Abstract
Theranostics refers to the combination of a radioactive drug to identify (diagnose) and another radioactive drug to deliver therapy to cancer. In adult cancer several radiopharmaceuticals ...with specificity for receptors like cx-chemokine-receptor type 4 (CXCR-4), prostate-membrane specific antigen (PSMA), and somatostatine receptor (SSTR2a) are used. Especially PSMA for prostate cancer and SSTR2a ligands for neuro-endocrine tumors have proven their value. Moreover, novel promising targets like B7-H3 are upcoming. In children the potential of such theranostic drugs have been minimally explored.
AIM of this study is to explore the expression of theranostic markers CXCR-4, PSMA, SSTR2a and B7-H3 in a broad cohort of high-grade pediatric CNS tumors to determine the potential of these imaging ligands in this cohort.
METHODS The expression of CXCR-4, PSMA, SSTR2a and B7-H3 were examined both by RNA (by bulk RNAsequencing) and protein level (by immunohistochemistry (IHC)) (RNA n=161/IHC n=52) in pediatric high-grade CNS tumors: ependymomas (n=33/11), atypical teratoid rhabdoid tumors (ATRT) (n=9/7), medulloblastomas (n=51/11), diffuse midline gliomas H3K27-altered (n=27/9) and other high-grade gliomas (n=41/15).
RESULTS mRNA expression of CXCR-4 was present but low in most tumor types, with the highest expression in medulloblastoma. Immunohistochemistry showed variable CXCR-4 expression, with the highest expression in some medulloblastomas, ependymomas and ATRTs. PSMA (FOLH1) mRNA and protein expression was generally very low. As expected SSTR2a showed a very high mRNA and protein expression only in medulloblastoma samples. Remarkably, B7-H3 (CD276) showed a relatively high expression in all high-grade pediatric CNS tumor types, both on RNA and protein level.
CONCLUSION Of the four potential theranostic targets tested, SSTR2a is an interesting antigen in medulloblastoma. CXCR-4 could be of interest for individual patients with medulloblastoma, ATRT or ependymoma. Finally, B7-H3 is widely but variably expressed on all different tumor types, and seems a promising novel target for theranostics in pediatric CNS tumors.
Cardiovascular disease is an important contributor to cognitive impairment. This likely involves prototypical vascular disease mechanisms like ischemia, but cardiovascular disease might also impact ...the brain by accelerating cerebral amyloid-β accumulation. We aimed to determine whether there is an association between heart disease or carotid occlusive disease (COD) and cerebral amyloid-β burden.
We conducted a systematic review of studies investigating cerebral amyloid-β burden, measured with positron emission tomography, in adults with and without heart disease or COD. Where possible, we obtained standardized mean differences (SMD) of amyloid-β standardized uptake volume ratios (SUVr) for meta-analysis.
Eight cross-sectional studies were identified (1478 participants, aged 60–81 years, 51% female). Three studies on heart disease (two on atrial fibrillation (AF) only, one on AF, coronary artery disease and heart failure) did not find a difference in amyloid-β burden between patients and controls. The pooled difference for 746 participants with and without AF did not reach significance (SMD SUVr 0.14, 95%CI -0.06–0.34). Of the five studies on COD (one on differences between participants with and without COD, four on differences between hemispheres in unilateral COD), four did not find a difference in amyloid-β between participants or hemispheres. The pooled difference in amyloid-β load between hemispheres in 24 patients with unilateral COD was not significant (SMD SUVr −0.13, 95%CI -0.70–0.43).
Based on current studies, although limited and heterogeneous, there is insufficient evidence to support the hypothesis that heart disease or COD are associated with increased cerebral amyloid-β burden.
•Cardiovascular disease is an important contributor to cognitive impairment.•Cardiovascular disease may impact the brain by accelerating amyloid-β accumulation.•We found no link between heart or carotid occlusive disease and amyloid-β load.
Background
Cardiovascular disease is increasingly recognized as a contributor to cognitive impairment. Reduced cerebral blood flow alone does not explain this association. Another contributing ...mechanism could be increased cerebral amyloid‐β accumulation. We hypothesized that patients with diseases of the heart or carotid arteries have more cerebral amyloid‐β accumulation than patients without these diseases.
Method
We conducted a systematic review to determine whether there is an association between diseases of the heart (heart failure, myocardial infarction, heart valve diseases, arrhythmias and cardiomyopathies) or carotid arteries (stenosis or occlusion of the extracranial internal carotid arteries (ICA)) and cerebral amyloid‐β accumulation, measured with positron emission tomography. We searched Pubmed, EMBASE and Scopus for studies that matched inclusion and exclusion criteria. Where possible, we obtained standardized mean differences (SMD) of amyloid‐β standardized uptake volume ratios (SUVr) with a meta‐analysis using a random‐effects model.
Result
Seven cross‐sectional studies, two on heart diseases and five on carotid artery diseases, were identified, including a total of 1262 participants (mean age 60‐76 years, 53% female). Six of the seven studies did not find a difference in cerebral amyloid‐β accumulation between patients with or without heart or carotid artery disease. One study including 11 participants found more amyloid‐β in the hemisphere ipsilateral to an ICA stenosis than in the hemisphere of healthy controls. SMD were calculated for atrial fibrillation (AF) (two studies including 746 participants) and unilateral ICA stenosis or occlusion (two studies including 24 participants). Patients with AF tended to have more cerebral amyloid‐β than reference participants (SMD in SUVr 0.14, 95% CI ‐0.06 – 0.34). There was less amyloid‐β in the hemisphere ipsilateral to the ICA stenosis or occlusion compared to the contralateral hemisphere (SMD in SUVr ‐0.13, 95% CI ‐0.70 – 0.43). Although we did not find significant effects.
Conclusion
Currently available evidence does not support the notion that diseases of the heart or carotid arteries predispose for a higher burden of cerebral amyloid‐β.
Sex differences in brain physiology and the mechanisms of drug action have been extensively reported. These biological variances, from structure to hormonal and genetic aspects, can profoundly ...influence healthy functioning and disease mechanisms and might have implications for treatment and drug development. Molecular neuroimaging techniques may help to disclose sex's impact on brain functioning, as well as the neuropathological changes underpinning several diseases. This narrative review summarizes recent lines of evidence based on PET and SPECT imaging, highlighting sex differences in normal conditions and various neurological disorders.
Abstract Regional functional connectivity (FC) of 39 patients with Alzheimer's disease (AD), 23 patients with mild cognitive impairment (MCI), and 43 healthy elderly controls was studied using ...resting-state functional magnetic resonance imaging (rs-fMRI). After a mean follow-up of 2.8 ± 1.9 years, 7 MCI patients converted to AD, while 14 patients remained cognitively stable. Resting-state functional magnetic resonance imaging scans were analyzed using independent component analysis (ICA), followed by a “dual-regression” technique to create and compare subject-specific maps of each independent spatiotemporal component, correcting for age, sex, and gray matter atrophy. AD patients displayed lower FC within the default-mode network (DMN) in the precuneus and posterior cingulate cortex compared with controls, independent of cortical atrophy. Regional FC values of MCI patients were numerically in between AD patients and controls, but only the difference between AD and stable MCI patients was statistically significant. Correlation with cognitive dysfunction demonstrated the clinical relevance of FC changes within the DMN. In conclusion, clinically relevant decreased FC within the DMN was observed in AD.
