Neurology October 2012 Volume 79 Issue 16

Objectives: Florbetapir F 18 PET can image amyloid-[beta] (A[beta]) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting A[beta] pathology using florbetapir PET in subjects at risk for progressive cognitive decline.Methods: A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (A[beta]+) or negative (A[beta]-) for pathologic levels of [beta]-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.Results: In both MCI and CN, baseline A[beta]+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating-sum of boxes (CDR-SB) (p < 0.02). In MCI A[beta]+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). A[beta]+ MCI tended to convert to AD dementia at a higher rate than A[beta]- subjects (p < 0.10).Conclusions: Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.GLOSSARY: A[beta]: amyloid-[beta]AD: Alzheimer diseaseADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive subscaleADCS-ADL: Alzheimer's Disease Cooperative Study-Activities of Daily Living ScaleANCOVA: analysis of covarianceCDR-SB: Clinical Dementia Rating-Sum of BoxesCN: cognitively normalDSS: Digit Symbol SubstitutionGDS: Geriatric Depression ScaleLOCF: last observation carried forwardMCI: mild cognitive impairmentMMSE: Mini-Mental State ExaminationPiB: Pittsburgh compound BSUVr: standardized uptake value ratioVOI: volume of interest.(C)2012 American Academy of Neurology

Objectives: Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes.Methods: A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Student's t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression.Results: Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X).Conclusions: RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations.GLOSSARY: ANOVA: analysis of varianceBMI: body mass indexCSS: Clinical Severity ScoreEDF: equivalent degrees of freedomFDR: false discovery rateFOC: fronto-occipital head circumferenceMBA: Motor Behavioral Assessmentnon-RTT: participants possessing MECP2 mutation but without Rett syndromeRNHS: Rett Natural History StudyRTT: Rett syndrome.(C)2012 American Academy of Neurology

Background: Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the CNS in which a pathogenic role of anti-aquaporin-4 (AQP4) antibodies has been suggested. Although AQP4 is expressed in human cortex, recent histologic studies have failed to find any evidence of cortical demyelination in NMO.Objective: To evaluate, in vivo, the occurrence of focal and diffuse cortical pathology in NMO.Methods: We studied 30 patients with NMO, 30 patients with relapsing-remitting multiple sclerosis (RRMS), and 30 normal controls (NC). RRMS and NC were age- and gender-matched to NMO. The presence of cortical lesions (CLs) was evaluated on double inversion recovery sequence and cortical thickness (CTh) by the application of Freesurfer on 3 volumetric fast field echo T1-weighted images.Results: No CL was observed in NC or in NMO, while 83 CLs were identified in 20/30 (66.7%) patients with RRMS. Although NMO did not differ from NC in the global CTh, a mild thinning was observed in some cortical areas (postcentral [p = 0.018], precentral [p = 0.009], and calcarine [p = 0.015] gyri) and in the thalamus (p = 0.036). Global and regional cortical thickness was significantly decreased in RRMS compared to both NMO and NC.Discussion: Our in vivo data further suggest that the immune-mediated pathologic process occurring in NMO spares most of the cortex. NMO differs from multiple sclerosis, where CLs and atrophy are frequently found, even in early disease phases. Thus, MRI analysis of the cortex may be a potential diagnostic tool, especially in ambiguous cases.GLOSSARY: AQPR: aquaporin-4CL: cortical lesionCTh: cortical thicknessDIR: double inversion recoveryETL: echo train lengthFLAIR: fluid-attenuated inversion recoveryFOV: field of viewGM: gray matterMS: multiple sclerosisNC: normal controlNMO: neuromyelitis opticaRRMS: relapsing-remitting multiple sclerosisTE: echo timeTI: inversion timeTR: repetition timeWM: white matter.(C)2012 American Academy of Neurology

Background: The objective of this study was to examine the joint associations of estimated glomerular filtration rate (eGFR) and urinary albumin excretion with incident stroke in a large national cohort study.Methods: Associations of urinary albumin to creatinine ratio (ACR) and eGFR with incident stroke were examined in 25,310 participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a prospective study of black and white US adults >=45 years of age.Results: A total of 548 incident strokes were observed over a median of 4.7 years of follow-up. Higher ACR values were associated with lower stroke-free survival in both black and white participants. Among black participants, as compared to an ACR <10 mg/g, the hazard ratios of stroke associated with an ACR of 10-29.99, 30-300, and >300 mg/g were 1.41 (95% confidence interval [CI] 1.01-1.98), 2.10 (95% CI 1.48-2.99), and 2.70 (95% CI 1.58-4.61), respectively, in analyses adjusted for traditional stroke risk factors and eGFR. In contrast, the hazard ratios among white subjects were only modestly elevated and not statistically significant after adjustment for established stroke risk factors. eGFR <60 mL/min/1.73 m2 was not associated with incident stroke in black or white participants after adjustment for established stroke risk factors.Conclusions: Higher ACR was independently associated with higher risk of stroke in black but not white participants from a national cohort. Elucidating the reasons for these findings may uncover novel mechanisms for persistent racial disparities in stroke.GLOSSARY: ACR: albumin to creatinine ratioCHD: coronary heart diseaseCI: confidence intervalCKD: chronic kidney diseaseeGFR: estimated glomerular filtration rateHR: hazard ratioREGARDS: Reasons for Geographic and Racial Differences in StrokeWHO: World Health Organization(C)2012 American Academy of Neurology

Objective: To determine optimal resections in the 3 dysembryoplastic neuroepithelial tumor (DNT) histologic subtypes (simple, complex, and nonspecific) based on MRI features.Methods: In 78 consecutive epilepsy patients operated for DNT, MRI features were classified as follows: type 1 (cystic/polycystic-like, well-delineated, strongly hypointense T1), type 2 (nodular-like, heterogeneous), or type 3 (dysplastic-like, iso/hyposignal T1, poor delineation, gray-white matter blurring). Correlations between histology, neurophysiologic findings, and surgical outcome were established for each MRI subtype.Results: Type 1 MRI (25 cases, in temporal and extratemporal areas) always corresponded to simple or complex DNTs. Type 2 MRI (25 cases, predominantly in neocortical areas) and type 3 MRI (28 cases, mainly in the mesial temporal lobe) corresponded to nonspecific forms. The epileptogenic zone (EZ) differed significantly according to the MRI subtype (p = 0.0029). It colocalized with the tumor in type 1 MRI, included perilesional cortex in type 2 MRI, and involved extensive areas in type 3 MRI. Cortical dysplasia was predominantly found in type 3 MRI (p < 0.0001). The main prognostic factors for seizure-free outcome (83%) were complete tumor (p < 0.0001) and EZ (p = 0.0115) removal. Other factors favorably influencing the outcome were a short epilepsy duration (p = 0.013) and absence of cortical-subcortical damage at the resection site (p = 0.053). Age at surgery was not related to outcome; however, cortical-subcortical damage was correlated with old age (p = 0.021). Treatment discontinuation was correlated with young age at surgery (p = 0.004) and short epilepsy duration (p = 0.001).Conclusion: We propose that resection might be restricted to the tumor in type 1 MRI and be more extensive in other MRI subtypes, especially in type 3 MRI. Early surgery and clean surgical margins are crucial for curing epilepsy.GLOSSARY: AED: antiepileptic drugAH: amygdalo-hippocampectomyATL: anterior temporal lobectomyCD: cortical dysplasiaDNT: dysembryoplastic neuroepithelial tumorEcoG: electrocorticographyEZ: epileptogenic zoneFLAIR: fluid-attenuated inversion recoveryGWM: gray-white matterSEEG: stereo-EEGTLE: temporal lobe epilepsyWM: white matter(C)2012 American Academy of Neurology

Objective: To evaluate the reliability and accuracy of skeletal muscle CT to correctly identify different muscular dystrophies manifesting with limb-girdle weakness.Methods: Four evaluators assessed scans from 118 patients with limb-girdle muscular dystrophy (LGMD) caused by mutations in 7 different genes and from 32 controls. The conditions studied were scans of genetically confirmed cases of Becker muscular dystrophy (BMD) (n = 28), LGMD2C-F (sarcoglycanopathies) (n = 11), LGMD2I (n = 4), LGMD1B (n = 26), LGMD2A (n = 24), Bethlem myopathy (n = 14), and LGMD2L (n = 11). The control group (n = 32) consisted of patients with neuromuscular disorders manifesting with limb-girdle weakness in which the aforementioned muscular dystrophies were excluded. The scans were compared with the characteristic patterns described in literature.Results: The overall interobserver agreement was poor ([kappa] = 0.27), with markedly higher scores for BMD ([kappa] = 0.51) and Bethlem myopathy ([kappa] = 0.59). The sensitivity to detect selective patterns in relation to the genetic diagnosis was 40% if all LGMDs were taken together. The specificity was 58%, positive predictive value (PPV) 77%, and 1 - negative predictive value (NPV) 79%. Markedly better scores were observed for BMD (sensitivity 91%, PPV 66%, 1 - NPV 3%) and Bethlem myopathy (sensitivity 90%, PPV 69%, 1 - NPV 1%).Conclusions: Our findings suggest that muscle CT might be an adjunct to the clinical diagnosis of BMD and Bethlem myopathy. However, pattern recognition was cumbersome in the other LGMDs.GLOSSARY: BMD: Becker muscular dystrophyLGMD: limb-girdle muscular dystrophyNPV: negative predictive valuePPV: positive predictive valueT1-WI: T1-weighted MRI.(C)2012 American Academy of Neurology

GLOSSARY: ADLD: adult-onset autosomal dominant leukodystrophyCMT: Charcot-Marie-ToothEDMD: Emery-Dreifuss muscular dystrophyLAP: lamin-associated polypeptideLBR: lamin B receptorLGMD1B: autosomal dominant limb-girdle muscular dystrophy(C)2012 American Academy of Neurology