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Year of Publication
1.  The Evaluation of Distal Symmetric Polyneuropathy: A Physician Survey of Clinical Practice 
Archives of neurology  2011;69(3):339-345.
Objective
To define current clinical practice in the evaluation of distal symmetric polyneuropathy (DSP).
Deisgn
Using a modified Dillman method, surveys were sent to 600 internists, 600 neurologists, and 45 neuromuscular specialists selected from the AMA Physician Masterfile. Survey questions pertained to which tests providers would order in the following three scenarios: 1) the initial evaluation of DSP, 2) additional tests if the initial evaluation was unrevealing, and 3) patients with diabetes. T-tests were used to compare the number of tests ordered by physician type and chi-square tests to compare proportions of tests ordered.
Setting
National survey of physicians
Participants
Internists and neurologists
Results
The response rate was 35%. Overall, many tests are ordered in the full evaluation of DSP (16.5 ± 7.2), and there is substantial variation within and between provider types. Internists planned to order fewer tests (14.5 ± 6.1) than neurologists (17.5 ± 7.9) (p<0.0001). Regarding the glucose tolerance test (GTT), substantial differences were found between physician types, with neurologists and neuromuscular specialists ordering this test more frequently than internists (28.6% and 72.3% versus 4.1%, respectively). A brain and/or spine MRI was ordered by 19.8% of internists and 12.9% of neurologists.
Conclusions
Practice intent for the evaluation of DSP is highly variable and differs widely from the supporting evidence. A high yield test, the GTT, is rarely utilized; whereas, MRIs are likely over-utilized in this disorder of peripheral nerves. Research that defines the optimal evaluation of DSP has the potential to result in more efficient care.
doi:10.1001/archneurol.2011.1735
PMCID: PMC4254745  PMID: 22083798
2.  Acute Severe Animal Model of Muscle-Specific Kinase Myasthenia: Combined Postsynaptic and Presynaptic Changes 
Archives of neurology  2011;69(4):453-460.
Objective
To determine the pathogenesis of anti-muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies, characterized by focal muscle weakness and wasting, and absence of acetylcholine receptor antibodies; also to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ.
Design/Methods
Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically and by repetitive stimulation of median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy.
Results
Animals immunized with 100ug of MuSK 60 develop severe progressive weakness, starting at day 16, with 100% mortality by day 27. The weakness is associated with high MuSK antibody titers, weight loss, axial muscle wasting and decrementing compound muscle action potentials. Light and electron microscopy demonstrate fragmented NMJs with varying degrees of postsynaptic muscle endplate destruction along with abnormal nerve terminals, lack of registration between endplates and nerve terminals, local axon sprouting and extrajunctional dispersion of cholinesterase activity.
Conclusions
These findings: 1) support the role of MuSK antibodies in the human disease; 2) demonstrate the role of MuSK, not only in the development of the NMJ, but also in the maintenance of the mature synapse; and 3) demonstrate involvement in this disease of both pre- and post-synaptic components of the NMJ.
doi:10.1001/archneurol.2011.2200
PMCID: PMC3915865  PMID: 22158720
3.  Antibodies to Low Density Lipoprotein Receptor-Related Protein 4 in Seronegative Myasthenia Gravis 
Archives of neurology  2011;69(4):434-435.
doi:10.1001/archneurol.2011.2855
PMCID: PMC3903387  PMID: 22158717
4.  Spinal Muscular Atrophy 
Archives of neurology  2011;68(8):10.1001/archneurol.2011.74.
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons in the anterior horn of the spinal cord and resultant weakness. The most common form of SMA, accounting for 95% of cases, is autosomal recessive proximal SMA associated with mutations in the survival of motor neurons (SMN1) gene. Relentless progress during the past 15 years in the understanding of the molecular genetics and pathophysiology of SMA has resulted in a unique opportunity for rational, effective therapeutic trials. The goal of SMA therapy is to increase the expression levels of the SMN protein in the correct cells at the right time. With this target in sight, investigators can now effectively screen potential therapies in vitro, test them in accurate, reliable animal models, move promising agents forward to clinical trials, and accurately diagnose patients at an early or presymptomatic stage of disease. A major challenge for the SMA community will be to prioritize and develop the most promising therapies in an efficient, timely, and safe manner with the guidance of the appropriate regulatory agencies. This review will take a historical perspective to highlight important milestones on the road to developing effective therapies for SMA.
doi:10.1001/archneurol.2011.74
PMCID: PMC3860273  PMID: 21482919
5.  Observational Study of Spinal Muscular Atrophy Type 2 and 3 
Archives of neurology  2011;68(6):10.1001/archneurol.2010.373.
Objective
To characterize the short-term course of spinal muscular atrophy (SMA) in a genetically and clinically well-defined cohort of patients with SMA.
Design
A comprehensive multicenter, longitudinal, observational study.
Setting
The Pediatric Neuromuscular Clinical Research Network for SMA, a consortium of clinical investigators at 3 clinical sites.
Participants
Sixty-five participants with SMA types 2 and 3, aged 20 months to 45 years, were prospectively evaluated.
Intervention
We collected demographic and medical history information and determined the SMN2 copy number.
Main Outcome Measures
Clinical outcomes included measures of motor function (Gross Motor Function Measure and expanded Hammersmith Functional Motor Scale), pulmonary function (forced vital capacity), and muscle strength (myometry). Participants were evaluated every 2 months for the initial 6 months and every 3 months for the subsequent 6 months. We evaluated change over 12 months for all clinical outcomes and examined potential correlates of change over time including age, sex, SMA type, ambulatory status, SMN2 copy number, medication use, and baseline function.
Results
There were no significant changes over 12 months in motor function, pulmonary function, and muscle strength measures. There was evidence of motor function gain in ambulatory patients, especially in those children younger than 5 years. Scoliosis surgery during the observation period led to a subsequent decline in motor function.
Conclusions
Our results confirm previous clinical reports suggesting that SMA types 2 and 3 represent chronic phenotypes that have relatively stable clinical courses. We did not detect any measurable clinical disease progression in SMA types 2 and 3 over 12 months, suggesting that clinical trials will have to be designed to measure improvement rather than stabilization of disease progression.
doi:10.1001/archneurol.2010.373
PMCID: PMC3839315  PMID: 21320981
6.  Use of Acetazolamide in Sulfonamide-Allergic Patients With Neurologic Channelopathies 
Archives of neurology  2011;69(4):527-529.
Objective
To report the safe and successful use of the carbonic anhydrase inhibitor acetazolamide for treatment of patients with episodic ataxia and periodic paralysis who had been denied treatment because of a history of severe allergic reactions to antibiotic sulfonamides.
Design
Case reports.
Setting
University of Rochester Medical Center, Rochester, New York.
Patients
A 61-year-old man with late-onset episodic ataxia, an 83-year-old woman with mutation-positive Andersen-Tawil syndrome, and a 21-year-old woman with mutation-positive episodic ataxia 2, all of whom had a history of severe skin rash with the use of sulfonamides for treatment of infection.
Results
The 3 patients had been considered for carbonic anhydrase inhibitor treatment but a pharmacist had refused to fill a prescription for acetazolamide for 1 patient and the other 2 patients were denied treatment because of the allergy history. All 3 patients were prescribed acetazolamide and had no adverse reaction. Two patients improved substantially and are continuing treatment. A review of the pharmacology literature suggests that cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors is unlikely. Moreover, a review of case reports does not suggest cross-reactivity. Previous reports in the ophthalmology literature also indicate that acetazolamide can be administered to patients with a history of antibiotic sulfonamide allergic reaction.
Conclusions
These 3 cases confirm that the carbonic anhydrase inhibitor acetazolamide can be given to patients with a history of allergic skin rash with antibiotic sulfonamide.
doi:10.1001/archneurol.2011.2723
PMCID: PMC3785308  PMID: 22158718
7.  Neuropathy in Human and Mice with PMP22 null 
Archives of neurology  2011;68(6):814-821.
Background/Objective
Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies (HNPP). However, the biological functions of PMP22 in humans are largely unexplored due to the absence of patients with PMP22 null mutations.
Design, Setting and Participants
We have evaluated a 7-year-old boy with PMP22 null. Findings were compared with those from nerves of Pmp22 null mice.
Results
Motor and sensory deficits in the proband were non-length dependent. Weakness was found in cranial muscles, but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and DRG during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells that were more significant in motor nerve fibers than in sensory nerve fibers.
Conclusions
Taken together, these data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with absence of PMP22.
doi:10.1001/archneurol.2011.110
PMCID: PMC3711535  PMID: 21670407
8.  Stroke-Related Translational Research 
Archives of neurology  2011;68(9):1110-1123.
Stroke-related translational research is multifaceted. Herein, we highlight genome-wide association studies and genetic studies of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1 mutations, and cerebral cavernous malformations; advances in molecular biology and biomarkers; newer brain imaging research; and recovery from stroke emphasizing cell-based and other rehabilitative modalities.
doi:10.1001/archneurol.2011.99
PMCID: PMC3691989  PMID: 21555605
9.  Rett Syndrome: Exploring the Autism Link 
Archives of neurology  2011;68(8):985-989.
The presence of autism in individuals with neurodevelopmental disorders, whether transient as in Rett syndrome (RTT) or enduring as in fragile X syndrome (FXS) or Down syndrome (DS), suggests the possibility of common neurobiological mechanisms whose elucidation could advance fundamentally their understanding. This review explores the commonalities and differences of autism and RTT at clinical and molecular levels with respect to current status and challenges for each, highlights recent findings from the Rare Disease Network Natural History study on RTT, and summarizes the broad range of phenotypes resulting from mutations in MECP2, the gene responsible for 95% of individuals with RTT. For RTT, animal models have been critical resources for advancing pathobiologic discovery and promise to be important testbeds for evaluating new therapies. Fundamental understanding of autism based on unique genetic mechanism(s) must await similar advances.
doi:10.1001/archneurol.2011.149
PMCID: PMC3674963  PMID: 21825235
10.  The Emerging Role of Epigenetics in Stroke 
Archives of neurology  2011;68(3):294-302.
The transplantation of exogenous stem cells and the activation of endogenous neural stem and progenitor cells (NSPCs) are promising treatments for stroke. These cells can modulate intrinsic responses to ischemic injury and may even integrate directly into damaged neural networks. However, the neuroprotective and neural regenerative effects that can be mediated by these cells are limited and may even be deleterious. Epigenetic reprogramming represents a novel strategy for enhancing the intrinsic potential of the brain to protect and repair itself by modulating pathologic neural gene expression and promoting the recapitulation of seminal neural developmental processes. In fact, recent evidence suggests that emerging epigenetic mechanisms are critical for orchestrating nearly every aspect of neural development and homeostasis, including brain patterning, neural stem cell maintenance, neurogenesis and gliogenesis, neural subtype specification, and synaptic and neural network connectivity and plasticity. In this review, we survey the therapeutic potential of exogenous stem cells and endogenous NSPCs and highlight innovative technological approaches for designing, developing, and delivering epigenetic therapies for targeted reprogramming of endogenous pools of NSPCs, neural cells at risk, and dysfunctional neural networks to rescue and restore neurologic function in the ischemic brain.
doi:10.1001/archneurol.2011.6
PMCID: PMC3671373  PMID: 21403016
11.  Autoimmune autonomic ganglionopathy with reversible cognitive impairment 
Archives of Neurology  2011;69(4):461-466.
Background
Autoimmune autonomic ganglionopathy (AAG) is a rare disorder of antibody mediated impaired transmission across the autonomic ganglia resulting in severe autonomic failure. Some patients with AAG report cognitive impairment of unclear etiology despite treatment of autonomic symptoms.
Objectives
To investigate the relationship between orthostatic hypotension, antibody titers and cognitive impairment in patients with AAG.
Design
Prospective cohort.
Setting
Academic medical center.
Participants
Three patients with AAG underwent neuropsychological testing before and after cycles of plasma exchange in both the seated and standing position to determine the effects of orthostatic hypotension and antibody titers on cognition.
Main Outcome Measures
Patient responses to neuropsychological tests were measured by percent change from baseline in the seated and standing positions pre- and post-plasma exchange to determine the effects of orthostatic hypotension and antibody titers on cognition.
Results
Orthostatic hypotension and elevated antibody titer were associated independently with neuropsychological impairment (P<0.05), particularly in domains of executive function, sustained attention, and working memory. Cognitive dysfunction improved, even in the seated normotensive position, after plasmapheresis and consequent reduction in antibody levels.
Conclusion
The data presented in this study demonstrate reversible cognitive impairment is independently associated with both orthostatic hypotension and elevated nicotinic acetylcholine receptor autoantibodies thereby expanding the clinical spectrum of autonomic ganglionopathy and, in so doing, providing an additional treatable cause of cognitive impairment.
doi:10.1001/archneurol.2011.2372
PMCID: PMC3359761  PMID: 22158721
Autoimmune autonomic ganglionopathy; autonomic failure, orthostatic hypotension, cognitive impairment
12.  Archetypal and New Families with Alexander Disease and Novel Mutations in GFAP 
Archives of neurology  2011;69(2):208-214.
Objective
Alexander disease typically results from dominant mutations in GFAP that arise de novo. However, several instances of multigenerational familial cases have been reported, with some of the most extensive having been described prior to the identification of GFAP as the related gene. These historically seminal families continue to be of interest due to their clinical variability and suggestions of recessive inheritance or germline mosaicism. We here describe genetic analyses of the two most thoroughly studied historical families, as well as one newly discovered family.
Design
Clinical histories were obtained and DNA was analyzed from blood, cheek epithelial cells, or fixed paraffin embedded surgical samples.
Subjects
Affected and unaffected adult members of three families and affected children were included.
Results
Family A contains four siblings in whom we found a novel p.Ser247Pro mutation that was paternally inherited. The phenotypes of these siblings include one unaffected adult, one juvenile onset, and two adult onset. Family B spans four generations, including the first described adult-onset patient originally reported in 1968. Analysis of members of the later generations revealed a novel p.Asp417Ala mutation. Family C contains three generations. We detected a novel p.Gln426Leu mutation that is the farthest C-terminal mutation known.
Conclusions
These families display clear evidence of variable phenotypes, but do not support recessive inheritance. While germline mosaicism cannot be excluded for one family (A), we propose that for genetic counseling purposes the risk of germline mosaicism should be described as less than 1%.
doi:10.1001/archneurol.2011.1181
PMCID: PMC3574575  PMID: 21987397
Alexander disease; GFAP; inheritance patterns; expressivity; phenotypic variation
13.  Large Kindred Evaluation of Mitofusin 2 Novel Mutation, Extremes of Neurologic Presentations, and Preserved Nerve Mitochondria 
Archives of neurology  2011;68(10):1295-1302.
Background
Mitofusin 2 (MFN2) is a mitochondrial membrane protein mediating mitochondrial fusion and function. Mutated MFN2 is responsible for Charcot-Marie-Tooth type 2A2. In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system. The results of the nerve biopsy specimens suggested that the mitochondria are structurally abnormal in patients with MFN2 mutations.
Objective
To study a newly identified MFN2 mutation, Leu146Phe, and the associated phenotypes in a large kindred.
Patients
An American kindred of Northern European and Cherokee American Indian descent.
Results
Genetic analysis revealed a novel GTPase domain MFN2 mutation Leu146Phe that associated with clinical status of 15 studied persons (10 affected and 5 unaffected) and not found in 800 control persons. Clinical manifestations were markedly different. In 1 affected person, optic atrophy and brain magnetic resonance imaging abnormalities led to multiple sclerosis diagnosis and interferon β-1a treatment when neuropathy was initially unrecognized. Age of onset ranged from 1 to 45 years. In some affected family members, severe and rapid-onset motor sensory neuropathy led to early loss of ambulation, whereas other family members experienced minimal neuropathic sensory symptoms. Despite histologically significant loss of nerve fibers, the mitochondria were not distinguishable from diseased sural nerve biopsy specimens and healthy controls.
Conclusions
Novel MFN2 mutation Leu146Phe causes Charcot-Marie-Tooth type 2A2. Intrafamilial clinical phenotype variability is emphasized and has important implications in genetic counseling. The clinical phenotype may mimic multiple sclerosis when optic atrophy and the characteristic brain lesions of MFN2 on magnetic resonance imaging are present and neuropathy is mild or unrecognized. The predicted molecular pathogenesis may occur without evident histological abnormalities of mitochondria in nerve.
doi:10.1001/archneurol.2011.225
PMCID: PMC3543870  PMID: 21987543
14.  Effects of Age and Amyloid Deposition on Aβ Dynamics in the Human Central Nervous System 
Archives of Neurology  2011;69(1):51-58.
Objective
The amyloid hypothesis predicts that increased production or decreased clearance of amyloid beta (Aβ) leads to amyloidosis, ultimately culminating in Alzheimer’s disease (AD). Dynamic changes in human CNS Aβ levels may be altered by aging or AD pathology and contribute to the risk of AD.
Designs
In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, PIB PET amyloid status and electroencephalography (EEG) and video recording data.
Results
Linear increases of CSF Aβ concentrations over time were observed in younger control participants and older Amyloid- participants, but not in older Amyloid+ participants. Significant CSF Aβ circadian patterns were observed in younger control participants; however circadian amplitudes were decreased in both Amyloid- and Amyloid+ older participants. Aβ diurnal concentrations were correlated to the amount of sleep, but not various awake activities.
Conclusions
Decreased linear rise of CSF Aβ levels associated with amyloid deposition, and decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics, and may contribute to AD.
doi:10.1001/archneurol.2011.235
PMCID: PMC3254706  PMID: 21911660
15.  Autosomal Recessive Causes Likely in Early-Onset Alzheimer Disease 
Archives of Neurology  2011;69(1):59-64.
Background
There is a widespread belief that dominant mutations cause most cases of early-onset Alzheimer's Disease (onset ≤ 60 years, EOAD) yet epidemiologic evidence suggests they explain ≤ 10% of all EOAD cases.
Objective
To determine the genetic contribution to the remaining ~90% of non-autosomal dominant EOAD cases and identify the likely mechanism of inheritance in those cases.
Design, Subjects
A liability threshold model of disease was used to estimate heritability of EOAD and late-onset AD (LOAD) using concordance for AD among parent-offspring pairs. Individuals with probable AD and detailed parental history (n =5,370) were identified in the Uniform Dataset (UDS) whose participants were collected from 32 Alzheimer's Disease Centers.
Results
For LOAD (n = 4,302), we found sex-specific parent–offspring concordance that ranged from ~10-30% resulting in a heritability of 69.8% (95% CI: 64.6–75.0%) and equal heritability for both sexes regardless of parental gender. For EOAD (n = 702), we found that the parent–offspring concordance is ≤ 10% and concordance among siblings is 21.6%. EOAD heritability is 92–100% for all likely values of EOAD prevalence.
Conclusion
We confirm LOAD is a highly polygenic disease. By contrast, the data for EOAD suggest it is an almost entirely genetically based disease, and the pattern of observed concordance for parent–offspring pairs and among siblings lead us to reject the hypotheses that EOAD is a purely dominant, mitochondrial, X-linked, or polygenic disorder. The most likely explanation of the data is that ~90% of EOAD cases are due to autosomal recessive causes.
doi:10.1001/archneurol.2011.221
PMCID: PMC3332307  PMID: 21911656
16.  Large proportion of amyotrophic lateral sclerosis cases in Sardinia are due to a single founder mutation of the TARDBP gene 
Archives of neurology  2011;68(5):594-598.
Objective
To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)–related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.
Design
Population-based, prospective cohort study.
Patients
A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.
Intervention
Patients underwent mutational analysis for SOD1, FUS, and TARDBP.
Results
Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94–single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.
Conclusions
The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.
doi:10.1001/archneurol.2010.352
PMCID: PMC3513278  PMID: 21220647
17.  Neurodegeneration Across Stages of Cognitive Decline in Parkinson Disease 
Archives of Neurology  2011;68(12):1562-1568.
Objective
To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).
Design
Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.
Setting
The Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania.
Subjects
Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.
Results
The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β=−0.37; P=.001), and PDD patients demonstrated hippocampal (β=−0.32; P=.004) and additional medial temporal lobe atrophy (β=−0.36; P=.003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P=.04) and a similar pattern to that of PDD patients (P=.81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.
Conclusions
Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.
doi:10.1001/archneurol.2011.725
PMCID: PMC3290902  PMID: 22159053
18.  Neuromyelitis Optica Unresponsive to Monoclonal Antibody Therapy 
Archives of neurology  2011;68(9):1207-1209.
doi:10.1001/archneurol.2011.194
PMCID: PMC3495590  PMID: 21911704
Neuromyelitis optica; Immunosuppressive and B cell therapies
19.  Diffusion Tensor Imaging in Acute Optic Neuropathies 
Archives of neurology  2011;69(1):65-71.
Objective
To evaluate directional diffusivities within the optic nerve in a first event of acute optic neuritis to determine whether decreased axial diffusivity (AD) would predict 6-month visual outcome and optic nerve integrity measures.
Design
Cohort study.
Setting
Academic multiple sclerosis center.
Patients
Referred sample of 25 individuals who presented within 31 days after acute visual symptoms consistent with optic neuritis. Visits were scheduled at baseline, 2 weeks, and 1, 3, 6, and 12 months.
Main Outcome Measures
Visual acuity, contrast sensitivity, visual evoked potentials (VEPs), and thickness of the retinal nerve fiber layer (RNFL).
Results
An incomplete 6-month visual recovery was associated with a lower baseline AD (1.50 μm2/ms [95% confidence interval {CI}, 1.36–1.64 μm2/ms for incomplete recovery vs 1.75 μm2/ms [95% CI, 1.67–1.83 μm2/ms] for complete recovery). Odds of complete recovery decreased by 53% (95% CI, 27%–70%) for every 0.1-unit decrease in baseline AD. A lower baseline AD correlated with worse 6-month visual outcomes in visual acuity (r=0.40, P=.03), contrast sensitivity (r=0.41, P=.02), VEP amplitude (r=0.55, P<.01), VEP latency (r=−0.38, P=.04), and RNFL thickness (r=0.53, P=.02). Radial diffusivity increased between months 1 and 3 to become higher in those with incomplete recovery at 12 months than in those with complete recovery (1.45 μm2/ms [95% CI, 1.31–1.59 μm2/ms] vs 1.19 μm2/ms [95% CI, 1.10–1.28 μm2/ms]).
Conclusions
Decreased AD in acute optic neuritis was associated with a worse 6-month visual outcome and correlated with VEP and RNFL measures of axon and myelin injury. Axial diffusivity may serve as a marker of axon injury in acute white matter injury.
doi:10.1001/archneurol.2011.243
PMCID: PMC3489058  PMID: 21911658
20.  Cholesterol and Statins in Alzheimer’s Disease 
Archives of neurology  2011;68(11):1385-1392.
Substantial evidence has accumulated in support of the hypothesis that elevated cholesterol levels increase the risk of developing Alzheimer’s disease (AD). As a result, much work has been done investigating the potential use of lipid-lowering agents (LLAs), particularly statins, as preventive or therapeutic agents for AD. While epidemiology and preclinical statin research (described in Part 1 of this review) have generally supported an adverse role of high cholesterol regarding AD, human studies of statins (reviewed here) show highly variable outcomes, making it difficult to draw firm conclusions. We identify several confounding factors among the human studies, including differing blood-brain barrier permeabilities among statins, the stage in AD at which statins were administered, and the drugs’ pleiotropic metabolic effects, all of which contribute to the substantial variability observed to date. We recommend that future human studies of this important therapeutic topic 1) take the blood-brain barrier permeabilities of statins into account when analyzing results, 2) include specific analyses of effects on low-density and high-density lipoprotein cholesterol, and most importantly, 3) conduct statin treatment trials solely in mild AD patients, who have the best chance for disease modification.
doi:10.1001/archneurol.2011.242
PMCID: PMC3248784  PMID: 22084122
21.  Positron Emission Tomography and Neuropathologic Estimates of Fibrillar Amyloid-β in a Patient With Down Syndrome and Alzheimer Disease 
Archives of Neurology  2011;68(11):1461-1466.
Background
Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined.
Objectives
To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death.
Design/Methods
With the family’s informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient’s diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient’s diagnosis or PET measurements.
Results
Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan.
Conclusions
Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.
doi:10.1001/archneurol.2011.535
PMCID: PMC3346179  PMID: 22084131
22.  Cholesterol and Statins in Alzheimer’s Disease 
Archives of neurology  2011;68(10):1239-1244.
Over the past twenty years, evidence has accumulated that high cholesterol levels may increase the risk of developing Alzheimer’s disease (AD). With the global use of statins to treat hypercholesterolemia, this finding has led to the hope that statins could prove useful in treating or preventing AD. However, the results of work on this topic are inconsistent: some studies find beneficial effects, others do not. In this first segment of a two-part review, we examine the complex preclinical and clinical literature on cholesterol and AD. First, we review epidemiological research on cholesterol levels and the risk of AD and discuss the relevance of discrepancies among studies as regards participants’ age and clinical status. Next, we assess studies correlating cholesterol with AD-type neuropathology. The potential molecular mechanisms for cholesterol’s apparent adverse effect on the development of AD are then discussed. Finally, we review preclinical studies of statins and AD. Thus, this first portion of our review provides the background and rationale for investigating statins as potential therapeutic agents in AD patients, the subject of the second part.
doi:10.1001/archneurol.2011.203
PMCID: PMC3211071  PMID: 21987540
23.  A Controlled Study of Medial Arterial Calcification of Legs 
Archives of Neurology  2011;68(10):1290-1294.
Background
Diabetes mellitus (DM) is associated with an increased prevalence of peripheral arterial disease and medial arterial calcification (MAC), possibly related to prevalence and severity of diabetic polyneuropathy (DPN).
Objective
To assess the prevalence, risk covariates, and implication of MAC in a controlled study of healthy subjects and patients with DM.
Design
Masked evaluation of radiographs.
Setting
Olmsted County, Minnesota.
Patients
Ambulatory volunteers with DM from the Rochester Diabetic Neuropathy Study cohort (n=260) and matched healthy subjects from the Rochester Diabetic Neuropathy Study–Healthy Subject cohort (n=221).
Methods
Patients and controls underwent standard radiographs of distal legs and feet from January 1, 1995, through December 31, 2002. The radiographs were independently read by masked, experienced radiologists for vessel calcification. Medial arterial calcification prevalence, risk covariates, correlation with peripheral arterial disease, and implication for distal, length-dependent sensorimotor polyneuropathy (DSPN) were studied.
Results
Of 481 study participants, MAC was found in 66 (13.7%): 55 of 260 (21.2%) in patients with DM and 11 of 221 (5.0%) in healthy subjects (P<.001). Inter-rater agreement of MAC was 94.1% (κ coefficient of 0.7). Medial arterial calcification was significantly associated with DSPN (P<.001). In stepwise logistic regression analysis, the significant risk covariates for MAC were advancing age, male sex, DM, and stage of microvessel disease (retinopathy).
Conclusions
Medial arterial calcification of legs was approximately 4 times as prevalent in population-representative ambulatory persons with DM as in healthy subjects. Advancing age, male sex, DM, and retinopathy were the significant risk covariates for MAC of legs. Medial arterial calcification of legs, although significantly associated with DSPN, was not a useful surrogate marker of DSPN. Also, MAC was not shown to be a risk covariate for late worsening of DSPN, although other lines of evidence suggest that peripheral arterial disease may worsen DSPN.
doi:10.1001/archneurol.2011.211
PMCID: PMC3271858  PMID: 21987542
24.  Cerebrospinal Fluid Biomarkers, Education, Brain Volume and Future Cognition 
Archives of neurology  2011;68(9):1145-1151.
Objective
To evaluate the combination of cerebrospinal fluid biomarkers of Aβ42, tau, and phosphorylated tau (ptau181) with education and normalized whole brain volume (nWBV) to predict incident cognitive impairment and test the cognitive/brain reserve hypothesis.
Design
Longitudinal cohort study.
Setting
Charles F. and Joanne Knight Alzheimer’s Disease Research Center of Washington University, St. Louis, Missouri.
Participants
Convenience sample of 197 participants aged 50 years and above, with normal cognition (Clinical Dementia Rating [CDR] of 0) at baseline, followed for a mean of 3.3 years.
Main outcome measure
Time to cognitive impairment (CDR ≥ 0.5).
Results
Three-factor interactions between the baseline biomarker values, education, and nWBV were found for Cox proportional hazards models testing tau (p=.03) and ptau (p=.008). Among those with lower tau values, nWBV (hazard ratio [HR]=.54, 95% confidence interval [CI]=.31–.91; p=.02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (p=.01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment among those with higher ptau values (p=.02). In models testing Aβ42, larger nWBV was associated with a slower time to cognitive impairment (HR=.84, 95%CI=.71–.99, p=.0348), but there was no effect of Aβ42 or education.
Conclusions
Among individuals with higher levels of CSF tau and ptau, but normal cognition at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.
doi:10.1001/archneurol.2011.192
PMCID: PMC3203689  PMID: 21911695
25.  Rituximab-Associated Progressive Multifocal Leukoencephalopathy in Rheumatoid Arthritis 
Archives of neurology  2011;68(9):1156-1164.
Objective
To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab.
Design
Case study.
Setting
Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver.
Patients
Four patients developing PML in the setting of rituximab therapy for RA.
Intervention
Rituximab therapy.
Main Outcome Measures
Clinical and pathological observations.
Results
Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease.
Conclusion
These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low.
doi:10.1001/archneurol.2011.103
PMCID: PMC3428054  PMID: 21555606

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