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1.  Brain Excitability in Stroke 
Archives of neurology  2011;69(2):161-167.
There is no current medical therapy for stroke recovery. Principles of physiological plasticity have been identified during recovery in both animal models and human stroke. Stroke produces a loss of physiological brain maps in adjacent peri-infarct cortex and then a remapping of motor and sensory functions in this region. This remapping of function in peri-infarct cortex correlates closely with recovery. Recent studies have shown that the stroke produces abnormal conditions of excitability in neuronal circuits adjacent to the infarct that may be the substrate for this process of brain remapping and recovery. Stroke causes a hypo-excitability in peri-infarct motor cortex that stems from increased tonic γ-aminobutyric acid activity onto neurons. Drugs that reverse this γ-aminobutyric acid signaling promote recovery after stroke. Stroke also increases the sensitivity of glutamate receptor signaling in peri-infarct cortex well after the stroke event, and stimulating α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptors in peri-infarct cortex promotes recovery after stroke. Both blocking tonic γ-aminobutyric acid currents and stimulating α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors promote recovery after stroke when initiated at quite a delay, more than 3 to 5 days after the infarct. These changes in the excitability of neuronal circuits in peri-infarct cortex after stroke may underlie the process of remapping motor and sensory function after stroke and may identify new therapeutic targets to promote stroke recovery.
doi:10.1001/archneurol.2011.1175
PMCID: PMC4698890  PMID: 21987395
2.  Chorea-Acanthocytosis Genotype in the Original Critchley Kentucky Neuroacanthocytosis Kindred 
Archives of neurology  2011;68(10):1330-1333.
Objective
To determine the molecular nature of the neurological disease in the seminal family reported by Critchley et al in the 1960s, characterized by a hyperkinetic movement disorder and the appearance of acanthocytosis on peripheral blood smear. The eponym Levine-Critchley syndrome, subsequently termed neuroacanthocytosis, has been applied to symptomatically similar, but genetically distinct, disorders, resulting in clinical and diagnostic confusion.
Design
DNA analysis.
Setting
Molecular biology research laboratories.
Participants
First- and second-degree relatives of the original Critchley et al proband from Kentucky.
Main Outcome Measures
Mutations in the VPS13A gene.
Results
A mutation was identified in the VPS13A gene, responsible for autosomal recessive chorea-acanthocytosis. Haplotype reconstruction suggested that this mutation was homozygous in the proband.
Conclusion
These findings strongly support the diagnosis of chorea-acanthocytosis as the disorder described in the original report.
doi:10.1001/archneurol.2011.239
PMCID: PMC4615612  PMID: 21987550
3.  Association between in vivo [18F]-flutemetamol amyloid PET imaging and in vivo cerebral cortical histopathology 
Archives of neurology  2011;68(11):1398-1403.
Objective
To determine the correspondence of in vivo quantitative estimates of brain uptake of [18F]-flutemetamol with immunohistochemical estimates of amyloid levels in previously biopsied patients.
Design
Cross-sectional study of [18F]-flutemetamol positron emission tomography (PET) findings in patients with prior cortical biopsy stained for the presence or absence of amyloid plaques.
Setting
University Hospital.
Patients
Seven patients who previously had a prior right frontal cortical biopsy obtained at the site of ventriculo-peritoneal (VP) placement for presumed Normal Pressure Hydrocephalus (NPH) were recruited. Inclusion criteria included an adequate biopsy for detection and quantification of Aβ pathology and age greater than 50 years.
Intervention
All patients underwent an [18F]-flutemetamol PET scan.
Main Outcome Measures
Quantitative measures of [18F]-flutemetamol uptake (SUVR – ratio of mean target cortex activity divided by that in a cerabellar reference region) were made at a location contralateral to the biopsy site and compared to estimates of amyloid load based on immunohistochemical and histological staining.
Results
There was complete agreement between visual reads of [18F]-flutemetamol PET scans (three blinded readers with majority rule) and histology. A regression model, including time from biopsy as a covariate, demonstrated a significant relationship (p=0.011) between [18F]-flutemetamol uptake and percent area of amyloid measured by a monoclonal antibody raised against amyloid (NAB228). Similar results were found with the amyloid specific monoclonal antibody 4G8 and Thioflavin S.
Conclusions
These data are the first to demonstrate the concordance of [18F]-flutemetamol PET imaging with histopathology, supporting its sensitivity to detect amyloid and potential use in the study and detection of Alzheimer’s Disease.
doi:10.1001/archneurol.2011.153
PMCID: PMC4532383  PMID: 21747004
4.  Deep Brain Stimulation for Parkinson Disease 
Archives of neurology  2010;68(2):165-171.
Objective
To provide recommendations to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD).
Data Sources and Study Selection
An international consortium of experts organized, reviewed the literature, and attended the workshop. Topics were introduced at the workshop, followed by group discussion.
Data Extraction and Synthesis
A draft of a consensus statement was presented and further edited after plenary debate. The final statements were agreed on by all members.
Conclusions
(1) Patients with PD without significant active cognitive or psychiatric problems who have medically intractable motor fluctuations, intractable tremor, or intolerance of medication adverse effects are good candidates for DBS. (2) Deep brain stimulation surgery is best performed by an experienced neurosurgeon with expertise in stereotactic neurosurgery who is working as part of a interprofessional team. (3) Surgical complication rates are extremely variable, with infection being the most commonly reported complication of DBS. (4) Deep brain stimulation programming is best accomplished by a highly trained clinician and can take 3 to 6 months to obtain optimal results. (5) Deep brain stimulation improves levodopa-responsive symptoms, dyskinesia, and tremor; benefits seem to be long-lasting in many motor domains. (6) Subthalamic nuclei DBS may be complicated by increased depression, apathy, impulsivity, worsened verbal fluency, and executive dysfunction in a subset of patients. (7) Both globus pallidus pars interna and subthalamic nuclei DBS have been shown to be effective in addressing the motor symptoms of PD. (8) Ablative therapy is still an effective alternative and should be considered in a select group of appropriate patients.
doi:10.1001/archneurol.2010.260
PMCID: PMC4523130  PMID: 20937936
5.  Clinical Prediction of Fall Risk and White Matter Abnormalities 
Archives of neurology  2012;69(6):733-738.
Background
The Tinetti scale is a simple clinical tool designed to predict risk of falling by focusing on gait and stance impairment in elderly persons. Gait impairment is also associated with white matter (WM) abnormalities.
Objective
To test the hypothesis that elderly subjects at risk for falling, as determined by the Tinetti scale, have specific patterns of WM abnormalities on diffusion tensor imaging.
Design, Setting, and Patients
Community-based cohort of 125 homebound elderly individuals.
Main Outcome Measures
Diffusion tensor imaging scans were analyzed using tract-based spatial statistics analysis to determine the location of WM abnormalities in subjects with Tinetti scale scores of 25 or higher (without risk of falls) and lower than 25 (with risk of falls). Multivariate linear least squares correlation analysis was performed to determine the association between Tinetti scale scores and local fractional anisotropy values on each skeletal voxel controlling for possible confounders.
Results
In subjects with risk of falls (Tinetti scale score <25), clusters of abnormal WM were seen in the medial frontal and parietal subcortical pathways, genu and splenium of corpus callosum, posterior cingulum, prefrontal and orbitofrontal pathways, and longitudinal pathways that connect frontal-parietal-temporal lobes. Among these abnormalities, those in medial frontal and parietal subcortical pathways correlated with Mini-Mental State Examination scores, while the other locations were unrelated to these scores.
Conclusions
Elderly individuals at risk for falls as determined by the Tinetti scale have WM abnormalities in specific locations on diffusion tensor imaging, some of which correlate with cognitive function scores.
doi:10.1001/archneurol.2011.2272
PMCID: PMC4443844  PMID: 22332181
6.  Association of C-Reactive Protein to Cognitive Impairment 
Archives of neurology  2010;67(1):87-92.
Background
High sensitivity C-reactive protein (hsCRP) is a biomarker of cardiovascular risk suggested as a biomarker for cognitive impairment.
Objective
To explore the association between hsCRP and cognitive impairment
Design
Cross-sectional analysis of a population-based community aging study
Setting
Northern Manhattan, New York
Subjects
1331 participants from a longitudinal study of aging without dementia and available hsCRP and neuropsychological testing at baseline.
Main Outcome Measures
Four cognitive scores (memory, visuospatial, executive, language) derived from a neuropsychological battery. Cognitive impairment was defined by scores below 1.5 SD of demographically corrected means.
Results
Participants with the highest hsCRP tertile had higher adjusted odds of impaired memory (OR=1.5, 95%CI: 1.0–2.1; p for trend = 0.03) than participants with the lowest tertile Subjects in the highest hsCRP tertile also had greater odds of visuospatial impairment (OR=1.6, 95% CI: 1.0–2.3; p for trend-0.03). Higher hsCRP was not associated with executive or language impairment. Persons with at least one APOE-ε4 allele and hsCRP in the highest tertile had the greatest odds of impaired memory (OR=2.7, 95% CI: 1.6–4.4).
Conclusion
High hsCRP may be a marker of memory and visuspatial impairment in the elderly. The role of APOE-ε4 requires further exploration.
doi:10.1001/archneurol.2009.308
PMCID: PMC4426905  PMID: 20065134
7.  Executive Dysfunction in Alzheimer Disease 
Archives of neurology  2004;61(4):556-560.
Background
Executive dysfunction (EDF) is common in Alzheimer disease (AD); however, its relationship to other symptoms is difficult to assess in patients with AD.
Objectives
To determine the prevalence of EDF and study its relationship to cognitive, functional, and neuropsychiatric symptoms in patients with AD.
Design, Setting, and Patients
A retrospective analysis of data from participants in the English Instruments Protocol of the Alzheimer’s Disease Cooperative Study. Subjects were drawn from a sample of patients evaluated at tertiary referral centers.
Results
A total of 64% of AD patients were classified as having EDF. Patients with EDF performed worse on tests of cognition (P<.001), dementia severity (P<.001), and activities of daily living (P = .01) and had more frequent symptoms of psychosis (P=.03) with greater emergence during the 12-month interval (P=.03) compared with patients with normal executive function. Less than 30% of the variance in executive function performance was explained by cognitive measures.
Conclusion
These findings support the assessment of executive function in persons with AD and the importance of frontal lobe dysfunction in AD.
doi:10.1001/archneur.61.4.556
PMCID: PMC4419376  PMID: 15096405
8.  Emergent Epidural Blood Patch 
Archives of neurology  2009;66(5):670-671.
doi:10.1001/archneurol.2009.33
PMCID: PMC4419730  PMID: 19433672
9.  Prospective Study of Endogenous Circulating Estradiol and Risk of Stroke in Older Women 
Archives of neurology  2010;67(2):195-201.
Objective
To test the hypothesis that circulating endogenous estradiol is associated with stroke risk in older postmenopausal women. Stroke incidence increases after menopause, when endogenous estrogen levels fall, yet exogenous estrogen increases strokes in older postmenopausal women. The relation between endogenous estrogen and stroke is unclear.
Design
Prospective case-control study.
Setting
Study of Osteoporotic Fractures.
Patients or Other Participants
Women at least age 65 years (99% follow-up) who were not taking estrogen at baseline.
Main Outcome Measures
Free estradiol index (FEI) was calculated by dividing total estradiol by sex hormone–binding globulin concentrations measured in banked baseline serum. Using logistic regression, odds ratios were estimated for a first-ever atherothrombotic stroke associated with endogenous FEI in 196 women who had a subsequent validated stroke (median follow-up, 8 years) compared with 219 randomly selected women who did not. Potential mediators were assessed in multivariable models.
Results
The age-adjusted odds of atherothrombotic stroke increased with increasing FEI quartiles (Ptrend=.007). Women in the highest FEI quartile had an age-adjusted 2.31-fold (odds ratio, 2.31; 95% confidence interval, 1.28–4.17) higher odds than women in the lowest quartile. Women with greater central adiposity had a suggestively stronger association (P =.08). Atherogenic dyslipidemia, type 2 diabetes mellitus, and C-reactive protein level were potential mediators of this relation.
Conclusions
Endogenous estradiol level is an indicator of stroke risk in older postmenopausal women, especially in those with greater central adiposity. Potential mediators, including atherogenic dyslipidemia, insulin resistance, and inflammation, might underlie this association. Whether estradiol, independent of atherogenic adiposity, influences such mediators and stroke risk needs to be determined. Estrogen-altering agents might be harmful or beneficial depending on endogenous estradiol levels, especially in women with greater central adiposity.
doi:10.1001/archneurol.2009.322
PMCID: PMC4406483  PMID: 20142527
10.  Differential Diagnosis of Jakob-Creutzfeldt Disease 
Archives of neurology  2012;69(12):1578-1582.
Objectives
To identify the misdiagnoses of patients with sporadic Jakob-Creutzfeldt disease (sCJD) during the course of their disease and determine which medical specialties saw patients with sCJD prior to the correct diagnosis being made and at what point in the disease course a correct diagnosis was made.
Design
Retrospective medical record review.
Setting
A specialty referral center of a tertiary academic medical center.
Participants
One hundred sixty-three serial patients over a 5.5-year period who ultimately had pathologically proven sCJD. The study used the subset of 97 patients for whom we had adequate medical records.
Main Outcome Measures
Other diagnoses considered in the differential diagnosis and types of medical specialties assessing patients with sCJD.
Results
Ninety-seven subjects’ records were used in the final analysis. The most common disease categories of misdiagnosis were neurodegenerative, autoimmune/paraneoplastic, infectious, and toxic/metabolic disorders. The most common individual misdiagnoses were viral encephalitis, paraneoplastic disorder, depression, vertigo, Alzheimer disease, stroke, unspecified dementia, central nervous system vasculitis, peripheral neuropathy, and Hashimoto encephalopathy. The physicians who most commonly made these misdiagnoses were primary care physicians and neurologists; in the 18% of patients who were diagnosed correctly at their first assessment, the diagnosis was almost always by a neurologist. The mean time from onset to diagnosis was 7.9 months, an average of two-thirds of the way through their disease course.
Conclusions
Diagnosis of sCJD is quite delayed. When evaluating patients with rapidly progressive dementia with suspected neurodegenerative, autoimmune, infectious, or toxic/metabolic etiology, sCJD should also be included in the differential diagnosis, and appropriate diagnostic tests, such as diffusion brain magnetic resonance imaging, should be considered. Primary care physicians and neurologists need improved training in sCJD diagnosis.
doi:10.1001/2013.jamaneurol.79
PMCID: PMC4401069  PMID: 23229042
11.  Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA 
Archives of neurology  2009;66(2):226-233.
Background
In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons.
Objective
To determine whether genetic variation influences clinical MS patterns.
Design
Retrospective multicenter cohort study.
Participants
Six hundred seventy-three African American and 717 white patients with MS.
Main Outcome Measures
Patients with MS were geno-typed for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset.
Results
Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti–aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1* 15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) andriskof cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001).
Conclusions
These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes.
doi:10.1001/archneurol.2008.541
PMCID: PMC4334456  PMID: 19204159
12.  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
13.  Preservation of Neurons of the Nucleus Basalis in Subcortical Ischemic Vascular Disease 
Archives of neurology  2012;69(7):879-886.
Object
To compare loss of neurons in the nucleus basalis of Meynert (NB) in subcortical ischemic vascular disease (SIVD) to normal controls, Alzheimer’s disease (AD), and cases with mixed AD/SIVD pathology.
Design
Autopsied cases drawn from a longitudinal observational study with SIVD, AD and normal aging.
Subjects
Pathologically defined SIVD (n = 16), AD (n = 20), mixed pathology (n = 10), and age- and education-matched normal control (n = 17) groups were studied.
Main Outcome measures
NB neuronal cell counts in each group and their correlation with the extent of MRI white matter lesions (WML) and Clinical Dementia Rating (CDR) scores closest to death.
Results
No significant loss of neurons was found in SIVD compared to age-matched controls in contrast to AD and mixed groups, where there was significant neuronal loss. A significant inverse correlation between NB neurons and CDR scores was found in AD, but not in the SIVD and mixed groups. NB cell counts were not correlated with either the extent of white matter lesions or cortical gray matter volume in SIVD or AD groups.
Conclusions
These findings inveigh against primary loss of cholinergic neurons in SIVD, but do not rule out the possibility of secondary cholinergic deficits due to disruptions of cholinergic projections to cerebral cortex.
doi:10.1001/archneurol.2011.2874
PMCID: PMC4184885  PMID: 22393167
14.  Natalizumab and Progressive Multifocal Leukoencephalopathy: What are the causal factors? Can it be avoided? 
Archives of neurology  2010;67(8):923-930.
Natalizumab (Tysabri®) was the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS). After its initial approval, three patients undergoing natalizumab therapy in combination with other immunoregulatory and immunosuppressive agents were diagnosed with progressive multifocal leukoencephalopathy (PML). The agent was later re-approved, and its use restricted to monotherapy in patients with relapsing forms of MS. Over the past year, five additional cases of PML were reported in MS patients receiving natalizumab monotherapy. Thus, there is currently no convincing evidence that natalizumab-associated PML is restricted to combination therapy with other disease modifying or immunosuppressive agents.
The initial section of this review focuses on the scientific rationale for natalizumab in MS treatment. In the second part, our understanding of PML will be outlined. Thirdly, recent results on altered immune surveillance under natalizumab treatment are reviewed. In the forth section, the link of viral reactivation and very late activation antigen 4 (VLA-4) antagonism will be discussed. Finally, this review will address the potential impact of our current knowledge on the use of natalizumab in clinical practice.
doi:10.1001/archneurol.2010.161
PMCID: PMC4157908  PMID: 20697042
15.  Adult-Onset Vanishing White Matter Disease Due to a Novel EIF2B3 Mutation 
Archives of neurology  2012;69(6):765-768.
Objective
To report a novel mutation in the gene EIF2B3 responsible for a late-onset form of vanishing white matter disease.
Design
Case report.
Setting
University teaching hospital.
Patient
A 29-year-old pregnant woman with a history of premature ovarian failure and hemiplegic migraines presented with a 10-week history of progressive confusion and headaches. Magnetic resonance imaging of the brain revealed a diffuse leukoencephalopathy.
Results
Sequencing of the exons and intron boundaries of EIF2B3 uncovered 2 missense mutations: c.260C>T (p.Ala87Val) and c.272G>A (p.Arg91His). To our knowledge, the latter missense mutation has never been previously reported.
Conclusion
This is the second report of adult-onset vanishing white matter disease due to mutations in EIF2B3 and the first report of the c.272G>A (p.Arg91His) missense mutation.
doi:10.1001/archneurol.2011.1942
PMCID: PMC4154510  PMID: 22312164
16.  Novel Infantile-Onset Leukoencephalopathy With High Lactate Level and Slow Improvement 
Archives of neurology  2012;69(6):718-722.
Objective
To describe a novel pattern of magnetic resonance imaging (MRI) abnormalities as well as the associated clinical and laboratory findings.
Design
The MRIs of more than 3000 patients with an unclassified leukoencephalopathy were systematically reviewed. Clinical and laboratory data were retrospectively collected.
Setting
University hospital.
Patients
Seven patients (3 male) shared similar MRI abnormalities and clinical features.
Main Outcome Measures
Pattern of MRI abnormalities and clinical and laboratory findings.
Results
The MRIs showed signal abnormalities of the deep cerebral white matter, corpus callosum, thalamus, basal ganglia, brainstem, and cerebellar white matter between the ages of 9 months and 2 years. On follow-up, abnormalities gradually improved. Clinical regression occurred in the second half-year of life with spasticity and loss of milestones. From the second year on, clinical improvement occurred. So far, no second episode of regression has happened. Lactate levels were elevated during clinical regression.
Conclusion
These patients represent a single novel leukoencephalopathy, probably caused by a mitochondrial defect.
doi:10.1001/archneurol.2011.1048
PMCID: PMC4154514  PMID: 22312165
17.  A Randomized, Placebo-Controlled Trial of Latrepirdine in Huntington Disease 
Archives of neurology  2010;67(2):154-160.
Objectives
To evaluate the safety and tolerability of latrepirdine in Huntington disease (HD) and explore its effects on cognition, behavior, and motor symptoms.
Design
Double-blind, randomized, placebo-controlled trial.
Setting
Multicenter outpatient trial.
Participants
Ninety-one participants with mild to moderate HD enrolled at 17 US and UK centers from July 18, 2007, through July 16, 2008.
Intervention
Latrepirdine, 20 mg 3 times daily (n=46), or matching placebo (n=45) for a 90-day treatment period.
Main Outcome Measures
The primary outcome variable was tolerability, defined as the ability to complete the study at the assigned drug dosage. Secondary outcome variables included score changes from baseline to day 90 on the Unified Huntington's Disease Rating Scale (UHDRS), the Mini-Mental State Examination (MMSE), and the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog).
Results
Latrepirdine was well tolerated (87% of the patients given latrepirdine completed the study vs 82% in the placebo group), and adverse event rates were comparable in the 2 groups (70% in the latrepirdine group and 80% in the placebo group). Treatment with latrepirdine resulted in improved mean MMSE scores compared with stable performance in the placebo group (treatment effect, 0.97 points; 95% confidence interval, 0.10-1.85; P=.03). No significant treatment effects were seen on the UHDRS or the ADAS-cog.
Conclusions
Short-term administration of latrepirdine is well tolerated in patients with HD and may have a beneficial effect on cognition. Further investigation of latrepirdine is warranted in this population with HD.
doi:10.1001/archneurol.2009.334
PMCID: PMC4134015  PMID: 20142523
18.  A Renaissance for Antisense Oligonucleotide Drugs in Neurology 
Archives of neurology  2009;66(1):32-38.
Antisense oligonucleotides are short nucleic acid sequences designed for use as small-molecule drugs. They recognize and bind to specific messenger RNA (mRNA) or pre-mRNA sequences to create small double-stranded regions of the target mRNA that alter mRNA splicing patterns or inhibit protein translation. Antisense approaches have been actively pursued as a form of molecular medicine for more than 20 years, but only one has been translated to a marketed drug (intraocular human immunodeficiency virus treatment). Two recent advances foreshadow a change in clinical applications of antisense strategies. First is the development of synthetic DNA analogues that show outstanding stability and sequence specificity yet little or no binding to modulator proteins. Second is the publication of impressive preclinical and clinical data using antisense in an exon-skipping strategy to increase dystrophin production in Duchenne muscular dystrophy. As long-standing barriers are successfully circumvented, attention turns toward scale-up of production, long-term toxicity studies, and the challenges to traditional drug regulatory attitudes presented by tightly targeted sequence-specific drugs.
doi:10.1001/archneurol.2008.540
PMCID: PMC4111150  PMID: 19139297
19.  Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals 
Archives of Neurology  2012;69(2):223-229.
Background
Subjective cognitive impairment (SCI) as an early clinical manifestation in Alzheimer disease (AD) is a central and highly debated question.
Objective
To study the relationship between subjective cognition and the neuropathological hallmark of AD, amyloid-beta (Aβ) deposition, imaged with [11C]-Pittsburg compound B (PiB) - positron emission tomography (PET), in normal elderly individuals.
Design
Cross-sectional analysis.
Subjects
Forty-eight cognitively normal elderly subjects (11 with high PiB uptake and 28 with low PiB uptake) were included. All underwent clinical and neuropsychological evaluations and MRI and PET scanning.
Results
High PiB subjects showed significantly lower performance than low PiB subjects on an episodic memory measure, and were less confident about their general memory abilities when required to evaluate themselves relative to other people of the same age. High and low PiB groups did not differ on the accuracy of their cognitive self-reports compare to objective cognitive performance. General memory self-reports from the whole group were significantly correlated to regional PiB uptake in the right medial prefrontal cortex (PFC)/anterior cingulate cortex (ACC) and in the right precuneus/posterior cingulate cortex (PCC). Reduced confidence about memory abilities was associated with greater PiB in these brain regions. All results are independent of demographic variables and depressive affects.
Conclusions
Our findings suggest that a decrease of self-confidence about memory abilities in cognitively normal elderly subjects is related to the neuropathological hallmark of AD measured with PiB-PET imaging. The relevance of SCI in the early stages of the AD pathological process is addressed.
doi:10.1001/archneurol.2011.666
PMCID: PMC4004919  PMID: 22332189
Aged; Aged, 80 and over; Aging; physiology; Amyloid beta-Peptides; metabolism; Aniline Compounds; Biological Markers; Cerebral Cortex; radionuclide imaging; Cognition; physiology; Cognition Disorders; metabolism; psychology; radionuclide imaging; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory; physiology; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Prefrontal Cortex; radionuclide imaging; Radiopharmaceuticals; Reference Values; Thiazoles; subjective cognition; normal aging; Alzheimer's disease (AD); amyloid-beta (Aβ); [11C]-Pittsburgh compound B (PiB) - positron emission tomography (PET)
20.  Investigation of C9orf72 in 4 Neurodegenerative Disorders 
Archives of neurology  2012;69(12):1583-1590.
Objective
To estimate the allele frequency of C9orf72 (G4C2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD).
Design
The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes.
Setting
Hospitals specializing in neurodegenerative disorders.
Subjects
We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation.
Main Outcome Measure
The expansion frequency.
Results
Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20–29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43–positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus.
Conclusions
The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.
doi:10.1001/archneurol.2012.2016
PMCID: PMC4005900  PMID: 22964832
21.  Spreading Depolarization 
Archives of neurology  2010;68(1):31-36.
A neurysmal subarachnoid hemorrhage (SAH) is a devastating disease with a high mortality and morbidity rate. Gradual improvements have been made in the reduction of mortality rates associated with the disease during the last 30 years. However, delayed cerebral ischemia (DCI), the major delayed complication of SAH, remains a significant contributor to mortality and morbidity despite substantial research and clinical efforts. During the last several years, the predominant role of cerebral vasospasm, the long-accepted etiologic factor behind DCI, has been questioned. It is now becoming increasingly clear that the pathophysiology underlying DCI is multifactorial. Cortical spreading depression is emerging as a likely factor in this complex web of pathologic changes after SAH. Understanding its role after SAH and its relationship with the other pathologic processes such as vasospasm, microcirculatory dysfunction, and microemboli will be vital to the development of new therapeutic approaches to reduce DCI and improve the clinical outcome of the disease.
doi:10.1001/archneurol.2010.226
PMCID: PMC3998646  PMID: 20837823
22.  Age-Dependent Structural Connectivity Effects in Fragile X Premutation 
Archives of neurology  2012;69(4):482-489.
Objective
To examine the effects of premutation alleles on major brain fiber tracts in males.
Design
Cross-sectional study performed in 2007–2009.
Setting
Institutional practice.
Patients
Fifteen younger (18–45 years old) carriers, 11 older (>45 years old) unaffected carriers, and 15 older carriers with fragile X–associated tremor/ataxia syndrome, together with 19 younger and 15 older controls matched by age and educational level.
Main Outcome Measures
Diffusion tensor imaging was performed on all study participants. Eleven fiber tracts important for motor, social, emotional, and cognitive functions were reconstructed and quantified. Complementary tract-based spatial statistical analyses were performed in core white matter.
Results
In the younger carriers, premutation status was associated with a greater age-related connectivity decline in the extreme capsule. Among older carriers, unaffected individuals did not display structural alterations, whereas the affected carriers showed connectivity loss in 5 fiber tracts and exhibited greater age-related connectivity decline in all 11 tracts compared with the controls. In addition, 9 fiber tracts showed significantly higher variability relative to the controls, and symptom severity explained the variability in 6 measurements from the superior cerebellar peduncle, corpus callosum, and cingulum.
Conclusions
The findings revealed widespread alterations in structural connectivity associated with fragile X–associated tremor/ataxia syndrome and preserved or subtle changes in structural connectivity in unaffected carriers. Diffusion tensor imaging is sensitive to pathologic changes in the white matter associated with this neurodegenerative disorder.
Wang et al examine the effects of premutation alleles on major brain fiber tracts in males, who are at risk of developing fragile X-associated tremor/ataxia syndrome and may manifest subtle cognitive, social, and emotional disturbances before clinical involvement.
doi:10.1001/archneurol.2011.2023
PMCID: PMC3979438  PMID: 22491193
23.  Continued High Prevalence and Adverse Clinical Impact of Human Immunodeficiency Virus–Associated Sensory Neuropathy in the Era of Combination Antiretroviral Therapy 
Archives of neurology  2010;67(5):552-558.
Objective
To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus−associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era.
Design
Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models.
Setting
Six US academic medical centers.
Patients
One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study.
Main Outcome Measures
The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey.
Results
We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95%confidence interval, 1.8–2.5] per 10 years), lower CD4 nadir (1.2 [1.1–1.2] per 100-cell decrease), current CART use (1.6 [1.3–2.8]), and past “D-drug” use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3–2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir.
Conclusions
Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
doi:10.1001/archneurol.2010.76
PMCID: PMC3924778  PMID: 20457954
24.  A purpose “driven” life: Is it potentially neuroprotective? 
Archives of neurology  2010;67(8):1010-1011.
doi:10.1001/archneurol.2010.170
PMCID: PMC3918477  PMID: 20697053
25.  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

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