Randomized Controlled Trial to Evaluate the Efficacy of Intrathecal Dexmedetomidine to Low dose hyperbaric 0.5% Bupivacaine in Elective Lower Segment Caesarean Section

Introduction: Dexmedetomidine has been safely used as an adjuvant for subarachnoid block in obstetric as well as non-obstetric surgeries and was found to be effective without adverse effects. Hence, this study was conducted to determine the efficacy of intrathecal Dexmedetomidine for elective lower segment caesarean sections with reduction of local anesthetic dose. Objectives: This double blinded, randomized controlled study was designed to compare the effects of addition of Dexmedetomidine on 1) Sensory and motor block 2) Maternal hemodynamics 3) Post-operative analgesia and 4) Neonatal outcome. Methods: Eighty parturients were enrolled in study and randomized into two groups as of 40 each and named as Group D and Group B. Group D received 0.5% Hyperbaric Bupivacaine 9mg (1.8ml) + Dexmedetomidine 5µg (0.2ml of 25 µg per ml ) and for Group B received 0.5% Hyperbaric Bupivacaine 10mg (2ml) . Characteristics of block, maternal hemodynamics and neonatal outcome were recorded. P value <0.05 was considered as significant. Results: Sensory onset was rapid in D group as compared to B group (3.7 ± 1.1vs 4.5±1.2) and motor onset was also rapid in D group (3.8±2.0 vs 4.9 ±1.9) with 95% CI. Duration of analgesia was also significantly high in Group D (230.5±40.5 vs 145.1±28.5). No adverse maternal and fetal outcomes were reported. Conclusion: Intrathecal Dexmedetomidine with low dose bupivacaine for cesarean section hastens the sensory as well as motor onset without adversely affecting mother and neonate.

Genetic factors affecting dopaminergic deterioration during the premotor stage of Parkinson disease

To estimate dopaminergic dysfunction in patients with Parkinson disease (PD) during the premotor stage and to investigate the effect of genetic factors on the trajectories. Using longitudinal dopamine transporter single-photon emission computed tomography data from 367 sporadic PD (sPD), 72 LRRK2 (G2019S), and 39 GBA (N370S) PD patients in the Parkinson’s Progression Markers Initiative (PPMI) study, we estimated the temporal trajectories of putaminal-specific binding ratios using an integrating function between baseline values and their annual change rates. In order to test reproducibility, we computed another trajectory for sPD using positron emission tomography data of 38 sPD patients at Gangnam Severance Hospital (GSH). Temporal trajectories of sPD were compared between the groups separated by age at onset (AAO) and polygenic load for common PD risk variants, and also compared with genetic PD. sPD patients in both the PPMI and GSH cohorts showed similar onset of dopaminergic degeneration around 10 years before motor onset. Early-onset PD patients exhibited later onset of degeneration and a faster decline in dopaminergic activity during the premotor period than late-onset patients. sPD patients with high polygenic load were associated with earlier onset and slower progression of dopaminergic dysfunction. Compared to the sPD and LRRK2 PD groups, GBA PD patients exhibited faster deterioration of dopaminergic function during the premotor stage. Dopaminergic dysfunction in PD appears to start about 10 years before motor onset. Genetic factors may be contributing to the heterogeneity of dopaminergic deterioration during the premotor stage.

Quantifying the Onset of Unintended Weight Loss in Huntington’s Disease: A Retrospective Analysis of Enroll-HD

Background: Unintended weight loss and decreased body mass indexes (BMIs) are common symptoms of individuals with manifest HD. It is unknown at what point during disease progression weight loss starts to accelerate relative to a healthy individual’s weight and when recommended interventions should be initiated to have the strongest impact on patient care. Objective: The objective of this study was to identify a point in time relative to age at motor onset when the decline in weight in HD starts to accelerate relative to a non-HD population. The relationship between initiation of weight loss interventions and changes in weight loss was also explored. Methods: Participants from the fifth version of the Enroll-HD study were identified for this research. Linear mixed-effects piecewise regression models were used to estimate the point in time relative to the reported age of motor onset in which BMI started to decline in participants with HD compared to healthy non-HD controls. A post-hoc descriptive analysis was performed to look at when nutritional supplements and swallow therapy were initiated in participants with HD relative to motor onset. Results: BMI decline in the HD group began to accelerate compared to controls approximately 5.7 years after the reported age of motor onset (95% CI: 4.7–6.9). The average initiation times of swallow therapy and nutritional supplements were 7.7 years (SD = 5.5 years) and 6.7 years (SD = 6.5 years) after motor onset, respectively. Conclusion: Our findings suggest a potential point for intervention of nutrition programs or therapies used to prevent future weight loss.

Pure Motor Onset and IgM-Gammopathy Occurrence in Multifocal Acquired Demyelinating Sensory and Motor Neuropathy

Objectives:To longitudinally investigate patients with multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, quantifying timing and location of sensory involvements in motor-onset patients, along with clinico-histopathological and electrophysiological findings to ascertain differences in patients with and without monoclonal gammopathy of uncertain significance (MGUS).Methods:Patients with MADSAM neuropathy seen at Mayo Clinic and tested for monoclonal gammopathy and ganglioside antibodies, were retrospectively reviewed (January 1st, 2007-December 31st, 2018).Results:Of 76 patients with MADSAM, 53% had pure motor, 16% pure sensory, 30% sensorimotor and 1% cranial nerve onsets. Motor-onset patients were initially diagnosed as multifocal motor neuropathy (MMN). MGUS occurred in 25% (89% IgM subtype), associating with ganglioside autoantibodies (p<0.001) and higher IgM titers (p<0.04). Median time to sensory involvements (confirmed by electrophysiology) in motor-onset patients was 18 months (range: 6-180). Compared to initial motor nerve involvements, subsequent sensory findings were within the same territory 35% (14/40), outside 20% (8/40), or both 45% (18/40). Brachial and lumbosacral plexus MRI was abnormal in 87% (34/39) and 84% (21/25), respectively, identifying hypertrophy and increased T2 signal predominantly in brachial plexus trunks (64%), divisions (69%), and cords (69%), and intrapelvic sciatic (64%) and femoral (44%) nerves. Proximal fascicular nerve biopsies (n=9) more frequently demonstrated onion-bulb pathology (p=0.001) and endoneurial inflammation (p=0.01) than distal biopsies (n=17). MRI and biopsy findings were similar amongst patient subgroups. Initial Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores were higher in patients with MGUS relative to without (p=0.02). Long-term treatment responsiveness by INCAT score reduction ≥1 or motor Neuropathy Impairment Score (mNIS) >8 point reduction occurred in 75% (49/65) irrespective of MGUS or motor-onsets. Most required ongoing immunotherapy (86%). Patients with MGUS more commonly required dual-agent immunotherapy for stability (p=0.02).Discussion:Pure motor-onsets are the most common MADSAM presentation. Long-term follow-up, repeat electrophysiology and nerve pathology help distinguish motor-onset MADSAM from MMN. Better long-term immunotherapy responsiveness occurs in motor-onset MADSAM compared to MMN reports. Patients having MGUS commonly require dual immunotherapy.Classification of Evidence:This study provides Class II evidence that most clinical, electrophysiological, and histopathological findings were similar between patients with MADSAM with and without monoclonal gammopathy of unknown significance.

Huntington's disease age at motor onset is modified by the tandem hexamer repeat in TCERG1

Background: Huntington's disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington's disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. Methods: We developed a novel method for calling perfect and imperfect repeats from exome sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington's disease via regression analysis. Results: We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1x10-9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. Conclusions: The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.

Cohort Study in Parkinsonism: Delayed Transit, Accelerated Gastric Emptying, and Prodromal Dysmotility

ABSTRACTObjectives:To evaluate gastric emptying and colonic transit in a cohort of patients with Parkinson disease and other parkinsonism disorders, and to determine whether abnormal gut transit precedes motor-onset of parkinsonism.Methods:Medical record review of 84 patients with parkinsonism who underwent clinically-indicated transit studies at Mayo Clinic (2001-2019); and 11 patients with transit studies who subsequently developed parkinsonism. Data are summarized as median (IQR).Results:The 84 patients (52% female) with parkinsonism were aged 72 (66, 76) years with a disease duration of 5 (2, 8) years: Parkinson disease=70, multiple system atrophy=7, dementia with Lewy bodies=4, progressive supranuclear palsy=2, parkinsonian syndrome=1. Ten had delayed GE, 10 slow colonic transit, 16 accelerated GE (14 Parkinson disease, 1 multiple system atrophy, 1 parkinsonian syndrome), and 49 normal transit. One parkinsonian syndrome patient had both slow colonic and accelerated gastric transit. Longer disease duration and higher levodopa equivalent daily dose were observed for Parkinson disease compared to other parkinsonisms and with slow compared to normal colonic transit. Of 11 patients (5 female) with transit studies who later developed motor parkinsonism after 4 (3, 5) years: 1 had accelerated GE, 1 had delayed GE, and 1 had both delayed GE and colonic transit.Conclusions:Accelerated GE was newly identified in patients with parkinsonism, in addition to delayed GE or colonic transit. Furthermore, gut dysmotility was objectively identified to precede the motor-onset of parkinsonism.

Functional evolution of visual involvement in experimental autoimmune encephalomyelitis

Background Experimental autoimmune encephalomyelitis (EAE) is a common animal model of multiple sclerosis (MS). C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein exhibit chronic disease course, together with optic neuritis, consisting of demyelination/axonal loss of the optic nerve. Objectives To characterize functional and structural visual damages in two different phases of EAE: pre- and post-motor onset. Methods Visual alterations were detected with Visual Evoked Potential (VEP), Electroretinogram (ERG) and Optical Coherence Tomography (OCT). Optic nerve histology was performed at 7 (pre-motor onset) or 37 (post-motor onset) days post-immunization (dpi). Results At 7 dpi, optic nerve inflammation was similar in EAE eyes with and without VEP latency delay. Demyelination was detected in EAE eyes with latency delay (p < 0.0001), while axonal loss (p < 0.0001) and ERG b-wave amplitude (p = 0.004) were decreased in EAE eyes without latency delay compared to Healthy controls. At 37 dpi, functional and structural optic nerve damage were comparable between EAE groups, while a decrease of ERG amplitude and NGCC thickness were found in EAE eyes with VEP latency delay detected post-motor onset. Conclusions Thanks to non-invasive methods, we studied the visual system in a MS model, which could be useful for developing specific therapeutic strategies to target different disease phases.

9 Aberrant striatal value representation in Huntington’s disease gene carriers 25 years before onset

AimsHuntington’s disease (HD) is a devastating genetic neurodegenerative condition typically manifesting clinically in the fourth or fifth decade. With the advent of genetic therapies there is increased need to identify the earliest changes associated with carrying the HD gene. In this study we sought to determine the earliest functional imaging differences between HD gene carriers and matched controls. Based on previous work, we hypothesised that as compared to controls, HD gene carriers decades from onset would show a neural ‘reward bias’ – an exaggerated striatal response to gains as compared to losses.MethodsWe recruited 35 HD gene carriers, estimated to be on average 26 years from motor onset, and 35 controls. Groups were well matched for age, gender and education level.Participants completed a reinforcement learning task in a fMRI scanner using a sequence optimised for orbitofrontal and striatal signal. In this task participants were required to learn to choose between stimuli with the aim of maximise rewards and avoiding losses. Task behaviour was modelled using a computational model and computational variables from the best fitting model was used to probe fMRI data.ResultsAs hypothesised, we found that, in comparison to matched controls, gene carriers over 25 years from motor onset showed exaggerated striatal responses to gain as compared to loss predicting stimuli (p=0.003) in a reinforcement learning task. Using computational analysis, we also found group differences in striatal representation of stimulus value (p=0.0007).ConclusionThese represent the earliest functional imaging differences between HD gene carriers and controls. Behaviourally gene carriers, 9 years from predicted onset, have shown enhanced learning from gains as compared to losses. Importantly, we found no group differences in behaviour, or caudate volumes. Our data suggests a therapeutic window exists whereby HD- related functional neural changes are detectable 25 years before predicted onset.