Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB1 (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ~4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB1 receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.

Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.

Alzheimer’s disease (AD) is associated with increase in brain of the 18 kDa translocator protein (TSPO), which is over-expressed in activated microglia and reactive astrocytes. Measuring the density of TSPO with PET typically requires absolute quantitation with arterial blood sampling, because a reference region devoid of TSPO does not exist in brain. We sought to determine whether a simple ratio method could substitute for absolute quantitation of binding with 11C-PBR28, a second generation radioligand for TSPO. Methods 11C-PBR28 PET imaging was performed in 21 healthy controls, 11 individuals with mild cognitive impairment (MCI), and 25 AD patients. Group differences in 11C-PBR28 binding were compared using two methods. First, the “gold standard” method of calculating total distribution volume (VT), using the two-tissue compartmental model with the arterial input function, corrected for plasma free fraction of radiotracer (fP). Second, a ratio of brain uptake in target regions to that in cerebellum—i.e., standardized uptake value ratio (SUVR). Results Using absolute quantitation, we confirmed that TSPO binding (VT/fP): 1) was greater in AD patients than in healthy controls in expected temporo-parietal regions, and 2) was not significantly different among the three groups in cerebellum. Using the cerebellum as a pseudo-reference region, the SUVR method detected greater binding in AD patients than controls in the same regions as absolute quantification and in one additional region, suggesting SUVR may have greater sensitivity. Coefficients of variation of SUVR measurements were about two-thirds lower than those of absolute quantification, and the resulting statistical significance was much higher for SUVR when comparing AD and healthy controls (e.g. P < 0.0005 for SUVR vs. P = 0.023 for VT/fP in combined middle and inferior temporal cortex). Conclusion To measure TSPO density in AD and control subjects, a simple ratio method SUVR can substitute for, and may even be more sensitive than, absolute quantitation. The SUVR method is expected to improve subject tolerability by allowing shorter scan time and not requiring arterial catheterization. In addition, this ratio method allows smaller sample sizes for comparable statistical significance because of the relatively low variability of the ratio values.

Ten percent of humans lack specific binding of [11C]PBR28 to 18 kDa translocator protein (TSPO), a biomarker for inflammation. “Non-binders” have not been reported using another TSPO radioligand, [11C]-(R)-PK 11195, despite its use for more than two decades. This study asked two questions: 1) What is the cause of non-binding to PBR28? 2) Why has this phenomenon not been reported using [11C]-(R)-PK 11195? Methods Five binders and five non-binders received whole-body imaging with both [11C]-(R)-PK 11195 and [11C]PBR28. In vitro binding was performed using leukocyte membranes from binders and non-binders and the tritiated versions of the ligand. Rhesus monkeys were imaged with [11C]-(R)-PK 11195 at baseline and after blockade of TSPOs. Results Using [11C]PBR28, uptake in all five organs with high densities of TSPO (lung, heart, brain, kidney, and spleen) was 50% to 75% lower in non-binders than in binders. In contrast, [11C]-(R)-PK 11195 distinguished binders and non-binders in only heart and lung. For the in vitro assay, [3H]PBR28 had more than ten-fold lower affinity to TSPO in non-binders than in binders. The in vivo specific binding of [11C]-(R)-PK 11195 in monkey brain was ∼80-fold lower than that reported for [11C]PBR28. Conclusions Based on binding of [3H]PK 11195 to leukocyte membranes, both binders and non-binders express TSPO. Non-binding to PBR28 is caused by its low affinity for TSPO in non-binders. Non-binding may be differentially expressed in organs of the body. The relatively low in vivo specific binding of [11C]-(R)-PK 11195 may have obscured its detection of non-binding in peripheral organs.