Regional changes in the type 1 cannabinoid receptor are associated with cognitive dysfunction in Parkinson's disease.

PURPOSE: The endocannabinoid system plays a regulatory role in a number of physiological functions, including motor control but also mood, emotion, and cognition. A number of preclinical studies in Parkinson's disease (PD) models demonstrated that modulating the type 1 cannabinoid receptor (CB1R) may improve motor symptoms and components of cognitive processing. However, the relation between CB1R, cognitive decline and behavioral symptoms has not been investigated in PD patients so far. The aim of this study was to examine whether CB1R availability is associated with measures of cognitive and behavioral function in PD patients. METHODS: Thirty-eight PD patients and ten age- and gender-matched controls underwent a [18F]MK-9470 PET scan to assess CB1R availability, as well as volumetric MR imaging. Neuropsychological symptoms were evaluated using an extensive cognitive and behavioral battery covering the five cognitive domains, depression, anxiety, apathy, and psychiatric complications, and were correlated to CB1R availability using vowel-wise regression analysis (P < 0.05, corrected for familywise error). RESULTS: PD patients with poorer performance in episodic memory, executive functioning, speed and mental flexibility (range P 0.003-0.03) showed lower CB1R availability in predominantly the midcingulate cortex and middle to superior frontal gyrus (Tpeak-level > 4.0). Also, PD patients with more severe visuospatial dysfunction showed decreased CB1R availability in the precuneus, midcingulate, supplementary motor cortex, inferior orbitofrontal gyrus and thalamus (Tpeak-level = 5.5). These correlations were not related to cortical gray matter atrophy. No relationship was found between CB1R availability and mood or behavioral symptom scores. CONCLUSIONS: Decreased CB1R availability in the prefrontal and midcingulate cortex in PD patients is strongly correlated with disturbances in executive functioning, episodic memory, and visuospatial functioning. Further investigation of regional CB1R expression in groups of PD patients with mild cognitive impairment or dementia is warranted in order to further investigate the role of CB1R expression in different levels of cognitive impairment in PD.

Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer's disease.

PURPOSE: The cannabinoid type 2 receptor (CB2R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB2R is primarily found on microglia. CB2R upregulation has been reported in animal models of Alzheimer's disease, with a preferential localization near amyloid beta (Aß) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB2R tracer [11C]NE40 in healthy controls (HC) and in patients with Alzheimer's disease (AD) to investigate whether higher CB2R availability regionally colocalized to Aß deposits is present in vivo. METHODS: Dynamic 90-min [11C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [11C]PIB scan 40 min after injection. In four HC, a retest scan with [11C]NE40 PET was performed within 9 weeks to investigate test-retest characteristics. RESULTS: [11C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time-activity curves best; both binding potential (BPND) and distribution volume (V T) parameters could be used. Brain uptake was generally low with an average K 1 value of 0.07 ml/min/ml tissue. V T and BPND were in the range of 0.7 - 1.8 and 0.6 - 1.6, respectively. Test values in HC were about 30 % for V T and BPND. AD patients showed overall significantly lower CB2R binding. No relationship was found between regional or global amyloid load and CB2R availability. CONCLUSION: Kinetic modelling of [11C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [11C]NE40 PET shows lower CB2R availability in vivo in AD patients, with no relationship to Aß plaques. A possible explanation for these findings is that [11C]NE40 binds to CB2R with lower affinity and/or selectivity than to CB1R.

Functional brain changes underlying irritability in premanifest Huntington's disease.

The clinical phenotype of Huntington's disease (HD) consists of motor, cognitive and psychiatric symptoms, of which irritability is an important manifestation. Our aim was to identify the functional and structural brain changes that underlie irritability in premanifest HD (preHD). Twenty preHD carriers and 20 gene-negative controls from HD families took part in the study. Although the 5-year probability of disease onset was only 11%, the preHD group showed striatal atrophy and increased clinical irritability ratings. Functional MRI was performed during a mood induction experiment by means of recollection of emotional (angry, sad, and happy) and neutral autobiographical episodes. While there were no significant group differences in the subjective intensity of the emotional experience, the preHD group showed increased anger-selective activation in a distributed network, including the pulvinar, cingulate cortex, and somatosensory association cortex, compared to gene-negative controls. Pulvinar activation during anger experience correlated negatively with putaminal grey matter volume and positively with irritability ratings in the preHD group. In addition, the preHD group showed a decrease in anger-selective activation in the amygdala, which correlated with putaminal and caudate grey matter volume. In conclusion, compared to gene-negative controls, anger experience in preHD is associated with activity changes in a distributed set of regions known to be involved in emotion regulation. Increased activity is related to behavioral and volumetric measures, providing insight in the pathophysiology of early neuropsychiatric symptoms in preHD.

Human biodistribution and dosimetry of 18F-JNJ42259152, a radioligand for phosphodiesterase 10A imaging.

PURPOSE: Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP-hydrolysing enzyme with a central role in striatal signalling and implicated in neuropsychiatric disorders such as Huntington's disease, Parkinson's disease, schizophrenia and addiction. We have developed a novel PDE10A PET ligand, (18)F-JNJ42259152, and describe here its human dynamic biodistribution, safety and dosimetry. METHODS: Six male subjects (age range 23-67 years) underwent ten dynamic whole-body PET/CT scans over 6 h after bolus injection of 175.5 ± 9.4 MBq (18)F-JNJ42259152. Source organs were delineated on PET/CT and individual organ doses and effective dose were determined using the OLINDA software. RESULTS: F-JNJ42259152 was readily taken up by the brain and showed exclusive retention in the brain, especially in the striatum with good washout starting after 20 min. The tracer was cleared through both the hepatobiliary and the urinary routes. No defluorination was observed. Organ absorbed doses were largest for the gallbladder (239 µSv/MBq) and upper large intestine (138 µSv/MBq). The mean effective dose was 24.9 ± 4.1 µSv/MBq. No adverse events were encountered. CONCLUSION: In humans, (18)F-JNJ42259152 has an appropriate distribution, brain kinetics and safety. The estimated effective dose was within WHO class IIb with low interindividual variability. Therefore, the tracer is suitable for further kinetic evaluation in humans.

Epigenetics: The Key to Future Diagnostics and Therapeutics of Lung Cancer.

Lung cancer is still the major cause of cancer-related mortality around the globe. The interplay of permanent genetic and dynamic epigenetic changes leads to the onset and progression of lung cancer. The diagnosis is often made at an advanced stage when the prognosis is dismal and therapy choices are restricted. Epigenetic association with lung cancer has long been studied but with fewer success rates. Research is still progressing, and with an advanced understanding of human genomics, more and more information is being unveiled. In the last decade, epigenetics and particularly research on DNA methylation and histone modification have provided vital information to understand lung cancer pathogenesis better. As a result, stage-specific epigenetic modifications can be employed as strong and reliable tools for early lung cancer detection and patient prognosis monitoring. The information on epigenetic biomarkers for lung cancer is summarised in this review, which focuses on DNA methylation and histone modification, as well as its implications for early detection, diagnosis, prognostication, and treatments.

Behavioral Symptoms in Premanifest Huntington Disease Correlate with Reduced Frontal CB1R Levels.

Many Huntington disease (HD) mutation carriers already have cognitive and psychiatric symptoms in the premanifest (premotor) phase of the disease (pre-HD), but the molecular underpinnings of these symptoms are not well understood. Previous work has shown reduced availability of the cerebral type 1 cannabinoid receptor (CB1R) in manifest HD. Here, we investigated whether CB1R binding is related to cognitive and psychiatric symptoms in pre-HD mutation carriers. Methods: CB1R binding was measured with 18F-MK-9470 (N-[(2S,3S)-3-(3-cyanophenyl)-4-(4-ethoxyphenyl)butan-2-yl]-2-methyl-2-(5-methylpyridin-2-yl)oxypropanamide) PET in 15 pre-HD subjects (8 men, 7 women; age, 39.3 ± 9.9 y), 15 gene-negative controls from HD families (9 men, 6 women; age, 37.0 ± 10.6 y), and 12 community controls (6 men and 6 women; age, 39.9 ± 15.1 y). All subjects also underwent extensive assessment of motor and cognitive function, as well as a behavioral test battery including the Problem Behavior Assessment for HD (PBA-HD), and MRI. Parametric binding images of 18F-MK-9470 were corrected for partial-volume effect. Results: There was no difference in CB1R binding, gray matter volume, cognitive function, or psychiatric scores between gene-negative controls from HD families and community controls, which were therefore pooled to one control group. Compared with controls, pre-HD subjects showed striatal atrophy, a decrease in CB1R binding in the prefrontal cortex, and higher PBA-HD scores on depression, apathy, and irritability (range, P = 0.01-0.005). The PBA-HD scores inversely correlated with CB1R binding in prefrontal regions and cingulate cortex in pre-HD (range: r = -0.64 to -0.72; P = 0.01-0.008). Conclusion: The association between behavioral symptoms and reduced prefrontal CB1R levels may provide new insight into the molecular basis of neuropsychiatric symptoms in pre-HD and suggest new therapeutic avenues.

PET imaging shows loss of striatal PDE10A in patients with Huntington disease.

Phosphodiesterase 10A (PDE10A) belongs to a family of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate.(1) PDE10A is highly enriched in striatal medium spiny neurons (MSNs), where it regulates intracellular signaling.(1) PDE10A has been proposed as a therapeutic target for Huntington disease (HD), a disorder that preferentially affects MSNs, based on the observation that pharmacologic inhibition of PDE10A in transgenic HD mice significantly improved behavioral and neuropathologic abnormalities.(2) However, earlier work had shown that striatal PDE10A levels in HD mice already decline to minimal levels before onset of motor symptoms,(3) possibly because mutant huntingtin represses PDE10A transcription. Also, postmortem analysis of striatum of 3 patients with HD revealed strong reduction of PDE10A levels.(3) Depletion of PDE10A in HD striatum would at first sight seem hard to reconcile with a beneficial effect of PDE10A inhibitors in HD. However, a recent study reported a dramatic increase, rather than decrease, of PDE10A protein in MSNs of HD mice.(4) In light of these conflicting results and the strong interest in development of PDE10A inhibitors for clinical use in HD, it is important to determine whether PDE10A levels are affected in the striatum of patients with HD in vivo.

In vivo type 1 cannabinoid receptor availability in Alzheimer's disease.

The endocannabinoid system (ECS) is an important modulatory and potentially neuroprotective homeostatic system in the brain. In Alzheimer's disease (AD), the role of type 1 cannabinoid receptor (CB1R) is unclear, with contradictory findings in post-mortem studies showing upregulation, downregulation or unchanged CB1R status. We have investigated CB1R availability in vivo in patients with AD, in relation to amyloid deposition, cognitive functioning and apolipoprotein E (ApoE) genotype. Eleven AD patients and 7 healthy volunteers (HV) underwent combined [¹8F]MK-9470 PET and [¹¹C]PIB PET scans to assess CB1R availability and amyloid deposition, respectively, and T1 volumetric MRI for partial volume correction. We found no difference in CB1R availability between AD and HV, VOI-based fractional uptake values (FUR) were 0.043±0.01 for AD and 0.045±0.01 for controls (p=0.9). CB1R availability did not correlate with neuropsychological test scores and was not modulated by ApoE genotype. As expected, global [¹¹C]PIB SUVR (standardized uptake value ratio) was increased in AD (SUVR 1.9±0.3) compared to HV (1.2±0.1) with p<0.001, but no correlation was found between amyloid ß (Aß) deposition and CB1R availability. In conclusion, we found no in vivo evidence for a difference in CB1R availability in AD compared to age-matched controls. Taken together with recently reported in vivo CB1R changes in Parkinson's and Huntington's disease, these data suggest that the CB1R is differentially involved in neurodegenerative disorders.

Whole-body biodistribution and radiation dosimetry of the cannabinoid type 2 receptor ligand [11C]-NE40 in healthy subjects.

PURPOSE: The type 2 cannabinoid receptor (CB2R) is part of the human endocannabinoid system and is involved in central and peripheral inflammatory processes. In vivo imaging of the CB2R would allow study of several (neuro)inflammatory disorders. In this study we have investigated the safety and tolerability of [11C]-NE40, a CB2R positron emission tomography (PET) ligand, in healthy human male subjects and determined its biodistribution and radiation dosimetry. PROCEDURE: Six healthy male subjects (age 20-65 years) underwent a dynamic series of nine whole-body PET/CT scans for up to 140 min, after injection of an average bolus of 286 MBq of [11C]-NE40. Organ absorbed and total effective doses were calculated through OLINDA. RESULTS: [11C]-NE40 showed high initial uptake in the spleen and a predominant hepatobiliary excretion. In the brain, rapid uptake and swift washout were seen. Organ absorbed doses were largest for the small intestine and liver, with 15.6 and 11.5 µGy/MBq, respectively. The mean effective dose was 3.64±0.81 µSv/MBq. There were no changes with aging observed. No adverse events were encountered. CONCLUSIONS: This first-in-man study of [11C]-NE40 showed an expected biodistribution compatible with lymphoid tissue uptake and appropriate fast brain kinetics in the healthy human brain, underscoring the potential of this tracer for further application in central and peripheral inflammation imaging. The effective dose is within the typical expected range for 11C ligands.

Quantification of 18F-JNJ-42259152, a novel phosphodiesterase 10A PET tracer: kinetic modeling and test-retest study in human brain.

UNLABELLED: Phosphodiesterase 10A (PDE10A) plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders, such as movement disorders and schizophrenia. We performed initial brain kinetic modeling of the novel PDE10A tracer (18)F-JNJ-42259152 (2-[[4-[1-(2-(18)F-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]methyl]-3,5-dimethyl-pyridine) and studied test-retest reproducibility in healthy volunteers. METHODS: Twelve healthy volunteers (5 men, 7 women; age range, 42-77 y) were scanned dynamically up to 135 min after bolus injection of 172.5 ± 10.3 MBq of (18)F-JNJ42259152. Four volunteers (2 men, 2 women) underwent retest scanning, with a mean interscan interval of 37 d. Input functions and tracer parent fractions were determined using arterial sampling and high-performance liquid chromatography analysis. Volumes of interest for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were delineated using individual volumetric T1 MR imaging scans. One-tissue (1T) and 2-tissue (2T) models were evaluated to calculate total distribution volume (VT). Simplified models were also tested to calculate binding potential (BPND), including the simplified reference tissue model (SRTM) and multilinear reference tissue model, using the frontal cortex as the optimal reference tissue. The stability of VT and BPND was assessed down to a 60-min scan time. RESULTS: The average intact tracer half-life in blood was 90 min. The 2T model VT values for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were 1.54 ± 0.37, 0.90 ± 0.24, 0.64 ± 0.18, 0.42 ± 0.09, 0.35 ± 0.09, 0.30 ± 0.07, and 0.36 ± 0.12, respectively. The 1T model provided significantly lower VT values, which were well correlated to the 2T VT. SRTM BPND values referenced to the frontal cortex were 3.45 ± 0.43, 1.78 ± 0.35, 1.10 ± 0.31, and 0.44 ± 0.09 for the respective target regions putamen, caudate nucleus, ventral striatum, and substantia nigra, with similar values for the multilinear reference tissue model. Good correlations were found for the target regions putamen, caudate nucleus, ventral striatum, and substantia nigra between the 2T-compartment model BPND and the SRTM BPND (r = 0.57, 0.82, 0.70, and 0.64, respectively). SRTM BPND using a 90- and 60-min acquisition interval showed low bias. Test-retest variability was 5%-19% for 2T VT and 5%-12% for BPND SRTM. CONCLUSION: Kinetic modeling of (18)F-JNJ-42259152 shows that PDE10A activity can be reliably quantified and simplified using a reference tissue model with the frontal cortex as reference and a 60-min acquisition period.