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.
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.
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.
Although [18F]fluoro-L-dopa [FDOPA] positron emission tomography (PET) has been used as a surrogate outcome measure in Parkinson's disease therapeutic trials, this biomarker has not been proven to reflect clinical status longitudinally. We completed a retrospective analysis of relationships between computerized sampling of motor performance, FDOPA PET, and clinical outcome scales, repeated over 4 years, in 26 Parkinson's disease (PD) patients and 11 healthy controls. Mixed effects analyses showed that movement time and tongue strength best differentiated PD from control subjects. In the treated PD cohort, motor performance measures changed gradually in contrast to a steady decline in striatal FDOPA uptake. Prolonged reaction and movement time were related to lower caudate nucleus FDOPA uptake, and abnormalities in hand fine force control were related to mean striatal FDOPA uptake. These findings provide evidence that regional loss of nigrostriatal inputs to frontostriatal networks affects specific aspects of motor function.
Fluorodopa; motor control; Parkinson's disease; positron emission tomography; ageing; Tongue/*physiopathology; Facial Muscles/*physiopathology
examine the distribution of striatal dopaminergic function in humans
with parkinsonism induced by
to determine if there is a caudate-putamen gradient as is seen in idiopathic Parkinson's disease.
nine humans exposed to MPTP with parkinsonism ranging from minimal to
severe using [18F]fluorodopa (FD) and high resolution
PET. The results were compared with those of 10 patients with
Parkinson's disease and six normal subjects.
RESULTS—In the MPTP
group there was an equal degree of reduction of dopaminergic function
in the caudate and putamen. This was different from the greater
putaminal than caudate loss in Parkinson's disease (p<0.001).
disease is not caused by transient exposure to MPTP.
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.
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).
and 18F-dopa PET, reductions in both striatal and nigral
brain dopaminergic function could be demonstrated in early Parkinson's disease.
OFF-l-dopa dyskinesias have been a surprising side-effect of intrastriatal foetal ventral mesencephalic transplantation in patients with Parkinson's disease. It has been proposed that excessive and unregulated dopaminergic stimulation of host post-synaptic striatal neurons by the grafts could be responsible for these dyskinesias. To address this issue we transplanted foetal dopaminergic neurons from mice lacking the dopamine transporter (DATKO) or from wild-type mice, into a rat model of Parkinson's disease and l-dopa-induced dyskinesias. Both wild-type and DATKO grafts reinnervated the host striatum to a similar extent, but DATKO grafts produced a greater and more diffuse increase in extra-cellular striatal dopamine levels. Interestingly, grafts containing wild-type dopaminergic neurons improved parkinsonian signs to a similar extent as DATKO grafts, but provided a more complete reduction of l-dopa induced dyskinesias. Neither DATKO nor wild-type grafts induced OFF-l-dopa dyskinesias. Behavioural and receptor autoradiography analyses demonstrated that DATKO grafts induced a greater normalization of striatal dopaminergic receptor supersensitivity than wild-type grafts. Both graft types induced a similar downregulation and normalization of PEnk and fosb/Δfosb in striatal neurons. In summary, DATKO grafts causing high and diffuse extra-cellular dompamine levels do not per se alter graft-induced recovery or produce OFF-l-dopa dyskinesias. Wild-type dopaminergic neurons appear to be the most effective neuronal type to restore function and reduce l-dopa-induced dyskinesias.
Parkinson's disease; transplantation; dyskinesia; dopamine; synapse
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.
positron emission tomography; Parkinson’s disease/radionuclide imaging; dopamine/metabolism
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.
MPTP; Parkinson’s disease; PET; dopaminergic; 18F-DOPA; compensatory mechanisms
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.
dopamine; Parkinson's disease; fMRI; functional connectivity; striatum; neural oscillation
Neuroleptic medication in three patients with prior isolated postural arm tremor led to a conspicuous deterioration; the postural tremor increased in amplitude, tremor appeared at rest, and other signs of mild parkinsonism developed. Withdrawal of neuroleptic drugs led to improvement in tremor and disappearance of parkinsonism. Positron emission tomography showed no reduction in uptake of [18F]dopa into nigrostriatal terminals suggesting that these patients did not have Parkinson's disease. Neuroleptic drugs can convert postural essential arm tremor into that characteristic of Parkinson's disease in patients with no evident nigrostriatal lesion.
Dysfunction of the dopaminergic pathway has been postulated to underlie the symptomatology of Tourette's syndrome. Presynaptic functional integrity of dopaminergic terminals was assessed with 18F-dopa PET in 10 patients with Tourette's syndrome, three of whom were drug free and seven of whom were on neuroleptic treatment. Dopamine D2 receptor site density was measured with 11C-raclopride PET in a further group of five drug free patients with Tourette's syndrome. Mean caudate and putamen 18F-dopa influx constants were similar in patients with Tourette's syndrome and controls, and there was no difference in striatal 18F-dopa uptake between the treated and untreated Tourette's syndrome groups. Mean caudate and putamen 11C-raclopride binding potentials in patients with Tourette's syndrome were also similar to control values. The findings suggest that striatal metabolism of exogenous levodopa and the density of striatal D2 receptors are both normal in patients with Tourette's syndrome and that Tourette's syndrome does not arise from a primary dysfunction of dopaminergic terminals.
Six patients diagnosed as Parkinson's disease on a clinical basis alone are described, and their response to L-dopa and to alpha methyl dopa hydrazine (MK 486) and L-dopa. They are compared with 239 other patients with Parkinson's disease treated in the same time period. These six patients were unusual in that they did not have a clinical response to L-dopa, nor did they develop dyskinesias on L-dopa or on L-dopa with MK 486, although they showed high blood levels of L-dopa and high homovanillic acid levels in the spinal fluid. Unresponsiveness to L-dopa is attributed to a specific brain mechanism and not to problems of transport of L-dopa to the brain or to abnormal peripheral metabolism of L-dopa. The term `motor unresponsiveness to L-dopa' may be useful to describe such patients who may eventually be shown to be suffering from diseases other than Parkinsonism.
High-frequency stimulation of the subthalamic nucleus (STN-HFS) is a powerful approach for treating the motor symptoms of Parkinson’s disease. It results in clinical improvement in PD patients, further reducing L-3, 4-dihydroxyphenylalanine (L-DOPA) requirement and thus L-DOPA-induced dyskinesia. However, it remains unclear how STN-HFS modifies the response to L-DOPA. We investigated the effect of STN-HFS on striatal extracellular concentrations of dopamine and its metabolites following acute L-DOPA administration in intact or partially dopaminergic denervated (DA PL) rats. L-DOPA treatment significantly increased striatal dopamine levels in intact and DA PL animals, with the maximal effect observed 1 h after L-DOPA injection. This increase was more pronounced in DA PL rats (ipsilateral to the lesion) than in intact animals. It remained fairly stable 1 h after the maximal effect of L-DOPA and then decreased towards basal values. STN-HFS in intact rats had no effect on the maximal L-DOPA-induced increase in striatal extracellular dopamine concentration or the return to basal values, the profiles observed being similar to those for non-stimulated intact animals. Conversely, STN-HFS amplified the L-DOPA-induced increase in striatal dopamine levels during the stimulation period (1 h) in DA PL rats, and this increase was sustained throughout the post-stimulation period (2.5 h), without the return to basal levels observed in stimulated intact and non-stimulated rats. These new neurochemical data suggest that STN-HFS interferes with L-DOPA effects, probably synergically, by stabilising dopamine levels in the striatum, and shed light on the mechanisms of STN-HFS in PD.
3,4-Dihydroxyphenylacetic Acid; metabolism; Animals; Data Interpretation, Statistical; Denervation; Dihydroxyphenylalanine; pharmacology; Dopamine; metabolism; Dopamine Agents; pharmacology; Electric Stimulation; Extracellular Space; drug effects; metabolism; Homovanillic Acid; metabolism; Male; Microdialysis; Neostriatum; drug effects; metabolism; physiology; Oxidopamine; Rats; Rats, Sprague-Dawley; Subthalamic Nucleus; physiology; Synaptic Transmission; drug effects; physiology; Parkinson's disease; high-frequency stimulation; subthalamic nucleus; dopamine; L-DOPA treatment
Parkinson’s disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor L-dopa is the mainstay of current treatment. After several years, however, the patients develop L-dopa–induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein–coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson’s disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the anti-parkinsonian effects of L-dopa and even prolonged the antiparkinsonian effect of a lower dose of L-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of L-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson’s disease.
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.
Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.
PMID: 19346328 CAMSID: cams2369
Parkinson’s disease; dopamine; impulse control disorders; pathological gambling; PET; functional imaging
Parkinson's disease is a common disabling disease of old age. The diagnosis of idiopathic Parkinson's disease is based on clinical signs and has poor sensitivity, with about 25% of patients confidently diagnosed as having the disease actually having other conditions such as multi-system atrophy and other parkinsonism-plus syndromes. Benign essential tremor and arteriosclerotic pseudo-parkinsonism can easily be confused with Parkinson's disease. The cause of Parkinson's disease remains unknown. Speculative research highlights the role of oxidative stress and free radical mediated damage to dopaminergic cells. Parkinson's disease is the one neurodegenerative disorder in which drugs have been demonstrated to be of value. There is now a wide variety of drugs and formulations available, including anticholinergics, amantidine, L-dopa, dopamine agonists including apomorphine, selegiline and soon to be available catechol-O-methyltransferase inhibitors. Disabling side-effects of treatment, fluctuations, dyskinesias and psychiatric problems require strategic use of the drugs available. There is an increasing potential for neurosurgical intervention.
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.
To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.
A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated.
Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations.
The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss.
The dopamine receptor agonist apomorphine has been used successfully to treat on-off swings in Parkinson's disease. Its value as a predictor of dopa responsiveness in idiopathic Parkinson's disease (IPD) was assessed and its potential role in differentiating IPD from the Parkinsonian plus syndromes (PPS) of multisystem atrophy, progressive supranuclear palsy and olivopontocerebellar atrophy was investigated. The response to an injection of apomorphine was observed in 20 patients with IPD and eight with PPS after being off levodopa for 12 hours. Patients were reassessed after taking levodopa for one month. Nineteen of the 20 patients (95%) with IPD showed a positive response to apomorphine and 18 (90%) to oral levodopa. In the PPS group, two patients (25%) responded to the apomorphine injection but not to oral levodopa. Apomorphine produced severe drowsiness in the PPS patients. It is suggested that the test can predict dopa responsiveness in IPD and may be of help in confirming a doubtful diagnosis. It has potential value in differentiating IPD from PPS.
Degeneration of nigrostriatal neurons in Parkinson's disease (PD) causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa (l-DOPA) into dopamine in the striatum. Because loss of this enzyme appears to be a major driver of progressive impairment of response to the mainstay drug, l-DOPA, one promising approach has been to use gene therapy to restore AADC activity in the human putamen and thereby restore normal l-DOPA response in patients with PD. An open-label phase I clinical trial of this approach in patients with PD provided encouraging signs of improvement in Unified Parkinson's Disease Rating Scale scores and reductions in antiparkinsonian medications. However, such improvement was modest compared with the results previously reported in parkinsonian rhesus macaques. The reason for this discrepancy may have been that the relatively small volume of vector infused in the clinical study restricted the distribution of AADC expression, such that only about 20% of the postcommissural putamen was covered, as revealed by l-[3-18F]-α-methyltyrosine-positron emission tomography. To achieve more quantitative distribution of vector, we have developed a visual guidance system for parenchymal infusion of AAV2. The purpose of the present study was to evaluate the combined magnetic resonance imaging-guided delivery system with AAV2-hAADC under conditions that approximate the intended clinical protocol. Our data indicate that this approach directed accurate cannula placement and effective vector distribution without inducing any untoward effects in nonhuman primates infused with a high dose of AAV2-hAADC.
San Sebastian and colleagues evaluate a magnetic resonance imaging-guided delivery system for CNS parenchymal infusion of adeno-associated viral type 2 (AAV2) vector encoding human aromatic l-amino acid decarboxylase (hAADC), a key enzyme lost during Parkinson's disease progression. This visual guidance approach directs accurate cannula placement and allows for effective distribution of a high AAV2-hAADC dose in nonhuman primates without any adverse effects.
The present behavioral study re-addresses the question of habit learning in Parkinson's disease (PD). Patients were early onset, non-demented, dopa-responsive, candidates for surgical treatment, similar to those we found earlier as suffering greater dopamine depletion in the putamen than in the caudate nucleus. The task was the same conditional associative learning task as that used previously in monkeys and healthy humans to unveil the striatum involvement in habit learning. Sixteen patients and 20 age- and education-matched healthy control subjects learned sets of 3 visuo-motor associations between complex patterns and joystick displacements during two testing sessions separated by a few hours. We distinguished errors preceding vs. following the first correct response to compare patients' performance during the earliest phase of learning dominated by goal-directed actions with that observed later on, when responses start to become habitual. The disease significantly retarded both learning phases, especially in patients under 60 years of age. However, only the late phase deficit was disease severity-dependent and persisted on the second testing session. These findings provide the first corroboration in Parkinson patients of two ideas well-established in the animal literature. The first is the idea that associating visual stimuli to motor acts is a form of habit learning that engages the striatum. It is confirmed here by the global impairment in visuo-motor learning induced by PD. The second idea is that goal-directed behaviors are predominantly caudate-dependent whereas habitual responses are primarily putamen-dependent. At the advanced PD stages tested here, dopamine depletion is greater in the putamen than in the caudate nucleus. Accordingly, the late phase of learning corresponding to the emergence of habitual responses was more vulnerable to the disease than the early phase dominated by goal-directed actions.
feedback-based learning; striatum; habits; goal-directed actions; Parkinson's disease
Parkinson’s disease is a common neurodegenerative disorder caused by the degeneration of midbrain substantia nigra dopaminergic neurons that project to the striatum. Despite extensive investigation aimed at finding new therapeutic approaches, the dopamine precursor molecule, 3,4-dihydroxyphenyl-l-alanine (l-DOPA), remains the most effective and commonly used treatment. However, chronic treatment and disease progression lead to changes in the brain’s response to l-DOPA, resulting in decreased therapeutic effect and the appearance of dyskinesias. l-DOPA-induced dyskinesia (LID) interferes significantly with normal motor activity and persists unless l-DOPA dosages are reduced to below therapeutic levels. Thus, controlling LID is one of the major challenges in Parkinson’s disease therapy. LID is the result of intermittent stimulation of supersensitive D1 dopamine receptors located in the very severely denervated striatal neurons. Through increased coupling to Gαolf, resulting in greater stimulation of adenylyl-cyclase, D1 receptors phosphorylate DARPP-32, and other protein kinase A targets. Moreover, D1 receptor stimulation activates extracellular signal-regulated kinase and triggers a signaling pathway involving mammalian target for rapamycin and modifications of histones that results in changes in translation, chromatin modification, and gene transcription. In turn, sensitization of D1 receptor signaling causes a widespread increase in the metabolic response to D1 agonists and changes in the activity of basal ganglia neurons that correlate with the severity of LID. Importantly, different studies suggest that dyskinesias may share mechanisms with drug abuse and long term memory involving D1 receptor activation. Here we review evidence implicating D1 receptor signaling in the genesis of LID, analyze mechanisms that may translate enhanced D1 signaling into dyskinetic movements, and discuss the possibility that the mechanisms underlying LID are not unique to the Parkinson’s disease brain.
l-DOPA-induced dyskinesia; D1 dopamine receptor; Parkinson’s disease
Methods: FA values were compared in the extrapyramidal system of 12 patients with Parkinson's disease and eight age matched normal controls.
Results: Patients with Parkinson's disease had significantly decreased FA in the region of interest along a line between the substantia nigra and the lower part of the putamen/caudate complex, in which most of the nigrostriatal dopaminergic neurones are included. Loss of FA in this region was obvious even during the early clinical stages of Parkinson's disease.
Conclusions: Assuming that the loss of FA parallels the neuronal change in the brain, the results are consistent with the view that more than half the dopaminergic neurones in the nigrostriatal projection are lost before the onset of Parkinson's disease. Close comparison of FA in the basal ganglia may contribute to the early diagnosis of Parkinson's disease.