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Erratum: Interlaboratory comparison of neuropathology assessments in Alzheimer's disease: A study of the consortium to establish a registry for Alzheimer's disease (CERAD) (Journal of Neuropathology and Experimental Neurology (May 1994) 53:3 (303-15))
... For neuropathologic diagnosis, established semi-quantitative scales are used to assess plaque burden (Fig. 1a) 4,8,11,12 . The standard semi-quantitative criteria put forth by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) based on the manual assessment of the highest density of neocortical neuritic plaques 4,13 . Diffuse plaques, which may be the initial morphological type of Aβ 14,15 , can account for over 50% of plaque burden in preclinical cases but are not included in CERAD 16 . ...
... Manual counts or stereological 22,23 methods can be tedious, difficult to score, and time-consuming. Consequently, studies using limited-range scores or overall pathology burden 3,8,13,24 are powerful but have interrater variability, 4,13 are difficult to adapt to statistically meaningful disease-correlation analysis, or are blind to selected locational vulnerability 20 . New methods introducing detailed and sensitive quantification of pathologies would reduce the burden placed on pathologists, increase reliability, and enable studies at a scale that is currently prohibitive. ...
... Manual counts or stereological 22,23 methods can be tedious, difficult to score, and time-consuming. Consequently, studies using limited-range scores or overall pathology burden 3,8,13,24 are powerful but have interrater variability, 4,13 are difficult to adapt to statistically meaningful disease-correlation analysis, or are blind to selected locational vulnerability 20 . New methods introducing detailed and sensitive quantification of pathologies would reduce the burden placed on pathologists, increase reliability, and enable studies at a scale that is currently prohibitive. ...
Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline that identifies specific neuropathologies—amyloid plaques and cerebral amyloid angiopathy—in immunohistochemically-stained archival slides. Using automated segmentation of stained objects and a cloud-based interface, we annotate > 70,000 plaque candidates from 43 whole slide images (WSIs) to train and evaluate convolutional neural networks. Networks achieve strong plaque classification on a 10-WSI hold-out set (0.993 and 0.743 areas under the receiver operating characteristic and precision recall curve, respectively). Prediction confidence maps visualize morphology distributions at high resolution. Resulting network-derived amyloid beta (Aβ)-burden scores correlate well with established semi-quantitative scores on a 30-WSI blinded hold-out. Finally, saliency mapping demonstrates that networks learn patterns agreeing with accepted pathologic features. This scalable means to augment a neuropathologist’s ability suggests a route to neuropathologic deep phenotyping.
... In addition, technical variables often confound the assessment of NFTs and NPs in situ. Standard neuropathologic metrics for NFTs and NPs (Braak staging, Consortium to Establish a Registry for Alzheimer's Disease [CERAD], and National Institute on Aging-Reagan criteria) (11)(12)(13)(14)(15)(16) are only semiquantitative, thereby further limiting our ability to make accurate correlations of antemortem cognitive status and the severity of neuropathologic findings. Confounding disease processes that coexist with AD include cerebrovascular disease (CVD), dementia with Lewy bodies, argyrophilic grain disease, and hippocampal sclerosis (HS). ...
... Furthermore, as shown in Table 1, Group I and Group II subjects showed nearly identical age, sex, time since last MMSE, and educational parameters. A third potential limitation of this study involves the difficulties inherent to quantifying neuropathologic lesions in neurodegenerative diseases (12,32). These methods have been published previously and used for productive studies in AD (17). ...
... These methods have been published previously and used for productive studies in AD (17). Consensus diagnostic guidelines (13,33) recommend semiquantitative methods rather than lesion counts because these are less laborious with satisfactory inter-rater reliability when counts between different laboratories are compared (12,14,34). However, if performed consistently, counts of NFTs, NPs, and DPs produce a more finely graded readout that can be linked to other clinical and pathologic variables. ...
There is uncertainty regarding the association of cognitive decline in Alzheimer disease (AD) with classic histopathologic features- neurofibrillary tangles (NFTs) and "neuritic" amyloid plaques (NPs). This uncertainty fuels doubts about the diagnostic importance of NFTs and NPs and leads to confusion regarding hypotheses of AD pathogenesis. Three hundred ninety subjects who underwent longitudinal premortem clinical workup and postmortem quantitative neuropathologic assessment served as the group to address this issue. Subjects with concomitant brain disease(s) were analyzed independently to more accurately assess the contribution of distinct pathologies to cognitive decline. More than 60% of patients of all age groups had important non-AD brain pathologies. However, subjects without superimposed brain diseases showed strong correlations between AD-type pathology counts (NFTs > NPs) and premortem Mini-Mental State Examination scores. The observed correlation was stronger in isocortex than in allocortex and was maintained across age groups including patients older than 90 years. A theoretical model is proposed in which our results are interpreted to support the "amyloid cascade hypothesis" of AD pathogenesis. Our data show that there are many important contributory causes to cognitive decline in older persons. However, NFTs and NPs should not be dismissed as irrelevant in AD based on clinicopathologic correlation.
... This becomes nuanced when differences in classification could possibly lead to differences in prognosis, treatment, and prevention measures [8][9][10] . Therefore, we posited that pathology assessment could benefit from more standardized approaches to improve quality and reliability, especially for imaging data 7,11 . In cases of diagnostic discrepancy, it can be difficult to determine what is objective truth. ...
... Additionally, pathological annotation can be a laborious and time-intensive process that reflects the unique training of the neuropathologist 2,11,13 . In previous work, we automated a single expert's annotations using DL 14 . ...
Pathologists can have complementary assessments and focus areas when identifying and labeling neuropathologies. A standardized approach would ideally draw on the expertise of the entire cohort. We present a deep learning (DL) framework that consistently labels cored, diffuse, and cerebral amyloid angiopathy (CAA) neuropathologies using expert consensus. We collected 100,495 annotations, comprising 20,099 candidate neuropathologies from three institutions, independently annotated by five experts. We compared DL methods that learned the annotation behaviors of individual experts (AUPRC=0.67±0.06 cored; 0.48±0.06 CAA) versus those that reproduced expert consensus, yielding 8.9-13% improvements (AUPRC=0.73±0.03 cored; 0.54±0.06 CAA). Saliency mapping on neuropathologies illustrated how human expertise may progress from novice to expert. In blind prospective tests of 52,555 subsequently expert-annotated images, the models accurately labeled pathologies similar to their human counterparts (consensus model AUPRC=0.73 cored; 0.68 CAA).
... Late-Onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease that is characterized by neuropathology consisting of amyloid beta (Aß) plaques, neurofibrillary tangles and clinical dementia. Genome-wide association studies (GWAS) have implicated immune cell-specific genes associated with AD risk that point to microglia as a causal cell type [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Microglial cells are resident innate immune cells of the central nervous system [19] and play an important role in abolishing apoptotic cells, Aß deposits and synapse removal by phagocytosis. ...
... Control subjects each had Braak[6] NFT stage of 3.0 or less, CERAD[7] neuritic and cortical plaque densities of 0 (none) or 1 (sparse) and lacked any of the following pathologic diagnoses: AD, Parkinson's disease (PD), DLB, VaD, PSP, motor neuron (HipScl) or dementia lacking distinctive histology (DLDH). ...
Late-Onset Alzheimer's Disease (LOAD) results from a complex pathological process influenced by genetic variation, aging and environment factors. Genetic susceptibility factors indicate that myeloid cells such as microglia play a significant role in the onset of LOAD. Here, we developed a computational systems biology approach to construct probabilistic causal and predictive network models of genetic regulatory programs of microglial cells under LOAD diagnosis by integrating two independent brain transcriptome and genome-wide genotype datasets from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and Mayo Clinic (MAYO) studies in the AMPAD consortium. From this network model, we identified and replicated novel microglialspecific master regulators predicted to modulate network states associated with LOAD. We experimentally validated three microglial master regulators (FCER1G, HCK and LAPTM5) in primary human microglia-like cells (MDMi) by demonstrating the molecular impact these master regulators have on modulating downstream genomic targets identified by our top-down/bottom-up method and the causal relations among the three key drivers. These master regulators are involved in phagocytosis, a process associated with LOAD. Thus, we propose three new master regulator (key driver) genes that emerged from our network analyses as robust candidates for further evaluation in LOAD therapeutic development efforts.
... Subjects with AD each had a definite neuropathologic diagnosis according to the NINCDS-ADRDA criteria[156] and a Braak [157] neurofibrillary tangle (NFT) stage of ≥4.0. Control subjects each had a Braak NFT stage of 3.0 or less and CERAD [158] neuritic and cortical plaque densities of 0 (none) or 1 (sparse), and each lacked any of the following pathologic diagnoses: AD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), vascular dementia (VaD), progressive supranuclear palsy (PSP), motor neuron disease (MND), corticobasal degeneration (CBD), Pick's disease (PiD), Huntington's disease (HD), frontotemporal lobar degeneration (FTLD), hippocampal sclerosis (HipScl), or dementia lacking distinctive histology (DLDH). In the MAYO dataset, all disease subjects had ages at death ≥60 years; a more relaxed age cutoff of ≥50 years was applied for CN controls to achieve a sample size similar to that of the AD subjects, but we note there were only two additional control subjects with age at death below 60. ...
Despite decades of genetic studies on late onset Alzheimer disease (LOAD), the molecular mechanisms of Alzheimer disease (AD) remain unclear. Furthermore, different cell types in the central nervous system (CNS) play distinct roles in the onset and progression of AD pathology. To better comprehend the complex etiology of AD, we used an integrative approach to build robust predictive (causal) network models which were cross-validated over multiple large human multi-omics datasets in AD. We employed a published method to delineate bulk-tissue gene expression into single cell-type gene expression and integrated clinical and pathologic traits of AD, single nucleotide variation, and deconvoluted gene expression for the construction of predictive network models for each cell type in AD. With these predictive causal models, we are able to identify and prioritize robust key drivers of the AD-associated network state. In this study, we focused on neuron-specific network models and prioritized 19 predicted key drivers modulating AD pathology. These targets were validated via shRNA knockdown in human induced pluripotent stem cell (iPSC) derived neurons (iNs), in which 10 out of the 19 neuron-related targets (JMJD6, NSF, NUDT2, YWHAZ, RBM4, DCAF12, NDRG4, STXBP1, ATP1B1, and FIBP) significantly modulated levels of amyloid-beta and/or phosphorylated tau peptides in the postmitotic iNs. Most notably, knockdown of JMJD6 significantly altered the neurotoxic ratios of Aβ to 40 and p231-tau to total tau, indicating its potential therapeutic relevance to both amyloid and tau pathology in AD. Molecular validation by RNA sequencing (RNAseq) in iNs further confirmed the network structure, showing significant enrichment in differentially expressed genes after knockdown of the validated targets. Interestingly, our network model predicts that these 10 key drivers are upstream regulators of REST and VGF, two recently identified key regulators of AD pathogenesis.
... The cerebellar cortex was selected as the reference region for [ 18 F]THK5317 and [ 11 C]PIB estimates due to previous reports of it lacking neurofibrillary tangles and Congo red/thioflavin-S positivity, respectively. 31,32 Although consensus has yet to be reached as to which reference region is most suitable for normalisation of [ 18 F]FDG SUV images, the pons has frequently been selected due to it being purported to be the brain region that is least affected, from a metabolic standpoint, in AD. 33 The cerebellar cortex was used in the present study, however, to achieve consistency with respect to the reference region used for [ 18 F]THK5317 and [ 11 C]PIB; in this respect, the metabolism of the cerebellar cortex has been shown to be well preserved in mildto-moderate AD, 34 and has likewise been shown to be a good reference region for brain perfusion. 35,36 Certain methodological aspects, however, limit interpretation of the present findings. ...
For amyloid positron emission tomography tracers, the simplified reference tissue model derived ratio of influx rate in target relative to reference region (R1) has been shown to serve as a marker of brain perfusion, and, due to the strong coupling between perfusion and metabolism, as a proxy for glucose metabolism. In the present study, 11 prodromal Alzheimer’s disease and nine Alzheimer’s disease dementia patients underwent [18F]THK5317, carbon-11 Pittsburgh Compound-B ([11C]PIB), and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography to assess the possible use of early-phase [18F]THK5317 and R1 as proxies for brain perfusion, and thus, for glucose metabolism. Discriminative performance (prodromal vs Alzheimer's disease dementia) of [18F]THK5317 (early-phase SUVr and R1) was compared with that of [11C]PIB (early-phase SUVr and R1) and [18F]FDG. Strong positive correlations were found between [18F]THK5317 (early-phase, R1) and [18F]FDG, particularly in frontal and temporoparietal regions. Differences in correlations between early-phase and R1 ([18F]THK5317 and [11C]PIB) and [18F]FDG, were not statistically significant, nor were differences in area under the curve values in the discriminative analysis. Our findings suggest that early-phase [18F]THK5317 and R1 provide information on brain perfusion, closely related to glucose metabolism. As such, a single positron emission tomography study with [18F]THK5317 may provide information about both tau pathology and brain perfusion in Alzheimer’s disease, with potential clinical applications.
... The cerebellar cortex was selected as the reference region for [ 18 F]THK5317 and [ 11 C]PIB estimates due to previous reports of it lacking neurofibrillary tangles and Congo red/thioflavin-S positivity, respectively. 31,32 Although consensus has yet to be reached as to which reference region is most suitable for normalisation of [ 18 F]FDG SUV images, the pons has frequently been selected due to it being purported to be the brain region that is least affected, from a metabolic standpoint, in AD. 33 The cerebellar cortex was used in the present study, however, to achieve consistency with respect to the reference region used for [ 18 F]THK5317 and [ 11 C]PIB; in this respect, the metabolism of the cerebellar cortex has been shown to be well preserved in mildto-moderate AD, 34 and has likewise been shown to be a good reference region for brain perfusion. 35,36 Certain methodological aspects, however, limit interpretation of the present findings. ...
... This new data acquisition form reflects the new NACC guidelines for the standard neuropathologic assessment of AD at NIAfunded Alzheimer Disease Centers (ADCs) and incorporates the new neuropathologic diagnostic criteria for AD of the National Institute on Aging-Alzheimer's Association (NIA-AA)[2], which underscore the importance of Ab plaques as a key morphologic lesion that best discriminates AD pathology from non-AD[2]. The ADNI-NPC also applies three other sets of neuropathologic criteria: Khachaturian[3], Consortium to Establish a Registry for Alzheimer's disease (CERAD)[4], and NIA-Reagan[5]to each autopsied brain to allow coherence with legacy data as appropriate and to enable investigators who have yet to adopt the NIAAA criteria to benefit from the brain tissues collected by the ADNI-NPC[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. This approach allows investigators maximal utility in applying the neuropathologic diagnoses most appropriate to their research aims. ...
The Alzheimer's Disease Neuroimaging Initiative Neuropathology Core (ADNI-NPC) facilitates brain donation, ensures standardized neuropathologic assessments, and maintains a tissue resource for research.
The ADNI-NPC coordinates with performance sites to promote autopsy consent, facilitate tissue collection and autopsy administration, and arrange sample delivery to the NPC, for assessment using National Institute on Aging-Alzheimer's Association neuropathologic diagnostic criteria.
The ADNI-NPC has obtained 45 participant specimens, and neuropathologic assessments have been completed in 36 to date. Challenges in obtaining consent at some sites have limited the voluntary autopsy rate to 58%. Among assessed cases, clinical diagnostic accuracy for Alzheimer disease (AD) is 97%; however, 58% of cases show neuropathologic comorbidities.
Challenges facing autopsy consent and coordination are largely resource related. The neuropathologic assessments indicate that ADNI's clinical diagnostic accuracy for AD is high; however, many AD cases have comorbidities that may impact the clinical presentation, course, and imaging and biomarker results. These neuropathologic data permit multimodal and genetic studies of these comorbidities to improve diagnosis and provide etiologic insights.
Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
... The data were then normalized to the corresponding uptake in a reference region generating late scan ratio data (ROI/ref). The cerebellar cortex was chosen as reference region because of its previous reported lack of Congo red and thioflavin-S-positive plaques [174,175]. ...
... Neuritic plaques were first defined based on ultrastructural criteria by Wisniewski and Terry (17), but our usage of the term is necessarily that of Mirra et al (14) as both of the publications on which the present study is based used the CERAD definition of neuritic plaques. Although not informative with respect to molecular composition, the CERAD definition of neuritic plaques as particular morphological entities has the great advantages of being sufficiently unambiguous to result in relatively high inter-observer agreement (18,19); moreover, there is a wealth of studies that have assess its clinicopathological significance. The adoption of the CERAD definition of neuritic plaques by the NIA ADCs enabled the accumulation of statistically large autopsied subject numbers that had all been assessed with relatively equivalent methods. ...
In 2012, florbetapir (F) (Amyvid) received US Food and Drug Administration approval as a diagnostic agent for detecting neuritic (β-amyloid) plaques in living patients. Although such approval is specifically not extended to the use of florbetapir as a single definitive diagnostic test for Alzheimer disease dementia (ADD), it is of considerable importance to examine its potential in this regard. To estimate the ability of florbetapir amyloid imaging to detect specified densities of postmortem-identified neuritic plaques, we used the data of Clark et al [Clark CM, Pontecorvo MJ, Beach TG, et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: A prospective cohort study. Lancet Neurol 2012;11:669-78]. We then used the data of Beach et al [Beach TG, Monsell SE, Phillips LE, et al. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 2012;71:266-73], derived from the National Alzheimer's Coordinating Center, to estimate the fraction of subjects who would have been called florbetapir-positive and, among these, the fraction of subjects who would also meet neuropathologic criteria for the presence of ADD. The accuracy of a positive florbetapir β-amyloid scan for the detection of neuropathologically defined ADD is estimated at between 69% and 95% sensitivity and between 83% and 89% specificity. From the same National Alzheimer's Coordinating Center data set, 144 subjects were recorded as having normal cognition. Among these, 84 (58%) had at least sparse neuritic plaques at autopsy and, among these, florbetapir imaging was estimated to detect 47 (56%). These findings suggest that amyloid imaging may significantly improve the clinical identification of ADD.
... The results from these studies are in favour of IHC stains, in comparison with conventional ones, from a reliability perspective. Furthermore, there are several studies on intraand/or interrater reliability, showing that neuropathologists, regardless of staining method, do not exhibit perfect agreement when assessing Alzheimer [Paulus et al. 1992;Chui et al. 1993;Mirra et al. 1994;Nagy et al. 1997;Nagy et al. 1998c;Alafuzoff et al. 2008a;Alafuzoff et al. 2008b], CAA [Alafuzoff et al. 2009a] or Lewy-related pathology [Müller et al. 2005;Leverenz et al. 2008;Alafuzoff et al. 2009b]. In the cited studies, the kappa values were in the range of 0.19-0.98 and 0.61-0.97 ...
... The main histopathologic changes, depositions of amyloid and accumulation of neurofibrillary tangles, are similarly pronounced in these regions, although not following an identical pattern. While these changes are the hallmark of the pathological diagnosis of AD such as the Khachaturian or CERAD criteria (see Tables 1, 2)202122, these are by themselves insufficient. There is no biological dividing line between the identical changes that are the inevitable consequences of aging, and any separation is arbitrary. ...
Because of the aging of the population, dementia – already the third most expensive disease in developed countries – will become even more common in the next few decades, reaching pandemic proportions. Understanding of this problem, with its huge clinical, social and economic implications, necessitates action. Like in other epidemics, prevention is easier than cure. Due to epidemiologic research, several common risk factors for dementia have been identified which can be treated. In the present paper, we shall discuss the nosology of old age dementia, and particularly Alzheimer's disease and vascular dementia, and the effect of the definitions of these disorders on our understanding of the epidemiology of dementia and of measures which can be taken to reduce its prevalence. Because it is impossible to discuss at length all risk factors, we shall focus on the relationship between smoking with dementia and the role of brain trauma in triggering dementia.
... Another limitation is that CAA or CMI severity could not be related to the apolipoprotein E genotype [36], due to ethical and legal constraints of genotype extraction. In addition, the use of the CERAD criteria for assessing the burden of neuritic plaques and the Braak staging for the burden of NFTs both based on the modified Bielschowsky staining may be the third limitation , considering that the CERAD is semiquantitative rather than quantitative measures of neuropathology [28] and the Braak staging criteria for tau pathology have been recently modified [2], although the two neuropathologists agreed on their final grading of the 31 CAA patients enrolled in the current study. In summary, using postmortem brain analysis of relevant patients and models of transgenic mice, our study provides strong evidence for the relationship between CAA and microinfarcts with cerebral hypoperfusion as the mediating factor. ...
Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer’s disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer’s disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm² in mild, 0.584/cm² in moderate, and 4.370/cm² in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-011-0925-9) contains supplementary material, which is available to authorized users.
... For neuropathological diagnosis, tissue blocks were selected from standardized regions of the left cerebral hemisphere. Tissue blocks were embedded in paraffin, sectioned at 6 m, and stained with a battery of conventional and immunohistochemical stains (McKeel et al., 1993; Mirra et al., 1994; Morris et al., 1996). Blinded counts of total diffuse, neuritic, and cored SPs and NFTs were made in midfrontal, superior temporal, and inferior parietal lobule neocortex, in hippocampal area CA1, and in the EC, using modified Bielschowsky silver methods (Berg et al., 1993; McKeel et al., 1993). ...
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.
... In the present follow-up study the mean uptake values of the ROI obtained in a late time interval (40-60 min) were normalized to the corresponding uptake in a reference region (ROI/ref) ( Lopresti et al., 2005). The cerebellar cortex was chosen as reference because of its previously reported lack of Congo red-and thioflavin-S-positive plaques (Yamaguchi et al., 1989;Mirra et al., 1994). Among several different PIB evaluation methods the late scan reference method has shown a large size effect ( Lopresti et al., 2005). ...
Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand N-methyl[11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 +/- 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-[18F]fluoro-2-deoxy-d-glucose (FDG) after 2.0 +/- 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-d-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test-retest). Relative PIB retention in cortical regions differed by 3-7% in the test-retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P < 0.01) 20% decrease in rCMRGlc was observed in cortical brain regions. A significant negative correlation between rCMRGlc and PIB retention was observed in the parietal cortex in the Alzheimer patients at follow-up (r = 0.67, P = 0.009). A non-significant decline in Mini-Mental State Examination (MMSE) score from 24.3 +/- 3.7 (mean +/- standard deviation) to 22.7 +/- 6.1 was measured at follow-up. Five of the Alzheimer patients showed a significant decline in MMSE score of >3 (21.4 +/- 3.5 to 15.6 +/- 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 +/- 3.1 to 25.9 +/- 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.
... 21 The cerebellar cortex was chosen as reference because of its previously reported lack of Congo red-and thioflavin-S-positive plaques. 22,23 Among several different PIB evaluation methods, the late scan reference method has shown a large effect size. 24 In this study, percentage changes in the CMRglc and PIB retention values were used, defined by the following formula: %PET data 100 (PET data (f) /PET data (b) 100) 100, with f and b indicating CMRglc and PIB retention values at the times of follow-up and at baseline, respectively. ...
The effects of (-)-phenserine (phenserine) and placebo/donepezil treatment on regional cerebral metabolic rate for glucose (rCMRglc) and brain amyloid load were investigated by positron emission tomography in 20 patients with mild Alzheimer's disease in relation to cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive function.
The first 3 months of the study was a randomized, double-blind, placebo-controlled phase, during which 10 patients received phenserine (30 mg/day) and 10 patients the placebo. Three to 6 months was an open-label extension phase, during which the placebo group received donepezil (5 mg/day) and the phenserine group remained on phenserine. After 6 months, all patients received phenserine treatment up to 12 months. The patients underwent positron emission tomography examinations to measure rCMRglc (8F-FDG) and amyloid load (11C-PIB) at baseline and after 3 and 6 months of the treatment. Neuropsychological and biomarker data were collected at the three times of positron emission tomography imaging.
Statistically significant effects on a composite neuropsychological test score were observed in the phenserine-treated group compared with the placebo and donepezil group at 3 and 6 months, respectively. Values of rCMRglc were significantly increased in several cortical regions after 3 months of phenserine treatment, compared with baseline, and correlated positively with cognitive function and CSF beta-amyloid 40 (Abeta40). Cortical Pittsburgh Compound B retention correlated negatively with CSF Abeta40 levels and the ratio Abeta/beta-secretase-cleaved amyloid precursor protein. In CSF, Abeta40 correlated positively with the attention domain of cognition.
Phenserine treatment was associated with an improvement in cognition and an increase in rCMRglc.
Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue (n = 408) and single nucleus RNAseq (n = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM, and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas (https://rtools.mayo.edu/PSP_RNAseq_Atlas/). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases.
Previous genome-wide association studies (GWAS), conducted by our group and others, have identified loci that harbor risk variants for neurodegenerative diseases, including Alzheimer's disease (AD). Human disease variants are enriched for polymorphisms that affect gene expression, including some that are known to associate with expression changes in the brain. Postulating that many variants confer risk to neurodegenerative disease via transcriptional regulatory mechanisms, we have analyzed gene expression levels in the brain tissue of subjects with AD and related diseases. Herein, we describe our collective datasets comprised of GWAS data from 2,099 subjects; microarray gene expression data from 773 brain samples, 186 of which also have RNAseq; and an independent cohort of 556 brain samples with RNAseq. We expect that these datasets, which are available to all qualified researchers, will enable investigators to explore and identify transcriptional mechanisms contributing to neurodegenerative diseases.
To determine the reliability of assessment of alpha-synucleinimmunoreactive (alpha S-IR) structures by neuropathologists, 28 evaluators from 17 centers of BrainNet Europe examined current methods and reproducibility of alpha S-IR evaluation using a tissue microarray (TMA) technique. Tissue microarray blocks were constructed of samples from the participating centers that contained aS-IR structures. Slides from these blocks were stained in each center and assessed for neuronal perikaryal inclusions, neurites, and glial cytoplasmic inclusions. The study was performed in 2 phases. First, the TMA slides were stained with the antibody of the center's choice. In this phase, 59% of the sections were of good or acceptable quality, and 4 of 9 antibodies used performed consistently. Differences in interpretation and categorization of alpha S-IR structures, however, led to differing results between the laboratories. Prior to the second phase, the neuropathologists participated in a training session on the evaluation of alpha S-IR structures. Based on the results of the first phase, selected antibodies using designated antigen retrieval methods were then applied to TMA slides in the second phase. When the designated methods of both staining and evaluation were applied, all 26 subsequently stained TMA sections evaluated were of good/acceptable quality, and a high level of concordance in the assessment of the presence or absence of specific alpha S-IR structures was achieved. A semiquantitative assessment of alpha S-IR neuronal perikaryal inclusions yielded agreements ranging from 49% to 82%, with best concordance in cortical core samples. These results suggest that rigorous methodology and dichotomized assessment (i.e. determining the presence or absence of alpha S-IR) should be applied, and that semiquantitative assessment can be recommended only for the cortical samples. Moreover, the study demonstrates that there are limitations in the scoring of alpha S-IR structures.
The neuropathologic examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently used clinical diagnostic methods, clinical and neuropathologic data from the National Alzheimer's Coordinating Center, which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer Disease Centers (ADCs), were collected as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on "probable" and "possible" AD levels of clinical confidence and 4 levels of neuropathologic confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathologic criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathologic diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in subjects with dementia than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiologic studies.
Here we report studies of the burden of neurodegenerative neuropathologies in a cohort of Medical Examiner (ME) subjects from the County of Santa Clara (California) to determine if this unique population of decedents manifested evidence of neurodegeneration that might underlie causes of death seen in an ME practice. We found that 13% of the brains from ME cases showed significant tau pathology, including 55% of those 65 years old and older and 63% of those 70 years old and older. The histochemical and immunohistochemical findings were consistent with Alzheimer's disease (AD) in 7 subjects and frontotemporal lobar degeneration (FTLD) tauopathy type in six cases. There were no cases of Parkinson's disease, dementia with Lewy Bodies or other neurodegenerative conditions. Our study suggests that decedents >65 years of age in an ME practice are afflicted by common causes of dementia such as AD and FTLD which could contribute wholly or in part to their causes of death.
Aging and metabolism-related disorders are risk factors for Alzheimer disease (AD). Because sirtuins may increase the life span through regulation of cellular metabolism, we compared the concentration of sirtuin 1 (SIRT1) in the brains of AD patients (n = 19) and controls (n = 22) using Western immunoblots and in situ hybridization. We report a significant reduction of SIRT1 (messenger RNA [mRNA], -29%; protein, -45%) in the parietal cortex of AD patients, but not in the cerebellum. Further analyses in a second cohort of 36 subjects confirmed that cortical SIRT1 was decreased in AD but not in individuals with mild cognitive impairment. SIRT1 mRNA and its translated protein correlated negatively with the duration of symptoms (mRNA, r2 = -0.367; protein, r2 = -0.326) and the accumulation of paired helical filament tau (mRNA, r2 = -0.230; protein, r2 = -0.119), but weakly with insoluble amyloid-beta 42 (mRNA, r2= -0.090; protein, r2 = -0.072). A significant relationship between SIRT1 levels and global cognition scores proximate to death was also found (r2= +0.09, p = 0.049). In contrast, cortical SIRT1 levels remained unchanged in a triple-transgenic animal model of AD. Collectively, our results indicate that loss of SIRT1 is closely associated with the accumulation of amyloid-beta and tau in the cerebral cortex of persons with AD.
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.
NEUROLOGY 1995;45: 461-466
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.
This interlaboratory study evaluated the reproducibility of the assessments of neuritic plaques and neurofibrillary tangles (NFTs)--the hallmark lesions of Alzheimer disease--and compared the staining between the BrainNet Europe centers. To reduce the topography-related inconsistencies in assessments, we used a 2-mm tissue microarray (TMA) technique. The TMA block included 42 core samples taken from 21 paraffin blocks. The assessments were done on Bielschowsky and Gallyas silver stains using an immunohistochemical (IHC) method with antibodies directed to beta-amyloid (IHC/Abeta) and hyperphosphorylated tau (IHC/HPtau). The staining quality and the assessments differed between the participants, being most diverse with Bielschowsky (good/acceptable stain in 53% of centers) followed by Gallyas (good/acceptable stain in 57%) and IHC/Abeta (good/acceptable stain in 71%). The most uniform staining quality and assessment was obtained with the IHC/HPtau method (good/acceptable stain in 94% of centers). The neuropathologic diagnostic protocol (Consortium to Establish a Registry for Alzheimer Disease, Braak and Braak, and the National Institute of Aging and Reagan [NIA-Reagan] Institute) that was used significantly influenced the agreement, being highest with NIA-Reagan (54%) recommendations. This agreement was improved by visualization of NFTs using the IHC/HPtau method. Therefore, the IHC/HPtau methodology to visualize NFTs and neuropil threads should be considered as a method of choice in a future diagnostic protocol for Alzheimer disease.
To test the hypothesis that beta-amyloid (Abeta) burden is associated with rates of brain atrophy.
Forty-five subjects who had been prospectively studied, died, and had an autopsy diagnosis of low, intermediate, or high probability of Alzheimer's disease who had two volumetric head magnetic resonance imaging scans were identified. Compact and total (compact + diffuse) Abeta burden was measured using a computerized image analyzer with software program to detect the proportion of gray matter occupied by Abeta. Visual ratings of Abeta burden were also performed. The boundary shift integral was used to calculate change over time in whole-brain and ventricular volume. All boundary shift integral results were annualized by adjusting for scan interval. Demographics, cognitive measures, clinical diagnoses, apolipoprotein E genotype, neurofibrillary tangle (NFT) pathology, and vascular lesion burden were determined.
There was no correlation between compact or total Abeta burden, or visual Abeta ratings, and rates of brain loss or ventricular expansion in all subjects. However, significant correlations were observed between rates of brain loss and age, Braak NFT stage, and change over time in cognitive measures. These features also correlated with rates of ventricular expansion. The rates of brain loss and ventricular expansion were greater in demented compared with nondemented subjects.
These findings suggest that rate of brain volume loss is not determined by the amount of insoluble Abeta in the gray matter.
To determine the reliability of assessment of alpha-synuclein-immunoreactive (alphaS-IR) structures by neuropathologists, 28 evaluators from 17 centers of BrainNet Europe examined current methods and reproducibility of alphaS-IR evaluation using a tissue microarray (TMA) technique. Tissue microarray blocks were constructed of samples from the participating centers that contained alphaS-IR structures. Slides from these blocks were stained in each center and assessed for neuronal perikaryal inclusions, neurites, and glial cytoplasmic inclusions. The study was performed in 2 phases. First, the TMA slides were stained with the antibody of the center's choice. In this phase, 59% of the sections were of good or acceptable quality, and 4 of 9 antibodies used performed consistently. Differences in interpretation and categorization of alphaS-IR structures, however, led to differing results between the laboratories. Prior to the second phase, the neuropathologists participated in a training session on the evaluation of alphaS-IR structures. Based on the results of the first phase, selected antibodies using designated antigen retrieval methods were then applied to TMA slides in the second phase. When the designated methods of both staining and evaluation were applied, all 26 subsequently stained TMA sections evaluated were of good/acceptable quality, and a high level of concordance in the assessment of the presence or absence of specific alphaS-IR structures was achieved. A semiquantitative assessment of alphaS-IR neuronal perikaryal inclusions yielded agreements ranging from 49% to 82%, with best concordance in cortical core samples. These results suggest that rigorous methodology and dichotomized assessment (i.e. determining the presence or absence of alphaS-IR) should be applied, and that semiquantitative assessment can be recommended only for the cortical samples. Moreover, the study demonstrates that there are limitations in the scoring of alphaS-IR structures.
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