Head-to-head comparison of leading blood tests for Alzheimer's disease pathology.

INTRODUCTION: Blood tests have the potential to improve the accuracy of Alzheimer's disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes. METHODS: Plasma samples from the Alzheimer's Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes. RESULTS: Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes. DISCUSSION: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes. HIGHLIGHTS: Plasma p-tau217 measures most accurately classified amyloid and tau status. Plasma Aß42/Aß40 had relatively low accuracy in classification of amyloid status. Plasma p-tau217 measures had higher correlations with cortical thickness than NfL. Correlations of plasma biomarkers with dementia symptoms were relatively low.

The T-N tract involvement as a new prognostic factor for PORT in locally advanced oral cavity tumors.

OBJECTIVE: The space comprised between tumor and neck lymph nodes (T-N tract) is one of the main routes of tumor spread in oral cavity tumors. Aim of the study was to investigate the impact of T-N tract involvement on the postoperative radiotherapy (PORT) outcomes. MATERIALS AND METHODS: Patients (pts) treated between 2000 and 2016 with indication to PORT were retrospectively retrieved. Inclusion criteria were: (a) locally advanced tumors of the oral cavity, (b) who received with indication to PORT (c) with a minimum follow-up of six months. RESULTS: One hundred and fifty-seven pts met the inclusion criteria (136 pts treated with PORT and 21 pts not treated with PORT). In the PORT cohort, the T-N tract involvement had no impact on both OS (p = .09) and LRFS (p = .2). Among the non-PORT cohort, both OS (p = .007) and LRFS (p = .017) were worse for pts with positive T-N tract compared to those with negative T-N tract. PORT improved both OS (p = .008) and LRFS (p = .003) in pts with positive T-N tract but not in those with negative T-N tract (p = .36 and p = .37, respectively). CONCLUSIONS: Our results suggest that involvement of T-N tract should be considered as prognostic factors informing the indication to PORT.

Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy.

INTRODUCTION: To examine the extent to which positron emission tomography (PET)-, cerebrospinal fluid (CSF)-, and plasma-related amyloid-ß/tau/neurodegeneration (A/T/N) biomarkers are associated with Alzheimer's disease (AD) neuropathology at autopsy. METHODS: A total of 100 participants who respectively underwent antemortem biomarker measurements and postmortem neuropathology were included in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined the associations of PET-, CSF-, and plasma-related A/T/N biomarkers in combinations or alone with AD neuropathological changes (ADNC). RESULTS: PET- and CSF-related A/T/N biomarkers in combination showed high concordance with the ADNC stage and alone showed high accuracy in discriminating autopsy-confirmed AD. However, the plasma-related A/T/N biomarkers alone showed better discriminative performance only when combined with apolipoprotein E (APO)E ε4 genotype. DISCUSSION: This study supports that PET- and CSF-related A/T/N profiles can be used to predict accurately the stages of AD neuropathology. For diagnostic settings, PET-, CSF-, and plasma-related A/T/N biomarkers are all useful diagnostic tools to detect the presence of AD neuropathology. HIGHLIGHTS: PET- and CSF-related A/T/N biomarkers in combination can accurately predict the specific stages of AD neuropathology. PET- and CSF-related A/T/N biomarkers alone may serve as a precise diagnostic tool for detecting AD neuropathology at autopsy. Plasma-related A/T/N biomarkers may need combined risk factors when used as a diagnostic tool. Aß PET and CSF p-tau181/Aß42 were most consistent with Aß pathology, while tau PET and CSF p-tau181/Aß42 were most consistent with tau pathology.

A Kind of (t, n) Threshold Quantum Secret Sharing with Identity Authentication.

Quantum secret sharing (QSS) is an important branch of quantum cryptography. Identity authentication is a significant means to achieve information protection, which can effectively confirm the identity information of both communication parties. Due to the importance of information security, more and more communications require identity authentication. We propose a d-level (t,n) threshold QSS scheme in which both sides of the communication use mutually unbiased bases for mutual identity authentication. In the secret recovery phase, the sharing of secrets that only the participant holds will not be disclosed or transmitted. Therefore, external eavesdroppers will not get any information about secrets at this phase. This protocol is more secure, effective, and practical. Security analysis shows that this scheme can effectively resist intercept-resend attacks, entangle-measure attacks, collusion attacks, and forgery attacks.

The A/T/N model applied through imaging biomarkers in a memory clinic.

PURPOSE: The A/T/N model is a research framework proposed to investigate Alzheimer's disease (AD) pathological bases (i.e., amyloidosis A, neurofibrillary tangles T, and neurodegeneration N). The application of this system on clinical populations is still limited. The aim of the study is to evaluate the topography of T distribution by 18F-flortaucipir PET in relation to A and N and to describe the A/T/N status through imaging biomarkers in memory clinic patients. METHODS: Eighty-one patients with subjective and objective cognitive impairment were classified as A+/A- and N+/N- through amyloid PET and structural MRI. Tau deposition was compared across A/N subgroups at voxel level. T status was defined through a global cut point based on A/N subgroups and subjects were categorized following the A/T/N model. RESULTS: A+N+ and A+N- subgroups showed higher tau burden compared to A-N- group, with A+N- showing significant deposition limited to the medial and lateral temporal regions. Global cut point discriminated A+N+ and A+N- from A-N- subjects. On A/T/N classification, 23% of patients showed a negative biomarker profile, 58% fell within the Alzheimer's continuum, and 19% of the sample was characterized by non-AD pathologic change. CONCLUSION: Medial and lateral temporal regions represent a site of significant tau accumulation in A+ subjects and possibly a useful marker of early clinical changes. This is the first study in which the A/T/N model is applied using 18F-flortaucipir PET in a memory clinic population. The majority of patients showed a profile consistent with the Alzheimer's continuum, while a minor percentage showed a profile suggestive of possible other neurodegenerative diseases. These results support the applicability of the A/T/N model in clinical practice.

Surgical resection of oral cancer: en-bloc versus discontinuous approach.

OBJECTIVES: In the past literature agreed on treating oral carcinomas, using an "en-bloc" resection (EBR) but recently minimally invasive transoral surgery has spread as the preferable treatment for selected cases. This latter technique, which is performed with a discontinuous resection (DR), allows for a satisfactory postoperative quality of life (QoL) maintaining good survival rates. MATERIALS AND METHODS: In this study, we analyzed data about 147 surgically treated patients with oral cancer involving tongue and floor of the mouth. The sample was divided according to the surgical approach: EBR and DR group which were compared in terms of recurrence, overall survival, disease-free survival, and QoL. RESULTS: In the DR group, survival analysis showed better results in term of survival, locoregional control, and postoperative anxiety, while the other QoL scores were similar in the two groups. CONCLUSION: The more invasive approach does not correlate to a better outcome. In selected cases, DR is an oncologically safe technique; EBR is still a valid option to treat advanced oral cancers.

The recency ratio is related to CSF amyloid beta 1-42 levels in MCI-AD.

OBJECTIVE: As anti-amyloid therapeutic interventions shift from enrolling patients with Alzheimer's disease (AD) dementia to individuals with pre-clinical disease, the need for sensitive measures that allow for non-invasive, fast, disseminable, and cost-effective identification of preclinical status increases in importance. The recency ratio (Rr) is a memory measure that relies on analysis of serial position performance, which has been found to predict cognitive decline and conversion to early mild cognitive impairment (MCI). The aim of this study was to test Rr's sensitivity to cerebrospinal fluid (CSF) levels of the core AD biomarkers in individuals with MCI-AD and controls. METHODS: Baseline data from 126 (110 controls and 16 MCI-AD) participants from the Wisconsin Alzheimer's Disease Research Center were analysed. Partial correlations adjusting for demographics were carried out between CSF measure of amyloid beta (Aß40, Aß42, and the 40/42 ratio) and tau (total and phosphorylated), and memory measures (Rr, delayed recall, and total recall) derived from the Rey's Auditory Verbal Learning Test. RESULTS: Results indicated that Rr was the most sensitive memory score to Aß42 levels in MCI-AD, while no memory score correlated significantly with any biomarker in controls. CONCLUSIONS: This study shows that Rr is a sensitive cognitive index of underlying amyloid ß pathology in MCI-AD.

Introduction of a standardized multimodality image protocol for navigation-guided surgery of suspected low-grade gliomas.

OBJECT Surgery of suspected low-grade gliomas (LGGs) poses a special challenge for neurosurgeons due to their diffusely infiltrative growth and histopathological heterogeneity. Consequently, neuronavigation with multimodality imaging data, such as structural and metabolic data, fiber tracking, and 3D brain visualization, has been proposed to optimize surgery. However, currently no standardized protocol has been established for multimodality imaging data in modern glioma surgery. The aim of this study was therefore to define a specific protocol for multimodality imaging and navigation for suspected LGG. METHODS Fifty-one patients who underwent surgery for a diffusely infiltrating glioma with nonsignificant contrast enhancement on MRI and available multimodality imaging data were included. In the first 40 patients with glioma, the authors retrospectively reviewed the imaging data, including structural MRI (contrast-enhanced T1-weighted, T2-weighted, and FLAIR sequences), metabolic images derived from PET, or MR spectroscopy chemical shift imaging, fiber tracking, and 3D brain surface/vessel visualization, to define standardized image settings and specific indications for each imaging modality. The feasibility and surgical relevance of this new protocol was subsequently prospectively investigated during surgery with the assistance of an advanced electromagnetic navigation system in the remaining 11 patients. Furthermore, specific surgical outcome parameters, including the extent of resection, histological analysis of the metabolic hotspot, presence of a new postoperative neurological deficit, and intraoperative accuracy of 3D brain visualization models, were assessed in each of these patients. RESULTS After reviewing these first 40 cases of glioma, the authors defined a specific protocol with standardized image settings and specific indications that allows for optimal and simultaneous visualization of structural and metabolic data, fiber tracking, and 3D brain visualization. This new protocol was feasible and was estimated to be surgically relevant during navigation-guided surgery in all 11 patients. According to the authors' predefined surgical outcome parameters, they observed a complete resection in all resectable gliomas (n = 5) by using contour visualization with T2-weighted or FLAIR images. Additionally, tumor tissue derived from the metabolic hotspot showed the presence of malignant tissue in all WHO Grade III or IV gliomas (n = 5). Moreover, no permanent postoperative neurological deficits occurred in any of these patients, and fiber tracking and/or intraoperative monitoring were applied during surgery in the vast majority of cases (n = 10). Furthermore, the authors found a significant intraoperative topographical correlation of 3D brain surface and vessel models with gyral anatomy and superficial vessels. Finally, real-time navigation with multimodality imaging data using the advanced electromagnetic navigation system was found to be useful for precise guidance to surgical targets, such as the tumor margin or the metabolic hotspot. CONCLUSIONS In this study, the authors defined a specific protocol for multimodality imaging data in suspected LGGs, and they propose the application of this new protocol for advanced navigation-guided procedures optimally in conjunction with continuous electromagnetic instrument tracking to optimize glioma surgery.

Intraprocedural yttrium-90 positron emission tomography/CT for treatment optimization of yttrium-90 radioembolization.

Radioembolization with yttrium-90 ((90)Y) microspheres relies on delivery of appropriate treatment activity to ensure patient safety and optimize treatment efficacy. We report a case in which (90)Y positron emission tomography (PET)/computed tomography (CT) was performed to optimize treatment planning during a same-day, three-part treatment session. This treatment consisted of (i) an initial (90)Y infusion with a dosage determined using an empiric treatment planning model, (ii) quantitative (90)Y PET/CT imaging, and (iii) a secondary infusion with treatment planning based on quantitative imaging data with the goal of delivering a specific total tumor absorbed dose.

Predictive value for cerebrospinal fluid Alzheimer's disease profile of different measures of verbal episodic memory in patients with MCI.

Neuropsychological evidence of memory impairment represents the main feature of the clinical onset of typical Alzheimer's disease (AD). Rey's Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) are two tests both assessing verbal episodic memory, widely used in clinical practice. Our aim was to investigate the added value of their combined use in predicting cerebrospinal fluid (CSF) AD biomarkers positivity in a retrospective consecutive series of patients with mild cognitive impairment (MCI). 169 MCI patients were included. For all of them neuropsychological assessment and CSF analysis were available. According to CSF A/T/(N) profile, 109 were defined as MCI due to AD (A+T+), and 60 were non-AD MCI (A-T-). Logistic regression model and receiver-operating characteristic (ROC) curves were analyzed to evaluate the discriminatory power of single and combined sub-measures between AD and non-AD patients. The combination of RAVLT-del with LM could acceptably discriminate the two groups (AUC: 0.69, CI 95% 0.617-0.761, sens: 0.75, spec. 0.58, p < 0.001), while the single tests did not show sufficient discriminative performance. Our study shows that the combination of RAVLT delayed recall with LM better predicts the biological AD diagnosis (A+T+), showing a good discriminative power between MCI-AD from non-AD MCI. Since RAVLT and LM assess different components of verbal episodic memory, they should be considered as complementary, rather than interchangeable, tests.

Prognostic assessment of 18F-boronophenylalanine positron emission tomography (BPA-PET) in salvage boron neutron capture therapy for malignant brain tumors.

Background: Boron neutron capture therapy (BNCT) stands out as a propitious anti-cancer modality. 18F-boronophenylalanine positron emission tomography (BPA-PET) holds the potential to ascertain the concentration of BPA within the tumor, enabling meticulous treatment planning and outcome evaluation. However, no studies have been conducted on comparing the outcomes of those treated with BNCT to those who did not undergo this therapy. This study endeavors to analyze the correlation between BPA-PET and BNCT in the context of malignant brain tumors, and assess the survival outcomes following BNCT. Methods: A cohort study was performed on patients who underwent BPA-PET between February 2017 and April 2022 in our hospital. Patients were stratified into two groups: those subjected to BNCT (Group 1) and those not (Group 2). The tumor to normal tissue (T/N) ratio derived from BPA-PET was set at 2.5. The findings were scrutinized based on clinical follow-up. Student's t-test and Chi-squared test were employed to discern differences between the groups. A cumulative survival curve was constructed employing the Kaplan-Meier method. Differences were considered statistically significant at P<0.05. Results: In total, 116 patients with T/N ratios obtained from BPA-PET were enrolled. BNCT was administered to 58 patients, while mortality was observed in 100 patients. The median overall survival (OS) for the two groups was 8.5 and 6.0 months, respectively. The cumulative OS exhibited no significant discrepancy between the two groups, nor in their T/N ratios. Within Group 1, 44 out of 58 (75.9%) patients exhibited T/N ratios exceeding 2.5. Excluding 3 patients who expired within 3 months, 55 out of 58 patients were evaluated for response after BNCT. The objective response rate (ORR) was 30.9%. Patients achieving ORR displayed substantially higher survival rates compared to those without (median OS 13.5 vs. 8.3 months, P=0.0021), particularly when T/N ratio exceeded 2.5 (median OS 14.8 vs. 9.0 months, P=0.0199). Conclusions: BNCT does not appear indispensable for prolonging the survival of patients afflicted with malignant brain tumors. Nevertheless, it proves advantageous when ORR is attained, a condition closely linked to the values of T/N ratio derived from BPA-PET.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients.

INTRODUCTION: The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Highlights: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

Physiological adaptations to prolonged fasting in the overwintering striped skunk (Mephitis mephitis).

Wintertime physiology of captive striped skunks (Mephitis mephitis) in response to cold ambient temperature (Ta) and fasting was investigated with body temperature (Tb) and activity recordings and analyses of hematology, plasma biochemistry and tissue fatty acids (FA). After 105 days of food deprivation, the skunks were in phase II of fasting indicated by the elevated plasma nonesterified FA and glycerol but no accumulation of nitrogen end products. Shorter-chain saturated and monounsaturated FA together with C18-20 n-3 polyunsaturated FA were preferentially mobilized. Individual amino acids responded to fasting in a complex manner, while essential and nonessential amino acid sums remained stable. Increases in hemoglobin and hematocrit suggested dehydration. The activity levels were lower in mid-January-early March, and the activity bouts were mostly displayed between 17:00-23:00 h. Daily torpor was observed in two females with 29 and 46 bouts. The deepest torpor (Tb<31 °C) occurred between dawn and early afternoon and lasted for 3.3 ± 0.18 h. The average minimum Tb was 29.2 ± 0.15 °C and the lowest recorded Tb was 25.8 °C. There was significant relation between the average 24-h Tb and Ta. Increases in wintertime Ta, as predicted by climate change scenarios, could influence torpor patterns in the species.

Evaluation of tumor blood flow after feeder embolization in meningiomas by arterial spin-labeling perfusion magnetic resonance imaging.

Preoperative embolization changes the amount of blood flow and pattern of flow distribution in meningioma. Tumor blood flow was investigated in eight meningioma patients before and after embolization using arterial spin-labeling (ASL) perfusion imaging. Although blood flow was significantly reduced in the whole tumor after embolization, changes in flow distribution patterns varied from one case to another. The findings suggest that evaluation of post-embolization tumor blood flow by ASL perfusion imaging would be useful in the surgical planning of meningioma.

Discriminative accuracy of the A/T/N scheme to identify cognitive impairment due to Alzheimer's disease.

Introduction: The optimal combination of amyloid-ß/tau/neurodegeneration (A/T/N) biomarker profiles for the diagnosis of Alzheimer's disease (AD) dementia is unclear. Methods: We examined the discriminative accuracy of A/T/N combinations assessed with neuroimaging biomarkers for the differentiation of AD from cognitively unimpaired (CU) elderly and non-AD neurodegenerative diseases in the TRIAD, BioFINDER-1 and BioFINDER-2 cohorts (total n = 832) using area under the receiver operating characteristic curves (AUC). Results: For the diagnosis of AD dementia (vs. CU elderly), T biomarkers performed as well as the complete A/T/N system (AUC range: 0.90-0.99). A and T biomarkers in isolation performed as well as the complete A/T/N system in differentiating AD dementia from non-AD neurodegenerative diseases (AUC range; A biomarker: 0.84-1; T biomarker: 0.83-1). Discussion: In diagnostic settings, the use of A or T neuroimaging biomarkers alone can reduce patient burden and medical costs compared with using their combination, without significantly compromising accuracy.

Comparison of the Signal Intensity of Vestibular Schwannoma Between Growing and Nongrowing Tumors.

OBJECTIVES/HYPOTHESIS: To determine the relationship between signal intensity on gadolinium (Gd)-enhanced magnetic resonance images and growth of vestibular schwannomas (VSs). STUDY DESIGN: Cross-sectional study. METHODS: In this cross-sectional study, we retrospectively reviewed the data of 31 patients with VSs who underwent magnetic resonance imaging (MRI). The mean signal intensities within the regions of interest in the tumor, pons, and temporal muscles were measured on Gd-enhanced T1-weighted MRI. Relative intensity ratios were calculated as follows: T/N pons ratio (T/Np) is the tumor signal intensity/pons signal intensity and T/N muscle ratio (T/Nm) is the tumor signal intensity/temporal muscle signal intensity. Volume measurements were used to assess the tumor size. Growth rate was determined by assessing previous imaging studies. Growing VS was defined as a tumor with a growth rate >100 mm3 /year. RESULTS: The mean (standard deviation) T/Np and T/Nm were 1.47 (0.27) and 1.50 (0.24), respectively, in nongrowing tumors and 1.78 (0.17) and 1.90 (0.12), respectively, in growing tumors. The T/Np and T/Nm differed significantly between the two groups (T/Np, P < .001; T/Nm, P < .001). Receiver operating characteristic curve analysis showed that cutoffs of 1.56 and 1.76 for T/Np (93.33% sensitivity, 75.00% specificity) and T/Nm (100.00% sensitivity, 93.75% specificity), respectively, could be used to diagnose a growth rate of >100 mm3 /year. The area under the curve was 0.85 (95% confidence interval, 0.70-1.00) for T/Np and 0.94 (0.82-1.00) for T/Nm. CONCLUSION: Growing VSs show higher signal intensities on Gd-enhanced MRI. Thus, measuring the signal intensity of VS on Gd-enhanced MRI may aid in predicting VS growth. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:198-203, 2022.

Cross-Sectional and Longitudinal Hippocampal Atrophy, Not Cortical Thinning, Occurs in Amyloid-Negative, p-Tau-Positive, Older Adults With Non-Amyloid Pathology and Mild Cognitive Impairment.

Introduction: Alzheimer's disease (AD) is a degenerative disease characterized by pathological accumulation of amyloid and phosphorylated tau. Typically, the early stage of AD, also called mild cognitive impairment (MCI), shows amyloid pathology. A small but significant number of individuals with MCI do not exhibit amyloid pathology but have elevated phosphorylated tau levels (A-T+ MCI). We used CSF amyloid and phosphorylated tau to identify the individuals with A+T+ and A-T+ MCI as well as cognitively normal (A-T-) controls. To increase the sample size, we leveraged the Global Alzheimer's Association Interactive Network and identified 137 MCI+ and 61 A-T+ MCI participants. We compared baseline and longitudinal, hippocampal, and cortical atrophy between groups. Methods: We applied ComBat harmonization to minimize site-related variability and used FreeSurfer for all measurements. Results: Harmonization reduced unwanted variability in cortical thickness by 3.4% and in hippocampal volume measurement by 10.3%. Cross-sectionally, widespread cortical thinning with age was seen in the A+T+ and A-T+ MCI groups (p < 0.0005). A decrease in the hippocampal volume with age was faster in both groups (p < 0.05) than in the controls. Longitudinally also, hippocampal atrophy rates were significant (p < 0.05) when compared with the controls. No longitudinal cortical thinning was observed in A-T+ MCI group. Discussion: A-T+ MCI participants showed similar baseline cortical thickness patterns with aging and longitudinal hippocampal atrophy rates as participants with A+T+ MCI, but did not show longitudinal cortical atrophy signature.

Stable cerebrospinal fluid neurogranin and ß-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer's disease patients.

Cerebrospinal fluid (CSF) ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer's disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer's disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer's disease continuum and controlled with normal markers (A-/T-/N-, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n = 12), from A+/T-/N- to A+/T or N+ (n = 12), remained stable A+/T-/N- (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A-/T-/N- (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T-/N- (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = -0.29, P = 0.0006) than neurogranin (b = -0.20, P = 0.002) and BACE1 (b = -0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer's disease subgroups, putatively with different options for treatment.

A tannic acid doped hydrogel with small extracellular vesicles derived from mesenchymal stem cells promotes spinal cord repair by regulating reactive oxygen species microenvironment.

Spinal cord injury (SCI) is a serious disease of the central nervous system that is associated with a poor prognosis; furthermore, existing clinical treatments cannot restore nerve function in an effective manner. Inflammatory responses and the increased production of reactive oxygen species (ROS) in the microenvironment of the lesion are major obstacles that inhibit the recovery of SCI. Small extracellular vesicles (sEVs), derived from mesenchymal stem cells, are suitable options for cell-free therapy and have been shown to exert therapeutic effects in SCI, thus providing a potential strategy for microenvironment regulation. However, the effective retention, controlled release, and integration of small extracellular vesicles into injured spinal cord tissue are still a major challenge. Herein, we fabricated an N-acryloyl glycinamide/gelatin methacrylate/Laponite/Tannic acid (NAGA/GelMA/LPN/TA, NGL/T) hydrogel with sustainable sEV release (sEVs-NGL/T) to promote the recovery of motor function after SCI. The newly developed functional sEVs-NGL/T hydrogel exhibited excellent antioxidant properties in an H2O2-simulated peroxidative microenvironment in vitro. Implantation of the functional sEVs-NGL/T hydrogel in vivo could encapsulate sEVs, exhibiting efficient retention and the sustained release of sEVs, thereby synergistically inducing significant restoration of motor function and urinary tissue preservation. These positive effects can be attributed to the effective mitigation of the inflammatory and ROS microenvironment. Therefore, sEVs-NGL/T therapy provides a promising strategy for the sEV-based therapy in the treatment of SCI by comprehensively regulating the pathological microenvironment.

Machine learning application in personalised lung cancer recurrence and survivability prediction.

Machine learning is an important artificial intelligence technique that is widely applied in cancer diagnosis and detection. More recently, with the rise of personalised and precision medicine, there is a growing trend towards machine learning applications for prognosis prediction. However, to date, building reliable prediction models of cancer outcomes in everyday clinical practice is still a hurdle. In this work, we integrate genomic, clinical and demographic data of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) patients from The Cancer Genome Atlas (TCGA) and introduce copy number variation (CNV) and mutation information of 15 selected genes to generate predictive models for recurrence and survivability. We compare the accuracy and benefits of three well-established machine learning algorithms: decision tree methods, neural networks and support vector machines. Although the accuracy of predictive models using the decision tree method has no significant advantage, the tree models reveal the most important predictors among genomic information (e.g. KRAS, EGFR, TP53), clinical status (e.g. TNM stage and radiotherapy) and demographics (e.g. age and gender) and how they influence the prediction of recurrence and survivability for both early stage LUAD and LUSC. The machine learning models have the potential to help clinicians to make personalised decisions on aspects such as follow-up timeline and to assist with personalised planning of future social care needs.