[11C]-PK11195 PET: Quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson's disease?

[¹¹C]-PK11195 PET has been used for in vivo brain imaging of microglia activation in Parkinson's disease (PD) patients. COX-2 inhibition has been shown to reduce neuroinflammation and neurodegeneration in animal models of PD. This pilot study assessed the use of [¹¹C]-PK11195 PET to quantify neuroinflammation and evaluate the ability of COX-2 inhibition to reduce neuroinflammation in PD patients.MethodsFourteen PD patients and eight healthy, age matched controls underwent a [¹¹C]-PK11195 PET and MRI scan. Five PD patients were scanned before and after one month of celecoxib treatment 200 mg/day. Arterial plasma sampling and metabolite analysis were performed to create plasma input curves. A 2-compartment model and Logan analysis were applied and parametric DV images were compared using t-test in SPM2. In addition a simplified reference region model (SRTM) was applied, with both the cerebellum and a reference region derived from cluster analysis.ResultsUsing the cluster analysis, PD patients showed higher contralateral putamen BP and midbrain BP compared to controls, although considerable overlap was seen and differences were not statistically significant. Unexpectedly, BP and DV after celecoxib were slightly higher. Cerebellum as reference region resulted in lower BP values and k₃/k₄ gave 10-fold higher BP values. Linearization of the data did not show differences between PD patients and controls.ConclusionsIn current practice, [¹¹C]-PK11195 seems an unsuitable tracer for accurate or reliable quantification of neuroinflammation. Refinement of [¹¹C]-PK11195 uptake analysis and, more importantly, further development of better tracers is necessary to enable accurate measurement of neuroinflammation and effects of anti-inflammatory treatment in patients.     

Gene–environment interactions in Parkinson's disease and other forms of parkinsonism

It is widely recognized that both genetic and environmental factors are likely to contribute to the pathogenesis of human parkinsonism. While the identification of specific predisposing conditions and mechanisms of disease development remain elusive, new discoveries coupled with technological advances over the past decade have provided important clues. From the genetic standpoint, both causal and susceptibility genes have been identified, with some of these genes pointing to gene–environment interactions. The application of emerging genomic technologies, such as Genome Wide Association Studies (GWAS), will certainly further our knowledge of Parkinson's disease (PD)-related genes. From the environmental perspective, toxicant-induced models of parkinsonian syndromes, such as those associated with exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or β-N-methylamino-l-alanine (BMAA), have revealed potential mechanisms of increased susceptibility based on genetic predisposition. Finally, new hypotheses on mechanisms of disease development include the possibility that exposure to neurotoxicants triggers an upregulation and pathological modifications of α-synuclein. Mutations in the α-synuclein gene are responsible for rare familial cases of parkinsonism, and polymorphisms in the promoter region of this gene confer a higher susceptibility to idiopathic PD. Thus, toxicant–α-synuclein interactions could have deleterious consequences and play a role in pathogenetic processes in human parkinsonism.     

“On-off” phenomenon in Parkinson's disease: Correlation to the concentration of dopa in plasma

Summary To investigate the relation between on-off fluctuations in symptomatology and bioavailability of dopa in patients with Parkinson's disease, five Parkinsonian patients with pronounced on-off symptoms were studied. Continuously during the study the degree of disability in the patients was registered. Every one hour, and in addition, whenever there was a change from on to off or vice versa, a blood sample was collected for dopa determination. Since dopa is transported from plasma into the brain by a saturable carrier for which it has to compete with endogenous large neutral amino acids (LNAA), the concentrations of these competitors were measured too.In four of the patients there were considerable oscillations in the plasma dopa concentration during the day; in one of these patients the highest value was as much as 12 times higher than the lowest value. These dramatic fluctuations in the absolute concentration of dopa in plasma had a major influence on the relative dopa concentrations (calculated as the ratio dopa/sum of LNAA) as the fluctuations in the concentrations of LNAA in plasma were much less pronounced. Consequently, the absolute and the relative concentrations of dopa in plasma were highly parallelled.In four of the five patients on-periods began within one hour after a peak in the concentration of dopa in plasma and in the fifth patient five out of seven on-periods were preceded by a rise in plasma dopa concentration within the same time interval.From the present data it could be concluded that the on-off phenomenon in Parkinson's disease, at least partly, is due to oscillations in the concentration of dopa in plasma. A reduction in the variations of the concentration of dopa in plasma seems to be necessary to overcome the on-off problem. The introduction of a slow release preparation of dopa is therefore urgently warranted. The concentration of LNAA in plasma must, however, also be considered in this context.     

A longitudinal study of motor performance and striatal [18F]fluorodopa uptake in Parkinson��s disease

Although [(18)F]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.     

Striatal [123I]β-CIT SPECT and prefrontal cognitive functions in Parkinson's disease

Summary. Twenty non-demented patients with idiopathic Parkinson's disease (PD) underwent single photon emission computed tomography (SPECT) with [¹²³I]β-CIT to further investigate the contribution of nigrostriatal dysfunction to cognitive and motor deficits. Compared to matched controls PD patients showed normal verbal intelligence, short-term memory and phasic alertness. There were significant (p < 0.05) deficits in tests of verbal working memory (digit ordering, reading span), strategic memory (story recall) and executive functions (card sorting), indicating a "prefrontal" cognitive deficit. Significant (p < 0.05) correlations were observed between dopamine transporter (DAT) density in the putamen and motor deficits as well as between DAT density in both striatal compartments (head of the caudate nucleus and putamen) and prefrontal functioning. Age was a major contributing factor to both cognitive status and nigrostriatal integrity as measured by [¹²³I]β-CIT SPECT. These results support the view that the striatum is part of a neuronal network that is mediating prefrontal cognitive functions. Received February 26, 1999; accepted August 18, 1999     

Relationship between baseline brain metabolism measured using [18F]FDG PET and memory and executive function in prodromal and early Alzheimer’s disease

Differences in brain metabolism as measured by FDG-PET in prodromal and early Alzheimer’s disease (AD) have been consistently observed, with a characteristic parietotemporal hypometabolic pattern. However, exploration of brain metabolic correlates of more nuanced measures of cognitive function has been rare, particularly in larger samples. We analyzed the relationship between resting brain metabolism and memory and executive functioning within diagnostic group on a voxel-wise basis in 86 people with AD, 185 people with mild cognitive impairment (MCI), and 86 healthy controls (HC) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We found positive associations within AD and MCI but not in HC. For MCI and AD, impaired executive functioning was associated with reduced parietotemporal metabolism, suggesting a pattern consistent with known AD-related hypometabolism. These associations suggest that decreased metabolic activity in the parietal and temporal lobes may underlie the executive function deficits in AD and MCI. For memory, hypometabolism in similar regions of the parietal and temporal lobes were significantly associated with reduced performance in the MCI group. However, for the AD group, memory performance was significantly associated with metabolism in frontal and orbitofrontal areas, suggesting the possibility of compensatory metabolic activity in these areas. Overall, the associations between brain metabolism and cognition in this study suggest the importance of parietal and temporal lobar regions in memory and executive function in the early stages of disease and an increased importance of frontal regions for memory with increasing impairment.     

Evaluation of 2-[18F]fluoroacetate kinetics in rodent models of cerebral hypoxia–ischemia

Glia account for 90% of human brain cells and have a significant role in brain homeostasis. Thus, specific in vivo imaging markers of glial metabolism are potentially valuable. In the brain, 2-fluoroacetate is selectively taken up by glial cells and becomes metabolically trapped in the tricarboxylic acid cycle. Recent work in rodent brain injury models demonstrated elevated lesion uptake of 2-[¹⁸F]fluoroacetate ([¹⁸F]FACE), suggesting possible use for specifically imaging glial metabolism. To assess this hypothesis, we evaluated [¹⁸F]FACE kinetics in rodent models of cerebral hypoxia–ischemia at 3 and 24 hours post insult. Lesion uptake was significantly higher at 30 minutes post injection (P<0.05). An image-based method for input function estimation using cardiac blood was validated. Analysis of whole blood showed no significant metabolites and plasma activity concentrations of ∼50% that of whole blood. Kinetic models describing [¹⁸F]FACE uptake were developed and quantitatively compared. Elevated [¹⁸F]FACE uptake was found to be driven primarily by K₁/k₂ rather than k₃, but changes in the latter were detectable. The two-tissue irreversible uptake model (2T3k) was found to be necessary and sufficient for modeling [¹⁸F]FACE uptake. We conclude that kinetic modeling of [¹⁸F]FACE uptake represents a potentially useful tool for interrogation of glial metabolism.     

β-Hexachlorocyclohexane levels in serum and risk of Parkinson's disease

Pesticide exposure has been implicated as an environmental risk factor for the development of Parkinson's disease (PD). However, few studies have identified specific pesticides. Previously, we identified elevated serum levels of the organochlorine pesticide β-hexachlorocyclohexane (β-HCH) in PD patients from a small clinical sample. Here, we conducted a case-control study to confirm the association between β-HCH and PD in a larger sample size (n=283) with serum samples of PD patients and controls obtained from UT Southwestern Medical Center and Emory University. Samples were obtained from two discrete periods at both sites, 2001-2003 and 2006-2008, and were analyzed for β-HCH levels. Adjusted odds ratios (ORs) for PD were estimated using logistic regression and generalized estimating equations. The mean serum β-HCH level across all cohorts in this study was 22.3 ng/mg cholesterol (range: 0-376.7), and the levels were significantly higher and samples collected in 2001-2003 vs. 2006-2008. After controlling for age and gender, the OR for increased risk of PD for every 1 ng/mg increase in serum β-HCH ranged from 1.02 to 1.12 across the four different cohorts, and 1.03 (95% CI: 1.00-1.07, p value=0.031) in the pooled analysis. Furthermore, the OR for increased risk of PD of subjects having serum β-HCH levels above the inter-quartile range of 39.08 ng/mg cholesterol was 2.85 (95% CI: 1.8, 4.48; p value<0.001). These data are consistent with environmental decreases in β-HCH levels between 2001 and 2008, but they indicate that elevated levels of serum β-HCH are still associated with heightened risk for PD.     

[18F]-AV-1451 tau PET imaging in Alzheimer’s disease and suspected non-AD tauopathies using a late acquisition time window

Journal of Neurology - The utility of tau PET imaging in non-Alzheimer’s disease (AD) tauopathies like behavioural frontotemporal dementia (bvFTD), which is mainly underlain by TDP-43 or tau...     

Involvement of α-synuclein in Parkinson's disease and other neurodegenerative disorders

Summary. A major step in the elucidation of the pathogenesis of neurodegenerative disorders was the identification of a mutation in the α-synuclein gene in autosomal dominant Parkinson's disease (PD). α-Synuclein is the main component of Lewy bodies (LB), the neuropathological hallmark of PD. Moreover, a fragment of α-synuclein (NAC) is the second major component of amyloid plaques in Alzheimer's disease (AD). Recent studies of other neurodegenerative disorders such as dementia with LB (DLB), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) also revealed intracellular accumulations of α-synuclein in affected brain regions. This may indicate that these disorders partially share common pathogenic mechanisms. Recent data provide first insights into the physiological function of α-synuclein and support the concept of an essential role of α-synuclein in neurodegeneration. Increasing knowledge on the pathogenic molecular mechanisms of neurodegeneration and of the pathophysiological function of α-synuclein in particular may influence future development of therapeutic strategies in neurodegenerative disorders. Received April 9, 1999; accepted June 16, 1999     

Establishing test–retest reliability of an adapted [18F]fallypride imaging protocol in older people

[¹⁸F]fallypride is a high-affinity dopamine D2/3 receptor tracer with the ability to reliably quantify D2/3 receptor sites in both striatal and corticolimbic regions. The translational potential of [¹⁸F]fallypride imaging is, however, limited by the lengthy scanning sessions (60–80 minutes duration over a total of 3–4 hours) required by current protocols. The aims of our study were to adapt [¹⁸F]fallypride imaging for use in clinical populations with neurological and neuropsychiatric disorders, by reducing the duration of individual scanning sessions; and to establish the reproducibility and reliability of our adapted protocol in healthy older people. Eight participants (five male and three female; mean age=75.87±4.39 years) were scanned twice, 4–6 weeks apart. [¹⁸F]fallypride binding potential was determined from image data collected during three sampling times: 0–30; 60–90; and 210–240 minutes post injection. High reproducibility and reliability (test–retest variability <8% intraclass correlation coefficient >0.8) were observed in all but the prefrontal regions, and remained so when sampling times were reduced to 20 minutes (0–20; 70–90; 220–240 minutes). The adapted protocol is feasible for use across neuropsychiatric disorders in which dopamine has been implicated and is sufficiently sensitive to detect within-subject changes between 2.7% and 5.5% in striatal and limbic regions.     

[11C]d-threo-methylphenidate PET in patients with Parkinson’s disease and essential tremor

Summary. Twenty Parkinson’s disease (PD) patients, 6 patients with essential tremor and 10 healthy controls were studied with the dopamine transporter ligand [¹¹C]d-threo-methylphenidate ([¹¹C]dMP) and positron emission tomography (PET) to assess dopamine terminal loss in relation to disease duration and motor disability. Dopamine transporter availability was expressed as [¹¹C]dMP binding potential (BP_dMP) in percentage of the mean of healthy controls. In PD patients (age at onset 57.7 ± 8.9 yrs; disease duration 5.2 ± 3.3 yrs; UPDRS motor score 24.2 ± 9.8; Hoehn & Yahr 2.1 ± 0.8; mean ± SD) BP_dMP was reduced to 30% (range: 11–55%) in the putamen and 52% (range: 14–96%) in the caudate nucleus. BP_dMP in the putamen closely correlated with the UPDRS motor score (r = −0.79, p < 0.001), and disease duration (r = −0.76, p < 0.001) but not with age at onset. The correlation with the UPDRS score depended on akinesia and rigidity, while the tremor scores were related neither to putamen nor caudate BP_dMP. Interestingly, when plotted over disease duration, PD patients with severe asymmetry of symptoms showed significantly lower BP_dMP in the contralateral putamen (exponential fit: 34% at onset) than the other PD patients (41% at onset), indicating a different symptomatic threshold of these subgroups and an even closer correlation with the hypothetical “true” disease duration. The exponential fit across all patients indicated a mean symptomatic threshold of 37% contra- and 62% ipsilateral, corresponding with an observed mean BP_dMP of 51% (average contra- and ipsilateral) in those patients with disease duration less than one year. No differences in BP_dMP were observed between patients with essential tremor and healthy controls. [¹¹C]dMP appears to be a useful and sensitive marker of dopaminergic dysfunction in PD and can be used to assess and monitor disease severity. Both authors contributed equally     

Measuring the progression of idiopathic Parkinson's disease with [123I] β-CIT SPECT

Summary. Idiopathic Parkinson's disease (PD) is the most common neurodegenerative disorder. An important step in diagnosing the dis-ease has been achieved with the development of the cocaine derivative [¹²³I] β-CIT for single photon emission computed tomography (SPECT). The aim of this study was to demonstrate the disease progression by repeated measuring presynaptic dopamine transporter density and relating it to clinical data. Methods: The presynaptic dopamine transporter densitiy of 15 PD patients was measured two times with a mean interval of 15 months. All patients were clinically assessed at the time of the experiments according to the classification scheme of Hoehn and Yahr. 11 healthy volunteers were used as a control group. [¹²³I] β-CIT was injected intravenously and measured with a triple-headed camera twenty hours later. The pictures were evaluated semiquantitatively by using the ratio of specific to non-displaceable binding. Results: Presynaptic dopamine transporter density differed significantly between controls and PD patients. A significant correlation between imaging data and clinical stages (H/Y I −27%, H/Y II −40%, H/Y III −58%) was observed for the patient group in the initial experiment. The subsequent decrease of dopamine transporter binding depended on the initial clinical stage (H/Y I −6.81%; H/Y II −6.05%; H/Y III −1.25%) of the patients, and regression analysis revealed that. 91.4% of the variance of the second measurement were predicted by the initial measurement. No correlations were found for age, gender and disease progression. All patients were treated with L-DOPA and those given a higher dose showed a more rapid decrease of dopamine transporter density. This result could be interpreted as an indication for in vivo neurotoxicity of high concentrations of L-DOPA. Conclusion: We conclude that combining [¹²³I] β-CIT with SPECT imaging is not only a powerful tool for diagnosing PD patients, but may also be used to demonstrate neurodegeneration in vivo. Received June 9, 1999; accepted October 6, 1999     

Patterns of α-synuclein pathology in incidental cases and clinical subtypes of Parkinson's disease

Parkinson's disease (PD) is characterized by a gradual accumulation of neuropathology that may begin many years before a clinical diagnosis can be made using currently accepted criteria. Here, we first review the prevalence of α-synuclein neuropathology in elderly and discuss its clinical relevance in Parkinson patients. Subsequently, the results of a retrospective study focussing on the distribution of neuropathology in Parkinson patients with a tremor-dominant (TD), non-tremordominant (NTD) or rapid disease progression (RDP) subtype are presented. The study population recruited by the Netherlands Brain bank consisted of 149 non-neurological donors, 26 donors with incidental Lewy body disease (iLBD) and 111 Parkinson patients. In total, 89% of these cases could be classified in accordance with the Braak staging when taking into account the severity of α-synuclein pathology and adding an amygdala-predominant category of synucleinopathy. The pathological progression seemed to be non-linear. Interestingly, a strong correlation between neuronal loss and α-synuclein pathology was observed in the substantia nigra in Braak stages 3-6 (P < 0.01). However, there was no correlation between Hoehn & Yahr and Braak stages. Neuropathological progression may, however, vary between subtypes as cortical Lewy body load and Braak stages were higher in patients with NTD compared to TD and Alzheimer pathology was more prevalent in RDP patients. Recognition of clinical subtypes in neuropathological studies is essential to identify selective vulnerability to protein accumulation that may determine the clinical phenotype in PD.     

Does botulinum toxin decrease frequency and severity of sialorrhea in Parkinson's disease?

This study analysed if botulinum toxin type A (BTX-A) decreases drooling in 21 Parkinson's disease patients. BTX-A injections were given in the parotid glands. The severity of drooling decreased in 18 (86%) patients, while frequency was reduced in 8 (38%). In 11(52%) patients, the frequency of drooling remained constant, which may reflect more difficulties in swallowing, compared to the group that presented such improvement. Future trials assessing the level of swallowing dysfunction may be important to establish a prognosis for patients who keep the frequency of drooling in spite of decreased severity after BTX injection.     

Are quantitative and clinical measures of bradykinesia related in advanced Parkinson's disease?

Introduction

Bradykinesia is usually assessed using clinical rating scales. In some circumstances, a laboratory assessment of bradykinesia using tools of higher resolution is required. One task often used for the evaluation of bradykinesia is a rapid alternating movement (RAM) of the hand. However, the relationship between clinical scores of bradykinesia and the properties of a RAM task assessed quantitatively has yet to be determined.

Objective

Identify which of the commonly used properties of a RAM task are related to a clinical score of bradykinesia and assess the strength of this relationship.

Methods

Nineteen patients with idiopathic Parkinson's disease were tested ON and OFF medication. They performed three trials of the RAM task and were assessed clinically using the Unified Parkinson's disease rating scale in each condition and with each hand.

Results

A statistically significant correlation was observed between the clinical score of bradykinesia and two of the properties of the RAM task; namely mean and maximal velocity.

Comparison with existing methods

These results indicate that a RAM task does provide a measure of bradykinesia but it is only moderately correlated to a clinical rating of this motor symptom.

Conclusion

We propose that the results from the RAM task represent a measure of “core bradykinesia” while a clinical evaluation represents a composite score of bradykinesia, movement amplitude and motor coordination.     

Comparison of the behavioural and histological characteristics of the 6-OHDA and α-synuclein rat models of Parkinson's disease

Development of relevant models of Parkinson's disease (PD) is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising targets for therapeutic intervention. To date, most pre-clinical studies have been performed in the well-established rodent and non-human primate models using injection of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). Overexpression of the disease-causing protein α-synuclein (α-syn), using adeno-associated viral (AAV) vectors, has provided a novel model that recapitulates many features of the human disease. In the present study we compared the AAV-α-syn rat model with models where the nigro-striatal pathway is lesioned by injection of 6-OHDA in the striatum (partial lesion) or the medial forebrain bundle (full lesion). Examination of the behavioural changes over time revealed a different progression and magnitude of the motor impairment. Interestingly, dopamine (DA) neuron loss is prominent in both the toxin and the AAV-α-syn models. However, α-syn overexpressing animals were seen to exhibit less cell and terminal loss for an equivalent level of motor abnormalities. Prominent and persistent axonal pathology is only observed in the α-syn rat model. We suggest that, while neuronal and terminal loss mainly accounts for the behavioural impairment in the toxin-based model, similar motor deficits result from the combination of cell death and dysfunction of the remaining nigro-striatal neurons in the AAV-α-syn model. While the two models have been developed to mimic DA neuron deficiency, they differ in their temporal and neuropathological characteristics, and replicate different aspects of the pathophysiology of the human disease. This study suggests that the AAV-α-syn model replicates the human pathology more closely than either of the other two 6-OHDA lesion models.