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1.  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
2.  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
3.  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
4.  A Novel POLG Gene Mutation in 4 Children With Alpers-like Hepatocerebral Syndromes 
Archives of neurology  2010;67(2):10.1001/archneurol.2009.332.
Objective
To describe a novel POLG missense mutation (c.3218C>T; p.P1073L) that, in association with 2 previously described mutations, caused an Alpers-like hepatocerebral syndrome in 4 children.
Design
Genotype-phenotype correlation.
Setting
Tertiary care universities.
Patients
Four children, 2 related and 2 unrelated, with the novel p.P1073L mutation (all patients) and either the p.A467T (2 patients), p.G848S (1 patient), or p.W748S (1 patient) mutation presented with psychomotor delay, encephalopathy, and liver failure.
Interventions
Detailed clinical and laboratory examinations including brain magnetic resonance imaging, muscle biopsy, measurement of mitochondrial DNA, and sequencing of the POLG gene.
Main Outcome Measures
Definition of clinical variability.
Results
All 4 patients had psychomotor delay, seizures, and liver disease. Three patients had severe gastrointestinal dysmotility, which may be associated with the new p.P1073L mutation.
Conclusions
The heterozygous presence of the novel p.P1073L mutation in trans with another recessive POLG mutation causes a hepatocerebral disorder identical or very similar to Alpers syndrome. This adds to the already striking clinical heterogeneity of POLG mutations. In the Belgian patients, the familial occurrence without consanguinity is related to the high frequency of the recessive p.A467T and p.W748S mutations in northwestern Europe and reveals a pitfall for diagnosis and genetic counseling.
doi:10.1001/archneurol.2009.332
PMCID: PMC3826985  PMID: 20142534
5.  Autoimmune autonomic ganglionopathy treated with long-term rituximab in a patient with lymphoma 
Archives of neurology  2010;68(3):372-375.
Objective
To report on response to therapy in a patient with Autoimmune Autonomic Ganglionopathy, with a high titer of an autoantibody directed against the alpha-3 subunit of the nicotinic ganglionic acetylcholine receptor (nAChR).
Design
Case Report
Setting
University based referral center for Autonomic Dysfunction.
Patient
Patient with prior indolent B cell lymphoma who presented with symptomatic orthostatic hypotension and autonomic failure and was found to have a high titer of nAChR antibody.
Intervention
Plasma exchange and rituximab (both initial 4 week cycle and maintenance therapy).
Outcome Measures
Autonomic ganglionic antibody titer; Autonomic assessments including orthostatic hypotension, plasma norepinephrine, and quantitative sweat testing.
Results
Rituximab followed by plasma exchange significantly decreased the nAChR antibody titer for a short time, and then the titers increased. The titers suppressed to almost undetectable levels once regular maintenance therapy with rituximab was initiated. Reduction of nAChR antibody titer resulted in less orthostatic hypotension, increased upright plasma norepinephrine, improvement in some sweat function and improvement in symptoms.
Conclusions
Long-term rituximab therapy suppressed autoantibody production to undetectable levels over the course of two years, and resulted in sustained clinical improvement in this patient with debilitating Autoimmune Autonomic Ganglionopathy. Further data is needed before rituximab can be recommended as routine therapy for this disorder.
doi:10.1001/archneurol.2010.289
PMCID: PMC3725638  PMID: 21059985
Autoimmune autonomic ganglionopathy; Pure autonomic failure; Rituximab; Plasma exchange
6.  Management of Thrombolysis-Associated Symptomatic Intracerebral Hemorrhage 
Archives of neurology  2010;67(8):965-969.
Background
Symptomatic intracerebral hemorrhage (sICH) is the most devastating complication of thrombolytic therapy for acute stroke. It is not clear whether patients with sICH continue to bleed after diagnosis, nor has the most appropriate treatment been determined.
Methods
We performed a retrospective analysis of our prospectively collected Get With the Guidelines–Stroke database between April 1, 2003, and December 31, 2007. Radiologic images and all procoagulant agents used were reviewed. Multivariable logistic regression was performed to identify factors associated with in-hospital mortality.
Results
Of 2362 patients with acute ischemic stroke during the study period, sICH occurred in 19 of the 311 patients (6.1%) who received intravenous tissue plasminogen activator and 2 of the 72 (2.8%) who received intra-arterial thrombolysis. In-hospital mortality was significantly higher in patients with sICH than in those without (15 of 20 [75.0]% vs 56 of 332 [16.9%], P<.001). Eleven of 20 patients (55.0%) received therapy for co-agulopathy: 7 received fresh frozen plasma; 5, cryoprecipitate; 4, phytonadione (vitamin K1); 3, platelets; and 1, aminocaproic acid. Independent predictors of inhospital mortality included sICH (odds ratio, 32.6; 95% confidence interval, 8.8–120.2), increasing National Institutes of Health Stroke Scale score (1.2; 1.1–1.2), older age (1.3; 1.0–1.7), and intra-arterial thrombolysis (2.9; 1.4–6.0). Treatment for coagulopathy was not associated with outcome. Continued bleeding (>33% increase in intracerebral hemorrhage volume) occurred in 4 of 10 patients with follow-up scans available (40.0%).
Conclusions
In many patients with sICH after thrombolysis, coagulopathy goes untreated. Our finding of continued bleeding after diagnosis in 40.0% of patients suggests a powerful opportunity for intervention. A multicenter registry to analyze management of thrombolysis-associated intracerebral hemorrhage and outcomes is warranted.
doi:10.1001/archneurol.2010.175
PMCID: PMC3690951  PMID: 20697046
7.  Emerging Role of Epigenetics in Stroke 
Archives of neurology  2010;67(11):1316-1322.
Epigenetic mechanisms refer to the complex and interrelated molecular processes that dynamically modulate gene expression and function within every cell in the body. These regulatory systems represent the long-sought-after molecular interfaces that mediate gene × environment interactions. Changes in the epigenome throughout life are responsible not only for controlling normal development, adult homeostasis, and aging but also for mediating responses to injury. Emerging evidence implicates a spectrum of epigenetic processes in the pathophysiology of stroke. In this review, we describe conventional epigenetic mechanisms (including DNA methylation, histone code modifications, nucleosome remodeling, and higher-order chromatin formation) and highlight the emerging roles each of these processes play in the pathobiology of stroke. We suggest that understanding these mechanisms may be important for discovering more sensitive and specific biomarkers for risk, onset, and progression of stroke. In addition, we highlight epigenetic approaches for stroke therapy, including the inhibition of DNA methyltransferase and histone deacetylase enzyme activities. These therapeutic approaches are still in their infancy, but preliminary results suggest that contemporary agents targeting these pathways can regulate the deployment of stress responses that modulate neural cell viability and promote brain repair and functional reorganization. Indeed, these agents even appear to orchestrate sophisticated cognitive functions, including learning and memory.
doi:10.1001/archneurol.2010.275
PMCID: PMC3685873  PMID: 21060009
8.  Translational Research in Neurology and Neuroscience 2010 
Archives of neurology  2010;67(11):1307-1315.
Over the past 2 decades, enormous progress has been made with regard to pharmacotherapies for patients with multiple sclerosis. There is perhaps no other subspecialty in neurology in which more agents have been approved that substantially alter the clinical course of a disabling disorder. Many of the pharmaceuticals that are currently approved, in clinical trials, or in preclinical development were initially evaluated in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis. Two Food and Drug Administration–approved agents (glatiramer acetate and natalizumab) were developed using the experimental autoimmune encephalomyelitis model. This model has served clinician-scientists for many decades to enable understanding the inflammatory cascade that underlies clinical disease activity and disease surrogate markers detected in patients.
doi:10.1001/archneurol.2010.158
PMCID: PMC3670826  PMID: 20625066
9.  The Emerging Role of Epigenetics in Stroke 
Archives of neurology  2010;67(12):1435-1441.
Recent scientific advances have demonstrated the existence of extensive RNA-based regulatory networks involved in orchestrating nearly every cellular process in health and various disease states. This previously hidden layer of functional RNAs is derived largely from non–protein-coding DNA sequences that constitute more than 98% of the genome in humans. These non–protein-coding RNAs (ncRNAs) include subclasses that are well known, such as transfer RNAs and ribosomal RNAs, as well as those that have more recently been characterized, such as microRNAs, small nucleolar RNAs, and long ncRNAs. In this review, we examine the role of these novel ncRNAs in the nervous system and highlight emerging evidence that implicates RNA-based networks in the molecular pathogenesis of stroke. We also describe RNA editing, a related epigenetic mechanism that is partly responsible for generating the exquisite degrees of environmental responsiveness and molecular diversity that characterize ncRNAs. In addition, we discuss the development of future therapeutic strategies for locus-specific and genome-wide regulation of genes and functional gene networks through the modulation of RNA transcription, posttranscriptional RNA processing (eg, RNA modifications, quality control, intracellular trafficking, and local and long-distance intercellular transport), and RNA translation. These novel approaches for neural cell- and tissue-selective reprogramming of epigenetic regulatory mechanisms are likely to promote more effective neuroprotective and neural regenerative responses for safeguarding and even restoring central nervous system function.
doi:10.1001/archneurol.2010.300
PMCID: PMC3667617  PMID: 21149808
10.  Amyotrophic Lateral Sclerosis–Frontotemporal Lobar Dementia in 3 Families With p.Ala382Thr TARDBP Mutations 
Archives of neurology  2010;67(8):1002-1009.
Background
TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of frontotemporal lobar dementia (FTLD) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only 1 description of 2 patients with FTLD and TARDBP gene mutations who later developed motor neuron disease.
Objective
To describe cognitive abnormalities in 3 Italian families with familial ALS and TARDBP gene mutations.
Design, Setting, and Participants
Genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial non–superoxide dismutase 1 gene (SOD1) ALS and 280 healthy controls.
Main Outcome Measure
We identified 3 index cases of familial ALS carrying the p.Ala382Thr missense mutation of the TARDBP gene and with clinical, neuroimaging, and neuropsychological features of FTLD.
Results
The p.Ala382Thr missense mutation of the TARDBP gene was absent in the 280 controls. It was present in all affected members of the 3 families for whom DNA was available. All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with fludeoxyglucose F 18 positron emission tomography and computed tomography.
Conclusions
Three apparently unrelated families with familial ALS carrying the p.Ala382Thr TARDBP missense mutation developed FTLD. In these families, FTLD co-segregates with ALS. Patients with ALS carrying TARDBP mutations may develop FTLD.
doi:10.1001/archneurol.2010.173
PMCID: PMC3535689  PMID: 20697052
11.  Tarenflurbil 
Archives of neurology  2010;67(6):750-752.
doi:10.1001/archneurol.2010.94
PMCID: PMC3526376  PMID: 20558395
12.  Regionally Selective Atrophy after Traumatic Axonal Injury 
Archives of neurology  2010;67(11):1336-1344.
Objectives
To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.
Design
Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging (MRI)-based morphometric analysis.
Setting
Inpatient traumatic brain injury unit
Patients or Other Participants
Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.
Main Outcome Measure
Changes in global and regional brain volumes between initial and follow-up MRI were used to assess the spatial distribution of post-traumatic volume loss. The Glasgow Outcome Scale – Extended was the primary measure of functional outcome.
Results
Patients underwent substantial global atrophy with mean brain parenchymal volume loss of 4.5% (95% Confidence Interval: 2.7 – 6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.
Conclusion
Traumatic axonal injury leads to substantial post-traumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.
doi:10.1001/archneurol.2010.149
PMCID: PMC3465162  PMID: 20625067
13.  Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease 
Archives of Neurology  2010;67(1):27-32.
Background
Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood.
Objective
To examine the effects of a dopamine agonist on the motor response to levodopa.
Design
Double-blind, randomized, placebo-controlled, crossover clinical trial.
Setting
Ambulatory academic referral center.
Patients
Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia.
Interventions
Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment.
Main Outcome Measures
Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to “ON” (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC.
Results
Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute×minutes (P=.006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P=.02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P=.004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion.
Conclusions
Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia.
Trial Registration
clinicaltrials.gov Identifier: NCT00666653
doi:10.1001/archneurol.2009.287
PMCID: PMC3390306  PMID: 20065126
14.  An Open-Label Trial of Recombinant Human Insulin-Like Growth Factor-I/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 (rhIGF-1/rhIGFBP-3) in Myotonic Dystrophy Type 1 
Archives of Neurology  2010;68(1):37-44.
Objective
To evaluate the safety and tolerability of recombinant human insulin-like growth factor-1 (rhIGF-1) complexed with IGF binding protein-3 (rhIGF-1/rhIGFBP-3) in patients with myotonic dystrophy type 1 (DM1).
Design
Open-label dose-escalation clinical trial.
Setting
University medical center.
Participants
Fifteen moderately affected ambulatory participants with genetically-proven DM1.
Intervention
Participants received escalating dosages of subcutaneous rhIGF-1/rhIGFBP-3 over 24 weeks followed by a 16 week washout period.
Outcome Measures
Serial assessments of safety, muscle mass, muscle function, and metabolic state were performed. The primary outcome variable was the ability of participants to complete 24 weeks on rhIGF-1/rhIGFBP-3 treatment.
Results
All participants tolerated rhIGF-1/rhIGFBP-3. There were no significant changes in muscle strength or functional outcomes measures. Lean body muscle mass measured by dual energy x-ray absorptiometry increased by 1.95 kg (p=0.0007) after treatment. Participants also experienced a mean reduction in triglyceride levels of 47 mg/dL (p=0.002), a mean increase in HDL levels of 5.0 mg/dL (p=0.03), a mean reduction in HbA1c of 0.15% (p=0.03), and a mean increase in testosterone level (in men) of 203 ng/dL (p=0.002) while on rhIGF-1/rhIGFBP-3. Mild reactions at the injection site occurred (n=9 participants), as did mild transient hypoglycemia (n=3), lightheadedness (n=2), and transient papilledema (n=1).
Conclusions
rhIGF-1/rhIGFBP-3 treatment was generally well tolerated in DM1. rhIGF-1/rhIGFBP-3 was associated with increased lean body mass and improvements in metabolism, but not with increased muscle strength or function. Larger randomized controlled trials would be needed to further evaluate the efficacy and safety of this medication in patients with neuromuscular disease.
doi:10.1001/archneurol.2010.227
PMCID: PMC3374954  PMID: 20837825
15.  Frequency of known mutations in early onset PD; implication for genetic counseling: the CORE-PD study 
Archives of Neurology  2010;67(9):1116-1122.
Objective
To assess the frequency and clinical characteristics of carriers of previously identified mutations in six genes associated with early onset Parkinson disease (EOPD) and provide empirical data that can be used to inform genetic counseling.
Methods
Mutations in SNCA, PRKN, PINK1, DJ1, LRRK2 and GBA were assessed in 953 individuals with EOPD ascertained based on age at onset (AAO) ≤50 years. Participants included 77 Hispanics and 139 of Jewish ancestry. A validated family history interview and the Unified Parkinson’s Disease Rating Scale (UPDRS) were administered. Demographic and phenotypic characteristics were compared among groups defined by mutation status.
Results
One hundred and fifty eight (16.6%) had mutations including 64 (6.7%) PRKN, 35 (3.6%) LRRK2 G2019S, 64 (6.7%) GBA and one (0.2%) DJ1. Mutation carriers were more frequent among cases with AAO ≤30 than among cases with AAO between 31 and 50 (40.6% vs. 14.6% p<0.001), Jews compared to non-Jews (32.4% vs. 13.7% p<0.001) and those reporting a first degree family history of PD than among those who did not (23.9% versus 15.1% p=0.012). Hispanics were more likely to be PRKN carriers than non-Hispanics (15.6% versus 5.9% p=0.003). The GBA L444P mutation was associated with a higher mean UPDRS-III score after adjustment for covariates.
Conclusion
EOPD individuals of Jewish or Hispanic ancestry, those with AAO ≤ 30, and those with a family history of PD in a first-degree relative may benefit from genetic counseling.
doi:10.1001/archneurol.2010.194
PMCID: PMC3329730  PMID: 20837857
16.  Predictors of Parkin Mutations in Early Onset Parkinson disease: the CORE-PD Study 
Archives of Neurology  2010;67(6):731-738.
Background
Mutations in the parkin gene are the most common genetic cause of early-onset Parkinson’s disease (EOPD). Results from a multi-center study of cases with PD systematically sampled by age at onset (AAO) have not been reported.
Objective
To determine risk factors associated with carrying mutations in the parkin gene.
Design
Cross-sectional observational study
Setting
13 movement disorders centers
Participants
956 EOPD cases defined as AAO <51.
Main Outcome Measures
Presence of heterozygous, homozygous or compound heterozygous parkin mutations.
Results
14.7% of cases reported a family history of PD in a first-degree relative using a previously validated interview. Sixty-four cases (6.7%) had parkin mutations (3.9% heterozygous, 0.6% homozygotes, 2.2% compound heterozgyotes). Copy Number Variation (CNV) was present in 52.3% (31.6% of heterozygotes, 83.3% of homozygotes, 81.0% of compound heterozygotes). Deletions in exons 3–4 and 255delA, were common in Hispanics, and specifically, in the Puerto Rican population. Earlier AAO, Hispanic ethnicity (OR compared to White non-Hispanic 2.7 95% CI 1.3–5.7, p<0.009) and family history of PD in a first-degree relative (OR 2.8 95%CI 1.5–5.3, p<0.002) were associated with carrying any mutation in the parkin gene (heterozygous, homozygous, compound heterozygous). Hispanic ethnicity was associated with carrying a heterozygous mutation (OR compared to non-Hispanic Caucasian 2.8 95%CI 1.1–7.2, p<0.03) after adjustment for covariates.
Conclusion
AAO, Hispanic ethnicity and family history of PD are associated with carrying any parkin mutation (heterozygous, homozygous, compound heterozygous) and heterozygous mutations alone. The increased odds of carrying a parkin mutation in Hispanics warrants further study.
doi:10.1001/archneurol.2010.95
PMCID: PMC3329757  PMID: 20558392
17.  Pediatric Neurological Complications of 2009 Pandemic Influenza A (H1N1) 
Archives of neurology  2010;68(4):455-462.
Objective
To analyze the spectrum of neurological manifestations in children hospitalized with pandemic influenza A H1N1 virus of 2009 (pH1N1).
Design
Retrospective case series of children hospitalized from May 1, 2009, through November 30, 2009.
Setting
Tertiary-care children’s hospital in Colorado.
Patients
All hospitalized patients with pH1N1 with neurological consult or diagnosis, lumbar puncture, electroencephalogram, or neuroimaging were selected as suspected cases. These were systematically reviewed and selected for final analysis if confirmed by pre-established definitions as a neurological complication.
Results
Of 307 children with pH1N1, 59 were selected as having suspected cases of neurological complications. Twenty-three children were confirmed to have a neurological complication. Of these 23, 15 (65%) required intensive care monitoring. The median length of stay was 4 days. Seventeen (74%) had a preexisting neurological diagnosis. The most common manifestation was seizure with underlying neurological disease (in 62% of cases) followed by encephalopathy with or without neuroimaging changes (in 26% of cases). Results from a lumbar puncture showed elevated protein levels in 3 of 6 patients but no significant pleocytosis. Seven of the 9 electroencephalograms showed diffuse slowing, and findings from magnetic resonance imaging were abnormal in 5 of 6 children. Deaths occurred in 13% of patients, and short-term disability in 22%.
Conclusions
Children infected with pH1N1 presented with a wide spectrum of neurological manifestations, which occurred primarily in individuals with preexisting neurological conditions. These individuals had a severe disease course, evidenced by need for intensive care services and relatively high rates of mortality or neurological disability. Children with underlying neurological conditions should be particularly targeted for influenza prevention and aggressive supportive treatment at the onset of influenzalike symptoms.
doi:10.1001/archneurol.2010.318
PMCID: PMC3096015  PMID: 21149805
18.  Temporoparietal hypometabolism is common in FTLD and is associated with imaging diagnostic errors 
Archives of neurology  2010;68(3):329-337.
Objective
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Design
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Setting
Academic medical centers
Patients
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Results
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Conclusions
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
doi:10.1001/archneurol.2010.295
PMCID: PMC3058918  PMID: 21059987
19.  Amyloid neuropathy type is distinguished by mass spectrometric based proteomic analysis of nerve tissue 
Archives of neurology  2010;68(2):195-199.
Objective
To determine specific type of amyloid from nerve biopsies using laser microdissection (LMD) and mass spectrometry (MS) based proteomic analysis.
Methods
Twenty one nerve biopsies (17 sural, 3 sciatic, 1 root amyloidoma) infiltrated by amyloid were studied. Immunohistochemical subtyping was unable to determine the specific amyloid for these 21 cases, but the clinical diagnosis was made based on additional testing. Clinical diagnosis was made through evaluation of serum monoclonal proteins, biopsy of bone marrow for acquired monoclonal immunoglobulin light-chain amyloidosis (AL) and kindred evaluations with DNA sequencing of transthyretin (TTR) and gelsolin (GSN). Our study included 8 cases of AL-type amyloidosis, 11 cases of TTR amyloidosis (3 Val30Met, 2 Val32Ala, 2 Thr60Ala, 1Ala109Ser, 1 Phe64Leu, 1 Ala97Ser, 1 not sequenced), and 2 cases of gelsolin amyloidosis (1 Asp187Asn, 1 not sequenced). One TTR and one gelsolin amyloidosis patients with no specific mutation identified were diagnosed based on the genetic confirmation in their first degree relative. Congophilic proteins in the tissues of these 21 cases were laser microdissected, digested into tryptic peptides and analyzed utilizing liquid chromatography electrospray tandem mass spectrometry. Identified proteins were reviewed using bioinformatics tools with interpreters blinded to clinical information.
Results
Specific types of amyloid were accurately detected by LMD/MS in all cases (8 AL-type, 2 gelsolin, and 11 transthyretin). Incidental serum monoclonal proteins did not interfere with detection of TTR amyloidosis in two patients. Additionally, specific TTR mutations were identified in ten cases by LMD/MS. Serum amyloid P-component and apolipoprotein E proteins were commonly found among all cases.
Conclusions
Proteomic analysis of nerve tissue using LMD/MS distinguishes specific types of amyloid independent of clinical information. This new proteomic approach will enhance both diagnostic and research efforts in amyloidosis and other neurologic diseases.
doi:10.1001/archneurol.2010.261
PMCID: PMC3167172  PMID: 20937937
Mass spectrometry; amyloidosis; gelsolin; transthyretin
20.  Identification of Novel Loci for Alzheimer Disease and Replication of CLU, PICALM, and BIN1 in Caribbean Hispanic Individuals 
Archives of Neurology  2010;68(3):320-328.
Objectives
To identify novel loci for late-onset Alzheimer disease (LOAD) in Caribbean Hispanic individuals and to replicate the findings in a publicly available data set from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study.
Design
Nested case-control genome-wide association study.
Setting
The Washington Heights–Inwood Columbia Aging Project and the Estudio Familiar de Influencia Genetica de Alzheimer study.
Participants
Five hundred forty-nine affected and 544 unaffected individuals of Caribbean Hispanic ancestry.
Intervention
The Illumina HumanHap 650Y chip for genotyping.
Main Outcome Measure
Clinical diagnosis or pathologically confirmed diagnosis of LOAD.
Results
The strongest support for allelic association was for rs9945493 on 18q23 (P=1.7 × 10−7), but 22 additional single-nucleotide polymorphisms (SNPs) had a P value less than 9 × 10−6 under 3 different analyses: unadjusted and stratified by the presence or absence of the APOE ε4 allele. Of these SNPs, 5 SNPs (rs4669573 and rs10197851 on 2p25.1; rs11711889 on 3q25.2; rs1117750 on 7p21.1; and rs7908652 on 10q23.1) were associated with LOAD in an independent cohort from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study. We also replicated genetic associations for CLU, PICALM, and BIN1.
Conclusions
Our genome-wide search of Caribbean Hispanic individuals identified several novel genetic variants associated with LOAD and replicated these associations in a white cohort. We also replicated associations in CLU, PICALM, and BIN1 in the Caribbean Hispanic cohort.
doi:10.1001/archneurol.2010.292
PMCID: PMC3268783  PMID: 21059989
21.  INSULIN RESISTANCE IS ASSOCIATED WITH ALZHEIMER-LIKE REDUCTIONS IN REGIONAL CEREBRAL GLUCOSE METABOLISM FOR COGNITIVELY NORMAL ADULTS WITH PRE-DIABETES OR EARLY TYPE 2 DIABETES 
Archives of neurology  2010;68(1):51-57.
Background
Insulin resistance is a causal factor in pre-diabetes and type 2 diabetes (T2D), and also increases the risk of developing Alzheimer’s disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu) as measured by fluorodeoxyglucose positron emission tomography (FDG PET) in parietotemporal, frontal, and cingulate cortex are also associated with increased AD risk, and can be observed years before dementia onset.
Objectives
We examined whether greater insulin resistance as indexed by the homeostasis model assessment (HOMA-IR) would be associated with reduced resting CMRglu in areas known to be vulnerable in AD in a sample of cognitively normal adults with newly diagnosed pre-diabetes or T2D (P-D/T2D). We also determined whether P-D/T2D adults have abnormal patterns of CMRglu during a memory encoding task.
Design
Randomized crossover design of resting and activation [F-18] FDG-PET.
Setting
University Imaging Center and VA Clinical Research Unit.
Participants
Participants included 23 older adults (mean age±SEM=74.4±1.4) with no prior diagnosis of or treatment for diabetes, but who met American Diabetes Association glycemic criteria for pre-diabetes (n=11) or diabetes (n=12) based on fasting or 2-h oral glucose tolerance test (OGTT) glucose values, and 6 adults (mean age±SEM=74.3±2.8) with normal fasting glucose and glucose tolerance. No participant met Petersen criteria for mild cognitive impairment (MCI).
Intervention
Fasting participants rested with eyes open in a dimly lit room and underwent resting and cognitive activation [F-18]FDG PET imaging on separate days, in randomized order, at 9 am. Following a 30-min transmission scan, subjects received an intravenous injection of 5 mCi [F-18]FDG, and the emission scan commenced 40 min post-injection. In the activation condition, a 35-min memory encoding task was initiated at the time of tracer injection. Subjects were instructed to remember a repeating list of 20 words that were randomly presented in series through earphones. Delayed free recall for items on the word list was assessed once the emission scan was complete.
Main Outcome Measures
HOMA-IR was calculated for each participant using fasting glucose and insulin values obtained during OGTT screening, and then correlated with CMRglu values obtained during the resting scan. Resting CMRglu values were also subtracted from CMRglu values obtained during the memory encoding/activation scan to examine task-related patterns of CMRglu.
Results
Greater insulin resistance as indexed by HOMA-IR was associated with an AD-like pattern of reduced CMRglu in frontal, temporal-parietal, and cingulate regions in adults with P-D/T2D. The relationship between CMRglu and HOMA-IR was independent of age, 2-h OGTT glucose concentration, or apolipoprotein E-ε4 allele carriage. During the memory encoding task, normal adults showed activation in right anterior and inferior prefrontal cortex, right inferior temporal cortex, and medial and posterior cingulate regions. Compared to the normal group, adults with P-D/T2D showed a different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test.
Conclusions
Our results suggest that insulin resistance may be a marker of AD risk that is associated with reduced CMRglu and subtle cognitive impairments at the earliest stage of disease, even before the onset of MCI.
doi:10.1001/archneurol.2010.225
PMCID: PMC3023149  PMID: 20837822
Alzheimer’s disease; FDG PET; insulin; insulin resistance; diabetes; pre-diabetes; memory
22.  Plasma Amyloid β predicts cognitive decline 
Archives of neurology  2010;67(12):1485-1490.
Context
Amyloid β (Aβ) is a key pathophysiological feature of Alzheimer’s disease (AD). Baseline and change values of plasma Aβ have been associated with AD risk.
Objective
To determine if plasma Aβ levels: 1) can be linked to specific cognitive changes which constitute conversion to AD; and 2) correspond to cognitive change independent of dementia.
Setting
Northern Manhattan community.
Design
Longitudinal study including three visits over ~4.5 years (2000–2006).
Participants
880 individuals, from a population based and ethnically diverse sample, who had two plasma Aβ measurements and were dementia-free at the time of the first Aβ sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired at any point, and 70 converted to AD.
Main Outcome Measures
General Estimating Equations tested the association between plasma Aβ (baseline and change values) and cognitive change (composite score, and memory, language, and visuospatial indices).
Results
High baseline plasma Aβ42 (p=.01)and Aβ40 (p=.01), and decreasing/relatively stable Aβ42 (p=.01) were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aβ42 (p=.01) and decreasing/relatively stable plasma Aβ42 (p=.01) was associated with faster cognitive decline, primarily in memory.
Conclusions
The association between plasma Aβ and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aβ with AD onset. The predominant association with memory seen only in healthy elders also suggests that plasma Aβ is linked with even earlier neurologic changes that may or may not culminate in dementia.
doi:10.1001/archneurol.2010.189
PMCID: PMC3006003  PMID: 20697031
23.  Meta-Analysis confirms CR1, CLU, and PICALM as Alzheimer’s disease risk loci and reveals interactions with APOE genotypes 
Archives of neurology  2010;67(12):1473-1484.
Objectives
To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer’s disease (AD) and whether risk for AD associated with these genes is influenced by APOE genotypes.
Design
Association study of AD and CLU, PICALM, CR1 and APOE genotypes.
Setting
Academic research institutions in the United States, Canada, and Israel.
Participants
7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively normal controls, 1,092 with autopsies from 12 different studies, including Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.
Results
Unadjusted, CLU [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85 – 0.96 for single nucleotide polymorphism (SNP) rs11136000], CR1 (OR = 1.14, CI = 1.07 – 1.22, SNP rs3818361), and PICALM (OR = 0.89, CI = 0.84 – 0.94, SNP rs3851179) were associated with AD in Caucasians. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least one APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, APOE ε4 (+/−), and an interaction term showed significant interaction between APOE ε4 (+/−) and PICALM.
Conclusions
We confirm in a completely independent dataset that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subject. Thus, APOE and PICALM synergistically interact.
doi:10.1001/archneurol.2010.201
PMCID: PMC3048805  PMID: 20697030
24.  Validation of Consensus Panel Diagnosis in Dementia 
Archives of neurology  2010;67(12):1506-1512.
Background
The clinical diagnosis of dementing diseases largely depends upon the subjective interpretation of patient symptoms. Consensus panels are frequently used in research to determine diagnoses when definitive pathological findings are unavailable. Nevertheless, research on group decision-making indicates many factors can adversely influence panel performance.
Objective
To determine conditions that improve consensus panel diagnosis.
Design
Comparison of neuropathological diagnoses with individual and consensus panel diagnoses based on clinical summaries, FDG-PET scans, and summaries with scans.
Setting
Expert and trainee individual and consensus panel deliberations using a modified Delphi method in a pilot research study of the diagnostic utility of FDG-PET imaging.
Patients and Methods
Forty-five patients with pathologically confirmed Alzheimer’s disease or frontotemporal dementia. Statistical measures of diagnostic accuracy, agreement, and confidence for individual raters and panelists before and after consensus deliberations.
Results
The consensus protocol using trainees and experts surpassed the accuracy of individual expert diagnoses when clinical information elicited diverse judgments. In these situations, consensus was 3.5 times more likely to produce positive rather than negative changes in the accuracy and diagnostic certainty of individual panelists. A rule that forced group consensus was at least as accurate as majority and unanimity rules.
Conclusions
Using a modified Delphi protocol to arrive at a consensus diagnosis is a reasonable substitute for pathologic information. This protocol improves diagnostic accuracy and certainty when panelist judgments differ and is easily adapted to other research and clinical settings while avoiding potential pitfalls of group decision-making.
doi:10.1001/archneurol.2010.301
PMCID: PMC3178413  PMID: 21149812
25.  Ascertainment Bias in the Clinical Diagnosis of Alzheimer's Disease 
Archives of neurology  2010;67(11):1364-1369.
Objective:
The clinical diagnosis of Alzheimer's disease is often based, at least in part, on poor cognitive test performance compared with normative values. The presence and extent of an ascertainment bias (omission of affected individuals) produced by such criteria when applied as early as possible in the course of the disease was examined.
Design:
Longitudinal study from 1979 to 2008.
Setting:
Washington University in St. Louis Alzheimer Disease Research Center.
Participants:
Of 78 individuals aged 65 to 101 years enrolled as healthy controls 55 later developed autopsy-confirmed AD; 23 remained cognitively healthy and did not have neuropathologic AD.
Main Outcome Measures:
Criteria for diagnosis of Alzheimer disease based on various cut-points (1.5, 1.0, and 0.5 standard deviations below the mean for robust test norms) for two standard psychometric measures from each of three cognitive domains (episodic memory, visusospatial ability, working memory) were applied to data from the first assessment associated with an independent clinical diagnosis of cognitive impairment for those who developed symptomatic AD and the last assessment for those who did not.
Results:
Areas under the curve from ROC analyses ranged from .71 to .49; sensitivities and specificities were unsatisfactory even after adjusting for age and education, using combinations of tests, or examining longitudinal decline prior to clinical diagnosis.
Conclusions:
Reliance on divergence from group normative values to determine initial cognitive decline caused by Alzheimer disease results in failure to include people in the initial symptomatic stage of the illness.
doi:10.1001/archneurol.2010.272
PMCID: PMC2999470  PMID: 21060013

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