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1.  In Vivo Evidence of Glutamate Toxicity in Multiple Sclerosis 
Annals of neurology  2014;76(2):269-278.
There is increasing evidence that altered glutamate (Glu) homeostasis is involved in the pathophysiology of multiple sclerosis (MS). The aim of this study was to evaluate the in vivo effects of excess brain Glu on neuroaxonal integrity measured by N-acetylaspartate (NAA), brain volume, and clinical outcomes in a large, prospectively followed cohort of MS subjects.
We used multivoxel spectroscopy at 3T to longitudinally estimate Glu and NAA concentrations from large areas of normal-appearing white and gray matter (NAWM and GM) in MS patients (n = 343) with a mean follow-up time of 5 years. Using linear mixed-effects models, Glu was examined as a predictor of NAA decline, annualized percentage brain volume change, and evolution of clinical outcomes (Multiple Sclerosis Functional Composite [MSFC], Paced Auditory Serial Addition Test-3 [PASAT], and Expanded Disability Status Scale). Glu/NAA ratio was tested as a predictor of brain volume loss and clinical outcomes.
Baseline Glu[NAWM] was predictive of accelerated longitudinal decline in NAA[GM] (–0.06mM change in NAA[GM]/yr for each unit increase in Glu; p = 0.004). The sustained elevation of Glu[NAWM] was predictive of a loss of 0.28mM/yr in NAA[NAWM] (p < 0.001) and 0.15mM/yr in NAA[GM] (p = 0.056). Each 10% increase in Glu/NAA[NAWM] was associated with a loss of 0.33% brain volume/yr (p = 0.001), 0.009 standard deviations/yr in MSFC z-score (p < 0.001), and 0.17 points/yr on the PASAT (p < 0.001).
These results indicate that higher Glu concentrations increase the rate of NAA decline, and higher Glu/NAA[NAWM] ratio increases the rate of decline of brain volume, MSFC, and PASAT. This provides evidence of a relationship between brain Glu and markers of disease progression in MS.
PMCID: PMC4142752  PMID: 25043416
2.  Two different mechanisms associated with ripple-like oscillations (100-250 Hz) in the human epileptic subiculum in vitro 
Annals of neurology  2014;77(2):281-290.
Transient high-frequency oscillations (150-600 Hz) in local field potential generated by human hippocampal and parahippocampal areas have been related to both physiological and pathological processes. The cellular basis and effects of normal and abnormal forms of high-frequency oscillations (HFO) has been controversial. Here, we searched for HFOs in slices of the subiculum prepared from human hippocampal tissue resected for treatment of pharmacoresistant epilepsy. HFOs occurred spontaneously in extracellular field potentials during interictal discharges (IID) and also during pharmacologically induced preictal discharges (PID) preceding ictal-like events. While most of these events might be considered pathological since they invaded the fast ripple band (>250 Hz), others were spectrally similar to physiological ripples (150-250 Hz). Do similar cellular mechanisms underly IID-ripples and PID-ripples? Are ripple-like oscillations a valid proxy of epileptogenesis in human TLE? With combined intra- or juxta-cellular and extracellular recordings, we showed that, despite overlapping spectral components, ripple-like IID and PID oscillations were associated with different cellular and synaptic mechanisms. IID-ripples were associated with rhythmic GABAergic and glutamatergic synaptic potentials with moderate neuronal firing. In contrast, PID-ripples were associated with depolarizing synaptic inputs frequently reaching the threshold for bursting in most cells. Thus ripple-like oscillations (100-250 Hz) in the human epileptic hippocampus are associated with different mechanisms for synchrony reflecting distinct dynamic changes in inhibition and excitation during interictal and pre-ictal states.
PMCID: PMC4409108  PMID: 25448920
3.  Genetic association signal near NTN4 in Tourette Syndrome 
Annals of neurology  2014;76(2):310-315.
Tourette Syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (SNPs)(p<10−3) from the recent TS genome-wide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p=3.3×10−4) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p=5.8×10−7). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case/control status (p=0.042), suggesting that many of these variants are true TS risk alleles.
PMCID: PMC4140987  PMID: 25042818
4.  Cell-surface CNS autoantibodies: clinical relevance and emerging paradigms 
Annals of neurology  2014;76(2):168-184.
The recent discovery of several potentially pathogenic autoantibodies has helped identify patients with clinically-distinctive central nervous system diseases that appear to benefit from immunotherapy. The associated autoantibodies are directed against the extracellular domains of cell-surface expressed neuronal or glial proteins such as LGI1, the NMDA-receptor and aquaporin-4. The original descriptions of the associated clinical syndromes were phenotypically well-circumscribed. However, as availability of antibody testing has increased, the range of associated patient phenotypes and demographics has expanded. This, in turn, has led to the recognition of more immunotherapy-responsive syndromes in patients presenting with cognitive and behavioural problems, seizures, movement disorders, psychiatric features, and demyelinating disease. While antibody detection remains diagnostically important, clinical recognition of these distinctive syndromes should ensure early and appropriate immunotherapy administration.
We review the emerging paradigm of cell-surface directed antibody-mediated neurological diseases, describe how the associated disease spectrums have broadened since the original descriptions, discuss some of the issues regarding antibody detection and syndrome definitions, and emphasize considerations surrounding immunotherapy administration. As these disorders continue to reach mainstream neurology, and even psychiatry, more cell-surface directed antibodies will be discovered and their possible relevance to other commoner disease presentations should become more clearly defined.
PMCID: PMC4141019  PMID: 24930434
autoimmune; autoantibody; encephalitis; LGI1 (leucine-rich glioma inactivated 1); NMDA (N-Methyl, D-Aspartate); aquaporin-4
5.  Functional anatomy of subthalamic nucleus stimulation in Parkinson disease 
Annals of neurology  2014;76(2):279-295.
We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3D brain region and to assign statistical significance after stringent Type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS.
Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t-tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site.
Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory).
Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, since movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive and limbic information in STN.
PMCID: PMC4172323  PMID: 24953991
6.  A fatal case of JC virus meningitis presenting with hydrocephalus in an HIV-seronegative patient 
Annals of neurology  2014;76(1):140-147.
JC virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy and JCV encephalopathy. Whether JCV can also cause meningitis, has not yet been demonstrated. We report a case of aseptic meningitis resulting in symptomatic hydrocephalus in an HIV-seronegative patient. Brain imaging showed enlargement of ventricles but no parenchymal lesion. She had a very high JC viral load in the CSF and developed progressive cognitive dysfunction despite ventricular drainage. She was diagnosed with pancytopenia and passed away after 5 ½ months. Post-mortem exam revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement. Sequencing of JCV CSF strain showed an archetype-like regulatory region. Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalus are warranted.
PMCID: PMC4112354  PMID: 24895208
7.  C9orf72 and UNC13A are shared risk loci for ALS and FTD: a genome-wide meta-analysis 
Annals of neurology  2014;76(1):120-133.
Substantial clinical, pathological and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD.
We used published GWAS data of 4,377 ALS patients and 13,017 controls and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes.
Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) at C9orf72 on chromosome 9p21.2 (lowest p=2.6×10−12) and one SNP in UNC13A on chromosome 19p13.11 (p=1.0×10−11) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin, (p=3.91×10−7) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p=0.026; combined analysis p=1.01×10−7).
We identified common genetic variants at C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.
PMCID: PMC4137231  PMID: 24931836
8.  Copy number variation plays an important role in clinical epilepsy 
Annals of neurology  2014;75(6):943-958.
To evaluate the role of copy number abnormalities detectable by chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center.
We identified patients with ICD-9 codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children’s Hospital. We reviewed medical records and included patients meeting criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA.
Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1–4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18 kb to 142 Mb, and 34% were over 500 kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or “hotspots.” We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy.
Copy number abnormalities play an important role in patients with epilepsy. Given that the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.
PMCID: PMC4487364  PMID: 24811917
Epilepsy; array comparative genomic hybridization (aCGH); chromosomal microarray; copy number variants; deletions; duplications; chromosomal abnormalities
9.  JC virus Reactivation During Prolonged Natalizumab Monotherapy for Multiple Sclerosis 
Annals of neurology  2014;75(6):925-934.
To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS).
We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy>18 months, 6 on interferon β-1a monotherapy>36 months and 5 untreated controls. We performed QPCR in cerebrospinal fluid (CSF), blood and urine for JCV DNA and we determined JCV-specific T cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides.
JCV DNA was detected in the CSF of 2/27 (7.4%) natalizumab-treated MS patients who had no symptoms or MRI lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12/43 (27.9%) and in urine of 11/43 (25.6%) subjects without difference between natalizumab-treated patients and controls. JC viral load was higher in CD34+ cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot, and JCV-specific T cell responses, mediated by both CD4+ and CD8+ T-lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4+ T-cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34+ (p=0.05) and B cells (p=0.03).
Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34+ cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4+ T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment.
PMCID: PMC4425205  PMID: 24687904
JC virus; natalizumab; progressive multifocal leukoencephalopathy
10.  Gain-of-Function ADCY5 Mutations in Familial Dyskinesia with Facial Myokymia 
Annals of neurology  2014;75(4):542-549.
To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM).
Whole exome sequencing was performed on 2 parent–child trios. The effect of mutations in ADCY5 was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions.
The same de novo mutation (c.1252C>T, p.R418W) in ADCY5 was found in both studied cases. An inherited missense mutation (c.2176G>A, p.A726T) in ADCY5 was previously reported in a family with FDFM. The significant phenotypic overlap with FDFM was recognized in both cases only after discovery of the molecular link. The inherited mutation in the FDFM family and the recurrent de novo mutation affect residues in different protein domains, the first cytoplasmic domain and the first membrane-spanning domain, respectively. Functional studies revealed a statistically significant increase in β-receptor agonist-stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild-type protein, indicative of a gain-of-function effect.
FDFM is likely caused by gain-of-function mutations in different domains of ADCY5—the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis-free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in ADCY5 should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history.
PMCID: PMC4457323  PMID: 24700542
11.  Gp120 in the pathogenesis of human HIV-associated pain 
Annals of neurology  2014;75(6):837-850.
Chronic pain is a common neurological comorbidity of HIV-1 infection, but the etiological cause remains elusive. The objective of this study was to identify the HIV-1 causal factor that critically contributes to the pathogenesis of HIV-associated pain.
We first compared the levels of HIV-1 proteins in postmortem tissues of the spinal cord dorsal horn (SDH) from HIV-1/AIDS patients who developed chronic pain (‘pain-positive’ HIV-1 patients) and HIV-1 patients who did not develop chronic pain (‘pain-negative’ HIV-1 patients). Then, we used the HIV-1 protein that was specifically increased in the ‘pain-positive’ patients to generate mouse models. Finally, we performed comparative analyses on the pathological changes in the models and the HIV-1 patients.
We found that HIV-1 gp120 was significantly higher in ‘pain-positive’ HIV-1 patients (vs. ‘pain-negative’ HIV-1 patients). This finding suggested that gp120 was a potential causal factor of the HIV-associated pain. To test this hypothesis, we used a mouse model generated by intrathecal injection (i.t.) of gp120 and compared the pathologies of the model and the ‘pain-positive’ human HIV-1 patients. The results showed that the mouse model and ‘pain-positive’ human HIV-1 patients developed extensive similarities in their pathological phenotypes, including pain behaviors, peripheral neuropathy, glial reactivation, synapse degeneration and aberrant activation of pain-related signaling pathways in the SDH.
Our findings suggest that gp120 may critically contribute to the pathogenesis of HIV-associated pain.
PMCID: PMC4077969  PMID: 24633867
12.  Losartan prevents acquired epilepsy via TGF-β signaling suppression 
Annals of neurology  2014;75(6):864-875.
Acquired epilepsy is frequently associated with structural lesions following trauma, stroke and infections. While seizures are often difficult to treat, there is no clinically applicable strategy to prevent the development of epilepsy in patients at risk. We have recently shown that vascular injury is associated with activation of albumin-mediated transforming growth factor β (TGF-β) signaling, and followed by local inflammatory response and epileptiform activity ex vivo. Here we investigated albumin-mediated TGF-β signaling and tested the efficacy of blocking the TGF-β pathway in preventing epilepsy.
We addressed the role of TGF-β signaling in epiletogenesis in two different rat models of vascular injury, combining in vitro and in vivo biochemical assays, gene expression, magnetic resonance and direct optical imaging for blood-brain barrier (BBB) permeability and vascular reactivity. Long-term electrocorticographic (ECoG) recordings were acquired in freely behaving animals.
We demonstrate that serum-derived albumin preferentially induces activation of the activin receptor-like kinase 5 (ALK5) pathway of TGF-β receptor I in astrocytes. We further show that the angiotensin II type 1 receptor antagonist (AT1), losartan, previously identified as a blocker of peripheral TGF-β signaling, effectively blocks albumin-induced TGF-β activation in the brain. Most importantly, losartan prevents the development of delayed recurrent spontaneous seizures, an effect that persists weeks after drug withdrawal.
TGF-β signaling, activated in astrocytes by serum-derived albumin, is involved in epileptogenesis. We propose losartan, an FDA-approved drug, as an efficient anti-epileptogenic therapy for epilepsy associated with vascular injury.
PMCID: PMC4077937  PMID: 24659129
13.  NeuroGenesis feature Careers in Global Neurology 
Annals of neurology  2014;75(6):805-809.
PMCID: PMC4116612  PMID: 24942697
14.  Stroke Risk After Non-Stroke ED Dizziness Presentations: A Population-Based Cohort Study 
Annals of neurology  2014;75(6):899-907.
Acute stroke is a serious concern in Emergency Department (ED) dizziness presentations. Prior studies, however, suggest that stroke is actually an unlikely cause of these presentations. Lacking are data on short- and long-term follow-up from population-based studies to establish stroke risk after presumed non-stroke ED dizziness presentations.
From 5/8/2011 to 5/7/2012, patients ≥ 45 years of age presenting to EDs in Nueces County, Texas, with dizziness, vertigo, or imbalance were identified, excluding those with stroke as the initial diagnosis. Stroke events after the ED presentation up to 10/2/2012 were determined using the Brain Attack Surveillance in Corpus Christi (BASIC) study, which uses rigorous surveillance and neurologist validation. Cumulative stroke risk was calculated using Kaplan-Meier estimates.
1,245 patients were followed for a median of 347 days (IQR 230- 436 days). Median age was 61.9 years (IQR, 53.8-74.0 years). After the ED visit, fifteen patients (1.2%) had a stroke. Stroke risk was 0.48% (95% CI, 0.22%-1.07%) at 2 days; 0.48% (95% CI, 0.22%-1.07%) at 7 days; 0.56% (95% CI, 0.27%-1.18%) at 30 days; 0.56% (95% CI, 0.27%-1.18%) at 90 days; and 1.42% (95% CI, 0.85%-2.36%) at 12 months.
Using rigorous case ascertainment and outcome assessment in a population-based design, we found that the risk of stroke after presumed non-stroke ED dizziness presentations is very low, supporting a non-stroke etiology to the overwhelming majority of original events. High-risk subgroups likely exist, however, because most of the 90-day stroke risk occurred within 2-days. Vascular risk stratification was insufficient to identify these cases.
PMCID: PMC4286199  PMID: 24788511
15.  APOEε2 is associated with milder clinical and pathological Alzheimer's disease 
Annals of neurology  2015;77(6):917-929.
The Alzheimer disease (AD) APOEε4 risk allele associates with an earlier age of onset and increased amyloid-β deposition, whereas the protective APOEε2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOEε2 remain uncertain because of its relative rarity. We investigated the effects of APOE ε2 and ε4 alleles on AD pathology and cognition in a large US dataset of well characterized AD patients.
We studied individuals from the National Alzheimer's Coordinating Center (NACC) autopsy cohort across the entire clinico-pathological continuum of AD. Multivariable models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOEε3/ε3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (CDR-SOB and MMSE).
Compared to APOEε3/ε3, APOEε2 is independently associated with lower Braak NFT stages and, possibly, fewer neuritic plaques, but has no direct effect on CAA severity, whereas APOEε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (ε2>ε3>ε4). Mediation analysis suggests that this is largely explained through effects on pathology.
Even when adjusted for age of onset, symptom duration and other demographic variables, APOEε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOE ε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOEε2 in AD.
PMCID: PMC4447539  PMID: 25623662
Alzheimer disease; amyloid plaques; apolipoprotein E; cerebral amyloid angiopathy; neurofibrillary tangles
16.  Reactive oxygen species and NLRP3 inflammasome activation (Reply) 
Annals of neurology  2014;75(6):972-973.
PMCID: PMC4145719  PMID: 24805252
17.  Residual Tumor Cells Are Unique Cellular Targets in Glioblastoma 
Annals of neurology  2010;68(2):264-269.
Residual tumor cells remain beyond the margins of every glioblastoma (GBM) resection. Their resistance to postsurgical therapy is considered a major driving force of mortality, but their biology remains largely uncharacterized. In this study, residual tumor cells were derived via experimental biopsy of the resection margin after standard neurosurgery for direct comparison with samples from the routinely resected tumor tissue. In vitro analysis of proliferation, invasion, stem cell qualities, GBM-typical antigens, genotypes, and in vitro drug and irradiation challenge studies revealed these cells as unique entities. Our findings suggest a need for characterization of residual tumor cells to optimize diagnosis and treatment of GBM.
PMCID: PMC4445859  PMID: 20695020
18.  A Novel Recessive NEFL Mutation Causes a Severe, Early-Onset Axonal Neuropathy 
Annals of neurology  2009;66(6):759-770.
To report the first cases of homozygous recessive mutations in NEFL, the gene that encodes the light subunit of neurofilaments (NFL).
Clinical and electrophysiologic data of all family members were evaluated, and a sural nerve biopsy from one affected child was examined by immunohistochemistry and electron microscopy. The ability of the mutant protein to form filaments was characterized in an established cell culture system.
Four of five siblings developed a severe, progressive neuropathy beginning in early childhood. Serial nerve conduction studies showed progressively reduced amplitudes with age, and pronounced slowing at all ages. Visual evoked responses were slowed in three children, indicating that CNS axons were subclinically involved. All four affected children were homozygous for a nonsense mutation at glutamate 210 (E210X) in the NEFL gene; both parents were heterozygous carriers. A sural nerve biopsy from an affected patient at age 16 revealed markedly reduced numbers of myelinated axons; the remaining myelinated axons were small and lacked intermediate filaments. The E210X mutant protein did not form an intermediate filament network, and did not interfere with the filament formation by wild type human NFL in SW-13 vim- cells.
This is the first demonstration of a recessive NEFL mutation, which appears to cause a simple loss-of-function, resulting in a severe, early-onset axonal neuropathy with unique features. These results confirm that neurofilaments are the main determinant of axonal caliber and conduction velocity, and demonstrate for the first time that neurofilaments are required for the maintenance of myelinated PNS axons.
PMCID: PMC4439312  PMID: 20039262
neurofilament; Charcot-Marie-Tooth disease; CMT; myelin; axon; conduction velocity
Annals of neurology  2014;75(5):771-781.
Nonconvulsive seizures (NCSz) are frequent following acute brain injury and have been implicated as a cause of secondary brain injury but mechanisms that cause NCSz are controversial. Pro-inflammatory states are common after many brain injuries and inflammatory mediated changes in blood-brain-barrier permeability have experimentally been linked to seizures.
In this prospective observational study of aneurysmal subarachnoid hemorrhage (SAH) patients we explored the link between the inflammatory response following SAH and in-hospital NCSz studying clinical (systemic inflammatory response syndrome,SIRS) and laboratory markers of inflammation (tumor necrosis factor receptor 1,TNF-R1; high sensitivity C-reactive protein,hsCRP). Logistic regression, cox proportional hazards regression, and mediation analyses were performed to investigate temporal and causal relationships.
Among 479 SAH patients, 53(11%) had in-hospital NCSz. Patients with in-hospital NCSz had a more pronounced SIRS response (OR1.9 per point increase in SIRS; 95%-CI1.3-2.9), inflammatory surges were more likely immediately preceding NCSz onset, and the negative impact of SIRS on functional outcome at 3 months was mediated in part through in-hospital NCSz. In a subset with inflammatory serum biomarkers we confirmed these findings linking higher serum TNF-R1 and hsCRP to in-hospital NCSz (OR1.2 per 20 point hsCRP increase [95%-CI1.1-1.4]; OR2.5 per 100 point TNF-R1 increase [95%-CI2.1-2.9]). The association of inflammatory biomarkers with poor outcome was mediated in part through NCSz.
In-hospital NCSz were independently associated with a pro-inflammatory state following SAH reflected in clinical symptoms and serum biomarkers of inflammation. Our findings suggest that inflammation following SAH is associated with poor outcome and this effect is at least in part mediated through in-hospital NCSz.
PMCID: PMC4084968  PMID: 24771589
inflammation; electrographic seizures; nonconvulsive seizures; subarachnoid hemorrhage; continuous EEG monitoring; brain metabolism
20.  Pathologic Heterogeneity Persists in Early Active Multiple Sclerosis Lesions 
Annals of neurology  2014;75(5):728-738.
Multiple sclerosis (MS) lesions demonstrate immunopathological heterogeneity in patterns of demyelination. Previous cross-sectional studies reported immunopatterns of demyelination were identical among multiple active demyelinating lesions from the same individual, but differed between individuals, leading to the hypothesis of intraindividual pathological homogeneity and interindividual heterogeneity. Other groups suggested a time-dependent heterogeneity of lesions. The objective of our present study was to analyze tissue samples collected longitudinally to determine whether patterns of demyelination persist over time within a given patient.
Archival tissue samples derived from patients with pathologically confirmed CNS inflammatory demyelinating disease who had undergone either diagnostic serial biopsy or biopsy followed by autopsy, were analyzed immunohistochemically. Inclusion criteria was the presence of early active demyelinating lesions - required for immunopattern classification - obtained from the same patient at two or more time points.
Among 1321 surgical biopsies consistent with MS, 22 cases met study inclusion criteria. Twenty-one patients (95%) showed a persistence of immunopathological patterns in tissue sampled from different time points. This persistence was demonstrated for all major patterns of demyelination. A single patient showed features suggestive of both pattern II and pattern III on biopsy, but only pattern II among all active lesions examined at autopsy.
These findings continue to support the concept of patient-dependent immunopathological heterogeneity in early MS and suggest that the mechanisms and targets of tissue injury may differ among patient subgroups. These observations have potentially significant implications for individualized therapeutic approaches.
PMCID: PMC4070313  PMID: 24771535
Multiple sclerosis; histopathology; intra-individual; homogeneity; heterogeneity; active demyelination; persistence over time
21.  Hyperintense cortical signal on MRI reflects focal leukocortical encephalitis and seizure risk in PML 
Annals of neurology  2014;75(5):659-669.
To determine the frequency of hyperintense cortical signal (HCS) on T1-weighted pre-contrast MRI in progressive multifocal leukoencephalopathy (PML) patients, its association with seizure risk and immune reconstitution inflammatory syndrome (IRIS), and its pathologic correlate.
We reviewed clinical data including seizure history, presence of IRIS, and MRI scans from PML patients evaluated at our institution between 2003 and 2012. Cases that were diagnosed either by CSF JC Virus (JCV) PCR, brain biopsy or autopsy, and who had MRI images available were included in the analysis (n=49). We characterized pathologic findings in areas of the brain displaying HCS in two patients and compared them with isointense cortex in the same individuals.
Of 49 patients, 17 (34.7%) had seizures and 30 (61.2%) had HCS adjacent to subcortical PML lesions on MRI. Of the 17 PML patients with seizures, 15 (88.2%) had HCS compared to 15/32 (46.9%) patients without seizures (p= 0.006). HCS was associated with seizure development with a relative risk (RR) of 4.75 (95% confidence interval of 1.2 to 18.5; p=0.006). Of the 20 patients with IRIS, 16 (80.0%) had HCS compared to 14/29 (49.3%) of those without IRIS (p=0.04). On histological examination, HCS areas were associated with striking JCV-associated demyelination of cortical and sub-cortical U-fibers, significant macrophage infiltration and a pronounced reactive gliosis in the deep cortical layers.
Seizures are a frequent complication in PML. HCS is associated with seizures as well as IRIS, and correlates histologically with JCV focal leukocortical encephalitis (JCV FLE).
PMCID: PMC4426496  PMID: 24752885
23.  UBQLN2 Mutation Causing Heterogeneous X-linked Dominant Neurodegeneration 
Annals of neurology  2014;75(5):793-798.
We report a five-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year-old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X-linked inheritance in all studied affected individuals. As ubiquilin-2 positive inclusions were identified in brain we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations.
PMCID: PMC4106259  PMID: 24771548
24.  Persistent Ischemic Stroke Disparities despite Declining Incidence in Mexican Americans 
Annals of neurology  2013;74(6):778-785.
To determine trends in ischemic stroke incidence among Mexican Americans and non-Hispanic whites.
We performed population-based stroke surveillance from January 1, 2000 to December 31, 2010 in Corpus Christi, Texas. Ischemic stroke patients 45 years and older were ascertained from potential sources, and charts were abstracted. Neurologists validated cases based on source documentation blinded to ethnicity and age. Crude and age-, sex-, and ethnicity-adjusted annual incidence was calculated for first ever completed ischemic stroke. Poisson regression models were used to calculate adjusted ischemic stroke rates, rate ratios, and trends.
There were 2,604 ischemic strokes in Mexican Americans and 2,042 in non-Hispanic whites. The rate ratios (Mexican American:non-Hispanic white) were 1.94 (95% confidence interval [CI] = 1.67–2.25), 1.50 (95% CI = 1.35– 1.67), and 1.00 (95% CI = 0.90–1.11) among those aged 45 to 59, 60 to 74, and 75 years and older, respectively, and 1.34 (95% CI = 1.23–1.46) when adjusted for age. Ischemic stroke incidence declined during the study period by 35.9% (95% CI = 25.9–44.5). The decline was limited to those aged ≥60 years, and happened in both ethnic groups similarly (p > 0.10), implying that the disparities seen in the 45- to 74-year age group persist unabated.
Ischemic stroke incidence rates have declined dramatically in the past decade in both ethnic groups for those aged ≥60 years. However, the disparity between Mexican American and non-Hispanic white stroke rates persists in those <75 years of age. Although the decline in stroke is encouraging, additional prevention efforts targeting young Mexican Americans are warranted.
PMCID: PMC4418450  PMID: 23868398
25.  Modulation of APP Expression Reduces Aβ Deposition in a Mouse Model 
Annals of neurology  2014;75(5):684-699.
Proteolytic cleavage of the amyloid precursor protein (APP) generates β-amyloid (Aβ) peptides. Prolonged accumulation of Aβ in the brain underlies the pathogenesis of Alzheimer’s disease (AD) and is regarded as a principal target for development of disease-modifying therapeutics.
Using CHO APP751SW cells we identified and characterized effects of 2-[(pyridine-2-ylmethyl)-amino]-phenol (2-PMAP) on APP steady-state level and Aβ production. Outcomes of 2-PMAP treatment on Aβ accumulation and associated memory deficit were studied in APPSW/PS1dE9 AD transgenic model mice.
In CHO APP751SW cells, 2-PMAP in a dose-response manner lowered the steady-state APP level and inhibited Aβx-40 and Aβx-42 production with minimum effective concentration ≤0.5μM. The inhibitory effect of 2-PMAP on translational efficiency of APP mRNA into protein was directly confirmed using 35S-methionine/cysteine metabolic labeling technique, while APP mRNA level remained unaltered. Administration of 2-PMAP to APPSW/PS1dE9 mice reduced brain levels of full length APP and its C-terminal fragments along with lowering levels of soluble Aβx-40 and Aβx-42. Four-month chronic treatment of APPSW/PS1dE9 mice revealed no observable toxicity and improved animals’ memory performance. 2-PMAP treatment also caused significant reduction in brain Aβ deposition determined by both unbiased quantification of Aβ plaque load and biochemical analysis of formic acid extracted Aβx-40 and Aβx-42 levels and the level of oligomeric Aβ.
We demonstrate the potential of modulating APP steady-state expression level as a safe and effective approach for reducing Aβ deposition in AD transgenic model mice.
PMCID: PMC4247163  PMID: 24687915
amyloid precursor protein (APP); β-amyloid (Aβ); behavioral testing; disease modifying therapy; transgenic mice; protein translation

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