Brain Development

Brain Development

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Description: Brain Imaging Center Collaborators, MRS in Human Development, Biochemistry in Normal Developing Brains of Human, Glial Metabolism, Neurotransmitter, Proton MRS, MRS Brain Spectrum, N-Acetyl-Aspartate, Measure of High Energy Phosphate Stores, Phosphocholine Glycerophosphocholine, Intracellular Sodium Content, Normal and Pathologic Brain, Proton Magnetic Resonance Spectroscopy.

Author: Perry F. Renshaw, Young-Hoon Sung, In Kyoon Lyoo (Fellow) | Visits: 2306 | Page Views: 2807
Domain:  Medicine Category: Imaging Subcategory: Neurology 
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MRS Studies of Human Brain Development
APA 2007 Annual Meeting
Perry F. Renshaw, M.D. Ph.D. Young-Hoon Sung, M.D. In Kyoon Lyoo, M.D. Ph.D. Brain Imaging Center McLean Hospital / Harvard Medical School

Brain Imaging Center Collaborators
Carl Anderson Suzann Babb Tanya Barros Lino Becerra Nicolas Bolo David Borsook Barbara Bradley Melanie Brimson Kenroy Cayetano Ashley Cerney Chrissy Cintron Jeanette Cohan Sadie Cole Melissa Daniels Brian Dunn Chelsea Finn Brent Forester Blaise Frederick Staci Gruber Charlotte Haws Mike Henry Bob Irvin Eric Jensen William Jones Gen Kanayama Mark Kaufman Mary Knapman Matt Lammens Kim Lindsey John Logue Steven Lowen In Kyoon Lyoo Terry Mancini Carissa Medeiros Eric Moulton Constance Moore Susie Morris Donna Murray Lisa Nickerson David Olsen Dost Ongur Gautam Pendse Srini Pillay Andrew Prescot Perry Renshaw Ika Rogowska Mike Rohan Amy Ross Isabelle Rosso Margaret Ricciuti Katherine Rudich Megan Shanahan Marisa Silveri Jennifer Sneider Chris Streeter Young-Hoon Sung Doug Hyun Han Kathleen Thangaraj Jean Theberge Rose Villafuerte Megan Wardrop Paul Wilson Rinah Yamamoto Debroah Yurgelun-Todd Chun Zuo

What and Why MRS in human development? What happens in the adolescent brain specifically? Examples of MRS studies for neurodevelopment The brief picture of metabolite changes through whole life Applications

Why MRS ?
Understanding in vivo Biochemistry in normal developing brains of human Further, contribution to the biological knowledge and application for psychiatric disorders

What can MR spectroscopy inform us about brain and development?
1H MRS, 31P MRS, ...

First Answer
NAA, Cr, Cho, mI, Glx, Lac
Neuronal viability/funtion Glial metabolism, Neurotransmitter

PME, Pi, PDE, PCr, -,-,-ATP
Brain neuronal membrane metabolism High energy phosphate metabolism

Proton MRS
Now, let's see what NAA, Cr,.. stands for and means before going to the brain metabolites of adolescent.

The in vivo 4T 1H-MRS Brain Spectrum

N-acetyl-aspartate (NAA)
GM � neuronal viability or damage WM � diffuse axonal damage or loss Neuronal death and/or dysfunction can also cause reduced metabolite levels (Ende, 1997) NAA is made in mitochondria by the membrane-bound enzyme L-aspartate N-acetyltrasferase, a catalyst that is found only in the brain(Truckenmiller, 1985) The synthesis of NAA is energy dependent (Patel, 1979) Reductions in NAA are consistent with impaired mitochondrial energy production (Clark, 1998; Stork, 2005)

Creatine (Cr)
Measure of high energy phosphate stores Decrease means reduction of the ATP supply and high-energy phosphate pool The resonance arises from both creatine and phosphocreatine Higher concentration in glial cell than neurons could mean glial proliferation with concurrent mI increase Cr is synthesized in the liver hepatic pathology may affect overall conc. Historically used as an internal reference

Choline (Cho)
Choline-containing compounds
Precursor for phosphatidylcholine (constituent of cell membrane) Phosphocholine + Glycerophosphocholine Related with
Cell membranes formation and myelination Membrane turn-over Marker of cellular density

Myo-inositol (mI)
Related to intracellular sodium content Glial marker
gliosis and reactive astrocytosis

Myoinositol (75%) + myoinositol monophosphate (15%) +-protons of glycine (15%)
Ross, 1991

Lactate (Lac)
Increases with impairments in oxidative metabolism

What happens in adolescent brain?
Period of behavioral, cognitive and emotional reorganization/integration
Which means notable changes in brain

Brain maturation may include
Arborization, neuritic sprouting Myelination with oligodendrocyte Pruning, loss of dendrite process

Let's see how does MRS provide above pictures ?

Healthy children (41 subjects)
Age: 1 � 16 years

van der Knaap et al (1990)

Paraventricular white matter


Rapid change for 3 years of life Continued to age 16

Kreis et al (1993)

50 children 34.5 ~ 926 gestational weeks
1 to 18 years

normal and pathologic brain absolute quantitation presents normative curves for normal development ROI
occipital cortex parieto-occipital lobe

Kreis et al (1993)
NAA Cr Cho mI

Gestational Age

Gestational Age

most rapid change � within first 2 years

Hashimoto et al (1995)
Healthy 47 children and 6 adults Frontal, Parietal
NAA/Cho, NAA/Cr: increase Cho/Cr: decrease Rapid changes � 1 to 3 years of age

Regional variation
Metabolite conc: Rt. Frontal < Rt. Parietal

GM, WM, cerebllum, thalamus Subjects
97 children
1-18 years Healthy Disease brain: unaffected area

Pouwels et al (1999)

72 adults
Healthy 18-39 years

Pouwels et al (1999)
GM, cerebellum, thalamus NAA increase WM, thalamus NAAG increase Glutamine decrease Cr, PCr, Cho, mI, glutamate
remain constant after first year

Cr: Pcr=2:1
regardless of age or region

Kadota et al (2001)
90 normal subjects 4 to 88 years WM, GM
ant, mid, post

Metabolite ratios
NAA/Cho Cr/Cho

Kadota et al (2001)
peak: average - 18.5 years
fontal 21.9 years, precentral 17.6, parietal 15.9 dorsal to rostral direction

first decade � third

after third decade

gradual decline

Kadota et al (2001)
Cerebral lateralization
Right side WM mature 1.1~4.0 years faster than left in terms of NAA/Cho levels

Gender difference
Male reached maximum level of NAA/Cho 1.4 ~ 3.2 years earlier than female in WM After peak, the NAA/Cho levels declined faster in male than in female
may be due to sex hormone difference

15 healthy Age 3 to 19 years Metabolites of interest
NAA, Cho, Cr

Horska et al (2002)

GM (prefrontal, parietal, premotor/motor) WM (premotor/motor, parietal) Basal ganglia Thalamus

Horska et al (2002)
peak around 11 years decrease thereafter

increase (3 to 19 years)

increase until 10 years

Costa et al (2002)

37 healthy subjects Age 3 � 18 years Cerebellum, Parietal WM NAA/Cr, Cho/Cr NAA/H2O, Cr/H2O

Costa et al (2002)
increasing tendency with age (p=0.062)

increase with age in cerebellum, parietoccipital

Topologic variation
NAA, Cho
higher in cerebellum than parietoccipital

Summary of 1H metabolites[1]
Brain metabolite profiles of life
Rapid change of metabolite occurs first several years in life But, some maturation such as myelination continue to adolescence

Consideration in MRS
Inconsistencies in studies partially due to ...
Regional variations in each ROI Different acquisition parameters for different MRS studies

Some conflicting MRS results but generally, ....

Summary of 1H metabolites [2]
Before maturation
From fetus/neonate to adults
d/t increasing neuronal function/density increased energy demand

Cho , mI

Summary of 1H metabolites[3]
Aging (from adult to elderly, moore et al 1999)
NAA or Cr , PCr
slight decrease or stability of neuronal marker Due to increased energy demand Due to phospholipid breakdown

Cho , mI

Summary of 1H metabolites [3]
NAA levels Different profile between .. GM
Peak � 11 years
Horska et al (2002)

Peak � 19 years
Kadota et al (2001)

Could mean...pruning, loss of dendrite process in GM, myelination in WM
Schematic diagram of NAA with age in gray and white matter


MR Spectrum

Typical 31P MR spectrum at 4 Tesla

Lower sensitivity than proton Require more sophisticated hardware Relatively small number of studies


Phosphorus metabolites

Phospholipid precursor
phosphocholine (PCho) +phosphoethanolamine

Phospholipid breakdown
glycerophosphocholine + glycerophosphoethanolamine

PME/PDE ratio
Reflects membrane phospholipid turnover

High energy phosphate metabolism

Healthy children (41 subjects)
Age: 1 � 16 years

van der Knaap et al (1990)

Before the age of three



After the age of three
No change

Hanaoka et al (1998)

37 healthy children 4 month ~ 13 years Metabolites: PME/PDE TR: 3 or 15 seconds ROI
Frontoparietal region Cerebellum

Hanaoka et al (1998)
PME/PDE in cerebrum and cerebellum
Rapid decrease during first 2 years. Slight decrease afterwards (adolescence) Regional difference
Higher in cerebellum than in cerebrum

Stanley et al (2000)
151 healthy subjects 7 to 81 years Brain ROI
Prefrontal lobe Centrum semiovale WM

Higher in adolescents compared to adults
Increased membrane phospholipid turnover in adolescents relative to adults

Hinsberger et al (1997)

P-31 MRS with MR volumetric study in schizophrenia
Prefrontal region

10 healthy subjects, 10 schizophrenics
PME decreased with age only in healthy subjects PME of schizophrena had no correlation with age

Summary of 31P metabolites[1]
Before maturation
PME � high, PDE � low in young
high membrane precursor, low breakdown product related to increased membrane turnover

From neonates to adults (mmol/L), Buchli et al. (1994)
PME (from 4.5 to 3.5) PDE (3.2 to 11.7) PCr (1.4 to 3.4) Pi (0.6 to 1.0) ATP (1.6 to 2.9)

Summary of 31P metabolites[2]
Aging (adults to elderly, moore et al 1999)
Due to neuronal membrane degeneration

Excessive synpatic prunning clinical model
exaggerated normal process of neuro-development PME decrease, PDE increase might be related to pathophysiology of schizophrenia
McGlashan, 1999; Keshavan 2003, 1994

Summary of 31P metabolites[3]
PME PDE Decreasing precursor, increasing breakdown product of phospholipid of membrane
Schematic diagram of PME and PDE with age

MRS, MRSI can provide valuable information of in vivo adolescent brain development through neuronal chemistry and can evaluate normal or diseased brain The metabolite levels show different profile with maturation and topology, therefore the data of normal development provide fundamental and valuable basis for pathologic process or disorders


MRS as a component of multimodal imaging studies

DA09448-09S1 Results Neuroimaging of Methamphetamine Dependent Subjects 2003-2005

Completed studies
Seven neuroimaging studies with publications
A multimodal brain imaging approach enables in-depth and complementary understanding of prefrontal cortical deficits and the pattern of recovery with abstinence.

MRS study of brain chemistry (Sung et al, 2007)
30 MA dependent and 20 healthy comparison subjects NAA concentration was lower in the frontal white matter of MA users with greater MA dose compared to a smaller dose and to healthy subjects myo-Inositol concentration in the frontal white matter was higher for the MA users compared to healthy subjects In MA dependent subjects, NAA concentrations correlated inversely with MA dose MA related abnormalities may, in part, recover with abstinence in gray matter, but not in the white matter regions

MA subjects are...

MA dependent subjects had less gray matter density in the right middle frontal brain ; Voxel-based morphometry study (Kim et al, 2006)

Gray matter density reduction in right middle frontal cortex (corrected p < 0.05)


Gray matter density reduction in right middle frontal cortex (corrected p < 0.05)

Lower cerebral glucose metabolism levels in the right superior frontal white matter ; FDG-PET study of brain glucose metabolism (Kim et al., 2005) Decreased relative rCBF in the right anterior cingulate cortex ; SPECT study of relative blood flow in brain (Hwang et al., 2006)

MA subjects are...
Increased curvature in the genu; decreased width in posterior midbody; decreased width in isthmus area ; Corpus callosum shape and size analysis (Oh et al., 2005)

MA dependent adults had lower white matter integrity values in frontal WM compared to healthy subjects ; DTI study (Chung et al., In press)

MA users had greater severity of WMH compared to healthy subjects ; White matter hyperintensities study (Bae et al, 2006)

Pilot study
14 MA users (age=18.8�2.26 years; male/female=10/4) and 14 healthy comparison subjects (age=18.7�2.29 years; male/female=10/4) matching for age, sex, education and parent's socioeconomic status Months of active MA use=21.0�7.65 lifetime cumulative number of intravenous shots=139.8�113.2. (One intravenous shot of 0.3 gram is typically used at a time in South Korea typically induces 3-5 hours of euphoria and 48-72 hours of excitement and hypervigilance.) Structural T1, DTI and 1H-MRS Sponsored in part by a Strategic Priority Research Grant of Seoul National University Hospital (SNUH)(21-2003-007-0), matched funds for DA09448-09S1

MA dependent adolescents will have neurobiological deficits in the frontal lobes (decreased gray matter density, white matter integrity, and neuronal viability) A more profound neurobiological deficit in adolescents with early-onset MA abuse will be observed when compared to those with late-onset MA abuse.

MRS study in adolescent and young adult MA users
NAA concentrations lower in adolescent MA users (n=12) compared to healthy subjects (n=13) in frontal white matter ROI Age of onset positively correlated with frontal white matter NAA concentration

NAA level

Gray matter density differences in adolescent and young adult MA users
Adolescent MA users had decreased gray matter densities in the left orbitofrontal lobe Age of onset of MA exposure positively correlated with orbitofrontal gray matter densities

White matter integrity differences in adolescent and young adult MA users
ROI analysis: Adolescent MA users had smaller white matter integrity values in the frontal ROI compared to healthy subjects Voxel-based analysis: Decreased white matter integrity values in bilateral medial frontal regions of the brain Age of onset of MA abuse strongly correlated with left medial frontal white matter integrity values

Summary of pilot study
Adolescent MA users may have neurobiological deficits in frontal regions of the brain:
Gray matter density decrease in orbitofrontal region Neuronal viability decrease in the frontal white matter White matter integrity decrease in several frontal regions of the brain

The pattern of MA-related toxicity on the developing brain may differ from the adult brain Age of MA exposure seems to play an important role in MA-induced neurobiological deficit