Parkinsonism and Related Disorders 14 (2008) 224–228 Striatal FDOPA uptake and cognition in advanced non-demented Parkinson’s disease: A clinical and FDOPA-PET study Marije van Beilena,b,Ã, Axel T. Portmana, Henk A.L. Kiersc, Ralph P. Maguirea,b, Valtteri Kaasinena, Marthe Koninga, Jan Pruimb,d, Klaus L. Leendersa,b aDepartment of Neurology, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands bSchool for Behavioral and Cognitive Neurosciences (BCN), University Medical Center, Groningen, The Netherlands cHeymans Institute, University of Groningen, The Netherlands dPET Center, University Medical Center Groningen, University of Groningen, The Netherlands Received 30 January 2007; received in revised form 18 July 2007; accepted 14 August 2007 This study sought to determine the nature of the relationship between cognition and striatal dopaminergic functioning in 28 patients with advanced Parkinson’s disease (PD) using fluorodopa Positron emission tomography (FDOPA-PET) and neuropsychological testscores. Mental flexibility was related to putamen activity while mental organization (executive memory and fluency) was related tocaudate FDOPA uptake. Interestingly, the caudate may be more important in the mental components of executive functioning, while theputamen may be more important in the motor components of executive functioning.
r 2007 Elsevier Ltd. All rights reserved.
Keywords: Parkinson; Cognition; Striatum; FDOPA-PET components of memory performance are disturbed, while thenon-executive storage components are relatively intact.
Idiopathic Parkinson’s disease (PD) is a neurodegenera- A possible explanation for the cognitive deficits can be tive disorder of unknown etiology, characterized by found in the striatal connections with the frontal lobes .
progressive loss of dopaminergic neurons in the nigros- Positron emission tomography (PET), using the radiotracer triatal pathway PD is clinically featured by its motor 6-L (18F)-fluorodopa (FDOPA), provides a means of symptoms consisting of an insidious (asymmetric) onset of quantifying the loss of striatal dopaminergic terminal bradykinesia, rigidity and (rest) tremor .
function in vivo in PD. Specific striatal FDOPA uptake However, PD is also often accompanied by cognitive reflects nigrostriatal dopamine storage capacity and enzy- impairments. Cognitive deficits are found in several domains matic decarboxylase activity in surviving neurons .
including Memory and the Executive functions, i.e. deficient According to the current model of basal ganglia organiza- cognitive switching, impaired concept formation and res- tion, dopaminergic connections between the caudate nucleus ponse-inhibition, impaired planning abilities and impaired and frontal areas are more strongly related to cognition and fluency performance Deficits in the Executive functions less strongly related to motor function. Putaminal FDOPA can negatively influence other cognitive domains too. Most uptake has been related to motor function in both early and importantly, memory profiles show that in PD, the executive advanced PD patients but until recently not to cognition,although Marie et al. reported an inverse correla-tion between putamen [11C] nomifensine uptake and ÃCorresponding author. Department of Neurology, University Medical associative learning. Most studies have shown that dimin- Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB ished (posterior) putamen FDOPA uptake correlates with Groningen, The Netherlands. Tel.: +31 503616161; fax: +31 503611707.
clinical severity of PD motor symptomatology.
1353-8020/$ - see front matter r 2007 Elsevier Ltd. All rights reserved.
doi: M. van Beilen et al. / Parkinsonism and Related Disorders 14 (2008) 224–228 This study was performed to determine whether striatal PD following the criteria of the UK Parkinson’s Disease Society Brain FDOPA uptake is related to cognitive functioning in a Bank criteria and showed sustained levodopa responsiveness. They wererecruited from our outpatients’ Movement Disorder Unit between sample of advanced PD patients. While previous cognition October 1999 and July 2003. All patients suffered from severe FDOPA-PET studies with PD patients involved early or pharmacotherapy resistant tremor or intractable motor fluctuations, heterogeneous (both early and advanced patients) samples despite optimal antiparkinsonian treatment (levodopa and dopamine of patients, our study included only moderately to severely agonists, n ¼ 28; amantadine, n ¼ 6; anticholinergics, n ¼ 5) and were advanced PD patients. The nature of these relationships suitable candidates for bilateral deep brain stimulation (DBS) of thethalamus (thalamus DBS, n ¼ 3) or subthalamic nucleus (STN-DBS, between striatal dopamine uptake and cognitive function- n ¼ 25), respectively. On a 1 (elementary school not finished) to 7 ing was studied to find an answer to the following question: (university degree) Dutch scale for education the patients’ median score are these deficits mainly related to the dopaminergic was 4 (S.D. 1.4). All patients gave their informed consent prior to study function in the caudate, the putamen, or both? inclusion according to the Declaration of Helsinki.
Preoperatively all patients were clinically and neuropsychologically evaluated following the Core Assessment Program for Surgical Interven-tional Therapy in Parkinson’s Disease (CAPSIT-PD) . Additional in- Twenty-eight right-handed PD patients with moderately to severely and exclusion criteria were: a positive levodopa response (at least 33% advanced disease (modified Hoehn and Yahr Staging in off-medication improvement of the motor part (III) of the Unified Parkinson’s Disease condition: 2.5 (n ¼ 1), 3 (n ¼ 13), 4 (n ¼ 9), 5 (n ¼ 5)) participated in the Rating Scale (UPDRS III) , no depression (Montgomery and Asberg study. There were 15 men and 13 women (age 6077.4 years, disease Depression Rating Scale (MADRS), scoreo19) or recent psychiatric duration 11.874.5 years) (see also ). All patients had idiopathic illness, no dementia (Mattis Dementia Rating Scale, score4130), and noabnormalities on cerebral MRI suggestive of atypical parkinsonism.
All clinical, neuropsychological and FDOPA-PET assessments were Clinical characteristics and striatal FDOPA uptake values of the study performed on separate successive days during hospitalization for 2–4 days within 3–6 months prior to planned surgery (bilateral thalamus-DBS orSTN-DBS). Antiparkinsonian medication was kept unchanged during a period of at least 2 weeks prior to every assessment. The UPDRS part IIIscore was assessed in the off-medication condition (after withholding regular antiparkinsonian drugs for 12 h overnight) and performed by the same investigator (ATP). The neuropsychological testing were performed in the medication-on condition following the recommendations of CAPSIT-PD. All subjects were scanned in the medication-on condition.
Neuropsychological tests included measures for Memory, Executive functioning, and Fluency. Memory was tested with the memory scale of the Matthis Dementia Rating Scale (MDRS) and the 15 Words Test (15 WT) Learning score (sum score of 15 words that were presented five times) and Recall score (words remembered after a 20 min delay).
Executive functioning was tested with the Odd Man Out (OMO) test for cognitive switching, the Stroop Color-Word Card divided by the Stroop Color Card (Stroop Interference Index), and the time needed on theTrailmaking B divided by the time needed on the Trailmaking A (TRAIL AB, cognitive switching). Fluency performance was measured with several tests including two categorical tests (Animals and Professions, 1 min each), and three letter Fluency tests. As will be seen later, for each concept (Memory, Executive functioning, and Fluency) aggregate scores across the All PET measurements were performed at the UMCG PET Center on a Siemens ECAT Exact HR+ (n ¼ 13) or ECAT 951 (n ¼ 15) scanner. The two different scanners were optimally calibrated so as to ensure that the bLEDD: Levodopa Equivalent Daily Dose ¼ levodopa dose (100 mg)  1 measurements are comparable for all practical purposes. Subjects were (added with 0.2  levodopa dose if using entacapone with each dose)+(slow positioned supine in a resting state with their eyes closed and ears release levodopa  0.7)+bromocriptine  10+ropinirole  20+pergolide  unplugged. After pretreatment with 2 mg/kg carbidopa to block peripheral dopa-decarboxylase activity, 180733 MBq of FDOPA was intravenously cReference values FDOPA uptake, UMC Groningen: healthy volunteers injected over 1 min with an infusion pump. All subjects were measured (n ¼ 10, age 56719 years): 1.6970.29 (putamen), 1.6870.25 (caudate); following a static or dynamic protocol with identical time range for data PD (n ¼ 18, age 6476 years, disease duration 973 years): 0.7970.1 analysis. The static protocol consisted of one single scan from 90 to 120 min post-injection, while the dynamic protocol consisted of 21 time M. van Beilen et al. / Parkinsonism and Related Disorders 14 (2008) 224–228 frames with increasing duration over 120 min: then the last two frames component of the variables at hand. These turned out to correlate strongly (2  900 s) were averaged to create a equivalent volume to the static scan.
(over 0.95) with the simple composite scores, and correlations of these Linear normalization with SPM99 was used to align the measured with the variables of interest (caudate and putamen FDOPA uptake) volume data to a rCBF template fixed in Talairach coordinate space .
differed by no more than 0.5 from those based on the simple composite Region of interest (ROI) analysis was based on a standardized template scores, and were therefore ignored in the sequel.
fixed in Talairach coordinate space. This template, consisting of 6 ROIs(putamen, caudate and occipital lobe on both sides) was used to sample the volume data and compute mean ROI activity concentration.
Specific FDOPA uptake was expressed as a striato-occipital ratio (SOR) index following the equation: SOR index ¼ C In , we see summaries of various characteristics (CROI ¼ average (left and right) ROI activity concentration, CREF ¼ of the study group. It can be seen that striatal FDOPA average occipital activity in the occipital reference region).
uptake values of the study PD group were lower than thePD norm group. Female subjects showed higher putamenFDOPA uptake than males. Significant relationships between the Disease duration, and Executive functioningwith putamen FDOPA uptake were found (see ), First three composite scores were computed for the cognitive variables.
This has two reasons, first, neuropsychological tests on their own are not while disease duration, UPDRS motor speed and the three always valid and reliable enough; a test relies on multiple cognitive cognitive functioning composite variables all correlated functions. In order to measure on cognitive domain level, we need to significantly with caudate FDOPA uptake. To get further combine test results. Second, this keeps numbers of variables small.
insight into the shape and strength of the association Specifically, all original cognitive variables were converted to Z-scoresusing mean values and standard deviations. Composite cognitive scores between the cognitive variables and the FDOPA uptake were computed by averaging the Z-scores on the related variables for variables, scatterplots for these relations are given in .
Memory (MDRS memory scale, 15 WT Learning score, and 15 WT Recallscore), Executive functioning (OMO, Stroop Interference Index, Trail AB), and Fluency (Animals, Professions, and three letter tests). Theresulting dependence of scores of the observation units is handledadequately in the inferential analysis reported below.
Putamen and caudate FDOPA uptake in our study The main analyses carried out here consisted of assessing the degree of group were lower than in our PD norm group, and also association between mean FDOPA uptake values (combined left and right within the lower range of those stated in literature , putamen; combined left and right caudate) and the composite scores for probably as a result of more advanced disease status. In Memory, Executive functioning and Fluency. For these, and other our study, putaminal FDOPA uptake was not significantly quantitative variables involved in the analyses carried out here, it wasverified to what extent the sample distributions deviated from normal related to the clinically evaluated level of motor dysfunc- distributions, so as to get an impression of possible violations of the tion (as assessed by the UPDRS part III), although assumption of normality, by means of visual inspection of QQ plots. The the correlation was in the expected negative direction.
distribution of the scores on UPDRS, Disease duration, Memory, Caudate FDOPA uptake was related to motor dysfunction.
Fluency, and Mean FDOPA caudate uptake were nearly normally A possible explanation for these inconsistent results may be distributed, while those for LEDD (Levodopa Equivalent Daily Dose),Hoehn and Yahr Staging, Executive functioning, and Mean FDOPA the fact that UPDRS III scores were measured off-medi- caudate uptake deviated somewhat more strongly from normality. Even cation, while FDOPA-PET was measured on-medication.
though due to the small sample sizes, we can infer little on the plausibility However, this was not tested since this study was aimed at of population distributions being normal, to be on the safe side, we the relationships between cognition and FDOPA-PET and decided to do a nonparametric inferential analysis of all results computed UPDRS on-medication scores were not measured.
here. Specifically, to give confidence intervals for all reported correlations,we used the bootstrap procedure (e.g., see to compute the so-called Caudate FDOPA uptake was positively related to 95% percentile intervals, which are known to be good approximations of cognition. These relationships were expected, based on 95% confidence intervals for correlations. A further advantage of using (a) previous PD literature on caudate dopaminergic the bootstrap procedure, is that it is not adversely affected by the function and cognition; (b) on the findings in other patient dependence between scores of different observation units as far as this was groups such as patients with Huntington’s disease , created by our procedure of forming composite scores. This is because thebootstrap procedure used here relies on repeatedly (1000 times) resampling caudate hemorrhage , and (c) on the findings in healthy observation units with scores on all original variables involved, and then subjects In PD, caudate dopaminergic function has doing all computations for the resulting bootstrap sample in the same wayas done for the original sample. Thus, construction of composites was completely mimicked in the bootstrap analysis. An important property of Correlation coefficients between disease duration, motor score, and the bootstrap procedure is that it gives good confidence intervals for values computed by whatever statistical analysis procedure used, providedthat this is mimicked exactly for each individual bootstrap sample. In this way, for each correlation, a 95% confidence interval was reported, soas to indicate its accuracy as an estimate of the correlation in the population. This interval can also be used for significance testing by verifying whether the null hypothesis value (e.g. a correlation of 0) is in the interval (not significant for a two-sided test at 0.05 level) or outside For verification purposes, in addition to the simple composite scores as computed above, we used composite scores computed as the first principal M. van Beilen et al. / Parkinsonism and Related Disorders 14 (2008) 224–228 Fig. 1. Scatterplots of Pearson’s R in striatal FDOPA uptake and cognition. PUTM: mean putamen FDOPA uptake; CAUM: mean caudate FDOPAuptake; Exe: composite score for executive functions; Memory: composite score for memory; Fluency: composite score for fluency.
been linked to tests measuring Executive function and organization of verbal material. However, different and Memory In particular the interference effect on aspects of Executive functioning can be distinguished from the Stroop test has been associated with caudate dopami- each other; our variable ‘Executive functioning’ concerned nergic function in addition to measurement of mostly mental flexibility, while the others concerned the cognitive switching that included reward for the right organization of behavior. Mental flexibility includes cogni- response . However, measurements of cognitive switch- tive switching and inhibition, while by organization we ing that did not include reward (i.e. WCST) have not mean the (semantic) clustering of information (words) we revealed significant relationships with caudate FDOPA apply as a retrieval strategy in both verbal memory tasks uptake in PD . Similarly, Memory has not been and fluency tests. Putamen FDOPA uptake was related to consistently related to caudate FDOPA uptake or the ‘flexibility’ factor in Executive functioning. Monchi may only show this relationship in more advanced patients et al. offer a possible explanation for this finding with their Rinne et al. reported Memory to be related to frontal activation study in which they investigated brain activation FDOPA uptake but not to caudate FDOPA uptake .
patterns during neuropsychological testing instead of Fluency performance was studied in two larger FDOPA- relying on correlational analyses . They concluded that PET studies with interesting results: Broussolle et al.
the putamen was activated during actions that followed a concluded that Fluency is independent from striatal cognitive switch, i.e. actions according to specific beha- FDOPA uptake, and Rinne et al. found Fluency to be vioral rules. The mental components of this cognitive related to frontal but not to striatal uptake .
switch were unrelated to putamen activity. Since most Our main finding compared to previous studies is the neuropsychological tests require such a motor response association found between putamen FDOPA uptake and after mental switching, it may be this motor component of Executive functioning. This is a surprising finding, since test performance that is related to putamen FDOPA previous reports and neuroanatomical findings suggest that uptake. Indeed, our tests (e.g. Trail Making Test and the putamen is involved in motor functioning but not in OMO Test) and those of Lozza et al. required motor cognition. However, other authors have also suggested an actions after cognitive switching while some of the studies association between FDOPA uptake in the putamen and that did not find a relation between putamen FDOPA cognitive processing using comparable paradigms uptake and neuropsychological test behavior did not (FDG-PET and [123I]b-CIT SPECT, respectively), in include tests that require motor actions after cognitive addition to findings with other paradigms switching . However, results are not consistent, some In our patients, putamen FDOPA uptake was related to authors did include such a test but did not find putaminal Executive functioning and Fluency, but not to Memory. It should be noted that, as addressed in the introduction, the relationship between putamen and cognition found in the measures for Memory and Fluency also concern Executive study of Mu¨ller et al. did involve tests with an action functioning since they reflect cognitive searching strategies component, but not specifically an action after switching.
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