DRAFT 8 JULY, 2011National Institute on Aging–Alzheimer’s Association guidelines for theneuropathologic assessment of Alzh...
DRAFT 8 JULY, 2011The current consensus criteria for the neuropathologic diagnosis of Alzheimer’s disease(AD), the Nationa...
DRAFT 8 JULY, 2011focus of recent NIA-AA sponsored consensus reports on three defined stages in aclinical continuum that i...
DRAFT 8 JULY, 2011AD Neuropathologic ChangeThere are several characteristic neuropathologic changes of AD, of which neurof...
DRAFT 8 JULY, 2011non-neuritic structures called diffuse plaques, cored plaques, amyloid lakes and subpialbands. The situa...
DRAFT 8 JULY, 2011atrophy, gliosis, and other neuronal lesions like TDP-43 immunoreactive inclusions,granulovacuolar degen...
DRAFT 8 JULY, 2011and death = 288 days), or if there was a medical condition felt to be a major contributorto cognitive or...
DRAFT 8 JULY, 2011Other diseases that commonly co-exist with AD neuropathologic changeWhile AD is the most common cause of...
DRAFT 8 JULY, 2011mutations.19, 20 LB are considered to be independent in some circumstances, since notall cases with LB o...
DRAFT 8 JULY, 2011CVD and VBI, which describes parenchymal damage from CVD as well as systemicdysfunction like prolonged h...
DRAFT 8 JULY, 2011Hemorrhages in the brain also are usually classified as grossly visible hemorrhages ormicrohemorrhages, ...
DRAFT 8 JULY, 2011possible co-morbidities is beyond the scope of this paper, we highlight two importantexamples: “tauopath...
DRAFT 8 JULY, 2011Finally, not only can the neuropathologic changes of prion disease be co-morbid withAD, but some forms o...
DRAFT 8 JULY, 2011highlight here issues that would benefit from additional study, recognizing that each"consensus" confere...
DRAFT 8 JULY, 2011assess lesion burden include brain regions investigated, volume of tissue examined,differing sensitivity...
DRAFT 8 JULY, 2011The three parameters of AD neuropathologic change need to be investigated inrelationship to clinical out...
DRAFT 8 JULY, 2011pathologic changes, and to consider the role of new genetic and biomarker data in theneuropathologic eva...
DRAFT 8 JULY, 2011Text Box 1. AD Neuropathologic ChangeMethod. Recommended brain regions for evaluation are in Table 2. Pr...
DRAFT 8 JULY, 2011It is important to recognize that pathologic evaluation can be applied to specimens fromsurgery as well ...
DRAFT 8 JULY, 2011Text Box 2. LBDMethod. Recommended brain regions for evaluation are in Table 2. IHC for α-synucleinis st...
DRAFT 8 JULY, 2011Text Box 3. CVD and VBIMethod. CVD in large vessels should be evaluated by macroscopic examination.Macro...
DRAFT 8 JULY, 2011Text Box 4. HSMethod and Classification. Recommended regions for evaluation are in Table 2. HSshould be ...
DRAFT 8 JULY, 2011Table 1. Frequency (proportion and confidence interval) of each CDR sum of boxesscore for each Braak NFT...
DRAFT 8 JULY, 2011 Table 2. Minimum recommended brain regions to be sampled and regional evaluation. Each brain region sho...
DRAFT 8 JULY, 2011    Table 3. Level of AD Neuropathologic Change                                                         ...
DRAFT 8 JULY, 2011     References     TEXT REQUIRES ADDITIONAL REFERENCES1.     Hyman BT, Trojanowski JQ. Consensus recomm...
DRAFT 8 JULY, 20119.    Nagy Z, Yilmazer-Hanke DM, Braak H, Braak E, et al. Assessment of the      pathological stages of ...
DRAFT 8 JULY, 201120.   Leverenz JB, Fishel MA, Peskind ER, Montine TJ, et al. Lewy body pathology in      familial Alzhei...
DRAFT 8 JULY, 2011      disease center autopsy cohort: neuritic plaques and neurofibrillary tangles "do      count" when s...
DRAFT 8 JULY, 201145.   Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, et al. TDP-43 immunoreactivity      in hippocampal s...
DRAFT 8 JULY, 201156.   Kosaka K. Diffuse neurofibrillary tangles with calcification: a new presenile      dementia. J Neu...
DRAFT 8 JULY, 2011      Aging 31:1805-13. Prodromal clinical manifestations of neuropathologically      confirmed Lewy bod...
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Neuropathologic asses alzh dis

  1. 1. DRAFT 8 JULY, 2011National Institute on Aging–Alzheimer’s Association guidelines for theneuropathologic assessment of Alzheimer’s diseaseCo-chairs: Montine and HymanMembers: Beach, Bigio, Cairns, Dickson, Duyckaerts, Frosch, Masliah, Mirra, Nelson,Phelps, Schneider, Trojanowski, and Vinters 1
  2. 2. DRAFT 8 JULY, 2011The current consensus criteria for the neuropathologic diagnosis of Alzheimer’s disease(AD), the National Institute on Aging/Reagan Institute of the Alzheimer AssociationConsensus Recommendations for the Postmortem Diagnosis of Alzheimer’s Disease orNIA-Reagan Criteria,1 were published in 1997 (hereafter “1997 Criteria”). Knowledge ofAD and the tools used for clinical investigation have advanced substantially since thenand have prompted this update for the neuropathologic assessment of AD.Revised Neuropathologic criteria for Alzheimer’s diseaseThe criteria proposed here for the neuropathologic assessment of AD differ from the1997 Criteria in several respects.The 1997 Criteria require a history of dementia, insofar as they were designed to helpaddress 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 withmilder symptoms,2 including the proposition that there is a preclinical phase of theillness.3 Moreover, data have emerged demonstrating that at least some individualswho, to all reports were cognitively intact during life, are found at autopsy to have arelatively high level of AD neuropathologic change.4, 5 Indeed, substantial evidence nowexists to show that the pathophysiologic processes of AD are present in brain well inadvance of subjective or objective deficits.3 There is consensus to disentangle theclinicopathologic term "Alzheimer disease" from AD neuropathologic change. Theformer refers to clinical signs and symptoms of cognitive and behavioral changes thatare typical for patients who have substantial AD neuropathologic change and is the 2
  3. 3. DRAFT 8 JULY, 2011focus of recent NIA-AA sponsored consensus reports on three defined stages in aclinical continuum that include preclinical,3 mild cognitive impairment,2 and dementia.6The latter refers to the presence and extent of neuropathologic changes of AD observedat autopsy regardless of the clinical setting.The current criteria provide guidance on clinicopathologic correlations to pathologistsreporting autopsy findings based on the literature and analysis of the National AlzheimerCoordinating Center (NACC) database. They emphasize the importance of assessingnon-AD brain lesions in recognition of commonly co-morbid conditions in cognitivelyimpaired elderly. Indeed, pathologic findings for all potentially contributing diseasesneed to be recorded and then integrated with clinical findings in the neuropathologyreport for each person. 3
  4. 4. DRAFT 8 JULY, 2011AD Neuropathologic ChangeThere are several characteristic neuropathologic changes of AD, of which neurofibrillarytangles (NFT) and senile plaques are considered essential for the neuropathologicdiagnosis of AD (Text Box 1). NFT can be visualized with a variety of histochemicalstains or with immunohistochemistry directed against tau or phospho-tau epitopes. NFTcommonly are observed in limbic regions early in the disease but, depending ondisease stage, also involve other brain regions, including association cortex and somesubcortical nuclei.7 The 1997 Criteria utilized a staging scheme for NFT described byBraak and Braak,8 which proposes six stages that can be reduced to four with improvedinter-rater reliability:9 no NFT, stages I/II with NFT predominantly in entorhinal cortexand closely related areas, stages III/IV with NFT more abundant in hippocampus andamygdala while extending slightly into association cortex, and stages V/VI with NFTwidely distributed throughout the neocortex^ and ultimately involving primary motor andsensory areas. Neuropil threads and dystrophic neurites, lesions often associated withNFT, likely represent dendrites and axons of NFT-containing soma that can be used tofurther 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 sixlayers, and is synonymous with “isocortex” and “neopallium”.Senile plaques, the other major component of AD neuropathologic change, areextracellular deposits of the amyloid (A) β peptide but their nomenclature andmorphologic features are complex. Aβ deposits can be at the center of a cluster ofdystrophic neurites that frequently, but not always, have phospho-tau immunoreactivity;these are neuritic plaques. Aβ deposits are morphologically diverse and also include 4
  5. 5. DRAFT 8 JULY, 2011non-neuritic structures called diffuse plaques, cored plaques, amyloid lakes and subpialbands. The situation is further complicated because different types of plaques tend todevelop in different brain regions, and even though all genetic causes of AD have Aβdeposits, they do not invariably have many neuritic plaques.11 Further, Aβ peptides arediverse proteins with heterogeneous lengths, amino- and carboxy-termini and assemblystates that span from small oligomers and protofibrils to fibrils with the physical-chemical properties of amyloid.12Among these different forms of Aβ plaques, neuritic plaques have been considered tobe most closely associated with neuronal injury. Indeed, neuritic plaques are defined bydystrophic neurites within or around deposits of Aβ, and are characterized by greaterlocal synapse loss and glial activation. The 1997 Criteria adopted a previouslydeveloped Consortium to Establish a Registry for AD (CERAD) neuritic plaque scoringsystem, which ranks the amount of neuritic plaques identified histochemically in severalregions of neocortex.13 Several alternative protocols for assessing plaque accumulationhave been proposed, including that of Thal, et al., that proposes phases ofAβ distribution in brain,14 and a hybrid that uses CERAD scoring of Aβ depositsidentified by immunohistochemistry.15 Which, or which combination, of these protocolsoptimally represents this facet of AD neuropathologic change is not clear.Other features of AD neuropathologic change are less straightforward to assess byconventional histopathologic methods or are considered less closely related to neuralsystem damage than NFT and plaques. These include, synapse loss, neuron loss, 5
  6. 6. DRAFT 8 JULY, 2011atrophy, gliosis, and other neuronal lesions like TDP-43 immunoreactive inclusions,granulovacuolar degeneration, and actin immunoreactive Hirano bodies, as well ascongophilic amyloid angiopathy (CAA). In addition, soluble forms of both Aβ and tauhave been implicated in AD pathogenesis, but would not be apparent by morphologicaltechniques.12 It is important to recognize that the recommended use of NFT,parenchymal Aβ deposits, and neuritic plaques as the tractable histopathologic lesionsof AD neuropathologic change in the current criteria does not preclude the possibilitythat other processes or lesions may contribute critically to the pathophysiology of AD.NFT and senile plaques do, however, correlate with the presence of the clinicalsymptoms of AD. For example, the national Alzheimer Coordinating Center (NACC)has collected data on individuals who have come to autopsy and who had beenclinically evaluated in a standardized fashion in one of the approximately 30 AD Centerslocated throughout the United States. While there are limitations to these data, includingthe potential biases introduced by varied cohort selection criteria, and the fact that it isnot a population-based sample, this nonetheless represents one of the largestclinicopathologic correlations yet assembled; as of the end of 2010, data from over 1200autopsies has been collected. We analyzed these data to provide a general guide topathologists for the clinical correlations of various levels of AD neuropathologic change.The sample was narrowed by several criteria: subjects were excluded if the primaryneuropathologic diagnosis was a dementia other than AD, if they had not had a formalclinical evaluation within 2 years of death (mean duration between clinical evaluation 6
  7. 7. DRAFT 8 JULY, 2011and death = 288 days), or if there was a medical condition felt to be a major contributorto cognitive or behavioral impairments. The remaining 562 individuals were thenanalyzed in terms of Braak NFT stage, CERAD neuritic plaque score, and the clinicalDementia Rating Scale sum of boxes score (Table 1). Of these individuals, 95 werereported as being cognitively normal (CDR sum of boxes 0), 52 had very mild symptomsof cognitive impairment (CDR sum of boxes 0.5 to 3.0), and 415 had dementia; of thepatients with dementia, 63 were mild (CDR sum of boxes 3.5 to 6.0), 108 weremoderate (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 overallpattern supports the 1997 Criteria. For individuals with Braak NFT stage V or VI andfrequent CERAD neuritic plaque score, 91% were had moderate or severe dementia.Similarly, there was an intermediate probability of cognitive impairment in individualswith an intermediate level of AD neuropathologic change. For example, just over halfthe individuals with Braak NFT stage III or IV and intermediate CERAD neuritic plaquescore had a diagnosis of at least mild dementia. Finally, although most individuals whowere cognitively normal clustered in the cells with no or low levels of ADneuropathologic change, rare individuals appeared to be able to withstand at least someAD neuropathologic change and remain cognitively intact. Similarly, individuals who hadvery little AD neuropathologic change and no other detected lesions were generallynormal clinically, but an occasional case was reported with dementia despite no obviousneuropathologic explanation. 7
  8. 8. DRAFT 8 JULY, 2011Other diseases that commonly co-exist with AD neuropathologic changeWhile AD is the most common cause of dementia and can exist a in “pure” form, itcommonly co-exists with pathologic changes of other diseases that also can contributeto cognitive impairment. The most common co-morbidities are Lewy body disease(LBD), vascular brain injury (VBI), and hippocampal sclerosis (HS), although these alsomay occur in “pure” forms without co-existing AD neuropathologic change or asneuropathologic features in other diseases. For a given amount of AD neuropathologicchange, cognitive symptoms tend to be worse in the presence of co-morbidities such asLBD or VBI.16 However, it is difficult to judge the extent to which each disease processobserved 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 ofindividuals with AD neuropathologic change.Lewy Body DiseaseLBD 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) areimmunoreactive for α-synuclein and IHC is used for their identification. LBD includes notonly LB but also α-synuclein-immunoreactive neurites (so called “Lewy neurites”) anddiffuse cellular immunoreactivity; these features can be useful even in the absence ofclassical LB.LB are frequent in the setting of moderate to severe levels of AD neuropathologicchange,17, 18 including some early-onset familial AD cases with APP or PSEN1 8
  9. 9. DRAFT 8 JULY, 2011mutations.19, 20 LB are considered to be independent in some circumstances, since notall cases with LB or related changes have AD neuropathologic change; however, thereappears to be a relationship between AD neuropathologic change and LBD because inmost series, subjects with dementia who have the most neocortical LBs also haveconcomitant AD neuropathologic change.21In the clinical setting of cognitive impairment, pure LBD with no or low level of ADneuropathologic 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 ofpatients with Parkinson’s disease, with or without cognitive impairment or dementia, andmay also be observed in some older individuals without clinical history of motor orcognitive deficits; these cases potentially represent preclinical disease.22Following the previous consensus paper on LBD,23 we recommend that LBD beclassified as No LB, Brainstem-Predominant, Limbic (Transitional), Neocortical(Diffuse), or Amygdala-Predominant, understanding that in the clinical context ofcognitive impairment and dementia, LBD may not follow the proposed caudal-rostralprogression of accumulation as reported in the setting of Parkinson’s disease.24 Whilethe olfactory bulb can be involved early in LBD,25-27 we have not included its sampling inthe proposed classification scheme for practical reasons.Cerebrovascular Disease and Vascular Brain Injury 9
  10. 10. DRAFT 8 JULY, 2011CVD and VBI, which describes parenchymal damage from CVD as well as systemicdysfunction like prolonged hypotension or hypoxia,28 increase exponentially with agebeyond the 7th decade of life, similar to AD (Text Box 3). Not surprisingly, evidence ofCVD and VBI commonly is encountered in the brains of those who die with ADneuropathologic change.28-30 The current ability to estimate the relative contributions ofAD or VBI to cognitive impairment in a given individual is limited.31-34The major types of CVD that cause VBI are atherosclerosis, arteriolosclerosis(sometimes described as lipohyalinosis) and CAA.35-38 The presence of CAA, inparticular, further interweaves AD and VBI, since Aβ-positive CAA often occurs togetherwith the other neuropathologic changes of AD.39-41 There are many less common formsof CVD including various forms of vasculitis, CAA from non- Aβ amyloidoses, andinherited diseases that affect vessel integrity, some of which are associated with thedevelopment of cognitive impairment in the absence of AD, e.g., cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).VBI usually is characterized as infarcts or hemorrhages. Infarcts often are classified bysize: territorial infarcts (larger than 1 cm in greatest dimension) in the region supplied bya large basal artery), lacunar infarcts (smaller than 1 cm in greatest dimension butgrossly visible) and microinfarcts (not grossly visible but seen only on microscopicsections).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 whitematter injury; however, these are more difficult to judge objectively than infarcts. 10
  11. 11. DRAFT 8 JULY, 2011Hemorrhages in the brain also are usually classified as grossly visible hemorrhages ormicrohemorrhages, and both are strongly associated with CAA and arteriolosclerosis. Itmay be impossible to distinguish microinfarcts from remote microhemorrhages, and forthis reason, these lesions have been called microvascular lesions (MVL).Hippocampal sclerosisOur 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 pyramidalcell loss and gliosis in CA1 and subiculum of the hippocampal formation that is out ofproportion to AD-type pathology in the same structures.44 HS and TDP-43immunoreactive inclusions are found in 30% or more of cases with AD neuropathologicchange,45, 46 and TDP-43 immunoreactive inclusions are present in as many as 90% ofcases of HS.45, 47, 48 Large autopsy series have shown that HS is correlated withimpaired cognition although this relationship is complex and variable.16, 49 HS in thecontext of VBI or epilepsy may lack aberrant TDP-43 inclusions.49, 50Other Diseases in the Differential Diagnosis of DementiaAD neuropathologic change should be assessed in all cases of dementia. There aremany other neurodegenerative disorders that can cause dementia in addition to thosediscussed 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 11
  12. 12. DRAFT 8 JULY, 2011possible co-morbidities is beyond the scope of this paper, we highlight two importantexamples: “tauopathies” and CJD.The neuropathologic evaluation of FTLD and its subtypes is the subject of anotherrecent consensus conference. For FTLD-TDP and FTLD-FUS, IHC for ubiquitin, alpha-internexin, TDP-43 and FUS can assist.51-53 For FTLD-tau, a careful determination ofthe morphologic changes and distribution of the abnormal tau and neuron loss areimportant in the differential diagnosis. IHC for 3R and 4R tau may be useful in somecases, 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 plaquesmust be carefully observed, since TPSD, CTE, DP, and DNTC tangles, like AD-typeNFT, also contain both 3R and 4R tau.51-56 At this point, making the diagnosis of eitherconcomitant 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 tauopathiessince neuronal lesions in some these diseases may be undetectable by somehistochemical staining methods useful for AD neuropathologic change. Indeed, somecases of FTLD-tau may be Braak NFT stage “None” despite widespread abnormal tauin the neocortex or hippocampus detected by IHC or biochemical methods. 12
  13. 13. DRAFT 8 JULY, 2011Finally, not only can the neuropathologic changes of prion disease be co-morbid withAD, but some forms of prion disease can present neuropathologic changes that overlapwith AD and need to be distinguished with special stains.57Recommendation on BiomarkersWe recommend that genetic risk and biomarkers (chemical and neuroimaging) be usedin research settings to complement neuropathologic data for the postmortem diagnosisof AD. We emphasize, however, that no single finding or combination of findings fromthese modalities currently is known to define better the disease state thanneuropathologic examination. We recognize that this is a rapidly advancing field ofinvestigation and that in the future some combination of genetic testing and biomarkersmay be used as surrogates for neuropathologic changes or functional decline.Comments and Areas for Further ResearchThere is broad agreement in numerous clinicopathologic studies that the extent of NFTcorrelates with severity of dementia, while the extent of senile plaques is less closelytied to the degree of cognitive impairment, perhaps in part due to the heterogeneity ofsenile plaques, the range of methods for their detection, and varying schemes for theirclassification. In agreement with the 1997 Criteria, any AD neuropathologic change isviewed as evidence of disease, and is abnormal. Nonetheless, there are multipleaspects of the neuropathologic evaluation of AD, and of their relationship to cognitivechanges, that may require refinement, both methodologically and conceptually. We 13
  14. 14. DRAFT 8 JULY, 2011highlight 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 ofevaluating all three parameters (A, B, C) of AD neuropathologic change. Since therelative independent value of these three parameters is not currently known, we suggestcollecting data on all three parameters and evaluating their independent value in futureanalyses.Both quantitative and qualitative aspects of AD neuropathologic change havesignificance, but current diagnostic methods are not robustly quantitative and/or notsystematically qualitative. Evaluating the degree of Aβ and phospho-tau accumulationmay rely on estimates of the burden of the lesions in a given region or on a qualitativeassessment of their distribution throughout the brain. For example, the widely employedBraak NFT staging protocol evaluates NFT distribution rather than density. Methods forAβ deposition are less standardized. For example, Thal phases of anatomicaldistribution of amyloid deposits, CERAD ranking of neuritic plaque density, and imageanalysis based evaluation of amyloid load are three methods in common use toestimate this facet of AD. Biochemical assays provide a fourth approach that has theadvantage of also discriminating soluble forms and specific peptides. It was the opinionof 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 additionaldata. Important issues to address when comparing different methods that attempt to 14
  15. 15. DRAFT 8 JULY, 2011assess lesion burden include brain regions investigated, volume of tissue examined,differing sensitivity and specificity among tests, standardization across laboratories andgroups of neuropathologists, and ultimately correlation with function.The idea that Aβ deposition, abnormal tau accumulation, and neuritic plaques reflect themolecular pathology of AD is an oversimplification. The view that they are but a by-product 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 oflesions. New ways of evaluating additional molecular species and of determining theirrelation to the clinical and neuropathologic data need to be developed. Moreover,neuropathologists should continue to pursue the study of the molecular content of themicroscopic changes by established methods and new approaches in both experimentalanimals and in human brain.In addition to the autosomal dominant PSEN1, PSEN2 and APP gene mutations orAPOE ε4 allele, which clearly have a major impact on degree of both plaques and CAAin AD, numerous other genetic variations and environmental risk factors have recentlybeen described; the extent to which these impact the neuropathologic changes of ADremains largely unknown.As new treatments are being evaluated, interpretation of neuropathologic assessmentsmay need to be adapted to the changes that therapeutics may induce. 15
  16. 16. DRAFT 8 JULY, 2011The three parameters of AD neuropathologic change need to be investigated inrelationship to clinical outcomes and laboratory testing, including biofluid biomarkersand neuroimaging.Current consensus pathologic criteria for dementia with LB (DLB) utilize the 1997Criteria 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 havebeen proposed. The revisions in criteria proposed here for the neuropathologicassessment of AD need to be assessed with respect to their impact on DLBclassification using established well-characterized cohorts.Ischemic injury to gray and white matter is much more complex than formation ofinfarcts, hemorrhages, or MVL; however, current pathologists’ tools are limited inassessing this type of damage and need to be expanded.SummaryThe goals of the consensus Committee were to update the 1997 Criteria so as tobroaden the criteria to include all individuals, regardless of clinical history of cognitiveimpairments (which had been required in 1997), emphasizing the nature of thecontinuum of neuropathologic changes that underlie AD and ultimately are associatedwith dementia. The Committee goals also included a renewed emphasis on thecommon role of co-morbid diseases in the neuropathologic evaluation, to define betterthe role of neuropathologic changes of AD in individuals with intermediate levels of 16
  17. 17. DRAFT 8 JULY, 2011pathologic changes, and to consider the role of new genetic and biomarker data in theneuropathologic evaluation of AD changes. A consensus was reached that criteriashould be data based, focused primarily on neuropathologic rather than clinical criteria,and to the extent possible reflect current molecular understanding of diseasemechanisms. The Committee recommends an ABC staging protocol for theneuropathologic changes of AD, based on three morphologic characteristics of thedisease. A change in nomenclature to allow reporting of AD neuropathologic changes inindividuals regardless of cognitive status is recommended. Finally, several issues thatrequire further investigation are highlighted to guide further clinicopathologic studies. 17
  18. 18. DRAFT 8 JULY, 2011Text Box 1. AD Neuropathologic ChangeMethod. Recommended brain regions for evaluation are in Table 2. Preferred methodfor Aβ plaques is IHC for Aβ, and for NFT is IHC for tau or phospho-tau (otheracceptable methods are Thioflavin S or sensitive silver histochemical stains). Preferredmethod for neuitic plaques is Thioflavin S or modified Bielschowsky as recommendedby the CERAD protocol.13 Note that IHC probes for neuritic processes within senileplaques, such as amyloid precursor protein, ubiquitin, neurofilament or phospho-tau, willidentify specific, and partially overlapping, subtypes of dystrophic neurites; thesignificance 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 plaquesA1: neocortical Aβ or amyloid plaques in sections of frontal, temporal, or parietal lobesA2: plus hippocampal Aβ or amyloid plaquesA3: plus neostriatal Aβ or amyloid plaques. Consider determining all five Thal phasesand record these results.B. NFT (modified from Braak and Braak8)B0: no NFTB1: Braak stage I or IIB2: Braak stage III or IVB3: Braak stage V or VIC. Neuritic plaques (modified from CERAD13)C0: no NPC1: CERAD score sparseC2: CERAD score moderateC3: CERAD score frequentNote that while CAA is not considered in these rankings it should be reported (e.g., theVonsattel, et al., staging system for CAA58).Reporting. For all cases, regardless of clinical history, reporting should follow theformat 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 thelevel of AD neuropathologic change according to Table 3. 18
  19. 19. DRAFT 8 JULY, 2011It is important to recognize that pathologic evaluation can be applied to specimens fromsurgery as well as autopsy; however, regional evaluation will be limited in biopsyspecimens. Nevertheless, involvement of the neocortex by NFT indicates B3, whileinvolvement of cerebral cortex by Aβ deposits indicates A1 or possibly a higher score. Inthese 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 ispossible that AD neuropathologic change may predate onset of symptoms by years.3For individuals with cognitive impairment at the time tissue was obtained, “Intermediate”or “High” level (Table 3) of AD neuropathologic change should be considered adequateexplanation of cognitive impairment or dementia. When “Low” level of ADneuropathologic change is observed in the setting of cognitive impairment it is likely thatother diseases are present. In all cases with cognitive impairment, regardless of theextent of AD neuropathologic change, it is essential to determine the presence orabsence as well as extent of other disease(s) that might have contributed to the clinicaldeficits.For cases with incomplete clinical history, large clinicopathologic studies indicate thathigher levels of AD neuropathologic change typically are correlated with greaterlikelihood of cognitive impairment. The National Alzheimer Coordinating Center (NACC)experience is outlined in Table 1. These data may help guide interpretation of resultsfrom autopsies with insufficient clinical history. 19
  20. 20. DRAFT 8 JULY, 2011Text Box 2. LBDMethod. Recommended brain regions for evaluation are in Table 2. IHC for α-synucleinis strongly preferred.59-61 LB may be detected in neurons of medulla, pons and midbrainwith H&E-stained sections; however greater sensitivity can be achieved with IHC, andrelated 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 brainsteminvolvement-Neocortical (Diffuse): LB in frontal, temporal or parietal cortices usually withinvolvement of brainstem and limbic sites, which may include amygdala-Amygdala-Predominant: LB in amygdala with paucity of LB elsewhereReporting. 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 specimensfrom surgery as well as autopsy with the same limitations discussed for ADneuropathologic change.Clinicopathologic correlations should follow these guidelines.For individuals without cognitive impairment at the time tissue was obtained, we stressthat, although much less common than AD, large autopsies series have observed LBDin individuals without apparent cognitive or motor deficit.62-64 This may represent pre-clinical LBD;65-68 however, proof awaits methods of in vivo testing and longitudinalstudies.For individuals with cognitive impairment at the time tissue was obtained, werecommend that Neocortical LBD be considered adequate explanation of cognitiveimpairment or dementia; this does not preclude contribution from other diseases.Brainstem-Predominant or Limbic LBD in the setting of cognitive impairment shouldstimulate consideration of other pathologic processes. Amygdala-Predominant LBDtypically occurs in the context of AD neuropathologic change.18For cases with incomplete clinical history, we note that large clinicopathologic studiesindicate that “Neocortical” LBD is correlated with greater likelihood of cognitiveimpairment.25, 69 20
  21. 21. DRAFT 8 JULY, 2011Text Box 3. CVD and VBIMethod. CVD in large vessels should be evaluated by macroscopic examination.Macroscopic examination also will reveal infarcts and hemorrhages. Screening sectionsfor 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 notbeen rigorously demonstrated.Classification. The extent of different types of CVD should be reported according to astandardized approach.70 All infarcts and hemorrhages observed macroscopicallyshould be documented and include location, size, and age. The location, age, andnumber 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 asautopsy.Clinicopathologic correlations for grossly visible infarcts or hemorrhages shouldfollow classic neuropathologic approaches. Clinical correlations for MVL have beeninvestigated in a few large cohorts. Although there are some differences in approach,the following guidelines have emerged: one MVL identified in standard sections of brainlike those proposed in Table 2 is of unclear relationship to cognitive function, whilemultiple MVL are associated with increased likelihood of cognitive impairment ordementia. 21
  22. 22. DRAFT 8 JULY, 2011Text Box 4. HSMethod and Classification. Recommended regions for evaluation are in Table 2. HSshould 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 andassociated 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 fromIHC.Clinicopathologic correlations are complicated because HS can occur in severaldifferent diseases and may derive from multiple mechanisms. Indeed, HS observed inthe setting of VBI, epilepsy, or FTLD have different clinical implications. Relativelyisolated HS may occur in up to 30% of very old individuals, and in this context it isassociated with TDP-43 immunoreactive inclusions and with cognitive impairment,which may be domain specific.16, 49 22
  23. 23. DRAFT 8 JULY, 2011Table 1. Frequency (proportion and confidence interval) of each CDR sum of boxesscore for each Braak NFT stage and CERAD neuritic plaque score combination fromthe National Alzheimer Coordinating Center Data Set, 2005-2010. 23
  24. 24. DRAFT 8 JULY, 2011 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. AD LBD MVL & HS A B C Region Stain Stain Stain Stain for H&E for Aβ for NFT for NP LBMedulla including DMV H&E3Pons including LC H&E3Midbrain including SN Consider H&E3Cerebellar cortex and dentate n. ConsiderThalamus and subthalamic n.1 MVLBasal ganglia at level of AC with Yes Consider MVLbasal nucleus of Meynert1Hippocampus and EC1 Yes2 Yes Consider One or HSCingulate, anterior both if screen +Amygdala IHC3Middle frontal gyrus1 Yes 2 Yes Yes At least MVLSuperior & middle temporal gyri1 Yes2 Yes Yes one if MVLInferior parietal lobule1 Yes2 Yes Yes screen + MVLOccipital cortex1 Consider Yes Consider MVL 1 consider taking bilateral sections if both cerebral hemispheres are available 2 screen leptomeningeal and parenchymal vessels for CAA 3 Screen 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 24
  25. 25. DRAFT 8 JULY, 2011 Table 3. Level of AD Neuropathologic Change B NFT Stage (Braak)1 A C 0 1 2 3 Aβ deposits Neuritic Plaque Score (CERAD)3 (none) (I/II) (III/IV) (V/VI)(Thal Phases)2 0 0 Not AD Not AD4 Not AD4 Not AD4 (none) 0 1, 2, or 3 Low Low Low Low to Intermediate5 (none) 1 1, 2, or 3 Low Low Low Intermediate5 (sparse) 2 or 3 1, 2, or 3 (moderate or Low6 Low6 Intermediate High frequent) 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. 25
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