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Objective The objective of this study was to characterize the clinical features, developmental milestones, and the natural history of Pelizaeus Merzbacher disease (PMD) associated with PLP1 gene duplications. Methods The study examined 16 PMD Patients ranging in age from 7 to 48, who had a documented PLP1 gene duplication. The

Although Charcot characterized classic cerebellar symptoms in people with multiple sclerosis (PwMS) in 1877, the impact of cerebellar dysfunction on MS symptoms has predominately been evaluated in the last two decades. Recent studies have clearly demonstrated the association between cerebellar pathology, including atrophy and reduced fractional anisotropy in the peduncles, and motor impairments, such as reduced gait velocity and time to complete walking tasks. However, future studies using novel imaging techniques are needed to elucidate all potential pathophysiology that is associated with disability in PwMS. Additionally, future studies are required to determine the most effective treatments for motor impairments in PwMS, including the specific type and duration of exercise interventions, and potential means to amplify their effects, such as transcranial direct current stimulation (tDCS). This mini-review critically discusses the distinct role of cerebellar dysfunction in motor impairments in PwMS, potential treatments, and directions for future studies.

Interest in transcranial direct current stimulation (tDCS) to alter cortical excitability, facilitate neural plasticity, and improve performance is increasing. Subjects often report temporary stimulation-related sensations, which might distract from the task being performed or compromise blinding. tDCS is also prone to high outcome irregularity and one potential variability source is the biological sex of the subject. The purpose of this study was to re-analyze existing tolerability data to ascertain any sex differences in sensation severity and blinding guesses from tDCS at 2 mA and 4 mA. Each subject underwent tDCS at three randomly-ordered intensities (sham, 2 mA, 4 mA), reported the severity sensations of experienced, and guessed which tDCS condition they underwent (blinding). Women reported higher sensation severities than men from 2 mA and 4 mA tDCS and higher severities with increasing intensity (sham < 2 mA < 4 mA). Men reported similar severities in all stimulation conditions. Both sexes distinguished sham from 2 mA and 4 mA, and neither were able to discriminate between 2 mA from 4 mA. This study highlights differences in severity reports between women and men and adds to the growing body of literature indicating that current sham methodologies might be inadequate to maintain blinding.

Background and ObjectiveEmerging evidence suggests a role for diet in multiple sclerosis (MS) care; however, owing to methodological issues and heterogeneity of dietary interventions in preliminary trials, the current state of evidence does not support dietary recommendations for MS. The objective of this study was to assess the efficacy of different dietary approaches on MS-related fatigue and quality of life (QoL) through a systematic review of the literature and network meta-analysis (NMA).MethodsElectronic database searches were performed in May 2021. Inclusion criteria were (1) randomized trial with a dietary intervention, (2) adults with definitive MS based on McDonald criteria, (3) patient-reported outcomes for fatigue and/or QoL, and (4) minimum intervention period of 4 weeks. For each outcome, standardized mean differences (SMDs) were calculated and included in random effects NMA to determine the pooled effect of each dietary intervention relative to each of the other dietary interventions. The protocol was registered at PROSPERO (CRD42021262648).ResultsTwelve trials comparing 8 dietary interventions (low-fat, Mediterranean, ketogenic, anti-inflammatory, Paleolithic, fasting, calorie restriction, and control [usual diet]), enrolling 608 participants, were included in the primary analysis. The Paleolithic (SMD −1.27; 95% CI −1.81 to −0.74), low-fat (SMD −0.90; 95% CI −1.39 to −0.42), and Mediterranean (SMD −0.89; 95% CI −1.15 to −0.64) diets showed greater reductions in fatigue compared with control. The Paleolithic (SMD 1.01; 95% CI 0.40–1.63) and Mediterranean (SMD 0.47; 95% CI 0.08–0.86) diets showed greater improvements in physical QoL compared with control. For improving mental QoL, the Paleolithic (SMD 0.81; 95% CI 0.26–1.37) and Mediterranean (SMD 0.36; 95% CI 0.06–0.65) diets were more effective compared with control. However, the NutriGRADE credibility of evidence for all direct comparisons is very low because of most of the included trials having high or moderate risk of bias, small sample sizes, and the limited number of studies included in this NMA.DiscussionSeveral dietary interventions may reduce MS-related fatigue and improve physical and mental QoL; however, because of the limitations of this NMA, which are driven by the low quality of the included trials, these findings must be confirmed in high-quality, randomized, controlled trials.

BACKGROUND: Usher syndrome is the most common hereditary syndrome combining deafness and blindness (1, 2). In the 2017 National Child Count of Children and Youth who are Deaf-Blind, Usher syndrome represented 329 of 10,000 children, but there were also at least 70 other etiologies of deaf-blindness documented (3). The purpose of this study was to analyze the work-up and ultimate diagnoses of 21 consecutive families who presented to the Genetic Eye-Ear Clinic (GEEC) at the University of Iowa. Our hypothesis was that most families referred to the GEEC would have initial and final diagnoses of Usher syndrome. MATERIALS AND METHODS: Patients were identified through an IRB approved retrospective chart review of referrals to the GEEC between 2012 and 2019. Details about each patient’s history, exam, and clinical and genetic work-up were recorded. RESULTS: From 2012 to 2019, 21 families (25 patients) were referred to the collaborative GEEC. Overall molecular diagnostic rate in this cohort was 14/21 (67%). Evaluation resulted in a change of diagnosis in 11/21 (52%) families. Ultimately, there were eleven unique diagnoses including hereditary, non-hereditary, and independent causes of combined visual impairment and hearing loss. The most common diagnosis was Usher Syndrome, which represented 6/21 (29%) families. CONCLUSIONS: Providing a correct diagnosis for patients with visual impairment and hearing loss can be challenging for clinicians and their patients, but it can greatly improve clinical care and outcomes. We recommend an algorithm that includes multidisciplinary collaboration, careful clinical evaluation, strategic molecular testing, and consideration of a broad differential diagnosis.

Transcranial direct current stimulation (tDCS) using intensities ≤ 2 mA on physical and cognitive outcomes has been extensively investigated. Studies comparing the effects of different intensities of tDCS have yielded mixed results and little is known about how higher intensities (> 2 mA) affect outcomes. This study examined the effects of tDCS at 2 mA and 4 mA on leg muscle fatigability. This was a double-blind, randomized, sham-controlled study. Sixteen healthy young adults underwent tDCS at three randomly ordered intensities (sham, 2 mA, 4 mA). Leg muscle fatigability of both legs was assessed via isokinetic fatigue testing (40 maximal reps, 120°/s). Torque- and work-derived fatigue indices (FI-T and FI-W, respectively), as well as total work performed (TW), were calculated. FI-T of the right knee extensors indicated increased fatigability in 2 mA and 4 mA compared with sham (p = 0.01, d = 0.73 and p

Background: While it has been shown that aerobic exercise interventions are well tolerated in participants with the Huntington disease (HD) gene mutation, no study to date has tested whether an aerobic exercise intervention benefits brain structure and function in pre-manifest HD. Objective: In this study we utilized magnetic resonance (MR) imaging techniques to assess the efficacy of moderate-to-vigorous exercise treatment relative to active stretching and toning control. Methods: Forty pre-manifest participants with confirmed HD gene expansion were recruited into a two-arm intervention study that included a moderate-to-vigorous intensity home-based walking exercise intervention (N=34) and an active stretching and toning control intervention (N=6). Participants were assessed at baseline and after 26 weeks in one of the two study arms. Results: 25 of the 34 (74%) participants assigned to the moderate-to-vigorous intensity group completed the intervention while 4 of the 6 (67%) participants in the stretching and toning intervention completed the study. The primary analyses compared the two arms of the study and found no statistical differences between the groups. Both groups were found to have improved their cardiorespiratory fitness as assessed by maximal oxygen uptake (VO2max). A secondary analysis combined the two arms of the study and there was a significant relationship (p

Pelizaeus–Merzbacher disease is an X-linked recessive leucodystrophy of the central nervous system caused by mutations affecting the major myelin protein, proteolipid protein 1. The extent of the altered in vivo neurochemistry of protein, proteolipid protein 1 duplications, the most common form of Pelizaeus–Merzbacher disease, is, however, poorly understood. Phosphorus magnetic resonance spectroscopy is the only in vivo technique that can assess the biochemistry associated with high-energy phosphate and membrane phospholipid metabolism across different cortical, subcortical and white matter areas. In this cross-sectional study, whole-brain, multi-voxel phosphorus magnetic resonance spectroscopy was acquired at 3 T on 14 patients with Pelizaeus–Merzbacher disease with protein, proteolipid protein 1 duplications and 23 healthy controls (all males). Anabolic and catabolic levels of membrane phospholipids (phosphocholine and phosphoethanolamine, and glycerophosphoethanolamine and glycerophosphocholine, respectively), as well as phosphocreatine, inorganic orthophosphate and adenosine triphosphate levels relative to the total phosphorus magnetic resonance spectroscopy signal from 12 different cortical and subcortical areas were compared between the two groups. Independent of brain area, phosphocholine, glycerophosphoethanolamine and inorganic orthophosphate levels were significantly lower (P = 0.0025, P

This exploratory pilot study investigated the effects of chronic Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on cerebral glucose metabolism in people with multiple sclerosis (PwMS). Compared with nonusers, THC users had hypermetabolism of 3 regions (p < 0.039, d >1.17) in left temporal areas, while CBD users had hypometabolism of 5 regions (p < 0.032, d > 1.31) in left temporal areas. This study highlights the need to discriminate between THC and CBD in future cannabis studies. Novelty Chronic THC and CBD use had disparate effects on cerebral glucose metabolism in PwMS.

Much of the spotlight for coronavirus disease 2019 (COVID-19) is on the acute symptoms and recovery. However, many recovered patients face persistent physical, cognitive, and psychological symptoms well past the acute phase. Of these symptoms, fatigue is one of the most persistent and debilitating. In this “perspective article,” we define fatigue as the decrease in physical and/or mental performance that results from changes in central, psychological, and/or peripheral factors due to the COVID-19 disease and propose a model to explain potential factors contributing to post-COVID-19 fatigue. According to our model, fatigue is dependent on conditional and physiological factors. Conditional dependency comprises the task, environment, and physical and mental capacity of individuals, while physiological factors include central, psychological, and peripheral aspects. This model provides a framework for clinicians and researchers. However, future research is needed to validate our proposed model and elucidate all mechanisms of fatigue due to COVID-19.

Trillions of microbes such as bacteria, fungi, and viruses exist in the healthy human gut microbiome. Although gut bacterial dysbiosis has been extensively studied in multiple sclerosis (MS), the significance of the fungal microbiome (mycobiome) is an understudied and neglected part of the intestinal microbiome in MS. The aim of this study was to characterize the gut mycobiome of patients with relapsing-remitting multiple sclerosis (RRMS), compare it to healthy controls, and examine its association with changes in the bacterial microbiome. We characterized and compared the mycobiome of 20 RRMS patients and 33 healthy controls (HC) using Internal Transcribed Spacer 2 (ITS2) and compared mycobiome interactions with the bacterial microbiome using 16S rRNA sequencing. Our results demonstrate an altered mycobiome in RRMS patients compared with HC. RRMS patients showed an increased abundance of Basidiomycota and decreased Ascomycota at the phylum level with an increased abundance of Candida and Epicoccum genera along with a decreased abundance of Saccharomyces compared to HC. We also observed an increased ITS2/16S ratio, altered fungal and bacterial associations, and altered fungal functional profiles in MS patients compared to HC.This study demonstrates that RRMS patients had a distinct mycobiome with associated changes in the bacterial microbiome compared to HC. There is an increased fungal to bacterial ratio as well as more diverse fungal-bacterial interactions in RRMS patients compared to HC. Our study is the first step towards future studies in delineating the mechanisms through which the fungal microbiome can influence MS disease.

Transcranial direct current stimulation (tDCS) has been shown to alter cortical excitability. However, it is increasingly accepted that tDCS has high inter- and intra-subject response variability, which currently limits broad application and has prompted some to doubt if the current can reach the brain. This study reports individual cerebral blood flow responses in people with multiple sclerosis and neurologically healthy subjects that experienced 5 min of anodal tDCS at 1 mA, 2 mA, 3 mA, and 4 mA over either the dorsolateral prefrontal cortex (DLPFC) or the primary motor cortex (M1). The most notable results indicated anticipated changes in regional cerebral blood flow (rCBF) in two regions of one DLPFC subject (2 mA condition), and expected changes in one M1 subject in the 2 mA and 4 mA conditions and in another M1 subject in the 2 mA condition. There were also changes contrary to the expected direction in one DLPFC subject and in two M1 subjects. These data suggest the effects of tDCS might be site-specific and highlight the high variability and individualized responses increasingly reported in tDCS literature. Future studies should use longer stimulation durations and image at various time points after stimulation cessation when exploring the effects of tDCS on cerebral blood flow (CBF).

Asymmetrical lower limb strength is a significant contributor to impaired walking abilities in people with multiple sclerosis (PwMS). Transcranial direct current stimulation (tDCS) may be an effective technique to enhance cortical excitability and increase neural drive to more-affected lower limbs. A sham-controlled, randomized, cross-over design was employed. Two women with MS underwent two 20 min sessions of either 3 mA tDCS or Sham before 20 min of treadmill walking at a self-selected speed. During walking, the participants were injected with the glucose analogue, [18F] fluorodeoxyglucose (FDG). Participants were then imaged to examine glucose metabolism and uptake asymmetries in the legs. Standardized uptake values (SUVs) were compared between the legs and asymmetry indices were calculated. Subject 2 was considered physically active (self-reported participating in at least 30 min of moderate-intensity physical activity on at least three days of the week for the last three months), while Subject 1 was physically inactive. In Subject 1, there was a decrease in SUVs at the left knee flexors, left upper leg, left and right plantar flexors, and left and right lower legs and SUVs in the knee extensors and dorsiflexors were considered symmetric after tDCS compared to Sham. Subject 2 showed an increase in SUVs at the left and right upper legs, right plantar flexors, and right lower leg with no muscle group changing asymmetry status. This study demonstrates that tDCS may increase neural drive to leg muscles and decrease glucose uptake during walking in PwMS with low physical activity levels.

Factors regulating self-antigen directed immune-responses in autoimmunity are poorly understood. Signal regulatory protein gamma (SIRPγ) is a human T-cell specific protein with genetic variants associated with type 1 diabetes (T1D). SIRPγ's function in the immune system remains unclear. We show that T1D and relapsing remitting multiple sclerosis (RRMS) subjects have significantly greater frequency of rs2281808 T genetic variant, that correlates with reduced SIRPγ-expression in T-cells. Importantly, reduced SIRPγ-expression in RRMS and T1D subjects was not restricted to T variant, suggesting SIRPγ-expression is also regulated by disease specific factors in autoimmunity. Interestingly, increased frequencies of SIRPγlow T-cells in RRMS and T1D positively correlated with proinflammatory molecules from T-cells. Finally, we show that SIRPγlow T-cells have enhanced pathogenecity in vivo in a GVHD model. These findings suggest that decreased-SIRPγ expression, either determined by genetic variants or through peripherally acquired processes, may have a mechanistic link to autoimmunity through induction of hyperactive T-cells.

Introduction Huntington's chorea (HC) is commonly managed with neuroleptic medications, though there is little evidence to support their use. This study aimed to perform a real-world comparison of the efficacy of risperidone and olanzapine to tetrabenazine (TBZ) for HC. Methods The Enroll-HD database was used to perform a propensity score-matched comparison of risperidone and olanzapine to TBZ, regarding their efficacy in controlling chorea. Participants with motor manifest Huntington's disease (HD) were grouped according to their use of risperidone, olanzapine, or TBZ. For the three groups, independent propensity score matching was performed on participants' baseline total functional score (TFC), baseline total motor score (TMS), disease burden score, CAG repeat length, baseline age, region, sex, and body mass index. Independent samples t test was used to calculate the differences between the groups in the annual rate of change of the TMS from the baseline to the second available visit. Results The risperidone (n = 72) and olanzapine groups (n = 77) had annualized increases (worsening) in the TMS of only 1.47 points and 3.20 points, respectively, compared to 5.70 points in the two matched TBZ groups (n = 72) (P = 0.019) and (n = 77) (P = 0.143), respectively. Conclusions In the absence of prospective data, this analysis of the Enroll-HD database found that the neuroleptics risperidone and olanzapine seemed to at least be comparable to TBZ at controlling HC. These results demonstrate that neuroleptics may have comparable efficacy to TBZ for the treatment of HC. Further prospective studies are needed to confirm these findings.

Transcranial direct current stimulation (tDCS) modulates cortical excitability and affects a variety of outcomes. tDCS at intensities &le, 2 mA is well-tolerated, but the tolerability and efficacy of tDCS at intensities &gt, 2 mA merits systematic investigation. The study objective was to determine the tolerability and effects of 4 mA tDCS on leg muscle fatigability. Thirty-one young, healthy adults underwent two randomly ordered tDCS conditions (sham, 4 mA) applied before and during an isokinetic fatigue test of the knee extensors and flexors. Subjects reported the severity of the sensations felt from tDCS. Primary outcomes were sensation tolerability and the fatigue index of the knee extensors and flexors. A repeated-measures ANOVA determined statistical significance (p &lt, 0.05). Sensation severity at 4 mA tDCS was not substantially different than sham. However, two subjects reported a moderate&ndash, severe headache, which dissipated soon after the stimulation ended. The left knee flexors had significantly greater fatigability with 4 mA tDCS compared with sham (p = 0.018). tDCS at 4 mA was well-tolerated by young, healthy subjects and increased left knee flexor fatigability. Exploration of higher intensity tDCS (&gt, 2 mA) to determine the potential benefits of increasing intensity, especially in clinical populations with decreased brain activity/excitability, is warranted.

ObjectiveTo determine whether tetrabenazine (TBZ) use is associated with an increased incidence of depression and/or suicidal ideation.MethodsIn this retrospective cross-sectional study of the Enroll-HD database, we used multiple logistic regression analyses to determine whether TBZ use is associated with an increased incidence of depression and/or suicidal ideation. For both dependent variables (depression and suicidality), separate analyses were conducted on (1) all participants, (2) only participants with a history of depression, and (3) only participants with no history of depression. Adjustments were made for CAG repeat length, total motor score, total functional capacity, Symbol Digit Modalities Test score, sex, disease duration, history of depression (when applicable), antipsychotic use, and antidepressant use.ResultsCompared to participants who were not using TBZ (n = 3,548), TBZ users (n = 543) did not have an increased risk of depression (odds ratio [OR] = 0.78, p = 0.064). Participants taking TBZ actually had a relatively lower risk of suicidality (OR = 0.61, p = 0.043). Among only participants with a history of depression, those using TBZ had a lower incidence of depression (OR = 0.71, p = 0.016) and suicidal ideation (OR = 0.57, p = 0.028) compared to those not using TBZ. Finally, among only participants with no history of depression, TBZ use was not associated with a higher incidence of depression (OR = 1.59, p = 0.18) or suicidality (OR = 1.43, p = 0.66) compared to those who were not using TBZ.ConclusionsTBZ use was not associated with an increased incidence of depression or suicidality. These findings suggest that TBZ may be safe to use in patients with Huntington disease who have a history of depression.

Proteolipid protein (PLP), besides its adhesive role in myelin, has been postulated to have multiple cellular functions. One well-documented function of PLP is regulation of oligodendrocyte (Olg) apoptosis. In contrast, DM20, an alternatively spliced product of the PLP1/Plp1 gene, has been proposed to have functions that are unique from PLP but these functions have never been elucidated. Here, we compare metabolism of PLP and DM20, and show that oxidative phosphorylation (OxPhos) was significantly decreased in Plp1 but not DM20 or EGFP expressing cells. The reserve OxPhos capacity of Plp1 expressing cells was half of control cells, suggesting that they are very vulnerable to stress. ATP in media of Plp1 expressing cells is significantly increased more than two-fold compared to controls; markers of apoptosis are increased in cells over-expressing Plp1, indicating that abnormal metabolism of PLP is most likely the direct cause leading to Olg apoptosis. We hypothesize that abnormal metabolism, mediated by increased insertion of PLP into mitochondria, underlies demyelination in Pelizaeus-Merzbacher Disease (PMD) and in models of PMD. To understand why PLP and DM20 function differently, we mutated or deleted amino acids located in the PLP-specific region. All these mutations and deletions of the PLP-specific region prevented insertion of PLP into mitochondria. These findings demonstrate that the PLP-specific region is essential for PLP’s import into mitochondria, and now offer an explanation for deciphering unique functions of PLP and DM20.

Objective To compare the effect of the modified Paleolithic elimination (Wahls) and low-saturated fat (Swank) diets in relapsing-remitting MS (RRMS). Methods Individuals (n = 87) with RRMS were randomized to the Swank or Wahls diets in a parallel group clinical trial consisting of four timepoints: 1) run-in, 2) baseline, 3) 12-weeks, and 4) 24-weeks. Results 77 participants completed 12 weeks and 72 completed 24 weeks. The 12-week change from baseline in fatigue was -0.94 ± 0.18 (FSS) and -9.87 ± 1.93 (MFIS; both p Conclusions Both diets were associated with clinically meaningful within-group reductions in fatigue and improvements in QoL. Trial Registration: Clinicaltrials.gov Identifier: NCT02914964

Objective To determine whether predicted fork stalling and template switching (FoSTeS) during mitosis deletes exon 4 in peripheral myelin protein 22 KD (PMP22) and causes gain‐of‐function mutation associated with peripheral neuropathy in a family with Charcot–Marie–Tooth disease type 1E. Methods Two siblings previously reported to have genomic rearrangements predicted to involve exon 4 of PMP22 were evaluated clinically and by electrophysiology. Skin biopsies from the proband were studied by RT‐PCR to determine the effects of the exon 4 rearrangements on exon 4 mRNA expression in myelinating Schwann cells. Transient transfection studies with wild‐type and mutant PMP22 were performed in Cos7 and RT4 cells to determine the fate of the resultant mutant protein. Results Both affected siblings had a sensorimotor dysmyelinating neuropathy with severely slow nerve conduction velocities (

We previously showed that MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1, also CHCHD2) functions in two subcellular compartments, displaying a different function in each. In the mitochondria it is a stress regulator of respiration that binds to cytochrome c oxidase (COX) whereas in the nucleus it is a transactivator of COX4I2 and other hypoxia-stimulated genes. We now show that binding of MNRR1 to COX is promoted by phosphorylation at tyrosine-99 and that this interaction stimulates respiration. We show that phosphorylation of MNRR1 takes place in mitochondria and is mediated by Abl2 kinase (ARG). A family with Charcot-Marie-Tooth disease type 1A with an exaggerated phenotype harbors a Q112H mutation in MNRR1, located in a domain that is necessary for transcriptional activation by MNRR1. Furthermore, the mutation causes the protein to function suboptimally in the mitochondria in response to cellular stress. The Q112H mutation hinders the ability of the protein to interact with Abl kinase, leading to defective tyrosine phosphorylation and a resultant defect in respiration.

Infarction of the spinal cord is a rare entity in clinical practice. Limited literature exists on spinal cord stroke treatment, and the management is often symptomatic. The anterior spinal cord syndrome is the most common phenomenology, but here we present 2 nontraumatic spinal hemicord infarctions in elderly patients and discuss the clinical and radiological characteristics.

Pelizaeus-Merzbacher disease (PMD) is an X-linked inherited hypomyelinating disorder caused by mutations in the gene encoding proteolipid protein (PLP), the major structural protein in central nervous system (CNS) myelin. Prior to our study, whether hypomyelination in PMD was caused by demyelination, abnormally thin sheaths or failure to form myelin was unknown. In this study, we compared the microscopic pathology of myelin from brain tissue of 3 PMD patients with PLP1 duplications to that of a patient with a complete PLP1 deletion. Autopsy tissue procured from PMD patients was embedded in paraffin for immunocytochemistry and plastic for electron microscopy to obtain highresolution fiber pathology of cerebrum and corpus callosum. Through histological stains, immunocytochemistry and electron microscopy, our study illustrates unique pathologic findings between the two different types of mutations. Characteristic of the patient with a PLP1 deletion, myelin sheaths showed splitting and decompaction of myelin, confirming for the first time that myelin in PLP1 deletion patients is similar to that of rodent models with gene deletions. Myelin thickness and g-ratios of some fibers, in relation to axon diameter was abnormally thin, suggesting that oligodendrocytes remain metabolically functional and/or are attempting to make myelin. Many fibers showed swollen, progressive degenerative changes to axons in addition to the dissolution of myelin. All three duplication cases shared remarkable fiber pathology including swellings, constriction and/or transection and involution of myelin. Characteristic of PLP1 duplication patients, many axons showed segmental demyelination along their length. Still other axons had abnormally thick myelin sheaths, suggestive of continued myelination. Thus, each type of mutation exhibited unique pathology even though commonality to both mutations included involution of myelin, myelin balls and degeneration of axons. This pathology study describes findings unique to each mutation that suggests the mechanism causing fiber pathology is likewise heterogeneous.

Animal and transcranial magnetic stimulation motors have evoked potential studies suggesting that the currently used transcranial direct current stimulation (tDCS) intensities produce measurable physiological changes. However, the validity, mechanisms, and general efficacy of this stimulation modality are currently being scrutinized. The purpose of this pilot study was to investigate the effects of dorsolateral prefrontal cortex tDCS on cerebral blood flow. A sample of three people with multiple sclerosis underwent two blocks of five randomly assigned tDCS intensities (1, 2, 3, 4 mA, and sham; 5 min each) and [15O]water positron emission tomography imaging. The relative regional (i.e., areas under the electrodes) and global cerebral blood flow were calculated. The results revealed no notable differences in regional or global cerebral blood flow from the different tDCS intensities. Thus, 5 min of tDCS at 1, 2, 3, and 4 mA did not result in immediate changes in cerebral blood flow. To achieve sufficient magnitudes of intracranial electrical fields without direct peripheral side effects, novel methods may be required.

Multiple GWAS studies have shown that the SNP rs2281808 TT variant, present within the SIRPG gene, is associated with autoimmune diseases, such as type 1 diabetes. However, the role of SIRPγ in human T-cells is not known, neither is the functional significance of TT variant. Here we investigated SIRPG genotypes and their effects on the fate and function of human T-cells. We found that the presence of T variant resulted in reduction of SIRPγ expression on T-cells. Functionally, SIRPγlow CD8 T-cells in CT and TT individuals existed in a heightened effector state with lower activation threshold and had greater expression of genes and molecules associated with migratory and cytotoxic potential. Further, SIRPγlow CD8 T-cells were deficient in transcription factors associated with long-term functional memory formation. Our study reveals biological consequences of the SNP rs2281808 and provides novel insights into the potential mechanisms by which SIRPγ might regulate human immune responses.

Background There is evidence to suggest that 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) may be beneficial in Huntington's disease (HD). Objective This study aimed to determine if statin use was associated with delayed motor diagnosis in participants with premotor HD. Methods Among premotor HD participants from the Enroll-HD database, statin users were propensity score matched with statin nonusers based on cytosine-adenine-guanine-age product score, cytosine-adenine-guanine repeat length, baseline age, sex, and region. A Cox regression survival analysis compared the annualized hazard ratio (HR) of receiving a motor diagnosis between the 2 groups. Results The annualized HR of progressing to an HD motor diagnosis was lower in the statin users (n = 89) when compared with the statin nonusers (n = 89; HR = 0.27 [95% CI 0.18-0.50], P Conclusions In patients with premotor HD, statin use was associated with a delayed motor diagnosis of HD. Further studies are warranted to investigate if statins would be an effective disease-modifying therapy for HD. © 2018 International Parkinson and Movement Disorder Society.

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