, Kukull, and Larson); statistical expertise (Drs Edland and McCormick); obtained funding (Drs
Peskind, Teri, Raskind, and Larson); administrative, technical, and
material support (Drs Leverenz, Peskind, Bowen, Raskind,
Kukull, and Larson, and Ms DiGiacomo); study supervision (Drs Leverenz, Teri, and Larson).
We thank Marla Gearing, PhD, and Suzanne Mirra, MD, for their assistance
in genotyping paraffin embedded tissue. We also thank Lynne Greenup, Christiana
Ulness and Randy Small for their technical assistance, Molly Wamble for her
graphic assistance and Susan Martin for secretarial assistance.
Corresponding author and reprints: James B. Leverenz, MD, Veterans
Affairs Puget Sound Health Care System, 1660 S Columbian Way, 116 MIRECC,
Seattle, WA 98108 (e-mail: leverenz{at}u.washington.edu).
From the Department of Veterans Affairs, Northwest Network Mental Illness
Research, Education, and Clinical Center, Seattle, Wash (Drs Leverenz, Tsuang,
Peskind, and Raskind); Departments of Epidemiology (Dr Kukull), Medicine (Drs
McCormick and Larson), Neurology (Drs Leverenz and Bowen), Nursing (Dr Teri),
Pathology, Division of Neuropathology (Dr Nochlin), and Psychiatry and Behavioral
Sciences (Drs Leverenz, Tsuang, Peskind, and Raskind, and Mss Agustin and
DiGiacomo), University of Washington, Seattle; and Mayo Clinic, Rochester,
Minn (Dr Edland).
REFERENCES
| |
1. Ala TA, Beh GO, Frey II WH. Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer's
disease. Neurology. 2000;54:843-848.
FREE FULL TEXT
2. Corey-Bloom J, Sabbagh MN, Bondi MW, et al. Hippocampal sclerosis contributes to dementia in the elderly. Neurology. 1997;48:154-160.
FREE FULL TEXT
3. Crystal HA, Dickson D, Davies P, Masur D, Grober E, Lipton RB. The relative frequency of "dementia of unknown etiology" increases
with age and is nearly 50% in nonagenarians. Arch Neurol. 2000;57:713-719.
FREE FULL TEXT
4. Dickson DW, Davies P, Bevona C, et al. Hippocampal sclerosis: a common pathological feature of dementia in
very old ( 80 years of age) humans. Acta Neuropathol. 1994;88:212-221.
PUBMED
5. Jellinger KA. Hippocampal sclerosis: a common pathological feature of dementia in
very old humans. Acta Neuropathol. 1994;88:599.
PUBMED
6. Jellinger K. Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer's
disease [letter]. Neurology. 2000;55:739-740.
7. Hedreen JC, Barr A, Devanny M, Price DL, Folstein MF. Hippocampal sclerosis (HS): a progressive dementia. J Neuropath Exp Neurol. 1993;52:291.
8. Zabar Y, Carson KA, Troncoso JC, Kawas CH. Dementia due to hippocampal sclerosis: clinical features and comparison
to Alzheimer's disease. Neurology. 1998;50:A59-A60.
9. Clark AW, White CLI, Manz HJ, et al. Primary degenerative dementia without Alzheimer pathology. Can J Neurol Sci. 1986;13:462-470.
ISI
| PUBMED
10. Gearing M, Mirra SS, Hedreen JC, Sumi SM, Hansen LA, Heyman A. The consortium to establish a registry for Alzheimer's disease (CERAD),
part X: neuropathology confirmation of the clinical diagnosis of Alzheimer's
disease. Neurology. 1995;45:461-466.
FREE FULL TEXT
11. Rasmusson DX, Brandt J, Steele C, Hedreen JC, Troncoso JC, Folstein MF. Accuracy of clinical diagnosis of Alzheimer's disease and clinical
features of patients with non-Alzheimer's disease neuropathology. Alzheimer Dis Assoc Disord. 1996;10:180-188.
ISI
| PUBMED
12. Tsuang D, Kukull W, Sheppard L, et al. Impact of sample selection on APOE 4 allele frequency: a comparison
of two Alzheimer's disease samples. J Am Geriatr Soc. 1996;44:704-707.
ISI
| PUBMED
13. Barnhart RL, van Belle G, Edland SD. Geographically overlapping Alzheimer's disease registries: comparisons
and implications. J Geriatr Psychiatry Neurol. 1995;8:203-208.
14. Lim A, Tsuang D, Kukull W, et al. Clinico-neuropathological correlation of Alzheimer's disease in a community-based
cases series. J Am Geriatr Soc. 1999;47:564-569.
ISI
| PUBMED
15. Larson EB, Kukull WA, Teri L, et al. University of Washington Alzheimer's Disease Patient Registry (ADPR):
1987-1988. Aging. 1990;2:404-408.
PUBMED
16. Brenner D, Kukull W, van Belle G, et al. Relationship between cigarette smoking and Alzheimer's disease in a
population-based case-control study. Neurology. 1993;43:293-300.
FREE FULL TEXT
17. Kukull WA, Hinds TR, Schellenberg GD, van Belle G, Larson EB. Increased platelet membrane fluidity as a diagnostic marker for Alzheimer's
disease: a test in population-based cases and controls. Neurology. 1992;42:607-614.
FREE FULL TEXT
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
19. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimer's disease. Neurology. 1984;34:939-944.
FREE FULL TEXT
20. Barnhart RL, Tsuang D, Leverenz JB, et al. Is there selection bias in autopsy completion? results from a community-based
study. Neurobiol Aging. 2000;21:S143.
21. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239-259.
FULL TEXT
| PUBMED
22. Mirra SS, Heyman A, McKeel D, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD),
part II: standardization of the neuropathologic assessment of Alzheimer's
disease. Neurology. 1991;41:479-486.
FREE FULL TEXT
23. Cummings JL. The neuropsychiatric inventory: assesssing psychopathology in dementia
patients. Neurology. 1997;48(suppl 6):S10-S16.
24. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state
of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
FULL TEXT
|
ISI
| PUBMED
25. Reitan RM. Validity of the trail-making test as an indication of organic brain
damage. Percept Mot Skill. 1958;8:271-276.
26. Wechsler D. Wechsler Adult Intelligence Scale-Revised Manual. New York, NY: Psychological Corp; 1981.
27. Wechsler DA. A standardized memory scale for clinical use. J Psychol. 1945;19:87-95.
ISI
28. Coblentz JM, Mattis S, Aingesser LH, Kasoff SS, Wisneiwski HM, Katzman R. Presenile dementia: clinical aspects and evaluation of cerebrospinal
fluid dynamics. Arch Neurol. 1973;29:299-308.
FREE FULL TEXT
29. Emi M, Wu LL, Robertson MA, et al. Genotyping and sequence analysis of apolipoprotein E isoforms. Genomics. 1988;3:373-379.
FULL TEXT
|
ISI
| PUBMED
30. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification
and cleavage with HhaI. J Lipid Res. 1990;31:545-548.
ABSTRACT
31. Gearing M, Schneider JA, Rebeck GW, Hyman BT, Mirra SS. Alzheimer's disease with and without coexisting Parkinson's disease
changes: apolipoprotein E genotype and neuropathologic correlates. Neurology. 1995;45:1985-1990.
ABSTRACT
32. Tsuang D, Larson EB, Bowen J, et al. The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer's
disease in a community-based case series. Arch Neurol. 1999;56:1489-1495.
FREE FULL TEXT
33. NIA-Reagan Working Group. Consensus recommendations for the postmortem diagnosis of Alzheimer's
disease. Neurobiol Aging. 1997;18(suppl 4):S1-S2.
34. Ala TA, Beh GO, Frey II WH. Reply from the authors. Neurology. 2000;55:739-740.
35. Volpe BT, Petito CK. Dementia with bilateral medical temporal lobe ischemia. Neurology. 1985;35:1793-1797.
FREE FULL TEXT
36. Zola-Morgan S, Squire LR, Amaral DG. Human amnesia and the medial temporal region: enduring memory impairment
following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci. 1986;6:2950-2967.
ABSTRACT
37. Babb TL, Brown WJ, Pretorius J. Temporal lobe volumetric cell density in temporal lobe epilepsy. Epilepsia. 1984;25:729-740.
ISI
| PUBMED
38. Kim JH, Kraemer DL, Spencer DD. The neuropathology of epilepsy. In: Hopkins S, Shorvon S, Cascino G, eds. Epilepsy. 2nd ed. New York, NY: Chapman & Hall; 1995:243-267.
39. Morris JC, Edland S, Clark C, et al. The consortium to establish a registry for Alzheimer's disease (CERAD),
part IV: rates of cognitive change in the longitudinal assessment of probable
Alzheimer's disease. Neurology. 1993;43:2457-2465.
FREE FULL TEXT
40. Albert MS. Cognitive and neurobiologic markers of early Alzheimer disease. Proc Natl Acad Sci U S A. 1996;93:13547-13551.
FREE FULL TEXT
41. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial
and sporadic Alzheimer's disease. Neurology. 1993;43:1467-1472.
FREE FULL TEXT
42. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's
disease in late onset families. Science. 1993;261:921-923.
FREE FULL TEXT
43. Knopman DS, Mastri AR, Frey WHI, Sung JH, Rustan T. Dementia lacking distintive histologic features: a common non-Alzheimer
degenerative dementia. Neurology. 1990;40:251-256.
FREE FULL TEXT
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Distinct genetic forms of frontotemporal dementia
Seelaar et al.
Neurology 2008;71:1220-1226.
ABSTRACT
| FULL TEXT
Is amnestic mild cognitive impairment always AD?
Jagust
Neurology 2008;70:502-503.
FULL TEXT
Frontotemporal Lobar Degeneration Without Lobar Atrophy
Josephs et al.
Arch Neurol 2006;63:1632-1638.
ABSTRACT
| FULL TEXT
Neuropathologic Features of Amnestic Mild Cognitive Impairment
Petersen et al.
Arch Neurol 2006;63:665-672.
ABSTRACT
| FULL TEXT
Hippocampal sclerosis in Alzheimer disease and other dementias
Attems and Jellinger
Neurology 2006;66:775-775.
FULL TEXT
Quantitative post-mortem study of the hippocampus in chronic epilepsy: seizures do not inevitably cause neuronal loss
Thom et al.
Brain 2005;128:1344-1357.
ABSTRACT
| FULL TEXT
Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia
Honig et al.
Neurology 2005;64:1102-1102.
FULL TEXT
Hippocampal sclerosis dementia: Expanding the phenotypes of frontotemporal dementias?
Lippa and Dickson
Neurology 2004;63:414-415.
FULL TEXT
Dementia in hippocampal sclerosis resembles frontotemporal dementia more than Alzheimer disease
Blass et al.
Neurology 2004;63:492-497.
ABSTRACT
| FULL TEXT
|
