Brain and Cognitive Correlates in Neurofibromatosis, type 1

Bart Moore, Ph.D.Bart Moore, Ph.D.

Children’s Cancer HospitalChildren’s Cancer Hospital

Univ. Texas M. D. Anderson Cancer CenterUniv. Texas M. D. Anderson Cancer Center

Houston, TexasHouston, Texas

Background

History of NF1History of NF1 First DescriptionFirst Description

Recognized for centuriesRecognized for centuries Friedrich von RecklinghausenFriedrich von Recklinghausen

• 18821882 Genetic nature noted in early 1900sGenetic nature noted in early 1900s Causative gene identified 1990Causative gene identified 1990

Background

GeneticsGenetics Autosomal dominant disorder Autosomal dominant disorder Fully penetrant, variably expressed Fully penetrant, variably expressed Mutations in NF1 geneMutations in NF1 gene Located on chromosome 17q11. 3 Located on chromosome 17q11. 3 Produces neurofibrominProduces neurofibromin

Background

Mortality Mortality Phenotypic features increase with agePhenotypic features increase with age Shortened life-spanShortened life-span Childhood deathsChildhood deaths

Intracranial tumorsIntracranial tumors MPNST, Leukemia, or embryonal tumorsMPNST, Leukemia, or embryonal tumors

Adult DeathsAdult Deaths MPNST, and sarcomasMPNST, and sarcomas GI bleeding, severe seizures, hydrocepahlus, and GI bleeding, severe seizures, hydrocepahlus, and

hypertensionhypertension

General Features of Neurofibromatosis, type 1 (NF)

Autosomal dominant genetic disorder resulting from a Autosomal dominant genetic disorder resulting from a mutation on chromosome 17mutation on chromosome 17

Has an incidence of about 1 in 3500Has an incidence of about 1 in 3500 One-half of new cases are spontaneous mutations One-half of new cases are spontaneous mutations

(50% (50% are inherited)are inherited) Offspring of a parent with NF have about a 50-50 Offspring of a parent with NF have about a 50-50

chance of inheriting the disorderchance of inheriting the disorder Clinical manifestations are quite variable, but Clinical manifestations are quite variable, but

generally generally become more severe with agebecome more severe with age Often mistaken for the “Elephant-Man” syndrome Often mistaken for the “Elephant-Man” syndrome

(Proteus syndrome)(Proteus syndrome) Currently, there is no cure or effective treatmentCurrently, there is no cure or effective treatment

Clinical Features of NF Cutaneous café-au-lait spotsCutaneous café-au-lait spots Axillary frecklingAxillary freckling Subcutaneous neurofibromasSubcutaneous neurofibromas Plexiform neurofibromasPlexiform neurofibromas Brain tumors, primarily optic gliomaBrain tumors, primarily optic glioma Orthopedic malformations (eg., scoliosis)Orthopedic malformations (eg., scoliosis) Family historyFamily history

Macrocephaly Macrocephaly Learning disability and behavioral problemsLearning disability and behavioral problems

A diagnosis of NF requires two of the above criteria

Manifestations of NF-1

What makes NF-1 so interesting from a neuropsychological standpoint

40-50% incidence of learning disability, specific 40-50% incidence of learning disability, specific cognitive impairments (eg., visual spatial cognitive impairments (eg., visual spatial abilities), and ADHDabilities), and ADHD

60-70% incidence of brain “hyperintensities” in 60-70% incidence of brain “hyperintensities” in cortical and subcortical white matter (UBOs) in children cortical and subcortical white matter (UBOs) in children but not adultsbut not adults

Cognitive profile similar to traumatic brain Cognitive profile similar to traumatic brain injury (language deficits are also common). injury (language deficits are also common).

15-20% incidence of brain tumors15-20% incidence of brain tumors

30-40% incidence of macrocephalyincidence of macrocephaly

Could there be a neuroanatomical basis for the Could there be a neuroanatomical basis for the cognitive and behavioral features of NF-1?cognitive and behavioral features of NF-1?

Neurological Factors

UBOs Macrocephaly

Corpus Callosum??

Brain tumors

White matter?

Cognitive, Learning, Behavioral, and Neuroanatomical Features of NF-1: Is There a Connection?

Cognitive Impairments

LearningDisability

Behavioral Factors

No. ofpatients % MR

MeanFSIQ VIQ and PIQ % LD

Riccardi & Eichner (1986) 67 11.4 90 NA 30

Varnhagen et al. (1988) 16 NA 94.5 VIQ = PIQ NA

Wadsby et al. (1989) 27 11 NA VIQ > PIQ 59

Stine and Adams (1989) 18 NA 91.8 VIQ = PIQ 41

Eldridge et al. (1989) 13 NA 93.9 PIQ > VIQ NA

North et al. (1994, 1995) 50 4.8 93.3 VIQ = PIQ 45

Legius et al. (1994) 38 5.2 89.9 VIQ > PIQ 61

Moore et al. 1994, 1996) 65 6 92.9 PIQ > VIQ 30

Denckla et al. (1996) 19 NA 94.8 NA NA

Ferner et al. (1996) 103 8 88.6 PIQ = VIQ NA

AVERAGE (416) 7.1% 92.9 44.3

Intelligence in Children and Adolescents with NF: A Meta Analysis

(From North, et al, 1997)

Proportion with scores at least 1 SD below average

Math Performance

Academic Profile

It is commonly reported that 40% It is commonly reported that 40% have a have a cognitive or learning disabilitycognitive or learning disability

50% are described by parents as 50% are described by parents as having having “school problems”“school problems”

One-third have repeated a gradeOne-third have repeated a grade One-half are in a special classOne-half are in a special class

Pediatric Research, 1994,35:25 (abstract)

(N=90)

Longitudinal research using individual growth curve statistical methodology

In general, growth in math and overall IQ is In general, growth in math and overall IQ is positive and comparable to normal, but positive and comparable to normal, but lower.lower.

But growth in Verbal IQ declines with ageBut growth in Verbal IQ declines with age Presence of UBOs resulted in Presence of UBOs resulted in fasterfaster growth growth

in Performance IQin Performance IQ

Long, Swank, Slopis, Moore (2000). Cognitive profile and academic achievement of children with neurofibromatosis: a longitudinal study using individual growth curves. J Intl Neuropsychological Soc,6(2):165.

What could cause these problems?

Cranial tumorsCranial tumors Brain “hyperintensities”Brain “hyperintensities” MacrocephalyMacrocephaly Abnormalities of cortical developmentAbnormalities of cortical development Abnormalities of cortical functionAbnormalities of cortical function

CNS Tumors in NF 1

In patients referred for non-ophthalmologic In patients referred for non-ophthalmologic reasons to NF clinic:reasons to NF clinic:

15% had optic gliomas15% had optic gliomas <20% with gliomas were symptomatic<20% with gliomas were symptomatic

Listernick et al. J Pediatr 1989;114:788-92

Optic Nerve & Pathway Gliomas

COG A9952 CHEMOTHERAPY FOR PROGRESSIVE LOW GRADE ASTROCYTOMA IN CHILDREN LESS THAN TEN YEARS OLD

A Phase III Intergroup COG Study

PRIMARY GOALS

To compare the event-free survival as a result of treatment with either carboplatin and vincristine (CV*) or a combination of thioguanine, procarbazine, CCNU, and vincristine (TPCV).

SECONDARY GOALS:

To estimate tumor response, toxicity, and QOL to each regimen of chemotherapy.

To investigate biological and clinical factors which may predict tumor response

To investigate factors contributing to neuropsychological and endocrine status

* NF-1 patients non-randomly assigned to CV regimen

Eligibility for COG 9952

Residual tumor after surgery or radiographic Residual tumor after surgery or radiographic diagnosisdiagnosis

Further resection would cause unacceptable Further resection would cause unacceptable morbiditymorbidity

Age less than 10 years old to delay radiation Age less than 10 years old to delay radiation Evidence of tumor progressionEvidence of tumor progression Objective growth on MRI - Required for NFObjective growth on MRI - Required for NF Progressive symptoms prior to diagnosisProgressive symptoms prior to diagnosis

Brain Tumors in Children with Neurofibromatosis: Additional Neuropsychological Morbidity?

De Winter AE, Moore BD, Slopis JM, Ater JL, Copeland DR, (2000). Neuro Oncology, 1(4):275-281.

Matched group analysis: Mean neuropsychologicaldomain scores for NF-alone (n = 36) and NF + brain

tumor (n = 36) groups

NF Alone NF + BTDomain Mean (SD) mean (SD) Prob.Intellectual

Full Scale IQ 91.7 (14.3) 92.9 (15.3) NSVerbal IQ 92.6 (14.6) 91.3 (15.1) NSPerformance IQ 92.2 (13.9) 96.3 (16.6) NS

Academic Achievement 89.3 (13.5) 86.1 (14.8) NSLanguage 9.1 (3.0) 8.8 (2.8) NSMemory 8.4 (3.1) 7.1 (2.8) .07 (marginal)Visual-Motor 7.9 (2.5) 7.3 (2.6) NSVisual-Spatial 6.1 (3.9) 5.8 (2.7) NSMotor 9.1 (3.9) 8.1 (3.3) NSAttention 8.2 (2.3) 7.9 (2.3) NS

De Winter, Moore, Slopis, Ater, & Copeland (1999) Neuro Oncology 1(4);275-281.

NF MRI Hyperintensities, orUBOs (“unidentified bright objects”)

DeBella, Poskitt, Szudek and Friedman, Use of "unidentified bright objects"on MRI for diagnosis of neurofibromatosis 1 in children. Neurology2000;54:1646-1651

Frequency of UBOs by age among 657 NF1patients aged 2 to 21 years

If UBOs diminish with age, does that mean learning disabilities will also?

MRI of 41 year old man with optic glioma and pheochromocytoma, but not NF-1

Neuropsychological Comparisons

Patients with NF (n=46) Comparisons

MEASUREWithout

hyperintensity(n=34)

Withhyperintensity

(n=12)

ControlSubjects(n=19)

+ / -Hyperintensity

NF vs.Controls

Verbal IQ 92.1 (18.4) 98.2 (14.7) 97.8 (11.0) ns nsPerf. IQ 93.3 (18.2) 96.8 (14.4) 99.6 (9.0) ns ns

Academic Ach. 93.5 (17.6) 90.7 (13.2) 100.7 (10.6) ns p<0.05Language 8.3 (3.5) 10.0 (2.2) 9.6 (2.1) ns nsMemory 9.8 (3.2) 8.5 (2.9) 9.5 (3.3) ns ns

Visual Spatial 7.4 (3.7) 6.2 (3.2) 9.3 (1.7) ns P<0.001Fine Motor 8.8 (2.6) 7.9 (2.9) 8.0 (3.6) ns ns

FDDQ 9.1 (3.2) 8.6 (2.4) 9.9 (2.1) ns nsJLO 5.8 (5.2) 3.6 (3.5) 9.3 (3.1) ns p<0.001

Age 122.9 (28.8) 135.7 (38.4) 129.0 (34.2) ns ns

School performance for those with and without hyperintensities

No Hyperintensity Hyperintensity Chi2 (df),P

Academic/school problems 58 % 46 % 2.00 (1), ns

Repeated a grade 31 % 35 % 0.86 (1), ns

In special classes 41 % 47 % 1.03 (1), ns

So, the mere presence of UBOs does not seem to explain the neurocognitive deficits of children with NF-1

What about their location???

Thalamus Basal Brainstem Cerebral Cerebe- Optic Ganglia Cortex llum paths

Moore BD, et al. (1996). Neuropsychological significance of areas of high signalintensity on brain MRIs of children with neurofibromatosis. Neurology, 46, 1660-8.

Visual Spatial and Visual Motor Tasks are a diagnostic predictor of NF-1

The multivariate combination of visual-spatial/motor tasks proved to be a strong confirmatory test of NF1 diagnosis in that it correctly identified 90% of individuals with clinically identified NF1 (p = .0007)

Schrimsher GW, Billingsley RL, Slopis JM, Moore BD (2003). Visual-Spatial performance deficits in children with neurofibromatosis type-1. Am J Med Gen. 120A(3):326-30

In the general population ADHD is more frequently diagnosed in boys than girls

Girls more frequently receive the diagnosis of ADD while boys are mostly ADHD or combined

What is the pattern of ADHD in children with NF-1?

ADHD Incidence, Subtypes, and Sex Ratios for 91 Children with NF-1

Inattentive Hyperactive Combined TotalAll

14/41(34.1%)

9/41(22.0%)

18/41(43.9%)

41/91(45.1%)

Girls4/16

(25.0%)7/16

(43.8%)5/16

(31.3%)16/41

(39.0%)Boys

10/25(40.0%)

2/25(8.0%)

13/25(52.0%)

25/50(50.0%)

Children in the general population with ADHD are reported to have abnormalities in the morphology of the corpus callosum

It is commonly reported that children with NF-1 have a high incidence (40-50%) of ADHD

Related Studies: ADHD vs. controls

Filipek et al. (1997): decreased volumes for Filipek et al. (1997): decreased volumes for subjects with ADHDsubjects with ADHD

Hynd et al. (1991): smaller regional areas Hynd et al. (1991): smaller regional areas for ADHD groupfor ADHD group

Semrud-Clikeman et al. (1994): smaller Semrud-Clikeman et al. (1994): smaller splenium measurements for ADHD groupsplenium measurements for ADHD group

Giedd et al. (1994): smaller rostral and Giedd et al. (1994): smaller rostral and rostral body areas for ADHD grouprostral body areas for ADHD group

Corpus Callosum, NF, & ADHD De Winter, et.al., 1999

1 2 3 4 5 6 70

20406080

100120140160180

Cro

ssec

tion

al A

rea

(mm

sq)

Crossectional Area of the Corpus Callosum

NF patients

Controls*

**

* p<0.01

Corpus Callosum Morphology

Brain Volume in Children with Neurofibromatosis, Type 1:

Relation to Neuropsychological Status

Moore BD, Slopis JM, Jackson EF, De Winter A, Leeds NE, (2000). Neurology,2000,54:914-920.

Brain Size“This law of proportion of course governs the

brain, as well as all else in Nature. …..Large brains must be, and are, more efficient than small ones, when the quality of both is alike…..”

Fowler OS. Human Science, or Phrenology. New York, Fowler & Wells, 1873 Washington, DC: 164-165.

Moore, et.al., 2000

The BIG MAC hypothesis

Bilateral Basal Ganglia Hyperintensities

Brain Volumes (Cm3) from MRI Segmentation

MEASURE NF Patients (n=52) Control Subjects (n=18) Prob.

Total Brain 1476 (190.4) 1316.3 (136.72) p<0.002

Left Hemisphere 735.4 (94.1) 654.2 (69.0) p<0.002

Right Hemisphere 741.5 (96.5) 650.8 (47.9) p<0.002

White Matter 588.1 (120.7) 568.9 (89.5) ns

Gray Matter 888.7 (129.1) 747.4 (99.2) p<0.0001

Cerebrospinal Fluid 105.9 (49.1) 89.0 (24.2) ns

Hyperintensity 5.02 (8.1) ------------------- --------

Moore, et.al., In Press

R=0.73

p<0.001

600 700 800 900 1000 1100 1200 1300 1400

Total Gray Matter Volume (cc)

-30

-20

-10

0

10

20

30

40

IQ-A

cad

. Ach

. D

iscr

ep

an

cy

Total Gray Matter Volume andIQ-Academic Achievement Discrepancy

r=0.73p<0.001

Moore, et.al., In Press

2 3 4 5 6 7 8 9101112131415161718

Age in years

0.50

1.00

1.50

2.00

2.50G

ray/W

hit

e M

att

er

volu

me

Gray/White Matter Ratios Relationship with Age

NF

patients

Control

Subjects

NF: r = - 0.62, P= 0.0001

Controls: r = - 0.20, P = 0.45

Moore, et.al., 2000, Neurology, 54:914-920

Why large brain volume in NF??

Neurofibromin Neurofibromin is a negative growth regulatoris a negative growth regulator

Neuronal pruning (Neuronal pruning (apoptosisapoptosis) is a normal) is a normaldevelopmental process.developmental process.

Pruning occurs after neurons are fully developedPruning occurs after neurons are fully developedand differentiated.and differentiated.

Malfunction of Malfunction of neurofibrominneurofibromin in NF-1 might in NF-1 mightresult in a result in a delaydelay in neuronal development and in neuronal development andconnections that would delay pruning.connections that would delay pruning.

Apoptosis (Neuronal Pruning)

Premature Premature apoptosis apoptosis results in acceleratedresults in accelerateddegeneration of an organ systemdegeneration of an organ system

Pathologically delayed Pathologically delayed apoptosis apoptosis results inresults inhyperplasiahyperplasia

Normally, neuronal “pruning” results in aNormally, neuronal “pruning” results in arestructuring of neuronal connections, andrestructuring of neuronal connections, and“without this remodeling, an abnormally large“without this remodeling, an abnormally largebrain with atypical patterns of connectivity wouldbrain with atypical patterns of connectivity wouldresult, and in many cases would be associated withresult, and in many cases would be associated withsevere cognitive dysfunction in humans”*severe cognitive dysfunction in humans”**Baron I, et al. (1995). Pediatric *Baron I, et al. (1995). Pediatric neuropsychology neuropsychology in the medical setting.in the medical setting.New York: Oxford University Press.New York: Oxford University Press.

Regional Cortical Morphology in NF-1

Reading disabilities and developmental language impairments in the general population have been associated with particular morphologic features in the inferior frontal gyrus (IFG) and Heschl’s gyrus (HG).

Billingsley, Slopis, Swank, Jackson, & Moore (2003)Brain and Language, 85:125 – 139.

Type I, “typical”

Type II, typical

Type IIIc, atypical

-5

-4

-3

-2

-1

0

1

2

3

Fac

tor

Z-S

core

PhonologicalFluency

VerbalKnowledge

Reading andSpelling

Verbal Memory

Typical(n=22)

Typical(n=17)

Atypical(n=16)

Atypical(n=21)

CONTROLNF-I

Relationship between language scores, group, and inferior frontal gyrus classification in the right hemisphere

Heschl’s Gyrus (HG)

Leonard et al. (1993, 2001) reported an increased incidence of HG duplication in individuals with dyslexia in the general population,

Inferior Frontal Gyrus Results Atypical IFG morphology involving an extra gyrus in the right

hemisphere was associated with better performance on language-related measures for the NF-1 group.

An extra gyrus in right inferior frontal cortex was associated with better scores on phonological fluency, verbal knowledge, reading and spelling, and verbal memory factors.

Heschl’s Gyrus Results In the left hemisphere, HG duplication was associated with poorer

performance on verbal memory for both groups. HG duplication in the right hemisphere for participants with NF-I,

however, was associated with better performance on math, and verbal memory.

Sylvian Fissure Morphology and Reading

Normally, there is a left>right asymmetry of the planum temporale. An absence of this asymmetry or rightward asymmetry is seen in reading-impaired populations.

Results of Planum Temporale study

Boys with NF-1 showed less asymmetry of the PT than girls with NF-1 or than the Control group regardless of gender.

Less asymmetry in the PT was associated with poorer performance relative to full-scale IQ in the NF-I group.

This might indicate that hemispheric specialization for language is less developed in those with NF-1 than in the general population.

Billingsley, Schrimsher, Jackson, Slopis, & Moore (2002). Significance of planum temporale and planum parietale morphology in neurofibromatosis, type-1. Archives of Neurology, 59: 616-622.

Structure/Function----Cause and Effect

Houston Art Car Parade

BOLD Contrast

BOLDBOLD = = BBlood lood OOxygenation xygenation LLevel evel DDependentependent

Increase in oxyhemoglobin in veins after neural Increase in oxyhemoglobin in veins after neural activation means magnetic field becomes more activation means magnetic field becomes more uniform inside voxeluniform inside voxel

How FMRI Experiments Are Done Alternate subject’s neural state between 2 (or more) Alternate subject’s neural state between 2 (or more)

conditions using sensory stimuli, tasks to perform, ...conditions using sensory stimuli, tasks to perform, ... Can only measure relative signals, so must look for changesCan only measure relative signals, so must look for changes

Acquire MR images repeatedly during this processAcquire MR images repeatedly during this process Search for voxels whose signal follows the stimulusSearch for voxels whose signal follows the stimulus Signal changes due to neural activity are smallSignal changes due to neural activity are small

Need 50+ images in time series (each slice) Need 50+ images in time series (each slice) takes minutes takes minutes Other small effects can corrupt the results Other small effects can corrupt the results postprocess postprocess

Some Sample Data Time Series

Task: phoneme discrimination: Task: phoneme discrimination:

20 s “on”, 20 s “rest”20 s “on”, 20 s “rest”

graphs of 9 voxel time series

t

“Active” voxels

Graphs vs. time of 33 voxel region

One Fast Image

Overlay on Anatomy

This voxel didnot respond

Colored voxels responded to the mentalstimulus alternation, whose pattern is shown in theyellow reference curve plotted in the central voxel

Letter Fluency Task, N = 14, p < 0.005 (ccz 0.24)

Passage Comprehension, N = 10, p < 0.005 (ccz 0.25)

42 21/

22

42

21/22

Functional MRI Results NF group showed greater right RH activation during an auditory NF group showed greater right RH activation during an auditory

phonetic task than did the controls.phonetic task than did the controls. NF group showed greater posterior than anterior activation during NF group showed greater posterior than anterior activation during

an orthographic phonetic task-opposite pattern as seen in the an orthographic phonetic task-opposite pattern as seen in the controls.controls.

NF group relied more than controls on posterior cortex relative to NF group relied more than controls on posterior cortex relative to inferior frontal during a visual spatial task.inferior frontal during a visual spatial task.

ConclusionConclusion: NF patients rely more on posterior cortex and the right : NF patients rely more on posterior cortex and the right hemisphere to perform tasks normally subserved by frontal cortex hemisphere to perform tasks normally subserved by frontal cortex and the left hemisphere.and the left hemisphere.

Billingsley RL, Jackson EF, Slopis JM, Swank PR, Mahankali S, Moore BD. (2003) Billingsley RL, Jackson EF, Slopis JM, Swank PR, Mahankali S, Moore BD. (2003) Functional MRI of phonological processing in neurofibromatosis, type-1. Functional MRI of phonological processing in neurofibromatosis, type-1. Journal of Journal of Child NeurologyChild Neurology, 18:731-740 , 18:731-740

   Billingsley RL, Jackson EF, Slopis JM, Swank PR, Mahankali S, Moore BD (2004). Billingsley RL, Jackson EF, Slopis JM, Swank PR, Mahankali S, Moore BD (2004). Functional MRI of visual-spatial processing in neurofibromatosis, type 1. Functional MRI of visual-spatial processing in neurofibromatosis, type 1. Neuropsychologia, 42:395-404Neuropsychologia, 42:395-404. .

Overall Conclusions Exploring Brain / Behavior relations is beginning to shed light on Exploring Brain / Behavior relations is beginning to shed light on

possible etiologies for learning and cognitive difficulties in possible etiologies for learning and cognitive difficulties in individuals with NF-1individuals with NF-1

Disorders of language, in addition to visual spatial abilities, may Disorders of language, in addition to visual spatial abilities, may have a demonstrable underlying neurological basis.have a demonstrable underlying neurological basis.

Promising avenues of researchPromising avenues of research Abnormalities in gross brain development: gray and white matter, Abnormalities in gross brain development: gray and white matter,

corpus callosum, etc.corpus callosum, etc. What is the relation between abnormal brain development and What is the relation between abnormal brain development and

learning status over the life span.learning status over the life span. Regional morphological analyses of brain structure.Regional morphological analyses of brain structure. Functional methods such as PET, MRS, and fMRIFunctional methods such as PET, MRS, and fMRI

And Lastly

Is the NF-1 mutation responsible for altered Is the NF-1 mutation responsible for altered structural and physiological brain structural and physiological brain development?development?

Are the learning and cognitive problems so Are the learning and cognitive problems so prevalent in those with NF-1 amenable to prevalent in those with NF-1 amenable to pharmacological intervention?pharmacological intervention?

Research Support Cheniere Energy: Cheniere Energy: Making Cancer HistoryMaking Cancer History cycle team in the cycle team in the

Race Across America 2005,2006Race Across America 2005,2006 National Institute of Neurological Disorders and Stroke. National Institute of Neurological Disorders and Stroke.

““Neurobiology of Cognitive impairment in children with NFNeurobiology of Cognitive impairment in children with NF”. ”. R01 NS-31950 1995 to 2004 R01 NS-31950 1995 to 2004

Department of Defense Department of Defense Congressionally Directed Medical Congressionally Directed Medical Research Programs (Department of Defense). “Social and Research Programs (Department of Defense). “Social and Emotional Functioning of Children with NF-1 and Their Emotional Functioning of Children with NF-1 and Their Families: A Case Controlled Study”Families: A Case Controlled Study” 1999 to 2002 1999 to 2002

Texas Neurofibromatosis Foundation, Dallas, Texas. 1993 to Texas Neurofibromatosis Foundation, Dallas, Texas. 1993 to 19961996

John Slopis, MD Neurology

Ian McCutcheon MD Neurosurgery

Louise Strong, MD Genetics/Epidemiology

Bart Moore, PhD Neuropsychology

Joann Ater, MD Pediatric Brain tumors

Ed Jackson, PhD Neuroimaging

Shriner’s Hospital Orthopedics

NEUROFIBROMATOSIS CORE GROUP

                              

Srikanth Mahankali, M.D.

Diagnostic Imaging

Trainees who contributed to this work

Rebecca Billingsley, Ph.D.; Greg Schrimsher, Ph.D.; Sandra Long, Ph.D.; Anne Kayl, Ph.D.; Christine Randall, Ph.D.

Cindy Trotter, M.S.; Andrea Atherton, MS; Dena Buchalter, MS

Special recognition to Bernadette Kopecky, Med, Research Coordinator

Johannes Wolff, M.D.

Neuro Oncology