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In contrast to protein kinases that participate in long-term potentiation (LTP) induction and memory consolidation, the autonomously active atypical protein kinase C isoform, protein kinase Mzeta (PKMζ), functions in the core molecular mechanism of LTP maintenance and long-term memory storage. Here, using multiple complementary techniques for light and electron microscopic immunolocalization, we present the first detailed characterization of the cellular and subcellular distribution of PKMζ in rat hippocampus and neocortex. We find that PKMζ is widely expressed in forebrain with prominent immunostaining in hippocampal and neocortical grey matter, and weak label in white matter. In hippocampal and cortical pyramidal cells, PKMζ expression is predominantly somatodendritic, and electron microscopy highlights the kinase at postsynaptic densities and in clusters within spines. In addition, nuclear label and striking punctate immunopositive structures in a paranuclear and dendritic distribution are seen by confocal microscopy, occasionally at dendritic bifurcations. PKMζ immunoreactive granules are observed by electron microscopy in cell bodies and dendrites, including endoplasmic reticulum. The widespread distribution of PKMζ in nuclei, nucleoli and endoplasmic reticulum suggests potential roles of this kinase in cell-wide mechanisms involving gene expression, biogenesis of ribosomes and new protein synthesis. The localization of PKMζ within postsynaptic densities and spines suggests sites where the kinase stores information during LTP maintenance and long-term memory.

We present a practical guide for the implementation of recently revised National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an "ABC" score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation., (Copyright © 2012 The Alzheimer's Association. All rights reserved.)

Impairment of synaptic plasticity underlies memory dysfunction in Alzheimer's disease (AD). Molecules involved in this plasticity such as PSD-95, a major postsynaptic scaffold protein at excitatory synapses, may play an important role in AD pathogenesis. We examined the distribution of PSD-95 in transgenic mice of amyloidopathy (5XFAD) and tauopathy (JNPL3) as well as in AD brains using double-labeling immunofluorescence and confocal microscopy. In wild type control mice, PSD-95 primarily labeled neuropil with distinct distribution in hippocampal apical dendrites. In 3-month-old 5XFAD mice, PSD-95 distribution was similar to that of wild type mice despite significant Aβ deposition. However, in 6-month-old 5XFAD mice, PSD-95 immunoreactivity in apical dendrites markedly decreased and prominent immunoreactivity was noted in neuronal soma in CA1 neurons. Similarly, PSD-95 immunoreactivity disappeared from apical dendrites and accumulated in neuronal soma in 14-month-old, but not in 3-month-old, JNPL3 mice. In AD brains, PSD-95 accumulated in Hirano bodies in hippocampal neurons. Our findings support the notion that either Aβ or tau can induce reduction of PSD-95 in excitatory synapses in hippocampus. Furthermore, this PSD-95 reduction is not an early event but occurs as the pathologies advance. Thus, the time-dependent PSD-95 reduction from synapses and accumulation in neuronal soma in transgenic mice and Hirano bodies in AD may mark postsynaptic degeneration that underlies long-term functional deficits.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer's disease (AD). The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.

Non-Alzheimer's disease of the frontal type, or frontotemporal dementia (FTD), is the second most common form of dementia. Yet, a detailed characterization of the disease has been especially limiting. To identify mechanisms possibly involved in disease pathology or progression, a proteomic analysis of proteins isolated from human frontal cortex with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was performed. We used 2D gel electrophoresis and MALDI-TOF to identify a total of 24 proteins differentially expressed in FTDP-17. We identified a ubiquitin C-terminal hydrolase, UCHL1, as well as several proteins involved in oxidative stress to be differentially expressed. Data presented implicate UCHL1 and ubiquitin-mediated degradation as well as oxidative stress response in disease pathology or progression.

To study the role of atypical protein kinase C (aPKC) in neurodegenerative disease, we investigated the distribution of PKCiota/lambda, an aPKC isoform, in a variety of tauopathies and alpha-synucleinopathies. Immunohistochemical study revealed PKCiota/lambda within tau-positive neurofibrillary inclusions in Alzheimer disease (AD), progressive supranuclear palsy, corticobasal degeneration (CBD), and Pick disease (PiD), within alpha-synuclein-positive Lewy bodies in idiopathic Parkinson disease and dementia with Lewy bodies, as well as within glial inclusions in multisystem atrophy. We also observed PKCiota/lambda label of actin-rich Hirano bodies in AD, PiD, and elderly individuals. Double immunolabeling and fluorescence resonance energy transfer demonstrated close physical association between PKCiota/lambda and phospho-tau or alpha-synuclein in some neurofibrillary tangles and Lewy bodies. Furthermore, PKCiota/lambda colocalized with p62, a chaperone protein that binds to both aPKC and ubiquitin, in most of these inclusions. PKCiota/lambda also closely associated with the inactivated form of glycogen synthase kinase-3beta, GSK-3beta[ser9]. Together, these findings suggest that PKCiota/lambda may play a role in common mechanisms involving the pathogenesis of neurodegenerative disease.

Protein kinase Mzeta (PKMzeta), an atypical protein kinase C (PKC) isoform, plays a key role in the maintenance of long-term potentiation (LTP), a persistent enhancement of AMPA receptor-mediated synaptic transmission, as well as in the persistence of memory in Drosophila. Because memory impairment in Alzheimer disease (AD) has been attributed to disruption of synaptic plasticity, we investigated the expression and distribution of PKMzeta in this disorder. We found that PKMzeta accumulated in neurofibrillary tangles (NFTs), whereas conventional and novel PKC isoforms did not. Unlike tau, which is present in all NFTs regardless of location, PKMzeta was found in a subset of NFTs restricted to limbic or medial temporal lobe structures (i.e. hippocampal formation, entorhinal cortex, and amygdala), areas implicated in memory loss in AD. Interestingly, PKMzeta was not identified in any NFTs in control brains derived from 6 elderly individuals without known cognitive impairment. In medial temporal lobe structures in AD, PKMzeta also occurred within abnormal neurites expressing MAP2, GluR1 and GluR2 as well as in perisomatic granules expressing GluR1 and GluR2, suggesting that aggregation of PKMzeta disrupts glutamatergic synaptic transmission. Together, these findings suggest a link between PKMzeta-mediated synaptic plasticity and memory impairment in AD.

Ultrastructural studies of neurofibrillary tangles in Alzheimer disease (AD) have demonstrated a close relationship between nuclear pores and the cytoplasmic paired helical filaments comprising the tangles, as well as nuclear irregularity in many tangle-bearing neurons; nuclear pore aggregation has been observed in nearby neurons. These observations prompted examination of the nuclear pore complex (NPC) and proteins critical to nucleocytoplasmic transport in neurons with and without tangles in AD and control cases. Light microscopic study of hippocampus and neocortex in AD and controls revealed that all nuclei were labeled by antibodies to NPC proteins, including the central transporter nucleoporin Nup62. Nucleoporin and tau label revealed significantly more nuclear irregularity in AD, often associated with neurofibrillary tangles. Double label of Nup62 with apoptotic markers (TUNEL and active caspase-3) and a cell-cycle protein (cyclin B1) revealed no clear relationship of nuclear irregularity to apoptosis or cell-cycle protein expression. However, cytoplasmic accumulation of nuclear transport factor 2 (NTF2), a protein that transports cargo from the cytoplasm into the nucleus, was observed in a subset of hippocampal neurons with and without tangles in AD but not control cases. Further investigation of the NPC and nucleocytoplasmic transport in AD is warranted.

A working group supported by the Office of Rare Diseases of the National Institutes of Health formulated neuropathologic criteria for corticobasal degeneration (CBD) that were subsequently validated by an independent group of neuropathologists. The criteria do not require a specific clinical phenotype, since CBD can have diverse clinical presentations, such as progressive asymmetrical rigidity and apraxia, progressive aphasia, or frontal lobe dementia. Cortical atrophy, ballooned neurons, and degeneration of the substantia nigra have been emphasized in previous descriptions and are present in CBD, but the present criteria emphasize tau-immunoreactive lesions in neurons, glia, and cell processes in the neuropathologic diagnosis of CBD. The minimal pathologic features for CBD are cortical and striatal tau-positive neuronal and glial lesions, especially astrocytic plaques and thread-like lesions in both white matter and gray matter, along with neuronal loss in focal cortical regions and in the substantia nigra. The methods required to make this diagnosis include histologic stains to assess neuronal loss, spongiosis and ballooned neurons, and a method to detect tau-positive neuronal and glial lesions. Use of either the Gallyas silver staining method or immunostains with sensitive tau antibodies is acceptable. In cases where ballooned neurons are sparse or difficult to detect, immunostaining for phospho-neurofilament or alpha-B-crystallin may prove helpful. Methods to assess Alzheimer-type pathology and Lewy body pathology are necessary to rule out other causes of dementia and Parkinsonism. Using these criteria provides good differentiation of CBD from other tauopathies, except frontotemporal dementia and Parkinsonism linked to chromosome 17, where additional clinical or molecular genetic information is required to make an accurate diagnosis.

JNK and p38, two members of the MAP kinase family, are strongly induced by various stresses including oxidative stress and have been involved in regulation of apoptosis. As both kinases phosphorylate tau protein in vitro, we have investigated their immunohistochemical localization in a group of neurodegenerative diseases characterized by intracellular deposits of hyperphosphorylated tau. Cases included Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Gerstmann-Sträussler-Scheinker disease-Indiana kindred, and frontotemporal dementia with parkinsonism linked to chromosome 17. In all tissue samples, strong immunoreactivity for both MAP kinases was found in the same neuronal or glial cells that contained tau-positive deposits. By double immunohistochemistry, JNK and p38 colocalized with tau in the inclusions. Analysis of apoptosis-related changes (DNA fragmentation, activated caspase-3) showed that the expression of JNK and p38 was unrelated to activation of an apoptotic cascade. Our data indicate that phospho-JNK and phospho-p38 are associated with hyperphosphorylated tau in a variety of abnormal tau inclusions, suggesting that these kinases may play a role in the development of degenerative diseases with tau pathology.

Context: A recent collaborative study found that apolipoprotein E (APOE) genotype, in conjunction with the clinical diagnosis of Alzheimer disease (AD), was useful in improving diagnostic specificity (correctly not diagnosing AD) relative to the clinical diagnosis alone. Since these samples are particularly enriched with patients with AD and the APOE epsilon4 allele, results may not be generalizable to patients seen in the general medical community., Objective: To evaluate the diagnostic utility of the APOE genotype in diagnosing AD in a community-based case series from the largest health maintenance organization in an urban area., Design: We examined the effect of including APOE genotype on the diagnosis of AD in a community-based case series of patients presenting with memory complaints., Patients: Clinical and neuropathologic diagnoses and APOE genotype were obtained from 132 patients who underwent evaluation for dementia and subsequent autopsy., Main Outcome Measures: Sensitivity, specificity, and positive and negative predictive values given various combinations of clinical diagnoses and the presence of an APOE epsilon4 allele., Results: Of the 132 patients, 94 had neuropathologically confirmed AD, yielding a prevalence of 71%. The clinical diagnosis alone yielded a sensitivity of 84%, an estimated specificity of 50%, and positive and negative predictive values of 81% and 56%, respectively. The presence of an epsilon4 allele alone was associated with an estimated sensitivity of 59%, specificity of 71%, and positive and negative predictive values of 83% and 41%, respectively. Using the presence of clinical AD and an epsilon4 allele decreased the sensitivity to 49% and increased the specificity to 84%. The positive and negative predictive values were 88% and 40%, respectively. Alternatively, the clinical diagnosis of AD or the presence of an epsilon4 allele in individuals not meeting clinical criteria for AD increases the estimated sensitivity to 94% but decreases the specificity to 37%. The positive and negative predictive values were 79% and 70%, respectively. The changes in the sensitivity and specificity for the combined tests relative to clinical diagnosis alone offset each other. For lower prevalence communities, the positive predictive value will be much lower than those observed herein., Conclusions: Our findings do not support the use of APOE genotyping alone in the diagnosis of AD in the general medical community. Although the presence of an epsilon4 allele in older persons with clinical AD increased the probability of having AD and the absence of an epsilon4 allele in this group decreased the probability of having AD, the association is not strong enough in the differential diagnosis of non-Alzheimer dementia and AD.

Although diffuse plaques in the neocortex may represent an early stage in the evolution of neuritic plaques, plaques in the striatum and cerebellum retain their predominantly diffuse nature in Alzheimer disease (AD), regardless of disease duration. We had the opportunity to explore the progression of these regional features by using autopsy brain specimens from 15 cognitively normal and five AD subjects, all Catholic sisters enrolled in the Nun Study, a longitudinal study on aging and AD. Neuropathologic changes were assessed in the temporal cortex, striatum, and cerebellum without knowledge of clinical status. We found diffuse plaques in the striatum in six (40%) and cerebellar plaques in none of the brains from the non-demented subjects. Striatal plaques were present in all five and cerebellar plaques in four of the five AD cases. In the 20 cases overall, the presence of striatal plaques generally paralleled the occurrence of neuritic plaques in neocortex and correlated with lower scores on several neuropsychologic tests assessing memory. Our findings suggest that striatal diffuse plaques occur relatively early in the progression of AD pathology and coincide with neocortical pathology and cognitive changes. Thus, it is unlikely that temporal factors alone account for regional differences in progression of AD neuropathology.

Familial forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have recently been associated with coding region and intronic mutations in the tau gene. Here we report our findings on 2 affected siblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive dementing illness clinically diagnosed as Alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. Autopsy in both cases revealed frontotemporal atrophy and degeneration of basal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene revealed a C to T transition at codon 301, resulting in a Pro to Leu substitution. Widespread neuronal and glial inclusions, neuropil threads, and astrocytic plaques similar to those seen in corticobasal degeneration were labeled with a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes spanning the entire tau sequence. Isolated tau filaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble tau exhibited 2 major bands of 64 and 68 kDa and a minor 72 kDa band, similar to the pattern seen in a familial tauopathy associated with an intronic tau mutation. These pathological tau bands predominantly contained the subset of tau isoforms with 4 microtubule-binding repeats selectively affected by the P301L missense mutation. Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.

Background: While NFT frequency is reportedly reduced in AD+DLB, we often encounter abundant neocortical NFTs in such cases and decided to investigate this discrepancy., Objective: To compare neurofibrillary tangle (NFT) frequency in Alzheimer disease with concomitant dementia with Lewy bodies (AD+DLB) with NFT frequency in "pure" AD., Methods: Neurofibrillary tangle frequency, as well as regional staging of neurofibrillary degeneration modified from Braak, was scored in 160 autopsy cases of primary dementia (80 AD+DLB cases and 80 pure AD cases)., Results: Neurofibrillary tangle and modified Braak scores were lower in AD+DLB, as reported previously. Yet, neocortical NFT scores assumed markedly different patterns in the 2 groups (P = .001). In pure AD, NFT scores of "frequent" were predominant: more cases exhibited frequent than moderate or sparse NFTs. In AD+DLB, the distribution of NFT scores was bimodal: NFTs were either frequent or few to absent. Neocortical NFT scores in the AD+DLB group tended to parallel the severity of other types of tau cytopathology (neuropil threads and tau-positive plaque neurites)., Conclusions: Cases of AD+DLB may be divided into 2 subgroups based on the extent of neocortical neurofibrillary pathology. These findings could have implications for disease pathogenesis and treatment.

Objective: To study the relation between cerebral infarction and clinical and neuropsychologic manifestations in patients with autopsy-proven Alzheimer's disease (AD) enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)., Background: Prior studies report that subjects with neuropathologic evidence of AD and concomitant brain infarcts had poorer cognitive function and higher frequency of dementia than those with AD alone., Methods: Clinical and neuropsychologic manifestations of dementia were studied in 74 subjects with neuropathologic findings of AD alone and 32 with AD and concomitant cerebral infarcts or lacunar lesions., Results: The 32 patients with both AD and vascular lesions were significantly older at time of death (median age, 81 years) than the 74 patients with AD alone (76 years; p = 0.02). At the final follow-up visit, the severity of the dementia was greater in AD patients with vascular lesions (median Clinical Dementia Rating [CDR] = 3) than in those with AD alone (CDR = 2; p = 0.03). Patients with AD and vascular lesions performed significantly worse on verbal fluency, Boston Naming, and Mini-Mental State Examination (MMSE) tests. No differences between the groups were observed, however, in the semiquantitative measures of frequency of neuritic plaques or neurofibrillary tangles., Conclusions: The clinical-neuropathologic correlations in CERAD patients generally confirm those in prior studies, indicating that the presence of cerebral infarction in patients with AD is associated with greater overall severity of clinical dementia and poorer performance on specific tests of language and cognitive function.

Objective: To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype., Setting: Washington University Alzheimer's Disease Research Center, St Louis, Mo., Design and Subjects: Consecutive neuropathologic series of 224 prospectively studied volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or "incipient" DAT and confirmed to have AD by postmortem examination and 13 cognitively intact subjects, confirmed to lack postmortem findings of AD., Main Outcome Measures: Brain densities (number per square millimeter) of senile plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy, cortical Lewy bodies, and apolipoprotein E genotype., Results: Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities. When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD, neurofibrillary tangle and senile plaque densities were lower. Plaque-predominant AD was found in a greater proportion of subjects with milder than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent in plaque-predominant AD than in the remaining AD cases. Increasing age at death was negatively correlated with dementia severity and densities of senile plaques and neurofibrillary tangles. The apolipoprotein E epsilon4 allele frequency was greater in AD than in control subjects but decreased with increasing age. After controlling for dementia severity, senile plaque densities were only weakly related to epsilon4 allele frequency, and only in hippocampus. However, the degree of cerebral amyloid angiopathy was clearly related to epsilon4 allele frequency. Among subjects diagnosed during life as having DAT or incipient DAT, only 7% were found to have a neuropathologic disorder other than AD causing their dementia., Conclusions: (1) The order of the strength of relationships between densities of histologic markers and dementia severity in AD is neurofibrillary tangles greater than cored senile plaques greater than total senile plaques. (2) Advanced age at death is associated with somewhat less severe dementia and fewer senile plaques and neurofibrillary tangles. (3) Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a substantial effect of apolipoprotein E epsilon4 as a risk factor for AD, on decreasing the age at AD onset, and increasing the amount of cerebral amyloid angiopathy, its effect on senile plaque densities is variable and complex, being confounded with age, dementia severity, and methodologic differences. (5) Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and senile plaque-based neuropathologic criteria for AD are highly accurate.

Reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemic heart disease, Alzheimer disease, Parkinson disease and aging. ROS are generated by mitochondria as the toxic by-products of oxidative phosphorylation, their energy generating pathway. Genetic inactivation of the mitochondrial form of superoxide dismutase in mice results in dilated cardiomyopathy, hepatic lipid accumulation and early neonatal death. We report that treatment with the superoxide dismutase (SOD) mimetic Manganese 5, 10, 15, 20-tetrakis (4-benzoic acid) porphyrin (MnTBAP) rescues these Sod2tm1Cje(-/-) mutant mice from this systemic pathology and dramatically prolongs their survival. The animals instead develop a pronounced movement disorder progressing to total debilitation by three weeks of age. Neuropathologic evaluation reveals a striking spongiform degeneration of the cortex and specific brain stem nuclei associated with gliosis and intramyelinic vacuolization similar to that observed in cytotoxic edema and disorders associated with mitochondrial abnormalities such as Leighs disease and Canavans disease. We believe that due to the failure of MnTBAP to cross the blood brain barrier progressive neuropathology is caused by excessive mitochondrial production of ROS. Consequently, MnTBAP-treated Sod2tm1Cje(-/-) mice may provide an excellent model for examining the relationship between free radicals and neurodegenerative diseases and for screening new drugs to treat these disorders.

Although neuritic and diffuse plaques generally coexist in Alzheimer disease (AD) neocortex, the predominance of diffuse plaques in the striatum prompted us to explore the potential influence of striatal features such as the striatal mosaic on beta-amyloid (A beta) deposition. Using double immunohistochemistry with an antibody to A beta in combination with antibodies to met-enkephalin or somatostatin, we investigated the relationship between diffuse plaques and neuropeptide distribution in the dorsal striatum. This relationship was examined in "pure" AD cases as well as in AD cases with coexisting Parkinson disease (PD) pathology, i.e. nigral degeneration and Lewy bodies at any site (AD + PD). Despite the presence of numerous A beta-positive diffuse plaques in both groups, the mosaic pattern, as exemplified by met-enkephalin-immunoreactive patches, was preserved. No obvious association was observed between the plaques and met-enkephalin-positive patches or somatostatin-immunoreactive neurons. Tyrosine hydroxylase immunoreactivity in the matrix was, however, diminished in AD + PD, most likely reflecting the nigral degeneration in these cases. Overall, these observations suggest that neostriatal A beta deposition in AD is not influenced by environmental factors associated with the striatal mosaic.

CERAD, a multicenter longitudinal study, has developed standardized instruments for the evaluation of individuals clinically diagnosed as having Alzheimer's disease (AD). The CERAD neuropathology protocol not only establishes levels of certainty for AD diagnosis, but also records information on other conditions occurring concomitantly with or misdiagnosed as AD. The protocol has been widely adopted because of its relative simplicity, adaptability, and reliability. Indeed, the Consensus principles proposed are, for the most part, consistent with CERAD guidelines. The recommendation that diagnosis rest upon both neuritic plaque and neurofibrillary tangle frequency/distribution in the neocortex, however, is worrisome. This change will eliminate or downgrade many cases now diagnosed as AD with concomitant Parkinson's disease changes. Reclassifying such cases at this time, without compelling pathobiological justification, is premature. Instead, I recommend retention or modest modification of the current CERAD protocol, and propose that neuropathology data available on autopsies of over 200 CERAD dementia subjects be used for testing potential modifications of the diagnostic algorithm.

Mutations of the presenilin PS1 and PS2 genes are closely linked to aggressive forms of early-onset (< 60 years) familial Alzheimer's disease. A highly specific monoclonal antibody was developed to identify and characterize the native PS1 protein. Western blot analyses revealed a predominant 32-kd immunoreactive polypeptide in a variety of samples, including PC12 cells transfected with human PS1 complementary DNA, brain biopsy specimens from demented patients, and postmortem samples of frontal neocortex from early-onset familial Alzheimer's disease cases (PS1 and PS2), late-onset sporadic Alzheimer's disease cases, and cases of other degenerative disorders. This truncated polypeptide contains the N-terminus of PS1 and appeared unchanged across cases. In 2 early-onset cases linked to missense mutations in the PS1 gene, a PS1 immunoreactive protein (approximately 49 kd) accumulated in the frontal cortex. This protein was similar in size to full-length PS1 protein present in transfected cells overexpressing PS1 complementary DNA, and in lymphocytes from an affected individual with a deletion of exon 9 of the PS1 gene, suggesting that mutations of the PS1 gene peturb the endoproteolytic processing of the protein. Immunohistochemical studies of control brains revealed that PS1 is expressed primarily in neurons, with the protein localized in the soma and dendritic processes. In contrast, PS1 showed striking localization to the neuropathology in early-onset familial Alzheimer's disease and sporadic Alzheimers' disease cases. PS1 immunoreactivity was present in the neuritic component of senile plaques as well as in neurofibrillary tangles. Localization of PS1 immunoreactivity in familial and sporadic Alzheimer's disease suggests that genetically heterogeneous forms of the disease share a common pathophysiology involving PS1 protein.

While apolipoprotein E (ApoE) and beta-amyloid (A beta) co-localize in senile plaques in cortex and cerebellum in Alzheimer disease (AD), the A beta-positive, predominantly diffuse plaques in the striatum do not exhibit ApoE immunoreactivity regardless of disease duration. As astrocytes are a major source of ApoE in the brain, we investigated potential regional differences in the ability of astrocytes to produce ApoE that might affect A beta processing and the progression of AD pathology. Using antibodies to ApoE, glial fibrillary acidic protein (GFAP), and A beta, we compared the pattern of immunoreactivity in senile plaques in AD autopsy tissue with that of reactive astrocytes surrounding subacute and old infarcts in both AD and non-AD cases. We found GFAP and ApoE immunoreactivity, but not A beta label in cell bodies and processes of reactive astrocytes in zones of infarction within cerebral cortex, striatum, and cerebellum, indicating that astrocytes are capable of upregulating ApoE within these 3 regions. In contrast, while astrocytes surrounded many neocortical neuritic plaques in AD, these GFAP-positive cells failed to label with ApoE; instead. ApoE label within plaques paralleled that of A beta. As expected, neither the ApoE-negative diffuse plaques of the striatum nor the ApoE-immunopositive diffuse plaques of the cerebellum were clearly associated with GFAP-immunoreactive astrocytes. The apparent absence of ApoE label in cortical plaque-associated astrocytes may signify a regulatory mechanism affecting ApoE synthesis and secretion, influenced by binding of ApoE to fibrillar amyloid within the plaques, neuritic changes, or other factors.

We investigated clinical and neuropathologic heterogeneity and apolipoprotein E (apoE) genotype in 11 cases of neuropathologically diagnosed corticobasal degeneration (CBD). Although seven of the 11 patients presented with unilateral limb dysfunction, the remaining four patients had less typical presentations including memory loss, behavioral changes, and difficulties with speech or gait. All 11 patients eventually developed extrapyramidal signs as well as cortical features, most commonly apraxia. At autopsy, the brains of seven of the 11 patients exhibited predominant neuronal loss and gliosis of perirolandic cortex; degeneration of more rostral frontal cortex was observed in three of the four patients with atypical clinical presentations. All cases displayed ballooned neurons, tau-positive neuronal and glial inclusions, threads and grains, and nigral degeneration. Six of the 11 cases manifested overlapping neuropathologic features of one or more disorders, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Parkinson's disease (PD), and hippocampal sclerosis. Interestingly, these six patients all exhibited memory loss early in the course of their illness. The 11 CBD cases exhibited increased frequency (0.32) of the epsilon 4 allele of apoE, relative to control populations; the frequency remained elevated (0.25) even when the three cases with concomitant AD were excluded. Beta-amyloid (A beta) deposition in hippocampus or cortex was present in five of the seven cases with an epsilon 4 genotype. These observations indicate that CBD is a pathologically and clinically heterogeneous disorder with substantial overlap with other neurodegenerative disorders.

While aged monkeys of several species show cerebral amyloid deposition in senile plaques and blood vessels similar to that seen in human aging and Alzheimer's disease (AD), studies of great apes have been limited. Using histological and immunohistochemical methods, we examined the brains of four orangutans aged 10, 28, 31, and 36 years. We encountered sparse beta-amyloid (A beta)-immunoreactive, silver-negative plaque-like structures in the brains of the three older apes. The 36-year-old orangutan also evidenced small A beta-positive deposits in subcortical white matter and sparse vascular amyloid deposition, primarily in meningeal vessels. Neurofibrillary tangles were not detected on silver stains or on tau or ubiquitin immunohistochemistry. Many of the A beta-positive plaque-like deposits in the orangutans were apolipoprotein E-immunoreactive, as we have previously reported in aged rhesus monkeys and an aged chimpanzee. Also, paralleling our earlier findings in these nonhuman primates, A beta 40 in plaques was more prominent in the orangutan than is typically seen in human aging, AD, and Down syndrome. These intriguing species differences may provide clues to the mechanisms of amyloid deposition and the development of neuropathologic changes in AD.

To clarify the neuropathologic criteria for the diagnosis of vascular dementia principally caused by large-vessel cerebral infarction, we solicited autopsy cases of vascular dementia from 10 university neuropathology laboratories. We included only those cases with progressive dementia clinically diagnosed as Alzheimer's disease (AD) or multi-infarct dementia, in whom autopsy revealed only cerebral infarction, without significant neuropathologic features of AD or other neurodegenerative disorders. Only six cases, all men, met these criteria. Each of them had, for a year or longer, gradually increasing cognitive impairment sufficient to interfere with daily activities, without clear evidence of "stepwise" progression. The age of onset of dementia was 66 years or less in five of the six patients. The duration of dementia ranged from 2 to 14 years. Five of the six cases had a history of either cerebral ischemia or acute stroke with residual focal neurologic deficits. Only two were known to have hypertension. At autopsy severe atherosclerosis of the cerebral arteries was present in three cases; two of these had a thrombotic occlusion of one internal carotid artery and one had partial obstruction of other cerebral arteries. In five of six brains, gross infarctions were present involving the thalamus, caudate, putamen, or large portions of the frontal, parietal, and temporal lobes of one or both hemispheres. Vascular amyloid was absent in all but one of these five brains. In four cases, the dementia was clinically indistinguishable from AD except for a history of focal neurologic deficits. The difficulty encountered in finding large numbers of cases of VaD without coexisting neuropathologic evidence of AD suggests that "pure" vascular dementia is very uncommon.

Apolipoprotein E (ApoE) epsilon4 allele is established to be a risk factor for the development of late-onset Alzheimer's disease (AD) which is associated with increased frequency of senile plaques and extent of amyloid angiopathy. In a recent report, we demonstrated that ApoE epsilon4 dosage correlates with an increase in A beta1-40 but not A beta1-42/43-immunoreactive plaques. In the present study, we sought to confirm this relationship at a biochemical level by using a sensitive ELISA to measure the amounts of A beta1-42/43 and A beta1-40 in cerebral cortex in 36 cases of sporadic AD. We found that dosage of ApoE epsilon4 allele correlated significantly with cortical A beta1-40 levels, while levels of A beta1-42 showed no significant association with genotype. These results parallel our immunohistochemical findings and suggest that A beta1-40 may play a key role in the pathogenesis of late-onset sporadic AD.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), a multicenter longitudinal study, has worked to establish standardized instruments for the evaluation of individuals clinically diagnosed as having Alzheimer's disease (AD). Since its formation in 1986, clinical neuropsychological, neuroimaging, and neuropathology assessment batteries have been developed. The neuropathology protocol not only establishes levels of certainty for the diagnosis of AD, but also facilitates correlations with clinical, genetic, and other data. We find a high rate of diagnostic accuracy: the clinical diagnosis of AD was confirmed in 176 of 201 (87.6%) CERAD dementia subjects. Coexistent vascular lesions, usually infarcts, were found in 32% of these confirmed AD cases, and 23% had coexisting Parkinson's disease (PD) changes (nigral degeneration and Lewy bodies at any site). In the remaining 25 cases (12.4%), neuropathologists attributed the primary cause of dementia to other conditions. In studies comparing neuropathology protocols for AD, several groups have found that the CERAD diagnosis most closely correlates with measures of dementia severity, such as the Mini-Mental State Examination (MMSE). Others have adopted the CERAD neuropathology protocol for multicenter brain banking, citing its relative simplicity and adaptability among laboratories, the experience of many AD centers with the protocol, and its application to other dementing conditions. The CERAD data set and batteries are increasingly used for a wide array of clinical, neuropathological, and genetic studies.

Because aged nonhuman primates show beta-amyloid (A beta) deposition in senile plaques and blood vessels similar to that seen in human aging and AD, we used C-terminal specific antibodies to A beta40 and A beta42 to investigate A beta peptide length in the brains of 11 aged rhesus monkeys and a 59-year-old chimpanzee. In contrast to AD, where the earliest and most prominent form of A beta in senile plaques is A beta42, in the monkey, A beta40-positive plaques predominated. The ratio of A beta40:A beta42-positive plaques averaged 2.08 in the monkey, as compared to a mean ratio of 0.37 in 68 human AD subjects (p < 0.001). A beta40 was also more prominent in the chimpanzee than in humans. Possible explanations for these findings include species differences in the cleavage of A beta from the amyloid precursor protein or in the activity of a putative carboxy peptidase forming A beta40 from A beta42 in situ.

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.

We studied the frequency, severity, and clinical correlations of cerebral amyloid angiopathy (CAA) in 117 CERAD subjects with autopsy-confirmed AD. Eighty-three percent showed at least a mild degree of amyloid angiopathy. Thirty of 117 brains (25.6%) showed moderate to severe CAA affecting the cerebral vessels in one or more cortical regions. These brains also showed a significantly higher frequency of hemorrhages or ischemic lesions than those of subjects with little or no amyloid angiopathy (43.3% versus 23.0%; odds ratio = 2.6, 95% CI = 1.1 to 6.2) High CAA scores also correlated with the presence of cerebral arteriosclerosis and with older age at onset of dementia. Our findings suggest that factors contributing to non-AD-related vascular pathology (e.g., atherosclerosis) may play a role in amyloid deposition in cerebral vessels in AD.

Apolipoprotein E (ApoE) epsilon4 allele, a risk factor for the development of Alzheimer's disease (AD), is associated with increased amyloid deposition. We examined cerebral cortex in 68 AD cases using antibodies to beta-amyloid (Abeta) peptides of different length (Abeta1-40 and Abeta1-42) and found that the increased plaque frequency observed with epsilon4 genotypes may be largely attributed to an increase in Abeta1-40-positive plaques. Indeed, both the number of Abeta1-40-positive plaques, as well as the ratio of Abeta1-40/Abeta1-42-positive plaques, increased with epsilon4 dosage. In contrast, the frequency of Abeta1-42-immunoreactive plaques was similar for epsilon3/epsilon3, epsilon3/epsilon4, and epsilon4/epsilon4 genotypes. ApoE may influence Abeta1 length by facilitating Abeta1-40 deposition onto Abeta1-42-seeded plaques or by modulating the activity of a putative carboxypeptidase that forms Abeta1-40 from Abeta1-42 in situ.

A questionnaire, collecting information on methods used at neuropathology core facilities for handling of brain autopsies on dementia and control subjects, was sent to 29 CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and/or Alzheimer's Disease Center (ADC) sites. Neuropathologists shared their successes and concerns in response to questions regarding administrative, technical, and neuropathological procedures for brain autopsies and tissue banking. Adequacy of fiscal support and staff, scarcity of control cases, and logistical aspects of autopsy coordination emerged as common problems. Successful strategies included the designation of dedicated autopsy coordinators, enhanced relationships with community hospital pathologists and funeral homes, and increased multilevel educational efforts on the importance of the autopsy.

While the epsilon 4 allele of apolipoprotein E (ApoE) has been identified as a risk factor in Alzheimer's disease (AD), the mechanism by which this risk is conveyed is not understood. Immunohistochemical studies demonstrating ApoE-A beta colocalization in senile plaques, neurofibrillary tangles, and blood vessels and in vitro studies of ApoE-A beta interactions suggest that ApoE plays a role in amyloid processing and/or fibrillogenesis. We examined the ApoE-A beta association in diffuse and neuritic plaques in the neocortex, striatum, and cerebellum, and determined the ApoE genotype in 100 brains derived from dementia patients with neuropathologically confirmed AD. As expected, the epsilon 4 allele was overrepresented in AD patients compared with patients without neurological disease (p < 0.001). ApoE-positive plaque counts in neocortex were higher in epsilon 4/4 individuals than in individuals with other genotypes (p < 0.0005). Overall, in the 100 cases, ApoE-positive plaques were less frequent than A beta-positive plaques in contiguous sections (p < 0.0001). In all cases, A beta-positive diffuse plaques in the striatum failed to label with ApoE antibody, whereas the majority of cerebellar diffuse plaques showed A beta-ApoE colocalization. Possible explanations for these discrepancies include regional variation in amyloid processing and fibrillogenesis, varying stages of plaque evolution, and technical considerations.

The frequency of the apolipoprotein E (ApoE) epsilon 4 allele and its relationship with coexistent Parkinson's disease (PD) neuropathology in Alzheimer's disease (AD) have not been extensively explored. We determined ApoE genotype in 100 dementia patients with neuropathologically confirmed AD with and without concomitant Parkinson's disease (PD) changes (nigral degeneration and Lewy bodies at various sites). Fifty "AD+PD" patients were matched closely with 50 "pure AD" patients for age, sex, and duration of dementia. We found identical overrepresentation of the epsilon 4 allele in the two groups: 72% of the patients in each group had at least one ApoE epsilon 4 allele, compared with approximately 25% in the general population (p < 0.005) and in our institutional autopsy population (p < 0.001). Age at onset varied inversely with epsilon 4 allele dosage in men but not in women in both the AD and the AD+PD groups. As with amyloid deposition and plaque frequency in AD, we observed an association between epsilon 4 dosage and PD-related changes. Specifically, the severity of ubiquitin-positive neuritic change in CA2/3 of the hippocampus, but not the frequency of cortical Lewy bodies, varied significantly with epsilon 4 dosage in the AD+PD cases.

Slowly progressive apraxia due to Alzheimer's disease was encountered in a 66 year old, right handed man whose initial impairments included coordinated movements of the left hand and some features of the alien hand syndrome. Over four years, the patient developed progressively worsening deficits of memory and language. A biopsy of his right temporal lobe showed numerous plaques and neurofibrillary tangles. Pronounced right parietal lobe hypoperfusion on serial SPECT suggests involvement of this region in contralateral praxis.

We investigated CA2/3 ubiquitin-immunoreactive neurites in 120 cases of diverse neurodegenerative diseases. This neuritic change occurred in 25 of 30 cases of Alzheimer's disease (AD) with coexistent Parkinson's disease (PD) changes, as well as two cases of PD and two cases of progressive supranuclear palsy. All 29 cases with neuritic change showed cortical Lewy bodies. Neuritic change was absent in 86 cases of neurodegenerative diseases without Lewy bodies, including 66 cases of pure AD. Thus, ubiquitin-immunoreactive CA2/3 neurites and cortical Lewy bodies, frequently coexist; this association appears to be independent of the presence or absence of coexistent pathologies, eg, AD. Moreover, in and of itself, nigral degeneration without Lewy bodies, such as that encountered in other (non-PD) movement disorders, apparently is not associated with CA2/3 neuritic change.

While the apolipoprotein E (ApoE) epsilon 4 allele is a recognized risk factor for Alzheimer's disease (AD), an association of epsilon 4 with other neurodegenerative diseases (NDs) has not been extensively explored. We examined 51 cases of neuropathologically confirmed ND. After eliminating 18 cases exhibiting pathology sufficient to warrant an additional diagnosis of AD, three disorders characterized by tau-related cytoskeletal pathology, i.e., Pick's disease, corticobasal degeneration, and progressive supra-nuclear palsy, showed increased epsilon 4 frequencies. Since the number of cases within each category was small, these increased epsilon 4 frequencies were not statistically significant. beta-Amyloid (beta A4) immunoreactive diffuse plaques were observed in many of these cases. While we cannot eliminate the possibility that these patients were destined to develop AD, these changes may merely reflect an independent association of epsilon 4 with amyloid deposition. These preliminary data affirm the need for further study of well-characterized cases to explore the relationship of ApoE to cytoskeletal pathology and ND.

This report summarizes the neuropathologic findings in the first 106 autopsies of CERAD (Consortium to Establish a Registry for Alzheimer's Disease) dementia patients diagnosed clinically as having Alzheimer's disease (AD). In 92 (87%) of the 106 cases, neuropathologists confirmed Alzheimer's disease (AD) as the primary dementing illness. Coexistent Parkinson's disease (PD) changes were present in 19 (21%) and vascular lesions of varying nature and size in 26 (28%) of these 92 AD cases. The 14 cases in which AD was not interpreted as the primary dementing illness can be divided into four major subgroups based on their neuropathology findings: PD and related pathology (n = 5), hippocampal sclerosis (n = 3), miscellaneous neurodegenerative and other disorders (n = 3), and no significant changes (n = 3). Despite the relatively high level of clinical diagnostic accuracy, further refinement of assessment batteries may facilitate distinction of non-AD dementias from AD.

We compared premortem neuroimaging findings with neuropathologic evidence of temporal lobe atrophy in 20 patients with Alzheimer's disease (AD) confirmed by autopsy. There were significant correlations between temporal horn enlargement observed by neuroimaging and hippocampal atrophy at autopsy, and between the overall cerebral atrophy severity on neuroimaging and scores on the Mini-Mental State Examination. This report confirms previous studies correlating temporal lobe atrophy on neuroimaging with a clinical diagnosis of AD, although more precise neuroimaging techniques are needed for use in multicenter studies of AD.