Bart N.M. van Berckel

Δ9-Tetrahydrocannabinol Induces Dopamine Release in the Human Striatum

The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Δ9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D2/D3 receptor tracer [11C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [11C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.

Blood–brain barrier P-glycoprotein function in Alzheimer's disease

A major pathological hallmark of Alzheimers disease is accumulation of amyloid-β in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-β from the brain may lead to these elevated amyloid-β levels. One of the clearance pathways of amyloid-β is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-β. P-glycoprotein function can be assessed in vivo using (R)-[(11)C]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimers disease compared with age-matched healthy controls using (R)-[(11)C]verapamil and positron emission tomography. In 13 patients with Alzheimers disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimers disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimers disease, higher (R)-[(11)C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimers disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimers disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic Alzheimers disease and suggests that decreased P-glycoprotein function may be involved in the pathogenesis of Alzheimers disease.

Optimizing Patient Care and Research: The Amsterdam Dementia Cohort

Since its opening in 2000, patient care and research go hand in hand at the Alzheimer center of the VU University Medical Center, both organized in such a way that they mutually strengthen each other. Our mission is to give patients a voice by lifting the stigma on dementia, to find new diagnostic and treatment strategies, and, ultimately, to cure diseases that cause dementia. Our healthcare pathway is uniquely designed to accommodate all necessary investigations for the diagnostic work-up of dementia in one day (one-stop shop). A second unique feature is that research has been fully integrated in the healthcare pathway. The resulting Amsterdam Dementia Cohort now includes over 4000 patients, and for the majority of these, we have MRI, EEG, blood (serum, plasma), DNA, and CSF available. The Amsterdam Dementia Cohort forms the basis of much of our research, which focuses on four major research lines: 1) variability in manifestation, 2) early diagnosis, 3) vascular factors, and 4) interventions. By answering research questions closely related to clinical practice, the results of our research can be looped back to improve clinical work-up for our patients.

Relationship of Cerebrospinal Fluid Markers to 11C-PiB and 18F-FDDNP Binding

The purpose of this study was to investigate the potential relationships between cerebrospinal fluid (CSF) measurements of β-amyloid-1–42 (Aβ1-42) and total tau to 11C-Pittsburgh compound B (11C-PiB) and 2-(1-{6-[(2-18F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile (18F-FDDNP) binding as measured using PET. Methods: A total of 37 subjects were included, consisting of 15 patients with Alzheimer disease (AD), 12 patients with mild cognitive impairment, and 10 healthy controls. All subjects underwent a lumbar puncture and PET using both 11C-PiB and 18F-FDDNP. For both PET tracers, parametric images of binding potential were generated. Potential associations of CSF levels of Aβ1-42 and tau with 11C-PiB and 18F-FDDNP binding were assessed using Pearson correlation coefficients and linear regression analyses. Results: For both global 11C-PiB and 18F-FDDNP binding, significant correlations with CSF levels of Aβ1-42 (r = −0.72 and −0.37, respectively) and tau (r = 0.58 and 0.56, respectively) were found across groups (all P < 0.001, except P < 0.05 for correlation between 18F-FDDNP and Aβ1-42). Linear regression analyses showed that, adjusted for regional volume, age, sex, and diagnosis, global 11C-PiB uptake had an inverse association with Aβ1-42 CSF levels (standardized β = −0.50, P < 0.001), whereas there was a positive association between global 18F-FDDNP binding and tau CSF levels (standardized β = 0.62, P < 0.01). Conclusion: The good agreement between these 2 different types of biomarkers (i.e., CSF and PET) provides converging evidence for their validity. The inverse association between 11C-PiB and CSF tau Aβ1-42 confirms that 11C-PiB measures amyloid load in the brain. The positive association between 18F-FDDNP and CSF tau suggests that at least part of the specific signal of 18F-FDDNP in AD patients is due to tangle formation.

Effect of age on functional P‐glycoprotein in the blood‐brain barrier measured by use of (R)‐[11C]verapamil and positron emission tomography

P‐glycoprotein (P‐gp) is an efflux transporter responsible for the transport of various drugs across the blood‐brain barrier (BBB). Loss of P‐gp function with age may be one factor in the development and progression of neurodegenerative diseases. The aim of this study was to assess the effect of aging on BBB P‐gp function. Furthermore, the relationship between BBB P‐gp activity and peripheral P‐gp activity in CD3‐positive leukocytes was investigated. Finally, plasma pharmacokinetics of carbon 11–labeled (R)‐verapamil was evaluated.

Prediction of dementia in MCI patients based on core diagnostic markers for Alzheimer disease

Objectives: The current model of Alzheimer disease (AD) stipulates that brain amyloidosis biomarkers turn abnormal earliest, followed by cortical hypometabolism, and finally brain atrophy ones. The aim of this study is to provide clinical evidence of the model in patients with mild cognitive impairment (MCI). Methods: A total of 73 patients with MCI from 3 European memory clinics were included. Brain amyloidosis was assessed by CSF Aβ42 concentration, cortical metabolism by an index of temporoparietal hypometabolism on FDG-PET, and brain atrophy by automated hippocampal volume. Patients were divided into groups based on biomarker positivity: 1) Aβ42− FDG-PET− Hippo−, 2) Aβ42+ FDG-PET− Hippo−, 3) Aβ42 + FDG-PET + Hippo−, 4) Aβ42 + FDG-PET+ Hippo+, and 5) any other combination not in line with the model. Measures of validity were prevalence of group 5, increasing incidence of progression to dementia with increasing biological severity, and decreasing conversion time. Results: When patients with MCI underwent clinical follow-up, 29 progressed to dementia, while 44 remained stable. A total of 26% of patients were in group 5. Incident dementia was increasing with greater biological severity in groups 1 to 5 from 4% to 27%, 64%, and 100% (p for trend < 0.0001), and occurred increasingly earlier (p for trend = 0.024). Conclusions: The core biomarker pattern is in line with the current pathophysiologic model of AD. Fully normal and fully abnormal pattern is associated with exceptional and universal development of dementia. Cases not in line might be due to atypical neurobiology or inaccurate thresholds for biomarker (ab)normality.

Detection of Alzheimer Pathology In Vivo Using Both 11C-PIB and 18F-FDDNP PET

11C-Pittsburgh Compound-B (11C-PIB) and 18F-(2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) (18F-FDDNP) have been developed as PET tracers for in vivo imaging of pathology in Alzheimers disease (AD). The purpose of this study was to directly compare these tracers in patients with AD, patients with mild cognitive impairment (MCI), and healthy controls. Methods: Paired 11C-PIB and 18F-FDDNP scans were acquired in 14 patients with AD, 11 patients with amnestic MCI, and 13 controls. For both tracers, parametric images of binding potential (BPND) were generated. Global cortical BPND was assessed using ANOVA. In addition, regional patterns of BPND were compared between diagnostic groups using ANOVA for repeated measures. Results: Global cortical BPND of 11C-PIB showed higher binding in patients with AD than in controls and patients with MCI. 18F-FDDNP uptake was higher in patients with AD than in controls, but MCI could not be distinguished from AD or from controls. Global BPND values of both tracers were moderately correlated (r = 0.45; P = 0.005). In MCI, BPND of 11C-PIB showed a bimodal distribution, whereas values for 18F-FDDNP were more widespread, with more MCI patients demonstrating increased uptake. Regional 11C-PIB binding showed different patterns across diagnostic groups, as AD patients showed an overall increase in binding, with the lowest binding in the medial temporal lobe. With 18F-FDDNP, patterns were similar across diagnostic groups. For all groups, highest values were observed in the medial temporal lobe. Conclusion: Differences in BPND between patients with AD, patients with MCI, and controls were more pronounced for 11C-PIB. The difference in regional binding, the moderate correlation, and the discrepant findings in MCI suggest that they measure related, but different, characteristics of the disease.

Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage.

Three sets of research criteria are available for diagnosis of Alzheimers disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimers disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimers disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimers disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimers disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimers disease at the mild cognitive impairment stage and progression to Alzheimers disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimers disease. Their 3-year progression rate to Alzheimers disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimers disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimers disease. Their 3-year progression rate to Alzheimers disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimers disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimers disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimers disease likelihood group. The 3-year progression rate to Alzheimers disease-type dementia was 59% in the high Alzheimers disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimers disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimers disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimers disease likelihood group or the International Working Group-2 prodromal Alzheimers disease group could be considered.

Impact of molecular imaging on the diagnostic process in a memory clinic

[11C]Pittsburgh compound B ([11C]PIB) and [18F]‐2‐fluoro‐2‐deoxy‐D‐glucose ([18F]FDG) PET measure fibrillar amyloid‐β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population.

Arterial spin labeling perfusion MRI at multiple delay times: a correlative study with H215O positron emission tomography in patients with symptomatic carotid artery occlusion

Arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) with image acquisition at multiple inversion times is a noninvasive ASL technique able to compensate for spatial heterogeneities in transit times caused by collateral blood flow in patients with severe stenosis of the cerebropetal blood vessels. Our aim was to compare ASL-MRI and H215O positron emission tomography (PET), the gold standard for cerebral blood flow (CBF) assessment, in patients with a symptomatic internal carotid artery (ICA) occlusion. Fourteen patients (63±14 years) with a symptomatic ICA occlusion underwent both ASL-MRI and H215O PET. The ASL-MRI was performed using a pulsed STAR labeling technique at multiple inversion times within 7 days of the PET. The CBF was measured in the gray-matter of the anterior, middle and posterior cerebral artery, and white-matter. Both PET and ASL-MRI showed a significantly decreased CBF in the gray-matter of the middle cerebral artery in the hemisphere ipsilateral to the ICA occlusion. The average gray-matter CBF measured with ASL-MRI (71.8±4.3 mL/min/100 g) was higher (P<0.01) than measured with H215O PET (43.1±1.0 mL/min/100 g). In conclusion, ASL-MRI at multiple TIs is capable of depicting areas of regions with low CBF in patients with an occlusion of the ICA, although a systematic overestimation of CBF relative to H215O PET was noted.