University of Thessaly
University of Thessaly


University of Thessaly-Medical Department

University of Thessaly-Medical School
   
ISSN: 1792-801X






Bibliographic
Search

PubMed



Heal link



Scorpus











September 25, 2011 9th HelMedica Issue  Article 4th
NATIONAL INSTITUTE ON AGING
Title : ALZHEIMER’S ASSOCIATION GUIDELINES FOR THE
NEUROPATHOLOGIC ASSESSMENT OF ALZHEIMER’S DISEASE.

  

Assiduity : Tsintou Magdalini*
Department : Medical School, University of Thessaly
*Editor in Chief, reviewer, webmaster.

Download this article.


        

          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.

 

 

 

 

References

TEXT REQUIRES ADDITIONAL REFERENCES

1. Hyman BT, Trojanowski JQ. Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 1997; 56:1095-7. Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease
2. Albert MS, Dekosky ST, Dickson D, Dubois B, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7:270-9. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
3. Sperling RA, Aisen PS, Beckett LA, Bennett DA, et al. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7:280-92. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
4. Crystal H, Dickson D, Fuld P, Masur D, et al. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology 1988; 38:1682-7. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease
5. Price JL, McKeel DW, Jr., Buckles VD, Roe CM, et al. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 2009; 30:1026-36. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease
6. McKhann GM, Knopman DS, Chertkow H, Hyman BT, et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7:263-9. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
7. Braak H, Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol 2011; 121:171-81. The pathological process underlying Alzheimer's disease in individuals under thirty
8. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82:239-59. Neuropathological stageing of Alzheimer-related changes
9. Nagy Z, Yilmazer-Hanke DM, Braak H, Braak E, et al. Assessment of the pathological stages of Alzheimer's disease in thin paraffin sections: a comparative study. Dement Geriatr Cogn Disord 1998; 9:140-4. Assessment of the pathological stages of Alzheimer's disease in thin paraffin sections: a comparative study
10. Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, et al. Staging of neurofibrillary pathology in Alzheimer's disease: a study of the BrainNet Europe Consortium. Brain Pathol 2008; 18:484-96. Staging of neurofibrillary pathology in Alzheimer's disease: a study of the BrainNet Europe Consortium
11. Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, et al. A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med 1998; 4:452-5. A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1
12. Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem 2007; 101:1172-84. A beta oligomers - a decade of discovery
13. Mirra SS, Heyman A, McKeel D, Sumi SM, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991; 41:479-86. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease
14. Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 2002; 58:1791-800. Phases of A beta-deposition in the human brain and its relevance for the development of AD
15. Alafuzoff I, Thal DR, Arzberger T, Bogdanovic N, et al. Assessment of beta- amyloid
deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol 2009; 117:309-20. Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium
16. Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, et al. Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons. Brain Pathol 2010; 20:66-79. Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons
17. Hamilton RL. Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 2000;10:378-84. Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry
18. Uchikado H, Lin WL, DeLucia MW, Dickson DW. Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 2006; 65:685-97. Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy
19. Lippa CF, Duda JE, Grossman M, Hurtig HI, et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 2007; 68:812-9. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers
20. Leverenz JB, Fishel MA, Peskind ER, Montine TJ, et al. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol 2006; 63:370-6. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype
21. Pletnikova O, West N, Lee MK, Rudow GL, et al. Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases. Neurobiol Aging 2005; 26:1183-92. Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases
22. Halliday G, Hely M, Reid W, Morris J. The progression of pathology in longitudinally followed patients with Parkinson's disease. Acta Neuropathol 2008;115:409-15. The progression of pathology in longitudinally followed patients with Parkinson's disease
23. McKeith IG, Dickson DW, Lowe J, Emre M, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863-72. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium
24. Braak H, Del Tredici K, Rub U, de Vos RA, et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003; 24:197-211. Staging of brain pathology related to sporadic Parkinson's disease
25. Beach TG, Adler CH, Lue L, Sue LI, et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 2009; 117:613-34. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction
26. Fujishiro H, Tsuboi Y, Lin WL, Uchikado H, et al. Co-localization of tau and alpha-synuclein in the olfactory bulb in Alzheimer's disease with amygdala Lewy bodies. Acta Neuropathol 2008; 116:17-24. Co-localization of tau and alpha- synuclein in the olfactory bulb in Alzheimer's disease with amygdala Lewy bodies
27. Beach TG, White CL, 3rd, Hladik CL, Sabbagh MN, et al. Olfactory bulb alpha- synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 2009; 117:169-74. Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders
28. Selnes OA, Vinters HV. Vascular cognitive impairment. Nat Clin Pract Neurol 2006; 2:538-47. Vascular cognitive impairment
29. Gearing M, Mirra SS, Hedreen JC, Sumi SM, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer's disease. Neurology 1995;45:461-6. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer's disease
30. Nelson PT, Jicha GA, Schmitt FA, Liu H, et al. Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles "do count" when staging disease severity. J Neuropathol Exp Neurol 2007; 66:1136-46. Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles "do count" when staging disease severity
31. Chui HC, Zarow C, Mack WJ, Ellis WG, et al. Cognitive impact of subcortical vascular and Alzheimer's disease pathology. Ann Neurol 2006; 60:677-87. Cognitive impact of subcortical vascular
and Alzheimer's disease pathology
32. Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA. The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol 2009;66:200-8. The neuropathology of probable Alzheimer disease and mild cognitive impairment
33. Schneider JA, Bennett DA. Where vascular meets neurodegenerative disease.
Stroke 2010; 41:S144-6. Where vascular meets neurodegenerative disease
34. Wilson RS, Leurgans SE, Boyle PA, Schneider JA, et al. Neurodegenerative basis of age-related cognitive decline. Neurology 2010; 75:1070-8. Neurodegenerative basis of age-related cognitive decline
35. Hachinski V, Iadecola C, Petersen RC, Breteler MM, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006; 37:2220-41. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards
36. Sonnen JA, Larson EB, Haneuse S, Woltjer R, et al. Neuropathology in the adult changes in thought study: a review. J Alzheimers Dis 2009; 18:703-11. Neuropathology in the adult changes in thought study: a review
37. Vinters HV. Cerebral amyloid angiopathy. A critical review. Stroke 1987; 18:311-24. Cerebral amyloid angiopathy. A critical review
38. Vinters HV, Ellis WG, Zarow C, Zaias BW, et al. Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 2000; 59:931-45. Neuropathologic substrates of ischemic vascular dementia
39. Greenberg SM. Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology 1998; 51:690-4. Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment
40. Vinters HV. Cerebral amyloid angiopathy: a microvascular link between parenchymal and vascular dementia? Ann Neurol 2001; 49:691-3. Cerebral amyloid angiopathy: a microvascular link between parenchymal and vascular dementia?
41. Vinters HV. Cerebral amyloid angiopathy and Alzheimer's disease: two entities or one? J Neurol Sci 1992; 112:1-3. Cerebral amyloid angiopathy and Alzheimer's disease: two entities or one?
42. Sonnen JA, Larson EB, Brickell K, Crane PK, et al. Different patterns of cerebral injury in dementia with or without diabetes. Arch Neurol 2009; 66:315-22. Different patterns of cerebral injury in dementia with or without diabetes
43. Soontornniyomkij V, Lynch MD, Mermash S, Pomakian J, et al. Cerebral microinfarcts associated with severe cerebral beta-amyloid angiopathy. Brain Pathol 2010; 20:459-67. Cerebral microinfarcts associated with severe cerebral beta-amyloid angiopathy
44. Amador-Ortiz C, Dickson DW. Neuropathology of hippocampal sclerosis. Handb Clin Neurol 2008; 89:569-72. Neuropathology of hippocampal sclerosis
45. Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, et al. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol 2007; 61:435-45. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease
46. Arai T, Mackenzie IR, Hasegawa M, Nonoka T, et al. Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies. Acta Neuropathol 2009;117:125-36. Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies
47. Hatanpaa KJ, Blass DM, Pletnikova O, Crain BJ, et al. Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia. Neurology 2004; 63:538-42. Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia
48. Zarow C, Sitzer TE, Chui HC. Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr Neurol Neurosci Rep 2008; 8:363-70. Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues
49. Nelson PT, Schmitt FA, Lin Y, Abner EL, et al. Hippocampal sclerosis in advanced age: clinical and pathological features. Brain 134:1506-18. Hippocampal sclerosis in advanced age: clinical and pathological features
50. Lee EB, Lee VM, Trojanowski JQ, Neumann M. TDP-43 immunoreactivity in anoxic, ischemic and neoplastic lesions of the central nervous system. Acta Neuropathol 2008; 115:305-11. TDP-43 immunoreactivity in anoxic, ischemic and neoplastic lesions of the central nervous system
51. Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 2010; 119:1-4. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update
52. Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, et al. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 2009; 117:15-8. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations
53. Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 2007; 114:5-22. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration
54. Jellinger KA, Bancher C. Senile dementia with tangles (tangle predominant form of senile
dementia). Brain Pathol 1998; 8:367-76. Senile dementia with tangles (tangle predominant form of senile dementia)
55. Schmidt ML, Zhukareva V, Newell KL, Lee VM, et al. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer's disease. Acta Neuropathol 2001; 101:518-24. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer's disease
56. Kosaka K. Diffuse neurofibrillary tangles with calcification: a new presenile dementia. J Neurol Neurosurg Psychiatry 1994; 57:594-6. Diffuse neurofibrillary tangles with calcification: a new presenile dementia
57. Dlouhy SR, Hsiao K, Farlow MR, Foroud T, et al. Linkage of the Indiana kindred of Gerstmann-Straussler-Scheinker disease to the prion protein gene. Nat Genet 1992; 1:64-7. Linkage of the Indiana kindred of Gerstmann-Straussler-Scheinker disease to the prion protein gene
58. Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, et al. Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 1991; 30:637-49. Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study
59. Beach TG, White CL, Hamilton RL, Duda JE, et al. Evaluation of alpha-synuclein immunohistochemical methods used by invited experts. Acta Neuropathol 2008;116:277-88. Evaluation of alpha-synuclein immunohistochemical methods used by invited experts
60. Alafuzoff I, Parkkinen L, Al-Sarraj S, Arzberger T, et al. Assessment of alpha- synuclein pathology: a study of the BrainNet Europe Consortium. J Neuropathol Exp Neurol 2008; 67:125-43. Assessment of alpha-synuclein pathology: a study of the BrainNet Europe Consortium
61. Alafuzoff I, Pikkarainen M, Al-Sarraj S, Arzberger T, et al. Interlaboratory comparison of assessments of Alzheimer disease-related lesions: a study of the BrainNet Europe Consortium. J Neuropathol Exp Neurol 2006; 65:740-57. Interlaboratory comparison of assessments of Alzheimer disease-related lesions: a study of the BrainNet Europe Consortium
62. Saito Y, Ruberu NN, Sawabe M, Arai T, et al. Lewy body-related alpha- synucleinopathy in aging. J Neuropathol Exp Neurol 2004; 63:742-9. Lewy body- related alpha-synucleinopathy in aging
63. Frigerio R, Fujishiro H, Ahn TB, Josephs KA, et al. Incidental Lewy body disease: do some cases represent a preclinical stage of dementia with Lewy bodies? Neurobiol Aging 32:857-63. Incidental Lewy body disease: do some cases represent a preclinical stage of dementia with Lewy bodies?
64. Adler CH, Connor DJ, Hentz JG, Sabbagh MN, et al. Incidental Lewy body disease: clinical comparison to a control cohort. Mov Disord 25:642-6. Incidental Lewy body disease: clinical comparison to a control cohort
65. Dickson DW, Fujishiro H, DelleDonne A, Menke J, et al. Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease. Acta Neuropathol 2008; 115:437-44. Evidence that incidental Lewy body disease is pre- symptomatic Parkinson's disease
66. DelleDonne A, Klos KJ, Fujishiro H, Ahmed Z, et al. Incidental Lewy body disease and preclinical Parkinson disease. Arch Neurol 2008; 65:1074-80. Incidental Lewy body disease and preclinical Parkinson disease
67. Beach TG, Adler CH, Sue LI, Peirce JB, et al. Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. Acta Neuropathol 2008; 115:445-51. Reduced striatal tyrosine hydroxylase in incidental Lewy body disease
68. Jicha GA, Schmitt FA, Abner E, Nelson PT, et al. Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease. Neurobiol Aging 31:1805-13. Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease
69. Nelson PT, Kryscio RJ, Jicha GA, Abner EL, et al. Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies. Neurology 2009;73:1127-33. Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies
70. Beach TG, Wilson JR, Sue LI, Newell A, et al. Circle of Willis atherosclerosis: association with Alzheimer's disease, neuritic plaques and neurofibrillary tangles. Acta Neuropathol 2007; 113:13-21. Circle of Willis atherosclerosis: association with Alzheimer's disease, neuritic plaques and neurofibrillary tangles
71. Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, et al. Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol 2009; 68:774-84. Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma

 

         

         

.

 

 

 

 
       
   
Copyright 2011 HelMedica • All rights reserved.
   
    Web page and journal designing - editorship: Tsintou Magdalini.    
www.000webhost.com