Track Disease Progression Research Articles

The Potential Influence of Advanced Glycation End Products and (s)RAGE in Rheumatic Diseases.

Advanced glycation end products (AGEs) are a class of compounds formed by nonenzymatic interactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs can alter the protein structure and activate one of their receptors, specifically the receptor for advanced glycation end products (RAGE). These phenomena impair the functions of cells, extracellular matrix, and tissues. RAGE is expressed by a variety of cells and has been linked to chronic inflammatory autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. The soluble (s)RAGE cleavage product is a positively charged 48-kDa cleavage product that retains the ligand binding site but loses the transmembrane and signaling domains. By acting as a decoy, this soluble receptor inhibits the pro-inflammatory processes mediated by RAGE and its ligands. In the present review, we will give an overview of the role of AGEs, sRAGE, and RAGE polymorphisms in several rheumatic diseases. AGE overproduction may play a role in the pathogenesis and is linked to accelerated atherosclerosis. Low serum sRAGE concentrations are linked to an increased cardiovascular risk profile and a poor prognosis. Some RAGE polymorphisms may be associated with increased disease susceptibility. Finally, sRAGE levels can be used to track disease progression.

Practical Understanding of Cancer Model Identifiability in Clinical Applications.

Mathematical models are a core component in the foundation of cancer theory and have been developed as clinical tools in precision medicine. Modeling studies for clinical applications often assume an individual's characteristics can be represented as parameters in a model and are used to explain, predict, and optimize treatment outcomes. However, this approach relies on the identifiability of the underlying mathematical models. In this study, we build on the framework of an observing-system simulation experiment to study the identifiability of several models of cancer growth, focusing on the prognostic parameters of each model. Our results demonstrate that the frequency of data collection, the types of data, such as cancer proxy, and the accuracy of measurements all play crucial roles in determining the identifiability of the model. We also found that highly accurate data can allow for reasonably accurate estimates of some parameters, which may be the key to achieving model identifiability in practice. As more complex models required more data for identification, our results support the idea of using models with a clear mechanism that tracks disease progression in clinical settings. For such a model, the subset of model parameters associated with disease progression naturally minimizes the required data for model identifiability.

Comprehensive ctDNA Measurements Improve Prediction of Clinical Outcomes and Enable Dynamic Tracking of Disease Progression in Advanced Pancreatic Cancer.

Circulating tumor DNA (ctDNA) has emerged as a promising tumor-specific biomarker in pancreatic cancer, but current evidence of the clinical potential of ctDNA is limited. In this study, we used comprehensive detection methodology to explore the utility of longitudinal ctDNA measurements in patients with advanced pancreatic cancer. A targeted eight-gene next-generation sequencing panel was used to detect point mutations and copy-number aberrations (CNA) in ctDNA from 324 pre-treatment and longitudinal plasma samples obtained from 56 patients with advanced pancreatic cancer. The benefit of ctDNA measurements to predict clinical outcome and track disease progression was assessed. We detected ctDNA in 35/56 (63%) patients at baseline and found that it was an independent predictor of shorter progression-free survival (PFS) and overall survival (OS). After initiation of treatment, ctDNA levels decreased significantly before significantly increasing by the time of progression. In some patients, ctDNA persistence was observed after the first chemotherapy cycles, and it was associated with rapid disease progression and shorter OS. Longitudinal monitoring of ctDNA levels in 27 patients for whom multiple samples were available detected progression in 19 (70%) patients. The median lead time of ctDNA measurements on radiologically determined progression/time of death was 19 days (P = 0.002), compared with 6 days (P = 0.007) using carbohydrate antigen 19-9. ctDNA is an independent prognostic marker that can be used to detect treatment failure and disease progression in patients with advanced pancreatic cancer.

Neurogranin in Alzheimer's disease and ageing: A human post-mortem study

Neurogranin (Ng), a post-synaptic protein involved in memory formation, has been investigated as a biomarker in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD) and ageing. CSF Ng levels are elevated in AD relative to healthy controls and correlate with cognition; however, few studies have focused on Ng abundance in the brain. Synapse loss in the brain correlates closely with cognitive decline in AD making synaptic biomarkers potentially important for tracking disease progression, but the links between synaptic protein changes in CSF and brain remain incompletely understood. In the current study, Ng abundance was examined in post-mortem human brain tissue across AD, healthy ageing (HA), and mid-life (ML) cohorts. Ng levels were quantified in three brain regions associated with cognitive change found during ageing and neurodegenerative diseases, namely the middle temporal gyrus, primary visual cortex and the posterior hippocampus using immunohistochemistry. To support immunohistochemical analysis, total homogenate and biochemically enriched synaptic fractions from available temporal gyrus tissues were examined by immunoblot. Finally, we examined whether Ng is associated with lifetime cognitive ageing. Ng levels were significantly reduced in AD relative to HA and ML cases across all regions. Additionally Ng was significantly reduced in HA in comparison to ML in the primary visual cortex. Immunoblotting confirms reduced Ng levels in AD cases supporting immunohistochemical results. Interestingly, there was also a significant reduction of synapse-associated Ng in our group who had lifetime cognitive decline in comparison to the group with lifetime cognitive resilience indicating loss of neurogranin in remaining synapses during ageing is associated with cognitive decline. Our findings indicate that increases in CSF Ng reflect loss of brain neurogranin and support the use of CSF Ng as a biomarker of AD and potentially of cognitive decline in healthy ageing.

Altered metabolic connectivity within the limbic cortico-striato-thalamo-cortical circuit in presymptomatic and symptomatic behavioral variant frontotemporal dementia

BackgroundBehavioral variant frontotemporal dementia (bvFTD) is predominantly considered a dysfunction in cortico-cortical transmission, with limited direct investigation of cortical-subcortical transmission. Thus, we aimed to characterize the metabolic connectivity between areas of the limbic cortico-striato-thalamic-cortical (CSTC) circuit in presymptomatic and symptomatic bvFTD patients.MethodsThirty-three bvFTD patients and 33 unrelated healthy controls were recruited for this study. Additionally, six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non-carriers who were all from the same family of bvFTD. Each participant underwent neuropsychological assessment, genetic testing, and a hybrid PET/MRI scan. Seed-based metabolic connectivity based on [18F]-fluorodeoxyglucose PET between the main components within the limbic CSTC circuit was explored according to the Oxford-GSK-Imanova Striatal Connectivity Atlas.ResultsBvFTD patients exhibited reduced metabolic connectivity between the relays in the limbic CSTC circuit, which included the frontal region (ventromedial prefrontal cortex, orbitofrontal cortex, rectus gyrus, and anterior cingulate cortex), the limbic striatum, and thalamus compared to controls. In the bvFTD patients, the involvement of the limbic CSTC circuit was associated with the severity of behavior disruption, as measured by the frontal behavior inventory, the disinhibition subscale, and the apathy subscale. Notably, asymptomatic MAPT carriers had weakened frontostriatal connectivity but enhanced striatothalamus and thalamofrontal connectivity within the limbic CSTC circuit compared with noncarriers.ConclusionThese findings suggested that aberrant metabolic connectivity within the limbic CSTC circuit is present in symptomatic and even asymptomatic stages of bvFTD. Thus, metabolic connectivity patterns could be used as a potential biomarker to detect the presymptomatic stage and track disease progression.

The effect of Omega-3 on bovine blood cells as a potential remedy for Cerebral Cavernous Malformations

Cerebral cavernous malformations (CCM) are lesions on the brain that occur due to a genetic mutation causing high membrane permeability between endothelial cell junctions. They can cause a myriad of symptoms including seizures and aneurysms. Current treatment plans include monitoring for symptoms, tracking disease progression, and surgical correction of malformations, but therapies that target the underlying changes in cell junctions are lacking. The purpose of the study was to investigate whether dietary Omega-3 fatty acids can strengthen compromised cell junctions. The hypothesis was that Omega-3 fatty acids would strengthen the compromised cell membranes due to their high lipid content, increasing membrane thickness. The cow in the treatment group was fed an Omega-3 diet, whereas a cow in the control group was fed the standard corn gluten meal. Blood was then drawn from each of the cows to use in the subsequent studies. Using a microscope, membrane rigidity of whole bovine blood (all blood cell types) was viewed. The whole blood cells were placed in hypertonic solutions as well as isotonic solutions, altering the size of the cells. Control tests on untreated, bovine blood from the corn gluten meal diet in both hypertonic and isotonic solutions were performed for comparison. In support of the hypothesis, the addition of Omega-3 in the bovine diet resulted in an increase in the cell membrane thickness when placed in hypertonic solutions, indicating decreased membrane rigidity. Based on these results, the use of dietary Omega-3 as a possible treatment for CCM should be explored in the future.

Stability Studies of Kynurenine Pathway Metabolites in Blood Components Define Optimal Blood Processing Conditions.

The kynurenine pathway (KP) is the main pathway of tryptophan (TRP) metabolism that generates energy for multiple cellular processes. The activity of this pathway has been shown to be dysregulated in multiple human diseases. The resultant modulation of metabolites has been suggested to comprise biomarkers to track disease progression or could identify new therapeutic targets. While metabolite changes can be measured readily in blood, there is limited knowledge on the effect of blood matrices and sample processing time may have on the stability of KP metabolites. Understanding the stability of KP metabolites in blood is integral to obtaining accurate KP data to correlate with clinical pathology. Hence, the aim of this study was to assess the concentration of KP metabolites in matched whole blood, plasma and serum. The impact of pre-analytical sample processing time in the various blood matrices was also analysed. Serum and plasma had the higher concentration of KP metabolites compared to whole blood. Furthermore, concentrations of KP metabolites declined when the collected blood was processed after 24 hours storage at 4°C. Our study shows that that type of blood matrix and the time to processing have an impact on the stability of the KP metabolites. Serum or plasma are the preferred choice of matrix and the isolation of these matrices from whole blood is best performed immediately after collection for optimal analytical KP data.

Functional brain networks in the evaluation of patients with neurodegenerative disorders.

Network analytical tools are increasingly being applied to brain imaging maps of resting metabolic activity (PET) or blood oxygenation-dependent signals (functional MRI) to characterize the abnormal neural circuitry that underlies brain diseases. This approach is particularly valuable for the study of neurodegenerative disorders, which are characterized by stereotyped spread of pathology along discrete neural pathways. Identification and validation of disease-specific brain networks facilitate the quantitative assessment of pathway changes over time and during the course of treatment. Network abnormalities can often be identified before symptom onset and can be used to track disease progression even in the preclinical period. Likewise, network activity can be modulated by treatment and might therefore be used as amarker of efficacy in clinical trials. Finally, early differential diagnosis can be achieved by simultaneously measuring the activity levels of multiple disease networks in an individual patient's scans. Although these techniques were originally developed for PET, over the past several years analogous methods have been introduced for functional MRI, a more accessible non-invasive imaging modality. This advance is expected to broaden the application of network tools to large and diverse patient populations.

149 QUANTIFICATION OF FIBROCALCIFIC VOLUME IN AORTIC VALVE STENOSIS BY A NOVEL CONTRAST COMPUTED TOMOGRAPHY METHOD BASED ON A GAUSSIAN MIXTURE MODEL

Abstract Background Discordant echocardiographic measurements are observed in up to one third of patients with aortic stenosis (AS), in whom computed tomography (CT) derived aortic valve calcium scoring is now recommended. Nonetheless, CT calcium scoring only evaluates calcific valve thickening and is unable to assess non-calcific fibrotic thickening, which could be a relevant contributor of AS. Aim of the present study was to generate a quick and robust contrast-CT method based on a gaussian mixture model (GMM) for the assessment of fibro-calcific aortic valve thickening in AS patients, and to investigate its reproducibility and associations with echocardiographic parameters of AS severity and disease progression. Methods A post-hoc analysis of 136 patients with calcific AS (24 with severe, 81 moderate and 31 mild AS) enrolled in the SALTIRE2 trial (Study Investigating the Effects of Drugs used to Treat Osteoporosis on the Progression of Aortic Stenosis) (NCT-02132026) was performed. Aortic valve fibrocalcific volume was calculated using a GMM applied on contrast-CT at baseline and at 1-year follow up. The software estimated the Hounsfield Units (HU) distribution of 3 compartments (blood pool, non-calcific and calcific tissue) within the aortic valve volume of interest, automatically generating thresholds for non-calcific and calcific volumes, respectively computed as the lower 99.7 and the upper 99.7 percentile of the blood pool HU distribution (Figure). Thus, Fibrocalcific volume was measured as the sum of non-calcific and calcific volumes, indexed for CT annulus area and compared to echo parameters of AS severity. Scan-rescan reproducibility and analysis of AS progression were also assessed. Results Image analysis took 5.8 ± 1.0 minutes per scan and showed excellent scan-rescan reproducibility (mean difference -1%, limits of agreement -9% to 7%). Indexed-fibrocalcific volume correlated well with echocardiographic aortic peak velocity (rho=0.70, p<0.0001), better than non-calcific and calcific volumes alone (rho=0.30 and rho=0.61 respectively, both p<0.0001) and Agatston calcium score (rho=0.63, p<0.0001). Baseline indexed-fibrocalcific volume was also the strongest predictor of subsequent AS progression in terms of change in aortic valve peak velocity (rho=0.29, p=0.006) and mean gradient (rho=0.39, p<0.0001). Progression-to-noise ratio for fibrocalcific volume was favourable (Cohen's statistic d=0.62), indicating that groups sizes of 21, 46 and 170 participants would be required to demonstrate 30%, 20% and 10% reductions in fibro-calcific volume progression with a novel drug respectively (alpha=0.05, power=80%). Conclusions This contrast CT-based approach based on a GMM is able to provide robust and relatively rapid assessment of fibrocalcific thickening in patients with AS. Fibrocalcific volume measured using this method, correlates well with other markers of AS severity, predicts disease progression and holds promise in tracking disease progression and response to novel therapies.

18F]RO‐948 Tau PET Retention and Correlation with Fluid Tau Biomarkers in the Early AD Continuum

AbstractBackgroundTau positron emission tomography (PET) imaging enables the in vivo visualization of tau aggregates occurring during the progression of Alzheimer’s disease (AD). Tau PET imaging is a promising biomarker for clinical diagnosis and tracking of disease progression. However, the sensitivity of tau PET in detecting early tau pathology within the early AD continuum and its association with fluid tau biomarkers remains to be established.MethodForty‐seven cognitively unimpaired individuals from the ALFA+ cohort had [18F]RO‐948 and [18F]flutemetamol PET, T1‐weighted magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma tau biomarkers available (Table1). CSF amyloid(A) and tau(T) positivity were defined using CSF Aß42/40 ratio and ptau181 measured by the exploratory NeuroToolKit and Elecsys® immunoassays, respectively, according to pre‐established thresholds (Milà‐Alomà et al., 2020). Centiloid (CL) values were obtained from [18F]flutemetamol PET scans using a validated pipeline. [18F]RO‐948 uptake was measured in entorhinal (BraakI/II), limbic (BraakIII/IV), and neocortical (BraakV/VI) regions and normalized to the inferior cerebellum to render SUVR values. Regional positivity thresholds per Braak stage were calculated as the median plus two robust standard deviations. Associations between [18F]RO‐948 SUVRs and fluid tau biomarkers were evaluated using Spearman’s rho correlations. P‐values<0.05 were considered statistically significant. [18F]RO‐948 SUVRs were modeled against CL values using the data‐driven robust LOWESS method.ResultIn BraakI/II, 5 cases were considered to be positive, 3 in BraakIII/IV and 2 in BraakV/VI (see Table2 for thresholds), all of them being A+T+. Significant correlations with fluid biomarkers were observed in all Braak stages (Table3, Figure1). [18F]RO‐948 SUVR in BraakI/II showed a linear trend with CL values and inflection points between 20 and 30 CLs were observed for all Braak stages (Figure2).ConclusionA progressively lower number of [18F]RO‐948 PET‐positive cases were detected for more advanced Braak stages as expected from neuropathological studies. [18F]RO‐948 uptake started increasing around 20‐30 CLs and correlated with wet tau biomarkers in cognitively unimpaired individuals, suggesting that [18F]RO‐948 PET can be more sensitive to initial tau pathology than previously thought. These preliminary findings demonstrate that the ALFA+ cohort is well‐suited to study early pathophysiological alterations in preclinical AD stages.

Machine learning‐enabled epileptiform spike detection stratifies patient subpopulations with Alzheimer’s disease

AbstractBackgroundA subpopulation of patients with Alzheimer’s disease exhibit epileptiform activity and have more rapidly progressing disease. Manual identification of these pathological events is infeasible at scale and machine learning tools may establish epileptiform activity as an actionable biomarker for stratification and endpoints within clinical trials.MethodsRoutine EEGs from 90 subjects with AD and 39 subjects with MCI from the Beacon data repository were analyzed via the Beacon Platform harnessing an ML‐enabled interictal epileptiform discharge (IED) detection algorithm, and by expert visual inspection.ResultsIEDs were found in 17 of the 90 subjects with AD (19%), and 8 out of the 39 MCI subjects (20%). In subcategorization, 13% (9 / 71) of AD subjects without epilepsy had IEDs, while 42% (8/19) of AD subjects with epilepsy had IEDs. In the AD/no epilepsy subgroup there were 24 patients taking an Anti‐Seizure Medication (ASM), and 4% (1/24) had IEDs (versus 17% (8/47) of the AD without epilepsy group that were not on ASMs).ConclusionMachine learning augmented detection of IEDs allows for rapid, quantitative identification of individuals with subclinical epileptiform activity in patients with AD and MCI. These results demonstrate that AI‐detectable IEDs are seen in a sizable minority of AD patients without epilepsy and in MCI patients, and more commonly in AD patients with epilepsy. Ultimately, automated analysis of EEG data is a promising way to stratify patients and track disease progression while enriching clinical trials with subjects most likely to respond to next‐generation treatments.

Relationship between clinician rated amyloid status and traditional AD biomarkers in cognitively healthy older adults

AbstractBackgroundAccumulating evidence suggests that Alzheimer’s Disease (AD) plasma biomarkers aid in screening for at‐risk individuals, tracking disease progression, and monitoring response to interventions. Plasma amyloid‐β (Aβ) and phosphorylated tau (pTau) have shown promise in predicting cerebral deposition of Aβ, while neurofilament light chain (NfL) serves as a more global marker of neurodegeneration. However, blood collection protocols often differ, and it is important to confirm the relationship between blood biomarker values and established neuroimaging markers for AD neuropathology.MethodHere, we examined which blood biomarkers could predict clinician rating of cerebral amyloid status. We leveraged available clinical, cognitive, and neuroimaging data for 140 cognitively healthy older adults (65+, mean 72 ± 6.4) who participated in the Alzheimer’s Prevention Program (APP) study and had blood specimens available. Participants were assessed by a trained clinician and neuropsychometric test battery to exclude the presence of MCI or dementia syndromes. Cerebral amyloid burden was measured by Florbetapir (18F) positron emission tomography and images were rated by three trained clinicians as “elevated” or “non‐elevated”. Biomarkers were measured in plasma collected in acid citrate dextrose (ACD) tubes using a Quanterix Simoa® HD‐X platform, and included NfL, Aβ42, Aβ40, and p‐tau181.ResultPlasma Aβ42/40 ratio was significantly lower in the “elevated” group than in the “non‐elevated” group (p < 0.001), while NfL (p =0.008) and p‐tau 181 (p = 0.001) were both significantly higher. Aβ42/40 ratio was able to discriminate the rating groups in a ROC analysis with an AUC of 0.835, significantly outperforming p‐tau 181 (AUC = 0.640) and NfL (AUC = 0.572).ConclusionDespite collecting samples with ACD rather than the traditional EDTA as an anti‐coagulant, expected group differences were observed. Our results suggest that Aβ42/40 ratio is useful in discriminating clinician‐rated elevated cerebral amyloid status, which has important implications regarding disclosure of blood biomarker results from different collection protocols in the context of AD risk.

Subcortical atrophy imaging biomarker performance across the sporadic and genetic frontotemporal dementias

AbstractBackgroundFrontotemporal dementia (FTD) is a common cause of young‐onset dementia, with promising disease‐modifying candidates. Cortical signatures are well established; however, comprehensive longitudinal investigations of subcortical atrophy are limited and sample size estimates to inform imaging biomarker choice are lacking. Therefore, the current study investigated the relative utility of automated subcortical atrophy measures to detect putative disease‐modifying treatment effects in clinical, genetic and pathologically‐confirmed FTD.MethodLongitudinal registration and segmentation algorithms were applied to a cohort of 262 people, 184 of whom were diagnosed with FTD, to measure atrophy in the amygdala, hippocampus, caudate and thalamus. Clinical diagnoses were behavioural variant FTD (n = 66) and primary progressive aphasia (PPA, n = 118), comprising semantic variant PPA (n = 45), non‐fluent variant PPA (n = 45), logopenic variant PPA (n = 21), and PPA‐not otherwise specified (n = 7). Fifty‐three patients had either a known pathogenic mutation (in the MAPT, C9orf72 or GRN genes) and/or underlying tau or TDP‐43 pathology confirmed at post‐mortem. Seventy‐eight cognitively normal controls were included for comparison. Sample size estimates were computed to explore the relative feasibility of subcortical atrophy measures to track disease progression and detect treatment‐related effects across the different subgroups.ResultRelatively distinct patterns of significantly increased atrophy across the amygdala, hippocampus, caudate and/or thalamus were detected (p < 0.001) for all sporadic, genetic, and pathology‐confirmed FTD subgroups, with a strong left‐dominant pattern evident for PPA‐NOS and GRN patients. The best performing marker (as determined by lowest sample size required to detect a treatment effect) varied by subgroup supporting the importance of informed regional biomarker choice based on the population enrolled. Measures of the caudate and thalamus performed particularly well across all the subgroups, producing estimates well below 100 patients per treatment arm. The left hippocampal BSI (boundary shift integral) measure produced the lowest estimate overall in PPA‐NOS, with 12 individuals required to detect a 30% reduction in atrophy.ConclusionThis work confirms the relative utility of subcortical atrophy measures across the FTD spectrum and provides valuable sample size information to inform non‐invasive biomarker choice for sporadic and genetic FTD trials.

Comparison of FreeSurfer inputs on estimates and reliability of volume and thickness measures

AbstractBackgroundAnatomical volume and cortical thickness are measures of neurodegeneration to track disease progression and evaluation of treatment efficacy. FreeSurfer software provides automatic structural parcellation and segmentation to estimate volume and thickness. T1‐weighted inputs are commonly used, but T2 or T2*FLAIR images can be added. This study compared FreeSurfer estimates for T1 only vs T1+T2 or T1+T2*FLAIR inputs with regard to reliability and its relation to amyloidosis.Method3‐Tesla MRI data were included for 379 scans (T1: 35%, T1+T2: 35%, T1+T2*FLAIR: 31% ‐ session 1: 39%, 2: 34%, 3: 27%) from 60 healthy older adults (mean age 71, 67% female). FreeSurfer‐derived estimates of volume and cortical thickness were obtained for T1, T1+T2, and T1+T2*FLAIR inputs. Kruskal Wallis tests followed by Dunn post hoc test were used to identify estimates that were significantly different across sequences. Two‐way mixed model analyses were performed on each estimate, including subject and session as grouping factors. Interclass correlation coefficients measured similarity and reliability. Amyloid‐PET SUVR levels were available for 54% of subjects. Bonferroni correction and estimated marginal means were used to correct for multiple comparisons.ResultFor volume estimates, 17% of pairwise combinations (7% T1+T2vsT1+T2*Flair, 6% T1vsT1+T2, and 4% T1vsT1+T2*FLAIR) showed significant differences between sequences adjusting for multiple comparisons. The cross‐sectional similarity between sequences had median ICC=0.87. Test‐retest reliability within sequences had median ICC=0.88 for T1, 0.87 for T1+T2 and 0.78 for T1+T2*FLAIR. For thickness estimates, 73% of pairwise combinations (27% T1+T2vsT1+T2*FLAIR, 23% T1vsT1+T2*FLAIR, and 22% T1vsT1+T2) showed significant differences between sequences after adjusting for multiple comparisons. The cross‐sectional similarity between sequences had median ICC=0.43. Test‐retest reliability within sequences had median ICC=0.78 for T1, 0.74 for T1+T2 and 0.30 for T1+T2*FLAIR. Amyloid SUVRs had non‐significant correlations with all ICC measures.ConclusionOverall, volumes had high similarity across sequence inputs and high test‐retest reliability. Thickness showed less reliability across sequences and sessions driven by low similarity and low reliability for T1+T2*FLAIR. Amyloid deposition did not impact reliability estimates. These results suggest that T1 only or T1+T2 inputs have high reliability across sessions and should be considered in clinical trials designs that measure change in volume or thickness.

Associations between performance on the Latin American Version of the Face‐Name and plasma Neurofilament Light Chain, NfL, in individuals with autosomal‐dominant Alzheimer’s disease: Preliminary findings from the Colombia‐Boston ‐COLBOS‐ remote study

AbstractBackgroundWe previously reported that performance on the Latin American Spanish version of the Face‐Name Associative Memory Exam (LAS‐FNAME) differentiated between cognitively intact Presenilin1 (PSEN1) E280A mutation carriers from non‐carriers and that this performance was also associated with greater amyloid and tau burden in the entorhinal and inferior temporal cortices, when examining all carriers. Neurofilament light chain (NfL), a plasma‐based biomarker for neurodegeneration and a promising marker for early Alzheimer’s disease (AD) detection, is less invasive and expensive than PET imaging. Here, we examined whether levels of plasma NfL were associated with LAS‐FNAME performance in non‐demented PSEN1‐E280A carriers and non‐carriers.MethodsA total of 51 PSEN1‐E280A carriers (mean age = 30.06 +/‐ 4.63), including 2 Mild Cognitive Impaired carriers and 50 age‐matched non‐carriers (mean age = 35.55 +/‐ 6.16) from the Colombia‐Boston (COLBOS) remote study were included. Participants underwent blood sampling and neuropsychological assessment, including the MMSE and LAS‐FNAME. Plasma NfL concentrations were measured with a single molecule array (Simoa) method. Mann‐Whitney and Spearman correlations were used to examine group differences and the relationships between LAS‐FNAME performance and NfL levels.ResultsThere were no significant group differences in NfL levels or in the LAS‐FNAME Total Score, Immediate and Delayed Memory subscales (all p>0.05). However, mutation carriers (mean= 27.90) had lower MMSE scores than non‐carriers (mean= 28.47; p = 0.05). LAS‐FNAME Total Score was negatively associated with age (r=‐.37; p=0.007), and positively associated with MMSE scores (r=.54; p<0.001) in the carrier group. Among the entire sample, associations between NfL levels and age trended toward significance (p = 0.06). NfL levels were not associated with cognitive performance, including LAS‐FNAME or MMSE.ConclusionsPreliminary findings suggest that LAS‐FNAME may be a useful tool to track disease progression in those at increased risk for dementia. Further, our findings suggest that NfL levels may not be associated with performance on associate memory tasks, such as LAS‐FNAME, in prodromal stages of ADAD. Future work with a larger sample of carriers, across the preclinical/prodromal spectrum will allow for a more comprehensive examination of these associations.

Brief risk rating scale: A preliminary screening and monitoring tool emphasizing individual differences for better prognosis in Alzheimer’s disease

Over the last several decades, significant progress has been made in the diagnostic criteria of Alzheimer’s disease (AD) to identify its early stages, including subjective cognitive decline and mild cognitive impairment. However, the previous research rarely took account of individual differences when evaluating AD-spectrum patients at different stages, thereby resulting in similar treatment, which was not only ineffective but also resulted in the missed window of opportunity for intervention. In this review, we propose the Brief Risk Rating Scale (BRRS), which is predominantly based on extant literature concerning AD risk factors and brain alterations, with the aim of providing a preliminary screening and monitoring tool that can facilitate the assessment of individual’s risk level, the prediction and tracking of disease progression, as well as precise treatment in a timely manner. Meanwhile, due to its simplicity and ease of use, it can be widely promoted and likewise accessible to clinicians in grassroots clinics. In general, the scale comprises two parts: The original score (O) related to patients’ risk factors and the variation score (V) related to brain abnormalities tested by different sequences of magnetic resonance imaging. In addition, the advantages along with its clinical application, such as introducing BRRS into cognitive training and brain stimulation, are also discussed. We conclude that BRRS positively contributes to enhancing the accuracy of clinical diagnosis and the efficiency of personalized treatment in AD-spectrum patients, with individual differences fully considered and little additional burden added. However, the weight coefficient of each item in BRRS should be thoroughly studied in future research.

Which motor-cognitive abilities underlie the digital Trail-Making Test? Decomposing various test scores to detect cognitive impairment in Parkinson’s disease—Pilot study

Since Parkinson’s disease (PD) is a heterogeneous disorder with symptoms, such as tremors, gait and speech disturbances, or memory loss, individualized diagnostics are needed to optimize treatment. In their current form, the typical paper-pencil methods traditionally used to track disease progression are too coarse to capture the subtleties of clinical phenomena. For this reason, digital biomarkers that capture, for example, motor function, cognition, and behavior using apps, wearables, and tracking systems are becoming increasingly established. However, given the high prevalence of cognitive impairment in PD, digital cognitive biomarkers to predict mental progression are important in clinical practice. This pilot study aimed to identify those components of our digital version of the TMT (dTMT) that allow discrimination between PD patients with and without cognitive deficits. A total of 30 healthy control (age 66.3 ± 8.61) and 30 participants with PD (age 68.3 ± 9.66) performed the dTMT using a touch-sensitive tablet to capture enhanced performance metrics, such as the speed between and inside circles. The decomposition of cognitive abilities based on integrating additional variables in the dTMT revealed that the Parkinson’s disease group was significantly more sensitive to parameters of inhibitory control. In contrast, the mild cognitive impairment group was sensitive to parameters of cognitive flexibility and working memory. The dTMT allows objective, ecologically valid, and long-term cognitive and fine-motor performance tracking, suggesting its potential as a digital biomarker in neurodegenerative disorders.

An integration into the diagnostic workflow in a pediatric patient suspected of having Marfan syndrome

BackgroundThe genetic approach to Marfan syndrome (MFS) has evolved over the last few decades, as has our understanding of the variants’ potential structural and functional consequences. It has been proposed that next-generation sequencing be used to improve genetic diagnosis and patient management. To this end, we used a targeted NGS custom panel to perform genetic analysis in a patient with MFS and his or her family members.Case presentationHere, we describe a novel germ-line heterozygous missense variant (transversion c.5371 T > A) found in exon 43 of the FBN1 gene of a patient (proband) with MFS. FBN1 (ENSG0000166147) and TGFB2 (ENSG0000166147) were included in a targeted sequencing panel for MFS (ENSG0000163513). This new variant c.5371 T > A was identified only in the proband, not in unaffected family members or healthy controls.ConclusionsGiven the massive amount of data generated by gene panel analysis, clinical interpretation of genetic variants may become more difficult. As a result, 3D modeling and multidisciplinary approaches should be used in the analysis and annotation of observed variants. The analysis of the protein’s conformational structure in relation to the identified variant could provide useful information. These data can be used to classify observed variants (pathogenic vs non-pathogenic) linked to the MFS phenotype, as well as to track disease progression and potential target treatments.

A Novel Antibody-Drug Conjugate Directed Towards the Surrogate Light Chain of Malignantly-Transformed B-Cell Precursors Reverses Leukemic Progression in NSG Mice

Background: Antibody-drug conjugates (ADC) utilizing AcBut-linked calicheamicin have improved survival for B- and myeloid lineage hematopoietic malignancies for both adults and children. We recently showed that the VpreB1 component (CD179a) of the B-cell surrogate light chain is ubiquitously expressed on B-lineage lymphoblasts, which may present a suitable target for an immunotherapeutic intervention. Specifically, the VpreB1 component of the surrogate light chain was identifiable in 36 / 36 (100%) of primary patient samples obtained from COG studies AALL0232 and AALL1131 (Blood Adv6(2): 585-589; 2022.) Materials and Methods: Using a human IgG1 subclass monoclonal antibody (mAb) against the VpreB1 component of the surrogate light chain, we created an ADC that is comprised of an AcBut-linker to calicheamicin. Using ex vivo testing conditions, we assessed 50% inhibitory concentrations (IC50s) in the Nalm6, REH and SEM B-ALL cells lines, and in PDXB1 and PDXB2 patient-derived xenographs (PDXs). We tested the VpreB1 ADC to evaluate its potential to rescue NSG mice that were engrafted with Nalm-6 B-lymphoblasts using VpreB1 ADC doses ranging from 0.1 to 3 mg/kg given intraperitonealy three times, four days at apart at leukemic engraftment to assess responses. To assess leukemic burden in the experimental and control conditions, we utilized human FITC-labelled CD45/CD19 antigen expression and Nalm-6-Luciferase imaging to track disease progression in mock, CD179a mAb (alone) and VpreB1 ADC-treated NSG mice. Results: We found a spectrum of IC50s in the B-ALL samples tested under ex vivo conditions, which ranged from 59 ng/ml (Nalm6), 81 ng/ml (REH), 108 ng/ml (PDXB2), 2499 ng/ml (PDXB1) to 5105 ng/ml (SEM), suggesting a range of sensitivities to the mAb. Using flow cytometric analyses of Nalm-6 engraftment, we found that human CD19-expressing cell populations were absent in the VpreB1 ADC treatment group, but present in the mock and CD179a mAb-alone control groups. We employed a series of dose-finding studies and found that a dose of 2 mg/kg (~105 mcg/kg calicheamicin dose) in the experimental group was sufficient to reverse progressive disease. Using Nalm-6-engrafted NSG mice, we found that the VpreB1 ADC (2 mg/kg) treatment cohort had significantly extended lifespans in comparison to those treated with mock or naked mAb control groups (Mantel-Cox log-rank; P<0.0001). Using Nalm-6-luciferase imaging, we determined that the surviving animal population showed no signs of leukemic infiltration in comparison to the negative control groups, and that (4/6; 67%) of the animals in the VpreB1 ADC treatment group survived without evidence for relapsed leukemia for more than 100 days. Two of the animals died for inexplicable reasons, but did not have progressive disease by luciferase imaging. At necropsy, none of the four surviving animals in the experimental treatment group had flow cytometric evidence for leukemia. These findings suggest that the VpreB1 ADC induced "cures” in the surviving Nalm-6-Luciferase treatment group. Conclusions: We have created a novel ADC that neutralizes leukemic progression in our NSG Nalm-6 engrafted murine model. Our preliminary data supports the further evaluation of the ADC in patient-derived xenografts (currently underway). Further studies will be performed in preparation for Phase 1 clinical testing in adults and children with B-lineage acute lymphoblastic leukemia/lymphoma.

Mobile App to Enhance Patient Activation and Patient-Provider Communication in Major Depressive Disorder Management: Collaborative, Randomized Controlled Pilot Study.

Enhanced patient-provider engagement can improve patient health outcomes in chronic conditions, including major depressive disorder (MDD). We evaluated the impact of a digitally enabled care mobile app, Pathway, designed to improve MDD patient-provider engagement. Patients used a mobile interface to assess treatment progress and share this information with primary care providers (PCPs). In this 52-week, real-world effectiveness and feasibility study conducted in primary care clinics, 40 patients with MDD who were recently prescribed antidepressant monotherapy were randomized to use a mobile app with usual care (20/40, 50%) or usual care alone (20/40, 50%). Patients in the app arm engaged with the app daily for 18 weeks; a report was generated at 6-week intervals and shared with the PCPs to facilitate shared treatment decision-making discussions. The patients discontinued the app at week 18 and were followed through year 1. Coprimary outcome measures, assessed via research visits, included change from baseline in the 13-item Patient Activation Measure (PAM-13) and 7-item Patient-Provider Engagement Scale scores at week 18. Additional outcome measures included depression severity (9-item Patient Health Questionnaire [PHQ-9]) and cognitive symptoms (5-item Perceived Deficits Questionnaire-Depression). All 37 patients (app arm: n=18, 49%; usual care arm: n=19, 51%) who completed the 18-week follow-up period (n=31, 84% female, mean age 36, SD 11.3 years) had moderate to moderately severe depression. Improvements in PAM-13 and PHQ-9 scores were observed in both arms. Increases in PAM-13 scores from baseline to 18 weeks were numerically greater in the app arm than in the usual care arm (mean 10.5, SD 13.2 vs mean 8.8, SD 9.4; P=.65). At 52 weeks, differences in PAM-13 scores from baseline demonstrated significantly greater improvements in the app arm than in the usual care arm (mean 20.2, SD 17.7 vs mean 1.6, SD 14.2; P=.04). Compared with baseline, PHQ-9 scores decreased in both the app arm and the usual care arm at 18 weeks (mean 7.8, SD 7.2 vs mean 7.0, SD 6.5; P=.73) and 52 weeks (mean 9.5, SD 4.0 vs mean 4.7, SD 6.0; P=.07). Improvements in 7-item Patient-Provider Engagement Scale and WHO-5 scores were observed in both arms at 18 weeks and were sustained through 52 weeks in the app arm. Improvements in WHO-5 scores at 52 weeks were significantly greater in the app arm than in the usual care arm (41.5 vs 20.0; P=.02). Patients with MDD will engage with a mobile app designed to track treatment and disease progression. PCPs will use the data generated as part of their assessment to inform clinical care. The study results suggest that an app-enabled clinical care pathway may enhance patient activation and benefit MDD management. ClinicalTrials.gov NCT03242213; https://clinicaltrials.gov/ct2/show/NCT03242213.