White Matter Structural Integrity in Healthy Aging Adults and Patients With Alzheimer Disease: A Magnetic Resonance Imaging Study Bartzokis, et al. UCLA School of Medicine & University of Arkansas for Medical Sciences Archives of Neurology. 2003;60:

Objectives To assess the integrity of FLWM by MRI and, thus: To assess the integrity of FLWM by MRI and, thus: To provide an important index of brain aging and: To provide an important index of brain aging and: Its relationship to Alzheimer disease (AD) Its relationship to Alzheimer disease (AD)

Background Imaging studies show: Imaging studies show: Volume of frontal lobe white matter (FLWM) expands until about 44.6 years, then declines. Volume of frontal lobe white matter (FLWM) expands until about 44.6 years, then declines. Consistent with postmortem studies: Consistent with postmortem studies: White matter myelination of frontal regions continues into middle age, followed by breakdown in myelin sheaths White matter myelination of frontal regions continues into middle age, followed by breakdown in myelin sheaths Especially in fiber systems formed later in development (such as frontal and temporal lobes) Especially in fiber systems formed later in development (such as frontal and temporal lobes)

Background, cont. Oligodendrocytes are heterogeneous based on when they differentiated during development Oligodendrocytes are heterogeneous based on when they differentiated during development Later-differentiating oligodendrocytes: Later-differentiating oligodendrocytes: Ensheath many more axons Ensheath many more axons With smaller axon diameters With smaller axon diameters Have different lipid properties Have different lipid properties May have slower myelin turnover rate, with reduced ability to repair myelin May have slower myelin turnover rate, with reduced ability to repair myelin May increase vulnerability to myelin breakdown May increase vulnerability to myelin breakdown Oligodendrocytes are more sensitive than neurons and astrocytes to various insults Oligodendrocytes are more sensitive than neurons and astrocytes to various insults

Background, cont. Changes in structural integrity of myelin can be measured by MRI Changes in structural integrity of myelin can be measured by MRI Myelination effects on white matter: Myelination effects on white matter: increases volume increases volume decreases water content decreases water content Myelin breakdown effects on white matter: Myelin breakdown effects on white matter: decreases volume decreases volume increases water content increases water content

Background, cont. Focal areas of myelin breakdown are easily identified visually in T2-weighted MR images Focal areas of myelin breakdown are easily identified visually in T2-weighted MR images Relatively small changes in amount of tissue water markedly alter the transverse relaxation time (T2) Relatively small changes in amount of tissue water markedly alter the transverse relaxation time (T2) T2 of water (e.g. CSF) – 2000ms T2 of water (e.g. CSF) – 2000ms T2 of brain parenchyma – 100ms T2 of brain parenchyma – 100ms Analysis of relaxation time facilitated by transforming T2 into R 2 (convention) Analysis of relaxation time facilitated by transforming T2 into R 2 (convention)

T2 basics Equilibrium magnetization, M 0 is parallel to magnetic field, B 0 Equilibrium magnetization, M 0 is parallel to magnetic field, B 0 (figures from “The Basics of MRI”,

T2 basics, cont. Exposing spin system to energy of a particular frequency can place net magnetization into XY-plane Exposing spin system to energy of a particular frequency can place net magnetization into XY-plane

T2 basics, cont. Magnetization rotates about Z-axis at frequency equal to the frequency of a photon with enough energy to change spin states Magnetization rotates about Z-axis at frequency equal to the frequency of a photon with enough energy to change spin states (figures from “The Basics of MRI”,

T2 basics, cont. Net magnetization begins to dephase due to slight differences in magnetic field between spin packets (different groups of spins). Net magnetization begins to dephase due to slight differences in magnetic field between spin packets (different groups of spins). (figures from “The Basics of MRI”,

T2 basics, cont. The time constant which describes the return to equilibrium of the transverse magnetization, M XY, is called the spin-spin relaxation time, T2 The time constant which describes the return to equilibrium of the transverse magnetization, M XY, is called the spin-spin relaxation time, T2 (figures from “The Basics of MRI”,

Background, cont. Focal areas of myelin breakdown are easily identified visually in T2-weighted MR images Focal areas of myelin breakdown are easily identified visually in T2-weighted MR images Relatively small changes in amount of tissue water markedly alter the transverse relaxation time (T2) Relatively small changes in amount of tissue water markedly alter the transverse relaxation time (T2) T2 of water (e.g. CSF) – 2000ms T2 of water (e.g. CSF) – 2000ms T2 of brain parenchyma – 100ms T2 of brain parenchyma – 100ms Analysis of relaxation time is facilitated by transforming T2 into R 2 (convention) Analysis of relaxation time is facilitated by transforming T2 into R 2 (convention)

Background, cont. R 2 =[(1/T2)*1000ms]/sec Can reveal brain myelination differences not visibly discernible with T2-weighted images. Can reveal brain myelination differences not visibly discernible with T2-weighted images. Myelination increases R 2, while age-related myelin breakdown decreases R 2 Myelination increases R 2, while age-related myelin breakdown decreases R 2

Hypotheses Based on previously observed changes in FLWM volume, white matter R 2 should show quadratic relationship with age Based on previously observed changes in FLWM volume, white matter R 2 should show quadratic relationship with age Because nonrandom age-related myelin breakdown may contribute to the pathophysiologic mechanisms of AD, FLWM R 2 decrease should be larger in AD subjects than healthy controls Because nonrandom age-related myelin breakdown may contribute to the pathophysiologic mechanisms of AD, FLWM R 2 decrease should be larger in AD subjects than healthy controls

Participants 252 healthy subjects 252 healthy subjects 127 men, 125 women 127 men, 125 women Aged (mean, 54.9; SD, 17.5) Aged (mean, 54.9; SD, 17.5) Screened for family history of neurodegenerative disorders Screened for family history of neurodegenerative disorders 34 AD subjects 34 AD subjects 16 men, 18 women 16 men, 18 women Aged (mean, 76.3; SD, 6.7) Aged (mean, 76.3; SD, 6.7) Screened for non-AD-related neurodegenerative disorders Screened for non-AD-related neurodegenerative disorders

Methods Axial image from 74- year-old healthy control subject. Axial image from 74- year-old healthy control subject. Regions of Interest (ROIs) selected by single blind rater Regions of Interest (ROIs) selected by single blind rater Left: early echo – avoids gray matter Left: early echo – avoids gray matter Right: late echo – avoids hyperintensities Right: late echo – avoids hyperintensities Early Echo Late Echo

Methods, cont. ROI transferred to T2 maps ROI transferred to T2 maps To further eliminate possible remnants of T2 hyperintense lesions, all pixels with T2 values above the right side inflection point on the histogram distribution of the ROI were eliminated. To further eliminate possible remnants of T2 hyperintense lesions, all pixels with T2 values above the right side inflection point on the histogram distribution of the ROI were eliminated. R 2 averaged within ROI from 2 slices, and then over both hemispheres R 2 averaged within ROI from 2 slices, and then over both hemispheres

Methods, cont. Education level, sex and race found to be statistically insignificant in separate regression analyses, and thus dropped from models Education level, sex and race found to be statistically insignificant in separate regression analyses, and thus dropped from models

Results As expected, relationship between age and FLWM R 2 best represented by quadratic function (p<0.001) As expected, relationship between age and FLWM R 2 best represented by quadratic function (p<0.001) In healthy adults, FLWM R 2 increased until age 38, then declined markedly In healthy adults, FLWM R 2 increased until age 38, then declined markedly R 2 of subjects with AD significantly lower than group of healthy controls (p<0.001) R 2 of subjects with AD significantly lower than group of healthy controls (p<0.001)

Regression line based on 252 healthy control subjects Regression line based on 252 healthy control subjects y=15.22+[(0.055*Age)-( *Age 2 )]

Results, cont. Healthy adults over 60: Healthy adults over 60: Mean residual: ; p=0.76 Mean residual: ; p=0.76 Individuals with AD: Individuals with AD: Mean residual: -0.55; p<0.001 Mean residual: -0.55; p<0.001 Mean R 2 : Mean R 2 : Normal-15.59(SD,0.53) Normal-15.59(SD,0.53) AD-14.65(SD,0.73) AD-14.65(SD,0.73) No meaningful association between duration of illness and FLWM R 2 No meaningful association between duration of illness and FLWM R 2

Results, cont. Bootstrap replication analysis confirmed that maximum FLWM R 2 is reached at earlier age than maximum FLWM volume (p=0.02) Bootstrap replication analysis confirmed that maximum FLWM R 2 is reached at earlier age than maximum FLWM volume (p=0.02)

Conclusions Healthy brain in constant state of change Healthy brain in constant state of change Roughly divided into period of maturation until middle age and then period of decline of myelin integrity Roughly divided into period of maturation until middle age and then period of decline of myelin integrity Clinically diagnosed AD associated with more severe myelin breakdown Clinically diagnosed AD associated with more severe myelin breakdown

Conclusions, cont. Noninvasive measure of R 2 may track trajectory of deteriorating white matter integrity during normal aging and development of AD Noninvasive measure of R 2 may track trajectory of deteriorating white matter integrity during normal aging and development of AD May be useful marker for medication development aimed at preventing AD May be useful marker for medication development aimed at preventing AD