Progression of corticospinal tract dysfunction in pre-ataxic spinocerebellar ataxia type 2: A two-years follow-up TMS study

Objective

Corticospinal tract (CST) dysfunction is common in the pre-ataxic stage of spinocerebellar ataxia type 2 (SCA2) but quantitative assessment of its progression over time has not been explored. The aim of this study was to quantify the progression of CST dysfunction in pre-ataxic SCA2 using transcranial magnetic stimulation (TMS).

Early corticospinal tract damage in prodromal SCA2 revealed by EEG-EMG and EMG-EMG coherence

Objective

Clinical data suggest early involvement of the corticospinal tract (CST) in spinocerebellar ataxia type 2 (SCA2). Here we tested if early CST degeneration can be detected in prodromal SCA2 mutation carriers by electrophysiological markers of CST integrity.

Cramps frequency and severity are correlated with small and large nerve fiber measures in type 1 diabetes

Objectives

To explore the correlations between different muscle cramp characteristics including cramp frequency and severity and clinical and large and small nerve fiber measures in patients with diabetes type 1 (DM 1) and 2 (DM 2).

A novel compound heterozygous mutation of the <Emphasis Type="Italic">L2HGDH</Emphasis> gene in a Chinese boy with L-2-hydroxyglutaric aciduria: case report and literature review

Objective

L-2-hydroxyglutaric aciduria is a genetic metabolic disorder. Its clinical features include elevated levels of hydroxyglutaric acid in body fluids and abnormal magnetic resonance imaging (MRI) in the subcortical white matter, which are affected by the accumulation of L-2-hydroxyglutaric acid.

Method

A boy with psychomotor retardation and progressive ataxia accompanied by abnormal brain MRI findings was tested using whole-exome sequencing.

Results

Next-generation sequencing (NGS) revealed two novel compound heterozygous frameshift mutations, c.407 del A (p.K136SfsTer3) and c.699_c700 ins A (p.D234RfsTer42), in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene, leading to premature termination codons and truncated FAD/NAD(P)-binding domain of L2HGDH protein. Further laboratory testing revealed an increase in the 2-hydroxyglutaric acid level in the urine.

Conclusion

The results suggested that NGS could provide clues for identifying patients with abnormal neuroradiological findings in the subcortical white matter.

     

Increased PLA2 activity in the hippocampus of patients with temporal lobe epilepsy and psychosis

Objective

The aim of this work was to investigate whether increased activity of the enzyme phospholipase A₂ (PLA₂) in the brain, as frequently reported in schizophrenia, is also related to psychosis in epilepsy. Our working hypothesis was based on the increased prevalence of schizophrenia-like psychosis in patients with temporal lobe epilepsy (TLE) secondary to mesial temporal sclerosis (MTS), as compared to patients with other forms of epilepsy.

Methods

We determined PLA₂ activity in hippocampal tissue from 7 patients with TLE-MTS and psychosis, as compared to 9 TLE-MTS patients without psychosis. Hippocampal tissue was obtained from patients who underwent an anterior temporal lobectomy due to therapy-resistant epilepsy.

Results

We found that patients with TLE-MTS and psychosis had a significantly increased calcium-independent PLA₂ activity as compared to patients without psychosis (p = 0.016).

Conclusion

Our finding suggest that an increment in brain PLA₂ activity is not specific for schizophrenia, but rather may be associated to the manifestation of schizophrenia-like psychotic symptoms in general.     

Heart-rate response to alpha<Subscript>2</Subscript>-adrenergic receptor antagonism by antipsychotics

Purpose

To explore the relationship between antipsychotic-associated antagonism of alpha₂-adrenergic receptors and resting heart rate in individuals with schizophrenia.

Methods

Thirty-one inpatients treated with antipsychotics were included in this exploratory analysis. Antipsychotic doses were converted to haloperidol equivalents for alpha₂-adrenergic receptor antagonism. Resting heart rate was measured with the patient in the seated upright posture.

Results

After controlling for confounding variables, the relationship between alpha₂-adrenergic receptor antagonism and resting heart rate demonstrated a positive linear effect (P = 0.002) as well as a nonlinear effect that accounted for an additional 14% of the variability in resting heart rate (P = 0.005).

Conclusion

The observed inverted-U relationship between alpha₂-adrenergic receptor antagonism and resting heart rate can possibly be attributed to an altered response of beta₁-adrenergic receptors to increased norepinephrine release. Further investigations are required to confirm this exploratory finding, taking into account additional variables that include other receptors which either directly or indirectly influence heart rate.

ClinicalTrials.gov Identifier

NCT01392885.

     

GRK2-Targeted Knockdown as Therapy for Multiple System Atrophy

Background

Multiple system atrophy (MSA) is a sporadic adult-onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G-protein-(heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling.

Objectives

We tested whether lowering brain GRK2 abundance may reverse insulin-resistance.

Methods

We lowered brain GRK2 abundance through viral-mediated delivery of a GRK2-specific miRNA and quantified the reversion of a developing or an established insulin-resistant phenotype using the transgenic PLP-SYN mouse model of MSA.

Results

Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP-SYN mice and (2) intrastriatally in adult PLP-SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high-molecular-weight species of α-synuclein, and reduced insulin resistance.

Conclusions

These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

The Effect of Cigarette Smoking on Chemosensory Perceptionof Common Beverages

Introduction

This study aimed to determine whether a smoking restriction prior to sensory evaluation affects sensory perception and liking of beverages that represent sweetness (sweetened cocoa), saltiness (vegetable juice), sourness (orange juice), and bitterness (black coffee).

Methods

Smokers were asked to either abstain from smoking for 2 h or to smoke a cigarette 5 min prior to sensory evaluation of beverages. As a control, non-smokers participated in this study.

Results

Smokers who smoked 5 min prior to tasting beverages rated black coffee as significantly more bitter than did those who either abstained from smoking for 2 h or non-smokers. No effect of cigarette smoking was found either in intensity of other taste qualities and flavor or in the liking of the four types of beverages.

Conclusion

This study provides empirical evidence that cigarette smokers should abstain from smoking for 2 h prior to sensory evaluation of bitter-tasting beverages such as black coffee.

     

Evidence for a relatively high proportion of DM2 mutations in a large group of Polish patients

Introduction

Myotonic dystrophies (DMs) type 1 (DM1) and type 2 (DM2) are autosomal dominant, multisystem disorders, considered the most common dystrophies in adults. DM1 and DM2 are caused by dynamic mutations in the DMPK and CNBP genes, respectively.

Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder

Background

Heterozygous NKX2-1 loss-of-function variants cause combinations of hyperkinetic movement disorders (MDs, particularly childhood-onset chorea), pulmonary dysfunction, and hypothyroidism. Mobile element insertions (MEIs) are potential disease-causing structural variants whose detection in routine diagnostics remains challenging.

Objective

To establish the molecular diagnosis of two first-degree relatives with clinically suspected NKX2-1-related disorder who had negative NKX2-1 Sanger (SS), whole-exome (WES), and whole-genome (WGS) sequencing.

Methods

The proband's WES was analyzed for MEIs. A candidate MEI in NKX2-1 underwent optimized SS after plasmid cloning. Functional studies exploring NKX2-1 haploinsufficiency at RNA and protein levels were performed.

Results

A 347-bp AluYa5 insertion with a 65-bp poly-A tail followed by a 16-bp duplication of the pre-insertion wild-type sequence in exon 3 of NKX2-1 (ENST00000354822.7:c.556_557insAlu541_556dup) segregated with the disease phenotype.

Conclusions

We identified a de novo exonic AluYa5 insertion causing NKX2-1-related disorder in SS/WES/WGS-negative cases, suggesting that MEI analysis of short-read sequencing data or targeted long-read sequencing could unmask the molecular diagnosis of unsolved MD cases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Beta2-adrenoceptor stimulation has no effect on skeletal muscle glucose uptake

Introduction

Blockade of the β-adrenergic receptor induces insulin resistance and chronic β-adrenoceptor stimulation improves insulin sensitivity in animals. We tested whether acute β₂-adrenoceptor stimulation increased insulin-induced glucose uptake in human forearm skeletal muscle.

Materials and Methods

During a hyperinsulinemic euglycemic clamp procedure, forearm glucose uptake was calculated by multiplying the arteriovenous glucose gradient and forearm blood flow before and during local infusion of the β₂-adrenoceptor salbutamol into the brachial artery.

Conclusions

β₂-adrenergic stimulation had no effect on insulin-stimulated glucose uptake in human forearm skeletal muscle.     

Urinary prostaglandin metabolites as Duchenne muscular dystrophy progression markers

Background

Patients with Duchenne muscular dystrophy (DMD) exhibit increased prostaglandin D₂ (PGD₂) expression in necrotic muscle and increased PGD₂ metabolites in their urine. In mouse models, inhibiting PGD₂ production suppresses muscle necrosis, suggesting a possible intervention through PGD₂-mediated activities.

Depressive symptoms in relation to physical functioning in pulmonary hypertension

Objective

To investigate the association between depressive symptoms and physical functioning in pulmonary hypertension (PH) patients.

Methods

Fifty-two patients diagnosed with precapillary or postcapillary PH completed self-report questionnaires of depressive symptoms and physical functioning. Cardiac catheterization reports of patients were reviewed for hemodynamic variables.

Results

Physical functioning was significantly associated with depressive symptoms on bivariate analysis. On multivariate analysis, after controlling for demographic and hemodynamic variables, depressive symptoms accounted for 9% of variance in physical functioning.

Conclusion

The association of depressive symptoms with decreased physical functioning in PH patients indicates the need for longitudinal research regarding the possible effect of depression on disease outcomes in this population.     

Personality subtypes in patients with panic disorder

Objective

This study examined personality subtypes of adults diagnosed with panic disorder (PD).

Methods

As part of a National Institute of Mental Health-funded study on personality in a clinical population, randomly selected psychologists and psychiatrists used a Q-sort instrument to describe 96 adults diagnosed with PD.

Results

Q-factor analysis yielded 4 personality subtypes: high functioning, emotionally dysregulated, inhibited/avoidant, and somatizing. Within the sample, the subtypes differed on Axis I and II pathology, adaptive functioning, and developmental and family history variables. Personality constellations in the sample showed substantial incremental validity in predicting adaptive functioning and treatment response above and beyond the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I diagnoses.

Conclusions

These distinctions may elucidate the high rates of comorbidity among patients with PD and are important in understanding treatment choice and outcome.     

Clinical and Pathological Features of Korean Patients with DNM2-Related Centronuclear Myopathy

Background and Purpose

Centronuclear myopathy (CNM) is characterized by the presence of central nuclei within a large number of muscle fibers. Mutations of the dynamin 2 gene (DNM2) are common causes of autosomal dominant or sporadic CNM. The aim of this study was to characterize the clinical and pathological features of CNM relative to the presence of DNM2 mutations.

Methods

Six patients with clinical and pathological features of CNM were recruited. Detailed clinical and pathological findings were analyzed according to the presence of DNM2 mutations.

Results

We detected DNM2 mutations in four of the six sporadic CNM patients, and identified the following distinct clinical and pathological features in those patients with DNM2 mutations: preferential involvement of the distal lower limbs, typical nuclear centralization, and radially distributed sarcoplasmic strands in muscle pathology. In contrast, those without DNM2 mutations exhibited rather diffuse muscular involvement, and nuclear internalization and myofibrillar disorganization were more pronounced features of their muscle pathology.

Conclusions

These findings suggest the presence of specific features in Korean CNM patients. A detailed clinical and pathological examination of CNM patients would be helpful for molecular genetic analyses of this condition.     

Contact heat evoked potentials: Reliable acquisition from lower extremities

Objective

To investigate test-retest reliability of contact heat evoked potentials (CHEPs) from lower extremities using two different stimulation protocols, i.e., normal and increased baseline temperature.

MEF2C mRNA expression and cognitive function in Japanese patients with Alzheimer's disease

Aim

Despite continuing research into Alzheimer's disease (AD), its pathological mechanisms and modulating factors remain unknown. Several genes influence AD pathogenesis by affecting inflammatory pathways. Myocyte‐enhancer factor 2C (MEF2C) is one such candidate gene for AD.

Methods

We examined MEF2C mRNA expression levels and methylation rates of CpG on its promoter region in peripheral leukocytes from Japanese AD patients compared with age‐ and sex‐matched control subjects.

Results

In peripheral leukocytes, MEF2C mRNA expression levels in AD subjects were significantly lower than those in control subjects (0.86 ± 0.25 vs 0.99 ± 0.27, respectively, P = 0.007) and were correlated with the Alzheimer's Disease Assessment Scale (r = ?0.345, P = 0.049) and the Mini Mental State Examination (r = 0.324, P = 0.02). No significant differences were found in methylation rates between AD and control subjects.

Conclusion

MEF2C mRNA expression in leukocytes may be a biological marker for cognitive decline in AD.

     

Increased expression of Akt2 and activity of PI3K and cell proliferation with the ascending of tumor grade of human gliomas

Objective

To study the expression of Akt2 and activation of PI3K in different grades of human gliomas and correlate the Akt2 expression with the proliferation activity of gliomas.

Methods

Akt2 expression and PI3K activity were examined in 48 different grades of human glioma specimens and six normal brain tissue samples by immunohistochemistry and Western blot analysis. The proliferation activity of tumors was evaluated by Ki-67 nuclear antigen labeling index (Ki-67 LI) using immunostaining.

Results

In contrast to the normal brain tissues, Akt2 expression and PI3K activity were greatly increased with the ascending of tumor grade and correlated positively with the proliferation activity of gliomas.

Conclusion

Akt2 may play a critical role in the development of gliomas and present a potential therapeutic target for malignant gliomas.     

Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation

Introduction

TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial.

Laser-evoked potentials in painful radiculopathy

Objective

The aims of this exploratory study were (1) to develop a standardized objective electrophysiological technique with laser-evoked potentials to assess dorsal root damage quantitatively and (2) to correlate these LEP measures with clinical parameters and sensory abnormalities (QST) in the affected dermatome.