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It is now established that oxidative stress is one of the earliest, if not the earliest, change that occurs in the pathogenesis of Alzheimer's disease (AD). Consistent with this, mild cognitive impairment (MCI), the clinical precursor of AD, is also characterized by elevations in oxidative stress. Since such stress does not operate in vacuo, in this study we sought to determine whether redox-active iron, a potent source of free radicals, was elevated in MCI and preclinical AD as compared to cognitively-intact age-matched control patients. Increased iron was found at the highest levels both in the cortex and cerebellum from the pre-clinical AD/MCI cases. Interestingly, glial accumulations of redox-active iron in the cerebellum were also evident in preclinical AD patients and tended to increase as patients became progressively cognitively impaired. Our findings suggests that an imbalance in iron homeostasis is a precursor to the neurodegenerative processes leading to AD and that iron imbalance is not necessarily unique to affected regions. In fact, an understanding of iron deposition in other regions of the brain may provide insights into neuroprotective strategies. Iron deposition at the preclinical stage of AD may be useful as a diagnostic tool, using iron imaging methods, as well as a potential therapeutic target, through metal ion chelators.

Extrapyramidal signs (EPS) are common in Alzheimer disease (AD) and increase in prevalence as AD advances. The neuropathologic substrate responsible for EPS in AD remains to be fully characterized.Subjects had a clinical diagnosis of AD confirmed by neuropathologic examination. EPS during life were documented by clinical methods assessing bradykinesia, cogwheel rigidity, rest tremor, and parkinsonian gait. Subjects with EPS and previous neuroleptic exposure were excluded. Twenty-eight subjects were in the EPS group and 104 subjects were without EPS. Neuron loss, alpha-synuclein (ASYN)-labeled pathology, and tau-labeled pathology in the substantia nigra were measured using semiquantitative techniques such that higher scores represented increased pathologic burden.Presence of nigral ASYN-labeled pathology was more common (50 vs 28.9%; p0.05) in the EPS group than in those without EPS. There was more nigral neuron loss in the EPS group (1.50 vs 1.11 in no-EPS group; p0.05). Tau-labeled burden was not different by group comparisons; however, EPS onset at later stages of dementia severity was associated with increased tau-labeled pathology (Kendall tau-B = 0.48, p0.01) and this association remained after controlling for dementia severity at death. Additionally, moderate to severe tau burden was more common in the subgroup with "pure AD" (definite AD without other neuropathology) with EPS (81.8%) than cases without EPS (49.0%; p0.05). Four subjects with EPS (14.3%) had little to no significant nigral pathologic changes.Clinically detected extrapyramidal signs (EPS) in Alzheimer disease (AD) are associated with substantia nigra pathology including alpha-synuclein aggregation, hyperphosphorylated tau accumulation, and neuron loss that may account for the increasing prevalence of EPS as AD progresses. In some cases, limited nigral pathology suggests extranigral factors in the clinical symptoms of EPS.

The activation of the classical complement (C)-system in early-stage Alzheimer disease (AD) and nondemented aging was examined with immunohistochemistry in subjects assessed by the Clinical Dementia Rating (CDR). Activation (staining for C3 and C4 fragments) was found in all brains with amyloid deposits, including all nondemented (CDR 0) cases, with either small numbers of diffuse plaques or with sufficient plaques and tangles to indicate preclinical AD. Staining for C3 and C4 increased in parallel with plaque density in very mild to severe clinical AD. A subset of very mild AD (CDR 0.5) cases also showed C1q (on plaques) and C5b-9 (on neuritic plaques and tangles), whereas these C-fragments were consistently found in severe AD (CDR 3). Mirror section (split-face) analysis showed that C1q, C3, and apoJ (clusterin) occurred on the same plaques. However, C-system regulators CD59, CR1, DAF, and MCP were not detected on plaques or tangles at any stage, indicating that C-activation related to AD is incompletely controlled.

Background: Atypical presentations of neurodegenerative dementing disorders include the syndrome of progressive posterior cortical dysfunction (PPCD) involving selective higher order visuospatial deficits. The neuropathologic correlates of PPCD remain poorly defined. Methods: This is a retrospective case series of 27 individuals (14 men, 13 women) diagnosed clinically with PPCD. Participants were either enrolled in the Alzheimer’s Disease Research Center (ADRC) or referred to the memory diagnostic center of an urban academic medical center. Clinical evaluations included physical and neurologic examinations, the Clinical Dementia Rating (CDR), and psychometric measures. Neuropathologic examinations were completed in 21 individuals with PPCD. Psychometric measures from 65 individuals with mild dementia of the Alzheimer type (DAT) enrolled in the ADRC were used for comparison. Results: Neuropathologic etiologies of PPCD were Alzheimer disease (AD) (n = 13), AD plus Parkinson disease (n = 1), AD-Lewy body variant (n = 2), dementia with Lewy bodies plus progressive subcortical gliosis of Neumann (n = 1), corticobasal degeneration (n = 2), and prion-associated diseases: Creutzfeldt-Jakob disease (n = 1) and fatal familial insomnia (n = 1). Confirming the clinical impression, psychometric profiles for individuals with PPCD differed from those of people with DAT alone and revealed disproportionate deficits on measures of visuospatial ability. Conclusions: AD was the most frequent cause of PPCD in this series, although non-Alzheimer’s dementing disorders also should be considered.

Universally accepted neuropathologic criteria for differentiating Alzheimer disease (AD) from healthy brain aging do not exist. We tested the hypothesis that Bielschowsky silver stained total, cored, and neuritic senile plaques (TSPs, CSPs, and NSPs, respectively), rather than neurofibrillary tangles (NFTs), best discriminate between the 2 conditions using rigorously defined nondemented (n = 7) and AD (n = 35) subjects with no known co-morbidities. We compared lesions in 3 neocortical regions, in hippocampal CA1, and in entorhinal cortex in 19 men and 13 women between 74 and 86 years at death. The Clinical Dementia Rating (CDR) was used to assess degree of cognitive impairment within a year of demise. Neocortical TSP measures provided the highest correlation with expiration CDR: area under the curve (AUC) = 0.986 with 97.8% sensitivity at 90% specificity with an estimated cut-point of 6.0 TSP/ mm2. All SP measures yielded higher estimated AUC and sensitivity for 90% specificity compared to NFTs. Derived TSP cut-points applied to 149 persons with clinical AD regardless of their neuropathologic diagnosis yielded a sensitivity of 97% and specificity of 84% for TSPs in the 3 neocortical areas. Thus cut-points based on both diffuse and neuritic SP in neocortical regions distinguished nondemented and AD subjects with high sensitivity and specificity.

Objective: To determine whether Alzheimer’s disease (AD) associated with comorbidities or atypical features (possible AD) is marked by differences in clinical course and outcomes compared with uncomplicated AD (probable AD).Methods: Annual evaluations were made of patients with AD, for up to 11 years. Six hundred forty subjects with AD were clinically classified into two groups: 1) possible AD (n = 208), and 2) probable AD (n = 432). Data on demographics, Mini-Mental State Examination (MMSE), Short Blessed Test (SBT), psychometric performance, and Clinical Dementia Rating (CDR) were collected at baseline. Kaplan–Meier survival curves and Cox proportional hazards models were conducted to evaluate whether possible AD would have different outcomes on dementia progression, nursing home placement, and death compared with probable AD.Results: The possible AD group was slightly younger and less well educated than the probable AD group, but there were no group differences at baseline in MMSE, SBT, and CDR scores. Controlling for age and education, the possible AD group had poorer baseline psychometric performance (p = 0.022). There were no group differences, however, for rate of dementia progression, nursing home admission, and death.Conclusions: Comorbidities and atypical features in this sample of patients with Alzheimer’s disease did not substantially affect dementia outcomes. The primary determinant of the clinical course of dementia in this sample was the presence of clinically diagnosed Alzheimer’s disease, independent of the presence or absence of comorbidities or atypical features. Therefore, patients with possible Alzheimer’s disease may be considered for inclusion in investigations of Alzheimer’s disease, including clinical trials, to improve the generalizability of the findings.

Neuritic plaques are one of the stereotypical hallmarks of Alzheimer's disease (AD) pathology. These structures are composed of extracellular accumulations of fibrillar forms of the amyloid-β peptide (Aβ), a variety of other plaque-associated proteins, activated glial cells, and degenerating nerve processes. To study the neuritic toxicity of different structural forms of Aβ in the context of regional connectivity and the entire cell, we crossed PDAPP transgenic (Tg) mice, a model with AD-like pathology, to Tg mice that stably express yellow fluorescent protein (YFP) in a subset of neurons in the brain. In PDAPP; YFP double Tg mice, markedly enlarged YFP-labeled axonal and dendritic varicosities were associated with fibrillar Aβ deposits. These varicosities were absent in areas where there were nonfibrillar Aβ deposits. Interestingly, YFP-labeled varicosities revealed changes that corresponded with changes seen with electron microscopy and the de Olmos silver staining technique. Other silver staining methods and immunohistochemical localization of phosphorylated neurofilaments or phosphorylated tau were unable to detect the majority of these dystrophic neurites. Some but not all synaptic vesicle markers accumulated abnormally in YFP-labeled varicosities associated with neuritic plaques. In addition to the characterization of the effects of Aβ on axonal and dendritic structure, YFP-labeled neurons in Tg mice should prove to be a valuable tool to interpret the localization patterns of other markers and for future studies examining the dynamics of axons and dendrites in a variety of disease conditions in living tissue both in vitro and in vivo. J. Comp. Neurol. 456:375–383, 2003. © 2003 Wiley-Liss, Inc.

In addition to pathology in the gray matter, there are also abnormalities in the white matter in Alzheimer's disease (AD). Sulfatide species are a class of myelin-specific sphingolipids and are involved in certain diseases of the central nervous system. To assess whether sulfatide content in gray and white matter in human subjects is associated with both the presence of Alzheimer's disease (AD) pathology as well as the stage of dementia, we analyzed the sulfatide content of brain tissue lipid extracts by electrospray ionization mass spectrometry from 22 subjects whose cognitive status at time of death varied from no dementia to very severe dementia. All subjects with dementia had AD pathology. The results demonstrate that: (i) sulfatides were depleted up to 93% in gray matter and up to 58% in white matter from all examined brain regions from AD subjects with very mild dementia, whereas all other major classes of lipid (except plasmalogen) in these subjects were not altered in comparison to those from age-matched subjects with no dementia; (ii) there was no apparent deficiency in the biosynthesis of sulfatides in very mild AD subjects as characterized by the examination of galactocerebroside sulfotransferase activities in post-mortem brain tissues; (iii) the content of ceramides (a class of potential degradation products of sulfatides) was elevated more than three-fold in white matter and peaked at the stage of very mild dementia. The findings demonstrate that a marked decrease in sulfatides is associated with AD pathology even in subjects with very mild dementia and that these changes may be linked with early events in the pathological process of AD.

Cerebrospinal fluid (CSF) contains proteins known to be involved in the pathogenesis of Alzheimer disease (AD), including amyloid-related proteins, tau protein and apolipoprotein E. While the CSF concentrations of these proteins have been compared in subjects with and without dementia of the Alzheimer type (DAT), they have not been simultaneously assessed in carefully staged DAT subjects and control subjects to examine correlations among them. In this study, CSF concentrations of soluble amyloid precursor protein (sAPP), two forms of β-amyloid protein (Aβ total and Aβ 1-42 ), tau, and apolipoprotein E were assessed in subjects with (n = 33) and without (n = 11) DAT. Direct correlations were found between CSF concentrations of sAPP and tau and Aβ total , and between apolipoprotein E and Aβ total within the DAT subjects and within the combined group of DAT and control subjects. A weak inverse correlation was also found between CSF concentrations of tau and Aβ 1-42 within the combined group of DAT and control subjects. Moreover, increased severity of dementia was correlated with increased CSF tau concentrations and decreased sAPP and Aβ total concentrations. Increased CSF concentrations of tau significantly discriminated DAT and control subjects, as did the ratios of tau to Aβ total and tau to Aβ 1-42 .

Variably protease-sensitive prionopathy (VPSPr) is a recently described novel prion disease biochemically characterized by abnormal prion protein (PrP) which has various degrees of sensitivity to proteases and generates a distinct profile on Western blots 1. VPSPr is the second most common sporadic prion protein disease after CJD 2. All reported cases to date have exhibited cognitive, behavioral, and psychiatric deficits with an age at onset range of 48-81 years and disease duration range of 7-72 months 1-4. Initial clinical diagnoses included normal pressure hydrocephalus (NPH), dementia with Lewy bodies (DLB), or frontotemporal dementia (FTD) 1,5, but Creutzfeldt-Jakob disease (CJD) often was considered clinically after rapid decline became apparent 1. All VPSPr cases evaluated have lacked mutations in the prion protein gene (PRNP) 1,2,5. Initial reports indicated all cases were homozygous for valine at codon 129 (VV) in PRNP 1. However, more recent reports have found VPSPr in all three codon 129 genotypes 2,5-7. Here we report a case of VPSPr in which there were no known clinical manifestations of prion disease during life and yet pathognomonic findings were revealed at autopsy.

To explore the hypothesis that alterations in ethanolamine plasmalogen may be directly related to the severity of dementia in Alzheimer's disease (AD), we performed a systematic examination of plasmalogen content in cellular membranes of gray and white matter from different regions of human subjects with a spectrum of AD clinical dementia ratings (CDR) using electrospray ionization mass spectrometry (ESI/MS). The results demonstrate: (1) a dramatic decrease in plasmalogen content (up to 40 mol% of total plasmalogen) in white matter at a very early stage of AD (i.e. CDR 0.5); (2) a correlation of the deficiency in gray matter plasmalogen content with the AD CDR (i.e. approximately 10 mol% of deficiency at CDR 0.5 (very mild dementia) to approximately 30 mol% of deficiency at CDR 3 (severe dementia); (3) an absence of alterations of plasmalogen content and molecular species in cerebellar gray matter at any CDR despite dramatic alterations of plasmalogen content in cerebellar white matter. Alterations of ethanolamine plasmalogen content in two mouse models of AD, APP(V717F) and APPsw, were also examined by ESI/MS. A plasmalogen deficiency was present (up to 10 mol% of total plasmalogen at the age of 18 months) in cerebral cortices, but was absent in cerebella from both animal models. These results suggest plasmalogen deficiency may play an important role in the AD pathogenesis, particularly in the white matter, and suggest that altered plasmalogen content may contribute to neurodegeneration, synapse loss and synaptic dysfunction in AD.

Objective: To determine whether clinically nondemented elderly individuals with pathologically confirmed preclinical AD are characterized by cognitive decline as measured by psychometric tests before death. Methods: Psychometric performance was examined retrospectively in 14 individuals who were nondemented at time of death and grouped in accordance with their neuropathologic findings: 1) Healthy brain (n = 9) was characterized by the absence of senile plaques or by only patchy neocortical deposits of plaques; 2) preclinical AD (n = 5) was characterized by neuritic and diffuse plaques distributed throughout the neocortex. All individuals showed neurofibrillary pathologic change in medial temporal lobe structures. For comparison, we also evaluated 10 individuals who died in the earliest symptomatic stage of dementia of the Alzheimer type (DAT). All individuals had been assessed by clinical and psychometric measures during life. The psychometric measures yielded a standardized factor score that represented global cognitive performance. Results: At the last assessment before death, individuals with very mild DAT were impaired on the factor score and on individual psychometric measures with respect to the nondemented individuals. Those nondemented individuals with preclinical AD did not differ in performance from those with healthy brains. For individuals with at least three psychometric assessments during life, there was no decline in performance for either those with healthy brains (n = 5) or preclinical AD (n = 3), although decline was evident for very mild DAT individuals (n = 5). Conclusions: Pathologically confirmed preclinical AD is not associated with cognitive impairment or decline, even on measures shown to be sensitive to very mild DAT.

Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (ɛ4 > ɛ3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-β (Aβ) peptide and its conversion to a fibrillar form. To determine the effect of apoE on Aβ deposition and AD pathology, we compared APP V717F transgenic (TG) mice expressing mouse, human, or no apoE (apoE −/− ). A severe, plaque-associated neuritic dystrophy developed in APP V717F TG mice expressing mouse or human apoE. Though significant levels of Aβ deposition also occurred in APP V717F TG, apoE −/− mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APP V717F TG, apoE −/− mice resulted in fibrillar Aβ deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APP V717F TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.

Tau proteins aggregate as cytoplasmic inclusions in a number of neurodegenerative diseases, including Alzheimer's disease and hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Over 10 exonic and intronic mutations in the tau gene have been identified in about 20 FTDP-17 families. Analyses of soluble and insoluble tau proteins from brains of FTDP-17 patients indicated that different pathogenic mutations differentially altered distinct biochemical properties and stoichiometry of brain tau isoforms. Functional assays of recombinant tau proteins with different FTDP-17 missense mutations implicated all but one of these mutations in disease pathogenesis by reducing the ability of tau to bind microtubules and promote microtubule assembly.

OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Mutations in presenilin genes PS1 and PS2 account for ∼50% of early-onset familial Alzheimer’s disease (FAD). The PS1 and PS2 genes encode highly homologous transmembrane proteins related to theCaenorhabditis eleganssel-12 and spe-4 gene products. A hydrophilic loop region facing the cytoplasmic compartment is likely to be functionally important because at least 14 mutations in FAD patients have been identified in this region. We report here that the loop regions of PS1 and PS2 interact with nonmuscle filamin (actin-binding protein 280, ABP280) and a structurally related protein (filamin homolog 1, Fh1). Overexpression of PS1 appears to modify the distribution of ABP280 and Fh1 proteins in cultured cells. A monoclonal antibody recognizing ABP280 and Fh1 binds to blood vessels, astrocytes, neurofibrillary tangles, neuropil threads, and dystrophic neurites in the AD brain. Detection of ABP280/Fh1 proteins in these structures suggests that these presenilin-interacting proteins may be involved in the development of AD and that interactions between presenilins and ABP280/Fh1 may be functionally significant. The ABP280 gene is located on the human X chromosome, whereas the newly identified Fh1 gene maps to human chromosome 3. These results provide a new basis for understanding the function of presenilin proteins and further implicate cytoskeletal elements in AD pathogenesis.

The presence of senile plaques in the neocortex of apparently nondemented elderly persons often is accepted as part of "normal" aging. Alternatively, because cerebral deposition of beta-amyloid may be a key mechanism in the development of Alzheimer's disease (AD), the presence of beta-amyloid-containing plaques may represent very early AD. To examine the relationships of cognitively normal aging, very mild dementia of the Alzheimer type, and the presence of neocortical senile plaques, we performed clinicopathologic correlation in 21 longitudinally studied healthy elderly subjects (84.5 +/- 6.6 years old at death). Nine subjects had strikingly high plaque densities in the neocortex; two of these subjects died of head injury before which there was no evidence of cognitive impairment. The other seven subjects with high plaque densities had clinical evidence for very mild cognitive impairment (Clinical Dementia Rating score of 0.5) at some time during their course and mildly impaired psychometric performance at last assessment before death. The remaining 12 subjects had no clinical or psychometric impairment and had few or no neocortical AD lesions. These results suggest that senile plaques may not be part of normal aging but instead represent presymptomatic or unrecognized early symptomatic AD. The high density of senile plaques (predominately of the diffuse subtype) in the cortex of subjects just at the threshold of detectable dementia is consistent with the hypothesis that beta-amyloid deposition is an initial pathogenetic event in the development of AD.

Although neuronal RNA oxidation is a prominent and established feature in age-associated neurodegenerative disorders such as Alzheimer disease (AD), oxidative damage to neuronal RNA in aging and in the transitional stages from normal elderly to the onset of AD has not been fully examined. In this study, we used an in situ approach to identify an oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the cerebral cortex of 65 individuals without dementia ranging in age from 0.3 to 86 years. We also examined brain samples from 20 elderly who were evaluated for their premortem clinical dementia rating score and postmortem brain pathological diagnoses to investigate preclinical AD and mild cognitive impairment. Relative density measurements of 8OHG-immunoreactivity revealed a statistically significant increase in neuronal RNA oxidation during aging in the hippocampus and the temporal neocortex. In subjects with mild cognitive impairment but not preclinical AD, neurons of the temporal cortex showed a higher burden of oxidized RNA compared to age-matched controls. These results indicate that although neuronal RNA oxidation fundamentally occurs as an age-associated phenomenon, more prominent RNA damage than in normal aging correlates with the onset of cognitive impairment in the prodromal stage of AD.

Senile plaques (SP) are the most characteristic neuropathologic lesions of Alzheimer's disease (AD) and studies of plaque cortical distribution, density, and morphology may lead to new information about the origin and pathogenesis of this disease. We have developed an automated computer image analysis program to detect SP (including diffuse and mature forms) and to measure SP size, shape, and fractional area or load in digital micrographs of silver-stained tissue sections. The plaques are detected with adaptive thresholding. requiring no user interaction. Measures of SP size, morphology, and load are readily calculated from the pixel values in the detected SP features. These measurements are achieved accurately and exhaustively, and this method offers an alternative to manual SP counting. We demonstrate its application to 4 cases spanning the full range of the severity of the disease.

Subjects with clinically diagnosed senile dementia of the Alzheimer type (n = 37) and healthy controls (n = 5) were assessed clinically until death. Postmortem examination of the brain was performed at age 80 years or older. The brains of all of the group with dementia (except one that was found to have a non-Alzheimer dementia) had substantial densities of neocortical senile plaques regardless of dementia severity; the control brains had very few senile plaques. In those subjects with Alzheimer's disease, moderate correlations were found between dementia duration and severity (cognitive portion of the Blessed Dementia Scale and the Sum of Boxes from the Clinical Dementia Rating) and certain neuropathological lesions, both gross and microscopic. Densities of neocortical neurofibrillary tangles were related to degree of dementia; densities of neocortical senile plaques were unrelated. We conclude that (1) neocortical senile plaque densities differentiate very old subjects with Alzheimer's disease from nondemented controls, but there is a need for more postmortem studies of older persons who are free of dementia; and (2) among the microscopic lesions studied, densities of neocortical neurofibrillary tangles were most closely related to the degree and duration of dementia.

Three investigators have applied different histopathologic methods (modified Bielschowsky silver methods, Congo red-gallocyanin) to differentiate Alzheimer's disease (AD) (n = 7 subjects; four with very mild dementia and three with moderate to advanced dementia) neuropathology from brain changes associated with aging in three nondemented individuals who had been evaluated using a validated dementia severity staging instrument [Washington University Clinical Dementia Rating (CDR)] generally within a year of death. The presence of elevated numbers of neocortical (frontal and temporal) diffuse, mature, and total senile plaques (SP) was strongly correlated with the presence of clinical AD but did not equate with CDR dementia severity. Neocortical neurofibrillary tangle (NFT) density as well as hippocampal NFT and SP density in this small series did not differentiate statistically between AD and controls. NFT density appeared to correlate with CDR better than SP density. Quantitative histopathologic assessment of AD markers in only a few brain regions can accurately predict the presence of clinical AD, including the very mild form of the disease. This is especially true for SP in the neocortex.

There is general agreement that postoperative radiation therapy is beneficial for patients with subtotally resected pituitary adenomas. We have identified 41 such patients treated during a 20-year period who received postoperative irradiation for a pituitary adenoma. The usual dose was 5040 cGy in 28 fractions. The mean follow-up time was 10.3 years. On routine hematoxylin and eosin (H&E) staining, there were thirty-three chromophobe, seven eosinophilic, and one basophilic adenoma. Tissue blocks were stained for growth hormone (GH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), prolactin (PRL), and/or adrenocorticotropin (ACTH) using the peroxidase-antiperoxidase immunohistochemistry (IHC) method. Routine H&E staining was a poor predictor of the IHC stain. While most patients with a known clinical endocrine syndrome stained positive on IHC for the suspected offending hormone, many patients without a clinical syndrome also stained positive indicating the presence of hormonally occult adenomas in this locally invasive group. The IHC stain results were compared to clinical outcome. The presence of positive GH IHC staining decreased the 15-year progression-free survival (PFS) from 100% to 64% compared to GH negative adenomas (p = 0.06). There was a trend toward decreased 15-year PFS in patients who did not stain for LH. Positive staining for prolactin, ACTH, or TSH had no influence on the progression-free survival. We conclude that additional prognostic information can be obtained in this subset of patients (by performing IHC analysis) that is not known by the clinical presentation or appearance on H&E stain.

The expression levels of three synaptic proteins (synaptophysin, synaptotagmin, and growth-associated protein 43 [GAP43]) in AD cases clinically classified by Clinical Dementia Rating (CDR) score were analyzed. Compared with control subjects (CDR = 0), mild (early) AD (CDR = 0.5 to 1) cases had a 25% loss of synaptophysin immunoreactivity. Levels of synaptotagmin and GAP43 were unchanged in mild AD, but cases with CDR of >1 had a progressive decrement in these synaptic proteins. Thus, synaptic injury in frontal cortex is an early event in AD.

Objective To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals. Design Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer's Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. Setting Washington University Alzheimer's Disease Research Center. Participants Ninety-seven nondemented participants who were age 60 years or older at death (mean = 84 years). Results About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs. Conclusions Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80–85 years, many nondemented older adults have substantial AD pathology.

The Energy Employees Occupational Illness Compensation Program Act of 2000 (EEOICPA) was passed into law by a bi-partisan Congress in October 2000 and signed into law by two presidents. Nuclear weapons workers who contracted various cancers, chronic beryllium disease, silicosis, or a host of other disabling and life threatening diseases as a result of their exposures to toxic substances believed they would now receive compensation. These workers were placed in harm’s way while employed at ultra-hazardous facilities without being fully informed of the potential health effects of working with the plethora of poisons. Finally, after decades of denial, these workers believed they would now be able to receive the medical care and monetary compensation for some of the diseases they had suffered from through a “nonadversarial” and claimant friendly process.

Alzheimer's Disease (AD) is the most widespread form of dementia during the later stages of life. If improved therapeutics are not developed, the prevalence of AD will drastically increase in the coming years as the world's population ages. By identifying differences in neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand the molecular mechanisms that drive AD pathogenesis, including the formation of amyloid plaques and neurofibrillary tangles. In this study, we expression profiled histopathologically normal cortical neurons collected with laser capture microdissection (LCM) from six anatomically and functionally discrete postmortem brain regions in 34 AD-afflicted individuals, using Affymetrix Human Genome U133 Plus 2.0 microarrays. These regions include the entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus, and primary visual cortex. This study is predicated on previous parallel research on the postmortem brains of the same six regions in 14 healthy elderly individuals, for which LCM neurons were similarly processed for expression analysis. We identified significant regional differential expression in AD brains compared with control brains including expression changes of genes previously implicated in AD pathogenesis, particularly with regard to tangle and plaque formation. Pinpointing the expression of factors that may play a role in AD pathogenesis provides a foundation for future identification of new targets for improved AD therapeutics. We provide this carefully phenotyped, laser capture microdissected intraindividual brain region expression data set to the community as a public resource.

In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer’s disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders.

Background Data from neuropathologic studies of the frequency of Alzheimer disease (AD) among African American persons conflict as to whether the neuropathologic phenotype of AD is identical in African American and white persons. Objectives To examine clinical and neuropathologic phenotypes of AD in African American individuals and to compare AD and vascular burdens between African American and white persons. Design, Setting, and Patients Ten African American decedents who underwent brain autopsy at the Washington University Alzheimer’s Disease Research Center were matched for age, sex, and Clinical Dementia Rating with 10 white decedents between January 1, 1990, and January 1, 2000. The presence and degree of neurofibrillary tangles, senile plaques, Lewy bodies, cerebral infarcts, and cerebral amyloid angiopathy were determined. Results All 20 individuals had a neuropathologic diagnosis of AD. There were no group differences in the presence or number of infarcts, plaques, tangles, Lewy bodies, or amyloid angiopathy. Conclusion In this small sample, we found no substantive differences in the neuropathology of AD among African American and white individuals.

Background: Cases of early-onset Alzheimer disease (AD) with an autosomal dominant inheritance pattern (familial AD [FAD]) are rare but have greatly advanced our understanding of the molecular pathogenesis of AD. We describe herein a kindred with very early-onset FAD (age,40 years) with unusual pathological features and anovelmutationinthepresenilin1(PSEN1)gene(S170F) andreviewtheexistingliteratureonveryearly-onsetFAD. Objective: To analyze the neuropathological and genetic features of a family with onset of AD in the third decade of life. Design, Setting, and Participants: The proband underwent full clinical assessment and postmortem examination at the Washington University Alzheimer’s DiseaseResearchCenter,StLouis,Mo.Limitedpathological samples and autopsy records of 2 affected family members were available. The proband underwent screening for mutations in genes linked with FAD. Results: Dementia developed in 3 family members in this kindred at a mean age of 27 years; the proband had myoclonus, seizures, and rigidity, similar to findings in previouslydescribedkindredswithPSEN1mutations.All 3 family members were confirmed to have AD by neuropathologicalexamination.Theprobandalsohadwidespread Lewy body pathology in the brainstem, limbic areas, and neocortex; specific staining for Lewy bodies was not performed in the other 2 family members. The proband had a single mutation (S170F) in exon 6 of the PSEN1 gene, which segregates with disease. Conclusions: A novel PSEN1 mutation causes veryearly-onset FAD with associated Lewy bodies. To our knowledge, this kindred has the earliest reported onset ofpathologicallyconfirmedFADanddementiawithLewy bodies.

Neurofibrillary tangles (NFT) constitute one of the cardinal histopathological features of Alzheimer's disease (AD). To explore in vivo molecular processes involved in the development of NFTs, we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients, adjacent non-NFT-bearing entorhinal cortex neurons from the same patients, and non-NFT-bearing entorhinal cortex neurons from 14 non-demented, histopathologically normal controls (ND). Of the differentially expressed genes, 225 showed progressively increased expression (AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons) or progressively decreased expression (AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons), raising the possibility that they may be related to the early stages of NFT formation. Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs, including apolipoprotein J, interleukin-1 receptor-associated kinase 1, tissue inhibitor of metalloproteinase 3, and casein kinase 2, beta. Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD.

This article studies the problem of combining correlated diagnostic tests to maximize the discriminating power between the diseased population and the healthy population. The authors consider all possible linear combinations of multiple diagnostic tests and search for the one that achieves the largest area under the receiver operating characteristic (ROC) curve. They discuss the statistical estimation of the optimum linear combination test and the associated maximum area under the ROC curve. Their approach is based on the assumption of multivariate normal distribution of the multiple diagnostic tests. They also present the application of the proposed techniques to the neuropathologic diagnosis of Alzheimer’s disease based on brain lesions from 5 different brain locations using a data set from the Washington University Alzheimer’s Disease Research Center.

Familial cases of dementia with Lewy bodies (DLB) are rare. The authors describe two small kindreds with familial DLB: one with pure DLB meeting consensus criteria for DLB and one with coexistent AD pathology that did not fulfill DLB criteria. The authors call attention to the diverse features of DLB and suggest that current clinical criteria may not detect all cases. Familial DLB is clinically heterogeneous and occurs with or without coexistent AD, suggesting the relevance of LB pathology for the developing dementia.

In addition to pathology in the gray matter, there are also abnormalities in the white matter in Alzheimer's disease (AD). Sulfatide species are a class of myelin-specific sphingolipids and are involved in certain diseases of the central nervous system. To assess whether sulfatide content in gray and white matter in human subjects is associated with both the presence of Alzheimer's disease (AD) pathology as well as the stage of dementia, we analyzed the sulfatide content of brain tissue lipid extracts by electrospray ionization mass spectrometry from 22 subjects whose cognitive status at time of death varied from no dementia to very severe dementia. All subjects with dementia had AD pathology. The results demonstrate that: (i) sulfatides were depleted up to 93% in gray matter and up to 58% in white matter from all examined brain regions from AD subjects with very mild dementia, whereas all other major classes of lipid (except plasmalogen) in these subjects were not altered in comparison to those from age-matched subjects with no dementia; (ii) there was no apparent deficiency in the biosynthesis of sulfatides in very mild AD subjects as characterized by the examination of galactocerebroside sulfotransferase activities in post-mortem brain tissues; (iii) the content of ceramides (a class of potential degradation products of sulfatides) was elevated more than three-fold in white matter and peaked at the stage of very mild dementia. The findings demonstrate that a marked decrease in sulfatides is associated with AD pathology even in subjects with very mild dementia and that these changes may be linked with early events in the pathological process of AD.

Recently, biochemical criteria were proposed to complement histological criteria for the diagnosis of dementia lacking distinctive histopathology (DLDH), the most common pathological variant of frontotemporal dementias (FTDs), based on evidence of a selective reduction of soluble tau proteins in brains from a large cohort of sporadic DLDH and hereditary FTD (HDDD2 family) patients. To ensure that these findings are not unique to the populations included in the initial report, we extended the previous work by analyzing 22 additional DLDH brains from the United States and international centers. Our biochemical analyses here confirmed the previous findings by demonstrating substantial reductions in soluble brain tau in gray and white matter of 14 cases and moderate reductions in 6 cases of DLDH. We also analyzed brain samples from an additional affected HDDD2 family member, and remarkably, unlike other previously studied members of this kindred, this patient's brain contained substantial amounts of pathological or insoluble tau. These findings confirm and extend the definition of DLDH as a sporadic or familial "tau-less" tauopathy with reduced levels of soluble brain tau and no insoluble tau or fibrillary tau inclusions, and the data also underline the phenotypic heterogeneity of HDDD2, which parallels the phenotypic heterogeneity of other hereditary neurodegenerative FTD tauopathies caused by tau gene mutations.

To determine whether nondemented subjects with pathological evidence of preclinical Alzheimer disease (AD) demonstrate neuronal loss in the entorhinal cortex and hippocampus, and whether the onset of cognitive deficits in AD coincides with the onset of neuronal degeneration.Preclinical AD cases have been defined by the absence of cognitive decline but with neuropathological evidence of AD. The hippocampus and entorhinal cortex were examined in 13 nondemented cases (Clinical Dementia Rating [CDR] 0) with healthy brains, 4 cases with preclinical AD, 8 cases with very mild symptomatic AD (CDR 0.5), and 4 cases with severe AD (CDR 3, hippocampus only). The volume and number of neurons were determined stereologically in 2 areas that are vulnerable to AD--the entorhinal cortex (as a whole and layer II alone) and hippocampal field CA1.There was no significant decrease in neuron number or volume with age in the healthy nondemented group and little or none between the healthy and preclinical AD groups. Substantial decreases were found in the very mild AD group in neuron number (35% in the entorhinal cortex, 50% in layer II, and 46% in CA1) and volume (28% in the entorhinal cortex, 21% in layer II, and 29% in CA1). Greater decrements were observed in CA1 in the severe AD group.There is little or no neuronal loss in aging or preclinical AD but substantial loss in very mild AD. The findings indicate that AD results in clinical deficits only when it produces significant neuronal loss.

Background Mild cognitive impairment (MCI) is considered to be a transitional stage between aging and Alzheimer disease (AD). Objective To determine whether MCI represents early-stage AD by examining its natural history and neuropathologic basis. Design A prospective clinical and psychometric study of community-living elderly volunteers, both nondemented and minimally cognitively impaired, followed up for up to 9.5 years. Neuropathologic examinations were performed on participants who had undergone autopsy. Setting An AD research center. Participants All participants enrolled between July 1990 and June 1997 with Clinical Dementia Rating (CDR) scores of 0 (cognitively healthy; n = 177; mean age, 78.9 years) or 0.5 (equivalent to MCI; n = 277; mean age, 76.9 years). Based on the degree of clinical confidence that MCI represented dementia of the Alzheimer type (DAT), 3 subgroups of individuals with CDR scores of 0.5 were identified: CDR 0.5/DAT, CDR 0.5/incipient DAT, and CDR 0.5/uncertain dementia. Main Outcome Measure Progression to the stage of CDR 1, which characterizes mild definite DAT. Results Survival analysis showed that 100% of CDR 0.5/DAT participants progressed to greater dementia severity over a 9.5-year period. At 5 years, rates of progression to a score of CDR 1 (or greater) for DAT were 60.5% (95% confidence interval [CI], 50.2%-70.8%) for the CDR 0.5/DAT group, 35.7% (95% CI, 21.0%-50.3%) for the CDR 0.5/incipient DAT group, 19.9% (95% CI, 8.0%-31.8%) for the CDR 0.5/uncertain dementia group, and 6.8% (95% CI, 2.2%-11.3%) for CDR 0/controls. Progression to greater dementia severity correlated with degree of cognitive impairment at baseline. Twenty-four of the 25 participants with scores of CDR 0.5 had a neuropathologic dementing disorder, which was AD in 21 (84%). Conclusions Individuals currently characterized as having MCI progress steadily to greater stages of dementia severity at rates dependent on the level of cognitive impairment at entry and they almost always have the neuropathologic features of AD. We conclude that MCI generally represents early-stage AD.

Neuropsychological profiles were assessed in a large group of nondemented control subjects (n = 261) and individuals with dementia of the Alzheimer type (DAT) (n = 407) by subjecting their psychometric test results to a factor analysis. Nondemented control subjects were functionally homogeneous with only one factor accounting for the results. The results of the factor analysis on the very mild DAT and mild DAT groups, however, yielded a mental control/frontal factor, a memory-verbal/temporal factor, and a visuospatial/parietal factor. Forty-one of the original set of participants came to autopsy an average of 5.1 years after psychometric testing and had neurofibrillary tangles, total senile plaques, and cored senile plaques estimated from frontal, temporal, and parietal regions. The results of correlations indicated that the relative burden of cored senile plaques was systematically related to the three psychometric factors. These results suggest a connection between the specific functions as defined by neuropsychological measures and specific neuropathology occurring in associated areas of cortex.

Article abstract-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.NEUROLOGY 1997;48: 668-672

The entorhinal cortex (EC) plays a crucial role as a gateway connecting the neocortex and the hippocampal formation. Layer II of the EC gives rise to the perforant pathway, the major source of the excitatory input to the hippocampus, and layer IV receives a major hippocampal efferent projection. The EC is affected severely in Alzheimer disease (AD), likely contributing to memory impairment. We applied stereological principles of neuron counting to determine whether neuronal loss occurs in the EC in the very early stages of AD. We studied 20 individuals who at death had a Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina-specific neuronal counts were carried out on sections representing the entire EC. In the cognitively normal (CDR = 0) individuals, there were approximately 650,000 neurons in layer II, 1 million neurons in layer IV, and 7 million neurons in the entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia (CDR = 0.5), all of whom had sufficient neurofibrillary tangles (NFTs) and senile plaques for the neuropathological diagnosis of AD, had 32% fewer EC neurons than controls. Decreases in individual lamina were even more dramatic, with the number of neurons in layer II decreasing by 60% and in layer IV by 40% compared with controls. In the severe dementia cases (CDR = 3), the number of neurons in layer II decreased by approximately 90%, and the number of neurons in layer IV decreased by approximately 70% compared with controls. Neuronal number in AD was inversely proportional to NFT formation and neuritic plaques, but was not related significantly to diffuse plaques or to total plaques. These results support the conclusion that a marked decrement of layer II neurons distinguishes even very mild AD from nondemented aging.

Digital photography of postmortem brain slices was compared with magnetic resonance imaging (MRI) for morphological analysis of human brain atrophy. In this study, we used two human brains obtained at autopsy: a cognitively defined nondemented control (70-yr-old male) and a demented Alzheimer's disease (AD) subject (82-yr-old female). For each of two brains, interactive manual image segmentation was performed by two observers on two image sets: (a) four coronal T1-weighted MR images (5 mm slices); and (b) four digitized photographic images from comparable rostrocaudal levels. Microcomputer image analysis software was used to measure the areas of three segmented cerebral compartments--gray matter (GM), white matter (WM) and CSF--for both image types. Resegmentation error was defined as the absolute difference between the areas derived from two segmentation trials divided by the value from trial 1 and multiplied by 100. This yielded the percent difference between the area measurements from the two trials. We found intra-observer agreement was better (error rates 1-18%) than inter-observer agreement (3-70%) with best agreement for WM and least for CSF, the smallest object class. MRI overestimated GM area relative to digitized photographs in the control but not the AD brain. The results define limitations of manual image segmentations and comparison of MRI with pathologic section photographic images.

Concerns about intercenter variation in methods and interpretation prompted CERAD investigators to examine standardization of the neuropathological assessment of Alzheimer's disease (AD). Contiguous frontal lobe sections derived from autopsy brains of eight patients clinically diagnosed as having probable AD and two cognitively normal individuals were distributed to 24 neuropathologists from 18 medical centers in the United States and Canada. Using their routine staining method(s), neuropathologists determined the rank order of severity of AD neuropathology in these cases, as well as semiquantitative and quantitative senile plaque and neurofibrillary tangle frequencies. Ranking of the ten cases revealed 75% inter-rater reliability among the 24 raters. Semiquantitative analyses showed reasonable inter-rater agreement, whereas quantitative measures yielded significant differences between raters for plaque and tangle counts (p < 0.0001). These differences reflected variation in stain sensitivity, staining technique (even when the same stain was used), and interpretation of the histological findings. Ratings on the cases with the highest proportions of diffuse plaques showed the greatest dependence upon stain sensitivity and variability in interpretation. This study indicates that greater attention to quality improvement is needed for the neuropathological evaluation of AD, particularly when pooling data in multicenter studies such as CERAD.

• Neuropathologic studies of dementia and normal aging suffer from a lack of individuals examined for the presence and severity of dementia before death. To increase clinical information in such cases, a retrospective collateral interview was developed. Thirty-nine individuals were studied; 27 had autopsies. In all cases, the autopsy confirmed the Retrospective Collateral Dementia Interview (RCDI) diagnosis of the presence or absence of dementia; the RCDI had a sensitivity of 88% and a specificity of 80% for specifically detecting probable Alzheimer's disease. Agreement between the RCDI and premortem diagnosis was 96%; between RCDI and medical records, 100%. Agreement between RCDI staging of dementia severity and the last assessment of the living subject was 70%; between the RCDI and a brief staging at death, 86%. This validation confirms the value of postmortem interviews with close informants to assess dementia presence and severity.