A review: Management of motor neuron diseases

Motor neuron diseases are a group of chronic sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons. These might affect the upper motor neurons, lower motor neurons, or both. The prognosis of the motor neuron disease depends upon the age at onset and the area of the central nervous system affected. Amyotrophic lateral sclerosis (ALS) has been documented to be fatal within three years of onset. This activity focuses on amyotrophic lateral sclerosis as the prototype of MND, which affects both the upper and the lower motor neurons and discusses the role of inter-professional team in the differential diagnosis, evaluation, treatment, and prognostication. It also discusses various other phenotypes of MND with an emphasis on their distinguishing features in requisite detail.

Mosaic deletions in X-linked dystonia-parkinsonism influence repeat stability and disease onset

Background: While multiple genetic causes of movement disorders have been identified in the past decade, modifying factors of disease expression are still largely unknown for most conditions. X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative disease caused by a SINE-VNTR-Alu (SVA)-type retrotransposon insertion that contains a hexanucleotide repeat within an intron of the TAF1 gene. To date, four putative genetic modifiers explain about 65% of variance in age at onset in XDP. However, additional genetic modifiers are conceivably at play in XDP and may include mismatches of the SVA hexanucleotide repeat motif. We aim to identify additional genetic modifiers of XDP expressivity and age at onset (AAO). Methods: Third-generation sequencing of PCR amplicons from XDP patients (n=202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment were used to confirm the presence of identified repeat mismatches. Results: An increased frequency of deletions at the beginning of the hexanucleotide repeat (CCCTCT)n domain was found. Specifically, three deletions at positions 11, 14, and 17 of the TAF1 SVA repeat motif of somatic mosaic origins were detected in different combinations. The most common one was three deletions (1-2-3) at a median frequency 0.425 (IQR:0.42-0.43) and deletions within positions 11 and 14 (1-2-wt) at a median frequency 0.128 (IQR:0.12-0.13). The frequency of deletions at positions 11 and 14 correlated with repeat number (r=-0.48, p=9.5x10-13) and AAO (r=0.34, p=9.5x10-7). The association with AAO still stands when including other modifier genotypes (MSH3 and PMS2) in a regression model. However, the association dissipates when including repeat numbers. Conclusion: We present a novel mosaic repeat motif deletion within the hexanucleotide repeat (CCCTCT)n domain of TAF1 SVA. Our study illustrates: 1) the importance of somatic mosaic genotypes; 2) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; 3) that these variations may remain undetected without assessment of single molecules.

Altered Taste Function in Young Individuals With Type 1 Diabetes

Past studies on altered taste function in individuals with type 1 diabetes have yielded inconsistent results. We therefore evaluated taste recognition and possible association with personal and diseases characteristics in young individuals with type 1 diabetes and healthy controls. Taste recognition and intensity for 6-n-propylthiouracil (PROP), quinine, citric acid, sucrose, and sodium chloride were assessed using a filter paper method in 276 participants with type 1 diabetes and 147 healthy controls. Personal and clinical data were recorded for all participants during a baseline visit. Regression analysis was adjusted for sex, age, and standardized BMI. Overall, 47% of participants with type 1 diabetes vs. 63.5% of healthy controls recognized all tastes (p = 0.006). Moreover, a lower capacity for recognizing the bitter taste of PROP and the sour taste of citric acid was found in participants with type 1 diabetes compared to healthy controls (p = 0.014 and p = 0.003, respectively). While no significant effect of glycemic control on taste recognition was found, an association with lower age at onset emerged. Our findings suggest an impaired taste perception in individuals with type 1 diabetes, possibly linked to age at onset.

Impact of age at onset on symptom profiles, treatment characteristics and health-related quality of life in Parkinson’s disease

Parkinson’s disease (PD) is typically considered an age-related disease, but the age at disease onset can vary by decades between patients. Aging and aging-associated diseases can affect the movement system independently of PD, and advanced age has previously been proposed to be associated with a more severe PD phenotype with accelerated progression. In this work, we investigated how interactions between PD progression and aging affect a wide range of outcomes related to PD motor and nonmotor symptoms as well as Health Related Quality of Life (HRQoL) and treatment characteristics. This population-based cohort study is based on 1436 PD patients from southern Sweden followed longitudinally for up to approximately 7.5 years from enrollment (3470 visits covering 2285 patient years, average follow-up time 1.7 years). Higher age at onset was generally associated with faster progression of motor symptoms, with a notable exception of dyskinesia and other levodopa-associated motor fluctuations that had less severe trajectories for patients with higher age at onset. Mixed results were observed for emergence of non-motor symptoms, while higher age at onset was generally associated with worse HRQoL trajectories. Accounting for these identified age-associated differences in disease progression could positively impact patient management and drug development efforts.

Individual Brain Metabolic Connectome Indicator Based on Jensen-Shannon Divergence Similarity Estimation Predicts Seizure Outcomes of Temporal Lobe Epilepsy

Objective: We aimed to use an individual metabolic connectome method, the Jensen-Shannon Divergence Similarity Estimation (JSSE), to characterize the aberrant connectivity patterns and topological alterations of the individual-level brain metabolic connectome and predict the long-term surgical outcomes in temporal lobe epilepsy (TLE).Methods: A total of 128 patients with TLE (63 females, 65 males; 25.07 ± 12.01 years) who underwent Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) imaging were enrolled. Patients were classified either as experiencing seizure recurrence (SZR) or seizure free (SZF) at least 1 year after surgery. Each individual’s metabolic brain network was ascertained using the proposed JSSE method. We compared the similarity and difference in the JSSE network and its topological measurements between the two groups. The two groups were then classified by combining the information from connection and topological metrics, which was conducted by the multiple kernel support vector machine. The validation was performed using the nested leave-one-out cross-validation strategy to confirm the performance of the methods.Results: With a median follow-up of 33 months, 50% of patients achieved SZF. No relevant differences in clinical features were found between the two groups except age at onset. The proposed JSSE method showed marked degree reductions in IFGoperc.R, ROL. R, IPL. R, and SMG. R; and betweenness reductions in ORBsup.R and IOG. R; meanwhile, it found increases in the degree analysis of CAL. L and PCL. L, and in the betweenness analysis of PreCG.R, IOG. R, PoCG.R, PCL. L and PCL.R. Exploring consensus significant metabolic connections, we observed that the most involved metabolic motor networks were the INS-TPOmid.L, MTG. R-SMG. R, and MTG. R-IPL.R pathways between the two groups, and yielded another detailed individual pathological connectivity in the PHG. R-CAU.L, PHG. R-HIP.L, TPOmid.L-LING.R, TPOmid.L-DCG.R, MOG. R-MTG.R, MOG. R-ANG.R, and IPL. R-IFGoperc.L pathways. These aberrant functional network measures exhibited ideal classification performance in predicting SZF individuals from SZR ones at a sensitivity of 75.00%, a specificity of 92.79%, and an accuracy of 83.59%.Conclusion: The JSSE method indicator can identify abnormal brain networks in predicting an individual’s long-term surgical outcome of TLE, thus potentially constituting a clinically applicable imaging biomarker. The results highlight the biological meaning of the estimated individual brain metabolic connectome.

Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?

Medulloblastoma is a rare malignancy of the posterior cranial fossa. Although until now considered a single disease, according to the current WHO classification, it is a heterogeneous tumor that comprises multiple molecularly defined subgroups, with distinct gene expression profiles, pathogenetic driver alterations, clinical behaviors and age at onset. Adult medulloblastoma, in particular, is considered a rarer “orphan” entity in neuro-oncology practice because while treatments have progressively evolved for the pediatric population, no practice-changing prospective, randomized clinical trials have been performed in adults. In this scenario, the toughest challenge is to transfer the advances in cancer genomics into new molecularly targeted therapeutics, to improve the prognosis of this neoplasm and the treatment-related toxicities. Herein, we focus on the recent advances in targeted therapy of medulloblastoma based on the new and deeper knowledge of disease biology.

Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer’s disease

Purpose Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [18F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD. Methods Seventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n = 35, age-at-PET = 59 ± 5, MMSE = 23 ± 4; LOAD: n = 44, age-at-PET = 71 ± 5, MMSE = 23 ± 4) underwent a 130-min dynamic [18F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BPND) and R1 (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital, and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language, and executive functioning. We first examined differences between EOAD and LOAD in BPND or R1 using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BPND/R1 on cognition. Results Both region-of-interest and voxel-wise contrasts showed higher [18F]flortaucipir BPND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R1 values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipitoparietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BPND − 0.76 ≤ stβ ≤ − 0.48 vs LOAD − 0.18 ≤ stβ ≤ − 0.02; EOAD R1 0.37 ≤ stβ ≤ 0.84 vs LOAD − 0.25 ≤ stβ ≤ 0.16). Conclusions Compared to LOAD, the degree of lateral temporal and occipitoparietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.

Food allergy in early childhood increases the risk of pollen-food allergy syndrome

Background: The level of pollen in Korea has increased over recent decades. Research suggests that pollen-food allergy syndrome (PFAS) may be more frequent in childhood than previously recognized. We aimed to investigate the prevalence and characteristics of PFAS in children aged 6–10 years from a general population-based birth cohort. Methods: We analyzed 930 children from the COhort for Childhood Origin of Asthma and allergic diseases (COCOA) birth cohort. Allergic diseases were diagnosed annually by pediatric allergists. The skin prick tests were performed with 14 common inhalant allergens and four food allergens for children aged 3 and 7 years. Results: Of the 930 eligible children, 44 (4.7%) aged 6–10 years were diagnosed with. The mean age at onset was 6.74 years. PFAS prevalence was 7.2% among children with allergic rhinitis (AR) and 19.1% among those with pollinosis, depending on comorbidity. PFAS was more prevalent in schoolchildren with atopic dermatitis, food allergy, and sensitization to food allergens and grass pollen in early childhood. In schoolchildren with AR, only a history of food allergy before 3 years increased the risk of PFAS (aOR 2.971, 95% CI: 1.159–7.615). Conclusion: Food allergy and food sensitization in early childhood was associated with PFAS in schoolchildren with AR. Further study is required to elucidate the mechanism by which food allergy in early childhood affects the development of PFAS.

Structural Lesions on Kidney Biopsy in Youth-Onset and Adult-Onset Type 2 Diabetes

OBJECTIVE Type 2 diabetes (T2D) is a leading cause of end-stage kidney disease worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease in youth-onset compared with adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth onset was associated with greater early tissue injury. RESEARCH DESIGN AND METHODS Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing, and participants were stratified as youth onset (age <25 years) or adult onset (age ≥25 years). Associations between clinical and morphometric parameters and age at onset were tested using linear models. RESULTS At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1 ± 9.9 vs. 51.4 ± 10.2 years; P < 0.0001), but their diabetes duration was similar (19.3 ± 8.1 vs. 17.0 ± 7.8 years; P = 0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25th–75th percentile 17–470] vs. 27 [13–73] mg/g; P = 0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552 ± 128 vs. 490 ± 114 nm; P = 0.002) and mesangial fractional volume (0.31 ± 0.10 vs. 0.27 ± 0.08; P = 0.001) than adult-onset participants. Glomerular sclerosis percentage, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age at diabetes onset as a continuous variable. CONCLUSIONS Younger age at T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.

Spectrum of Neurological Symptoms in Glycosylphosphatidylinositol Biosynthesis Defects: Systematic Review

Background: Mutations of genes involved in the synthesis of glycosylphosphatidylinositol and glycosylphosphatidylinositol-anchored proteins lead to rare syndromes called glycosylphosphatidylinositol-anchored proteins biosynthesis defects. Alterations of their structure and function in these disorders impair often fundamental processes in cells, resulting in severe clinical image. This study aimed to provide a systematic review of GPIBD cases reports published in English-language literature.Methods: The browsing of open-access databases (PubMed, PubMed Central. and Medline) was conducted, followed by statistical analysis of gathered information concerning neurological symptomatology. The inclusion criteria were: studies on humans, age at onset (<18 y.o.), and report of GPIBD cases with adequate data on the genetic background and symptomatology. Exclusion criteria were: publication type (manuscripts, personal communication, review articles); reports of cases of GPI biosynthesis genes mutations in terms of other disorders; reports of GPIBD cases concentrating on non-neurological symptoms; or articles concentrating solely on the genetic issues of GPI biosynthesis. Risk of bias was assessed using Joanna Brigs Institute Critical Appraisal Checklists. Data synthesis was conducted using STATISTICA 13.3.721.1 (StatSoft Polska Sp. z.o.o.). Used tests were chi-square, Fisher's exact test (for differences in phenotype), and Mann-Whitney U test (for differences in onset of developmental delay).Results: Browsing returned a total of 973 articles which, after ruling out the repetitions and assessing the inclusion and exclusion criteria, led to final inclusion of 77 articles (337 GPIBD cases) in the analysis. The main outcomes were prevalence of neurological symptoms, onset and semiology of seizures and their response to treatment, and onset of developmental delay. Based on this data a synthesis of phenotypical differences between the groups of GPIBD cases and the general GPIBD cases population was made.Discussion: A synthetical analysis of neurological components in clinical image of GPIBD patients was presented. It highlights the main features of these disorders, which might be useful in clinical practice for consideration in differential diagnosis with children presenting with early-onset seizures and developmental delay. The limitation of this review is the scarcity of the specific data in some reports, concerning the semiology and onset of two main features of GPIBD.