ORIGINAL ARTICLE

SPECT neuroimaging and neuropsychological functionsin different stages of Parkinson’s disease

Anna Paschali & Lambros Messinis &

Odysseas Kargiotis & Velissarios Lakiotis &

Zinovia Kefalopoulou & Costantinos Constantoyannis &

Panagiotis Papathanasopoulos & Pavlos Vassilakos

Received: 2 December 2009 /Accepted: 5 January 2010# Springer-Verlag 2010

AbstractPurpose The present study investigated differences andassociations between cortical perfusion, nigrostriatal dopa-mine pathway and neuropsychological functions in differ-ent stages of Parkinson’s disease (PD).Methods We recruited 53 non-demented PD patientsdivided into four groups according to the Hoehn and Yahr(HY) staging system and 20 healthy controls who wereused in the comparison of the neuropsychological findings.Each patient underwent two separate brain single photonemission computed tomography (SPECT) studies (perfu-sion and dopamine transporter binding) as well as neuro-psychological evaluation. Perfusion images of each patientwere quantified and compared with a normative databaseprovided by the NeuroGam software manufacturers. Meanvalues obtained from the cortical areas and neuropsycho-logical measures in the different groups were also comparedby analysis of covariance (ANCOVA) controlling fordisease duration and educational level.Results We found cognitive deficits especially in the latePD stages (HY 3, 4 and 5) compared to the early stages(HY 1 and 2) and associations between cognitive decre-

ments and cortical perfusion deterioration mainly in thefrontal and posterior cortical areas. Compared with con-trols, PD patients showed impairments of cognition andcerebral perfusion that increased with clinical severity.Furthermore, we found a significant correlation between theperformance on the phonemic fluency task and regionalcerebral blood flow (rCBF) in the left frontal lobe.Dopamine transporter binding in the left caudate nucleussignificantly correlated with blood flow in the left dorso-lateral prefrontal cortex (DLPFC), but not with measures ofexecutive functions.Conclusion There are significant cognitive and perfusiondeficits associated with PD progression, implying amultifactorial neurodegeneration process apart from dopa-mine depletion in the substantia nigra pars compacta (SNc).

Keywords Parkinson’s disease . Brain perfusion SPECT.

Dopamine transporter SPECT. Cognitive functions

Introduction

Parkinson’s disease (PD) is a chronic progressive neurode-generative disorder, characterized by motor and non-motorsigns. Most patients with PD experience some degree ofcognitive impairment, ranging from mild selective deficitsto global dementia [1]. Cognitive changes involve impair-ments mainly in executive functions (defined as the abilityto plan, organize and regulate goal-directed behaviour)present in the early stages, which progress to a dementiastate, called Parkinson’s disease dementia (PDD) during thelate stages of the disease. PD patients may also spendseveral years in a transition state called mild cognitiveimpairment (MCI). MCI is now recognized as one of thecardinal non-motor manifestations of PD. It is a major

A. Paschali (*) :V. Lakiotis : P. VassilakosDepartment of Nuclear Medicine,University of Patras Medical School,Patras, Greecee-mail: a_pashali@yahoo.gr

L. Messinis :O. Kargiotis : P. PapathanasopoulosDepartment of Neurology, Neuropsychology Section,University of Patras Medical School,Patras, Greece

Z. Kefalopoulou : C. ConstantoyannisDepartment of Neurosurgery,University of Patras Medical School,Patras, Greece

Eur J Nucl Med Mol ImagingDOI 10.1007/s00259-010-1381-9

cause of disability, and unlike the motor manifestations,there is currently no effective symptomatic treatment.Recent studies have reported a 21% prevalence rate ofMCI in a large PD population and consider MCI a riskfactor for developing PDD [2–4].

The neuropathophysiological basis in PD is complicatedand includes degeneration of dopaminergic neurons mainlyof the nigrostriatal pathway and, to a lesser degree, themesocortical and mesolimbic pathways. The striatum isclosely interrelated to cortical areas, mainly to the frontallobes. Modern models of basal ganglia/cortical physiologysuggest five adjacent but anatomically separate circuitswhere frontal cortical areas link with subcortical structureswithin the basal ganglia: motor, oculomotor, dorsolateralprefrontal, lateral orbitofrontal and anterior cingulate [5].

The most well-studied of these five circuits is the“motor’’ loop (striato-thalamo-cortical motor circuit).According to this model, dopamine deficiency in PD causesbasal ganglia dysfunction via excessive thalamic inhibitionof the primary motor cortex (PMC) and supplementarymotor area (SMA), resulting in bradykinesia and rigidity.

Other frontal/basal ganglia circuits originate from otherprefrontal structures and accordingly are predicted tosignificantly influence non-motor functions including cog-nition [6, 7]. The neuropathophysiological puzzle is furthercomplicated by multiple neurotransmitter deficits includingnoradrenaline, serotonin and acetylcholine pathway impair-ments as well as Lewy body-type degeneration in corticaland limbic structures [8].

It therefore appears that a multifactorial neurodegenera-tion process is involved in PD. A common expectation isthat alteration of dopaminergic and non-dopaminergicneurotransmission will be associated with changes inregional cerebral metabolism (rCMR) and regional cerebralblood flow (rCBF) in certain brain areas.

Perfusion brain single photon emission computed to-mography (SPECT) provides a well-established means ofstudying rCBF. On the other hand dopamine transporter(DAT) SPECT imaging can be used as a marker for thedegree of loss of dopaminergic nerve endings.

Numerous papers have addressed the issue of brainperfusion in PD with divergent results. Some papers havefocused on brain perfusion differences between PD patientswith and without dementia. These studies show a tendencytowards increased hypoperfusion in parietal and temporal lobesin PDD as compared to the non-demented PD groups [9–11].

Regarding PD patients with MCI there are conflictingresults in the literature ranging from either no differencecompared to controls [12, 13] or to hypoperfusion in theparietal [14] and frontal areas [15–17].

In the present study, we examined potential pathophys-iological changes in different stages of PD regarding thenigrostriatal pathway, cortical perfusion and neuropsycho-

logical functions. Our aim was to evaluate corticalperfusion changes in PD progression which is closelyrelated to the subcortical degeneration process and neuro-psychological functions. For this purpose each PD patientunderwent two separate brain SPECT studies (perfusion andDAT) as well as neuropsychological evaluation. We are notaware of any previous study that directly compared rCBFSPECT findings and associated neuropsychological func-tions in different stages of PD severity.

Materials and methods

Participants

A total of 53 patients referred to our tertiary care centre(Department of Neurology, University of Patras MedicalSchool, Greece) diagnosed with PD participated in thestudy. PD was defined according to the criteria of the UKParkinson’s Disease Brain Bank [18]. All PD patients werediagnosed by the same movement disorders specialist onthe basis of motor signs and responsiveness to levodopatherapy [40–80% improvement in Unified Parkinson’sDisease Rating Scale (UPDRS) III between “on” and“off” states]. Exclusion criteria were signs of Parkinson’splus syndromes, history of significant psychiatric distur-bance, stroke or severe head trauma and medication otherthan the one described below that could interfere withcognitive functioning of patients. We further excludeddemented PD patients according to DSM-IV-TR criteria[19], with a Mini-Mental State Examination (MMSE) scoreof ≤ 23 [20] and with a Clinical Dementia Rating score(CDR) of ≥1 [21]. Patients with dementia were alsoexcluded based on the Instrumental Activities of DailyLiving (IADL) Scale [22]. Depression level was assessedwith the Beck Depression Inventory Fast Screen (BDI-FS).We used this version of the scale in order to avoid theincrease in BDI (depression level) score usually associatedwith the somatic items in the original 21-item scale [23].All participants were native Greek speakers. The majorityof PD participants were right handed (n=52) and only onewas left handed. They were examined neurologically withthe assessment of stage and severity of PD [Hoehn andYahr (HY) scale, UPDRS]. Participants were divided intofour groups according to the HY scale (see Table 1). Thecontrol group (n=20) used in the comparison of theneuropsychological findings was composed of healthyindividuals regarding neurological, psychiatric or othermedical conditions known to affect cognition. Theseindividuals were also assessed for substance abuse or anymedication usage that could influence cognitive perfor-mance. They had normal (or corrected by visual aids)vision and hearing functions or had no visual or auditory

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deficits. There were 11 (55%) women and 9 (45%) men.Their mean age (SD) was 60.5 (1.6) and mean educationallevel (SD) 11.20 (24).

During all assessments patients were “on” standard PDmedication. Furthermore, ten PD patients were on antide-pressant medication [selective serotonin reuptake inhibitors(SSRIs) or selective norepinephrine reuptake inhibitors(SNRIs)], five on anticholinergics and four on neuroleptics.Patients receiving anticholinergics and neuroleptics wereasked to temporarily discontinue treatment at least 24 h priorto evaluation, therefore eliminating possible effects onoutcome measures. Regarding DaTSCAN imaging, nopatient was taking any medication known to interfere withthe FP-CIT. Informed consent was obtained from eachpatient. The study was approved by the regional EthicsCommittee at the University of Patras Medical School, andwritten informed consent was obtained from all participants.

Neuropsychological assessment

A neuropsychological test battery was administered to allparticipants according to standard procedures in a singlesession in order to assess cognitive functions known to beaffected in PD. Cognitive functions assessed and neuropsy-chological tests administered included the following: verballearning and memory: Rey Auditory Verbal Learning Test(RAVLT) [24] total learning (trials 1–5) and delayed recalltrial, visual learning and memory: figure copy test of theRepeatable Battery for the Assessment of Neuropsycholog-ical Status (RBANS) [25] copy and delayed recall trial,visuospatial perception: line orientation test (LOT) of theRBANS [25] and executive functions and verbal fluency:the Greek verbal fluency task: semantic and phonologicalfluency [26]. Neuropsychological testing was performed by

an experienced clinical neuropsychologist (LM) who wasblind to the neuroimaging results.

rCBF SPECT

rCBF SPECT scanning was performed 30 min followingintravenous injection of 555 MBq 99mTc-ethyl cysteinatedimer (ECD, Neurolite, Bristol-Myers Squibb Pharma,Brussels, Belgium). While lying supine with eyes closed ina dimly lit, quiet room, each subject received an intravenousinjection of 555 MBq of 99mTc-ECD. Brain SPECT wasperformed with a dual-head gamma camera (MillenniumVG, General Electric Medical System, Milwaukee, WI,USA) equipped with a low-energy and high-resolutionparallel-hole collimator. The head of each patient was heldwith fixation strips attached to a specially constructed carbonfibre head holder, which allowed the camera detector torotate very close to the head. The data were collected into a128×128 matrix, through 360° rotation at steps of 3° for 20s per view. Filtered backprojection using a Butterworth andRamp filter was used for SPECT image reconstruction.Attenuation correction based on Chang’s method [27] wasperformed on each slice, with a uniform attenuationcoefficient of 0.11.

rCBF SPECT image analysis using NeuroGam

Each perfusion brain SPECT study was quantified andcompared to an age- and gender-matched normal databaseusing NeuroGam™ Software package (GE Medical Sys-tems, Segami Corporation, Columbia, MD, USA). Thissoftware applies an affine anatomical coregistration byblocks of data defined in the Talairach space. We reorientedeach study according to the three-dimensional volume of

Table 1 Demographic and clinical characteristics of PD patients according to HY stages (n=53)

Variables Total PD PD group 1 (HY 1) PD group 2 (HY 2) PD group 3 (HY 3) PD group 4 (HY 4/5)

Number 53 9 10 19 15

Sex (M/F) 27/26 2/7 6/4 12/7 7/8

Mean age (±SD) 62.5 (±8.9) 58.1 (±10) 63.7 (±10.5) 63 (±8) 63.8 (±8.1)

Mean educationallevel (±SD)

11.05 (3.60) 12.67 (3.47) 10.20 (2.45) 11.63 (2.95) 10.93 (3.50)

Mean diseaseduration (±SD)

9.6 (±5.6) 2.6 (±2.1) 6.2 (±2.9) 9.8 (±3.7) 15.6 (±3.7)

Mean motor UPDRSscore (part III)(±SD)

15.6 (±8.7) 4.0 (±1.8) 9.2 (±3.4) 16.3 (±3.9) 26.0 (±4.6)

Mean MMSE score(±SD)

25.4 (±2.9) 27.6 (±2.3) 26.3 (±1.4) 25.5 (±2.1) 24.6 (±2.0)

Medication (meanL-dopa dosage)

L-dopa 700 mg +dopamine receptoragonist

L-dopa 400 mg +dopamine receptoragonist

L-dopa 600 mg +dopamine receptoragonist

L-dopa 800 mg +dopamine receptoragonist

L-dopa 850 mg +dopamine receptoragonist

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the brain defining a line that fits the inferior pole of theoccipital lobe and the inferior edge of the frontal lobe. Wecorrected raw data for lateral deviations and defined thevertical anterior commissure line (AC) and the posteriorcommissure line (PC). With this information, the Talairachtechnique rendered the brain volume into a normalizedvolume (according to the mean cerebellum rCBF value) andtherefore allowed a voxel by voxel comparison of the ECDuptake in the brain cortex with a normal database ofsubjects also corrected volumetrically.

In order to define with high reproducibility the exactlocalization of areas of hypoperfusion, we used for thesemiquantitative analysis a predefined anatomical andBrodmann’s area (Br) template. We investigated right andleft frontal lobes and more specifically the right and leftPMC (Br 4) and SMA (Br 6), right and left prefrontal areas(dorsolateral prefrontal cortex, frontopolar and orbitofrontalarea; Br 8, 9, 10) and right and left anterior cingulatecortex (Br 24, 32). We also investigated the parietal andtemporal lobes. Perfusion values of Brodmann’s areasfor each patient are expressed by means of standarddeviation from the values of the normal database (ageand gender adjusted) (Table 2). Abnormal areas weredefined as those with decreased uptake (below 2 standard

deviations of the normal mean uptake per area >50%pixels). For between-group comparisons we used the meanvalues of perfusion for each cortical area under study.Image analysis was performed by an experienced nuclearmedicine physician who was blind to the results ofneuropsychological testing.

DaTSCAN SPECT and image analysis

123I-fluoropropyl carbomethoxy iodophenyl nortropane (123I-FP-CIT DaTSCAN, GE Healthcare, Amersham, UK), aniodinated cocaine derivate, is a SPECT marker of DATlocated on dendritic and axonal plasma membranes ofpresynaptic dopaminergic neurons. Participants were injectedwith 185 MBq of 123I-FP-CIT following thyroid blocking(perchlorate 1 g, orally) and were scanned 4 h after injectionof 123I-FP-CIT. Brain SPECT was performed with a dual-head gamma camera (Millennium VG, General ElectricMedical System, Milwaukee, WI, USA) equipped with alow-energy and high-resolution parallel-hole collimator. Thedata were collected into a 128×128 matrix, through 360°rotation at steps of 3° for 35 s per view. Filtered back-projection using a Butterworth and Ramp filter was used forSPECT image reconstruction. Attenuation correction based

Table 2 Mean values (± standard deviation) of perfusion in cortical areas (Brodmann areas) in PD patients (n=53)

Group 1 (HY 1) Group 2 (HY 2) Group 3 (HY 3) Group 4 (HY 4/5)n=9 n=10 n=19 n=15Mean (±SD) Mean (±SD) Mean (±SD) Mean (±SD) F (df) p

Areas

FLL −1.07±0.41 −1.22±0.63 −1.82±0.34a −2.54±0.55a, b, c 20.645 (3.49) .001

FLR −1.17±0.46 −1.36±0.52 −1.63±0.44 −2.38±0.44a, b, c 14.919 (3.49) .001

PMC & SMA L (Br 4, 6) −1.12±0.60 −1.38±0.46 −1.83±0.42 −2.60±0.57a, b, c 19.601 (3.49) .001

PMC & SMA R (Br 4, 6) −1.31±0.62 −1.63±0.46 −1.71±0.47 −2.24±0.31a 6.967 (3.49) .001

PFLL (8, 9, 10) −1.69±0.66 −1.86±0.65 −2.19±0.34 −2.71±0.48a, b 9.524 (3.49) .001

PFLR (8, 9, 10) −1.72±0.56 −1.87±0.54 −2.13±0.20 −2.41±0.37a 5.919 (3.49) .002

ACC L (24, 32) −1.11±0.54 −1.30±0.48 −1.80±0.42 −2.32±0.59a, b 13.626 (3.49) .001

ACC R (24, 32) −1.21±0.49 −1.43±0.49 −1.59±0.48 −2.09±0.57a 6.481 (3.49) .001

LDLPFC L (9, 45, 46) −1.16±0.50 −1.34±0.58 −1.90±0.52 −2.60±0.60a, b, c 16.429 (3.49) .001

LDLPFC R (9, 45, 46) −0.99±0.14 −1.04±0.16 −1.34±0.49 −2.09±0.65a, b, c 14.927 (3.49) .001

PLL −0.78±0.34 −0.96±0.11 −1.78±0.52a, b −2.28±0.28a, b, c 36.028 (3.49) .001

PLR −0.93±0.29 −0.88±0.38 −1.64±0.55b −2.09±0.21a, b 15.564 (3.49) .001

TLL −0.86±0.41 −1.36±0.51 −1.76±0.45a −2.0±0.39a 11.123 (3.49) .001

TLR −0.92±0.57 −1.10±0.37 −1.42±0.41 −2.20±0.35a, b, c 17.531 (3.49) .001

FLL frontal lobe left, FLR frontal lobe right, PMC primary motor cortex, SMA supplementary motor area, PFLL prefrontal lobe left, PFLRprefrontal lobe right, ACCL anterior cingulate cortex left, ACCR anterior cingulate cortex right, LDLPFC L lateral dorsolateral prefrontal cortexleft, LDLPFC R lateral dorsolateral prefrontal cortex right, PLL parietal lobe left, PLR parietal lobe right, TLL temporal lobe left, TLR temporallobe righta p≤ .001 compared with PD group 1b p≤ .001 compared with PD group 2c p≤ .001 compared with PD group 3

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on Chang’s method [27] was performed on each slice, with auniform attenuation coefficient of 0.15 to minimize signalalterations from variably deep brain structures. SPECTanalysis was performed semiquantitatively using neuroana-tomical regions of interests (ROIs). ROIs for the head of thecaudate nuclei, putamen and occipital cortex were manuallydefined in transversal slices. The occipital cortex was chosenas a reference because 123I-FP-CIT uptake in the occipitalcortex is absent (or low). Uni- and bilateral count densityratios were calculated between striatum/occipital cortex, head(s) of the caudate nucleus/occipital cortex as well as betweenputamen/occipital cortex (Table 3).

Statistical analysis

We initially calculated the proportion of impaired patientson perfusion brain SPECT rCBF scanning, using ascriterion for impairment 2 standard deviations below anage- and sex-adjusted normative rCBF SPECT database,provided by the manufacturers. We then calculated the ratioof the total DAT striatum binding to the non-specificbinding in the ROI area of the occipital lobe for eachrespective patient. We also calculated the mean value of thisratio for each specific PD group according to HY stage. Inorder to examine the contribution of disease duration, age atonset, educational level, mood status (BDI-FS total score),UPDRS motor score and L-dopa dose we conducted a linearregression analysis. The analysis revealed that diseaseduration and educational level contributed significantly tothe outcome measures. Therefore these variables werecontrolled for in all further analyses. Mean values obtainedin the Brodmann areas and on neuropsychological measuresin the different groups of PD patients according to HYstage were then compared by analysis of covariance(ANCOVA) controlling for disease duration and education-al level. Correlations between neuropsychological measuresand rCBF and DAT SPECT were also performed withSpearman’s rank correlation or Pearson’s correlation coef-ficient, as appropriate. To control for multiple comparison

bias over the various relationships tested for each cognitivevariable, statistical significance was judged against a per-comparison alpha of 0.005.

Results

rCBF and DAT SPECT within group analysis

Within group comparisons with the normative perfusiondatabase revealed that five of nine (55%) HY stage 1 PDpatients presented with significant hypoperfusion in theprefrontal lobes bilaterally [dorsolateral prefrontal cortex(DLPFC); Br 9 and orbitofrontal cortex; Br 10] and twopatients (22%) presented significant hypoperfusion in theright PMC and SMA (see Fig. 1). The mean (SD) of thetotal striatum to the occipital lobe ratio was 2.26 (±0.47).The within group comparison of group 2 (HY stage 2 PDpatients) also revealed that five patients (50%) hadsignificant hypoperfusion in the right PMC and SMA andseven patients (70%) presented significant hypoperfusion inthe prefrontal lobes bilaterally (DLPFC; Br 9 and orbito-frontal cortex; Br 10) (see Fig. 2). The mean value of thetotal striatum to occipital lobe ratio was 1.85 (±0.39). Ingroup 3 (HY stage 3 PD patients) all 19 patients (100%)showed significant hypoperfusion in the prefrontal lobesbilaterally (DLPFC; Br 9 L, R and orbitofrontal cortex; Br10 L, R). Of the 19 patients, 14 (74%) showed significanthypoperfusion in the left PMC & SMA (Br 4, 6 L), in theleft lateral DLPFC (Br 9, 45, 46 L), left anterior cingulatecortex (Br 24, 32 L) and in the parietal lobes bilaterally. Ofthe 19 patients, 8 (42%) showed significant hypoperfusionin the right PMC & SMA and in the right anterior cingulatecortex (Br 24, 32 R) (see Fig. 3). The mean value of thetotal striatum to occipital lobe ratio was 1.42 (±0.21). Ingroup 4 (HY PD stages 4 and 5) most patients presentedwith significant hypoperfusion in the investigated corticalareas (see “rCBF SPECT image analysis using NeuroGam”for areas investigated) (see Fig. 4). There were 5 of 15

Table 3 DAT specific/non-specific ratios for each neuroanatomical ROI and each respective group of PD patients

Group 1 Group 2 Group 3 Group 4

SOR 2.26 (±0.47) 1.85 (±0.39) 1.42 (±0.21) 1.03 (±0.28)

CLOR 2.52 (±0.52) 2.09 (±0.51) 1.48 (±0.27) 1.04 (±0.34)

CROR 2.50 (±0.55) 2.06 (±0.45) 1.53 (±0.25) 1.09 (±0.37)

PLOR 2.05 (±0.47) 1.50 (±0.30) 1.30 (±0.19) 0.95 (±0.19)

PROR 1.98 (±0.42) 1.64 (±0.37) 1.35 (0.18) 1.00 (±0.25)

PD group 1 = HY stage 1, PD group 2 = HY stage 2, PD group 3 = HY stage 3, PD group 4 = HY stages 4 and 5

SOR striatal to occipital ratio, CLOR caudate left to occipital ratio, CROR caudate right to occipital ratio, PLOR putamen left to occipital ratio,PROR putamen right to occipital ratio

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patients who presented with normal perfusion in the rightlateral DLPFC, the left temporal lobe and the right anteriorcingulate cortex, whereas two patients showed normalperfusion in the right parietal and temporal lobe. Onepatient showed normal perfusion in the right frontal lobeand anterior cingulate cortex left. The mean value of thetotal striatum to occipital lobe ratio was 1.03 (±0.28).

We further found positive correlations between DATbinding in the left caudate and rCBF in the left DLPFC(r=.75, p<.001) and DAT binding in the left putamen withrCBF in the left PMC and SMA (r=.69, p<.001). We alsofound a negative correlation between the UPDRS motorscore and rCBF in the left PMC and SMA (r=−.606,p<.001).

rCBF SPECT between group comparisons

Between group comparisons revealed significant differ-ences regarding rCBF in various cortical areas (see Table 2).

Specifically, group 4 significantly differed from group 1 inall cortical areas under investigation (p<.005). Groups 2and 4 significantly differed in all cortical areas under study(p<.001) except from the right primary and supplementarymotor cortex, right anterior cingulate cortex, right prefrontalcortex and left temporal lobe. Groups 1 and 2 did not differsignificantly. Groups 1 and 3 differed significantly in theleft frontal, left parietal and left temporal lobe. Groups 2and 3 significantly differed in the left parietal lobe (p<.001)and right parietal lobe (p=.003). Groups 3 and 4 signifi-cantly differed in the frontal lobes bilaterally (p<.001), inthe left PMC and SMA (p<.001) and in the left and rightlateral DLPFC (p≤ .005),, in the left parietal lobe (p=.005)and right temporal lobe (p<.001).

Neuropsychological performance

Initial analyses regarding demographic and clinical charac-teristics between groups revealed that the PD patients in

Fig. 1 Example of DAT and brain perfusion of a PD patient HY stage1 compared with the normal database. Note: Perfusion brain maps aredisplayed on a 3-D anatomical topographic representation by means of

a specific colour scale (standard deviation from a normal age- and sex-matched database). In the current case there is hypoperfusion in theDLPFC bilaterally and in the SMA right. The SOR ratio=2.37

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group 3 (HY stage 3) differed significantly (higher level ofdepression, see Table 4) from the control group assessed forcognition. However, the PD groups (according to HYstaging) did not differ significantly on depression levels.

Regarding neuropsychological performance on the se-mantic fluency task we found significant differencesbetween PD patients in HY stages 1 and 3 (p=.003) andPD HY stages 1 and 4 (p=.004). Phonemic fluency alsoshowed significant differences between PD patients in HYstages 1 and 3 (p=.004) and PD HY stages 1 and 4(p=.005). All PD groups also differed significantly fromthe controls on both semantic and phonological fluency.Comparisons of verbal learning ability revealed differencesonly between PD patients in HY stages 1 and 4 (p=.003),i.e. HY stage 1 patients had a better verbal learning curvethan more advanced PD patients. There was also a

significant difference between PD patients in groups 3(p=.002) and 4 (p=.004) and the control group in totalverbal learning capacity. Ability to recall previously learnedverbal information (delayed recall) also differed betweenPD patients in HY stages 1 and 3 (p=.003) and HY stages 1and 4 (p=.004). It appears from this finding that althoughpatients in all stages are initially able to encode newverbal information the ability to later recall this informa-tion is substantially reduced with severity of PD. Thecontrol group also differed significantly from PD groups3 (p=.002) and 4 (p=.002), indicating differences in laterstage PD patients to recall information after a delayedperiod compared to age- and education-adjusted normalparticipants.

Further, on the RBANS figure copy delayed recall task,there were significant differences between PD patients in

Fig. 2 Example of DAT and brain perfusion of a PD patient HY stage2 compared with the normal database. Note: Perfusion brain maps aredisplayed on a 3-D anatomical topographic representation by means ofa specific colour scale (standard deviation from a normal age- and sex-

matched database). In the current case there is hypoperfusion inprefrontal lobes bilaterally, in anterior cingulate cortex bilaterally andin PMC & SMA right. The SOR ratio=2.12

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HY stages 1 and 3 (p=.004) and HY stages 1 and 4 (p=.005).This finding implies that visually learned informationappears intact as far as initial encoding is concerned betweenPD stages; however, delayed recall (retrieval of visuallylearned information) appears to be significantly differentbetween the earlier and more advanced stages in the PDprocess. Finally, on the LOT, pairwise comparison revealeddifferences between PD patients in HY stages 1 and 4(p=.004). This finding indicates that visual spatial orienta-tion is relatively intact in the earlier stages of PD comparedto the more severe and debilitating stages of PD. Further-more, PD patients in all stages appear to have poorervisuospatial perception abilities compared to age- andeducation-adjusted normal participants.

We further conducted partial correlations controlling fordisease duration and educational level on the total group ofPD patients and found a positive significant correlationbetween blood flow in the left frontal lobe and thephonemic fluency task (r=.75, p<.001) (see Fig. 5).However, the ratio of specific to non-specific binding in

the caudate total (left and right) did not show significantcorrelations with a measure of executive functioning foreither the semantic fluency task (r=.015, p=.917) or thephonemic fluency task (r=-.161, p=.250).

Discussion

PD is associated with abnormal activity in spatiallydistributed neural systems, mediating the motor andcognitive manifestations of the disorder. In the presentstudy we assessed brain perfusion, DAT binding andneuropsychological functions in different stages of PDprogression. DAT SPECT was used to quantify the primaryneurochemical lesion in PD and rCBF SPECT was used toprovide unique information regarding the topography ofmetabolic and perfusion changes in the brains of PDpatients.

We initially compared perfusion brain SPECT images ofeach patient with an age- and gender-matched normal

Fig. 3 Example of DAT and brain perfusion of a PD patient HY stage3 compared with the normal database. Note: Perfusion brain maps aredisplayed on a 3-D anatomical topographic representation by means ofa specific colour scale (standard deviation from a normal age- and sex-

matched database). In the current case there is hypoperfusion in leftfrontal lobe, in right prefrontal lobe and in parietal lobes bilaterally.The SOR ratio=1.34

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database using the NeuroGam software. The within groupanalysis showed that even in the first stages of the diseasethere were perfusion decrements in 55% of the patients inthe prefrontal lobes bilaterally and in 22% in the rightmotor and supplementary motor cortex area. This percent-age increased in stage 2 of the disease to 70 and 50%,respectively. Our results are in agreement with observationsthat point towards the hypothesis that the cerebral cortexand, particularly, the frontal cortex are affected at therelatively early stages of the disease [28]. In stage 3 ofthe disease, all of the patients showed hypoperfusion in theprefrontal lobes and 73% in the parietal lobes bilaterally. Inthe late stages of the disease (4 and 5) most of the patientspresented hypoperfusion in all cortical areas. From thesefindings we could suggest a possible perfusion profile inPD progression that seems to implicate, at least in part,hypoperfusion in the prefrontal lobes, in the motor andsupplementary motor cortex areas in HY stages 1and 2,which progresses to affect the frontal and parietal lobes in

stage 3. In the late stages of the disease (4 and 5) thehypoperfusion seems to extend to almost all cortical areas.This profile could possibly be explained by the earlydisruption of the frontal–subcortical (frontostriatal) circuitsin PD [29] and can further be enhanced by the presence ofmultiple neurotransmitter deficits as well as Lewy body-type depositions in cortical and limbic structures in the latestages of the disease [8, 30, 31].

Regarding neuropsychological performance, patients in theearly stages of the disease (1 and 2) significantly differed fromcontrols on both semantic and phonological fluency andvisuospatial perception abilities. That is in agreement with thenotion of cognitive dysfunction early in the course of PD [32].Patients in later stages (3, 4 and 5) significantly differed fromcontrols in all tests (semantic and phonological fluency,verbal and visual delayed recall and visuospatial perceptionabilities). Our results therefore provide evidence that non-demented PD patients show impairments in executivefunctions and achieve automaticity with difficulty [33].

Fig. 4 Example of DAT and brain perfusion of a PD patient HY stage5 compared with the normal database. Note: Perfusion brain maps aredisplayed on a 3-D anatomical topographic representation by means of

a specific colour scale (standard deviation from a normal age- and sex-matched database). In the current case there is hypoperfusion in allcortical areas. The SOR ratio=1.10

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Between group comparisons as regards rCBF andneuropsychological measurements were performed control-ling for disease duration and educational level, which werefound to contribute significantly to the outcome measures.A critical point in our study is that the PD groups did not

differ significantly on depression levels that could interferewith the results. As detailed above we did not findsignificant differences on rCBF and neuropsychologicalmeasurements between stages 1 and 2, but there weresignificant differences between the late stages of the disease(4 and 5) and the earlier stages (1 and 2). Especially theperformance on semantic and phonemic fluency signifi-cantly differed between stages 1 and 3, 4/5 and phonemicfluency correlated significantly with blood flow on the leftfrontal lobe. Furthermore, we found significant differ-entiations on verbal learning ability and ability to recallpreviously learned verbal or visual information (delayedrecall) between stages 1 and 3, 4/5. These cognitivefunctions mainly implicate areas of the left frontal lobe,parietal association cortex and temporal association cortex[34]. On visuospatial perception abilities there weresignificant differences between stages 1 and 4/5, whichcould be explained by the perfusion differences describedin frontal and parietal areas. Our results are thereforeindicative of cognitive deterioration in the late stages of thedisease compared to the early stages and are associated withcortical perfusion deterioration mainly in the frontal andposterior cortical areas.

Noteworthy, we found significant deterioration in theperfusion of the parietal lobes bilaterally in stage 3

Table 4 Neuropsychological performance of PD patients according to HY stage and normal controls matched for age and educational level: mean(SD)

Variable PD group 1 (n=9)

PD group 2 (n=10)

PD group 3 (n=19)

PD group 4/5 (n=15)

Control group (n=20)

Verbal memory and learning

RAVLT

Total learning (trials 1–5)b 36.50 (3.25) 35.60 (2.55) 33.60 (2.80) 31.65 (3.80) 40.55 (4.30)d

Delayed recall triala, b 6.8 (1.45) 6.2 (1.80) 5.2 (2.25) 4.8 (2.30) 7.9 (1.8)d

Visual memory and learning

RBANS

Figure copy 17.10 (1.50) 16.85 (1.80) 16.20 (1.65) 15.90 (2.30) 17.20 (1.35)

Delayed recall triala, b 12.55 (2.65) 12.20 (2.80) 10.50 (3.55) 10.10 (4.20) 13.5 (1.60)e

Visuospatial perception

RBANS

LOTb 14.50 (2.60) 13.60 (2.80) 12.80 (1.95) 10.30 (2.90) 17.50 (2.50)e

Executive functions and verbalfluencyGreek verbal fluency task

Semantic fluencya, b 25.30 (3.95) 22.40 (2.85) 19.50 (4.75) 15.80 (4.50) 38.60 (2.80)e

Phonemic fluencya, b 18.35 (2.25) 16.80 (3.60) 13.60 (4.20) 10.20 (3.50) 23.50 (1.90)e

Depression level

BDI-FS 5.85 (3.87) 5.20 (3.22) 6.10 (3.27) 5.80 (1.50) 4.90 (2.50)c

PD group 1 = HY stage 1, PD group 2 = HY stage 2, PD group 3 = HY stage 3, PD group 4 = HY stage 4 and 5, control group = normal controlsmatched for age and educational level to the PD groups

Note: Significant at the p≤ .005 level, all other comparisons were not significantly different.

Significant differences: a group 1 vs group 3, b group 1 vs group 4, c group 3 vs control, d group 3 and vs control, e all groups vs control

Fig. 5 Correlation between phonological verbal fluency and rCBF infrontal lobe left (% normalized value)

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compared to stage 2, which might explain the impairmentsin equilibrium on walking or standing in stage 3 of thedisease.

Disruption of the frontal–subcortical (frontostriatal) cir-cuits in PD is the most likely cause of frontal hypoperfusionand cognitive changes in PD. Disruption in the dorsolateralprefrontal circuit can result in deficits in executive function,memory retrieval and alterations in verbal and non-verbalfluency. The dorsolateral prefrontal circuits can be disruptedearly in PD; thus, even early PD patients often havedifficulties with maintaining sets, planning and retrievingmemories [29].

Furthermore, neuropathological investigations of post-mortem PD brains demonstrate neurodegeneration beyondsubstantia nigra pars compacta (SNpc) dopaminergicneuronal loss. To a lesser degree dopaminergic neurons inthe ventral tegmental area (VTA) are also affected in PD.These neurons directly project from VTA to cortical andlimbic areas. Outside the SNpc, another predominant areaof primary neuronal loss in PD is the catecholaminergicneurons of locus ceruleus, the cholinergic neurons of thenucleus basalis of Meynert and the serotoninergic neuronsof the raphe nuclei [35]. Non-dopaminergic neuronal losshas been associated with an increased incidence ofcognitive impairment and dementia in PD [36, 37].

The pathophysiology of cognition in PD has also beeninvestigated by positron emission tomography (PET)studies which demonstrate that cognitive deterioration isassociated mainly with prefrontal and posterior corticaldysfunction [38, 39].

The aspect of between group comparisons in PD, asregards brain perfusion, has been addressed in a few papers.In a previous study, Kikuchi et al. compared rCBF usingHMPAO SPECT in PD patients between stages 1/2 (7patients) and 3/4 (11 patients). They found that the DLPFCand insular cortex significantly differentiated between thetwo groups posing that the DLPFC or insular cortex may beresponsible for the impairments specifically observed inadvanced stages of PD, such as impaired working memory,postural instability or autonomic dysfunction. They alsofound a significant correlation between the rCBF decre-ments in the DLPFC or the insular cortex and the clinicalstaging of Hoehn and Yahr [40].

In our study we adhered to a strict classification of ourPD patients according to the HYahr staging system and wealso included neuropsychological testing for each patient.There are some common findings that concern areas of theleft frontal lobe and especially the DLPFC area as regardssignificant differentiations between early and late stages ofthe disease. We also found a significant correlation betweenthe UPDRS part III and rCBF in the left PMC and SMA,which implies that as rCBF is reduced in the left motorcortical area the motor disability scale of UPDRS increases.

In another ECD SPECT study using SPM, Imon et al.compared PD patients between stages 1/2 (n=16) and 3/4(n=12) with healthy volunteers. They found a diffusedecrease in absolute rCBF in the whole brain with sparingof the central grey matter, hippocampus and right lowertemporal lobe in stages 1/2 compared with healthyvolunteers. In patients with stage 3 or 4 of the disease,rCBF decreased throughout the whole brain [41].

Although this model of “between group comparison’’does not exactly follow the physical course of PD, there area few longitudinal studies that describe perfusion andmetabolic decrements in the prefrontal and parietal associ-ation cortex areas in PD progression in accordance to PD-related cognitive pattern (PDCP) [16, 42].

As regards DAT binding we found positive correlationsbetween the left caudate and rCBF in the left DLPFC, aswell as between the left putamen and the left rCBF in thePMC and SMA. This is in agreement with the parallelorganization circuits linking the basal ganglia and cortex[43]. Furthermore, examination of striatal anatomical andfunctional connections using the method of diffusion tensorimaging (DTI) and PET broadly supports the parallel loopmodel of striatal organization [44, 45].

In spite of the evidence suggesting involvement ofdopamine in cognitive functions in PD [46–48], we didnot find significant correlations between the ratio ofspecific to non-specific binding in the caudate total (leftand right) or total striatum with the measures of executivefunctioning (semantic fluency task or phonemic fluencytask). This is in agreement with a PET study in medicatedPD patients where there was no significant associationbetween the degree of overall cognitive impairment and[18F]fluorodopa uptake values in the striatum, but there wasa positive correlation between performance in the verbalfluency task and [18F]fluorodopa uptake in the frontalcortex [49]. 123I-FP-CIT SPECT does not allow measure-ment of mesocortical dopamine neurons that also contributeto cognitive function. Furthermore, it is quite clear thatcognitive impairment in PD can be more generalizedinvolving several brain areas and neurotransmitter systems.

Since all SPECT studies and neuropsychological evalua-tions were performed in the ‘’on’’ L-dopa condition, thepotential effects should be discussed. The results of 123I-FP-CIT SPECT are not influenced by treatment with L-dopaand dopaminergic drugs [50]. No global rCBF changeswere reported in the case of chronic L-dopa administration[51], while a focal rCBF increase in basal ganglia wasreported following the acute administration of L-dopa [52].Cognitive symptoms, especially those thought to be relatedto frontal lobe functioning, are alleviated by levodopa in theearly phase of the disease [53, 54]. Moreover, in patientsalready on levodopa therapy, temporary cessation ofmedication led to impairment on tests sensitive to frontal

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lobe functions [55]. On the other hand, even negativeeffects of levodopa on cognitive function in PD have beenreported [53, 56]. Therefore, the effect of dopaminergictherapy in PD may be beneficial for some cognitivebehaviours while being detrimental for others, but ingeneral these deficits are usually not found to improvewith dopaminergic treatment [57, 58].

Despite the efforts to control potential confounds onoutcome measures, there are some minor limitations in thisstudy, which need to be referred to. For the semiquantitativeanalysis of brain perfusion SPECT data, a range of softwaretools, following a similar workflow and processing algo-rithm, have been developed. The most widely used softwareis Statistical Parametric Mapping (SPM) (www.fil.ion.ucl.ac.uk/spm/) and is recognized as the reference technique,although it requires some resources (technical and human)not available in many sites. In our study, SPECT imageswere elaborated by the NeuroGam software, which is oneof the statistical analysis methods for automated diagnosisof brain perfusion SPECT images and can be used toinvestigate the rCBF objectively and easily. Manufacturersoffer an age-matched database of healthy subjects, volu-metrically corrected, and allow for statistical voxel-basedcomparisons of an individual SPECT study with thisdatabase. There is only one study that compared these twosoftware packages (SPM and NeuroGam) in diagnosingdementia. The measurements under the receiver-operatingcharacteristic (ROC) curve demonstrated that none of thetwo added a definitive diagnostic improvement to theexperts. However, for the non-experts the contribution ofSPM was lower than that of NeuroGam [59].

An additional confounding factor in our study was thatboth anticholinergics and clozapine which also has anti-cholinergic properties are bound to reduce performance inmany cognitive tasks. However, patients receiving anti-cholinergics and neuroleptics were asked to temporarilydiscontinue treatment at least 24 h prior to assessment.Further, the inclusion of a healthy demographicallymatched control group used in the between group compar-isons potentially reduces this limitation.

Another potential limitation is that we excluded patientswith dementia, so our results cannot be generalized to PDDpatients, normally in the late stages of disease progression.

In conclusion, as dopaminergic nerve endings degeneratein PD there is progressive cortical hypoperfusion affectingmainly the frontal lobes in the early stages, extending to theparietal and temporal lobes in the late stages of the disease.In parallel, neuropsychological performance graduallydeteriorates as the disease progresses. The findings of thisstudy support the multifactorial degeneration process in PD,as the degeneration of the nigrostriatal pathway ofdopamine alone cannot explain the perfusion and cognitivedeficits in PD progression.

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