Cerebral oxygen metabolism in patients with early Parkinson's disease

Cerebral Oxygen Consumption in Early Parkinson’s Disease

Cerebral Oxygen Metabolism in Patients with

Early Parkinson’s Disease.

Per Borghammer1,2, Paul Cumming3, Karen

Østergaard4,

Albert Gjedde5, Anders Rodell2, Christopher J.

Bailey6,

and Manoucher S. Vafaee5.

1Deparment of Nuclear Medicine, Aarhus University Hospital,

Denmark. 2PET Centre, Aarhus University Hospital, Denmark. 3Department of Nuclear Medicine, Ludwig Maximillian University,

Munich, Germany. 4Department of Neurology, Aarhus University

Hospital, Denmark. 5Institute of Neuroscience and Pharmacology, University of

Copenhagen, Denmark. 6Center of Functionally Integrative Neuroscience (CFIN), Aarhus

University, Denmark.

August 2nd, 2011

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Corresponding authorPer Borghammer, MD, Ph.DDepartment of Nuclear Medicine and PET centreAarhus University HospitalAarhus C, Denmark 8000Email: [email protected]: +0045 8949 4378Fax: +0045 8949 4400

Short Title: Cerebral Oxygen Consumption in Early

Parkinson’s Disease

Key Words: Parkinson's disease, energy metabolism, CBF,

CMRO2, oxygen, normalization, Positron Emission Tomography

ABSTRACT

Aim: Decreased activity of the mitochondrial electron

transport chain (ETC) has been implicated in the

pathogenesis of Parkinson’s disease (PD). This model

would most likely predict a decrease in the rate of

cerebral oxygen consumption (CMRO2). To test this

hypothesis, we compared CMRO2 and cerebral blood flow

(CBF) PET scans from PD patients and healthy controls.

Materials & Methods: Nine early-stage PD patients and 15

healthy age-matched controls underwent PET scans for

quantitative mapping of CMRO2 and CBF. Between-group

differences were evaluated for absolute data and

intensity-normalized values.

Results: No group differences were detected in regional

magnitudes of CMRO2 or CBF. Upon normalization using the

reference cluster method, significant relative CMRO2

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mailto:[email protected]


decreases were evident in widespread prefrontal, parieto-

occipital, and lateral temporal regions. Sensory-motor

and subcortical regions, brainstem, and the cerebellum

were spared. A similar pattern was evident in normalized

CBF data, as described previously.

Conclusion: While the data did not reveal substantially

altered absolute CMRO2 in brain of PD patients, employing

data-driven intensity normalization revealed widespread

relative CMRO2 decreases in cerebral cortex. The detected

pattern was very similar to that reported in earlier CBF

and CMRglc studies of PD, and in the CBF images from the

same subjects. Thus, the present results are consistent

with the occurrence of parallel declines in CMRO2, CBF,

and CMRglc in spatially contiguous cortical regions in

early PD, and support the hypothesis that ETC dysfunction

could be a primary pathogenic mechanism in early PD.

INTRODUCTION:

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Decreased activity in complex I of the mitochondrial

electron transport chain (ETC), which has been reported

in cortical regions from Parkinson’s disease (PD)

patients, (1), has been hypothesized to be a driving

force in the pathogenesis of PD (2). Impaired functioning

of the ETC would likely result in decreased cerebral

metabolic rate of oxygen consumption (CMRO2). Of the very

few quantitative positron emission tomography (PET)

studies of CMRO2 in early- to moderate-stage PD patients,

most have reported only non-significant decreases in CMRO2

(3-5). Surprisingly, a recent PET study (6) of early-

stage, untreated PD patients reported a significant 24%

increase in global CMRO2 and a concomitant nearly-

significant (p=0.056) 15% increase in global cerebral

rate of glucose consumption (CMRglc). This recent report,

although obtained with modern instrumentation and

methods, is thus at odds with the previous literature;

the authors proposed that increased CMRO2 and CMRglc could

be a characteristic of early-stage disease, due to

uncoupling of ATP production from oxidation of glucose

(7).

To investigate further the rate of brain oxygen

consumption in early-stage PD, we compared CMRO2 and CBF

parametric maps from groups of PD patients and healthy

control subjects. In addition to regional analyses, we

also performed voxel-based statistical comparisons to

evaluate whether possible regional differences in

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patterns of perturbed CMRO2 and CBF match the previously

described patterns of perturbed CBF and CMRglc. This type

of voxelwise statistical analysis has not previously been

reported for CMRO2 in PD.

MATERIALS AND METHODS:

Subjects

Nine non-demented, early-stage PD patients (disease

duration 10-76 months, mean 48 months) were recruited

from the Movement Disorders Clinic at the Department of

Neurology, Aarhus University Hospital (Table 1). A group

of fifteen healthy, age- and gender-matched control

subjects were recruited by advertisement in local

newspapers. The diagnosis of PD was performed by movement

disorder specialists, in accordance with established

research diagnostic criteria (8). Seven patients had

mainly right-sided symptoms and two had left-sided

symptoms. Exclusion criteria included dementia (minimal

mental state examination (MMSE) < 26), depression, severe

heart disease, liver or renal disorders, or any other

important medical disease at the time of PET scanning.

Anti-parkinsonian medication was paused for 12 hours in

the case of levodopa and for at least three plasma half-

lives for dopamine agonists (i.e. 36 h for ropinirole)

prior to the PET session. UPDRS-III tests were performed

immediately before PET scanning sessions, i.e. off

medication. Written informed consent was obtained from

all study subjects. The study was approved by the local

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ethics committee, and was in accordance with the

declaration of Helsinki.

Scanning procedures

Details on MR and PET scanning procedures were published

previously (9). In brief, a high resolution T1-weighted

MR was acquired for each subject with a GE Signa Excite

HDx 3.0T spectrometer using a 3D IR-fSPGR sequence

(TE=3.0 ms, TI=450 ms, flip angle=20 deg, slices=156,

slice thickness=1.1 mm, in-plane resolution=0.94 mm).

PET: Each subject underwent one [15O]H2O emission

recording. Two identical [15O]O2 recordings were acquired

to compensate for greater variance in oxygen recordings.

One PD patient had only a single O2 scan due to technical

failure. Recordings were performed at intervals of 15

minutes in a quiet room, with subjects resting in a

supine position with open eyes. All PET recordings were

acquired in 3D mode with the ECAT EXACT HR 47

(CTI/Siemens) PET camera. We utilized a neck shield, as

this has previously been demonstrated to reduce body

scatter by 75%, thus improving the signal to noise

relationship in brain emission images (10). Subjects also

wore nose clips so as to minimize [15O]O2 entry in the

sinuses. All PET scans consisted of 21 dynamic frames of

identical frame structures (12x5 sec, 6x10sec, 3x20sec).

Images were reconstructed using filtered back-projection

with a 0.5 cycles−1 ramp filter, followed by application

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of a 7mm Gaussian filter. Arterial blood was collected

continuously from the radial artery, and radioactivity

concentration was measured with an automated on-line

blood sampling system. Dynamic emission recordings

lasting three minutes were initiated upon bolus

intravenous injection of [15O]H2O (500 MBq), or inhalation

of [15O]O2 (1000 MBq). The order of scans was randomized

for each subject. Hematocrit and blood gas values were

measured in arterial blood samples collected immediately

prior to each PET recording.

Data analysis

Subjects’ PET images were co-registered, via their

individual MR images, to an MR template consisting of 85

young adults in Montreal Neurological Institute (MNI)

space, using combined linear and non-linear

transformations (see supplementary online material for

more details on the coregistration). As detailed

previously (9, 11), parametric maps of CBF and CMRO2 were

calculated with the single step, two-compartment, three-

weighted-integration method of Ohta et al (12, 13) which

has been successfully used in both normal subjects (11,

14, 15) and patient studies (16, 17), including PD

patients (18, 19). The parametric images were smoothed

with a Gaussian filter to a final resolution of 14x14x14

mm3. The two CMRO2 maps for each subject were averaged and

oxygen extraction fraction (OEF) maps were produced by

dividing CMRO2 maps CBF maps and by the arterial oxygen

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concentration (total hemoglobin concentration multiplied

by oxygen saturation fraction). The two PD patients with

left-sided symptoms had their scans mirrored

(right/left). For the volume of interest (VOI) analysis,

the subjects’ MRI images were automatically segmented in

total GM and total WM (20). Four VOIs were defined in the

frontal, parietal, temporal, and occipital lobes as

described previously (9). The VOIs were used to extract

regional mean CBF, CMRO2, and OEF values from all

subjects. VOI group comparisons were performed using t-

tests. One patient CBF scan was a significant outlier

(Grubb’s test), and was consequently excluded from the

analysis of absolute values.

Voxel-based analysis. The reconstructed CBF and CMRO2 maps in

stereotaxic coordinates were initially blurred with a

Gaussian filter (final isotropic resolution 14x14x14 mm).

Voxel-wise statistical analyses were performed on CBF,

CMRO2, and OEF data prior to intensity normalization and

also on normalized CBF and CMRO2 data. For normalization,

we employed the reference cluster normalization method

(21). This procedure has been validated for use in data,

in which unidirectional changes of low magnitude is

expected (details given in (22)). In brief, a standard

global mean normalized group comparison was initially

performed with a univariate voxel-based statistical

program. The resultant output t-map was used to make a

new reference region consisting only of intracerebral

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voxels where t>2. The basic assumption here is that

voxels displaying relative increases are in fact

unchanged by disease condition, and have merely been

inflated by biased GM normalization. Had true (absolute)

hypermetabolism or hyperperfusion been suspected anywhere

in the brain, these regions would have been excluded from

the reference cluster. The final mask used for

normalization of the CBF and CMRO2 data consisted mostly

of subcortical WM (Figure 1). We have previously

demonstrated that the use of a WM reference region yields

superior normalization (18), and is probably valid in PD,

since no previous quantitative studies has reported

absolute WM changes in CBF, CMRO2, or CMRglc (23).

In each analysis, all brain voxels were examined using

fMRIstat, which performs an SPM-style mass univariate

analysis. We used the mixed effect model analysis method

as advocated in Section Four of Worsley et al. (24), with

spatial smoothing of the random/fixed-effects variance to

achieve an effective 100 degrees of freedom for the fixed

effects analysis. Appropriate linear contrasts were

defined to reveal group differences in CMRO2 and CBF.

fMRIstat assigns a t-value to each voxel in the brain and

examines the map for significant focal changes (p < 0.05,

corrected), based on 3D Gaussian Random Field Theory

(25).

RESULTS

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VOI analysis

No significant differences were present in the age-

distributions of the groups (p>0.05). Table 2 presents

CMRO2, CBF, and OEF data for the two groups. No

significant differences were present in absolute values

of CBF (all p-values>0.44), CMRO2 (all p-values>0.30), or

OEF (all p-values>0.30).

Voxel-based analysis

No significant differences were detected in voxel-based

analysis of absolute CBF, CMRO2, and OEF maps (not shown).

Figure 2A displays the output t-map from the normalized

CMRO2 analysis projected onto the surface of an atlas

brain in MNI space. Our early PD patients displayed

significant relative CMRO2 decreases in medial and lateral

prefrontal regions, medial and lateral parieto-occipital

regions including precuneus, and in lateral temporal

regions. Primary sensory-motor cortices, inferior and

medial temporal lobe, the cingulate, the cerebellum, and

brainstem regions had unaltered relative CMRO2 in

comparison to the control group. MNI coordinates of

significant voxels are available online (Supplementary

Table 1). No relative hypermetabolism was detected

anywhere. Figure 2B depicts the voxel-based analysis of

CBF data. This analysis revealed significant relative CBF

decreases in cortex, matching that seen for CMRO2 data,

but of somewhat lesser spatial extent. Figure 2C shows

the CBF results at a less stringent t-threshold, which

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produces a pattern or relatively reduced CBF matching

more closely that seen for CMRO2, although of lesser

significance. Moreover, the present patterns of

relatively decreased CBF and CMRO2 in a large domain of

cerebral cortex are very similar to previously reported

cortical patterns (26) of decreased CBF and CMRglc in PD

patients (supplementary figure 1).

DISCUSSION

Quantitative analysis

In our comparison of early-stage PD patients and healthy

volunteers, we detected nearly identical absolute

magnitudes of CMRO2 and CBF throughout the brain. In

contrast, a recent PET study (6) reported a 24% increase

of absolute CMRO2 in a comparison of 12 PD patients to 12

control subjects, a finding at odds with earlier reports

(3-5). Our data set included CMRO2 scans from only nine

patients and 15 control subjects, so lack of statistical

power is potentially a matter of concern. However, the

relative standard deviation of our global mean CMRO2 was

9%. Simple power calculations show given the current

sample sizes, we had statistical power to detect a

between-group difference of about 12% with a power of

90%. Thus, we can claim with confidence that any between-

group difference in our data set, if present, is most

likely smaller than 12%, and almost certainly smaller

than the previously reported 24% difference. Our data

therefore concurs with the three early CMRO2 studies of PD

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in which any CMRO2 changes were of a too small magnitude

to allow detection in modest sample sizes of 10-20

subjects per group.

We note that our patient sample had longer mean disease

duration, but comparable H&Y stage to the subjects in the

study by Powers et al (6). Also, their patients were

drug-naive, whereas our patients were all under treatment

with anti-parkinsonian medication, with pause prior to

the PET scans. Five patients received only agonist

treatment, and the other four patients received agonist

plus small doses of levodopa. While drug-effects are a

potential confound, a previous study reported that

dopaminergic treatment results in increased cortical

CMRglc (27). Furthermore, many studies have also

demonstrated that dopaminergic treatment leads to

increased CBF (reviewed in (4)). Thus, the relatively

brief pause of medication in our patients seems

inadequate to explain the discrepancy with the study of

Powers et al.

While the occurrence of cerebral hypermetabolism at some

early disease stage in untreated PD patients is an

intriguing possibility, it must be remembered that this

proposition runs counter to more than 20 quantitative PET

studies of CBF, CMRglc, and CMRO2 (reviewed in (26)).

Moreover, one of the three previous CMRO2 studies did in

fact investigate drug naïve PD patients; the authors

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reported non-significantly decreased CMRO2 (5). Remaining

uncertainty about the early cerebrometabolic changes of

early PD should be investigated in de novo patients, at the

earliest possible stage of disease onset.

Voxel-based analysis

To our knowledge, this is the first voxel-based analysis

of resting state CMRO2 data in PD patients contrasted with

healthy age-matched subjects. Upon normalization, we

detected a widespread pattern of cortical CMRO2 decreases

(Figure 2A) in frontal, parieto-occipital, and lateral

temporal regions. It may seem surprising that such

widespread relative decreases were detected, in the

absence of significant differences in voxel-based and VOI

analyses of absolute data. However, this apparent

discrepancy is readily explicable. First and foremost,

physiological measurements of CBF, CMRglc and CMRO2

contain substantial variation, i.e. global mean values

typically display a coefficient of variation (COV) in the

range of 10-25% (see Table 2 of ref. (26)). This makes

the detection of small absolute differences unlikely

given sample sizes of 10-20 subjects per group, as is

typical of PET studies. Consider the following example:

given two groups of 12 subjects each and a COV of 10%,

there is statistical power of 69% to detect a 10%

between-group difference. If the COV is 25%, the

statistical power is only 16%. The process of

normalization reduces the COV to 3-6% making the

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detection of group differences much more probable. Thus,

in accord with our present findings, several previous PET

studies in PD reported no significant absolute changes,

but significant changes in normalized ratios (28-32).

In a previous methodology study (22) we specifically

explored the influence of normalization issues on

simulated PD data. In brief, we hypothesized that the

spatially extensive and high-magnitude cortical CBF and

CMRglc deficits reported at later PD stages (4, 33, 34),

are preceded by equally widespread metabolic deficits at

earlier disease-stages, but of a magnitude difficult to

detect in PET studies with typically used sample sizes.

We compared four different methods of normalization in

simulated data, in which widespread decreases of low-

magnitude were imposed in the cortex. The conclusion from

these simulations was clear - the reference cluster

method displayed by far the best performance and

recovered more than 66% of the true signal (22) . In

contrast, ratio normalization to an unbiased a priori

defined VOI recovered only 24% of the simulated cortical

deficit, and the standard method, i.e. proportional

scaling to the global mean recovered only traces of the

true signal. Importantly, there were no detectable

differences in absolute global or regional values in any

of the simulations, as was also the case in the present

CMRO2 data set.

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The results of the simulation study described above are

directly analogous to the present clinical study, in that

widespread cortical decreases were detected through

reference cluster normalized data, even though no

differences were detectable in the analyses of absolute

data. Importantly, the physiological validity of the CBF

and CMRglc patterns in PD, which are detected using

reference cluster methods, was recently independently

verified in a quantitative perfusion MRI study in a large

series of patients (33). Arterial spin labeling was used

to measure CBF in 61 PD patients and 29 healthy control

subjects. The authors reported subcortical preservation

and concomitant widespread cortical perfusion decreases

in a pattern greatly resembling the PET patterns seen

after reference cluster normalization, as in the present

study. This MRI study constitutes an independent, if

indirect, confirmation of the reference cluster method in

PD, since it demonstrated that the apparently

hyperperfused regions in GM normalized data were in fact

the only conserved regions, which is an essential

criterion for a valid normalization reference region.

This present finding of widespread reduction in relative

CBF matched that for CMRO2, but was somewhat less

extensive, perhaps reflecting a statistical advantage

imparted by having two CMRO2 scans but only one CBF scan

for each subject. This interpretation is supported by the

observation that a similar pattern was present in the CBF

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analysis, when the t-threshold was set at a less

stringent level (Figure 2C.) Moreover, very similar

patterns were seen in previously published CBF data of

early- and late-stage patients and in CMRglc data of

moderate- to late-stage PD patients (supplementary figure

1). The similarity of the CBF and CMRO2 patterns

reinforces the interpretation that decreased CMRO2 is

probably a real aspect of early PD, but that the decrease

is of low magnitude, thereby precluding its detection in

an analysis of non-normalized data with the small sample

sizes of studies to data.

Interestingly, the cortical pattern of decreased CMRO2 and

CMRglc in early PD resembles to a certain extent the

pattern of Lewy Body distribution in later disease-stages

of PD (35). This pathology is characterized by a

preferential involvement of medial and lateral prefrontal

and parieto-occipital cortices, along with the

characteristic sparing of primary and secondary sensory-

motor cortices. Since our PD patients were early-stage,

the present findings are in line with the hypothesis that

decreased activity of the ETC, manifesting as decreased

CMRO2, may be a forerunner for Lewy Body deposition in

cerebral cortex of PD patients. Another recent imaging

study reported decreased cholinergic innervation of the

cerebral cortex in early-stage PD patients (36). The

reported pattern seems to be similar to the patterns

presented in Figure 2, and raises the possibility that

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perturbations in cortical metabolism and cholinergic

innervation could be causally linked in early-stage PD,

or for that matter in Alzheimer’s dementia. We also note

that our earlier report of CMRO2 changes during deep brain

stimulation for treatment of PD revealed increases in

discrete cortical regions, rather than the expected

subcortical changes (19).

Limitations

The sample sizes of the present study were modest, which

raises the concern of limited statistical power. This

issue is discussed above. Another limitation is presented

by the use of differing methodology. The previous study

by Powers et al (6) utilized the three-step method, i.e.

three consecutive PET scans to obtain measurements of

CBF, cerebral blood volume (CBV), and an oxygen scan for

the final calculation of CMRO2 (37). This method is well

validated, but cumbersome, and assumes that a steady-

state is maintained during a scanning session lasting one

hour. The simplified single-scan Ohta method allows CMRO2

measurements using only one oxygen inhalation. However,

concerns have been raised about the lack of a constrained

CBV estimate, which might conceivably be different

between patients and control subjects (37). However, the

Ohta method was originally validated and compared against

the three-step method, and found to yield comparable

results in healthy subjects, at least (13). Indeed, the

Ohta method more faithfully described the dynamic brain

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tissue radioactivity concentration over the entire scan

interval than did the three-step method (13).

Additionally, Mintun and colleagues have themselves

subsequently implemented and used the Ohta method for the

measurement of CMRO2 under conditions of continuous visual

stimulation (38). While it remains possible that the

discrepancies between the present and some previous

findings (6) can be partly explained by differing

methodologies, it must be recalled that our findings are

in accordance with three other earlier CMRO2 studies of PD

patients, one of which employed the three-step Mintun

method (5), whereas the two other previous studies (3, 4)

used yet another method, the two-scan steady-state

procedure (39).

An additional limitation may be posed by our inclusion of

early stage PD patients, in whom the clinical diagnosis

was less clear. However, the present PET scans were

obtained in the years from 2005 to 2006 and we have

subsequently performed clinical follow-up examinations on

the five patients originally displaying the lowest UPDRS

scores (i.e. most uncertain diagnosis). In the online

Supplementary Table 2, we have added 25-45 months follow-

up clinical information. In the five years since PET

scanning, these patients have experienced significant

clinical deterioration and now receive higher doses of

anti-parkinsonian medication. All retain the original

diagnosis of idiopathic PD.

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Summary

The present study is the first voxel-based statistical

analysis of CMRO2 in PD. We demonstrated extensive

relative cortical decreases in CMRO2 in early PD patients,

when using a validated data-driven intensity

normalization approach. These findings agree with many

previous PD studies, in which matched widespread cortical

decreases in CBF and CMRglc were reported. Thus, the

present study suggests that cortical CMRO2, CBF, and

CMRglc all decline in a spatially similar pattern, and

that this decline is already established at early

disease-stages. While one recent PET study reported an

absolute 24% increase in global CMRO2 in early-stage PD

(6), which was proposed to be indicative of uncoupling of

ATP production from oxidation in early-stage PD patients,

the present study does not confirm that phenomenon in

early PD.

ACKNOWLEDGEMENTS

This work was supported by the Danish National Science

Foundation, Medical Research Council of Denmark, the

Lundbeck foundation and the Danish Parkinson Foundation.

DISCLOSURE

None stated.

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TABLES

Table 1. Clinical and demographic data of 9 PD patients and 15 controls.

Sex Age H&Y MMSE UPDRS-IIIPD

patients4F/5M

62.66

.01.30.4 29.10.7 11.56.1

Controls 8F/7M59.05

.528.21.2

All UPDRS-III and H&Y scores were obtained in the off medication state.

Table 2. Absolute CBF, CMRO2, and OEF values in VOI analysis.

GM WM Frontal Parietal

Temporal

Occipital

CBFControls 45.8±4.8 34.0±4.2 45.7±4.7 45.0±5.0 44.4±4.4 50.7±5.7

PD patients 46.0±7.9 35.8±5.9 46.2±8.4 44.4±9.4 45.0±7.4 48.8±10.0

CMRO2

Controls 142.9±12 114.4±11 142.7±14 152.0±10 143.7±14 141.6±11

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.6 .9 .6 .9 .2 .6

PD patients 141.7±11.6

118.6±9.8 142.1±13

.8147.6±11

.8141.6±10

.1140.8±9.

8OEF

Controls 34.7±4.5 37.3±6.0 35.2±4.7 36.1±5.4 36.2±5.3 34.2±4.8

PD patients 35.2±5.0 38.3±5.3 36.7±2.6 38.2±2.2 37.2±3.4 36.3±2.5

VOI data are displayed in absolute units of CBF (ml/100g/min) and CMRO2 (moles/100g/min). OEF is displayed in %. All values are mean±SD. [PD=Parkinson’s Disease, GM=Grey matter, WM=White matter.]

FIGURE LEGENDS

Figure 1. The reference cluster (red color) used in the CMRO2 analysis consisted mostly of white matter. All basal ganglia and thalamic structures were excluded, since animal evidence suggest thattrue hypermetabolism may be present in a few select structures (pallidum, ventro-lateral and ventro-anterior thalamic subnuclei).

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Figure 2. A. Output CMRO2 t-maps from the present voxel-based statistical analysis surface-projected onto an atlas brain in MNI space. Significant relative decreases were detected in lateral and medial prefrontal and parietooccipital cortices, and lateral temporalcortex. B-C. CBF t-maps displayed smaller clusters of significant cortical decreases, but generally in the same regions as CMRO2, whichis evident when the CBF maps were examined at a less significant threshold (C).

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Cerebral oxygen metabolism in patients with early Parkinson's disease

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