Neurological manifestations of nontuberculous mycobacteria in adults: case series and review of the literature.

Introduction: Nontuberculous mycobacteria (NTM) mediated infections are important to consider in cases with neuroinflammatory presentations. We aimed to characterize cases of NTM with neurological manifestations at the National Institutes of Health (NIH) Clinical Center and review the relevant literature. Materials and methods: Between January 1995 and December 2020, six cases were identified. Records were reviewed for demographic, clinical, and radiological characteristics. A MEDLINE search found previously reported cases. Data were extracted, followed by statistical analysis to compare two groups [cases with slow-growing mycobacteria (SGM) vs. those with rapidly growing mycobacteria (RGM)] and evaluate for predictors of survival. NIH cases were evaluated for clinical and radiological characteristics. Cases from the literature were reviewed to determine the differences between SGM and RGM cases and to identify predictors of survival. Results: Six cases from NIH were identified (age 41 ± 13, 83% male). Five cases were caused by SGM [Mycobacterium avium complex (MAC) n = 4; Mycobacterium haemophilum n = 1] and one due to RGM (Mycobacterium abscessus). Underlying immune disorders were identified only in the SGM cases [genetic (n = 2), HIV (n = 1), sarcoidosis (n = 1), and anti-interferon-gamma antibodies (n = 1)]. All cases were diagnosed using tissue analysis. A literature review found 81 reports on 125 cases (SGM n = 85, RGM n = 38, non-identified n = 2). No immune disorder was reported in 26 cases (21%). Within SGM cases, the most common underlying disease was HIV infection (n = 55, 65%), and seizures and focal lesions were more common. In RGM cases, the most common underlying condition was neurosurgical intervention or implants (55%), and headaches and meningeal signs were common. Tissue-based diagnosis was used more for SGM than RGM (39% vs. 13%, p = 0.04). Survival rates were similar in both groups (48% SGM and 55% in RGM). Factors associated with better survival were a solitary CNS lesion (OR 5.9, p = 0.01) and a diagnosis made by CSF sampling only (OR 9.9, p = 0.04). Discussion: NTM infections cause diverse neurological manifestations, with some distinctions between SGM and RGM infections. Tissue sampling may be necessary to establish the diagnosis, and an effort should be made to identify an underlying immune disorder.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.

BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD). OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.

White and Gray Matter Changes are Associated With Neurocognitive Decline in HIV Infection.

OBJECTIVE: To investigate the relationship between neurocognitive deficits and structural changes on brain magnetic resonance imaging in people living with HIV (PLWH) with good virological control on combination antiretroviral therapy, compared with socioeconomically matched control participants recruited from the same communities. METHODS: Brain magnetic resonance imaging scans, and clinical and neuropsychological data were obtained from virologically controlled PLWH (viral load of <50 c/mL and at least 1 year of combination antiretroviral therapy) and socioeconomically matched control participants. Magnetic resonance imaging was carried out on 3 T scanner with 8-channel head coils and segmented using Classification using Derivative-based Features. Multiple regression analysis was performed to examine the association between brain volume and various clinical and neuropsychiatric parameters adjusting for age, race, and sex. To evaluate longitudinal changes in brain volumes, a random coefficient model was used to evaluate the changes over time (age) adjusting for sex and race. RESULTS: The cross-sectional study included 164 PLWH and 51 controls, and the longitudinal study included 68 PLWH and 20 controls with 2 or more visits (mean 2.2 years, range 0.8-5.1 years). Gray matter (GM) atrophy rate was significantly higher in PLWH compared with control participants, and importantly, the GM and global atrophy was associated with the various neuropsychological domain scores. Higher volume of white matter hyperintensities were associated with increased atherosclerotic cardiovascular disease risk score, and decreased executive functioning and memory domain scores in PLWH. INTERPRETATION: These findings suggest ongoing neurological damage even in virologically controlled participants, with significant implications for clinical management of PLWH. ANN NEUROL 2024;95:941-950.

Electrical impedance myography in healthy volunteers.

INTRODUCTION/AIMS: Electrical impedance myography (EIM) is a noninvasive technique being used in clinical studies to characterize muscle by phase, reactance, and resistance after application of a low-intensity current. The aim of this study was to obtain 50-kHz EIM data from healthy volunteers (HVs) for use in future clinical and research studies, perform reliability tests on EIM outcome measures, and compare findings with muscle ultrasound variables. METHODS: Four arm and four leg muscles of HVs were evaluated using an EIM device with two sensors, P/N 20-0045 and P/N 014-009. Muscles were evaluated individually and eight-muscle average (8MU), four-muscle upper extremity average, and four-muscle lower extremity average. An intraclass correlation coefficient (ICC) was applied to assess interrater, intrarater, and intersensor reliability using a subset of HVs. Ultrasound studies on muscle thickness and elastography were also performed on a subset of HVs. RESULTS: For the P/N 20-0045 sensor, the 8MU EIM mean and standard deviation (n = 41) was 14.54 ± 3.31 for phase, 7.04 ± 1.22 for reactance, and 28.91 ± 7.63 for resistance. Reliability for 8MU phase (n = 22) was good to excellent for both interrater (n = 22, ICC = 0.920, 95% CI 0.820 to 0.966) and intrarater (n = 22, ICC = 0.950, 95% CI 0.778 to 0.983). The P/N 014-009 sensor had similar reliability findings. Correlation analyses showed no association between EIM and muscle thickness. DISCUSSION: EIM is a reproducible measure of muscle physiology. Obtaining EIM values from HVs allows us to gain a better understanding how EIM may be altered in diseased muscle.

Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases.

BACKGROUND: In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. METHODS: Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. RESULTS: Nine participants had low initial myocardial 18F-dopamine-derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) (P = 0.0009 by Fisher's exact test). Conversely, all 9 LBD+ participants had low 18F-dopamine-derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity (P < 0.0001 by Fisher's exact test). CONCLUSION: Cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not. CLINICALTRIALS: gov NCT00775853. FUNDING: Division of Intramural Research, NIH, NINDS.

Prospective, Longitudinal Study of Clinical Outcome and Morphometric Posterior Fossa Changes after Craniocervical Decompression for Symptomatic Chiari I Malformation.

BACKGROUND AND PURPOSE: The time course of changes in posterior fossa morphology, quality of life, and neurologic function of patients with Chiari I malformation after craniocervical decompression requires further elaboration. To better understand the pace of these changes, we longitudinally studied patients with Chiari I malformation, with or without syringomyelia, before and after the operation for up to 5 years. MATERIALS AND METHODS: Thirty-eight symptomatic adult patients (35 women, 3 men) diagnosed with Chiari I malformation only (n = 15) or Chiari I malformation and syringomyelia (n = 23) and without previous Chiari I malformation surgery were enrolled in a clinical study. Patients underwent outpatient study visits and MR imaging at 7 time points (ie, initial [before the operation], 3 months, 1 year, 2 years, 3 years, 4 years, and 5 years) during 5 years. The surgical procedure for all patients was suboccipital craniectomy, C1 laminectomy, and autologous duraplasty. RESULTS: Morphometric measurements demonstrated an enlargement of the CSF areas posterior to the cerebellar tonsils after the operation, which remained largely stable through the following years. There was a decrease in pain and improved quality of life after the operation, which remained steady during the following years. Reduction in pain and improved quality of life correlated with CSF area morphometrics. CONCLUSIONS: Most changes in MR imaging morphometrics and quality of life measures occurred within the first year after the operation. A 1-year follow-up period after Chiari I malformation surgery is usually sufficient for evaluating surgical efficacy and postoperative MR imaging changes.

Cognitive determinants of decisional capacity in neurodegenerative disorders.

OBJECTIVE: Cognitive contributions to decisional capacity are complex and not well understood. Capacity to consent for research has been linked to executive function, but executive function assessment tools are imperfect. In this study, we examine the relationship between decisional capacity and a newly developed executive function composite score and determine whether cognitive performance can predict impaired decisional capacity. METHODS: This is a cross sectional study of participants at the National Institutes of Health with frontotemporal dementia-amyotrophic lateral sclerosis spectrum disorders enrolled between 2017 and 2022. A structured interview tool was used to ascertain research decisional capacity. Study participant Uniform Data Set (v3.0) executive function (UDS3-EF) composite score, Clinical Dementia Rating Scale©, and Neuropsychiatric Inventory was determined. RESULTS: A decrease in UDS3-EF composite score significantly increased the odds of impaired decisional capacity (OR = 2.92, 95% CI [1.66-5.13], p = 0.0002). Executive function was most impaired in frontotemporal dementia (-2.86, SD = 1.26) and least impaired in amyotrophic lateral sclerosis (-0.52, SD = 1.25) participants. The UDS3-EF composite score was also strongly correlated to the Clinical Dementia Rating Scale©. INTERPRETATION: Decisional capacity is intrinsically related to executive function in neurodegenerative disorders, and executive dysfunction may predict a lack of decisional capacity alerting investigators of the need for additional scrutiny during the informed consent process.

Diurnal Range and Intra-patient Variability of ACTH Is Restored With Remission in Cushing's Disease.

CONTEXT: Single ACTH measurements have limited ability to distinguish patients with Cushing's disease (CD) from those in remission or with other conditions. OBJECTIVE: To investigate the changes in ACTH levels before and after transsphenoidal surgery (TSS) to identify trends that could confirm remission from CD and help establish ACTH cutoffs for targeted clinical trials in CD. DESIGN: Retrospective analysis of CD patients who underwent TSS from 2005 to -2019. SETTING: Referral center. PATIENTS: CD patients (n = 253) with ACTH measurements before and after TSS. INTERVENTIONS: TSS for CD. MAIN OUTCOME MEASURES: Remission after TSS. RESULTS: Remission was observed in 223 patients after TSS. Those in remission had higher ACTH variability at AM (P = .02) and PM (P < .001) time points compared to nonremission. The nonremission group had a significantly narrower diurnal range compared to the remission group (P = <.0001). A decrease in plasma ACTH of ≥50% from mean preoperative levels predicted CD remission after TSS, especially when using PM values. The absolute plasma ACTH concentration and ratio of preoperative to postoperative values were significantly associated with nonremission after multivariable logistic regression (adj P < .001 and .001, respectively). CONCLUSIONS: Our findings suggest that ACTH variability is suppressed in CD, and remission from CD is associated with the restoration of this variability. Furthermore, a decrease in plasma ACTH by 50% or more may serve as a predictor of remission post-TSS. These insights could guide clinicians in developing rational outcome measures for interventions targeting CD adenomas.

Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy.

BACKGROUND AND OBJECTIVES: Neurologic outcomes in people with HIV (PWH) on long-duration antiretroviral therapy (ART) are not fully understood, and the underlying pathophysiology is unclear. To address this, we established a cohort of such individuals and compared them with HIV-negative controls using a novel matching technique. Both groups underwent extensive cognitive testing, evaluation for psychiatric measures, and MRI and CSF analyses. METHODS: Participants underwent comprehensive neuropsychological testing and completed standardized questionnaires measuring depressive symptoms, perceptions of own functioning, and activities of daily living as part of an observational study. Brain MRI and lumbar puncture were optional. Coarsened Exact Matching was used to reduce between-group differences in age and sex, and weighted linear/logistic regression models were used to assess the effect of HIV on outcomes. RESULTS: Data were analyzed from 155 PWH on ART for at least 15 years and 100 HIV-negative controls. Compared with controls, PWH scored lower in the domains of attention/working memory (PWH least square mean [LSM] = 50.4 vs controls LSM = 53.1, p = 0.008) and motor function (44.6 vs 47.7, p = 0.009) and a test of information processing speed (symbol search 30.3 vs 32.2, p = 0.003). They were more likely to self-report a higher number of cognitive difficulties in everyday life (p = 0.011). PWH also reported more depressive symptoms, general anxiety, and use of psychiatric medications (all with p < 0.05). PWH had reduced proportions of subcortical gray matter on MRI (ß = -0.001, p < 0.001), and CSF showed elevated levels of neurofilament light chain (664 vs 529 pg/mL, p = 0.01) and tumor necrosis factor α (0.229 vs 0.156 ng/mL, p = 0.0008). DISCUSSION: PWH, despite effective ART for over a decade, displayed neurocognitive deficits and mood abnormalities. MRI and CSF analyses revealed reduced brain volume and signs of ongoing neuronal injury and neuroinflammation. As the already large proportion of virologically controlled PWH continues to grow, longitudinal studies should be conducted to elucidate the implications of cognitive, psychiatric, MRI, and CSF abnormalities in this group.

Role of supplementary motor area in cervical dystonia and sensory tricks.

Sensory trick is a characteristic feature of cervical dystonia (CD), where a light touch on the area adjacent to the dystonia temporarily improves symptoms. Clinical benefit from sensory tricks can be observed before tactile contact is made or even by imagination. The supplementary motor area (SMA) may dynamically interact with the sensorimotor network and other brain regions during sensory tricks in patients with CD. In this study, we examined the functional connectivity of the SMA at rest and during sensory trick performance and imagination in CD patients compared to healthy controls using functional magnetic resonance imaging. The functional connectivity between the SMA and left intraparietal sulcus (IPS) region was lower in CD patients at rest and it increased with sensory trick imagination and performance. SMA-right cerebellum connectivity also increased with sensory trick imagination in CD patients, while it decreased in healthy controls. In CD patients, SMA connectivity increased in the brain regions involved in sensorimotor integration during sensory trick performance and imagination. Our study results showed a crucial role of SMA in sensorimotor processing during sensory trick performance and imagination and suggest the IPS as a novel potential therapeutic target for brain modulation.

Comparison of Ultrasound and Electrical Stimulation Guidance for Onabotulinum Toxin-A Injections: A Randomized Crossover Study.

Background: Botulinum neurotoxin (BoNT) injection is an established therapy for limb spasticity and focal limb dystonia. Comparative benefits of injection guidance procedures have not been rigorously studied. Objectives: We compared 2 targeting techniques for onabotulinumtoxin-A (onabotA) injection for the treatment of focal hand dystonia and upper limb spasticity: electrophysiologic guidance using electrical stimulation (E-stim) and ultrasound (US). Methods: This was a 2-center, randomized, crossover, assessor-blinded trial. Participants with focal hand dystonia or upper limb spasticity, on stable onabotA therapy for at least 2 previous injection cycles, were randomly assigned to either E-stim or US with crossover at 3 months. The primary outcome was improvement in dystonia or spasticity severity on a visual analog scale (VAS; 0-100) measured 1 month after each injection. The secondary outcome was participant discomfort assessed on a VAS. Repeated-measures analysis of covariance was used with linear mixed-model covariate selection. Results: A total of 19 participants (13 men) completed the study, 10 with upper limb spasticity and 9 with dystonia. Benefit was equivalent between the 2 techniques (VAS least-square mean [LSmean] 51.5 mm with US and 53.1 with E-stim). E-stim was perceived as more uncomfortable by participants (VAS LSmean 34.5 vs. 19.9 for E-stim and US, respectively). Procedure duration was similar with the 2 procedures. There were no serious adverse events related to either approach. Conclusions: US and E-Stim localization guidance techniques provide equivalent efficacy in onabotA injections for spasticity and dystonia. US guidance injections are more comfortable for participants. Both techniques are effective guidance methods, with US potentially preferable based on participant comfort.

Retinal Thinning in People With Well-Controlled HIV Infection.

BACKGROUND: Retinal measurements correlate with disease progression in patients with multiple sclerosis; however, whether they associate with neurologic disease in people with controlled HIV is unknown. Using spectral domain optical coherence tomography, we evaluated retinal differences between people with HIV and HIV-negative controls and investigated clinical correlates of retinal thinning. METHODS: People with HIV on antiretroviral therapy for at least 1 year and HIV-negative controls recruited from the same communities underwent spectral domain optical coherence tomography, ophthalmic examination, brain MRI, and neuropsychological testing. Retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GC-IPL) thicknesses were compared between groups using analysis of covariance with relevant clinical variables as covariates. Linear regression was used to explore associations of HIV history variables, cognitive domain scores, and MRI volume measurements within the HIV group. RESULTS: The HIV group (n = 69), with long-duration HIV infection (median time from diagnosis 19 years) and outstanding viral control have thinner retinal layers than HIV-negative controls (n = 28), after adjusting for covariates (GC-IPL: P = 0.002; RNFL: P = 0.024). The effect of HIV on GC-IPL thickness was stronger in women than in men (Women: P = 0.011; Men: P = 0.126). GC-IPL thickness is associated with information processing speed in the HIV group (P = 0.007, semipartial r = 0.309). No associations were found with retinal thinning and MRI volumes or HIV factors. CONCLUSIONS: People with HIV on antiretroviral therapy have thinning of the RNFL and GC-IPL of the retina, and women particularly are affected to a greater degree. This retinal thinning was associated with worse performance on tests of information processing speed.

Logistic Regression-Based Model Is More Efficient Than U-Net Model for Reliable Whole Brain Magnetic Resonance Imaging Segmentation.

OBJECTIVES: Automated whole brain segmentation from magnetic resonance images is of great interest for the development of clinically relevant volumetric markers for various neurological diseases. Although deep learning methods have demonstrated remarkable potential in this area, they may perform poorly in nonoptimal conditions, such as limited training data availability. Manual whole brain segmentation is an incredibly tedious process, so minimizing the data set size required for training segmentation algorithms may be of wide interest. The purpose of this study was to compare the performance of the prototypical deep learning segmentation architecture (U-Net) with a previously published atlas-free traditional machine learning method, Classification using Derivative-based Features (C-DEF) for whole brain segmentation, in the setting of limited training data. MATERIALS AND METHODS: C-DEF and U-Net models were evaluated after training on manually curated data from 5, 10, and 15 participants in 2 research cohorts: (1) people living with clinically diagnosed HIV infection and (2) relapsing-remitting multiple sclerosis, each acquired at separate institutions, and between 5 and 295 participants' data using a large, publicly available, and annotated data set of glioblastoma and lower grade glioma (brain tumor segmentation). Statistics was performed on the Dice similarity coefficient using repeated-measures analysis of variance and Dunnett-Hsu pairwise comparison. RESULTS: C-DEF produced better segmentation than U-Net in lesion (29.2%-38.9%) and cerebrospinal fluid (5.3%-11.9%) classes when trained with data from 15 or fewer participants. Unlike C-DEF, U-Net showed significant improvement when increasing the size of the training data (24%-30% higher than baseline). In the brain tumor segmentation data set, C-DEF produced equivalent or better segmentations than U-Net for enhancing tumor and peritumoral edema regions across all training data sizes explored. However, U-Net was more effective than C-DEF for segmentation of necrotic/non-enhancing tumor when trained on 10 or more participants, probably because of the inconsistent signal intensity of the tissue class. CONCLUSIONS: These results demonstrate that classical machine learning methods can produce more accurate brain segmentation than the far more complex deep learning methods when only small or moderate amounts of training data are available (n ≤ 15). The magnitude of this advantage varies by tissue and cohort, while U-Net may be preferable for deep gray matter and necrotic/non-enhancing tumor segmentation, particularly with larger training data sets (n ≥ 20). Given that segmentation models often need to be retrained for application to novel imaging protocols or pathology, the bottleneck associated with large-scale manual annotation could be avoided with classical machine learning algorithms, such as C-DEF.

Correlation between intestinal microbiotal imbalance and 5-HT metabolism, immune inflammation in chronic unpredictable mild stress male rats.

To explore the role of intestinal microbiota on the occurrence of depression-like behavior. Twenty male adult Wistar rats were randomly divided into control and experimental groups. Depression-like behavior of the rats was validated using sucrose preference test (SPT) and forced swimming test (FST) after chronic unpredictable mild stress (CUMS) for 3 weeks. Fecal microbiota was analyzed through 16S rRNA sequence analysis. The levels of 5-HT and inflammatory factors in the colon, brain and sera were measured using enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR) and western blotting analyses. The percentage of different types of immune cells in the peripheral blood was determined through flow cytometry. CUMS caused depression-like symptoms, including anhedonia and desperate behavior. Significant differences were found in the structure and abundance of intestinal microbiota. CUMS intervention significantly increased the levels of 5-HT and Tph1 in the colon and decreased the level of Scl6a4. The concentrations of 5-HT and Tph2 in the prefrontal and hippocampal tissues were lower, while IDO1 was higher. Certain cytokines, such as IL-6, IL-1 and TNF-ɑ, were significantly elevated in peripheral blood, while the percentage of CD3+ CD4+ double-positive cells and CD4+ /CD8+ ratio were downregulated in the CUMS group. Pearson correlation analysis showed that intestinal microbiota was significantly associated with not only the metabolism of 5-HT in intestinal and brain tissues, but also with the proportion of immune cells and certain cytokines. Stress can lead to disturbances in the intestinal microbial structure, which may contribute to depression by interfering with 5-HT metabolism and immune inflammatory responses.

Diagnostic Neurophysiologic Biomarkers for Task-Specific Dystonia.

Background: Task-specific dystonia (TSD) is a challenging clinical diagnosis with no objective diagnostic biomarkers. Objective: The objective of this study was to test 2 neurophysiologic variables using transcranial magnetic stimulation as potential diagnostic biomarkers for TSD. Methods: We tested (1) cortical silent period (CSP) and (2) dorsal inferior parietal lobule-motor cortex (dIPL-M1) physiologic connectivity in 9 patients with the writer's cramp form of TSD and 12 healthy volunteers on 2 separate sessions. Results: CSP was significantly prolonged (P < 0.0001) in TSD and could classify TSD with high sensitivity and specificity with areas under the receiver operating characteristic curve (AUCs) = 0.94 and 0.90, respectively, for 2 separate sessions with an intraclass correlation = 0.79. dIPL-M1 interaction was notable for significant motor cortical inhibition in TSD compared with facilitation in healthy subjects (P < 0.0001) and could classify TSD with high sensitivity and specificity with AUCs = 0.96 and 0.86, respectively. Conclusion: CSP and dIPL-M1 physiologic connectivity can classify TSD with high sensitivity, specificity, reproducibility, and reliability.

Investigation of the posterior parietal cortex to ventral premotor connection in writer's cramp using transcranial magnetic stimulation.

The posterior parietal, premotor and motor cortices are brain regions relevant in the planning of movement. Previous transcranial magnetic stimulation (TMS) studies have shown ipsilateral premotor-to-motor inhibition in healthy subjects at rest. This premotor-to-motor inhibition has been found to be altered in patients with writer's cramp (WC), a common type of focal hand dystonia. We aimed to investigate the influence of the posterior parietal cortex on the ipsilateral ventral premotor cortex using a three single-pulse TMS paradigm. Nineteen right-handed subjects (eleven healthy volunteers and eight WC patients) completed the study. A three single-pulse TMS paradigm (preconditioning, conditioning, and test stimuli) was used to sequentially stimulate the left posterior parietal, ventral premotor, and primary motor cortices. We found that in both healthy subjects and patients, stimulating the ipsilateral posterior parietal cortex resulted in reversal of the resting premotor-to-motor inhibition. Resting premotor-to-motor inhibition was also found, with no statistically significant group difference. Furthermore, a facilitatory effect of the posterior parietal cortex on the primary motor cortex was found in both groups. Our results suggest that in the resting state, the inhibitory effect of the left posterior parietal cortex on the ipsilateral ventral premotor cortex found in healthy subjects is also intact in WC patients. While we are unable to identify any parietal-to-premotor connectivity abnormality in the resting state, an abnormality during a specific task cannot be excluded. Previously reported conductivity abnormalities in resting fMRI do not appear to translate into a TMS physiological abnormality.

Cortical lesion hotspots and association of subpial lesions with disability in multiple sclerosis.

BACKGROUND: Dramatic improvements in visualization of cortical (especially subpial) multiple sclerosis (MS) lesions allow assessment of impact on clinical course. OBJECTIVE: Characterize cortical lesions by 7 tesla (T) T2*-/T1-weighted magnetic resonance imaging (MRI); determine relationship with other MS pathology and contribution to disability. METHODS: Sixty-four adults with MS (45 relapsing-remitting/19 progressive) underwent 3 T brain/spine MRI, 7 T brain MRI, and clinical testing. RESULTS: Cortical lesions were found in 94% (progressive: median 56/range 2-203; relapsing-remitting: 15/0-168; p = 0.004). Lesion distribution across 50 cortical regions was nonuniform (p = 0.006), with highest lesion burden in supplementary motor cortex and highest prevalence in superior frontal gyrus. Leukocortical and white matter lesion volumes were strongly correlated (r = 0.58, p < 0.0001), while subpial and white matter lesion volumes were moderately correlated (r = 0.30, p = 0.002). Leukocortical (p = 0.02) but not subpial lesions (p = 0.40) were correlated with paramagnetic rim lesions; both were correlated with spinal cord lesions (p = 0.01). Cortical lesion volumes (total and subtypes) were correlated with expanded disability status scale, 25-foot timed walk, nine-hole peg test, and symbol digit modality test scores. CONCLUSION: Cortical lesions are highly prevalent and are associated with disability and progressive disease. Subpial lesion burden is not strongly correlated with white matter lesions, suggesting differences in inflammation and repair mechanisms.

Differences in peripheral neuropathy in xeroderma pigmentosum complementation groups A and D as evaluated by nerve conduction studies.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder with defective DNA nucleotide excision repair and associated with a high frequency of skin cancer. Approximately 25% of patients develop progressive neurological degeneration. Complementation groups XP-A and XP-D are most frequently associated with neurological disorders. DESIGN/METHODS: This is a retrospective review of patients with XP who were evaluated at NIH from 1986 to 2015 and had nerve conduction studies (NCS). In the complementation groups with peripheral neuropathy, further comparisons of the NCS were made with audiological, brain imaging, neuropsychological assessments that were also performed on most of the patients. Limited neuropathology of XP-A and XP-D patients were examined.. RESULTS: The 33 patients had NCS: XP-A (9 patients), XP-C (7 patients), XP-D (10 patients), XP-E (1 patient), XP-V (4 patients), and XP-unknown (2 patients). Peripheral neuropathy based on nerve conduction studies was documented only in two complementation groups: 78% (7/9) of XP-A patients had a sensorimotor neuropathy while 50% (5/10) of XP-D patients had a sensory neuropathy only. Analysis of sural sensory nerve amplitude in both complementation groups XP-A and XP-D correlated with sensorineural hearing loss (SNHL), MRI/CT severity, and Full-scale Intelligence Quotient (IQ). Analysis of fibular motor nerve amplitude in complementation XP-A correlated with SNHL and MRI/CT severity. Limited follow-up studies showed gradual loss of NCS responses compared to an earlier and more rapid progression of the hearing loss. CONCLUSIONS: Despite similar brain imaging and audiological findings patients, XP-A and XP-D complementation groups differ in the type of neuropathy, sensorimotor versus sensory alone. A few cases suggest that sensorineural hearing loss may precede abnormal NCS in XP and therefore serve as valuable clinical indicators of XP patients that will later develop peripheral neuropathy.

A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis.

Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans1-3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state4-6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define 'microglia inflamed in MS' (MIMS) and 'astrocytes inflamed in MS', glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.

Cervical and thoracic cord atrophy in multiple sclerosis phenotypes: Quantification and correlation with clinical disability.

OBJECTIVE: We sought to characterize spinal cord atrophy along the entire spinal cord in the major multiple sclerosis (MS) phenotypes, and evaluate its correlation with clinical disability. METHODS: Axial T1-weighted images were automatically reformatted at each point along the cord. Spinal cord cross-sectional area (SCCSA) were calculated from C1-T10 vertebral body levels and profile plots were compared across phenotypes. Average values from C2-3, C4-5, and T4-9 regions were compared across phenotypes and correlated with clinical scores, and then categorized as atrophic/normal based on z-scores derived from controls, to compare clinical scores between subgroups. In a subset of relapsing-remitting cases with longitudinal scans these regions were compared to change in clinical scores. RESULTS: The cross-sectional study consisted of 149 adults diagnosed with relapsing-remitting MS (RRMS), 49 with secondary-progressive MS (SPMS), 58 with primary-progressive MS (PPMS) and 48 controls. The longitudinal study included 78 RRMS cases. Compared to controls, all MS groups had smaller average regions except RRMS in T4-9 region. In all MS groups, SCCSA from all regions, particularly the cervical cord, correlated with most clinical measures. In the RRMS cohort, 22% of cases had at least one atrophic region, whereas in progressive MS the rate was almost 70%. Longitudinal analysis showed correlation between clinical disability and cervical cord thinning. CONCLUSIONS: Spinal cord atrophy was prevalent across MS phenotypes, with regional measures from the RRMS cohort and the progressive cohort, including SPMS and PPMS, being correlated with disability. Longitudinal changes in the spinal cord were documented in RRMS cases, making it a potential marker for disease progression. While cervical SCCSA correlated with most disability and progression measures, inclusion of thoracic measurements improved this correlation and allowed for better subgrouping of spinal cord phenotypes. Cord atrophy is an important and easily obtainable imaging marker of clinical and sub-clinical progression in all MS phenotypes, and such measures can play a key role in patient selection for clinical trials.