Purpose
The Alzheimer’s disease (AD) pathology is characterized by fibrillar amyloid deposits and neurofibrillary tangles, as well as the activation of astrocytosis, microglia activation, atrophy, ...dysfunctional synapse, and cognitive impairments. The aim of this study was to test the hypothesis that astrocytosis is correlated with reduced gray matter density in prodromal AD.
Methods
Twenty patients with AD or mild cognitive impairment (MCI) underwent multi-tracer positron emission tomography (PET) studies with
11
C-Pittsburgh compound B (
11
C-PIB),
18
F-Fluorodeoxyglucose (
18
F-FDG), and
11
C-deuterium-L-deprenyl (
11
C-DED) PET imaging, as well as magnetic resonance imaging (MRI) scanning, cerebrospinal fluid (CSF) biomarker analysis, and neuropsychological assessments. The parahippocampus was selected as a region of interest, and each value was calculated for four different imaging modalities. Correlation analysis was applied between DED slope values and gray matter (GM) densities by MRI. To further explore possible relationships, correlation analyses were performed between the different variables, including the CSF biomarker.
Results
A significant negative correlation was obtained between DED slope values and GM density in the parahippocampus in PIB-positive (PIB + ve) MCI patients (
p
= 0.025) (prodromal AD). Furthermore, in exploratory analyses, a positive correlation was observed between PIB-PET retention and DED binding in AD patients (
p
= 0.014), and a negative correlation was observed between PIB retention and CSF Aβ42 levels in MCI patients (p = 0.021), while the GM density and CSF total tau levels were negatively correlated in both PIB + ve MCI (
p
= 0.002) and MCI patients (
p
= 0.001). No significant correlation was observed with FDG-PET and with any of the other PET, MRI, or CSF biomarkers.
Conclusions
High astrocytosis levels in the parahippocampus of PIB + ve MCI (prodromal AD) patients suggest an early preclinical influence on cellular tissue loss. The lack of correlation between astrocytosis and CSF tau levels, and a positive correlation between astrocytosis and fibrillar amyloid deposition in clinical demented AD together indicate that parahippocampal astrocytosis might have some causality within the amyloid pathology.
Despite increased recognition of cognitive impairment in Multiple System Atrophy (MSA), its neuroanatomical correlates are not well defined. We aimed to explore cognitive profiles in MSA with ...predominant parkinsonism (MSA-P) and Parkinson's disease (PD) and their relationship to frontostriatal structural and metabolic changes.
Detailed clinical and neuropsychological evaluation was performed together with diffusion tensor imaging (DTI) and 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) in patients with MSA-P (n = 11) and PD (n = 11). We compared clinical and neuropsychological data to healthy controls (n = 9) and correlated neuropsychological data with imaging findings in MSA-P and PD.
Patients with MSA-P showed deficits in executive function (Trail Making Test B-A) and scored higher in measures of depression and anxiety compared to those with PD and healthy controls. Widespread frontostriatal white matter tract reduction in fractional anisotropy was seen in MSA-P and PD compared to an imaging control group. Stroop Test interference performance correlated with 18F-FDG uptake in the bilateral dorsolateral prefrontal cortex (DLPFC) and with white matter integrity between the striatum and left inferior frontal gyrus (IFG) in PD. Trail Making Test performance correlated with corticostriatal white matter integrity along tracts from the bilateral IFG in MSA-P and from the right DLPFC in both groups.
Executive dysfunction was more prominent in patients with MSA-P compared to PD. DLPFC metabolism and frontostriatal white matter integrity seem to be a driver of executive function in PD, whereas alterations in corticostriatal white matter integrity may contribute more to executive dysfunction in MSA-P.
•We explored cognitive profiles and their neural correlates in Multiple System Atrophy (MSA) and Parkinson’s disease (PD).•Patients with MSA-P showed deficits in executive function compared to those with PD and healthy controls.•Diffusion tensor imaging revealed widespread frontostriatal white matter tract damage in MSA and PD compared to controls.•Hypometabolism in the bilateral dorsolateral prefrontal cortex that seems to be a driver of executive impairment in PD.•In MSA, however, corticostriatal white matter pathology was correlated more strongly with executive dysfunction.
FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used ...conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials.
Objective
The aim of this study is to assess the impact of age at onset on the prognostic value of Alzheimer’s biomarkers in a large sample of patients with mild cognitive impairment (MCI).
Methods
...We measured Aβ42,
t
-tau, hippocampal volume on magnetic resonance imaging (MRI) and cortical metabolism on fluorodeoxyglucose–positron emission tomography (FDG-PET) in 188 MCI patients followed for at least 1 year. We categorised patients into earlier and later onset (EO/LO). Receiver operating characteristic curves and corresponding areas under the curve (AUCs) were performed to assess and compar the biomarker prognostic performances in EO and LO groups. Linear Model was adopted for estimating the time-to-progression in relation with earlier/later onset MCI groups and biomarkers.
Results
In earlier onset patients, all the assessed biomarkers were able to predict cognitive decline (
p
< 0.05), with FDG-PET showing the best performance. In later onset patients, all biomarkers but
t
-tau predicted cognitive decline (
p
< 0.05). Moreover, FDG-PET alone in earlier onset patients showed a higher prognostic value than the one resulting from the combination of all the biomarkers in later onset patients (earlier onset AUC 0.935 vs later onset AUC 0.753,
p
< 0.001). Finally, FDG-PET showed a different prognostic value between earlier and later onset patients (
p
= 0.040) in time-to-progression allowing an estimate of the time free from disease.
Discussion
FDG-PET may represent the most universal tool for the establishment of a prognosis in MCI patients and may be used for obtaining an onset-related estimate of the time free from disease.
The aims of the present study were to ascertain the activation status of Akt in the primary cells of chronic lymphocytic leukemia and to investigate the effects of specific Akt inhibition on chronic ...lymphocytic leukemia-cell survival.
Anti-phospho-Akt (Ser473 or Thr308) antibodies and western blotting were used to establish the activation status of Akt. The effects of two different, specific small-molecule inhibitors (A-443654 or Akti-1/2) or small interfering RNA on cell survival and downstream targets of Akt were assessed. Apoptosis was determined by fluorescence-activated cell sorting analysis of phosphatidylserine exposure and by measurement of PARP cleavage. The phosphorylation status of GSK-3 and MDM2, two immediate downstream substrates of Akt, levels of the anti-apoptotic proteins BCL2 and MCL1, and expression of p53 and p21 were all measured by western blotting.
Fully activated Akt was demonstrable in all chronic lymphocytic leukemia clones examined (n=26). These results were validated with extensive controls and it was shown that a harsh method of cell extraction is needed for detection of the active enzyme. Specific inhibition of Akt induced extensive apoptosis of chronic lymphocytic leukemia cells, which was associated with both a rapid loss of MCL1 through proteasomal degradation and increased expression of p53. Moreover, the Akt inhibitors, at concentrations that induced extensive apoptosis in chronic lymphocytic leukemia cells, had little or no effect on normal peripheral blood mononuclear cells.
Chronic lymphocytic leukemia clones consistently contain activated Akt which plays a pivotal role in maintaining cell survival. Inhibition of the Akt pathway may be of potential value as a novel therapeutic strategy in chronic lymphocytic leukemia.
Background
The purpose of this study was to describe outcomes of patients undergoing reverse total shoulder arthroplasty (rTSA) using a patient-specific, custom glenoid component to address severe ...glenoid deficiency.
Methods
Retrospective chart review identified patients at a single institution undergoing rTSA using the glenoid vault reconstruction system (VRS) between 2017 and 2022. Radiographic evaluation, range of motion and patient-reported outcome (PRO) measures, complications, and re-operations were assessed.
Results
Fourteen shoulders were included. There was 100% implant survivorship of the glenoid baseplate at mean follow-up of 26.6 months. Mean range of motion improved in forward elevation (62–106 degrees), abduction (41–100 degrees), and external rotation (11–36 degrees). In 7 of 13 patients available for PRO collection, the mean final Visual Analog Pain Scale (VAS) score was 1.29, Single Assessment Numeric Evaluation (SANE) score was 72.14, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score was 77.14, and Penn Shoulder score was 72.26.
Conclusions
Use of this custom glenoid resulted in encouraging clinical and radiographic outcomes, with no failures in implant survivorship seen at early follow-up. Larger prospective studies with longer-term follow-up should be undertaken in order to better determine the efficacy and longevity of this implant.
Study Design
Retrospective case series; Level of evidence, 4.
Amyloid pathology is the pathological hallmark in Alzheimer's disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment ...and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to find predictors of cognitive decline in these subjects. These goals can be accomplished by targeting twins, with additional benefits to identify genetic and environmental pathways for amyloid pathology, other AD biomarkers, and cognitive decline.
From December 2014 to October 2017 we enrolled cognitively normal participants aged 60 years and older from the ongoing Manchester and Newcastle Age and Cognitive Performance Research Cohort and the Netherlands Twins Register. In Manchester we included single individuals, and in Amsterdam monozygotic twin pairs. At baseline, participants completed neuropsychological tests and questionnaires, and underwent physical examination, blood sampling, ultrasound of the carotid arteries, structural and resting state functional brain magnetic resonance imaging, and dynamic amyloid positron emission tomography (PET) scanning with
Fflutemetamol. In addition, the twin cohort underwent lumbar puncture for cerebrospinal fluid collection, buccal cell collection, magnetoencephalography, optical coherence tomography, and retinal imaging.
We included 285 participants, who were on average 74.8 ± 9.7 years old, 64% female. Fifty-eight participants (22%) had an abnormal amyloid PET scan.
A rich baseline dataset of cognitively normal elderly individuals has been established to estimate risk factors and biomarkers for amyloid pathology and future cognitive decline.
PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain ...incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti-PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer.
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