J Neuropathol Exp Neurol
1
Copyright Ó 2008 by the American Association of Neuropathologists, Inc.
REVIEW ARTICLE
Neuropathology and Cognitive Impairment in Alzheimer Disease:
A Complex but Coherent Relationship
Peter T. Nelson, MD, PhD, Heiko Braak, MD, and William R. Markesbery, MD
Abstract
Amyloid plaques and neurofibrillary tangles (NFTs) are the
pathological hallmarks of Alzheimer disease (AD). There is con-
troversy regarding the use of current diagnostic criteria for AD and
whether amyloid plaques and NFTs contribute to cognitive impair-
ment. Because AD is specific to humans, rigorous and compre-
hensive clinicopathologic studies are necessary to test and refine
hypotheses of AD diagnosis and pathogenesis. Neither the clinical
nor the pathological aspects of AD evolve in a linear manner, but
the predictable sequence of AD pathology allows for stage-based
correlations with cognitive deterioration. We discuss subsets of
patients with clinical dementia who lack amyloid plaques and NFTs
and, conversely, whether individuals without antemortem cognitive
impairment can harbor severe AD-type pathological findings at au-
topsy. There are many medical, technical, and anatomical challenges
to clinicopathologic studies in AD. For example, at least two thirds
of persons older than 80 years have non-AD brain diseases that can
effect on cognitive function. We argue that existing data strongly
support the hypothesis that both amyloid plaques and NFTs
contribute to cognitive impairment.
Key Words: Acetylcholine, Aging, Cognition, Lewy, Mini-Mental
State Examination, Stroke, Tau.
INTRODUCTION
Clinicopathologic (CP) studies are essential for deter-
mining the pathobiological importance of amyloid plaques
and neurofibrillary pathology in Alzheimer disease (AD).
Research on CP correlation in AD has been active for sev-
eral decades, and meaningful data have accumulated from
many international centers. These investigations have been
aided by a detailed understanding of both clinical and path-
ological progression of AD. Along with advances, however,
From the Department of Pathology and Division of Neuropathology,
University of Kentucky Medical Center, Sanders-Brown Center on
Aging (PTN, WRM); and Alzheimer’s Disease Center, University of
Kentucky, Lexington, Kentucky (PTN, WRM); and Institute for Clinical
Neuroanatomy, Goethe University Frankfort, Frankfurt am Main,
Germany (HB).
Send correspondence and reprint requests to: Peter T. Nelson, MD, PhD,
Department of Pathology, Division of Neuropathology, Room 311,
Sanders-Brown Center on Aging, University of Kentucky, 800 S.
Limestone, Lexington, KY 40536-0230; E-mail: pnels2@email.uky.edu
This study was supported by Grant No. 5-P30-AG028383 and Grant No.
K08 NS050110 from the National Institutes of Health, Bethesda,
Maryland, by a grant from the Healy Family Foundation, and funding
from the Deutsche Forschungsgemeinschaft.
J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009
Copyright @ 2008 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.
Vol. 68, No.
January 2009
pp. 1Y14
there have been many controversies. This review of the lit-
erature on CP studies in AD is intended to describe the prog-
ress and complexities for a broad scientific audience.
We interpret CP studies to provide robust support for
the importance of both amyloid plaques and neurofibrillary
tangles (NFTs) in the clinical manifestations of AD (Fig. 1;
Table 1). We review the large body of pertinent literature
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and describe the medical, technical, and anatomical aspects
relevant to interpreting these data. Because the pathological
features of AD and many other aspects of the aged brain are
distinct in Homo sapiens, we focus primarily on studies on
humans.
CLINICOPATHOLOGIC CORRELATION IN THE
CONTEXT OF AD: THE GOALS AND THE
POTENTIAL OBSTACLES
The goal of CP studies is to understand the clinical and
biologic importance of identified pathological features. In
principle, pathological severity should correlate meaningfully
with the extent of clinical disease, that is, cognitive impair-
ment in AD. A desirable correlation is depicted in Figure 2A,
in which the ideal correlation requires a linear association
between 2 discrete entities: impairment of health and severity
of pathology. Such correlations are, however, seldom attained
in practice because of functional reserve capacity, biologic
variation between individuals in both protective and patho-
genetic pathways, and incomplete understanding of disease
mechanisms.
Furthermore, CP studies require assumptions with re-
spect to the pathological substrates. It has been suggested that
amyloid plaques and NFTs may not be pathogenetic in AD,
and that these abnormalities could instead be a neuroprotec-
tive response to other disease stimuli such as oxidative stress
and/or inflammation (1). Neither oxidative nor inflammatory
brain insults have, however, been shown to induce NFTs in
any wild-type animal model. Are NFTs Bneuroprotective[
exclusively in humans? Interpreting AD-related changes as
adaptive becomes even more difficult as one seeks explana-
tions for the peculiar amyloid plaque pattern and the selec-
tive vulnerability of only a few types of nerve cells in AD. In
principle, all nerve cells and nonneuronal cells can be ex-
pected to react similarly to oxidative stress and inflammation,
although not necessarily always to the same extent. We in-
terpret the genetic evidence (discussed later) and qualitative
pathological assessments of AD brains, particularly the neu-
rofibrillary pathology that appears to warp and impinge upon
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Nelson et al J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009

Additional questions have been raised regarding the

biologic relevance of amyloid plaques and NFTs (1). Eval-
uating these arguments requires consideration of the specificity
of plaques and NFTs in AD, the importance of concomitant
disease processes, and the challenges in performing cognitive
assessments.

Specificity of AD Lesions: Amyloid Plaques and

FIGURE 1. Histopathologic hallmarks of Alzheimer disease
demonstrated with Bielschowsky silver impregnation. (A)
Neuritic plaques are extracellular fibrillary amyloid deposits,
NFTs are Seen Outside of AD
It has been suggested that neurofibrillary pathology and
amyloid plaques are not specific to AD. If this is true, does
nonspecificity argue for or against the importance of NFTs
and amyloid plaques in AD?
Neurofibrillary tangles are not specific for AD, partic-
ularly if a broader definition of NFTs includes different tau
isoforms or if one expands the expectations of the morpholo-
gical characteristics of NFTs (2, 3). In addition to AD, NFTs
are also found in some frontotemporal dementias, myotonic

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surrounded by swollen, degenerating, argyrophilic neurites.
(B) Neurofibrillary tangles are composed of intracellular,
insoluble, and protease-resistant fibrillary polymers of tau
protein. In both panels, there are wispy argyrophilic neuropil
threads. Scale bars = 25 Km.
normal cell constituents (Fig. 1), to indicate more of a toxic
than protective role. There may be both harmful and adap-
tive aspects of a given phenomenon, of course, and AD le-
sions presumably both result from, and in turn stimulate,
other toxic factors.
dystrophy, viral panencephalitis, dementia pugilistica, some
prion diseases, and other brain diseases (4, 5). For many of
these disorders, the severity of NFT pathology is less than
that observed in end-stage AD. No condition characterized by
widespread neocortical NFTs lacks extensive neurodegenera-
tion and clinical dementia. On the other hand, there are many
subtypes of chronic brain diseases in which there are ex-
tensive neurodegeneration and clinical dementia without
NFTs, such as many subtypes of frontotemporal dementias,
synucleinopathies, subacute or chronic infarcts, metabolic,
demyelinating, developmental, and trinucleotide repeats dis-
eases. Nor is there any doubt that tau protein itself can

TABLE 1. Definition of Terms

Pathological terms
Neurofibrillary pathology
Neurofibrillary pathology comprises aberrant, insoluble, and protease-resistant tau aggregates in various cellular compartments. Neuropil threads and the
intracellular components of neuritic plaques are subsets of neurofibrillary pathology that are present within dendrites or neurites.
Neurofibrillary tangle
Neurofibrillary tangle is the term that describes neurofibrillary pathology found in cell bodies.
Amyloid plaques
Amyloid plaques are extracellular, often roughly spherical, proteinaceous deposits stainable with Congo red, silver stains, and thioflavine histologically.
Fibrillary polymers of the AA peptide comprise the structural core of amyloid plaques in Alzheimer disease. Different subsets of amyloid plaques are
defined later.
Neuritic plaques vs diffuse plaques
Neuritic plaques are extracellular amyloid deposits invested by swollen degenerating neurites. The swollen neurites contain filamentous tau protein
aggregates identical structurally to the inclusions within neurofibrillary tangles. Diffuse plaques lack the presumed degenerating and/or aberrant
tau-immunoreactive neuritis.
Braak Stages
Braak stages refer to the relatively predictable progression of neurofibrillary tangle-type pathology in the brain during the course of Alzheimer disease. In
early stages (IYIII) the pathology is mostly isolated to the mesial temporal lobe structures, but later stages (IVYVI) progressively affect the neocortex
(see later).
Anatomical terms
Mesial temporal lobe structures (allocortex)
Mesial temporal lobe structures in the human brain comprise allocortical structures including the entorhinal cortex, amygdala, and the cornu ammonis fields
(CA1-CA4) and subiculum of the hippocampus. Mesial temporal lobe areas functionally play an important role in consolidating short-term memory.
Isocortex or neocortex
Neocortex refers to areas of cerebral cortex, also known as isocortex, that have 6 cellular layers. Neocortical areas subserve higher-order functions
including aspects of judgment, executive function, and so on. The contradistinction between mesial temporal lobe areas and neocortical areas is
important in comprehending the predictable, but nonlinear, progression of pathology in Alzheimer disease.

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J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009 Neuropathology and Cognitive Decline in AD

(11Y13). Notably, without NFTs or amyloid angiopathy, am-

yloid plaques are not associated with neurodegeneration (see
later). In sum, AD involves a specific combination of neu-
ritic amyloid plaques and NFTs; the neuritic plaques are more
specific to the disease, and the NFTs seem more likely to
induce neurodegeneration.
Specificity of AD Lesions: General and
Theoretical Considerations About the Clinical
Context of AD, Neuroanatomy, and Synergy
Between Plaques and NFTs
One challenge of CP studies in AD is to place nonlinear
disease processes onto quasi-linear continua for purposes of
correlation. The pathological changes in AD follow a complex
stereotyped neuroanatomical pattern (14). Prior studies have
produced a general scheme for how the pathology correlates
with clinical outcomes (Figs. 2 and 3), but it is important
to consider the clinical context for this association.
Epidemiological studies indicate that clinical AD prev-

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alence doubles every half decade after age 65 years so that
approximately 25% of 90-year-olds carry the diagnosis of
AD (15, 16). The time from formal clinical diagnosis to death
is only approximately 8 years (17). Structural and cognitive

FIGURE 2. (A) An idealized clinicopathological correlation may

not be applicable to Alzheimer disease. (B) A conventional
metric for cognition, the Mini-Mental State Examination
(MMSE) and the Braak staging method provide a relatively
strong correlation between pathological severity and antemor-
tem cognitive decline. Data depicted are from the University of
Kentucky Alzheimer’s Disease Center (63). Each patient in this
series lacked concomitant pathological processes, for example,
advanced cerebrovascular disease, and died within a year of
their last MMSE score. Numbers of patients from each group:
Braak Stage 0, n = 8; I, n = 15; II, n = 18; III, n = 13; IV,
n = 12; V, n = 6; and VI, n = 25. Error bars are SD.

directly trigger neurodegeneration: many germ line mutations

in tau produce clinical dementia with NFTs (3, 6). These
tauopathies are distinct from AD, but common pathways may
be involved. The bottom line is that NFTs appear in multiple
brain diseases, and some researchers, including the present
authors, infer that NFTs contribute to neurodegeneration in
more than 1 disease state.
Unlike NFTs, the appearance of amyloid plaques in
AD brains is unique. Dystrophic neurites that contain
amyloid precursor protein are seen in traumatic brain injury
(7, 8), and Bdiffuse plaques[ can be observed in association FIGURE 3. Alzheimer disease (AD) progresses in a nonlinear
with dementia pugilistica (9). BLewy plaques[ have also been manner that renders clinicopathological correlation a chal-
described, with a corona of dystrophic >-synucleinYpositive lenge. The disease duration is long, there is a preclinical phase,
neurites (10). By contrast, the particular appearance of neu- in which pathological findings are present, but there are no
ritic plaques (i.e. AA peptideYcontaining extracellular lesions clinical manifestations. Further, each patient has a unique
surrounded by tau neurofibrillary pathology) is considered to constellation of clinical and pathological features. Nonetheless,
there is a relatively predictable progression of both clinical and
be specific for AD. Amyloid plaques are not a nonspecific
pathological indices. This schematic illustrates that the associ-
reaction to neurofibrillary pathology because non-AD tauo- ation between mesial temporal neurofibrillary tangles (NFTs)
pathies lack amyloid plaques. Further attesting to the spec- and neocortical neuritic plaques with cognitive decline may be
ificity of AD-type amyloid plaques is the fact that mutations weak, whereas the association between neocortical NFTs and
or duplications in the amyloid precursor protein gene pro- cognitive decline is strong. Early mesial temporal NFTs may
duce the specific features of AD, clinically and pathologically play a role in memory dysfunction in early AD.

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Nelson et al J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009

disease is present over a longer time span, however, certainly
over a decade before death and perhaps considerably longer
(18Y24). Using these data, we deduce that an average person
dying at age 78 years will have approximately 5% to 10%
likelihood of having an antemortem diagnosis of AD, but at
least approximately 20% to 40% likelihood of having signifi-
cant AD-type pathology. Thus, many individuals with AD-
related pathology and minimal or no detectable antemortem
cognitive deficits die of other causes. Theoretical and empiri-
cally derived data agree on this important point, as shown in
Figure 4. Figure 4B shows data of Del Tredici and Braak (25)
based on 3,928 cases. The existence of nondemented persons
with AD-type pathology is hence not a potential confound; it
is obvious that many persons die in the preclinical phase of
AD. Preclinical and subclinical diseases are well-accepted
ideas in cancer, atherosclerosis, and in many other diseases,
but seem to cause confusion in discussions of AD.
In addition to the concept of preclinical AD, there are
other potential pitfalls in CP studies. Distinct neuroanatom-
As if factoring in both the clinical course and the
anatomical aspects of the disease was not difficult enough,
there is added complexity in the lesions of AD. By definition,
AD is characterized by the presence of both amyloid plaques
and neurofibrillary pathology, and there seems to be some
synergy of the two, most definitely in neuritic plaques, but
the tracking of 2 separate pathologies renders CP correlations
challenging. In the multidecade course of AD progression,
amyloid plaques and NFTs may be first observed in different
parts of the brain: NFTs tend to appear first in allocortical
structures, whereas amyloid plaques may first be found in the
neocortex (26, 27, 31Y35). Because 2 different types of
pathology develop initially without apparent direct correla-
tion to each other, a linear continuum is difficult to establish.
A further layer of complexity is that amyloid plaques and
NFTs are probably not static lesions (see later).
These considerations help explain why some prior
studies have shown apparent general discrepancies with regard
to the correlation of extent of pathology and the severity of

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ical regions are affected at different stages of AD, and this
must be taken into account for CP correlations. For example,
portions of the allocortex (Table 1), including the hippo-
campus and entorhinal cortex, may be involved severely
early in AD (14, 26Y28) when neocortical areas are still
relatively well preserved. The involvement of neocortical
areas presumably underlies the later-stage cognitive impair-
ment. Therefore, study of hippocampus may be best for
assessing earlier memory changes, but a study limited to
hippocampus would be inappropriate for correlating overall
pathology with overall cognitive decline. An important case
study is that of Patient H.M., who had bilateral near-complete
temporal lobectomies in 1953 (29, 30). Although mostly
amnestic, Patient H.M. is still quite robust cognitively more
than 5 decades later without AD (30) because most cognitive
domains impaired in AD pertain to neocortical involvement
(i.e. nondeclarative memory, judgment, gnosia, visuospatial
skills, language, executive function, etc.).
premortem cognitive decline (1). However, apparent incon-
gruities have been asserted by a number of researchers, and a
discussion is provided later regarding specific studies.
Specificity of AD Lesions: Particular Cases and
Pathological Combinations
AD is defined by the presence of neuritic plaques and
neurofibrillary pathology, the abundance of which is hy-
pothesized to correlate with the severity of cognitive de-
terioration. If this is so, then certain corollaries must hold
true: 1) there should not be individuals with extremely abun-
dant plaques and tangles but no cognitive deterioration; 2)
there should not be clinical dementia cases with abundant
plaques and no NFTs; 3) there should not be patients with
clinical dementia in whose brains there is no detectable
pathological substrate; and 4) although there exist a number
of tauopathies (progressive supranuclear palsy, corticobasal
degeneration, Guamanian parkinsonism, FTDP-17, etc.),

FIGURE 4. (A) The epidemiology of Alzheimer disease (AD) and the duration of the disease process predict that many persons
with appreciable AD pathology die before the onset of dementia. Assuming a 10-year preclinical stage, approximately as many
individuals would have significant AD pathology without the clinical disease as would manifest the disease during life. The
epidemiological data represent an average of 6 large studies, as summarized previously (16). (B) Empirical data confirm the
prediction that many individuals who die of other causes show appreciable AD-type pathology. Empirical data are from 3,928
cases in the indicated age ranges (25). Note that Braak Stages III/IV correspond to National Institute on AgingYReagan Institute
Bintermediate likelihood[ for the diagnosis of AD (46).

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J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009 Neuropathology and Cognitive Decline in AD

there should not be a true Btau-only[ AD. These ideas have

TABLE 2. Autopsy Series on Nondemented Persons With
been tested repeatedly and have fostered controversy. Differ-
False-Positive Pathological Diagnosis of National Institute on
ent specific groups will be discussed in turn. AgingYReagan Institute High Likelihood for Alzheimer Disease
(Braak Stages V and VI)
Amyloid Plaques and Neurofibrillary Pathology
Nondemented, Braak Braak Total Braak
But No Dementia n Stage V Stage VI Stage V/VI Reference
Cases with considerable AD-type pathology but with- 1* 0 1* 1 (47)
out documented cognitive decline have been termed patho- 49 0 0 0† (48)
logical aging and presymptomatic aging (36Y38). Because 142 1 0 1 (33)
mild cognitive impairment is considered to constitute an early 39 1 0 1 (49)
expression of AD (39), we here discuss only nondemented 42 3 0 3 (50)
patients. Such patients with incipient AD-like changes have 18 0 0 0† (56)
also been called preclinical AD based on magnetic resonance 17 0 0 0† (55)
imaging data (19, 40), neuropsychological testing (21, 41), 89 ?‡ ?‡ 3‡ (57)
Pittsburgh Compound B positron emission tomography 31 0 0 0 (51)
imaging (42), and cerebrospinal fluid biomarkers (43). 68 1 1 2 (54)
Pathologically, many nondemented cases meet the older 59§ 3 1§ 4
Khachaturian diagnostic criteria (44) and a significant minority n = 555 n = 15
meet Consortium to Establish A Registry for Alzheimer’s

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Disease definite criteria for AD (41, 45). These criteria have
been superseded for the stand-alone AD diagnosis since 1997
(46). Moreover, these criteria are not relevant directly to a
discussion of false-positives because they were established for
making the diagnosis of AD in clinically demented patients.
The pathological diagnosis of Bintermediate likelihood[
for AD by the current National Institute on AgingYReagan
Institute (NIARI) criteria corresponds to Braak Stages III and
IV (46), neither of which is by itself a substrate for profound
cognitive impairment (Fig. 2). The NIARI criteria for
pathological diagnosis of Bhigh likelihood[ for AD corre-
spond to Braak Stages V and VI (46). Note that the average
final Mini-Mental State Examination (MMSE) score for
Braak Stage V is approximately 20 out of a possible 30
(Fig. 2), so may include some relatively normal individuals.
A recent case report described a 92-year-old nondemented
patient whose brain, on autopsy, contained Braak Stage VI
pathology (47), but neocortical NFTs from this patient did
not appear particularly dense, and the patient did demonstrate
cognitive deficits. In 3 different cognitive tests, she scored at
or below the 20th percentile for her age despite previously
normal test results (47). Because there is as yet no published
report of true end-stage pathology in a cognitively intact
individual, an assessment of larger studies is necessary.
In 2004, Fernando and Ince (48) described a population-
based autopsy series in which BIsevere neocortical NFTs were
not seen in any nondemented individual.[ This result has been
obtained repeatedly from multiple centers (33, 47Y57), as
shown in Table 2 (N = 555 nondemented subjects, of whom
15 were Braak Stages V or VI). These data from many research
centers indicate a 2.7% false-positive rate in the NIARI criteria
for high-likelihood AD diagnosis, with mostly Braak Stage V
cases. In addition, a number of other studies have noted that
nondemented patients have NFTs confined predominantly to
the mesial temporal lobe structures (58Y61). These data support
the accuracy of the high likelihood NIARI criteria, but leave
unanswered the important question: are there nondemented
persons with truly end-stage AD-type pathology?
We addressed this issue using data from the University
of Kentucky Alzheimer’s Disease Center autopsy series
*Case report (47).
†Braak stages inferred.
‡Cases designated as Braak V/VI.
§From the University of Kentucky Alzheimer’s Disease Center, Braak VI case with
relatively low neocortical neurofibrillary tangles (Fig. 5).
(62, 63). Of 59 longitudinally followed nondemented sub-
jects with MMSE scores within a year of death, 9 showed
Braak Stage IV, 3 Stage V, and 1 Stage VI (Table 2). The
single Braak Stage VI patient from this series had a final
MMSE score of 29 within a year of death. Note that in this
brain, there was a relatively low density of neocortical NFTs
(Fig. 5, rightmost data points). This person seems to dem-
onstrate the lowest-severity Braak Stage VI. Thus, even
among Braak Stage VI cases, individuals with lower neo-
cortical NFT densities tend to have better preservation of
cognitive faculties. Variability in Braak Stage VI severity is
underscored by different studies in which the median final
MMSE scores range from less than 2 (64) to 14 (53) in this
group. Moreover, in a study of 168 autopsied persons
(Fig. 6), every case with neocortical NFT density greater
than a particular threshold (blue arrow) had clinical dementia
(MMSE, G20), just as every case with low or absent
neocortical NFTs (red arrow) had final MMSE scores greater
than 20. In sum, whereas the correlation between AD-type
pathology and clinical impairment is not absolutely predict-
able in each patient, there seems to be a threshold of
pathology above which every patient, without exception, is
profoundly impaired.
‘‘Tangle-Only‘‘ Dementia
There are reports of autopsied patients with neuro-
fibrillary pathologyYpredominant dementia (5, 54, 65, 66).
These cases are characterized by abundant NFTs in medial
temporal lobe structures with no or few amyloid plaques
throughout the brain. The individuals are usually older and
primarily had memory decline and reduced activities of daily
living. Whether this is a subtype of AD or a different entity
remains to be elucidated.

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Nelson et al J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009

FIGURE 5. Variations in clinical and pathological indices in Braak Stage VI cases from the University of Kentucky Alzheimer’s
Disease Center database (63). Cases are arranged left-to-right by increasing Mini-Mental State Examination (MMSE) scores. All

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patients had undergone MMSE testing within a year before death. Patients with higher MMSE scores tended to have fewer
neocortical neurofibrillary tangles (NFTs). One nondemented patient (MMSE score, 29) had a relatively low number of neocortical
NFTs compared with the other more cognitively impaired patients.

Other diseases are now known to be characterized by

NFT formation and minimal or absent amyloid pathology.
These cases are now presumed to reflect tauopathies, which
are a diverse group of diseases that may be associated with
genetic (tau mutations) or environmental (Guamian or
postencephalitic parkinsonism) factors (3, 5). In most
population-based series, and in older patients, tauopathies
are uncommon (54, 57, 67).

‘‘Plaque-Only’’ Dementia
We have no personal experience of cases with
dementia, abundant neocortical neuritic plaques, or diffuse
plaques but with no other clinical or pathological explanation
for the cognitive decline. The phenomenon of plaque-only
dementia has been described (68, 69) but may partly
correspond to patients with dementia with cortical Lewy
bodies (70). Even in the recent series of plaque-only AD (68),
which described a group of 16 brains of persons with clinical
dementia but with no neocortical NFTs and a low number of
amyloid plaques, it is unclear whether or how other prevalent
brain diseases that are capable of contributing to dementia
were excluded. Thus, with the apparent exception of a rare
familial variant of historical significance (71), plaque-only
dementia has not been demonstrated beyond doubt despite
many studies addressing this topic. Without fuller clarifica-
tion, it is possible that the small numbers of plaque-only
dementia cases described to date had cognitive decline
caused by other neurodegenerative conditions.
Cases With Dementia Lacking Amyloid Plaques,
NFTs, and Other Pathological Substrates
The literature does not indicate an appreciable subset of
patients with clinical dementia and histopathologically pris-
tine brains on autopsy. Studies that show a significant
proportion of cases with dementia, low neurofibrillary
FIGURE 6. Data from the University of Kentucky Alzheimer’s
Disease Center database demonstrate that neocortical neuro-
fibrillary tangle (NFT) counts predict dementia in patients with-
out severe concomitant brain pathologies (n = 168). Neocortical
counts comprised total counts from occipital (Brodmann area
17 and 18), inferior parietal lobule, superior and midtemporal
gyri, and middle frontal gyrus (63). Neocortical amyloid plaque
counts are the combined amount of neuritic and diffuse amyloid
plaques in the same sections. Above a certain neocortical count
(blue arrow), all patients were demented (blue diamonds =
patients with the Mini-Mental State Examination [MMSE] G20).
By contrast, patients with mild or no dementia (MMSE, 920;
red circles) tend to have lower neocortical NFTs, and all patients
below a threshold of neocortical NFT counts (shown by red
arrow) have MMSE greater than 20. There is only a weak
correlation between the amyloid plaques (green triangles) and
the NFTs, but cases with high neocortical NFTs generally have
high amyloid plaques.

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J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009
pathology, and no other known pathological substrate, tend to
be the older studies that lack probes for recently described
diseases. In 2000, Crystal et al (72) described a cohort with
Bdementia of unknown etiology,[ however, cognitive impair-
ment in this cohort was not extreme, and these patients
showed specific contributory neuropathological features
including hippocampal sclerosis and vascular disease.
There are many additional causes of cognitive decline,
and these can be clinically diagnosed in most cases. For this
reason, in clinical series such as those at the University of
Kentucky Alzheimer’s Disease Center, which include rigor-
ous longitudinal clinical assessments followed by brain
autopsy, extremely rare patients with profound dementia
and the premortem diagnosis of AD have lacked histopathol-
ogic substrates at autopsy. We and others have found that
persons with concomitant pathologies die with less neuro-
fibrillary pathology (63, 64). Identifying and taking into
account the presence and magnitude of concomitant pathol-
ogies is probably the biggest challenge to studies of the aging
human brain.
Concomitant Pathology: The Large Impact of
Cerebrovascular Diseases
The most prevalent concomitant pathology in the
brains of aged persons, cerebrovascular disease (CVD), is
directly relevant to any discussion of CP studies in dementia
or AD. The challenges introduced by this widespread but
unpredictable comorbidity in aged persons have been
discussed previously (48, 64, 73Y79). Yet, the profound
impact of CVD on studies pertinent to cognition in the
elderly seems to be underappreciated, or even ignored, in the
broader field of AD research.
Cerebrovascular disease spans a wide spectrum includ-
ing small- and large-vessel ischemic disease, embolic, ve-
nous, inflammatory, hypertensive, hemorrhagic, aneurysmal,
hypoglycemia, hypoxia, amyloidogenic, and others. The
importance of CVD is at least 2-fold. First, some cerebrovas-
cular abnormalities are so common as to be the norm in ad-
vanced old age. Second, CVD induces an unpredictable
change in cognition and hence presents challenges to correlat-
ing the severity of cognitive decline with other diseases.
Clinical and subclinical CVD is common in elderly
subjects. Cerebrovascular disease is detectable in 75% to 90%
of persons older than 90 years (63, 80), and whereas frank
clinical strokes affect approximately 750,000 in America each
year, more than 11 million discrete but clinically silent cere-
brovascular events are thought to occur over the same interval
(81). The high frequency of cerebrovascular changes among
elderly patients means that both cognition and other pathology
need to be weighed in the context of an altered milieu.
Furthermore, unlike AD, CVD progresses in an anatomically,
clinically, and temporally unpredictable fashion, and there is
no systematic methodology for correlating pathological and
clinical findings (82). These are some reasons why CVD-
related pathology is frequent in cases termed dementia of
unknown origin (72).
Importantly for CP studies, CVD shifts the detection
threshold for cognitive changes during life. In elderly AD pa-
tients, CVD leads to more rapid cognitive deterioration (83, 84).
Ó 2008 American Association of Neuropathologists, Inc.
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Neuropathology and Cognitive Decline in AD
Subcortical and/or lacunar infarcts alter the detection threshold
for dementia (74, 85Y87). The change in clinical course is
mirrored by a different pathological appearance in the brain.
Persons with CVD tend to have lower AD-related pathology
with a given degree of cognitive impairment (63, 86). In other
words, the frequent presence of concomitant CVD severely
dampens the association for other pathologies, such as neuro-
fibrillary pathology and amyloid plaques, to the severity of
antemortem cognitive decline. For example, Braak Stage IV
pathology may combine with CVD to induce significant cog-
nitive impairment, whereas Braak Stage V pathology may it-
self have more biologic impact, yet still be clinically silent in
the absence of concomitant pathological abnormalities.
Concomitant Pathology: An Expanding List of
Non-AD Brain Diseases in Aged Persons
Although not as prevalent as CVD, non-AD neuro-
degenerative diseases are important for consideration. Synu-
cleinopathies are the second most prevalent neurodegenerative
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disease category after AD; these include dementia with Lewy
bodies and Parkinson disease dementia. Depending on the
study population, dementia with Lewy bodies and Parkinson
disease dementia constitute approximately 5% to 15% of all
neurodegenerative diseases (57, 88). Cortical Lewy body
pathology occurs frequently in association with AD (88, 89).
Whatever the reason for this clustering, the phenomenon is
important from the perspective of CP correlation. When cor-
tical Lewy bodies are present, the correlation between AD
pathology and cognitive impairment becomes far less strong
(63), probably because the Lewy body pathology is account-
ing for additional cognitive impairment. Accordingly, we and
others have found that patients with AD and dementia with
Lewy bodies decline at a faster rate than pure AD (90Y92).
The most reliable diagnostic tool for detection of neocortical
Lewy bodies (i.e. immunohistochemistry for >-synuclein)
was not developed until the late 1990s, so earlier studies had
less ability to detect these structures (93, 94). There are now
known non-AD dementias linked to mutations in valosin,
progranulin, TDP-43, CHMP2B, and various triplet-repeat
alleles (6, 95). These relatively newly discovered diseases
present an important caveat to interpreting older studies that
tackled the problem of CP correlation in dementia.
In addition to neurodegenerative diseases per se, some
other common diseases such as hippocampal sclerosis, sub-
stance abuse, mood disorders, cancer, hematomas, and hydro-
cephalus are directly contributory to cognitive impairment in
the elderly (96Y98). Together, neurodegenerative diseases,
CVD, and other aging-associated brain diseases weaken the
apparent association between AD pathology and antemortem
cognitive impairment. An analogy can be made to studying
heart disease: it would be difficult to study the CP correlation
between coronary atheromas and heart function if three quar-
ters of cases had bacterial endocarditis and/or severe arrhyth-
mias as well. That would be true even if clinical parameters
could be correctly and confidently assessed in each case.
Challenges Pertaining to Cognitive Assessment
Difficulties in CP correlation may have as much to
do with the clinical as to the pathological component. In
7
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AD-relevant CP studies, the clinical aspect is commonly the
severity of cognitive impairment as quantified by test
scores. First, it is problematic to align cognition and its
many substituent functions on a linear scale. Second, there is
added difficulty in correlating brain disease with test scores.
In other words, even if cognition could be placed on a valid
linear continuum (a test score), it would still be unsafe to
assume that regression along that continuum will occur in a
linear fashion that correlates with brain disease severity,
whether a histopathologic substrate exists.
Although outside the scope of this review, specific cog-
nitive assessments are used for differing applications. More
challenging, memory-oriented, and sensitive tests such as the
AD Assessment Scale, Cognitive component have been used
frequently in clinical trials and clinical imaging studies when
intraindividual assessments can be correlated as an outcome
measure. By contrast, most CP studies have relied on less
sensitive tests such as MMSE, the Blessed Test, or the even
more semiquantitative Clinical Dementia Rating Scale for
variety of techniques, including silver stains, thioflavine S,
and immunohistochemistry. Excellent studies have put forth
differing views of whether one should use neuritic plaques,
diffuse plaques, total plaque load, amyloid burden, or other
pathology metrics (107Y109). Studies also use differing
techniques for counting and/or scoring their density (107).
Despite the wide variations in study designs, several
points emerge consistently among CP studies about amyloid
plaques. First, compared with NFTs, there is a weaker direct
correlation between the density of amyloid plaques and the
severity of cognitive decline. Second, the amyloid plaque
subtype that seems to correlate best with the severity of

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CP correlation (26, 36, 52, 61, 63, 90, 99). These latter tests
have been more constantly used over time, assess multiple
cognitive domains, have relatively well-established norma-
tive values, and could be more specific for interpersonal and
cross-study CP correlations. It may be best to use a com-
prehensive battery of cognitive and functional tests such as
those used currently in the Uniform Data Set by Alzheimer’s
Disease Centers (100).
A further complication to CP studies is that many
nonstructural factors alter cognitive assessment in the elderly.
These include cardiovascular, metabolic, infectious, medica-
tion related, and mood disorders and debilities such as
fatigue, arthritis, hearing loss, and visual impairments that
can also change test-taking behavior.
Collectively, many clinical factors render inevitable
some degree of variation in the results of cognitive assess-
ments and hence in correlating test scores with any other
parameter. There are thus many layers of complexity to CP
studies of AD. Yet, by taking into account some of the above
challenges, we can begin to address the existing CP litera-
ture and evaluate the hypothesis that amyloid plaques and
NFTs contribute in a biologic sense to the clinical manifes-
tations of AD.

CLINICOPATHOLOGIC STUDIES IN AD: REVIEW

OF THE LITERATURE
Correlation of Amyloid Plaques and
Cognitive Decline
More than 30 CP studies have assessed correlations
between the density of amyloid plaques in human brains and
the severity of antemortem cognitive decline (26, 34, 36, 56,
61, 63, 99, 101Y106). These studies varied in research
cohorts, anatomical areas examined, pathological methods,
amyloid plaque subcategories, plaque-counting techniques,
metrics for cognition and the range of cognitive decline
tested, and the rigor with which concomitant pathologies
were evaluated and/or factored into the study. Controversy
exists about the best way to calculate the extent of amyloid
plaque pathology. Neuritic plaques can be visualized via a
FIGURE 7. Neurofibrillary tangles (NFTs) in ascending reticular
activating system (ARAS) including the acetylcholinergic
nucleus basalis of Meynert (NbM) do not map directly onto
most clinicopathologic studies. (A) Many NFTs are stained
using an antibody against phosphorylated tau protein in the
NbM of a midstage Alzheimer disease (AD). Scale bar =
50 KM. (B) Other ARAS nuclei, including the tuberomammil-
lary nucleus (TM), the locus caeruleus (LC), ventral tegmental
area (VTA), and the brainstem raphe areas also show many
NFTs and neuronal loss in AD patient. Neurotransmitters that
are known to augment memory, arousal, attention, and mood
are indicated alongside the ARAS cell groups that produce
them. The ARAS neurons are the only source of those neuro-
transmitters in cerebral cortex, and thus pathological alter-
ations in ARAS may contribute to clinical symptoms.

8 Ó 2008 American Association of Neuropathologists, Inc.

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J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009 Neuropathology and Cognitive Decline in AD

cognitive decline is the neuritic plaque. Third, the patterns
seen in aged persons’ brain seem to segregate into these 3
groups (note that many refers to counted lesions in neo-
cortex): 1) Few plaques, few NFTs, and no cognitive
impairment; 2) Many plaques, few NFTs, and no cognitive
impairment; and 3) many plaques, many NFTs and cognitive
impairment.
Because in part of the scarcity of neocortical NFTs in
the absence of plaques, it has been suggested that the path-
ogenetic effect of amyloid plaques may be mediated through
stimulating neurofibrillary pathology (63, 110). The relative
importance of amyloid plaques in terms of correlating with
cognitive decline may be greatest in the earliest stages of the
disease, before there are widespread NFTs and neocortical
neurodegeneration (99). By contrast, there is relatively little
evidence of a direct effect of amyloid plaques in contributing
to the later-stage cognitive decline in AD. Germane to this
topic but often neglected is the question of lesion turnover.
The apparent success of AA vaccine trials attests to the ability
deposits that are invested by degenerating or dying back
nerve cell processes (Table 1; Fig. 1). These abnormal
dendrites and axons contain aberrant tau fibrils identical to
those seen in NFTs. In a given neuritic plaque, axons from a
variety of different sources expressing distinct neurotrans-
mitter signatures may be present (114, 115). This is therefore
an important clue to AD pathogenesis because neuritic
plaques represent unambiguously a nidus in which extrac-
ellular amyloid plaque pathology induces intracellular neuro-
fibrillary pathology and apparent structural and functional
disruption (116, 117). Although the particular toxic sub-
stance(s) within neuritic plaques are still not definitively
known (i.e. they may represent specific conformation(s) of
the AA peptide [118]), this apparent Bsmoking gun[ is dif-
ficult to interpret in any other way.
CORRELATION OF NFTs AND
COGNITIVE DECLINE

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of the immune system to clear amyloid plaques (111), but it
is not known whether a toxic plaque substance is left unaf-
fected in these studies. Microglia appear to actively scavenge
the fibrillar material in amyloid plaques (112). There is more
direct evidence of amyloid plaque turnover in animal models
(113). This phenomenon would tend to dampen the correla-
tion between pathology and clinical features.
To a degree far greater than for NFTs, there is a strong
association between amyloid plaques and genetic factors of
risk for AD. As a rule, environmental and genetic factors that
predict AD risk also appear to directly potentiate amyloid
plaques. These risk factors include head trauma, the ApoE4
allele, Down syndrome, amyloid precursor protein mutations
and duplications, SORL1 variants, and mutations in PSEN1
and PSEN2 genes (13). This strong genetic association is
relevant to the question of the correlation with cognitive
symptoms because all of these alleles are also strong risk
factors for dementia.
The Neuritic Plaque: A Pathological Entity With
Strong Mechanistic Implications
Neuritic plaques deserve special consideration. Neuritic
plaques comprise roughly spherical extracellular amyloid
Dozens of research groups have assessed the associa-
tion between NFTs and the severity of cognitive decline
(26, 34, 36, 56Y58, 61, 63, 99, 101Y106, 119Y122). As with
amyloid plaque research, studies of NFTs have been defined
by different staining techniques, followed many different
study designs, and led to differing conclusions. Regardless of
the staining or counting method, however, the correlation
between neocortical NFTs and antemortem cognitive decline
is strong in studies that span the clinical spectrum of AD.
Several important themes emerge, including the importance
of neuroanatomical considerations and the different subtypes
of tau pathology in AD brains.
In the course of AD, the development of NFTs follows
a predictable pattern (14, 31, 123). This pattern seems to
correlate on the 1 hand with where neurons die (124Y127)
and on the other with the cognitive domains affected in AD.
For example, in the earliest stages of AD, symptoms tend to
relate to memory loss. At this stage of the disease, the
allocortical substrates of memory are strongly affected by
NFTs, but other areas are not. The cognitive domains
affected in midstage and late-stage AD expand to include
areas of executive function, judgment, visuospatial capacities,
and speech. This pattern is paralleled by the development of
NFTs in the neocortical areas that subserve those functions.

TABLE 3. Summary Points

Nonlinear clinicopathological correlations are expected in Alzheimer disease (AD)
& There are prevalent (9two thirds of patients) comorbidities in aged brains, including cerebrovascular diseases, synucleinopathies, frontotemporal, and
TDP-43Yrelated diseases that inevitably skew correlations between pathology and cognition
& The relationship between cognitive decline and brain disease is not linear, and both are difficult to quantify
& There are 2 separate important subtypes of AD pathologyVamyloid plaques and neurofibrillary tanglesVthat develop in different patterns in AD brains after a
predictable course
Summary
& Evidence from AD clinicopathological studies strongly supports the existence of a specific prevalent disease as defined by the presence of clinical dementia,
amyloid plaques, and neurofibrillary tangles
& End-stage AD patients have extremely high burden of plaques and tangles, and there is not a subset of cases with very dense AD-type lesions lacking cognitive
decline
& There is not a significant subset of cases with severe cognitive decline lacking a pathological substrate
& Results are compatible with the hypothesis that amyloid plaques and neurofibrillary tangle contribute to clinical decline in AD

Ó 2008 American Association of Neuropathologists, Inc. 9

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Nelson et al
A special anatomical consideration referent to NFTs in
AD is the impact of NFTs on the ascending reticular
activating system (ARAS). Ascending reticular activating
system neurons send strong inputs to the cerebral cortex that
augment memory, arousal, attention, and motivation. These
cells also are severely affected in AD. For example, although
the Bcholinergic hypothesis[ of AD (128, 129) is now
considered somewhat dated, the impact from NFTs on the
ARAS cholinergic nucleus basalis of Meynert (NbM) may be
profound. NFTs are numerous in the NbM starting early in
the disease (Fig. 7), and NFT density parallels cognitive
decline severity as does cerebral cortical cholinergic tone
(130Y132). The ARAS neurons, as a rule, supply neuro-
transmitters that are absent from intrinsic cortical neurons.
For example, the NbM is a major source of cholinergic
neurotransmission in the cerebral cortex, which itself harbors
no cholinergic cells (133). The importance of cortical
cholinergic tone is underscored by the fact that cholinergic
antagonists such as scopolamine induce transient but com-
plete amnesia in humans (134). NFTs are also thought to
affect adversely other ARAS neurotransmitters including
histamine, norepinephrine, dopamine, and serotonin (corre-
sponding to neurodegeneration and NFT-containing cells of
the tuberomammillary nucleus, locus caeruleus, ventral teg-
mental area, and pontine raphe, respectively) (135Y141).
There may be clinical manifestations associated with this
subcortical pathology, although this would not be detected in
most CP studies because consensus criteria for AD diagnosis
currently focus on cortical pathology (46).
As with amyloid plaques, there are subcategories of
neurofibrillary pathology; of these, NFTs are just one
(Table 1). Less attention has been focused on the other
subtypes possibly because neurofibrillary pathology is absent
in most animal models and not generally amenable to
positron emission tomographic scans. There is, however,
abundant dendritic and axonal neurofibrillary pathology in
AD brains (Fig. 1); these also are known as Bneuropil
threads[ and Bcurly fibers[ (142Y145). All the neurofibrillary
lesions, which contain tau polymer fibrils called paired
helical filaments (142), may contribute to cognitive decline
in AD (103). They provide another reason why a simple
linear correlation between Bplaques and tangles[ would not
be expected in relation to cognitive decline, although the
pathways involved in the formation of those lesions may
contribute to the disease.
Also in common with amyloid plaques, NFTs are
quantified only at death, so it is important to consider
whether some NFTs are removed from the brain in the course
of AD. This has not been proven either way. Some, but not
all, studies have indicated that more neurons disappear in AD
brains than can be explained directly by the number of NFTs
present at autopsy (126, 146, 147, but see Fukutani et al
[127]); this might indicate NFT turnover and/or a non-NFT
pathological mechanism. Extracellular NFTs are invested
by microglial cells and astrocytes, but it is unclear whether
these microglial scavengers successfully digest the protease-
resistant insoluble neurofibrillary material. Morsch et al (148)
modeled the correlation between NFT counts and neuron
loss in human hippocampi and concluded that individual
10
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J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009
neurons may harbor intracellular NFTs over several decades
(148, 149). This finding has been interpreted to indicate that
NFTs are benign (1), although a pathological process that
takes place over such a timeframe could well be toxic
ultimately, as in many other diseases of development or
aging. Before inducing cell death per se, these conspicuous
changes in cell bodies, axons, and dendrites might be
significantly impairing function.
LIMITATIONS TO CP STUDIES IN AD
Although many CP studies support the hypothesis that
NFTs and amyloid plaques contribute to the cognitive decline
in AD, there are important limitations to these studies and
significant unanswered questions. The schema of amyloid
plaques and NFTs Bcausing[ AD is oversimplistic and in-
complete. There are at least 2 relevant ideas that must be
acknowledged: 1) Correlation does not establish causation.
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Although the density of NFTs on autopsy correlates with
cognitive decline severity, and the experimental results align
with a plausible hypothesis, this does not prove that NFTs are
directly neurotoxic; and 2) Results raise the question of what
induces the formation of amyloid plaques and NFTs. For
many, if not most, AD patients, there are no known specific
genetic or environmental triggers that would account for the
development of amyloid plaques and NFTs. Yet, acknowl-
edging that these lesions probably contribute to cognitive
decline is important because it gives us a target for exper-
imental studies.
SUMMARY AND CONCLUSIONS
Neuropathology of aging-related brain disease must
take into account diverse medical, technical, biochemical,
and anatomical considerations (Table 3). For example,
concurrent pathologies are very common in aging brains.
These diseases and many other factors are, collectively,
formidable obstacles to aligning pathology and cognition
along linear scales. An extensive literature on CP correlations
in AD indicates a sequence that may begin with specific
genetic and environmental factors that increase risk of
widespread amyloid plaques. At some point, neuritic plaques
appear that combine extracellular amyloid and intracellular
neurofibrillary pathology. Whether independently or not,
NFTs develop first in the allocortex and spread to neocortical
areas. When neocortical NFTs are abundant, neurodegenera-
tion occurs and, over a certain threshold, cognitive impair-
ment is inevitable. The NIARI consensus Bhigh likelihood for
AD[ pathological criteria are approximately 97% specific for
measurable cognitive impairment, and the false-positives
(nondemented persons with plaques and tangles) are brains
in which the highest pathological burden has not been
reached. These results are within realistic expectations for
preclinical AD pathology. Among patients with measurable
clinical disease, the extent of cognitive impairment parallels
the severity of neurofibrillary pathology. In sum, the as-
sociation of plaques and tangles with cognitive impairment in
AD is complex but coherent.
Ó 2008 American Association of Neuropathologists, Inc.
J Neuropathol Exp Neurol  Volume 68, Number 1, January 2009
ACKNOWLEDGMENTS
The authors thank all of the participants in the
longitudinal aging study and brain banks. The authors thank
Richard Kryscio, PhD, and Marta Mendiondo, PhD, for data
management and statistical support; Ela Patel, Ann Tudor,
Paula Thomason, Dr Huaichen Liu, and Sonya Anderson for
technical support; Frederick Schmitt, PhD, Gregory Jicha,
MD, PhD, Charles Smith, MD, Gregory Cooper, MD, PhD,
Nancy Stiles, MD, and Allison Caban-Holt, PhD, for clinical
evaluations; and Daron Davis, MD, and Dianne Wilson,
MD, for pathological assessments.
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