Advent of Proteomic Tools for Diagnostic Biomarker Analysis in Alzheimer's Disease

Locating remedies for Alzheimer's disease (AD) has been majorly restricted by the inefficiency to establish a definitive detection model for early-stage diagnosis of pathological events. This current lapse in AD diagnosis also limits the therapeutic efficiency of the drugs, which might have been effective if given at the earlier stages of the disease. The indicated situation directs towards the burgeoned need for an effective biomarker technique that will help in early detection of AD and would be imminently useful to facilitate improved diagnosis and stimulate therapeutic trials. Till date, the major biomarkers, specifically associated with AD detection, may help in determining the early-stage AD diagnosis and identifying alterations in the cellular proteome, offering deeper insight into disease etiology. Currently existing multidisciplinary clinical diagnosis of AD is a very tedious, expensive procedure and requires highly trained and skilled professionals who are rarely available outside the specialty clinics. Mutations in amyloid precursor protein (APP) or Presenilin 1 and 2 (PSEN1 and PSEN2) are some biomarkers acting as critical checkpoints for AD diagnosis. However, the presence of some associated biomarkers in cerebrospinal fluid (CSF) such as total-Tau (tTau), phosphorylated-Tau (pTau) 181 and Amyloid-beta (A beta) 1-42 using structural or functional imaging techniques is considered for confirmatory diagnosis of AD. Furthermore, the molecular diagnosis of AD incorporates various sophisticated techniques including immuno-sensing, machine learning, nano conjugation-based detections, etc. In the current review description, we have summarized the various diagnostic approaches and their relevance in mitigating the long-standing urgency of targeted diagnostic tools for detection of AD

Development and validation of AIIMS modified INCLEN diagnostic instrument for epilepsy in children aged 1 month to 18 years

Objectives: There is shortage of specialists for the diagnosis of children with epilepsy, especially in resource limited settings. Existing INCLEN (International Clinical Epidemiology Network) instrument was validated for children aged 2–9 years. The current study validated modifications of the same including wider symptomatology and age group. Methods: The Modified INCLEN tool was validated by a team of experts by modifying the existing tools (2–9 years) to widen the age range from 1 month to 18 years and include broader symptomatology in a tertiary care teaching hospital of North India between January and June 2015. A qualified medical graduate applied the candidate tool which was followed by gold standard evaluation by a Pediatric Neurologist (both blinded to each other). Results: A total of 197 children {128 boys (65%) and 69 girls (35%)}, with a mean age of 72.08 (±50.96) months, completed the study. The sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio of the modified epilepsy tool were 91.5% (84.5–96.1), 88.6% (80.0–93.5), 89.7% (81.9–95.3), 90.8% (83.7–95.7), 8 (6.6–9.8) and 0.09 (0.07–0.12) respectively. Significance: The new modified diagnostic instruments for epilepsy is simple, structured and valid instruments covering 1month to 18 years for use in resource limited settings with acceptable diagnostic accuracy. All seizure semiologies as well as common seizure mimics like breath-holding spells are included in the tool. It also provides for identification of acute symptomatic and febrile seizures

Development of All India Institute of Medical Sciences-Modified International Clinical Epidemiology Network Diagnostic Instrument for Neuromotor Impairments in Children Aged 1 Month to 18 Years

IntroductionThere is shortage of specialists for the diagnosis of children with neuromotor impairments (NMIs), especially in resource limited settings. Existing International Clinical Epidemiology Network (INCLEN) instrument for diagnosing NMI have been validated for children aged 2–9 years. The current study modified the same including wider symptomatology and age group (1 month to 18 years).MethodsThe Modified INCLEN diagnostic tool (INDT) was developed by a team of experts by modifying the existing tool to widen the age range (1 month to 18 years) and include broader symptomatology (inclusion of milestones from the first 2 years of life and better elucidation of cerebellar and extrapyramidal features) in a tertiary care teaching hospital of North India between January and April 2015. A trained medical graduate applied the candidate tool, which was followed by gold standard evaluation by a Pediatric Neurologist (both blinded to each other).ResultsA total of 197 children (102 with NMI and 95 without NMI) were enrolled for the study. The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratio of the modified NMI tool were 90.4% (82.6–95.5), 95.5% (88.7–98.7), 95.5% (88.9–98.7), 90.3% (82.4–95.5), 19.9 (12.1–32.6), and 0.13 (0.08–0.12), respectively.ConclusionThe All India Institute of Medical Sciences modified INDT NMI tool is a simple and structured instrument covering a wider symptomatology in the 1 month to 18 years age group with acceptable diagnostic accuracy

Long-term efficacy of T3 analogue Triac in children and adults with MCT8 deficiency: a real-life retrospective cohort study

Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. Our previous trial showed improvement of key clinical and biochemical features during one year of treatment with the T3-analogue Triac. Long-term follow-up data are lacking

Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study

CONTEXT: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. OBJECTIVE: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. METHODS: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. RESULTS: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. CONCLUSIONS: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Abstract Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.</jats:p