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1.  Differential diagnosis of Parkinson's disease, multiple system atrophy, and Steele-Richardson-Olszewski syndrome: discriminant analysis of striatal 18F-dopa PET data. 
Clinicopathological series indicate that the clinical diagnosis of Parkinson's disease is correct in only 80% of cases. Multiple system atrophy (MSA) and Steele-Richardson-Olszewski syndrome (SRO) comprise most of the misdiagnoses. By means of 18F-dopa PET the pattern of nigrostriatal dopaminergic dysfunction in 28 patients with clinically probable Parkinson's disease, 25 with MSA, and 10 patients with SRO, was assessed and compared with the pattern in 27 normal subjects. Discriminant function analysis was used to assess the ability of 18F-dopa PET to categorize individual parkinsonian patients on the basis of their caudate and putamen tracer uptake. Discriminant function analysis assigned all control subjects a normal category. One Parkinsonian patient out of 63 was classified as "normal" on the basis of PET findings, although this patient had significantly reduced putamen 18F-dopa uptake. Discriminant function analysis was less effective at distinguishing different categories of akinetic-rigid syndrome on the basis of their striatal 18F-dopa uptake, as judged against clinical criteria. Patients clinically labelled as having typical or atypical Parkinsonian syndromes were assigned the same category on PET criteria 64% and 69% of the time, respectively. When all three categories of Parkinson's disease, MSA, and SRO were considered together, clinical and 18F-dopa PET findings correlated in 64% of patients assigned a diagnosis of Parkinson's disease and 70% of those given a diagnosis of SRO; MSA was less readily discriminated, patients with MSA being assigned to MSA, Parkinson's disease, and SRO groups with equal frequency. The correlation between clinical and discriminant function analysis assignment improved when separate comparisons were made between Parkinson's disease and MSA, or Parkinson's disease and SRO groups. In these analyses, clinical and PET categorisation of MSA and Parkinson's disease agreed in 60% of cases, and of SRO and Parkinson's disease in 90% of cases. In summary, (18)F-dopa PET successfully discriminates normal subjects from parkinsonian patients, and patients with Parkinson's disease from patients with SRO, but is less reliable in distinguishing Parkinson's disease from MSA. The concomitant assessment of striatal neuronal function with additional PET tracers may be necessary to reliably differentiate typical and atypical parkinsonian syndromes.
PMCID: PMC1072814  PMID: 8158173
2.  Parkinson’s Disease Subtypes Show a Specific Link between Dopaminergic and Glucose Metabolism in the Striatum 
PLoS ONE  2014;9(5):e96629.
Background
Previous studies have shown different clinical and imaging pattern in tremordominant and akinetic-rigid Parkinson’s disease (PD) subtypes. The association between dopaminergic and glucose metabolism has in contrast not been investigated yet. Therefore, this study compared PD subtypes with respect to clinical and imaging findings with the aim of establishing a relationship between clinical subtypes, dopamine and glucose metabolism.
Methods
Two groups of a total of 64 idiopathic PD patients (42 male, 22 female, mean age 56±10.9 years) were analysed: akinetic-rigid (AR, n = 32) and tremor-dominant (TD, n = 32) patients. Both were compared with respect to differential involvement of local striatal dopamine and glucose metabolism using [18F]-fluoro-L-dopa (F-dopa) and [18F]-fluorodeoxyglucose (FDG)-PET.
Results
The analysis of PD subgroups showed significant differences in the F-dopa uptake in the anterior putamen. Using the results of the local striatal dopamine difference as a volume of interest for the FDG-analysis, analysis of AR patients revealed a significantly lower normalised cerebral metabolic rate of glucose (nCMRGlc) within the ventral striatum.
Conclusions
The dual tracer study illlustrates clear differences between TD and AR subtypes in the ventral striatum. In accordance with previous FP-CIT-SPECT studies, it discloses congruent results for the presynaptic dopaminergic system and extends the knowledge about an additional involvement of local metabolic activity in the caudate and anterior putamen. The findings corroborate the specific role of distinct PD subtypes within the cerebello-thalamo-cortical-circuits. Multitracer PET imaging may thus enhance the knowledge about the clinical segregation into subtypes.
doi:10.1371/journal.pone.0096629
PMCID: PMC4029550  PMID: 24848641
3.  The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow 
Brain  2012;135(8):2440-2448.
Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with 18F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H215O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the pattern of dopamine loss in patients with both Parkinson and Gaucher disease was similar to sporadic Parkinson disease, indicating comparable damage in midbrain neurons. However, H215O positron emission tomography studies indicated that these subjects have decreased resting activity in a pattern characteristic of diffuse Lewy body disease. These findings provide insight into the pathophysiology of GBA-associated parkinsonism.
doi:10.1093/brain/aws174
PMCID: PMC3407426  PMID: 22843412
brain imaging; genetic risk; positron emission tomography (PET); Parkinson disease; lysosomal storage disorders
4.  Striatal Astrocytes Act as a Reservoir for L-DOPA 
PLoS ONE  2014;9(9):e106362.
L-DOPA is therapeutically efficacious in patients with Parkinson’s disease (PD), although dopamine (DA) neurons are severely degenerated. Since cortical astrocytes express neutral amino acid transporter (LAT) and DA transporter (DAT), the uptake and metabolism of L-DOPA and DA in striatal astrocytes may influence their availability in the dopaminergic system of PD. To assess possible L-DOPA- and DA-uptake and metabolic properties of striatal astrocytes, we examined the expression of L-DOPA, DA and DAT in striatal astrocytes of hemi-parkinsonian model rats after repeated L-DOPA administration, and measured the contents of L-DOPA, DA and their metabolite in primary cultured striatal astrocytes after L-DOPA/DA treatment. Repeated injections of L-DOPA induced apparent L-DOPA- and DA-immunoreactivities and marked expression of DAT in reactive astrocytes on the lesioned side of the striatum in hemi-parkinsonian rats. Exposure to DA for 4h significantly increased the levels of DA and its metabolite DOPAC in cultured striatal astrocytes. L-DOPA was also markedly increased in cultured striatal astrocytes after 4-h L-DOPA exposure, but DA was not detected 4 or 8h after L-DOPA treatment, despite the expression of aromatic amino acid decarboxylase in astrocytes. Furthermore, the intracellular level of L-DOPA in cultured striatal astrocytes decreased rapidly after removal of extracellular L-DOPA. The results suggest that DA uptaken into striatal astrocytes is rapidly metabolized and that striatal astrocytes act as a reservoir of L-DOPA that govern the uptake or release of L-DOPA depending on extracellular L-DOPA concentration, but are less capable of converting L-DOPA to DA.
doi:10.1371/journal.pone.0106362
PMCID: PMC4154692  PMID: 25188235
5.  Statistical parametric mapping with 18F-dopa PET shows bilaterally reduced striatal and nigral dopaminergic function in early Parkinson's disease 
OBJECTIVE—To apply statistical parametric mapping to 18F-dopa PET data sets, to examine the regional distribution of changes in dopaminergic metabolism in early asymmetric Parkinson's disease.
METHODS—Thirteen normal volunteers (age 57.7 (SD 16.5) years; four women, nine men ) and six patients (age 50.3 (SD 13.5) years; three women, three men) with asymmetric (right sided) Parkinson's disease were studied. Images from each dynamic dopa PET dataset were aligned and parametric images of 18F-dopa influx (Ki) were created for each subject. The Ki images were transformed into standard stereotactic space. The Ki values of the caudate and putamen on spatially normalised images were compared with the Ki values before normalisation. The application of statistical parametric mapping (SPM) allowed statistical comparison of regional Ki values on a voxel by voxel basis between healthy volunteers and patients with Parkinson's disease.
RESULTS—There was a strong correlation between the Ki values before and after spatial normalisation (r=0.898, p=0.0001). Significant decreases in the Ki values were found for the Parkinson's desease group throughout the entire left putamen (p< 0.001) and focally in the dorsal right putamen (p< 0.001). Decreased Ki values were also shown bilaterally in the substantia nigra (p< 0.01).
CONCLUSION—Using (SPM) and 18F-dopa PET, reductions in both striatal and nigral brain dopaminergic function could be demonstrated in early Parkinson's disease.


PMCID: PMC1736402  PMID: 10329749
6.  Measuring the rate of progression and estimating the preclinical period of Parkinson's disease with [18F]dopa PET 
OBJECTIVES—To measure the rate of progression in striatal [18F]dopa metabolism in a large group (n=32) of patients with Parkinson's disease, to estimate the average duration of preclinical period, and to examine the influence of the PET method on the assessment of rate of progression and preclinical period.
METHODS—Thirty two patients with Parkinson's disease (mean age 58 (SD 13) years, mean duration 39 (SD 33) months) were assessed with [18F]dopa PET and UPDRS scoring on two occasions a mean of 18 (SD 6) months apart. PET data were sampled with separate caudate and putamen and total striatal regions of interest, and both graphical (Ki) and ratio methods of analysis.
RESULTS—The mean annual rate of deterioration in [18F]dopa uptake varied according to structure and method of analysis, with putamen Ki showing the most rapid mean rate of progression (4.7% of normal mean per year). The group showed a significant deterioration (p<0.0004, paired two tailed t test) in UPDRS and in the putamen (p=0.008) and total striatal (p=0.012) [18F]dopa uptake measured using a graphical analysis, but no significant change in caudate or putamen uptake measured by a ratio approach. A study of sensitivity confirmed that putamen Ki was the most sensitive measure of disease progression, caudate ratio the least. Symptom onset in Parkinson's disease was estimated at a mean putamen [18F]dopa uptake (Ki) of 75% of normal and a mean caudate [18F]dopa uptake (Ki) of 91% of normal.
CONCLUSIONS—Estimation of mean rate of progression varies according to the sensitivity of a functional imaging method to clinical severity. Sensitivity and reproducibility of method must be considered when designing studies of disease progression and neuroprotection. The mean preclinical period in Parkinson's disease is unlikely to be longer than seven years.


PMCID: PMC2170010  PMID: 9527140
7.  Lateralisation of striatal function: evidence from 18F-dopa PET in Parkinson's disease 
Objectives: The aetiology of the cognitive changes seen in Parkinson's disease (PD) is multifactorial but it is likely that a significant contribution arises from the disruption of dopaminergic pathways. This study aimed to investigate the contribution of the dopaminergic system to performance on two executive tasks using 18F-6-fluorodopa positron emission tomography (18F-dopa PET) in PD subjects with early cognitive changes.
Methods: 16 non-demented, non-depressed PD subjects were evaluated with the Tower of London (TOL) spatial planning task, a verbal working memory task (VWMT) and 18F-dopa PET, all known to be affected in early PD. Statistical parametric mapping (SPM) localised brain regions in which 18F-dopa uptake covaried with performance scores. Frontal cortical resting glucose metabolism was assessed with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET.
Results: SPM localised significant covariation between right caudate 18F-dopa uptake (Ki) and TOL scores and between left anterior putamen Ki and VWMT performance. No significant covariation was found between task scores and 18F-dopa Ki values in either limbic or cortical regions. Frontal cortical glucose metabolism was preserved in all cases.
Conclusions: These findings support a causative role of striatal dopaminergic depletion in the early impairment of executive functions seen in PD. They suggest that spatial and verbal executive tasks require integrity of the right and left striatum, respectively, and imply that the pattern of cognitive changes manifest by a patient with PD may reflect differential dopamine loss in the two striatal complexes.
doi:10.1136/jnnp.2004.055079
PMCID: PMC1739780  PMID: 16107352
8.  Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers 
Brain  2014;137(9):2480-2492.
Mutations in the gene encoding the dopamine-synthetic enzyme GTP cyclohydrolase-1 (GCH1) cause DOPA-responsive dystonia (DRD). Mencacci et al. demonstrate that GCH1 variants are associated with an increased risk of Parkinson's disease in both DRD pedigrees and in patients with Parkinson's disease but without a family history of DRD.
GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson’s disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson’s disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson’s disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher’s exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4–25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson’s disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson’s disease.
doi:10.1093/brain/awu179
PMCID: PMC4132650  PMID: 24993959
GCH1; DOPA-responsive-dystonia; Parkinson’s disease; dopamine; exome sequencing
9.  [123I]FP-CIT SPECT shows a pronounced decline of striatal dopamine transporter labelling in early and advanced Parkinson's disease. 
OBJECTIVES: The main neuropathological feature in Parkinson's disease is a severe degeneration of the dopaminergic neurons in the substantia nigra resulting in a loss of dopamine (DA) transporters in the striatum. [123I]beta-CIT single photon emission computed tomography (SPECT) studies have demonstrated this loss of striatal DA transporter content in Parkinson's disease in vivo. However, studies with this radioligand also showed that an adequate imaging of the striatal DA transporter content could only be performed on the day after the injection of radioligand, which is not convenient for outpatient evaluations. Recently, a new radioligand [123I]FP-CIT, with faster kinetics than beta-CIT, became available for imaging of the DA transporter with SPECT, and the applicability of this ligand was tested in patients with early and advanced Parkinson's disease, using a one day protocol. METHODS: [123I]FP-CIT SPECT was performed in six patients with early and 12 patients with advanced Parkinson's disease, and in six age matched healthy volunteers. RESULTS: Compared with an age matched control group striatal [123I]FP-CIT uptake in patients with Parkinson's disease was decreased, and this result was measurable three hours after injection of the radioligand. In the Parkinson's disease group the uptake in the putamen was reduced more than in the caudate nucleus. The contralateral striatal uptake of [123I]FP-CIT was significantly lower than the ipsilateral striatal uptake in the Parkinson's disease group. Specific to non-specific striatal uptake ratios correlated with the Hoehn and Yahr stage. A subgroup of patients with early Parkinson's disease also showed significantly lower uptake in the putamen and lower putamen:caudate ratios than controls. CONCLUSION: [123I]FP-CIT SPECT allows a significant discrimination between patients with Parkinson's disease and age matched controls with a one day protocol, which will be to great advantage in outpatient evaluations.
Images
PMCID: PMC486723  PMID: 9048712
10.  How useful is [123I]ß-CIT SPECT in clinical practice? 
Objective: To assess the accuracy and clinical usefulness of [123I]ß-CIT (2ß-carbomethoxy-3ß-(4-iodophenyl)tropane) SPECT in the differential diagnosis of Parkinson's disease.
Subjects: 185 consecutive patients with symptoms of movement disorder were studied. The diagnoses were Parkinson's disease (92), essential tremor (16), vascular parkinsonism (15), various Parkinson plus syndromes (P+) (12), dementia with Lewy bodies (DLB) (5), dystonia (5), drug induced movement disorder (12), and other diagnoses (8). A reference group (psychogenic parkinsonism) comprised 20 subjects with complaints suggesting extrapyramidal disease but with no unequivocal signs on clinical examination and no abnormalities on brain imaging.
Results: ß-CIT uptake was significantly lower in the whole striatum as well as separately in the putamen and in the caudate nucleus in Parkinson's disease than in the reference group or in drug induced movement disorder, essential tremor, or dystonia. The uptake of ß-CIT in the vascular parkinsonism group was heterogeneous and mean ß-CIT uptake fell between the reference group and the Parkinson's disease group. In the P+ and DLB groups the striatal uptake ratios overlapped those of the Parkinson's disease group.
Conclusions: [123I]ß-CIT SPECT may not be as useful a tool in the clinical differential diagnosis of Parkinson's disease as was previously believed, but it was 100% sensitive and specific for the diagnosis in younger patients (age <55 years). In older patients (age >55 years) specificity was substantially lower (68.5%). This differential specificity reflected the different distribution of differential diagnostic disorders (P+, DLB, vascular parkinsonism) in the older and younger age groups.
doi:10.1136/jnnp.2004.045237
PMCID: PMC1739796  PMID: 16107353
11.  Evidence of d-phenylglycine as delivering tool for improving l-dopa absorption 
Background
l-Dopa has been used for Parkinson's disease management for a long time. However, its wide variety in the rate and the extent of absorption remained challenge in designing suitable therapeutic regime. We report here a design of using d-phenylglycine to guard l-dopa for better absorption in the intestine via intestinal peptide transporter I (PepT1).
Methods
d-Phenylglycine was chemically attached on l-dopa to form d-phenylglycine-l-dopa as a dipeptide prodrug of l-dopa. The cross-membrane transport of this dipeptide and l-dopa via PepT1 was compared in brush-boarder membrane vesicle (BBMV) prepared from rat intestine. The intestinal absorption was compared by in situ jejunal perfusion in rats. The pharmacokinetics after i.v. and p.o. administration of both compounds were also compared in Wistar rats. The striatal dopamine released after i.v. administration of d-phenylglycine-l-dopa was collected by brain microdialysis and monitored by HPLC. Anti-Parkinsonism effect was determined by counting the rotation of 6-OHDA-treated unilateral striatal lesioned rats elicited rotation with (+)-methamphetamine (MA).
Results
The BBMV uptake of d-phenylglycine-l-dopa was inhibited by Gly-Pro, Gly-Phe and cephradine, the typical PepT1 substrates, but not by amino acids Phe or l-dopa. The cross-membrane permeability (Pm*) determined in rat jejunal perfusion of d-phenylglycine-l-dopa was higher than that of l-dopa (2.58 ± 0.14 vs. 0.94 ± 0.10). The oral bioavailability of d-phenylglycine-l-dopa was 31.7 times higher than that of l-dopa in rats. A sustained releasing profile of striatal dopamine was demonstrated after i. v. injection of d-phenylglycine-l-dopa (50 mg/kg), indicated that d-phenylglycine-l-dopa might be a prodrug of dopamine. d-Phenylglycine-l-dopa was more efficient than l-dopa in lowering the rotation of unilateral striatal lesioned rats (19.1 ± 1.7% vs. 9.9 ± 1.4%).
Conclusion
The BBMV uptake studies indicated that d-phenylglycine facilitated the transport of l-dopa through the intestinal PepT1 transporter. The higher jejunal permeability and the improved systemic bioavailability of d-phenylglycine-l-dopa in comparison to that of l-dopa suggested that d-phenylglycine is an effective delivery tool for improving the oral absorption of drugs like l-dopa with unsatisfactory pharmacokinetics. The gradual release of dopamine in brain striatum rendered this dipeptide as a potential dopamine sustained-releasing prodrug.
doi:10.1186/1423-0127-17-71
PMCID: PMC2941486  PMID: 20815935
12.  Differential Diagnosis of Parkinsonism Using Dual-Phase F-18 FP-CIT PET Imaging 
Purpose
Dopamine transporter (DAT) imaging can demonstrate presynaptic dopaminergic neuronal loss in Parkinson’s disease (PD). However, differentiating atypical parkinsonism (APD) from PD is often difficult. We investigated the usefulness of dual-phase F-18 FP-CIT positron emission tomography (PET) imaging in the differential diagnosis of parkinsonism.
Methods
Ninety-eight subjects [five normal, seven drug-induced parkinsonism (DIP), five essential tremor (ET), 24 PD, 20 multiple system atrophy-parkinson type (MSA-P), 13 multiple system atrophy-cerebellar type (MSA-C), 13 progressive supranuclear palsy (PSP), and 11 dementia with Lewy bodies (DLB)] underwent F-18 FP-CIT PET. PET images were acquired at 5 min (early phase) and 3 h (late phase) after F-18 FP-CIT administration (185 MBq). Regional uptake pattern of cerebral and cerebellar hemispheres was assessed on early phase images and striatal DAT binding pattern was assessed on late phase images, using visual, quantitative, and statistical parametric mapping (SPM) analyses.
Results
Striatal DAT binding was normal in normal, ET, DIP, and MSA-C groups, but abnormal in PD, MSA-P, PSP, and DLB groups. No difference was found in regional uptake on early phase images among normal DAT binding groups, except in the MSA-C group. Abnormal DAT binding groups showed different regional uptake pattern on early phase images compared with PD in SPM analysis (FDR < 0.05). When discriminating APD from PD, visual interpretation of the early phase image showed high diagnostic sensitivity and specificity (75.4 % and 100 %, respectively). Regarding the ability to distinguish specific APD, sensitivities were 81 % for MSA-P, 77 % for MSA-C, 23 % for PSP, and 54.5 % for DLB.
Conclusions
Dual-phase F-18 FP-CIT PET imaging is useful in demonstrating striatal DAT loss in neurodegenerative parkinsonism, and also in differentiating APD, particularly MSA, from PD.
doi:10.1007/s13139-012-0182-4
PMCID: PMC4035208  PMID: 24895507
Atypical parkinsonism; Dual-phase; F-18 FP-CIT; Positron emission tomography; PET
13.  Alpha and beta EEG power reflects L-dopa acute administration in parkinsonian patients 
Aim: To evaluate the effect of an acute L-dopa administration on eye-closed resting state electroencephalographic (EEG) activity of cognitively preserved Parkinsonian patients.
Methods: We examined 24 right-handed patients diagnosed as uncomplicated probable Parkinson’s disease (PD). Each patient underwent Unified Parkinson’s Disease Rating Scale (UPDRS)-part-III evaluation before and 60 min after an oral load of L-dopa-methyl-ester/carbidopa 250/25 mg. Resting condition eyes-closed EEG data were recorded both pre- and post L-dopa load. Absolute EEG power values were calculated at each scalp derivation for Delta, Theta, Alpha and Beta frequency bands. UPDRS scores (both global and subscale scores) and EEG data (power values of different frequency bands for each scalp derivation) were submitted to a statistical analysis to compare Pre and Post L-Dopa conditions. Finally, a correlation analysis was carried out between EEG spectral content and UPDRS scores.
Results: Considering EEG power spectral analysis, no statistically significant differences arose on Delta and Theta bands after L-dopa intake. Conversely, Alpha and Beta rhythms significantly increased on centro-parietal scalp derivations, as a function of L-dopa administration. Correlation analysis indicated a significant negative correlation between Beta power increase on centro-parietal areas and UPDRS subscores (Rigidity of arms and Bradykinesia). A minor significant negative correlation was also found between Alpha band increase and resting tremor.
Conclusions: Assuming that a significant change in EEG power spectrum after L-dopa intake may be related to dopaminergic mechanisms, our findings are consistent with the hypothesis that dopaminergic defective networks are implicated in cortical oscillatory abnormalities at rest in non-demented PD patients.
doi:10.3389/fnagi.2014.00302
PMCID: PMC4233983  PMID: 25452725
Parkinson’s disease; levodopa; quantitative EEG; power spectrum analysis; alpha rhythm; beta rhythm
14.  A Within-Subject Comparison of 6-[18F]Fluoro-m-tyrosine and 6-[18F]Fluoro-l-dopa in Parkinson’s Disease 
Movement Disorders  2011;26(11):2032-2038.
Progression of Parkinson’s disease symptoms is imperfectly correlated with positron emission tomography biomarkers for dopamine biosynthetic pathways. The radiopharmaceutical 6-[18F]fluoro-m-tyrosine is not a substrate for catechol-O-methyltransferase and therefore has a more favorable uptake-to-background ratio than 6-[18F]fluoro-l-dopa. The objective of this study was to evaluate 6-[18F]fluoro-m-tyrosine relative to 6-[18F]fluoro-l-dopa with partial catechol-O-methyltransferase inhibition as a biomarker for clinical status in Parkinson’s disease. Twelve patients with early-stage Parkinson’s disease, off medication, underwent Unified Parkinson Disease Rating Scale scoring, brain magnetic resonance imaging, and 3-dimensional dynamic positron emission tomography using equivalent doses of 6-[18F]fluoro-m-tyrosine and 6-[18F]fluoro-l-dopa with tolcapone, a catechol-O-methyltransferase inhibitor. Images were realigned within subject, after which the tissue-derived uptake rate constant was generated for volumes of interest encompassing the caudate nucleus, putamen, and subregions of the putamen. We computed both bivariate (Pearson) and partial (covariate of age) correlations between clinical subscores and tissue-derived uptake rate constant. Tissue-derived uptake rate constant values were correlated between the radiopharmaceuticals (r = 0.8). Motor subscores were inversely correlated with the contralateral putamen 6-[18F]fluoro-m-tyrosine tissue-derived uptake rate constant (|r| > 0.72, P < .005) but not significantly with the 6-[18F]fluoro-l-dopa tissue- derived uptake rate constant. The uptake rate constants for both radiopharmaceuticals were also inversely correlated with activities of daily living subscores, but the magnitude of correlation coefficients was greater for 6-[18F]fluoro-m-tyrosine. In this design, 6-[18F]fluoro-m-tyrosine uptake better reflected clinical status than did 6-[18F]fluoro-l-dopa uptake. We attribute this finding to 6-[18F]fluoro-m-tyrosine’s higher affinity for the target, l-aromatic amino acid decarboxylase, and the absence of other major determinants of the uptake rate constant. These results also imply that l-aromatic amino acid decarboxylase activity is a major determinant of clinical status.
doi:10.1002/mds.23778
PMCID: PMC3278160  PMID: 21638324
positron emission tomography; Parkinson’s disease/radionuclide imaging; dopamine/metabolism
15.  Diffusion Tensor Imaging of Parkinson’s Disease, Atypical Parkinsonism and Essential Tremor 
Summary
Diffusion tensor imaging could be useful in characterizing movement disorders because it non-invasively examines multiple brain regions simultaneously. We report a multi-target imaging approach focused on the basal ganglia and cerebellum in Parkinson’s disease, parkinsonian variant of multiple system atrophy, progressive supranuclear palsy, essential tremor, and healthy controls. Seventy-two subjects were studied with a diffusion tensor imaging protocol at 3 Tesla. Receiver operating characteristics analysis was performed to directly compare groups. Sensitivity and specificity values were quantified for control vs. movement disorder (92% sensitivity, 88% specificity), control vs. parkinsonism (93% sensitivity, 91% specificity), Parkinson’s disease vs. atypical parkinsonism (90% sensitivity, 100% specificity), Parkinson’s disease vs. multiple system atrophy (94% sensitivity, 100% specificity), Parkinson’s disease vs. progressive supranuclear palsy (87% sensitivity, 100% specificity), multiple system atrophy vs. progressive supranuclear palsy (90% sensitivity, 100% specificity), and Parkinson’s disease vs. essential tremor (92% sensitivity, 87% specificity). The brain targets varied for each comparison, but the substantia nigra, putamen, caudate, and middle cerebellar peduncle were the most frequently selected brain regions across classifications. These results indicate that using diffusion tensor imaging of the basal ganglia and cerebellum accurately classifies subjects diagnosed with Parkinson’s disease, atypical parkinsonism, and essential tremor and clearly distinguishes them from control subjects.
doi:10.1002/mds.25491
PMCID: PMC3748146  PMID: 23674400
DTI; Parkinsonism; essential tremor; basal ganglia; cerebellum
16.  Entacapone improves the availability of l-dopa in plasma by decreasing its peripheral metabolism independent of l-dopa/carbidopa dose 
Aims
Entacapone is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor. To improve the benefits of oral l-dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of l-dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of l-dopa given as standard release l-dopa/carbidopa.
Methods
Six different doses of l-dopa/carbidopa were investigated in this placebo-controlled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups (n = 14–16). Two different l-dopa/carbidopa doses were administered to each subject (50/12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of l-dopa, its metabolites, carbidopa, and entacapone were determined.
Results
Entacapone increased the AUC(0,12 h) of l-dopa to a similar extent at all doses of l-dopa/carbidopa, that is by about 30–40% compared with placebo (P < 0.001, 95% CI 0.15, 0.40). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean Cmax values for l-dopa at all l-dopa/carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of l-dopa were maintained for a longer period at all doses of l-dopa/carbidopa. Entacapone also decreased the peripheral formation of 3-O-methyldopa (3-OMD) to about 55–60% of the placebo treatment level (P < 0.001, 95% CI −0.72, −0.35) and increased the mean AUC(0,12 h) of 3,4-dihydroxy-phenylacetic acid (DOPAC) 2–2.6-fold compared with placebo (P < 0.001, 95% CI 0.60, 1.10). The mean AUC(0,12 h) of 3-methoxy-4-hydroxy-phenylacetic acid (HVA) following entacapone was approximately 65–75% of that observed with placebo (P < 0.001–0.05, 95% CI –0.76, −0.01) at each l-dopa/carbidopa dose except the 50/12.5 mg dose (P > 0.05, 95% CI –0.59, 0.05). The metabolic ratios (MR, AUC metabolite/AUC l-dopa) also confirmed that entacapone significantly decreased the proportion of 3-OMD (P < 0.001, 95% CI −0.85, −0.68) and HVA (P < 0.001, 95% CI −1.01, −0.18) in plasma at each l-dopa/carbidopa dose, whereas the AUC DOPAC/AUC l-dopa ratio was increased again at all doses (P < 0.001, 95% CI 0.26, 0.90). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did l-dopa/carbidopa affect the pharmacokinetics of entacapone.
Conclusions
The 200 mg dose of entacapone similarly and significantly increases the AUC of l-dopa by changing the metabolic balance of l-dopa independent of the l-dopa/carbidopa dose and therefore entacapone is likely to have a similar l-dopa potentiating effect independent of l-dopa dose.
doi:10.1046/j.1365-2125.2002.01654.x
PMCID: PMC1874436  PMID: 12392583
3-OMD; carbidopa; DOPAC; entacapone; HVA; l-dopa; pharmacokinetics
17.  Dopamine Transporter Loss in 6-OHDA Parkinson’s Model Is Unmet by Parallel Reduction in Dopamine Uptake 
PLoS ONE  2012;7(12):e52322.
The dopamine transporter (DAT) regulates synaptic dopamine (DA) in striatum and modulation of DAT can affect locomotor activity. Thus, in Parkinson’s disease (PD), DAT loss could affect DA clearance and locomotor activity. The locomotor benefits of L-DOPA may be mediated by transport through monoamine transporters and conversion to DA. However, its impact upon DA reuptake is unknown and may modulate synaptic DA. Using the unilateral 6-OHDA rat PD model, we examined [3H]DA uptake dynamics in relation to striatal DAT and tyrosine hydroxylase (TH) protein loss compared with contralateral intact striatum. Despite >70% striatal DAT loss, DA uptake decreased only ∼25% and increased as DAT loss approached 99%. As other monoamine transporters can transport DA, we determined if norepinephrine (NE) and serotonin (5-HT) differentially modulated DA uptake in lesioned striatum. Unlabeled DA, NE, and 5-HT were used, at a concentration that differentially inhibited DA uptake in intact striatum, to compete against [3H]DA uptake. In 6-OHDA lesioned striatum, DA was less effective, whereas NE was more effective, at inhibiting [3H]DA uptake. Furthermore, norepinephrine transporter (NET) protein levels increased and desipramine was ∼two-fold more effective at inhibiting NE uptake. Serotonin inhibited [3H]DA uptake, but without significant difference between lesioned and contralateral striatum. L-DOPA inhibited [3H]DA uptake two-fold more in lesioned striatum and inhibited NE uptake ∼five-fold more than DA uptake in naïve striatum. Consequently, DA uptake may be mediated by NET when DAT loss is at PD levels. Increased inhibition of DA uptake by L-DOPA and its preferential inhibition of NE over DA uptake, indicates that NET-mediated DA uptake may be modulated by L-DOPA when DAT loss exceeds 70%. These results indicate a novel mechanism for DA uptake during PD progression and provide new insight into how L-DOPA affects DA uptake, revealing possible mechanisms of its therapeutic and side effect potential.
doi:10.1371/journal.pone.0052322
PMCID: PMC3530604  PMID: 23300642
18.  Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease 
Background
Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease.
Methods
In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere.
Results
Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher.
Conclusions
Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.
doi:10.1186/2045-8118-9-4
PMCID: PMC3298802  PMID: 22316420
Population pharmacokinetic modelling; Parkinson's disease; rat rotenone model; BBB transport; L-DOPA; microdialysis
19.  Differentiating multiple system atrophy from Parkinson's disease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging 
Objectives: The differential diagnosis between typical idiopathic Parkinson's disease (PD) and the striatonigral variant of multiple system atrophy (MSA-P) is often difficult because of the presence of signs and symptoms common to both forms of parkinsonism, particularly at symptom onset. This study investigated striatal and midbrain findings in MSA-P and PD patients in comparison with normal controls with the use of positron emission tomography (PET) and three dimensional magnetic resonance imaging (3D MRI) based volumetry to increase the differential diagnostic accuracy between both disease entities.
Methods: Nine patients with MSA-P, 24 patients with PD, and seven healthy controls were studied by MRI and PET with 6-[18F]-fluoro-L-dopa (FDOPA), [18F]fluoro-deoxyglucose (FDG), and 11-C-Raclopride (RACLO). Striatal and extrastriatal volumes of interest (VOI) were calculated on the basis of the individual MRI data. The PET data were transferred to the VOI datasets and subsequently analysed.
Results: MSA-P differed significantly from PD patients in terms of decreased putaminal volume, glucose metabolism, and postsynaptic D2 receptor density. The striatal FDOPA uptake was equally impaired in both conditions. Neither MRI volumetry nor PET imaging of the midbrain region further contributed to the differential diagnosis between PD and MSA-P.
Conclusions: The extent and spatial distribution of functional and morphological changes in the striatum permit the differentiation of MSA-P from PD. Both, multi-tracer PET and 3D MRI based volumetry, may be considered equivalent in the assessment of different striatal abnormality in both disease entities. In contrast, MRI and PET imaging of the midbrain does not provide a further gain in diagnostic accuracy.
doi:10.1136/jnnp.73.5.517
PMCID: PMC1738131  PMID: 12397143
20.  Altered Resting State Cortico-Striatal Connectivity in Mild to Moderate Stage Parkinson's Disease 
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI in mild to moderate stage Parkinson's patients on and off l-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off l-DOPA compared to controls. This enhanced connectivity was down-regulated by l-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off l-DOPA exhibited increased power in the frequency band 0.02–0.05 Hz compared to controls and to PD on l-DOPA. The l-DOPA associated decrease in the power of this frequency range modulated the l-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the l-DOPA associated decrease in power in this frequency band correlated with the l-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and l-DOPA modulate striatal resting state BOLD signal oscillations and cortico-striatal network coherence.
doi:10.3389/fnsys.2010.00143
PMCID: PMC3009475  PMID: 21206528
dopamine; Parkinson's disease; fMRI; functional connectivity; striatum; neural oscillation
21.  Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study 
PLoS Medicine  2013;10(6):e1001462.
In this study, Mendelian randomization was used to study genes known to modify iron levels, and the effect of iron on Parkinson's disease (PD) risk was estimated. Based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date, the findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson's disease for every 10 µg/dL increase in iron. The results of this analysis have potentially important implications for future research into the prevention of Parkinson's disease.
Please see later in the article for the Editors' Summary
Background
Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.
Methods and Findings
We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron.
Conclusions
Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Parkinson disease is a degenerative disorder of the central nervous system caused by the death of dopamine-generating cells in the substania nigra, a region of the midbrain. The earliest symptoms are usually movement-related and include tremor, slow movements, and difficulty walking, and later cognitive and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease. Parkinson disease affects around ten million people world-wide and incidence increases with age, with men more affected than women. To date, the causes of Parkinson disease remain unknown although a combination of genetic and environmental factors is thought to play a role. Identifying possible modifiable risks is an important step in the possible prevention of Parkinson disease.
Why Was This Study Done?
Previous studies have shown a possible association between lower blood levels of iron in people with Parkinson disease compared with controls, although the quality of these studies makes this finding difficult to interpret. So in this study, the researchers used a mendelian randomization approach to investigate whether there was any evidence of an effect of blood iron levels on the risk of Parkinson disease and if so to further explore the direction and scale of any link. Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in situations where it is inappropriate to perform a randomized controlled trial.
What Did the Researchers Do and Find?
The researchers estimated the effect of blood iron levels on the risk of Parkinson disease using three polymorphisms in two genes, HFE and TMPRSS6. For each polymorphism, they performed a meta-analysis combining the results of studies investigating the genetic effect on iron levels, which included almost 22,000 people from Europe and Australia, and a meta-analysis of studies investigating the genetic effect on the risk of Parkinson disease, which included a total of 20,809 people with Parkinson disease and 88,892 controls from Europe and North America. They then performed three separate mendelian randomization analyses to estimate the effect of iron on Parkinson disease for the three polymorphisms. By combining the three estimates, they obtained a statistically significant odds ratio of 0.97 for Parkinson disease per 10 µg/dl increase in iron, corresponding to a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in blood iron. Since genotype influences on blood iron levels represent differences that generally persist throughout adult life, the combined mendelian randomization estimate reflects an effect of iron over the course of a lifetime.
What Do These Findings Mean?
These findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in iron. This finding is important as it suggests that increased blood iron levels may have a protective effect against Parkinson disease, although the underlying mechanism remains unclear. Furthermore, although mendelian randomization is an increasingly used approach to address the issue of classical confounding, there may be remaining confounding factors specific of mendelian randomization that may influence the interpretation of this study. Nevertheless, the results of this analysis have potentially important implications for future research into the prevention of Parkinson disease. Further studies on the underlying mechanisms are needed before any specific treatment recommendations can be proposed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001462.
The National Institutes of Neurological Disorder and Stroke, MedlinePlus, and NHS Choices have several pages with comprehensive information on Parkinson disease
Wikipedia gives an explanation of mendelian randomization (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001462
PMCID: PMC3672214  PMID: 23750121
22.  Structural and Functional Imaging in Parkinsonian Syndromes 
Radiographics  2014;34(5):1273-1292.
A combination of structural imaging with MR imaging and functional assessment of cerebral metabolism with FDG PET, cortical amyloid deposition with 11C PiB and 18F florbetapir PET, and dopaminergic activity with 123I ioflupane SPECT can aid in differentiation and diagnosis of idiopathic Parkinson disease and atypical parkinsonian syndromes.
Movement disorders with parkinsonian features are common, and in recent years imaging has assumed a greater role in diagnosis and management. Thus, it is important that radiologists become familiar with the most common imaging patterns of parkinsonism, especially given the significant clinical overlap and diagnostic difficulty associated with these disorders. The authors review the most common magnetic resonance (MR) and molecular imaging patterns of idiopathic Parkinson disease and atypical parkinsonian syndromes. They also discuss the interpretation of clinically available molecular imaging studies, including assessment of cerebral metabolism with 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET), cortical amyloid deposition with carbon 11 (11C) Pittsburgh compound B and fluorine 18 (18F) florbetapir PET, and dopaminergic activity with iodine 123 (123I) ioflupane single photon emission computed tomography (SPECT). Although no single imaging test is diagnostic, a combination of tests may help narrow the differential diagnosis. Findings at 123I ioflupane SPECT can confirm the loss of dopaminergic neurons in patients with parkinsonism and help distinguish these syndromes from treatable conditions, including essential tremor and drug-induced parkinsonism. FDG PET uptake can demonstrate patterns of neuronal dysfunction that are specific to a particular parkinsonian syndrome. Although MR imaging findings are typically nonspecific in parkinsonian syndromes, classic patterns of T2 signal change can be seen in multiple system atrophy and progressive supranuclear palsy. Finally, positive amyloid-binding PET findings can support the diagnosis of dementia with Lewy bodies. Combined with a thorough clinical evaluation, multimodality imaging information can afford accurate diagnosis, allow selection of appropriate therapy, and provide important prognostic information.
©RSNA, 2014
doi:10.1148/rg.345140009
PMCID: PMC4319525  PMID: 25208280
23.  Malignant melanoma, breast cancer and other cancers in patients with Parkinson’s disease 
Previous studies report an atypical cancer pattern among patients with Parkinson’s disease. Here, we evaluate the cancer pattern among people diagnosed with Parkinson’s disease in an extension of our previous cohort study. For this Danish population-based cohort study, we identified 20,000 people with Parkinson’s disease diagnosed in 1977–2006, from the National Danish Hospital Register. Cohort members were followed up for cancer in the Danish Cancer Registry until December 31, 2008, and their incidence rates of cancer were compared to age-, sex- and calendar period-specific rates in the general population as standardized incidence rate ratios (SIRs). In subanalyses, we estimated the risk for cancer among patients with early onset Parkinson’s disease and we also compared breast tumor characteristics among women with Parkinson’s disease to that of a control group. The overall cancer risk in our cohort was decreased [SIR = 0.86; 95% confidence interval (CI) = 0.83–0.90], as were those for smoking-related (SIR = 0.65; 95% CI = 0.60–0.70) and nonsmoking-related cancers (SIR = 0.79; 95% CI = 0.71–0.86). The cohort had increased risks for malignant melanoma (SIR = 1.41; 95% CI = 1.09–1.80), nonmelanoma skin cancer (SIR = 1.29; 95% CI = 1.18–1.39) and female breast cancer (SIR = 1.17; 95% CI = 1.02–1.34). Among patients with early onset Parkinson’s disease, the risk for cancer was comparable to that of the general population. Of breast tumor characteristics, only grade of malignancy differed between Parkinson’s disease women and controls. This study confirms a lower cancer risk among people with Parkinson’s disease. Increased risks for malignant melanoma, nonmelanoma skin cancer and breast cancer might be due to shared risk factors with Parkinson’s disease.
doi:10.1002/ijc.27443
PMCID: PMC3636769  PMID: 22278152
Parkinson’s disease; cancer; population-based cohort; Denmark
24.  Multiple roles for nicotine in Parkinson’s disease 
Biochemical pharmacology  2009;78(7):677.
There exists a remarkable diversity of neurotransmitter compounds in the striatum, a pivotal brain region in the pathology of Parkinson’s disease, a movement disorder characterized by rigidity, tremor and bradykinesia. The striatal dopaminergic system, which is particularly vulnerable to neurodegeneration in this disorder, appears to be the major contributor to these motor problems. However, numerous other neurotransmitter systems in the striatum most likely also play a significant role, including the nicotinic cholinergic system. Indeed, there is an extensive anatomical overlap between dopaminergic and cholinergic neurons, and acetylcholine is well known to modulate striatal dopamine release both in vitro and in vivo. Nicotine, a drug that stimulates nicotinic acetylcholine receptors (nAChRs), influences several functions relevant to Parkinson’s disease. Extensive studies in parkinsonian animals show that nicotine protects against nigrostriatal damage, findings that may explain the well-established decline in Parkinson’s disease incidence with tobacco use. In addition, recent work shows that nicotine reduces L-dopa-induced abnormal involuntary movements, a debilitating complication of L-dopa therapy for Parkinson’s disease. These combined observations suggest that nAChR stimulation may represent a useful treatment strategy for Parkinson’s disease for neuroprotection and symptomatic treatment. Importantly, only selective nAChR subtypes are present in the striatum including the α4β2*, α6β2* and α7 nAChR populations. Treatment with nAChR ligands directed to these subtypes may thus yield optimal therapeutic benefit for Parkinson’s disease, with a minimum of adverse side effects.
doi:10.1016/j.bcp.2009.05.003
PMCID: PMC2815339  PMID: 19433069
L-Dopa-induced dyskinesias; Neuroprotection; Nicotine; Nicotinic; Nigrostriatal; Parkinson’s disease
25.  Inter-hemispheric asymmetry of nigrostriatal dopaminergic lesion: a possible compensatory mechanism in Parkinson’s disease 
The onset of Parkinson’s disease (PD) is characterized by focal motor features in one body part, which are usually correlated with greater dopaminergic depletion in the contralateral posterior putamen. The role of dopamine (DA) hemispheric differences in the onset and progression of motor symptoms of PD, however, remains undefined. Previous studies have demonstrated that unilateral manipulations of one nigrostriatal system affect contralateral DA turnover, indicating a functional and compensatory inter-dependence of the two nigrostriatal systems. In preliminary data obtained by our group from asymmetric PD patients, a higher asymmetry index as measured by 6-[18F]fluoro-L-dopa (18 F-DOPA) positron emission tomography (PET) was associated with a higher threshold (i.e., greater dopaminergic loss) for the onset of motor symptoms in the less-affected side. To further elucidate the underlying basis for this, we carried out a complementary study in monkeys using PET to assess and correlate the degree of dopaminergic striatal depletion with motor activity. Control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys with symmetrical lesions were characterized behaviorally and with 18F-DOPA PET. In parallel, an acute lesion was inflicted in the nigrostriatal projection unilaterally in one monkey, generating a 30% dopaminergic depletion in the ipsilateral striatum, which was not associated with any noticeable parkinsonian feature or deficit. The monkey remained asymptomatic for several months. Subsequently, this monkey received systemic MPTP, following which motor behavior and PET were repeatedly evaluated during progression of parkinsonian signs. The brains of all monkeys were processed using immunohistochemical methods. Our results suggest that the onset of motor signs is related to and influenced by the dopaminergic status of the less-affected, contralateral striatum. Although this work is still preliminary, the study agrees with our general hypothesis of hemispheric inter-dependence in the compensation of striatal DA deficit in PD.
doi:10.3389/fnsys.2011.00092
PMCID: PMC3258666  PMID: 22287944
MPTP; Parkinson’s disease; PET; dopaminergic; 18F-DOPA; compensatory mechanisms

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