MR Spectroscopy and Alzheimer’s DiseaseMR Spectroscopy and Alzheimer’s Disease

P. Murali Doraiswamy, MBBSP. Murali Doraiswamy, MBBS

Chief, Division of Biological PsychiatryChief, Division of Biological Psychiatry

Duke University Medical CenterDuke University Medical Center

Brain MR SpectroscopyBrain MR Spectroscopy

• Non-invasive biochemical windowNon-invasive biochemical window

• Concentrations of metabolites in whole brain or Concentrations of metabolites in whole brain or discrete regionsdiscrete regions

• MRS acquired with anatomical MRIMRS acquired with anatomical MRI

MRS Surrogate MarkersMRS Surrogate Markers

• N-Acetylaspartate (NAA)N-Acetylaspartate (NAA)

• function not fully known - acetyl donorfunction not fully known - acetyl donor

• abundant in human brain; increases during brain abundant in human brain; increases during brain developmentdevelopment

• gray matter >> white matter >> CSF; neurons >> gliagray matter >> white matter >> CSF; neurons >> glia

• Myo-inositol (MI)Myo-inositol (MI)

• possible marker of glial activation, possible marker of glial activation, in MCI in MCI

Doraiswamy et al. 2000Doraiswamy et al. 2000

N-Acetyl Aspartate (NAA): N-Acetyl Aspartate (NAA): Marker of Neuronal Loss or DysfunctionMarker of Neuronal Loss or Dysfunction

NAA ReducedNAA Reduced

• AlzheimerAlzheimer

• Multiple sclerosis*Multiple sclerosis*

• HIV*HIV*

• Stroke*Stroke*

• ALS*ALS*

• Temporal Lobe Epilepsy Temporal Lobe Epilepsy

• Traumatic Injury*Traumatic Injury*

• HypothryoidismHypothryoidism

Hippocampal Volume ReducedHippocampal Volume Reduced

• AlzheimerAlzheimer

• Geriatric depressionGeriatric depression

• SchizophreniaSchizophrenia

• Temporal lobe epilepsyTemporal lobe epilepsy

• Herpes encephalitisHerpes encephalitis

• MCIMCI

• PTSDPTSD

• Cushing’s disease*Cushing’s disease*

*? reversible changes reported following recovery or therapy

Adapted from various references

MRS Methodologic IssuesMRS Methodologic Issues

• AcquisitionAcquisition

– short or long TEshort or long TE

• Region of InterestRegion of Interest

– Whole brain Whole brain

– Multi VoxelMulti Voxel

• single slice single slice

• multiple slicesmultiple slices

– Single voxelSingle voxel

• Voxel size and locationVoxel size and location

• QC, Amplitude DriftQC, Amplitude Drift

• Reporting of DataReporting of Data

– Normalized internally Normalized internally (e.g. NAA/Cr)(e.g. NAA/Cr)

– Normalized externally Normalized externally (e.g. phantom)(e.g. phantom)

– Atrophy correctedAtrophy corrected

– Absolute concentrationAbsolute concentrationDoraiswamy et al 2000

Cross-sectional MRS Studies in ADCross-sectional MRS Studies in AD

Postmortem MRS StudiesPostmortem MRS Studies

• 4 studies4 studies

• Sample size: AD= 69, NC =22Sample size: AD= 69, NC =22

• Mostly of temporal and Mostly of temporal and frontal cortexfrontal cortex

• 20-50% 20-50% in NAA in NAA

• NAA loss correlated to NAA loss correlated to plaque density or tanglesplaque density or tangles

In-vivo MRS StudiesIn-vivo MRS Studies

• About 30 studies (N ranging About 30 studies (N ranging from <10 to >50)from <10 to >50)

• NAA NAA in AD (10%-37%) in AD (10%-37%)

• Some negative studiesSome negative studies

• NAA correlates with MMSE NAA correlates with MMSE in AD (r=.2 - .7)in AD (r=.2 - .7)

• MI increased in MCIMI increased in MCI

Adapted from various references

Prognostic Role for MI/NAA Ratio? Prognostic Role for MI/NAA Ratio?

Doraiswamy et al. Lancet 1998

Study of 51 MCI/AD PatientsStudy of 51 MCI/AD Patients

Predictive value of NAA/MI in stepwise regression model with age, education and MRS ratios

Test R2 P-valueAVLT .21 .0007DRST .28 .0001

Kantarci et al. JINS, 2002

Study of 12 Mild ADStudy of 12 Mild AD

Longitudinal MRS Studies in ADLongitudinal MRS Studies in AD

• 3 studies (Total N=34 AD, 14 controls) 3 studies (Total N=34 AD, 14 controls)

• Follow up MRS scans after 12- 23 mths Follow up MRS scans after 12- 23 mths

• MRS methods varied; therapies not controlledMRS methods varied; therapies not controlled

• NAA declined over time NAA declined over time

– Gray matter: 12%/yr in AD and 1% /yr in controlsGray matter: 12%/yr in AD and 1% /yr in controls

– Hippocampus: Decline 12%/yr in AD but not Hippocampus: Decline 12%/yr in AD but not statistically different from controlsstatistically different from controls

– NAA decline correlated with cognition in two studiesNAA decline correlated with cognition in two studies

Dixon 2002, Adalsteinsson 2000, Jensen 2000

A Preliminary Randomized Placebo-A Preliminary Randomized Placebo-Controlled Trial of the Effects of Donepezil Controlled Trial of the Effects of Donepezil on Neuronal Markers in Alzheimer’s diseaseon Neuronal Markers in Alzheimer’s disease KR Krishnan, HC Charles, PM Doraiswamy, J Mintzer, KR Krishnan, HC Charles, PM Doraiswamy, J Mintzer, R Weisler, X Yu, C Perdoma, J Ieni, and S Rogers. R Weisler, X Yu, C Perdoma, J Ieni, and S Rogers. Unpublished data. Study supported by Eisai Inc/PfizerUnpublished data. Study supported by Eisai Inc/Pfizer

Design of the Phase II StudyDesign of the Phase II Study

• Randomized, double-blind, placebo-controlled study of mild Randomized, double-blind, placebo-controlled study of mild to moderate (MMSE 10-26) probable ADto moderate (MMSE 10-26) probable AD

• 24 weeks of therapy with donepezil or placebo followed by 6-24 weeks of therapy with donepezil or placebo followed by 6-week placebo washoutweek placebo washout

• 11H-MRS and ADAS-Cog at Baseline, Weeks 6, 12, 18, 24, and H-MRS and ADAS-Cog at Baseline, Weeks 6, 12, 18, 24, and 3030

• Hippocampal volumes measured only at Baseline and Week Hippocampal volumes measured only at Baseline and Week 24; blinded post-hoc analyses24; blinded post-hoc analyses

• Subjects recruited at 3 sites but all scans done at DukeSubjects recruited at 3 sites but all scans done at Duke

Trial OutcomesTrial Outcomes

• Primary OutcomePrimary Outcome

– N-Acetylaspartate measured by MRS N-Acetylaspartate measured by MRS

• Secondary OutcomesSecondary Outcomes

– ADAS-Cog, other MRS metabolities ADAS-Cog, other MRS metabolities

• Post-hoc AnalysesPost-hoc Analyses

– Hippocampal volumesHippocampal volumes

StatisticsStatistics

• Slope analyses was pre-planned for MRS but nonlinearity Slope analyses was pre-planned for MRS but nonlinearity of data led to use of percent change from baseline of data led to use of percent change from baseline analysesanalyses

• ADAS-Cog data analyzed using ANCOVAADAS-Cog data analyzed using ANCOVA

• MR data analyzed using unpaired t-tests MR data analyzed using unpaired t-tests

Baseline Characteristics of AD PatientsBaseline Characteristics of AD Patients

DonepezilN=34

PlaceboN=33

Completed 28 23

Discontinued 6 (0) 10 (2)

Mean Age 74.4 72.4

MMSE 19.5 19.0

CDR = 1.0 76% 76%ITT sample included 31 on donepezil and 26 on placebo

Results: CognitionResults: Cognition

-4

-3

-2

-1

0

1

2

3

4

Baseline Week 6 Week 12 Week 18 Week 24 Week 30Mea

n C

han

ge

in A

DA

S-c

og

Sco

res

DonepezilPlacebo

ADAS cog

P =.002P =.007

P =.031

P =.019

Unpublished data

Results: Results: NN-Acetyl-Aspartate-Acetyl-Aspartate

-5

5

15

25

35

45

Baseline Week 6 Week 12 Week 18 Week 24 Week 30Mea

n %

cha

nge

from

bas

elin

e in

NA

A

leve

ls

Donepezil Placebo

Subcortical Gray Matter

P =.022

Unpublished data

Results: Results: NN-Acetyl-Aspartate-Acetyl-Aspartate

Cortical

-15

-5

5

15

25

35

45

Baseline Week 6 Week 12 Week 18 Week 24 Week 30Mea

n %

cha

nge

from

bas

elin

e in

NA

A

leve

ls

Donepezil Placebo

Unpublished data

Results: Results: NN-Acetyl-Aspartate-Acetyl-Aspartate

Peri/ventricular

-15

-5

5

15

25

35

45

Baseline Week 6 Week 12 Week 18 Week 24 Week 30Mea

n %

cha

nge

from

bas

elin

e in

NA

A

leve

ls

Donepezil Placebo

P =.011

P =.022

Unpublished data

Results: Results: NN-Acetyl-Aspartate-Acetyl-Aspartate

White

-15

-5

5

15

25

35

45

Baseline Week 6 Week 12 Week 18 Week 24 Week 30Mea

n %

cha

nge

from

bas

elin

e in

NA

A

leve

ls

Donepezil Placebo

Unpublished data

Conclusions - Donepezil MR study Conclusions - Donepezil MR study

• Donepezil improved cognition at weeks 6 through 24 Donepezil improved cognition at weeks 6 through 24 and increased brain NAA levels generally between and increased brain NAA levels generally between Weeks 6 and 18. However, drug-placebo differences Weeks 6 and 18. However, drug-placebo differences were not significant at Weeks 24 or 30. were not significant at Weeks 24 or 30.

• Variance was large Variance was large

• No definitive conclusions concerning effects on brain No definitive conclusions concerning effects on brain NAA or its relationship to cognition can be drawn NAA or its relationship to cognition can be drawn from this study. Results need confirmation in a larger from this study. Results need confirmation in a larger study. Provides data to plan future MRS studies. study. Provides data to plan future MRS studies.

Conclusions: MR SpectroscopyConclusions: MR Spectroscopy

• FDA QuestionsFDA Questions

– What AD outcome is NAA a surrogate for? What AD outcome is NAA a surrogate for?

– Does NAA reliably predict this outcome?Does NAA reliably predict this outcome?

– What is the biological basis for drug effects on NAA? What is the biological basis for drug effects on NAA?

– To what extent does NAA reflect pathophysiology? To what extent does NAA reflect pathophysiology?

• Future NeedsFuture Needs

– Longitudinal correlative clinical and MRS studiesLongitudinal correlative clinical and MRS studies

– MRS studies across multiple clinical drug trials MRS studies across multiple clinical drug trials