Cannabinoid Receptor Type 1 in Parkinson's Disease: A Positron Emission Tomography Study with [18 F]FMPEP-d2.

BACKGROUND: The endocannabinoid system is a widespread neuromodulatory system affecting several biological functions and processes. High densities of type 1 cannabinoid (CB1) receptors and endocannabinoids are found in basal ganglia, which makes them an interesting target group for drug development in basal ganglia disorders such as Parkinson's disease (PD). OBJECTIVE: The aim of this study was to investigate CB1 receptors in PD with [18 F]FMPEP-d2 positron emission tomography (PET) and the effect of dopaminergic medication on the [18 F]FMPEP-d2 binding. METHODS: The data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [18 F]FMPEP-d2 high-resolution research tomograph PET examination for the quantitative assessment of cerebral binding to CB1 receptors. To investigate the effect of dopaminergic medication on the [18 F]FMPEP-d2 binding, 15 subjects with PD underwent [18 F]FMPEP-d2 PET twice, both on and off antiparkinsonian medication. RESULTS: [18 F]FMPEP-d2 distribution volume was significantly lower in the off scan compared with the on scan in basal ganglia, thalamus, hippocampus, and amygdala (P < 0.05). Distribution volume was lower in subjects with PD off than in HCs globally (P < 0.05), but not higher than in HCs in any brain region. CONCLUSIONS: Subjects with PD have lower CB1 receptor availability compared with HCs. PD medication increases CB1 receptor toward normal levels. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Validation of the Finnish Version of the Unified Dyskinesia Rating Scale.

INTRODUCTION: The Unified Dyskinesia Rating Scale (UDysRS) was developed to provide a comprehensive rating tool of dyskinesia in Parkinson's disease (PD). Because dyskinesia therapy trials involve multicenter studies, having a scale that is validated in multiple non-English languages is pivotal to international efforts to treat dyskinesia. The aim of the present study was to organize and perform an independent validation of the UDysRS Finnish version. METHODS: The UDysRS was translated into Finnish and then back-translated into English using 2 independent teams. Cognitive pretesting was conducted on the Finnish version and required modifications to the structure or wording of the translation. The final Finnish version was administered to 250 PD patients whose native language is Finnish. The data were analyzed to assess the confirmatory factor structure to the Spanish UDysRS (the reference standard). Secondary analyses included an exploratory factor analysis (EFA), independent of the reference standard. RESULTS: The comparative fit index (CFI), in comparison with the reference standard factor structure, was 0.963 for Finnish. In the EFA, where variability from sample to sample is expected, isolated item differences of factor structure were found between the Finnish and Reference Standard versions of the UDysRS. These subtle differences may relate to differences in sample composition or variations in disease status. CONCLUSION: The overall factor structure of the Finnish version was consistent with that of the reference standard, and it can be designated as the official version of the UDysRS for Finnish speaking populations.

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [11C]PBR28 HRRT PET study.

PURPOSE: The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. METHODS: [11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. RESULTS: There were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. CONCLUSION: These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

No Efficacy with Noninvasive Brain Stimulation for Painful Legs and Moving Toes: A Case Report.

Introduction: Painful legs and moving toes (PLMT) is a rare neurological disorder characterized by neuropathic pain and involuntary movements in the lower limbs. The pathophysiological mechanisms are unclear, but central mechanisms might be involved, suggesting that noninvasive brain stimulation might be helpful. Thus far, no reports have been published on noninvasive brain stimulation to treat PLMT. Case Presentation: A 70-year-old female had a 1-year history of PLMT. After several unsuccessful medical attempts, the patient received repetitive transcranial magnetic stimulation and transcranial direct current stimulation to alleviate the pain and involuntary movements with no benefit. Conclusion: This is the first report on noninvasive brain stimulation in a PLMT patient. Although ineffective in our patient, noninvasive brain stimulation should be further studied in this often difficult to treat and debilitating syndrome.

Simple ratio analysis of 18F-fluorodopa uptake in striatal subregions separates patients with early Parkinson disease from healthy controls.

UNLABELLED: 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) is widely used to investigate dopaminergic hypofunction, for instance, in Parkinson disease (PD). Conventionally, a 90-min scan with either a graphical or a metabolite-purified plasma input approach has been used for quantification. In the clinical setting, to increase compliance, especially in patients with more advanced disease, and to increase the efficacy of tracer and scanner time use, a shorter acquisition and a simple quantitative analysis are desirable. Taking into account the asymmetry of clinical symptoms and the uneven distribution of striatal dopaminergic hypofunction may also improve the use of (18)F-FDOPA PET in early disease detection. Therefore, we compared subregional striatal (18)F-FDOPA PET data from a large group of nonmedicated patients with early PD and a set of healthy elderly volunteers to find out whether a simple ratio approach would reliably separate PD patients from healthy controls. METHODS: A total of 89 nonmedicated patients with early PD and 21 healthy volunteers were studied with (18)F-FDOPA PET, and both a region-to-reference (striatal-to-occipital) ratio (SOR) calculated from 75 to 90 min after injection and a graphical analysis of data calculated from 15 to 90 min after (18)F-FDOPA injection (yielding the influx constant [K(i)(ref)]) were used. RESULTS: Both SOR and K(i)(ref) values in the PD patients were lowest, relative to those in the healthy controls, in the posterior putamen contralateral to the side with predominant clinical symptoms. The contralateral posterior putamen showed the largest areas under the receiver operating characteristic (ROC) curve-0.994 for SOR and 0.998 for K(i)(ref)-indicating excellent separation of the PD and control groups. The caudate nucleus and the ventral striatum were less impressive in this respect. CONCLUSION: A single 15-min scan 75 min after tracer injection seems to be sufficient for separating patients with PD from healthy controls in a clinical research environment. This method represents a powerful and economical alternative for research on the disease mechanism and differential diagnosis.

A follow-up study on 6-[18F]fluoro-L-dopa uptake in early Parkinson's disease shows nonlinear progression in the putamen.

Sixteen subjects with de novo Parkinson's disease (PD) underwent three 6-[18F]fluoro-L-dopa (Fdopa) positron emission tomography (PET) scans during a follow-up time of 5 years (mean +/- SD 5.5 +/- 0.4 years) to study the progression of striatal dopaminergic hypofunction. Throughout the study, the smallest Fdopa uptake values were found in the dorso-caudal part of the putamen contralateral to the side with dominant motor symptoms. The rate of decline in Fdopa uptake in the contralateral putamen was faster in the beginning of the disease and slowed down as the disease progressed. The annual decline in Fdopa influx constant (Ki, unit x 10(-3) min(-1)) was on average 0.5 during the first 2 years and 0.2 during the subsequent 3 years (P = 0.002) in the contralateral putamen. In caudate, the rate of decline in Fdopa values was slower than in the putamen and did not change significantly during the follow-up time, annual decline in the contralateral caudate being 0.1 between baseline and 2 years and 0.3 between 2 and 5 years (P = 0.4). These results suggest that progression of putaminal dopaminergic hypofuncion in PD follows a nonlinear pattern at least in the contralateral side being faster in the beginning of the disease.

Impaired cognitive performance in Parkinson's disease is related to caudate dopaminergic hypofunction and hippocampal atrophy.

Frontal lobe dysfunction and other cognitive deficits have been described in Parkinson's disease (PD), which may lead to dementia. Both striatal dopaminergic deficiency and regional or global brain volume loss have been suggested to contribute to cognitive decline in PD. We therefore performed a neuropsychological evaluation, structural brain MRI and Fdopa PET in patients with PD and healthy elderly volunteers. PD patients had impaired cognitive performance in many neuropsychological tests compared to controls, not limited just to frontal lobe function tests. Caudate Fdopa correlated positively with performance in verbal (immediate and delayed) and visual memory. Patients with PD showed atrophy in the hippocampus and the prefrontal cortex and hippocampal atrophy was related to impaired memory. Our findings suggest that striatal dopaminergic depletion and global brain volume loss contribute to cognitive impairment in non-demented PD patients, but dysfunction of extra-striatal dopaminergic or non-dopaminergic systems probably plays a role especially in more generalized cognitive impairment.

1-11C-methyl-4-piperidinyl-N-butyrate radiation dosimetry in humans by dynamic organ-specific evaluation.

UNLABELLED: Deficits of cholinergic neurotransmission contribute to various neurologic and psychiatric conditions. The neurotransmitter acetylcholine is hydrolyzed in the synaptic clefts by 2 enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). 1-[(11)C]-Methyl-4-piperidinyl-N-butyrate ((11)C-MP4B) is a radioligand for the assessment study of BuChE activity in human brain with PET. In the present study the radiation-absorbed doses of the (11)C-MP4B were estimated in humans according to the guidelines of the International Commission on Radiological Protection. Two different data acquisition protocols-dynamic organ-specific evaluation (DOSE) and whole-body scanning-were compared. Both methods are widely used for evaluation of radiation burden of (11)C-labeled PET tracers. METHODS: Fixed-bed PET on the upper neck, thorax, abdomen, or pelvic region was performed on 7 healthy subjects after injection of 707 +/- 34 MBq (mean +/- SD) of (11)C-MP4B. Brain input was derived from our previous studies on 18 healthy control subjects and 10 patients with Alzheimer's disease. Regions of interest were drawn on transverse images of all visible organs. Radiation dose estimates were calculated from organ residence times using the MIRDOSE3 software. Urine samples were collected after imaging to estimate tracer extraction. To compare the estimates for absorbed doses between the whole-body scan approach and the DOSE method, we simulated whole-body data acquisition methods used in (11)C dosimetry studies with our fixed-bed data. RESULTS: The organs with the highest radiation-absorbed doses were the liver, urinary bladder, kidneys (renal cortex), upper large intestine, trabecular bone, salivary glands, and heart wall. Up to 60% of the injected dose was excreted via the urinary pathway, and the clearance was relatively rapid, as 30% of the radioactivity was excreted within 60 min after injection. With a 2-h voiding interval the effective dose was 4.2 microSv/MBq. CONCLUSION: (11)C-MP4B causes less radiation burden than previously studied (11)C-labeled PET tracers. No intolerably high absorbed doses were observed in critical organs. With 740 MBq of injected radioactivity, the radiation burden is equivalent to 3.11 mSv. This would allow multiple PET examinations per year to be performed on the same subject. The DOSE method and the simulated whole-body imaging approach produced similar results.

Cortical ß-amyloid burden, gray matter, and memory in adults at varying APOE ε4 risk for Alzheimer's disease.

Models of preclinical Alzheimer's disease (AD) propose that cerebral amyloidosis leads to neurodegeneration and subsequent cognitive decline. This study investigated whether APOE genotype is related to ß-amyloid (Aß) burden in brain regions preferentially affected by AD and whether Aß burden is associated with gray-matter (GM) fraction (as a marker of neurodegeneration) and episodic memory performance in cognitively normal middle-aged individuals at varying genetic risk for AD. Three groups of cognitively normal participants aged 50-65 years with a first-degree family history of AD (APOE genotype ε4ε4 [n = 15], ε3ε4 [n = 15], and ε3ε3 [n = 15]) underwent [11C]PiB positron emission tomography scans to quantify cortical Aß, brain magnetic resonance imaging, and neuropsychological testing. APOE ε4ε4 participants demonstrated significantly higher cortical Aß burden than APOE ε3ε3 (p < 0.001). Furthermore, cortical Aß burden was inversely associated with cortical GM fraction (p = 0.017) but not episodic memory performance. In cognitively normal, middle-aged individuals, Aß burden is significantly associated with GM fraction but not episodic memory performance. These findings are consistent with models of preclinical AD in which neurodegeneration occurs before manifest cognitive decline.

Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: a positron emission tomography study using the high-affinity dopamine D2 receptor ligand [11C]FLB 457.

Experimental studies on animals have shown that dopamine is a key neurotransmitter in the regulation of working memory (WM) functions in the prefrontal cortex. In humans, blood flow studies show prefrontal involvement in WM functions, but direct evidence for the involvement of the dopaminergic system in WM is lacking. Using positron emission tomography with a recently developed high-affinity dopamine D2 receptor tracer, [11C]FLB 457, we explored frontal, temporal, and parietal D2 receptor availability in 12 healthy volunteers while they were performing verbal WM and sustained attention tasks. During the performance of both tasks, reduced D2 receptor availability was observed in the left ventral anterior cingulate, suggesting an attention or arousal-related increase in dopamine release during these tasks. Compared with the sustained attention task, the verbal WM task reduced D2 receptor availability in the ventrolateral frontal cortex bilaterally and in the left medial temporal structures (amygdala, hippocampus), suggesting that dopamine release in these regions might have a specific role in WM. In addition, correlation analyses indicated that increased dopamine release in the right ventrolateral frontal cortex and the left ventral anterior cingulate during the WM task was associated with faster and more stable WM performance, respectively. Our results indicate that regionally specific components of the frontotemporal dopaminergic network are functionally involved in WM performance in humans.

Mobile phone affects cerebral blood flow in humans.

Mobile phones create a radio-frequency electromagnetic field (EMF) around them when in use, the effects of which on brain physiology in humans are not well known. We studied the effects of a commercial mobile phone on regional cerebral blood flow (rCBF) in healthy humans using positron emission tomography (PET) imaging. Positron emission tomography data was acquired using a double-blind, counterbalanced study design with 12 male subjects performing a computer-controlled verbal working memory task (letter 1-back). Explorative and objective voxel-based statistical analysis revealed that a mobile phone in operation induces a local decrease in rCBF beneath the antenna in the inferior temporal cortex and an increase more distantly in the prefrontal cortex. Our results provide the first evidence, suggesting that the EMF emitted by a commercial mobile phone affects rCBF in humans. These results are consistent with the postulation that EMF induces changes in neuronal activity.

Cortical 6-[18F]fluoro-L-dopa uptake and frontal cognitive functions in early Parkinson's disease.

Patients with Parkinson's disease (PD) have already at the early stages of the disease impaired performance especially in tests measuring frontal lobe functions such as attention. The pathophysiological basis of these deficits is unclear. In the present study, 21 non-demented, non-medicated patients at the early stage of PD and 24 healthy controls underwent a positron emission tomography (PET) scan with 6-[18F]fluoro-L-dopa (Fdopa) as the tracer. In addition, the PD patients performed a neuropsychological test battery, including a test measuring sustained attention (VIG) and a test requiring suppressed attention (Stroop). Both voxel-based Statistical Parametric Mapping (SPM) and automated region of interest (ROI) analysis were employed. Compared to controls, the PD patients had decreased Fdopa uptake in the striatum and a large cortical area of increased Fdopa uptake. The reaction time in the VIG test correlated positively with the Fdopa uptake of the dorsolateral prefrontal cortex and the performance in the Stroop test correlated negatively with the Fdopa uptake in an area including the medial frontal cortex and the anterior cingulate. The results show that cortical Fdopa uptake is increased in early non-medicated PD and suggest that the changes in frontal Fdopa uptake are related to cognitive impairments found in early PD.

Cognitive slowing in Parkinson's disease is related to frontostriatal dopaminergic dysfunction.

BACKGROUND: Frontostriatal and cognitive dysfunctions in Parkinson's disease (PD) are hypothesized to be linked predominately to dopaminergic dysfunction within neural networks linking dorsal striatum to dorsolateral prefrontal cortex. METHODS: The authors evaluated the relationship between frontostriatal dopaminergic function and cognitive performance, especially cognitive processing speed by performing [(18)F]fluorodopa PET and computerized tests of automatic and controlled cognitive processing speed (CogniSpeed) in 23 newly diagnosed and unmedicated PD patients and 14 controls. RESULTS: PD patients were slower than the controls in all the CogniSpeed measures studied. The Fdopa uptake in caudate nucleus correlated negatively with slowing on all the tests. Slower performance in relatively automatic processes measured by choice reaction tasks as well as in more controlled processes measured by a calculation task was related to reduced Fdopa uptake in the anterior cingulate gyrus. The reduced dopaminergic function in the thalamus was associated with the slower performance in the subtraction test. CONCLUSION: Our study indicates that dopaminergic dysfunction within neural networks linking striatum to prefrontal cortex is involved in the slowing of both automatic and controlled cognitive processing in PD patients.

Striatal subregional 6-[18F]fluoro-L-dopa uptake in early Parkinson's disease: a two-year follow-up study.

Thirty-one drug-naive patients with Parkinson's disease (PD) underwent 6-[18F]fluoro-L-dopa (F-dopa) positron emission tomography (PET) scan at the time of the diagnosis (baseline) and 2 years later in order to investigate F-dopa uptake in striatal and extrastriatal regions during the first years of early PD. Twenty-four healthy controls underwent one F-dopa PET scan. The regional differences in the striatal and extrastriatal regions were analyzed with statistical parametric mapping and automated region of interest analyses. Our study shows that the F-dopa uptake in unmedicated early PD is most severely decreased in the dorsal part of caudal putamen but significant decrease can be seen throughout the striatum compared with controls. During the first years of PD, there is a progressive regional decline in striatal F-dopa uptake, the dorsal part of caudal putamen being still the most severely affected region. The absolute decline is equal between the striatal subregions. This suggests that the decline of dopamine function starts from the dorsocaudal putamen, but once started, the rate of progression is equal between the subregions of the striatum. In contrast to the striatal decline, the increased cortical F-dopa uptake prevails at least during the first years of PD.