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26.  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
27.  Use of Anterior Temporal Lobectomy for Epilepsy in a Community-Based Population 
Archives of neurology  2012;69(11):1476-1481.
Objective
To assess the hypothesis that use of anterior temporal lobectomy (ATL) for temporal epilepsy has diminished over time.
Design
Population-based cohort study.
Setting
The Rochester Epidemiology Project based in Olmsted County, Minnesota.
Participants
Residents of Olmsted County.
Main Outcome Measures
Poisson regression was used to evaluate changes in ATL use over time by sex.
Results
Over a 17-year period, from 1993 to 2009, 847 ATLs were performed with the primary indication of epilepsy (average, 50 procedures/y). Of these, 26 occurred among Olmsted County residents. The use rates de clined significantly between 1993 and 2000 (8 years) and 2001 and 2009 (9 years) according to Poisson regression analysis, from 1.9 to 0.7 per 100 000 person-years (P=.01). The rate of ATL use among Olmsted County residents was 1.2 (95% CI, 0.9 to 2.4) per 100 000 person-years of follow-up over this 17-year period. The sex-specific rates were 1.6 (95% CI, 0.9 to 2.4) and 0.7 (95% CI, 0.2 to 1.3) per 100 000 person-years for females and males, respectively.
Conclusions
In this community-based cohort, the rate of ATL use was 1.2 per 100 000 person-years of follow-up. Use of this procedure has declined over time; the reasons for this are unknown but do not include referral pattern changes.
doi:10.1001/archneurol.2012.1200
PMCID: PMC3526693  PMID: 22911042
28.  Quantitative Pilomotor Axon-Reflex Test – A Novel Test of Pilomotor Function 
Archives of neurology  2012;69(11):1488-1492.
Objective
Cutaneous autonomic function can be quantified by the assessment of sudomotor and vasomotor responses. Although piloerector muscles are innervated by the sympathetic nervous system, there are, at present, no methods to quantify pilomotor function. This study aims to quantify piloerection using phenylephrine in humans.
Design
Pilot study.
Setting
Hospital based study.
Participants
Twenty-two healthy volunteers (18 males, 4 females) aged 24–48 years participated in several studies.
Interventions
Piloerection was stimulated by iontophoresis of 1% phenylephrine. Silicone impressions of piloerection were quantified by number and area. The direct and indirect response to phenylephrine iontophoresis was compared on both forearms, after pretreatment to topical and subcutaneous lidocaine and iontophoresis of normal saline.
Results
Iontophoresis of phenylephrine induced piloerection in both the direct and axon-reflex mediated regions with similar responses in both arms. Topical lidocaine blocked axon-reflex mediated piloerection post-iontophoresis (control 66.6±19.2 impressions vs. lidocaine 7.2±4.3 impressions; P<0.001). Subcutaneous lidocaine completely blocked piloerection. The area of axon-reflex mediated piloerection was also attenuated in the lidocaine treated region post-iontophoresis (46.2±16.1 cm2 vs. 7.2±3.9 cm2, P<0.0001). Piloerection was delayed in the axon-reflex region compared to the direct region. Normal saline did not cause piloerection.
Conclusions
Phenylephrine provokes piloerection directly and indirectly through an axon-reflex mediated response that is attenuated by lidocaine. Piloerection is not stimulated by iontophoresis of normal saline alone. The quantitative pilomotor axon-reflex test (QPART) may complement other measures of cutaneous autonomic nerve fiber function.
doi:10.1001/archneurol.2012.1092
PMCID: PMC3563419  PMID: 22868966
Pilomotor; Axon Reflex; Iontophoresis; Silicone Impression
29.  Amyloid-β Dynamics in Human Plasma 
Archives of neurology  2012;69(12):10.1001/archneurol.2012.18107.
Background
A marked decrease of Aβ42 in the cerebrospinal fluid (CSF) of patients with incipient Alzheimer's Disease (AD) has been well documented. However, contradictory results have been reported from studies on plasma Aβ levels as diagnostic markers for AD.
Objective
To investigate dynamic changes in human plasma Aβ levels, evaluate the effects of aging and amyloidosis on these dynamics, and determine their correlation with CSF Aβ levels.
Design, Settings, and Participants
This was a repeated plasma and CSF sampling study conducted at the Washington University School of Medicine in St. Louis. Older adults with amyloid deposition (Amyloid +), age-matched controls without amyloid deposition (Amyloid −), and younger normal controls (YNC) were enrolled for the study.
Main Outcome Measures
Hourly measurements of plasma Aβ were compared between groups by age and amyloidosis. Plasma Aβ and CSF Aβ levels were compared for correlation, linear increase, and circadian patterns.
Results
Circadian patterns were observed in plasma Aβ, with diminished amplitudes with aging. Linear increase of Aβ was only observed for CSF Aβ in YNC and Amyloid − groups, but not in the Amyloid + group. No linear increase was observed for plasma Aβ. No significant correlations were found between plasma and CSF Aβ levels.
Conclusions
Plasma Aβ, like CSF, demonstrates a circadian pattern which is reduced in amplitude with increasing age but is unaffected by amyloid deposition. However, we found no evidence that plasma and CSF Aβ levels were related on an hourly or individual basis.
doi:10.1001/archneurol.2012.18107
PMCID: PMC3808092  PMID: 23229043
30.  Association of Shorter Leukocyte Telomere Repeat Length with Dementia and Mortality 
Archives of neurology  2012;69(10):1332-1339.
Objective
Shortening of chromosomal telomeres is a consequence of cell division, and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging. We have hypothesized that shorter telomere length, as measured in human blood samples, is associated with the development of Alzheimer disease, and with mortality.
Design/Setting
Using data from a multiethnic community-based study of aging and dementia, we studied 1,983 subjects over age 65 yr, who had available stored leukocyte DNA. Mean age-at-blood-draw was 78.3 ± 6.9 yr. Mean age of death was 86.0 ± 7.4 yr. Median follow-up for mortality was 9.3 yr; 190 (9.6%) developed incident dementia. We used real-time PCR to determine mean telomere length (TL) in a modified telomere-sequence to single-copy-gene-sequence ratio method.
Results
TL was inversely related to age, and shorter in men than women. Persons dying during follow-up had shorter TL compared to survivors (6,218±819 vs. 6,491±881 basepairs, p<0.0001) even after adjustment for age, sex, education, and APOE genotype. Individuals who developed dementia had significantly shorter TL (6,131±798 for prevalent cases, and 6,315±817 for incident cases) compared with those remaining dementia-free (6,431±864). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (p=0.05), but stratified analyses for sex showed that this association of age-at-onset of dementia with shorter TL was significant in women, but not in men.
Conclusions
Our findings suggest that shortened leukocyte TL is associated with risks of dementia and mortality, and may therefore be a marker of biological aging.
doi:10.1001/archneurol.2012.1541
PMCID: PMC3622729  PMID: 22825311
biological aging; Alzheimer's disease; apolipoprotein E; leukocyte; DNA
31.  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
32.  Plasma Amyloid β as a Predictor of Dementia and Cognitive Decline: A Systematic Review and Meta-analysis 
Archives of neurology  2012;69(7):824-831.
Context
Preclinical prediction of Alzheimer’s disease is important, critical to effective intervention. Plasma levels of amyloid β-peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods and sample size, making it difficult to readily interpret the overall data.
Objective
To conduct a systematic review and meta-analysis of relevant prospective studies in order to determine if plasma amyloid β levels may predict development of dementia, Alzheimer’s disease, and cognitive decline.
Data Sources
Prospective studies published between 1995 and 2011 indexed in the PubMed, EMBASE, and PsycInfo databases were searched.
Study Selection
Selected studies included those measuring at least one relevant plasma amyloid β species (Aβ40, Aβ42, Aβ42:Aβ40 ratio) and reporting an effect estimate for dementia, Alzheimer’s disease, or cognitive change.
Data Extraction
Using a standardized extraction form, appropriate study parameters on subject information, exposure, and outcome were extracted. Random effects models were utilized to generate summary risk ratios and 95% confidence intervals, comparing the bottom versus top quantile for each plasma measure.
Results
Thirteen studies with a total of 10,303 subjects met inclusion criteria for meta-analysis. Lower Aβ42:Aβ40 ratios were significantly associated with development of Alzheimer’s disease (summary RR=1.60, 95% CI=1.04,2.46; p=0.03) and dementia (RR=1.67 95% CI=1.02,2.75; p=0.04). Significant heterogeneity was found for both summary estimates, which could not be explained by participants’ age, sex distribution, the study’s follow-up time, or year of publication. Plasma levels of Aβ40 and Aβ42 alone were not significantly associated with either outcome.
Conclusions
Overall, the literature indicates that plasma Aβ42:Aβ40 ratios predict development of Alzheimer’s disease and dementia. However, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma amyloid β levels as a preclinical biomarker.
doi:10.1001/archneurol.2011.1841
PMCID: PMC3772635  PMID: 22451159
33.  Ganglionic Acetylcholine Receptor Autoantibody 
Archives of neurology  2009;66(6):735-741.
Objective
To describe the clinical utility of the nicotinic ganglionic acetylcholine receptor (α3-AChR) autoantibody as a marker of neurological autoimmunity and cancer.
Design
Case-control study.
Setting
Mayo Clinic, Rochester, Minnesota.
Patients
A total of 15 000 patients seen at Mayo Clinic (2005–2007) and evaluated on a service basis for paraneoplastic neurological autoimmunity for whom clinical information was obtained retrospectively by medical record review as well as 457 neurologically asymptomatic patients or control subjects of whom 173 were healthy, 245 had lung cancer, and 39 had systemic lupus erythematosus or Sjögren syndrome.
Outcome Measures
Neurological, oncological, and serological associations of α3-AChR autoantibody seropositivity.
Results
Of 15 000 patients tested on a service basis, 1% were seropositive (median, 0.12 nmol/L; range, 0.03–18.8 nmol/L; normal, ≤0.02 nmol/L), 55% were male, and the median age was 65 years. Cancer was found (new or by history) in 24 of 78 patients evaluated for cancer while at Mayo Clinic (30%); 43% had adenocarcinoma (more patients had breast cancer than prostate, lung, and gastrointestinal cancers; each of the latter groups had about the same number of patients). Of 12 patients with high antibody values (≥1.00 nmol/L), 83% had pandysautonomia. Of 85 patients with medium antibody values (0.10–0.99 nmol/L), neurological presentations were more diverse and included peripheral neuropathies (36%), dysautonomia (20%, usually limited), and encephalopathy (13%). Of 58 patients with low antibody values (0.03–0.09 nmol/L), 54% had a nonautoimmune neurological disorder or no neurological disorder. Of 245 control patients with lung cancer, 7.8% were seropositive. Only 1 of 212 control patients without cancer (0.5%) was seropositive (P<.001).
Conclusion
The detection of α3-AChR autoantibody aids the diagnosis of neurological autoimmunity and cancer.
doi:10.1001/archneurol.2009.78
PMCID: PMC3764484  PMID: 19506133
34.  Effects of Growth Hormone–Releasing Hormone on Cognitive Function in Adults With Mild Cognitive Impairment and Healthy Older Adults 
Archives of neurology  2012;69(11):1420-1429.
Background
Growth hormone–releasing hormone (GHRH), growth hormone, and insulinlike growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pathogenesis of Alzheimer disease. Previously, we reported favorable cognitive effects of short-term GHRH administration in healthy older adults and provided preliminary evidence to suggest a similar benefit in adults with mild cognitive impairment (MCI).
Objective
To examine the effects of GHRH on cognitive function in healthy older adults and in adults with MCI.
Design
Randomized, double-blind, placebo-controlled trial.
Setting
Clinical Research Center, University of Washington School of Medicine in Seattle.
Participants
A total of 152 adults (66 with MCI) ranging in age from 55 to 87 years (mean age, 68 years); 137 adults (76 healthy participants and 61 participants with MCI) successfully completed the study.
Intervention
Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analog of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline, at weeks 10 and 20 of treatment, and after a 10-week washout (week 30), blood samples were collected, and parallel versions of a cognitive battery were administered. Before and after the 20-week intervention, participants completed an oral glucose tolerance test and a dual-energy x-ray absorptiometry scan to measure body composition.
Main Outcome Measures
Primary cognitive outcomes were analyzed using analysis of variance and included 3 composites reflecting executive function, verbal memory, and visual memory. Executive function was assessed with Stroop Color-Word Interference, Task Switching, the Self-Ordered Pointing Test, and Word Fluency, verbal memory was assessed with Story Recall and the Hopkins Verbal Learning Test, and visual memory was assessed with the Visual-Spatial Learning Test and Delayed Match-to-Sample.
Results
The intent-to-treat analysis indicated a favorable effect of GHRH on cognition (P=.03), which was comparable in adults with MCI and healthy older adults. The completer analysis showed a similar pattern, with a more robust GHRH effect (P=.002). Subsequent analyses indicated a positive GHRH effect on executive function (P=.005) and a trend showing a similar treatment-related benefit in verbal memory (P=.08). Treatment with GHRH increased insulinlike growth factor 1 levels by 117% (P<.001), which remained within the physiological range, and reduced percent body fat by 7.4% (P<.001). Treatment with GHRH increased fasting insulin levels within the normal range by 35% in adults with MCI (P<.001) but not in healthy adults. Adverse events were mild and were reported by 68% of GHRH-treated adults and 36% of those who received placebo.
Conclusions
Twenty weeks of GHRH administration had favorable effects on cognition in both adults with MCI and healthy older adults. Longer-duration treatment trials are needed to further examine the therapeutic potential of GHRH administration on brain health during normal aging and “pathological aging.”
Trial Registration
clinicaltrials.gov Identifier: NCT00257712
doi:10.1001/archneurol.2012.1970
PMCID: PMC3764914  PMID: 22869065
35.  Frontotemporal dementia in a Brazilian Caucasian kindred with the C9orf72 mutation 
Archives of neurology  2012;69(9):1149-1153.
Objective
Describe the clinical features of a Brazilian C9orf72 frontotemporal dementia – amyotrophic lateral sclerosis (FTD-ALS) kindred, and compare them to other reported C9orf72 families and FTD-ALS causing mutations.
Design
Report of a kindred.
Setting
Dementia center at an University hospital.
Patients
One kindred encompassing 3 generations.
Results
The presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed PCR and Southern blot. The observed phenotypes were behavioral variant FTD and ALS with dementia, with significant variability in age of onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations and more posterior atrophy on neuroimaging than is typical for FTD were seen.
Conclusions
bvFTD due to C9orf72 expansions displays some phenotypic heterogeneity, and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede by many years the diagnosis of dementia and may be a distinguishing feature of this mutation.
doi:10.1001/archneurol.2012.650
PMCID: PMC3625641  PMID: 22964910
36.  Cellular Immune Suppression in Paraneoplastic Neurologic Syndromes Targeting Intracellular Antigens 
Archives of neurology  2012;69(9):1132-1140.
Background
Tumor treatment is the mainstay of therapy for paraneoplastic neurologic disorders (PNDs), but it is only effective in some cases and other treatment options are limited.
Objective
To evaluate the short-term use of a combination of prednisone and tacrolimus for acute neurologic worsening in PND in which intracellular antigens are targeted.
Design
Retrospective single-center case series of patients with PND treated with tacrolimus.
Setting
The Rockefeller University Hospital, a research hospital in New York, New York.
Patients
Twenty-six patients with PND with high titer (≥1:1000) anti-HuD, anti-Yo, or anti-CRMP5 auto-antibodies were enrolled. Patients were referred from Memorial Sloan-Kettering Cancer Center or self-referred. Two patients discontinued intervention owing to adverse events.
Interventions
Patients were treated with tacrolimus, 0.15–0.30 mg/kg per day, in 2 divided oral doses with 60 mg per day of oral prednisone tapered off during 1 to 4 weeks.
Main Outcome Measures
The primary outcome measure was median survival. Neurologic examinations before and after treatment as well as adverse events are described.
Results
Median survival time was 52 months from time of diagnosis. Some patients experienced neurologic improvement that was functionally meaningful. The incidence of adverse events was similar to that generally reported with tacrolimus.
Conclusions
A short course of prednisone and tacrolimus to target central nervous system T cells in patients with PND with acute neurologic decline in which intracellular antigens are targeted was well tolerated and warrants further study.
doi:10.1001/archneurol.2012.595
PMCID: PMC3721351  PMID: 22566506
37.  Diabetes, glucose control and 9 year cognitive decline among non-demented older adults 
Archives of neurology  2012;69(9):1170-1175.
Background
While several studies report an association between prevalent diabetes mellitus (DM) and cognitive impairment, less is known about incident DM in late life and cognitive decline. Glycemic control among elders with DM may also be associated with cognitive function, but findings are inconsistent.
Objective
To determine if prevalent and incident DM increases risk of cognitive decline, and if, among elders with DM, poor glucose control is related to worse cognitive performance.
Design
Prospective cohort study.
Setting
Health Aging and Body Composition Study at two community clinics.
Participants
A total of 3,069 elders (mean age 74.2 years; 42% black; 52% female).
Main Outcome Measures
Participants completed the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and selected intervals over 10 years. DM status was determined at baseline and during follow-up visits. Glycosylated hemoglobin A1c (HbA1c) was measured at year 1 (baseline), 4, 6, and 10 from fasting whole blood.
Results
At baseline 717 (23.4%) participants had prevalent DM and 2352 (76.6%) were without diabetes, 159 of whom developed incident DM during follow-up. Participants with prevalent DM had lower baseline test scores than participants without DM (3MS: 88.8 vs. 90.9; DSST: 32.5 vs 36.3, respectively; |t|=6.09, p=0.001 for both tests). Results from mixed-effects models showed a similar pattern for 9-year decline (3MS: −6.0 vs. −4.5 point decline; |t|=2.66, p=0.008; DSST: −7.9 vs. −5.7, point decline; |t|=3.69, p=0.001, respectively). Participants with incident DM tended to have baseline and 9-year decline scores between the other two groups but were not statistically different from the group without diabetes. Multivariate adjustment for demographics and medical co-morbidities produced similar results. Among participants with prevalent DM, HbA1c level was associated with lower average mean cognitive scores (3MS p for overall=0.003; DSST p for overall=0.04), even after multivariate adjustment.
Conclusion
Among well-functioning older adults, DM and poor glucose control among those with DM are associated with worse cognitive function and greater decline. This suggests severity of DM may contribute to accelerated cognitive aging.
doi:10.1001/archneurol.2012.1117
PMCID: PMC3752423  PMID: 22710333
38.  Potential Use of γ-Secretase Modulators in the Treatment of Alzheimer Disease 
Archives of neurology  2012;69(10):1255-1258.
Although significant progress has occurred in the past 20 years regarding our understanding of Alzheimer disease pathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering the clinical course of this prevalent neurodegenerative disease. In this short review, we discuss 2 approaches that are currently being tested clinically (γ-secretase inhibition and γ-secretase modulation) and emphasize the significant differences between these 2 therapeutic approaches. We also discuss certain genetic- and biomarker-based translational and clinical trial paradigms that may assist in developing a useful therapeutic agent.
doi:10.1001/archneurol.2012.540
PMCID: PMC3747667  PMID: 22801784
39.  Association of Lifetime Cognitive Engagement and Low β-Amyloid Deposition 
Archives of neurology  2012;69(5):623-629.
Objective
To assess the association between lifestyle practices (cognitive and physical activity) and β-amyloid deposition, measured with positron emission tomography using carbon 11–labeled Pittsburgh Compound B ([11C]PiB), in healthy older individuals.
Design
Cross-sectional clinical study.
Setting
Berkeley, California.
Participants
Volunteer sample of 65 healthy older individuals (mean age, 76.1 years), 10 patients with Alzheimer disease (AD) (mean age, 74.8 years), and 11 young controls (mean age, 24.5 years) were studied from October 31, 2005, to February 22, 2011.
Main Outcome Measures
Cortical [11C]PiB average (frontal, parietal, lateral temporal, and cingulate regions) and retrospective, self-report scales assessing participation in cognitive activities (eg, reading, writing, and playing games) and physical exercise.
Results
Greater participation in cognitively stimulating activities across the lifespan, but particularly in early and middle life, was associated with reduced [11C]PiB uptake (P <.001, accounting for age, sex, and years of education). Older participants in the highest cognitive activity tertile had [11C]PiB uptake comparable to young controls, whereas those in the lowest cognitive activity tertile had [11C]PiB uptake comparable to patients with AD. Although greater cognitive activity was associated with greater physical exercise, exercise was not associated with [11C]PiB uptake.
Conclusions
Individuals with greater early- and middle-life cognitive activity had lower [11C]PiB uptake. The tendency to participate in cognitively stimulating activities is likely related to engagement in a variety of lifestyle practices that have been implicated in other studies showing reduced risk of AD-related pathology. We report a direct association between cognitive activity and [11C]PiB uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of β-amyloid, perhaps influencing the onset and progression of AD.
doi:10.1001/archneurol.2011.2748
PMCID: PMC3747737  PMID: 22271235
40.  Effects of Age and Sex on Aquaporin-4 Autoimmunity 
Archives of neurology  2012;69(8):1039-1043.
Objective
To determine the sex and age distribution of aquaporin-4 (AQP4) autoimmunity using data derived from clinical service laboratory testing of 56 464 patient samples.
Design
Observational analysis.
Setting
Mayo Clinic Neuroimmunology Laboratory.
Patients
Between October 1, 2005, and January 4, 2011, 56 464 patients were tested for AQP4-IgG; 2960 (5.2%) patients were seropositive.
Main Outcome Measure
Seropositivity for AQP4-IgG.
Results
Patients seropositive for AQP4-IgG were older than seronegative patients (mean [SD] age, 46 [16] vs 42 [15] years, respectively; P<.001). More females than males were tested (37 662 vs 16 810, respectively; P<.001). Among 2743 seropositive patients, 146 (5.3%) were pediatric (aged ≤18 years) and 333 (12.1%) were elderly (aged ≥65 years). The sex distribution of seropositive patients was 2465 females and 306 males (absolute female:male ratio, 8.1:1; P<.001). After adjusting for the number of females tested, an excess of females persisted (adjusted female:male ratio, 3.6:1). Female predominance for AQP4-IgG was more striking in adults (absolute female:male ratio, 8.4:1; adjusted female:male ratio, 3.5:1) than in pediatric patients (absolute female: male ratio, 4.3:1; adjusted female:male ratio, 2.9:1) (P<.001). Elderly women were more likely to be seropositive than individuals in other age categories (13.1% vs 6.0%, respectively; P<.001). The proportion of AQP4-IgG–seropositive individuals (detection rate), defined by decade of age, increased exponentially in women after age 50 years.
Conclusions
Seropositivity for AQP4-IgG occurs predominantly in females, particularly in individuals older than 18 years. Among seropositive patients, 1 in 6 is in the extremes of age. The detection rate of AQP4-IgG increased in women after age 50 years.
doi:10.1001/archneurol.2012.249
PMCID: PMC3746965  PMID: 22507888
41.  Varicella-Zoster Virus Expression in the Cerebral Arteries of Diabetic Subjects 
Archives of neurology  2012;69(1):142-144.
Primary varicella-zoster virus (VZV) infection causes varicella (chickenpox), after which VZV becomes latent in ganglionic neurons along the entire neuraxis. A decline in cell-mediated immunity to VZV in elderly and immunocompromised individuals results in zoster (shingles). Within the first year after herpes zoster, there is a 30% increased risk of stroke.1–2 Approximately one-third of patients with VZV vasculopathy do not have zoster rash and diabetic patients are at greater risk for both zoster3 and stroke; therefore, we examined the cerebral arteries of 4 diabetic subjects for the presence of VZV DNA and antigen.
doi:10.1001/archneur.69.1.142
PMCID: PMC3743235  PMID: 22232360
42.  Comparison of Cerebrospinal Fluid Levels of Tau and Aß1-42 in Alzheimer’s disease and Frontotemporal Degeneration Using Two Analytical Platforms 
Archives of neurology  2012;69(8):1018-1025.
Objective
To utilize values of cerebrospinal fluid (CSF) tau and ß-amyloid obtained from two different analytical immunoassays to differentiate Alzheimer’s disease (AD) from frontotemporal lobar degeneration (FTLD).
Design
CSF values of total tau (t-tau) and ß-amyloid (Aß1-42) obtained using the INNOTEST® ELISA were transformed using a linear regression model to equivalent values obtained using the INNO-BIA AlzBio3™ (xMAP Luminex) assay. Cutoff values obtained from the xMAP assay were developed in a series of autopsy-confirmed cases and cross-validated in another series of autopsy-confirmed samples using transformed ELISA values to assess sensitivity and specificity for differentiating AD from FTLD.
Setting
Tertiary memory disorders clinics and neuropathological and biomarker core centers.
Participants
75 samples from patients with CSF data obtained from both assays were used for transformation of ELISA values. 40 autopsy-confirmed cases (30 AD, 10 FTLD) were used to establish diagnostic cutoff values, and then cross-validated in a second sample set of 21 autopsy-confirmed cases (11 AD, 10 FTLD) with transformed ELISA values.
Main outcome measure
Diagnostic accuracy using transformed biomarker values.
Results
Data obtained from both assays were highly correlated. The t-tau:Aß1-42 ratio had the highest correlation between measures (r=0.928, p<0.001) and high reliability of transformation (ICC=0.89). A cutoff of 0.34 for the t-tau:Aß1-42 ratio had 90% and 100% sensitivity and 96.7% and 91% specificity to differentiate FTLD cases in the validation and cross-validation samples, respectively.
Conclusions
Values from two analytical platforms can be transformed into equivalent units, which can distinguish AD from FTLD more accurately than the clinical diagnosis.
doi:10.1001/archneurol.2012.26
PMCID: PMC3528180  PMID: 22490326
43.  TRANSLATIONAL RESEARCH IN NEUROLOGY: DEMENTIA 
Archives of neurology  2012;69(8):969-977.
Dementia disorders are characterized by clinicopathological criteria. Molecular understandings of these disorders, based on immunohistochemical studies, biochemical investigations, genetic approaches, and animal models have resulted in advances in diagnosis. Likewise translational research has allowed application of increasing basic scientific knowledge regarding neurodegeneration, to the rational development of new investigational therapies based on current understanding of disease pathogenesis. This review discusses application of translational research to both diagnosis and treatment of dementia disorders. The development of biomarkers has yielded imaging and biochemical methods that more assist in the diagnosis of neurodegenerative dementias, especially Alzheimer’s disease. New diagnostic criteria for disease are based on these molecular-based techniques. And these biomarkers are of potential use in monitoring disease activity during therapeutic trials. Translational investigations likewise have led towards new avenues in targeted dementia research. This is particularly so in the development and testing of disease-modifying treatments that might slow or deter progressive deterioration. Recent clinical trials have not been based on empiric trial of established drugs, but rather upon trial of drugs shown through culture and animal models to interfere with known elements of the pathogenetic cascade of Alzheimer disease.
doi:10.1001/archneurol.2011.2883
PMCID: PMC3644591  PMID: 22473767
44.  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
45.  Dementia Resulting From Traumatic Brain Injury 
Archives of neurology  2012;69(10):1245-1251.
Traumatic brain injury (TBI) is among the earliest illnesses described in human history and remains a major source of morbidity and mortality in the modern era. It is estimated that 2% of the US population lives with long-term disabilities due to a prior TBI, and incidence and prevalence rates are even higher in developing countries. One of the most feared long-term consequences of TBIs is dementia, as multiple epidemiologic studies show that experiencing a TBI in early or midlife is associated with an increased risk of dementia in late life. The best data indicate that moderate and severe TBIs increase risk of dementia between 2-and 4-fold. It is less clear whether mild TBIs such as brief concussions result in increased dementia risk, in part because mild head injuries are often not well documented and retrospective studies have recall bias. However, it has been observed for many years that multiple mild TBIs as experienced by professional boxers are associated with a high risk of chronic traumatic encephalopathy (CTE), a type of dementia with distinctive clinical and pathologic features. The recent recognition that CTE is common in retired professional football and hockey players has rekindled interest in this condition, as has the recognition that military personnel also experience high rates of mild TBIs and may have a similar syndrome. It is presently unknown whether dementia in TBI survivors is pathophysiologically similar to Alzheimer disease, CTE, or some other entity. Such information is critical for developing preventive and treatment strategies for a common cause of acquired dementia. Herein, we will review the epidemiologic data linking TBI and dementia, existing clinical and pathologic data, and will identify areas where future research is needed.
doi:10.1001/archneurol.2011.3747
PMCID: PMC3716376  PMID: 22776913
46.  Mechanisms Underlying Recovery of Motor Function After Stroke 
Archives of neurology  2004;61(12):1844-1848.
Stroke is the leading cause of long-term disability worldwide and a condition for which there is no universally accepted treatment. The development of new effective therapeutic strategies relies on a better understanding of the mechanisms underlying recovery of function. Noninvasive techniques to study brain function, including functional magnetic resonance imaging, positron emission tomography, transcranial magnetic stimulation, electroencephalography, and magnetoencephalography, led to recent studies that identified some of these operating mechanisms, resulting in the formulation of novel approaches to motor rehabilitation.
doi:10.1001/archneur.61.12.1844
PMCID: PMC3713312  PMID: 15596603
47.  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
48.  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
49.  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
50.  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

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