Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases.

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.

Multiomic Analyses of Dopaminergic Neurons Isolated from Human Substantia Nigra in Parkinson's Disease: A Descriptive and Exploratory Study.

Dopaminergic neurons (DA) of the substantia nigra pars compacta (SNpc) selectively and progressively degenerate in Parkinson's disease (PD). Until now, molecular analyses of DA in PD have been limited to genomic or transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined multiomic study examining the protein profile of these neurons is currently available. In this exploratory study, we used laser capture microdissection to extract regions from DA in 10 human SNpc obtained at autopsy in PD patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nanoliquid chromatography-mass spectrometry, respectively, and the differential expression between PD and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This multiomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in PD, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of laser-dissected neuronal parts from SNpc in PD. Data are available via ProteomeXchange with identifier PXD024748 and via GEO with identifier GSE 169755.

The 18 kDa translocator protein is associated with microglia in the hippocampus of non-demented elderly subjects.

Increase in the brain expression of the 18 kDa translocator protein (TSPO) is considered as a marker of neuroinflammation in the context of brain diseases, such as Alzheimer's disease (AD). However, in non-demented subjects with Alzheimer's neuropathology, TSPO accumulation in hippocampus subdivisions has not been fully characterized. To determine if TSPO is associated with the presence of amyloid ß plaques and/or phosphorylated Tau accumulation, we analyzed hippocampal sections using immunohistochemistry of 14 non-demented subjects with positive staining for Aß and/or phosphorylated Tau. TSPO expression was heterogenous with higher accumulation in the CA2/3 and subiculum subfields of the hippocampus. Its distribution closely resembled that of the microglial IBA1 marker and of the Aß42 amyloid form. In addition, positive correlations were observed between TSPO and IBA1 densities in CA4, CA2/3 and the subiculum but not with either the astrocyte GFAP marker or the AD-type Aß and Tau markers. This study sustains the hypothesis that TSPO is mainly associated with microglia and in Aß42-rich subdivisions in the hippocampus of non-demented elderly individuals.

Identification of hippocampal cortical microinfarcts on postmortem 3-T magnetic resonance imaging.

Cortical microinfarcts (CMI) are increasingly recognized in the neurological community as a biomarker related to cognitive impairment and dementia. If their radiological depiction has been largely described in experimental settings using ultra-high-field magnetic resonance imaging (MRI), less is known about their visibility on routinely used 3-T MRI. In this radiologic-pathologic correlation study, using 3-T post-mortem MRI, we searched for hippocampal CMI, in a double-blinded fashion, and found that only 4/36, or 11%, were clearly demonstrated on both radiological and histopathological exams.

Visualization of White Matter Fiber Tracts of Brain Tissue Sections With Wide-Field Imaging Mueller Polarimetry.

Identification of white matter fiber tracts of the brain is crucial for delineating the tumor border during neurosurgery. A custom-built Mueller polarimeter was used in reflection configuration for the wide-field imaging of thick sections of fixed human brain and fresh calf brain. The maps of the azimuth of the fast optical axis of linear birefringent medium reconstructed from the experimental Mueller matrix images of the specimen by applying a non-linear data compression algorithm showed a strong correlation with the silver-stained sample histology image, which is the gold standard for ex-vivo brain fiber tract visualization. The polarimetric maps of fresh calf brain tissue demonstrated the same trends in the depolarization, the scalar retardance and the azimuth of the fast optical axis as seen in fixed human brain tissue. Thus, label-free imaging Mueller polarimetry shows promise as an efficient intra-operative modality for the visualization of healthy brain white matter fiber tracts, which could improve the accuracy of tumor border detection and, ultimately, patient outcomes.

Medial temporal lobe volume is associated with neuronal loss but not with hippocampal microinfarcts despite their high frequency in aging brains.

Medial temporal lobe (MTL) atrophy is an important marker for the clinical diagnosis of Alzheimer's disease at its prodromal stages. Several brain lesions have been associated with MTL atrophy including hippocampal sclerosis, neurodegenerative neuronal loss, and vascular pathology. To better explore the relationship between MTL volume on MRI and age-related degenerative and microvascular hippocampal pathology, we compared MTL volume on postmortem whole brain MRI and stereological estimates of the total number of neurons, cortical microinfarcts (CMIs), and neurofibrillary tangles (NFTs) in a consecutive autopsy series of 21 older individuals (11 females and 10 males, mean age 83.3 ± 5.8; range: 74-93 years, 7 demented and 14 nondemented). Our results revealed a very high percentage of cases with hippocampal CMIs (52%), particularly in the CA1 field. MTL volume was closely related to neuronal loss in both the CA1 area of the hippocampus (p = 0.0109) and the entorhinal cortex (p = 0.0272). MTL volume was not related to total CMI volume or to the total number of NFTs in our sample. In conclusion, hippocampal CMIs are very common in old age. MTL volume is determined essentially by the number of neurons in the hippocampus and does not appear to be related to the presence of NFTs or CMIs in this region.

Astrocytic TSPO Upregulation Appears Before Microglial TSPO in Alzheimer's Disease.

BACKGROUND: In vivo PET/SPECT imaging of neuroinflammation is primarily based on the estimation of the 18 kDa-translocator-protein (TSPO). However, TSPO is expressed by different cell types which complicates the interpretation. OBJECTIVE: The present study evaluates the cellular origin of TSPO alterations in Alzheimer's disease (AD). METHODS: The TSPO cell origin was evaluated by combining radioactive imaging approaches using the TSPO radiotracer [125I]CLINDE and fluorescence-activated cell sorting, in a rat model of AD (TgF344-AD) and in AD subjects. RESULTS: In the hippocampus of TgF344-AD rats, TSPO overexpression not only concerns glial cells but the increase is visible at 12 and 24 months in astrocytes and only at 24 months in microglia. In the temporal cortex of AD subjects, TSPO upregulation involved only glial cells. However, the mechanism of this upregulation appears different with an increase in the number of TSPO binding sites per cell without cell proliferation in the rat, and a microglial cell population expansion with a constant number of binding sites per cell in human AD. CONCLUSION: These data indicate an earlier astrocyte intervention than microglia and that TSPO in AD probably is an exclusive marker of glial activity without interference from other TSPO-expressing cells. This observation indicates that the interpretation of TSPO imaging depends on the stage of the pathology, and highlights the particular role of astrocytes.

Fluorescence-activated cell sorting to reveal the cell origin of radioligand binding.

Many studies have explored the role of TSPO (18 kDa translocator protein) as a marker of neuroinflammation using single-photon emission computed tomography (SPECT) or positron emission tomography (PET). In vivo imaging does not allow to determine the cells in which TSPO is altered. We propose a methodology based on fluorescence-activated cell sorting to sort different cell types of radioligand-treated tissues. We compared left/right hippocampus of rats in response to a unilateral injection of lipopolysaccharide (LPS), ciliary neurotrophic factor (CNTF) or saline. We finally applied this methodology in human samples (Alzheimer's disease patients and controls). Our data show that the pattern of TSPO overexpression differs across animal models of acute neuroinflammation. LPS induces a microglial expansion and an increase in microglial TSPO binding. CNTF is associated with an increase in TSPO binding in microglia and astrocytes in association with an increase in the number of microglial binding sites per cell. In humans, we show that the increase in CLINDE binding in Alzheimer's disease concerns microglia and astrocytes in the presence of a microglial expansion. Thus, the cellular basis of TSPO overexpression is condition dependent, and alterations in TSPO binding found in PET/SPECT imaging studies cannot be attributed to particular cell types indiscriminately.

MRI detection of cerebral microbleeds: size matters.

PURPOSE: Cerebral microbleeds (CMB) play an important role as an imaging biomarker notably in vascular and neurodegenerative diseases. Current clinical brain MRI underestimates the number of CMB with respect to histopathology. It is expected that small CMBs are more likely to be false-negatives, yet this has not been demonstrated and the average size of false-negative and true-positive CMBs have not been established. METHODS: The radiologic-histopathologic correlation study was approved by the local review board and included 42 consecutive cases (mean age at death, 80.7 ± 10.0 years; 23 females and 19 men) between 12 January 2012 and 10 December 2012 having undergone brain autopsy. Postmortem SWI (susceptibility-weighted imaging) images were acquired on a clinical 3T system using parameters similar to clinical routine. The detection of CMB on postmortem MRI was compared with corresponding histopathological slices. RESULTS: Postmortem MRI detected 23 true-positive CMB. Histopathology additionally detected 68 CMBs (false-negative MRI CMBs). The average size true-positive MRI CMBs had on histopathology was 3.6 ± 7.1 mm3. The average size false-negative MRI CMBs was significantly smaller (p < 0.05), measuring 0.3 ± 1.2 mm3 on histopathology. CONCLUSION: Size matters. As expected, the average size of true-positive MRI CMB was around 10 times larger as compared with false-negative MRI CMB. Evidently, in addition to size, other factors will influence the detectability of CMB, including iron content, ratio of Fe2+/Fe3+, spatial configuration, and location, yet this remains to be elucidated in future studies.

A walk through tau therapeutic strategies.

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Several therapeutic approaches have been proposed, including the inhibition of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, the inhibition of tau aggregation, active and passive immunotherapies, and tau silencing by antisense oligonucleotides. New tau therapeutics, across the board, have demonstrated the ability to prevent or reduce tau lesions and improve either cognitive or motor impairment in a variety of animal models developing neurofibrillary pathology. The most advanced strategy for the treatment of human tauopathies remains immunotherapy, which has already reached the clinical stage of drug development. Tau vaccines or humanised antibodies target a variety of tau species either in the intracellular or extracellular spaces. Some of them recognise the amino-terminus or carboxy-terminus, while others display binding abilities to the proline-rich area or microtubule binding domains. The main therapeutic foci in existing clinical trials are on Alzheimer's disease, progressive supranuclear palsy and non-fluent primary progressive aphasia. Tau therapy offers a new hope for the treatment of many fatal brain disorders. First efficacy data from clinical trials will be available by the end of this decade.

TSPO and amyloid deposits in sub-regions of the hippocampus in the 3xTgAD mouse model of Alzheimer's disease.

The involvement of the 18kDa translocator protein (TSPO), a marker of neuroinflammation, in Alzheimer's disease (AD) remains controversial. In the present report, we used [125I]-CLINDE, a SPECT TSPO radiotracer never before used in AD, and we investigated the relationship between TSPO and amyloid plaque density (using [125I]-DRM106) in a triple transgenic mouse model of AD (3xTgAD, APPSWE, PS1M146V and TauP301L). Our results show that TSPO increases appear before those of amyloid deposits. Moreover, the different parts of the hippocampus are differentially affected. Indeed, for both TSPO and amyloid, the subiculum is affected earlier and the ventral hippocampus later than the dorsal hippocampus. In the subiculum and the dorsal hippocampus of 3xTgAD mice, a positive correlation between TSPO and of amyloid deposit levels is observed. This data supports the hypothesis that TSPO could be used as a predictive marker of amyloid pathology. In addition, our immunohistochemical data shows a segregation of TSPO in the hippocampus and immunofluorescence imaging revealed a mainly microglial origin of the TSPO expression. Thus, imaging TSPO with CLINDE may be a good alternative to PET radiotracers.

Air bubble artifact reduction in post-mortem whole-brain MRI: the influence of receiver bandwidth.

Air bubble artifacts on SWI post-mortem MRI studies may interfere with the detection of cerebral microbleeds. We investigated whether the utilization of a higher receiver bandwidth of 500 Hz/pixel could reduce cortical air bubble artifacts without compromising the detection of cerebral microbleeds in high-field MRI. All microbleeds remained clearly visible whereas a reduction of 17% of the long axis of the "halo" magnitude artifacts was achieved. On corresponding phase images, air bubble artifacts appeared identical.

Bacillus cereus bacteremia with central nervous system involvement: A neuropathological study.

Bacillus cereus is a widely-distributed, gram-positive or variable, rod-shaped bacterium frequently considered a contaminant in clinical specimens. It is recognized as a potential pathogen inducing self-limiting emetic or diarrheal food poisoning or localized infection in immunocompetent patients. True B. cereus bacteremia is uncommon and mainly observed in fragile patients, notably in immunocompromised individuals. We report clinical, radiological, and pathological findings of a 64-year-old patient with a history of acute myeloid leukemia who initially presented a fever while neutropenic after the induction of a second cycle of chemotherapy. He developed B. cereus bacteremia with invasive infection and a fatal outcome. The clinical and radiological data of this case are compared to a previously-published series of 21 patients from our institution with B. cereus bacteremia. This study highlights the clinical challenge to diagnose B. cereus and the importance of the delay between the detection of B. cereus and the initiation of an effective targeted antibiotic therapy. This case presented an aggressive evolution with multiple necrotic and hemorrhagic foci in the brain. Upon histological examination, B. cereus virulence was notably reflected by the dissection of blood vessel walls by the bacilli and luminal occlusion, a pattern that has not been yet reported.
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Early Alzheimer-type lesions in cognitively normal subjects.

Amyloid deposits and tau-immunoreactive neurofibrillary tangles, together with neuronal and synaptic loss, are the neuropathological hallmarks of Alzheimer's disease (AD). Both proteins are present in the normal brain during aging. However, the temporal sequence of their involvement in the onset of AD pathology remains controversial. To define whether amyloid ß protein deposits or tau protein lesions appear first during normal brain aging, we performed an immunohistological study on serial sections from 105 autopsy brains (age range: 40-104 years) from patients free of clinical signs of cognitive decline, using anti-tau (AT8) and anti-amyloid (4G8) antibodies in the hippocampus, entorhinal cortex, inferior temporal cortex (Brodmann area 20), prefrontal cortex (Brodmann area 9), occipital cortex (Brodmann areas 17 and 18), and in the brainstem. All cases older than 48 years displayed at least a few neurofibrillary tangles, which appeared more frequently in the entorhinal than in the transentorhinal cortex. Tau pathology in these areas preceded tau inclusions in the brainstem. Furthermore, the first site of the apparition of tau pathology is inconsistent, being the entorhinal cortex in most cases, and in fewer cases, the transentorhinal region. There was no case presenting with amyloid deposition in the absence of neurofibrillary tangles, lending evidence to the fact that neurofibrillary tangles appear earlier than amyloid plaques during normal brain aging. However, the role of amyloid in promoting tau deposition cannot be excluded in some cases but may not represent the sole mechanism of disease induction and progression.

Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG).

Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.

Targeting SUMO-1ylation Contrasts Synaptic Dysfunction in a Mouse Model of Alzheimer's Disease.

Synaptic dysfunction has been recognized as an early feature occurring at the onset of Alzheimer's disease (AD). Compromised neurotransmission leads over time to synaptic loss and these events correlate with the cognitive decline that progressively affects AD patients.Protein SUMOylation (Small Ubiquitin-like MOdifier) is a post-translational modification (PTM) involved in several cellular processes including synaptic transmission.We here demonstrate that cortical synaptosomes prepared from Tg2576 mice of 6 months of age show an increased SUMO-1ylation, which returns back to normal levels at 20 months although synaptic SUMOylation, at this age, resulted more sensible to KCl stimulus. Our previous findings have shown that increased SUMOylation at presynaptic level reduces the KCl-induced glutamate release. Accordingly, Tg2576 mice of 6 and 20 months show a reduced KCl-evoked neurotransmitter (NT) release. In order to target SUMOylation, we developed two cell penetrating HIV Tat-linked peptides, namely TU-1 and TS-1. This strategy allowed us to modulate the SUMO machinery either positively (TU-1) or negatively (TS-1). As expected, Tg2576 synaptosomes treated with TU-1 exhibited a reduced NT release evoked by KCl. On the contrary, TS-1 treatment, which decreased SUMOylation, was able to normalize impaired glutamate release. Notably, an analysis of autopsy human AD brains has shown an increased SUMOylation in both cortical tissue and synaptosomal lysate. Our data indicate that SUMOylation level changes contribute to the development of synaptic alterations typically occurring at the AD onset and that SUMOylation could be a pharmacological target in AD synaptic dysfunction.

Radiologic-Histopathologic Correlation of Cerebral Microbleeds Using Pre-Mortem and Post-Mortem MRI.

INTRODUCTION: Cerebral microbleeds (CMB), also known as cerebral microhemorrhages, are small areas of susceptibility on brain magnetic resonance imaging (MRI), that are increasingly detected due to the higher availability of high-field MRI systems and dedicated pulse sequences. The prevalence of CMBs increases in cases with cognitive decline. The current investigation assessed the poorly investigated radiologic-histopathologic correlation of CMBs on MRI. METHODS: The local ethical committee approved the current investigation. We retrospectively assessed a consecutive series of 1303 autopsy cases hospitalized in Geneva University Hospitals between 2000-2014. Of 112 cases with pre-mortem T2* sequences, we included 25 cases (mean age 77.3 ± 9.6, 9 females) with at least one CMB. We compared pre-mortem CMBs with targeted histopathology and post-mortem MRI. RESULTS: 25 cases had 31 CMB lesions detected by pre-mortem MRI. 25 additional CMB were detected on histopathology. 4 CMBs on pre-mortem MRI were false positives, resulting in a total of 52 CMBs. 27 CMBs on pre-mortem MRI were confirmed on histopathology, corresponding to a sensitivity or true positive rate of 51.9% (95% CI 37.6-66.0%). The false negative rate of pre-mortem MRI was 48.1% (95% CI 34.0-62.4%). Post-mortem MRI showed only 3 cases with additional CMBs. Overall, pre-mortem MRI significantly underestimated CMBs (p = 0.0001). CONCLUSIONS: Routine clinical brain MRI underestimates the prevalence of CMBs by approximately 50%, and 12% of radiologic pre-mortem MRI CMBs were false positives. Post-mortem MRI confirmed that this discordance is not explained by microbleeds occurring after the pre-mortem MRI.

The MAPT gene is differentially methylated in the progressive supranuclear palsy brain.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease causing parkinsonian symptoms. Altered DNA methylation of the microtubule-associated protein tau gene correlates with the expression changes in Alzheimer's disease and Parkinson's disease brains. However, few studies examine the sequences beyond the constitutive promoter. OBJECTIVES: Because activating different microtubule-associated protein tau gene control regions via methylation might regulate the differential tau expression constituting the specific signatures of individual tauopathies, we compared methylation of a candidate promoter, intron 0. METHODS: We assessed DNA methylation in the brains of patients with different tauopathies (35 Alzheimer's disease, 10 corticobasal degeneration, and 18 PSP) and 19 controls by intron 0 pyrosequencing. We also evaluated methylation in an independent cohort of 11 PSP cases and 12 controls. Frontal (affected by tau pathology) and occipital (unaffected) cortices were analyzed. RESULTS: In the initial samples, one CpG island site in intron 0 (CpG1) showed significant hypomethylation in PSP-affected frontal cortices when compared with controls (P = .022). Such hypomethylation was observed in replicate samples, but not in occipital cortices or other tauopathies. PSP and control samples (combining the initial and replicate samples) remained significantly different after adjustment for potential confounding factors (age, H1/H1 diplotype; P = .0005). PSP-affected tissues exhibited microtubule-associated protein tau RNA hyperexpression when compared with controls (P = .004), although no correlation with CpG1 methylation was observed. CONCLUSIONS: This exploratory study suggests that regions other than the constitutive promoter may be involved in microtubule-associated protein tau gene regulation in tauopathies and that intron 0 hypomethylation may be a specific epigenetic signature of PSP. These preliminary findings require confirmation. © 2016 International Parkinson and Movement Disorder Society.

Post-mortem assessment in vascular dementia: advances and aspirations.

BACKGROUND: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. DISCUSSION: Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer's disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer's disease, vascular dementia and mixed Alzheimer's disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. CONCLUSION: Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses.

A Study of Aß Oligomers in the Temporal Cortex and Cerebellum of Patients with Neuropathologically Confirmed Alzheimer's Disease Compared to Aged Controls.

BACKGROUND/AIMS: Investigations of Aß oligomers in neuropathologically confirmed Alzheimer's disease (AD) are still scarce. We report neurohistopathological and biochemical analyses using antibodies against tau and amyloid ß (Aß) pathology. METHODS: Thirty elderly AD patients and 43 age-matched controls with or without deposition of amyloid plaques (AP) were analyzed by immunohistochemistry. In 21 cases with available fresh tissue, Western blots were also performed. Neuropathological analysis included quantitative assessment of neurofibrillary tangles (NFT), AP and Aß oligomer densities in the mesial temporal cortex (TC). RESULTS: NFT, fibrillar amyloid and Aß oligomeric deposit densities were significantly higher in AD patients than in controls. There was no relationship between oligomeric Aß densities and Braak NFT staging scores. Furthermore, Aß oligomer expression was closely correlated with Aß plaques in the TC. By Western blot, Aß oligomers were observed in AD patients, in plaque-free controls, in 1 'tangle-only AD' case, as well as in the cerebellum. A band near 55 kDa was the only Western blot signal that was significantly increased in the TC of AD patients compared to controls as well as less expressed in the cerebellum. CONCLUSION: These results suggest that a putative dodecamer, near 55 kDa, may contribute to AD vulnerability of the TC.