Co-chairs:
Montine and Hyman
Members: Beach, Bigio, Cairns, Dickson,
Duyckaerts, Frosch, Masliah, Mirra, Nelson, Phelps, Schneider, Trojanowski,
and Vinters
The current consensus criteria for the neuropathologic diagnosis of
Alzheimer’sdisease (AD), the National Institute on Aging/Reagan Institute of
the Alzheimer Association Consensus Recommendations for the Postmortem
Diagnosis of Alzheimer’s Disease or NIA-Reagan Criteria,[1] were published
in 1997 (hereafter “1997 Criteria”). Knowledge of AD and the tools used for
clinical investigation have advanced substantially since then and have
prompted this update for the neuropathologic assessment of AD.
Revised Neuropathologic criteria for Alzheimer’s
disease
The criteria proposed here for the neuropathologic assessment of AD differ
from the 1997 Criteria in several respects.
The 1997 Criteria require a history of dementia, insofar as they were
designed to help address the question of whether AD was the underlying cause
of the patient’s dementia. From the clinical perspective, the concept of AD
has evolved to include patients with milder symptoms,[2] including the
proposition that there is a preclinical phase of the illness.[3] Moreover,
data have emerged demonstrating that at least some individuals who, to all
reports were cognitively intact during life, are found at autopsy to have a
relatively high level of AD neuropathologic change.[4, 5] Indeed,
substantial evidence now exists to show that the pathophysiologic processes
of AD are present in brain well in advance of subjective or objective
deficits.[3] There is consensus to disentangle the clinicopathologic term
"Alzheimer disease" from AD neuropathologic change. The former refers to
clinical signs and symptoms of cognitive and behavioral changes that are
typical for patients who have substantial AD neuropathologic change and is
the focus of recent NIA-AA sponsored consensus reports on three defined
stages in a clinical continuum that include preclinical,[3] mild cognitive
impairment,[2] and dementia.[6] The latter refers to the presence and extent
of neuropathologic changes of AD observed at autopsy regardless of the
clinical setting.
The current criteria provide guidance on clinicopathologic correlations to
pathologists reporting autopsy findings based on the literature and analysis
of the National Alzheimer Coordinating Center (NACC) database. They
emphasize the importance of assessing non-AD brain lesions in recognition of
commonly co-morbid conditions in cognitively impaired elderly. Indeed,
pathologic findings for all potentially contributing diseases need to be
recorded and then integrated with clinical findings in the neuropathology
report for each person.
AD Neuropathologic Change
There are several characteristic neuropathologic
changes of AD, of which neurofibrillary tangles (NFT) and senile plaques are
considered essential for the neuropathologic diagnosis of AD (Text
Box 1). NFT can be visualized with a
variety of histochemical stains or with immunohistochemistry directed
against tau or phospho-tau epitopes. NFT commonly are observed in limbic
regions early in the disease but, depending on disease stage, also involve
other brain regions, including association cortex and some subcortical
nuclei.[7] The 1997 Criteria utilized a staging scheme for NFT described by
Braak and Braak,[8] which proposes six stages that can be reduced to four
with improved inter-rater reliability:[9] no NFT, stages I/II with NFT
predominantly in entorhinal cortex and closely related areas, stages III/IV
with NFT more abundant in hippocampus and amygdala while extending slightly
into association cortex, and stages V/VI with NFT widely distributed
throughout the neocortex* and ultimately involving primary motor and sensory
areas. Neuropil threads and dystrophic neurites, lesions often associated
with NFT, likely represent dendrites and axons of NFT-containing soma that
can be used to further elaborate disease,[10] but are not part of NFT
staging.
*Neocortex refers to the evolutionarily most
recent portion of the cerebral cortex that is characterized by nerve cells
arranged in six layers, and is synonymous with “isocortex” and “neopallium”.
Senile plaques, the other major component of AD neuropathologic change, are
extracellular deposits of the amyloid (A) β peptide but their nomenclature
and morphologic features are complex. Aβ deposits can be at the center of a
cluster of dystrophic neurites that frequently, but not always, have
phospho-tau immunoreactivity; these are neuritic plaques. Aβ deposits are
morphologically diverse and also include non-neuritic structures called
diffuse plaques, cored plaques, amyloid lakes and subpial bands. The
situation is further complicated because different types of plaques tend to
develop in different brain regions, and even though all genetic causes of AD
have Aβ deposits, they do not invariably have many neuritic plaques.[11]
Further, Aβ peptides are diverse proteins with heterogeneous lengths, amino-
and carboxy-termini and assembly states that span from small oligomers and
protofibrils to fibrils with the physicalchemical properties of amyloid.[12]
Among these different forms of Aβ plaques, neuritic plaques have been
considered to be most closely associated with neuronal injury. Indeed,
neuritic plaques are defined by dystrophic neurites within or around
deposits of Aβ, and are characterized by greater local synapse loss and
glial activation. The 1997 Criteria adopted a previously developed
Consortium to Establish a Registry for AD (CERAD) neuritic plaque scoring
system, which ranks the amount of neuritic plaques identified
histochemically in several regions of neocortex.[13] Several alternative
protocols for assessing plaque accumulation have been proposed, including
that of Thal, et al., that proposes phases of Aβ distribution in brain,[14]
and a hybrid that uses CERAD scoring of Aβ deposits identified by
immunohistochemistry.[15] Which, or which combination, of these protocols
optimally represents this facet of AD neuropathologic change is not clear.
Other features of AD neuropathologic change are less straightforward to
assess by conventional histopathologic methods or are considered less
closely related to neural system damage than NFT and plaques. These include,
synapse loss, neuron loss, atrophy, gliosis, and other neuronal lesions like
TDP-43 immunoreactive inclusions, granulovacuolar degeneration, and actin
immunoreactive Hirano bodies, as well as congophilic amyloid angiopathy
(CAA). In addition, soluble forms of both Aβ and tau have been implicated in
AD pathogenesis, but would not be apparent by morphological techniques.[12]
It is important to recognize that the recommended use of NFT, parenchymal Aβ
deposits, and neuritic plaques as the tractable histopathologic lesions of
AD neuropathologic change in the current criteria does not preclude the
possibility that other processes or lesions may contribute critically to the
pathophysiology of AD.
NFT and senile plaques do, however, correlate with the presence of the
clinical symptoms of AD. For example, the national Alzheimer Coordinating
Center (NACC) has collected data on individuals who have come to autopsy and
who had been clinically evaluated in a standardized fashion in one of the
approximately 30 AD Centers located throughout the United States. While
there are limitations to these data, including the potential biases
introduced by varied cohort selection criteria, and the fact that it is not
a population-based sample, this nonetheless represents one of the largest
clinicopathologic correlations yet assembled; as of the end of 2010, data
from over 1200 autopsies has been collected. We analyzed these data to
provide a general guide to pathologists for the clinical correlations of
various levels of AD neuropathologic change.
The sample was narrowed by several criteria: subjects were excluded if the
primary neuropathologic diagnosis was a dementia other than AD, if they had
not had a formal clinical evaluation within 2 years of death (mean duration
between clinical evaluation and death = 288 days), or if there was a medical
condition felt to be a major contributor to cognitive or behavioral
impairments. The remaining 562 individuals were then analyzed in terms of
Braak NFT stage, CERAD neuritic plaque score, and the clinical Dementia
Rating Scale sum of boxes score (Table 1).
Of these individuals, 95 were reported as being cognitively normal (CDR sum
of boxes 0), 52 had very mild symptoms of cognitive impairment (CDR sum of
boxes 0.5 to 3.0), and 415 had dementia; of the patients with dementia, 63
were mild (CDR sum of boxes 3.5 to 6.0), 108 were moderate (CDR sum of boxes
6.5 to 12), and 244 were severe (CDR sum of boxes > 12). Although the number
of individuals in some cells is relatively modest, the overall pattern
supports the 1997 Criteria. For individuals with Braak NFT stage V or VI and
frequent CERAD neuritic plaque score, 91% were had moderate or severe
dementia. Similarly, there was an intermediate probability of cognitive
impairment in individuals with an intermediate level of AD neuropathologic
change. For example, just over half the individuals with Braak NFT stage III
or IV and intermediate CERAD neuritic plaque score had a diagnosis of at
least mild dementia. Finally, although most individuals who were cognitively
normal clustered in the cells with no or low levels of AD neuropathologic
change, rare individuals appeared to be able to withstand at least some AD
neuropathologic change and remain cognitively intact. Similarly, individuals
who had very little AD neuropathologic change and no other detected lesions
were generally normal clinically, but an occasional case was reported with
dementia despite no obvious neuropathologic explanation.
Other diseases that commonly co-exist with AD
neuropathologic change
While AD is the most common cause of dementia and can exist in a “pure”
form, it commonly co-exists with pathologic changes of other diseases that
also can contribute to cognitive impairment. The most common co-morbidities
are Lewy body disease (LBD), vascular brain injury (VBI), and hippocampal
sclerosis (HS), although these also may occur in “pure” forms without
co-existing AD neuropathologic change or as neuropathologic features in
other diseases. For a given amount of AD neuropathologic change, cognitive
symptoms tend to be worse in the presence of co-morbidities such as LBD or
VBI.[16] However, it is difficult to judge the extent to which each disease
process observed at autopsy may have contributed to a given patient’s
clinical course. Nevertheless, it is critical to document the type and
extent of co-morbidity in brains of individuals with AD neuropathologic
change.
Lewy Body Disease
LBD is a subset of diseases that shares the feature of abnormal accumulation
of α-synuclein in regions of brain (Text Box 2). Indeed, Lewy bodies (LB)
are immunoreactive for α-synuclein and IHC is used for their identification.
LBD includes not only LB but also α-synuclein-immunoreactive neurites (so
called “Lewy neurites”) and diffuse cellular immunoreactivity; these
features can be useful even in the absence of classical LB.
LB are frequent in the setting of moderate to severe levels of AD
neuropathologic change,[17, 18] including some early-onset familial AD cases
with APP or PSEN1 mutations.[19, 20] LB are considered to be independent in
some circumstances, since not all cases with LB or related changes have AD
neuropathologic change; however, there appears to be a relationship between
AD neuropathologic change and LBD because in most series, subjects with
dementia who have the most neocortical LBs also have concomitant AD
neuropathologic change.[21]
In the clinical setting of cognitive impairment, pure LBD with no or low
level of AD neuropathologic change is relatively rare and most often seen in
younger individuals, including those with mutations in the gene for
α-synuclein. LBD also is characteristic of patients with Parkinson’s
disease, with or without cognitive impairment or dementia, and may also be
observed in some older individuals without clinical history of motor or
cognitive deficits; these cases potentially represent preclinical
disease.[22]
Following the previous consensus paper on LBD,[23] we recommend that LBD be
classified as No LB, Brainstem-Predominant, Limbic (Transitional),
Neocortical (Diffuse), or Amygdala-Predominant, understanding that in the
clinical context of cognitive impairment and dementia, LBD may not follow
the proposed caudal-rostral progression of accumulation as reported in the
setting of Parkinson’s disease.[24] While the olfactory bulb can be involved
early in LBD,[25-27] we have not included its sampling in the proposed
classification scheme for practical reasons.
Cerebrovascular Disease and Vascular Brain Injury
CVD and VBI, which describes parenchymal damage from CVD as well as systemic
dysfunction like prolonged hypotension or hypoxia,[28] increase
exponentially with age beyond the 7th decade of life, similar to AD (Text
Box 3). Not surprisingly, evidence of CVD
and VBI commonly is encountered in the brains of those who die with AD
neuropathologic change.[28-30] The current ability to estimate the relative
contributions of AD or VBI to cognitive impairment in a given individual is
limited.[31-34]
The major types of CVD that cause VBI are atherosclerosis,
arteriolosclerosis (sometimes described as lipohyalinosis) and CAA.[35-38]
The presence of CAA, in particular, further interweaves AD and VBI, since
Aβ-positive CAA often occurs together with the other neuropathologic changes
of AD.[39-41] There are many less common forms of CVD including various
forms of vasculitis, CAA from non- Aβ amyloidoses, and inherited diseases
that affect vessel integrity, some of which are associated with the
development of cognitive impairment in the absence of AD, e.g., cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL).
VBI usually is characterized as infarcts or hemorrhages. Infarcts often are
classified by size: territorial infarcts (larger than 1 cm in greatest
dimension) in the region supplied by a large basal artery), lacunar infarcts
(smaller than 1 cm in greatest dimension but grossly visible) and
microinfarcts (not grossly visible but seen only on microscopic
sections).[35, 38, 42] The last appear to have various etiologies, including
emboli, arteriosclerosis, and CAA.[43] Other forms of ischemic injury occur,
such as diffuse white matter injury; however, these are more difficult to
judge objectively than infarcts.
Hemorrhages in the brain also are usually classified as grossly visible
hemorrhages or microhemorrhages, and both are strongly associated with CAA
and arteriolosclerosis. It may be impossible to distinguish microinfarcts
from remote microhemorrhages, and for this reason, these lesions have been
called microvascular lesions (MVL).
Hippocampal sclerosis
Our understanding of HS and its relationship to AD, frontotemporal lobar
degeneration (FTLD, vide infra), and VBI is evolving rapidly (Text
Box 4). HS is defined by pyramidal cell
loss and gliosis in CA1 and subiculum of the hippocampal formation that is
out of proportion to AD-type pathology in the same structures.[44] HS and
TDP-43 immunoreactive inclusions are found in 30% or more of cases with AD
neuropathologic change,[45, 46] and TDP-43 immunoreactive inclusions are
present in as many as 90% of cases of HS.[45, 47, 48] Large autopsy series
have shown that HS is correlated with impaired cognition although this
relationship is complex and variable.[16, 49] HS in the context of VBI or
epilepsy may lack aberrant TDP-43 inclusions.[49, 50]
Other Diseases in the Differential Diagnosis of
Dementia
AD neuropathologic change should be assessed in all cases of dementia. There
are many other neurodegenerative disorders that can cause dementia in
addition to those discussed so far, and any may be co-morbid with AD
neuropathologic change, especially in the elderly. Although providing
specific protocols for the diagnosis of all possible co-morbidities is
beyond the scope of this paper, we highlight two important examples:
“tauopathies” and CJD.
The neuropathologic evaluation of FTLD and its subtypes is the subject of
another recent consensus conference. For FTLD-TDP and FTLD-FUS, IHC for
ubiquitin, alphainternexin, TDP-43 and FUS can assist.[51-53] For FTLD-tau,
a careful determination of the morphologic changes and distribution of the
abnormal tau and neuron loss are important in the differential diagnosis.
IHC for 3R and 4R tau may be useful in some cases, while biochemical
characterization of tau abnormalities, e.g., Western blot, remains a
research adjunct to neuropathologic diagnosis.[51-53] For some tauopathies,
such as tangle-predominant senile dementia (TPSD), chronic traumatic
encephalopathy (CTE), dementia pugilistica (DP), or diffuse neurofibrillary
tangles with calcification (DNTC), the distribution and density of tangles
and the paucity of neocortical plaques must be carefully observed, since
TPSD, CTE, DP, and DNTC tangles, like AD-type NFT, also contain both 3R and
4R tau.[51-56] At this point, making the diagnosis of either concomitant
FTLD-UPS or FTLD-ni (DLDH) in cases with AD may not be possible.
A note of caution is warranted concerning Braak NFT staging in non-AD
tauopathies since neuronal lesions in some these diseases may be
undetectable by some histochemical staining methods useful for AD
neuropathologic change. Indeed, some cases of FTLD-tau may be Braak NFT
stage “None” despite widespread abnormal tau in the neocortex or hippocampus
detected by IHC or biochemical methods.
Finally, not only can the neuropathologic changes of prion disease be
co-morbid with
AD, but some forms of prion disease can present
neuropathologic changes that overlap with AD and need to be distinguished
with special stains.[57]
Recommendation on Biomarkers
We recommend that genetic risk and biomarkers (chemical and neuroimaging) be
used in research settings to complement neuropathologic data for the
postmortem diagnosis of AD. We emphasize, however, that no single finding or
combination of findings from these modalities currently is known to define
better the disease state than neuropathologic examination. We recognize that
this is a rapidly advancing field of investigation and that in the future
some combination of genetic testing and biomarkers may be used as surrogates
for neuropathologic changes or functional decline.
Comments and Areas for Further Research
There is broad agreement in numerous clinicopathologic studies that the
extent of NFT correlates with severity of dementia, while the extent of
senile plaques is less closely tied to the degree of cognitive impairment,
perhaps in part due to the heterogeneity of senile plaques, the range of
methods for their detection, and varying schemes for their classification.
In agreement with the 1997 Criteria, any AD neuropathologic change is viewed
as evidence of disease, and is abnormal. Nonetheless, there are multiple
aspects of the neuropathologic evaluation of AD, and of their relationship
to cognitive changes, that may require refinement, both methodologically and
conceptually. We highlight here issues that would benefit from additional
study, recognizing that each "consensus" conference both addresses issues as
well as raises questions.
A major point of discussion among committee members was the relative value
of evaluating all three parameters (A, B, C) of AD neuropathologic change.
Since the relative independent value of these three parameters is
not currently known, we suggest collecting data on all three parameters and
evaluating their independent value in future analyses.
Both quantitative and qualitative aspects of AD neuropathologic change
have significance, but current diagnostic methods are not robustly
quantitative and/or not systematically qualitative. Evaluating the degree of
Aβ and phospho-tau accumulation may rely on estimates of the burden of the
lesions in a given region or on a qualitative assessment of their
distribution throughout the brain. For example, the widely employed Braak
NFT staging protocol evaluates NFT distribution rather than density. Methods
for Aβ deposition are less standardized. For example, Thal phases of
anatomical distribution of amyloid deposits, CERAD ranking of neuritic
plaque density, and image analysis based evaluation of amyloid load are
three methods in common use to estimate this facet of AD. Biochemical assays
provide a fourth approach that has the advantage of also discriminating
soluble forms and specific peptides. It was the opinion of this committee
that it is not yet clear if one of these methods is superior to any other.
Indeed, this point engendered much discussion, highlighting the need for
additional data. Important issues to address when comparing different
methods that attempt to assess lesion burden include brain regions
investigated, volume of tissue examined, differing sensitivity and
specificity among tests, standardization across laboratories and groups of
neuropathologists, and ultimately correlation with function.
The idea that Aβ deposition, abnormal tau accumulation, and neuritic plaques
reflect the molecular pathology of AD is an oversimplification. The view
that they are but a byproduct of a hidden mechanism cannot be ruled out from
current data; for example, oligomeric Aβ and nonfibrillar tau have been
considered key players in the cascade of lesions. New ways of evaluating
additional molecular species and of determining their relation to the
clinical and neuropathologic data need to be developed. Moreover,
neuropathologists should continue to pursue the study of the molecular
content of the microscopic changes by established methods and new approaches
in both experimental animals and in human brain.
In addition to the autosomal dominant PSEN1, PSEN2 and APP gene mutations or
APOE ε4 allele, which clearly have a major impact on degree of both plaques
and CAA in AD, numerous other genetic variations and environmental risk
factors have recently been described; the extent to which these impact the
neuropathologic changes of AD remains largely unknown.
As new treatments are being evaluated, interpretation of neuropathologic
assessments may need to be adapted to the changes that therapeutics may
induce.
The three parameters of AD neuropathologic change need to be investigated in
relationship to clinical outcomes and laboratory testing, including biofluid
biomarkers and neuroimaging.
Current consensus pathologic criteria for dementia with LB (DLB) utilize the
1997 Criteria for AD and a method for assessing the severity and
distribution of LB (i.e., brainstem-predominant, limbic, and diffuse
neocortical types),[23] and refinements have been proposed. The revisions in
criteria proposed here for the neuropathologic assessment of AD need to be
assessed with respect to their impact on DLB classification using
established well-characterized cohorts. Ischemic injury to gray and white
matter is much more complex than formation of infarcts, hemorrhages, or MVL;
however, current pathologists’ tools are limited in assessing this type of
damage and need to be expanded.
Summary
The goals of the consensus Committee were to update the 1997 Criteria so as
to broaden the criteria to include all individuals, regardless of clinical
history of cognitive impairments (which had been required in 1997),
emphasizing the nature of the continuum of neuropathologic changes that
underlie AD and ultimately are associated with dementia. The Committee goals
also included a renewed emphasis on the common role of co-morbid diseases in
the neuropathologic evaluation, to define better the role of neuropathologic
changes of AD in individuals with intermediate levels of pathologic changes,
and to consider the role of new genetic and biomarker data in the
neuropathologic evaluation of AD changes. A consensus was reached that
criteria should be data based, focused primarily on neuropathologic rather
than clinical criteria, and to the extent possible reflect current molecular
understanding of disease mechanisms. The Committee recommends an ABC staging
protocol for the neuropathologic changes of AD, based on three morphologic
characteristics of the disease. A change in nomenclature to allow reporting
of AD neuropathologic changes in individuals regardless of cognitive status
is recommended. Finally, several issues that require further investigation
are highlighted to guide further clinicopathologic studies.
Text Box 1. AD Neuropathologic Change
Method.
Recommended brain regions for evaluation are in
Table 2.
Preferred method for Aβ plaques is IHC for Aβ, and for NFT is IHC for tau or
phospho-tau (other acceptable methods are Thioflavin S or sensitive silver
histochemical stains). Preferred method for neuitic plaques is Thioflavin S
or modified Bielschowsky as recommended by the CERAD protocol.[13] Note that
IHC probes for neuritic processes within senile plaques, such as amyloid
precursor protein, ubiquitin, neurofilament or phospho-tau, will identify
specific, and partially overlapping, subtypes of dystrophic neurites; the
significance of these specific subtypes of neuritic plaques has not been
established.
Classification.
AD Neuropathologic change should be ranked along three parameters (Table
3) to obtain an “ABC score”:
A. Aβ plaques (modified from Thal, et al.[14]):
A0: no Aβ or amyloid plaques
A1: neocortical Aβ or amyloid plaques in
sections of frontal, temporal, or parietal lobes
A2: plus hippocampal Aβ
or amyloid plaques
A3: plus neostriatal Aβ or amyloid plaques. Consider
determining all five Thal phases and record these results.
B. NFT
(modified from Braak and Braak[8])
B0: no NFT
B1: Braak stage I or II
B2: Braak stage III or IV
B3: Braak stage V or VI
C. Neuritic
plaques (modified from CERAD[13])
C0: no NP
C1: CERAD score sparse
C2: CERAD score moderate
C3: CERAD score frequent
Note that while CAA is not considered in these rankings it should be
reported (e.g., the Vonsattel, et al., staging system for CAA [58]).
Reporting. For
all cases, regardless of clinical history, reporting should follow the
format of these examples:
“Alzheimer Disease Neuropathologic Changes: A1, B0, C0” or
“Alzheimer Disease Neuropathologic Changes: A3, B3, C3”
The ABC scores are transformed into one of four tiered summary descriptors
of the level of AD neuropathologic change according to
Table 3.
It is important to recognize that pathologic evaluation can be applied to
specimens from surgery as well as autopsy; however, regional evaluation will
be limited in biopsy specimens. Nevertheless, involvement of the neocortex
by NFT indicates B3, while involvement of cerebral cortex by Aβ deposits
indicates A1 or possibly a higher score. In these circumstances, the
neuritic plaque score may be especially important.
Clinicopathologic correlations
should follow these guidelines.
For individuals without
cognitive impairment at the
time tissue was obtained, it is possible that AD neuropathologic change may
predate onset of symptoms by years.[3]
For individuals with cognitive impairment at the time tissue was
obtained, “Intermediate” or “High” level (Table
3) of AD neuropathologic change should be
considered adequate explanation of cognitive impairment or dementia. When
“Low” level of AD neuropathologic change is observed in the setting of
cognitive impairment it is likely that other diseases are present. In all
cases with cognitive impairment, regardless of the extent of AD
neuropathologic change, it is essential to determine the presence or absence
as well as extent of other disease(s) that might have contributed to the
clinical deficits.
For cases with incomplete clinical history, large clinicopathologic
studies indicate that higher levels of AD neuropathologic change typically
are correlated with greater likelihood of cognitive impairment. The National
Alzheimer Coordinating Center (NACC) experience is outlined in
Table 1. These
data may help guide interpretation of results from autopsies with
insufficient clinical history.
Text Box 2. LBD
Method.
Recommended brain regions for evaluation are in
Table 2. IHC
for α-synuclein is strongly preferred.[59-61] LB may be detected in neurons
of medulla, pons and midbrain with H&E-stained sections; however greater
sensitivity can be achieved with IHC, and related abnormalities in
α-synuclein will be unapparent by H&E.
Classification
(modified from McKeith, et al.[23])
-No LBD
-Brainstem-predominant: LB in medulla,
pons, or midbrain
-Limbic (Transitional): LB in cingulate or entorhinal
cortices usually with brainstem involvement
-Neocortical (Diffuse): LB in
frontal, temporal or parietal cortices usually with involvement of brainstem
and limbic sites, which may include amygdala
-Amygdala-Predominant: LB in
amygdala with paucity of LB elsewhere
Reporting.
Reporting should follow the format of these examples:
“Lewy Body Disease, Limbic” or
“Lewy Body Disease, Amygdala-Predominant”
Again, it is important to recognize that these classifications can be
applied to specimens from surgery as well as autopsy with the same
limitations discussed for AD neuropathologic change.
Clinicopathologic correlations should
follow these guidelines.
For individuals without cognitive impairment at the time tissue was
obtained, we stress that, although much less common than AD, large autopsies
series have observed LBD in individuals without apparent cognitive or motor
deficit.[62-64] This may represent preclinical LBD;[65-68] however, proof
awaits methods of in vivo testing and longitudinal studies.
For individuals with cognitive impairment at the time tissue was
obtained, we recommend that Neocortical LBD be considered adequate
explanation of cognitive impairment or dementia; this does not preclude
contribution from other diseases. Brainstem-Predominant or Limbic LBD in the
setting of cognitive impairment should stimulate consideration of other
pathologic processes. Amygdala-Predominant LBD typically occurs in the
context of AD neuropathologic change.[18]
For cases with incomplete clinical history, we note that large
clinicopathologic studies indicate that “Neocortical” LBD is correlated with
greater likelihood of cognitive impairment.[25, 69]
Text Box 3. CVD and VBI
Method. CVD in
large vessels should be evaluated by macroscopic examination. Macroscopic
examination also will reveal infarcts and hemorrhages. Screening sections
for MVL as potential contributors to cognitive impairment are listed in
Table 2. IHC,
such as for GFAP, may increase sensitivity for detection of MVL; however,
this has not been rigorously demonstrated.
Classification.
The extent of different types of CVD should be reported according to a
standardized approach.[70] All infarcts and hemorrhages observed
macroscopically should be documented and include location, size, and age.
The location, age, and number of MVL in standard screening sections should
be recorded.
Reporting.
Reporting should follow the format of these examples:
“Cerebrovascular
disease:
Atherosclerosis, non-occlusive, affecting
basilar artery, left internal carotid artery and middle cerebral
artery”
“Arteriolosclerosis, widespread involvement of
hemispheric white matter” |
“Vascular brain injury:
Infarct in the territory of the left
middle cerebral artery, remote, measuring 3 x 3 x 2 cm”
“Lacunar
infarct, right anterior caudate, remote, measuring 0.5 x 0.3 x 0.2
cm”
“Microvascular lesions: 2 remote lesions detected on standard
sections (right middle frontal gyrus and right inferior parietal
lobule)” |
Evaluation of CVD and VBI can be applied to specimens from surgery as well
as autopsy.
Clinicopathologic correlations
for grossly visible infarcts or hemorrhages should follow classic
neuropathologic approaches. Clinical correlations for MVL have been
investigated in a few large cohorts. Although there are some differences in
approach, the following guidelines have emerged: one MVL identified in
standard sections of brain like those proposed in
Table 2 is of
unclear relationship to cognitive function, while multiple MVL are
associated with increased likelihood of cognitive impairment or dementia.
Text Box 4. HS
Method and Classification.
Recommended regions for evaluation are in
Table 2. HS should be evaluated by
H&E-stained sections as described above. If HS is present, further
evaluation is indicated, including TDP-43 IHC. If negative for TDP-43 and
associated with other evidence to suggest FTLD, consider IHC for ubiquitin
or FUS.
Reporting. HS
should be reported as present or absent with description of results from
IHC.
Clinicopathologic correlations are
complicated because HS can occur in several different diseases and may
derive from multiple mechanisms. Indeed, HS observed in the setting of VBI,
epilepsy, or FTLD have different clinical implications. Relatively isolated
HS may occur in up to 30% of very old individuals, and in this context it is
associated with TDP-43 immunoreactive inclusions and with cognitive
impairment, which may be domain specific.[16, 49]
Table 1.
Frequency (proportion and confidence interval) of each CDR sum of boxes
score for each Braak NFT stage and CERAD neuritic plaque score combination
from the National Alzheimer Coordinating Center Data Set, 2005-2010.
Table 2. Minimum recommended brain regions to be
sampled and regional evaluation. Each brain region should receive a
hematoxylin and eosin (H&E) stain). H&E-stained sections for screening in
the evaluation for MVL and HS are designated. Regions for
immunohistochemical evaluation of AD neuropathologic change and LBD are
listed. Other lesions should be sampled as appropriate.
1consider taking bilateral sections if
both cerebral hemispheres are available
2screen leptomeningeal
and parenchymal vessels for CAA
3Screen for LB with H&E in
brainstem and IHC in amygdala. If positive, then expand IHC for LB in
brainstem, limbic, and neocortical regions.
Abbreviations:
DMV=dorsal motor nucleus of the vagus, LC=locus ceruleus, SN=substantia
nigra, AC=anterior commissure, EC=entorrhinal cortex
Table 3. Level of AD Neuropathologic Change
 |
1. NFT stage should be determined by the method
of Braak and Braak.[8] Note that Braak staging should be attempted in all
cases regardless of the presence of coexisting diseases.
2. Aβ deposits
should be determined by the method of Thal, et al.[14]
3. Neuritic plaque
score should be determined by the method of CERAD.[13]
4. Medial temporal
lobe NFT in the absence of significant Aβ or neuritic plaque accumulation.
This occurs in older people and may be seen in individuals without cognitive
impairment, mild impairment, or those with cognitive impairment from causes
other than AD. Consider other diseases when clinically indicated.[71]
5.
Widespread NFT with some Aβ accumulation but limited neuritic plaques. These
two categories are relatively infrequent and other diseases, particularly a
tauopathy, should be considered. Such cases may not fit easily into a
specific Braak stage, which is intended for categorization of AD-type NFT.
AD neuropathologic change should be categorized as “Low” for Thal phases 1
and 2 and “Intermediate” for Thal phase 3.
6. Moderate or Frequent NPs
with low Braak stage. Consider contribution of co-morbidities like vascular
brain injury, Lewy body disease, or hippocampal sclerosis. Also, consider
additional sections as well as repeat or additional protocols to demonstrate
other non-AD lesions.
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