Faster Progression Rate Research Articles

A classification algorithm for prioritizing surgery in Pediatric patients with idiopathic scoliosis when Long Surgical delays are expected.

To identify the clinical phenotypes associated with the rate of progression while waiting for surgery and propose a classification scheme for identifying subgroups of patients to prioritize for surgery when long surgical delays are expected. We reviewed the clinical and radiographic data of a prospective cohort of patients scheduled for IS surgery from 2004 to 2020 with a minimum 1-year wait prior to surgery. Candidate predictors consisted of age, sex, Risser sign, menarchal status, angle of trunk rotation, scoliotic curve type, and main Cobb angle at baseline when scheduled for surgery. Univariate and Regression Tree analysis were performed to identify predictors associated with the annual curve progression rate in the main Cobb angle between baseline and surgery. There were 214 patients (178 females) aged 15 ± 2 years, with a Risser sign 3.4 ± 1.6 and a main Cobb angle 55°±10° at baseline. The average wait prior to surgery was 1.3 ± 0.4 years. Only the Risser sign, menarchal status and sex were significantly associated with the annual progression rate. We have identified 3 clinically and significantly different groups of patients presenting slow (3 ± 4°/yr if Risser sign 3 to 5), moderate (8 ± 4°/yr if female with Risser sign 0 to 2 and post-menarchal), and fast (15 ± 10°/yr if Risser sign 0 to 2 and premenarchal or male) progression rates. We present an evidence-based surgical prioritization algorithm for pediatric idiopathic scoliosis that can easily be implemented in clinical practice when long surgical delays are expected.

Differences in brain aging between sexes in Parkinson’s disease

Parkinson’s disease (PD) is linked to faster brain aging. Male sex is associated with higher prevalence, severe symptoms, and a faster progression rate in PD. There remains a significant gap in understanding the function of sex in the process of brain aging in PD. The structural T1-weighted MRI-driven brain-predicted age difference (i.e., Brain-PAD: the actual age subtracted from the brain-predicted age) was computed in a group of 373 people with PD (mean age ± SD: 61.37 ± 9.81, age range: 33–85, 34% female) from the Parkinson’s Progression Marker Initiative database using a robust brain-age estimation framework that was trained on 949 healthy subjects. Linear regression models were used to investigate the association between Brain-PAD and clinical variables in PD, stratified by sex. Males with Parkinson’s disease (PD-M) exhibited a significantly higher mean Brain-PAD than their female counterparts (PD-F) (t(256) = 2.50, p = 0.012). In the propensity score-matched PD-M group (PD-M*), Brain-PAD was found to be associated with a decline in general cognition, a worse degree of sleep behavior disorder, reduced visuospatial acuity, and caudate atrophy. Conversely, no significant links were observed between these factors and Brain-PAD in the PD-F group. Having ‘older’ looking brains in PD-M than PD-F supports the idea that sex plays a vital function in PD, such that the PD mechanism may be different in males and females. This study has the potential to broaden our understanding of dissimilarities in brain aging between sexes in the context of PD.

Cystatin C is associated with poor survival in amyotrophic lateral sclerosis patients.

Cystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown. A total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan-Meier curve and Cox regression model were used for survival analysis. CysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p < 0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p < 0.001), a faster disease progression rate (0.75 vs. 0.67, p = 0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p = 0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r = -0.16, p < 0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p < 0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012-1.433). However, when treatment was included in the model, the result was no longer significant. CysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention.

Time from amyotrophic lateral sclerosis symptom onset to key disease milestones: analysis of data from a multinational cross-sectional survey

Objective To determine the average time from Amyotrophic Lateral Sclerosis (ALS) symptom onset to 11 pre-defined milestones, overall and according to ALS progression rate and geographic location. Methods Data were drawn from the Adelphi Real World ALS Disease-Specific ProgrammeTM, a point-in-time survey of neurologists caring for people living with ALS (pALS) conducted in France, Germany, Italy, Spain, the United Kingdom and the United States from 2020–2021. ALS progression rate was calculated using time since symptom onset and ALS Functional Rating Scale Revised score. Results Survey results were available for N = 1003 pALS (progression rate for N = 867). Mean time from symptom onset was 3.8 months to first consultation, 8.0 months to diagnosis, 16.2 months to employment change (part-time/sick leave/retirement/unemployment), 17.5 months to use of a walking aid, 18.5 months to first occurrence of caregiver support, 22.8 months to use of a wheelchair, 24.6 months to use of a communication aid, 27.3 months to use of a respiratory aid, 28.6 months to use of gastrostomy feeding, 29.7 months to use of eye gaze technology and 30.3 months to entering a care facility. Multivariate analysis indicated significant effects of fast (versus slow) progression rate on time to reach all 11 milestones, as well as US (versus European) location, age, body mass index and bulbar onset (versus other) on time to reach milestones. Conclusions pALS rapidly reached clinical and disease-related milestones within 30 months from symptom onset. Milestones were reached significantly faster by pALS with fast versus slow progression. Geographic differences were observed.

Hyperautofluorescent Ring Pattern in Retinitis Pigmentosa: Clinical Implications and Modifications Over Time.

The purpose of this study was to investigate the relation among hyperautofluorescent ring patterns, visual acuity (VA), and optical coherence tomography (OCT) features in patients with retinitis pigmentosa (RP), and to describe its modifications over time. This was a retrospective, longitudinal, and observational study. Clinical and imaging data from the first and last available visits of patients with a clinical diagnosis of RP were reviewed. The ellipsoid zone (EZ) width was measured on OCT acquisitions. Short-wavelength autofluorescence (SW-AF) images were classified based on the hyperautofluorescent ring pattern as absent, regular, and irregular, and their modifications over the follow-up were described. The VA, EZ width, and progression rate were compared among the three groups. One hundred eight eyes from 54 subjects were included in the study. The hyperautofluorescent ring was not present in 28 eyes (25.9%), appeared regular in 45 eyes (41.7%), and had an irregular pattern in 35 eyes (32.4%). The three groups differed in terms of age, VA, and EZ width (all P < 0.05). Additionally, the absence of a hyperautofluorescent ring indicated a faster rate of progression (P < 0.001). Throughout the follow-up period, 17 eyes (15.7%) experienced a change in the AF pattern, with irregular rings being more commonly affected. The hyperautofluorescent ring is a useful tool to frame patients based on their EZ width and VA. We described its possible modifications over time, the knowledge of which can aid clinicians in the interpretation of imaging finding changes of their patients.

Investigating the synergistic potential of TRAIL and SAHA in inducing apoptosis in MOLT-4 cancer cells

IntroductionT-cell acute lymphoblastic leukemia is characterized by its fast progression rate and high complications. TRAIL can be used to trigger apoptosis in cancer cells with minimal effects on normal cells, but most of cancer cells develop resistance to this agent through various mechanisms. HDAC inhibitors like SAHA can be used to make cancer cells more susceptible to TRAIL-induced apoptosis. In this study, this hypothesis was tested on MOLT-4 cancer cell line. Materials and methodsThe cells were divided into six groups including the control group, TRAIL 50 nM, TRAIL 100 nM, SAHA 2 μM, SAHA 2 μM + TRAIL 50 nM, and SAHA 2 μM + TRAIL 100 nM. Apoptosis was evaluated by flowcytometry after 24, 48 and 72 h. The expression levels of c-flip, DR4, DR5, CHOP, NF-κB, STAT3, Akt, and PI3K genes were investigated by quantitative real-time PCR. Data were analyzed using two-way variance analysis with Tukey's and Dunnett's multiple comparisons tests, and statistical significance was defined as having a p-value less than 0.05. ResultsGroups exposed to the combination of SAHA with TRAIL demonstrated the maximum apoptosis in MOLT-4 cells by increasing the expression of DR4, DR5, and CHOP and decreasing the expression of c-flip, STAT3, PI3k, Akt, and NF-kB genes. ConclusionIt can be concluded that SAHA increases the sensitivity of MOLT-4 cells to TRAIL-mediated apoptosis, which can be used as a strategy to overcome resistance to TRAIL in leukemic patients.

Prevalencia y significado pronóstico de las alteraciones pulmonares intersticiales precoces en TC de pacientes diagnosticados de enfermedad pulmonar intersticial tratados con antifibróticos

ObjectivesTo describe the prevalence and characteristics of interstitial lung abnormalities (ILA) in CT scans performed prior to the initiation of antifibrotics in a series of patients with interstitial lung disease (ILD), and to identify characteristics apparent on early CT scans that could help to predict outcomes. MethodsWe conducted a retrospective observational study. The original cohort consisted of 101 patients diagnosed with ILD and treated with antifibrotics in a tertiary hospital. Patients were included if they had a thoracic CT scan performed at least one year before initiation of therapy. They were classified radiologically in three groups: without ILA, with radiological ILA and extensive abnormalities. ILA were classified as subpleural fibrotic, subpleural non-fibrotic and non-subpleural. The initial scan and the latest CT scan performed before treatment were read for assessing progression. The relationship between CT findings of fibrosis and the radiological progression rate and mortality were analyzed. ResultsWe included 50 patients. Only1 (2%) had a normal CT scan, 25 (50%) had extensive alterations and 24 (48%) had radiological criteria for ILA, a median of 98.2months before initiation of antifibrotics, of them 18 (75%) had a subpleural fibrotic pattern. Significant bronchiectasis and obvious honeycombing in the lower zones were associated with shorter survival (P=.04). Obvious honeycombing in the lower zones was also significantly (P<.05) associated with a faster progression rate. ConclusionsFibrotic ILAs are frequent in remote scans of patients with clinically relevant ILD, long before they require antifibrotics. Findings of traction bronchiectasis and honeycombing in the earliest scans, even in asymptomatic patients, are related to mortality and progression later on.

Interleukin-8 and Interleukin-6 Are Biomarkers of Poor Prognosis in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) is a common type of cancer characterized by fast progression and high mortality rates, which generally implies a poor prognosis at time of diagnosis. Intricate interaction networks of cytokines produced by resident and inflammatory cells in the tumor microenvironment play crucial roles in ESCC development and metastasis, thus influencing therapy efficiency. As such, cytokines are the most prominent targets for specific therapies and prognostic parameters to predict tumor progression and aggressiveness. In this work, we examined the association between ESCC progression and the systemic levels of inflammatory cytokines to determine their usefulness as diagnostic biomarkers. We analyzed the levels of IL-1β, IL-6, IL-8, IL-10, TNF-α e IL-12p70 in a group of 70 ESCC patients and 70 healthy individuals using Cytometric Bead Array (CBA) technology. We detected increased levels of IL-1β, IL-6, IL-8, and IL-10 in ESCC patients compared to controls. However, multivariate analysis revealed that only IL8 was an independent prognostic factor for ESCC, as were the well-known risk factors: alcohol consumption, tobacco usage, and exposure to pesticides/insecticides. Importantly, patients with low IL-6, IL-8, TNM I/II, or those who underwent surgery had a significantly higher overall survival rate. We also studied cultured Kyse-30 and Kyse-410 cells in mice. We determined that the ESCC cell line Kyse-30 grew more aggressively than the Kyse-410 cell line. This enhanced growth was associated with the recruitment/accumulation of intratumoral polymorphonuclear leukocytes. In conclusion, our data suggest IL-8 as a valuable prognostic factor with potential as a biomarker for ESCC.

Immune-mediated myogenesis and acetylcholine receptor clustering promote a slow disease progression in ALS mouse models

BackgroundAmyotrophic lateral sclerosis (ALS) is a heterogeneous disease in terms of onset and progression rate. This may account for therapeutic clinical trial failure. Transgenic SOD1G93A mice on C57 or 129Sv background have a slow and fast disease progression rate, mimicking the variability observed in patients.Based on evidence inferring the active influence of skeletal muscle on ALS pathogenesis, we explored whether dysregulation in hindlimb skeletal muscle reflects the phenotypic difference between the two mouse models.MethodsEx vivo immunohistochemical, biochemical, and biomolecular methodologies, together with in vivo electrophysiology and in vitro approaches on primary cells, were used to afford a comparative and longitudinal analysis of gastrocnemius medialis between fast- and slow-progressing ALS mice.ResultsWe reported that slow-progressing mice counteracted muscle denervation atrophy by increasing acetylcholine receptor clustering, enhancing evoked currents, and preserving compound muscle action potential. This matched with prompt and sustained myogenesis, likely triggered by an early inflammatory response switching the infiltrated macrophages towards a M2 pro-regenerative phenotype. Conversely, upon denervation, fast-progressing mice failed to promptly activate a compensatory muscle response, exhibiting a rapidly progressive deterioration of muscle force.ConclusionsOur findings further pinpoint the pivotal role of skeletal muscle in ALS, providing new insights into underestimated disease mechanisms occurring at the periphery and providing useful (diagnostic, prognostic, and mechanistic) information to facilitate the translation of cost-effective therapeutic strategies from the laboratory to the clinic.

Risk factors for structural and functional progression of primary open-angle glaucoma in an African ancestry cohort

Background/aimsTo investigate the rates of structural and functional progression of primary open-angle glaucoma in an African ancestry cohort and identify risk factors for progression.MethodsThis retrospective study included 1424 eyes from...

Design, synthesis, and evaluation of pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as potent FLT3 inhibitors

Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as driver mutations in a subgroup of AML patients. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as FLT3 inhibitors. The compounds exhibited moderate to potent FLT3 kinase inhibitory potency and excellent antiproliferative activities against MV4-11 cells. Among them, compound 13 demonstrated the most potent kinase activity against FLT3-D835Y (IC50 = 29.54 ± 4.76 nM) and cellular potency against MV4-11 cells (IC50 = 15.77 ± 0.15 nM). Compound 13 also efficiently inhibited the growth of multiple mutant BaF3 cells expressing FLT3-D835V/F, FLT3-F691L, and FLT3-ITD/D835Y. Furthermore, compound 13 was metabolically stable in mouse liver microsomes. Moreover, the treatment with compound 13 led to robust inhibition of FLT3 autophosphorylation on Tyr589/591 in MV4-11 cells. In summary, our data demonstrated that 13 was worthy of further study for the treatment of AML.

Clinical and genetic characteristics of amyotrophic lateral sclerosis patients with ANXA11 variants.

Increasing genetic evidence supports the hypothesis that variants in the annexin A11 gene (ANXA11) contribute to amyotrophic lateral sclerosis pathogenesis. Therefore, we studied the clinical aspects of sporadic amyotrophic lateral sclerosis patients carrying ANXA11 variants. We also implemented functional experiments to verify the pathogenicity of the hotspot variants associated with amyotrophic lateral sclerosis-frontotemporal dementia. Korean patients diagnosed with amyotrophic lateral sclerosis (n = 882) underwent genetic evaluations through next-generation sequencing, which identified 16 ANXA11 variants in 26 patients. We analysed their clinical features, such as the age of onset, progression rate, initial symptoms and cognitive status. To evaluate the functional significance of the ANXA11 variants in amyotrophic lateral sclerosis-frontotemporal dementia pathology, we additionally utilized patient fibroblasts carrying frontotemporal dementia-linked ANXA11 variants (p.P36R and p.D40G) to perform a series of in vitro studies, including calcium imaging, stress granule dynamics and protein translation. The frequency of the pathogenic or likely pathogenic variants of ANXA11 was 0.3% and the frequency of variants classified as variants of unknown significance was 2.6%. The patients with variants in the low-complexity domain presented unique clinical features, including late-onset, a high prevalence of amyotrophic lateral sclerosis-frontotemporal dementia, a fast initial progression rate and a high tendency for bulbar-onset compared with patients carrying variants in the C-terminal repeated annexin homology domains. In addition, functional studies using amyotrophic lateral sclerosis-frontotemporal dementia patient fibroblasts revealed that the ANXA11 variants p.P36R and p.D40G impaired intracellular calcium homeostasis, stress granule disassembly and protein translation. This study suggests that the clinical manifestations of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia spectrum patients with ANXA11 variants could be distinctively characterized depending upon the location of the variant.

Association of Concurrent Olfactory Dysfunction and Probable Rapid Eye Movement Sleep Behavior Disorder with Early Parkinson's Disease Progression.

ABSTRACTBackgroundParkinson's disease (PD), with either rapid eye movement sleep behavior disorder (RBD) or olfactory dysfunction (OD), has been associated with disease progression. However, there is currently heterogeneity in predicting prognosis.ObjectivesTo identify whether the concurrent presence of OD and probable RBD (pRBD) in PD (Dual hit in PD, PD‐DH) is associated with disease progression.MethodsWe included 420 patients with de novo PD from the Parkinson's Progression Markers Initiative: 180 PD only (PD), 82 PD with OD (PD‐OD), 94 PD with pRBD (PD‐pRBD), and 64 PD with both OD and pRBD (PD‐DH). Participants underwent motor and nonmotor evaluations, dopamine transporter imaging, and cerebrospinal fluid (CSF) assessment. Data were analyzed with generalized estimating equations and Cox proportional hazards analysis.ResultsThe PD‐DH subtype was associated with higher scores and faster progression rates in Movement Disorder Society–Unified PD Rating Scale (MDS‐UPDRS) Parts II and III. Also, patients in PD‐DH group had faster deterioration in nonmotor symptoms, including MDS‐UPDRS Part I score, Montreal Cognitive Assessment, Hopkins Verbal Learning Test–Revised, Wechsler Memory Scale‐Third edition (WMS‐III) Letter Number Sequencing score, Symbol Digit Modalities Test, and Scales for Outcomes in PD–Autonomic scores, with all P values <0.002. Moreover, the PD‐DH subtype had a higher mild cognitive impairment risk (hazard ratio = 1.756, 95% confidence interval [CI] = 1.132–2.722; P = 0.012), faster decline in caudate standard uptake values (β = −0.03, 95% CI = −0.06 to −0.008, P = 0.012), and CSF α‐synuclein levels (β = −77, 95% CI = −149 to −5, P = 0.034) than the PD group.ConclusionCoexisting pRBD and OD in patients with PD may be associated with faster progressions in motor measurements and in cognitive and autonomic symptoms, indicating PD‐DH as a more aggressive subtype for PD.

Differences in clinical manifestations of late-onset, compared to earlier-onset essential tremor: A scoping review

Across the world, Essential Tremor (ET) is the most common tremor diagnosis but up to half of these diagnoses are inaccurate. The misdiagnosis rate is particularly high in late-onset ET, when tremor begins after the age of 60 years. Currently, ET is reported to affect 5.5% of those over 65 years old and 21.7% aged over 95 but there is emerging evidence that late-onset ET has associations with dementia, mortality and more rapid progression. With ageing populations, and a range of new surgical treatments for ET, there is urgent need to clarify whether the clinical manifestations of late-onset ET are the same as for earlier-onset ET. This scoping review used MEDLINE, EMBASE and CINAHL as the information sources of published peer-reviewed research articles between 2011 and 2021. Analysis was done by narrative synthesis. 14 relevant papers were retrieved from studies conducted in Denmark, India, Italy, Germany, Spain and the US and, together, they comprised 7684 participants in total. Compared to older adults with earlier-onset ET, there is evidence that late-onset ET is associated with higher risk of cognitive impairment and dementia, higher mortality rate, faster rate of progression, lack of family history, altered cortical electrical activity, prolonged pupillary responses, and less propensity to demonstrate characteristic alcohol sensitivity. There is evidence that late-onset ET has different clinical manifestations to earlier-onset ET; in particular there is higher risk of dementia and mortality. The prognosis is important for clinicians to consider when selecting candidates for deep brain stimulation surgery and also for advanced care planning.

The cross-sectional area of the median nerve: An independent prognostic biomarker in amyotrophic lateral sclerosis

IntroductionUltrasound changes in the cross-sectional area of the median nerve (CSAmn) could be of interest as biomarkers in patients with amyotrophic lateral sclerosis (ALS). MethodsEighty-four ALS patients (51 men [60.7%]; mean 62.0 [SD 11.46] years old) and forty-six controls (27 men [58.7%]; mean 59.9 [SD 8.08] years old) of two different cohorts were recruited between September 2013 and February 2018. The CSAmn was measured bilaterally in each cohort, by two different examiners with two different ultrasound machines (one in each cohort). Its association with clinical variables (disease duration, muscle strength, disability, progression rate and tracheostomy-free survival) was assessed. ResultsThe CSAmn was smaller in patients than in controls, and the study cohort did not influence its values. A mild correlation between the strength of the wrist flexor and the CSAmn was found. In the multivariable analysis, the probability of this association being true was 90%. In the cox regression, both a faster progression rate and a larger CSAmn independently predicted poor survival (HR=4.29, [Cr.I95%: 2.71–6.80], p<0.001; and HR=1.14, [Cr.I95%: 1.03–1.25], p=0.01), after adjusting by age, body mass index, bulbar onset, and diagnostic delay. ConclusionsThe CSAmn is an easy to assess biomarker that seems reliable and reproducible. Our data also suggest that it could act as a progression and prognostic biomarker in ALS patients. Longitudinal studies with repeated measures are warranted to confirm its usefulness in the clinical practice.

Natural history and remarkable psychiatric state of late-onset amyotrophic lateral sclerosis in China.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. The proportion of late-onset ALS in China were low and may have distinct clinical and genetic manifestations. We aimed to investigate the natural history and remarkable psychiatric state of ALS with age at onset over 60years in China. We collected all ALS cases from 2017 to 2020 in our center and focused on late-onset ALS patients particularly, by analyzing the clinical data, including the ALS onset and disease progression. Anxiety, depression, cognitive function, and sleep quality were assessed to reflect the psychiatric state. A total of 193late-onset ALS patients were included in this study. The median age at onset of late-onset ALS was 65years with the quartile from 62 to 68years. When compared with 446 non-late-onset ALS, late-onset ALS showed distinct clinical presentation, with lower ALS Functional Rating Scale-Revised at diagnosis and faster rate of progression. Remarkably, late-onset ALS were suffering from worse psychiatric state, including serious anxiety and depression, as well as worse cognitive function with sleep quality. The abnormal psychiatric state was more pronounced in female patients of late-onset. In the current study, ALS patients with late-onset showed unique clinical features. Severe psychiatric conditions and faster progression in the early stage of the disease of late-onset ALS indicated the need for more social and psychiatric support in this population.

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. In the last decade, it has become clear that cognitive and behavioral changes in patients with ALS are more frequent than previously recognized. Significantly, these non-motor features can impact the diagnosis, prognosis, and management of ALS. Partially overlapping neuropathological staging systems have been proposed to describe the distribution of TAR DNA-binding protein 43 (TDP-43) aggregates outside the corticospinal tract. However, the relationship between TDP-43 inclusions and neurodegeneration is not absolute and other pathophysiological processes, such as neuroinflammation (with a prominent role of microglia), cortical hyperexcitability, and synaptic dysfunction also play a central role in ALS pathophysiology. In the last decade, imaging and biofluid biomarker studies have revealed important insights into the pathophysiological underpinnings of extra-motor neurodegeneration in the ALS-FTLD continuum. In this review, we first summarize the clinical and pathophysiological correlates of extra-motor neurodegeneration in ALS. Next, we discuss the diagnostic and prognostic value of biomarkers in ALS and their potential to characterize extra-motor neurodegeneration. Finally, we debate about how biomarkers could improve the diagnosis and classification of ALS. Emerging imaging biomarkers of extra-motor neurodegeneration that enable the monitoring of disease progression are particularly promising. In addition, a growing arsenal of biofluid biomarkers linked to neurodegeneration and neuroinflammation are improving the diagnostic accuracy and identification of patients with a faster progression rate. The development and validation of biomarkers that detect the pathological aggregates of TDP-43 in vivo are notably expected to further elucidate the pathophysiological underpinnings of extra-motor neurodegeneration in ALS. Novel biomarkers tracking the different aspects of ALS pathophysiology are paving the way to precision medicine approaches in the ALS-FTLD continuum. These are essential steps to improve the diagnosis and staging of ALS and the design of clinical trials testing novel disease-modifying treatments.

Selective and Inverse U-Shaped Curve Alteration of the Retinal Nerve in Amyotrophic Lateral Sclerosis: A Potential Mirror of the Disease.

Introduction: Alterations in the visual pathway involving the retina have been reported in amyotrophic lateral sclerosis (ALS) but they lack consistency and subgroup analysis. We aimed to assess the retinal nerve fiber layer (RNFL) and retinal ganglion cells (RGCs) alterations in different stages of ALS patients and their association with ALS progression parameters.Methods: The study population consisted of 70 clinically diagnosed ALS patients and 55 age, sex matched controls. All of them underwent ophthalmic assessments and optical coherence tomography imaging. Four quadrants of the peripapillary RNFL and ganglion cell/inner plexiform complex (GCIP) were observed and automatically measured. Early-stage distal motor neuron axon dysfunction in ALS was detected by compound muscle action potential (CMAP) of the distal limbs within 12 months. The ALS disease parameters included the ALSFRS-R score and the disease progression rate (ΔFS).Results: Generally compared with controls, the nasal (p = 0.016) quadrant of the RNFL was thicker in ALS patients. When controlling for age and ΔFS, the RNFL(r = 0.37, p = 0.034) and GCIP(r = 0.40, p = 0.021) were significantly thickened as disease progressed within 12 months, while the RNFL declined with time after one year (r = −0.41, p = 0.037). ALS patients was subclassified into thickened RNFL (T-RNFL, >95th percentile of normal), impaired RNFL (I-RNFL, <5th percentile of normal) and normal RNFL. There were significant differences in the GCIP among the three groups (p < 0.001). In the T-RNFL group (n = 18), the RNFL was negatively correlated with the abductor pollicis brevis-CMAP amplitude within 12 months (r = −0.56, p = 0.01). Patients within 12 months in this group progressed faster than others (p = 0.039). In the normal RNFL group (n = 22), 13 patients were diagnosed beyond 12 months, whose ΔFS was remarkably lower (p = 0.007). In I-RNFL group (n = 30), the early stage patients (<12 months) had significant higher ΔFS (p = 0.006). One patient was with SOD1 pathogenic variant (p.A5V).Conclusion: Alterations of retinal nerve were not consistent in ALS patients with diverse phenotypes and progression rates. Generally speaking, the RNFL thickened during the first year and then gradually declined, which is related to but preceding the thickness change of the RGCs. Patients with a significant RNFL thinning in the early stage may have a faster progression rate. The inverse U-shaped curve transformation might be in accordance with early-stage motor neuron axonopathy.

The Impact of Superficial Vessel Density on Glaucoma Progression according to the Stage of Glaucoma.

Purpose: To investigate the clinical significance of vessel density (VD) on visual field (VF) progression regarding the severity of glaucoma. Methods: A total of 130 eyes were recruited in this retrospective and longitudinal study. Superficial and deep VDs in circumpapillary and macular regions were measured via ImageJ. The rate of VF progression was defined as the mean deviation (MD) slope (dB/year). Linear regression was used to verify factors affecting deterioration of VF. The eyes with lower superficial VD were further analyzed. Results: Fifty patients with early glaucoma (EG) (MD > −6 dB) and 52 patients with moderate-to-advanced glaucoma (MAG) (MD ≤ −6 dB) were included. A faster progression rate was found in MAG (p = 0.049). Superficial VD was noticeably related to the VF progression rate in total eyes and in MAG (Both Ps ≤ 0.007, respectively). With patients in the lower half of the superficial VD, the VD was significantly associated with the rate of progression (B, 0.049, p = 0.021). This association was independent of the baseline MD and OCT parameters. Conclusion: Decreased superficial VD might conversely affect the progression of glaucoma even in MAG, which suggests superficial VD could be used as a potential marker to foresee the disease progression even in progressed eyes.

Pancreatic Cancer Survival Prediction: A Survey of the State-of-the-Art.

Cancer early detection increases the chances of survival. Some cancer types, like pancreatic cancer, are challenging to diagnose or detect early, and the stages have a fast progression rate. This paper presents the state-of-the-art techniques used in cancer survival prediction, suggesting how these techniques can be implemented in predicting the overall survival of pancreatic ductal adenocarcinoma cancer (pdac) patients. Because of bewildering and high volumes of data, the recent studies highlight the importance of machine learning (ML) algorithms like support vector machines and convolutional neural networks. Studies predict pancreatic ductal adenocarcinoma cancer (pdac) survival is within the limits of 41.7% at one year, 8.7% at three years, and 1.9% at five years. There is no significant correlation found between the disease stages and the overall survival rate. The implementation of ML algorithms can improve our understanding of cancer progression. ML methods need an appropriate level of validation to be considered in everyday clinical practice. The objective of these techniques is to perform classification, prediction, and estimation. Accurate predictions give pathologists information on the patient's state, surgical treatment to be done, optimal use of resources, individualized therapy, drugs to prescribe, and better patient management.