Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis, but a contribution ...from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host derived. We next examined patient skin, colon, and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied, yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67+) and producing the proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD.
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis, but a contribution ...from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host derived. We next examined patient skin, colon, and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied, yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67+) and producing the proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD.
Chimerism testing is a valuable tool for determining the proportion of donor vs. recipient DNA in a sample. The commonly used polymerase chain reaction amplifications of short tandem repeats assay ...(Promega, Madison, WI) produces results for 21 loci, but only 9 loci are used in manual calculations. We sought to improve the tedious and time consuming process of manually calculating a patient’s percent chimerism by developing an automated chimerism calculator for rapid and accurate chimerism calculations based off of all 21 loci.
The calculator was developed using Microsoft Excel Macros and is able to report the percent donor chimerism +/− the margin of error. To determine whether precision is improved by using 21 loci, the results of a 21 loci analysis and a 9 loci analysis were compared in 111 patient samples. Additionally, each of the 21 loci was evaluated for its average deviation from the mean. Finally, 298 patient samples were analyzed by the program in order to determine if precision is equal at all chimerism percentages.
When the same loci are analyzed, the chimerism calculator results are identical to the manual calculations, but completed in 10% of the time. The analysis of patient samples using 21 and 9 loci yielded, on average, chimerism percentages within 2.0% of each other. The average margin of error using 9 loci for analysis is 2.41% compared to 0.8% using all 21 loci. Among the 21 loci, the average deviation from the mean was found to range from 8.9% and 5.9%. Finally, we found that the average margin of error for patients between 90 and 100 percent donor chimerism is 0.19% while patients between 30 and 40 percent donor chimerism have 10.1% margin of error.
The chimerism calculator allows for routine use of all 21 STR loci with significantly reduced analysis time, 30% less margin of error, and an informative statistical analysis. In various laboratory settings, similar methods of computer assisted chimerism analysis can be easily implemented.
OBJECTIVE:To study the usefulness of F-AV-1451 PET in patients with corticobasal syndrome (CBS).
METHODS:We recruited 8 patients with CBS, 17 controls, 31 patients with Alzheimer disease (AD), and 11 ...patients with progressive supranuclear palsy (PSP) from the Swedish BioFINDER study. All patients underwent clinical assessment, F-AV-1451 PET, MRI, and quantification of β-amyloid pathology. A subset of participants also underwent F-FDG-PET.
RESULTS:In the 8 patients with CBS, 6 had imaging findings compatible with the corticobasal degeneration pathology and 2 with typical AD pathology. In the 6 patients with CBS without typical AD pathology, there were substantial retentions of F-AV-1451 in the motor cortex, corticospinal tract, and basal ganglia contralateral to the most affected body side. These patients could be clearly distinguished from patients with AD dementia or PSP using F-AV-1451. However, cortical atrophy was more widespread than the cortical retention of F-AV1451 in these CBS cases, and cortical AV-1451 uptake did not correlate with cortical thickness or glucose hypometabolism. These results are in sharp contrast to AD dementia, where F-AV-1451 retention was more widespread than cortical atrophy, and correlated well with cortical thickness and hypometabolism.
CONCLUSIONS:Patients with CBS without typical AD pathology exhibited AV-1451 retention in the motor cortex, corticospinal tract, and basal ganglia contralateral to the affected body side, clearly different from controls and patients with AD dementia or PSP. However, cortical atrophy measured with MRI and decreased F-fluorodeoxyglucose uptake were more widespread than F-AV-1451 uptake and probably represent earlier, yet less specific, markers of CBS.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that F-AV-1451 PET distinguishes between CBS and AD or PSP.
OBJECTIVETo compare PET imaging of tau pathology with CSF measurements (total tau t-tau and phosphorylated tau p-tau) in terms of diagnostic performance for Alzheimer disease (AD).
METHODSWe compared ...t-tau and p-tau and F-AV-1451 in 30 controls, 14 patients with prodromal AD, and 39 patients with Alzheimer dementia, recruited from the Swedish BioFINDER study. All patients with AD (prodromal and dementia) were screened for amyloid positivity using CSF β-amyloid 42. Retention of F-AV-1451 was measured in a priori specified regions, selected for known associations with tau pathology in AD.
RESULTSRetention of F-AV-1451 was markedly elevated in Alzheimer dementia and moderately elevated in prodromal AD. CSF t-tau and p-tau was increased to similar levels in both AD dementia and prodromal AD. F-AV-1451 had very good diagnostic performance for Alzheimer dementia (area under the receiver operating characteristic curve AUROC ∼1.000), and was significantly better than t-tau (0.876), p-tau (0.890), hippocampal volume (0.824), and temporal cortical thickness (0.860). For prodromal AD, there were no significant AUROC differences between CSF tau and F-AV-1451 measures (0.836–0.939), but MRI measures had lower AUROCs (0.652–0.769).
CONCLUSIONSCSF tau and F-AV-1451 have equal performance in early clinical stages of AD, but F-AV-1451 is superior in the dementia stage, and exhibits close to perfect diagnostic performance for mild to moderate AD.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that CSF tau and F-AV-1451 PET have similar performance in identifying early AD, and that F-AV-1451 PET is superior to CSF tau in identifying mild to moderate AD.
Representational Oligonucleotide Microarray Analysis (ROMA) detects genomic amplifications and deletions with boundaries defined at a resolution of approximately 50 kb. We have used this technique to ...examine 243 breast tumors from two separate studies for which detailed clinical data were available. The very high resolution of this technology has enabled us to identify three characteristic patterns of genomic copy number variation in diploid tumors and to measure correlations with patient survival. One of these patterns is characterized by multiple closely spaced amplicons, or "firestorms," limited to single chromosome arms. These multiple amplifications are highly correlated with aggressive disease and poor survival even when the rest of the genome is relatively quiet. Analysis of a selected subset of clinical material suggests that a simple genomic calculation, based on the number and proximity of genomic alterations, correlates with life-table estimates of the probability of overall survival in patients with primary breast cancer. Based on this sample, we generate the working hypothesis that copy number profiling might provide information useful in making clinical decisions, especially regarding the use or not of systemic therapies (hormonal therapy, chemotherapy), in the management of operable primary breast cancer with ostensibly good prognosis, for example, small, node-negative, hormone-receptor-positive diploid cases.
Neuropathological studies have shown that the typical neurofibrillary pathology of hyperphosphorylated tau protein in Alzheimer's disease (AD) preferentially affects specific brain regions whereas ...others remain relatively spared. It has been suggested that the distinct regional distribution profile of tau pathology in AD may be a consequence of the intrinsic network structure of the human brain. The spatially distributed brain regions that are most affected by the spread of tau pathology may hence reflect an interconnected neuronal system. Here, we characterized the brain-wide regional distribution profile of tau pathology in AD using
F-AV 1451 tau-sensitive positron emission tomography (PET) imaging, and studied this pattern in relation to the functional network organization of the human brain. Specifically, we quantified the spatial correspondence of the regional distribution pattern of PET-evidenced tau pathology in AD with functional brain networks characterized by large-scale resting state functional magnetic resonance imaging (rs-fMRI) data in healthy subjects. Regional distribution patterns of increased PET-evidenced tau pathology in AD compared to controls were characterized in two independent samples of prodromal and manifest AD cases (the Swedish BioFINDER study,
= 44; the ADNI study,
= 35). In the BioFINDER study we found that the typical AD tau pattern involved predominantly inferior, medial, and lateral temporal cortical areas, as well as the precuneus/posterior cingulate, and lateral parts of the parietal and occipital cortex. This pattern overlapped primarily with the dorsal attention, and to some extent with higher visual, limbic and parts of the default-mode network. PET-evidenced tau pathology in the ADNI replication sample, which represented a more prodromal group of AD cases, was less pronounced but showed a highly similar spatial distribution profile, suggesting an earlier-stage snapshot of a consistently progressing regional pattern. In conclusion, the present study indicates that the regional deposition of tau aggregates in AD predominantly affects higher-order cognitive over primary sensory-motor networks, but does not appear to be specific for the default-mode or related limbic networks.
To elucidate the relationship between cerebrospinal fluid (CSF) total‐tau (T‐tau) and phosphorylated tau (P‐tau) with the tau PET ligand 18F‐AV‐1451 in Alzheimer's disease (AD), we examined 30 ...cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T‐tau and P‐tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F‐AV‐1451, and mainly in demented AD patients. 18F‐AV‐1451, but not CSF T‐tau or P‐tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18F‐AV‐1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18F‐AV‐1451 retention was always increased at this disease stage. We conclude that CSF T‐tau and P‐tau mainly behave as biomarkers of “disease state”, since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18F‐AV‐1451 is a biomarker of “disease stage”, since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.
Synopsis
Tau pathology is a key feature of Alzheimer's disease (AD) but the relationship between cerebrospinal fluid tau, the tau PET tracer 18F‐AV‐1451 and other hallmarks of AD is unclear. This is now studied in a cohort of cognitively healthy controls and patients with prodromal and dementia stages of AD.
Cerebrospinal fluid total‐tau and phosphorylated‐tau levels are moderately correlated with 18F‐AV‐1451 tau PET retention.
Correlations between cerebrospinal fluid tau and 18F‐AV‐1451 tau PET are seen primarily in the dementia stage of Alzheimer's disease.
Cerebrospinal fluid tau levels are increased already in preclinical AD.
18F‐AV‐1451 tau PET is more strongly related to neurodegeneration and cognitive decline than cerebrospinal fluid tau levels are.
Cerebrospinal fluid tau levels may be useful primarily to identify the presence of Alzheimer's disease, while 18F‐AV‐1451 tau PET may be useful also to track the progression of the disease.
Tau pathology is a key feature of Alzheimer's disease (AD) but the relationship between cerebrospinal fluid tau, the tau PET tracer 18F‐AV‐1451 and other hallmarks of AD is unclear. This is now studied in a cohort of cognitively healthy controls and patients with prodromal and dementia stages of AD.
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