The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamineinduced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [1231] The dopamine hypothesis of schizophrenia, formulated over 30 years ago, proposes that hyperactivity of dopaminergic transmission is associated with this illness (1). This hypothesis is based on the observation that dopamine D2 receptor antagonists alleviate symptoms of the illness (mostly positive symptoms), while dopamine agonists can induce psychotic states characterized by some salient features of schizophrenia (2). These pharmacological effects suggest, but do not establish, a dysregulation of dopamine systems in schizophrenia. Despite decades of effort to validate this hypothesis, documentation of abnormalities of dopamine function in schizophrenia has remained elusive. Postmortem studies measuring dopamine and its metabolites in the brain of schizophrenic patients have yielded inconsistent results (for review, see ref.3). Increased density of striatal dopamine D2 and D2-like receptors has been reported in postmortem studies, but this observation is difficult to interpret, given that neuroleptic drugs upregulate these receptors (4, 5). Positron emission tomography and single photon emission computerized tomography (SPECT) studies of striatal D2 and D2-like receptors density in neurolepticnaive schizophrenic patients have been inconclusive. While one group reported increased striatal D2-like receptors density in schizophrenia (6, 7), other groups reported negative results (8-12). The lack of clear evidence for increased dopaminergic indices in schizophrenia might indicate that dopaminergic transmission is enhanced only relative to other systems, such as serotonergic or glutamatergic systems (13,14). On the other hand, the absence of data supporting the dopamine hypothesis of schizophrenia might be due to the difficulty of obtaining direct measurement of dopamine transmission in the living human brain.Over the past few years, several groups have provided evidence that competition between neurotransmitters and radioligands for neuroreceptor binding allows measuring changes in synaptic neurotransmitter levels with in vivo binding techniques. In rodents, decreased uptake of D2 radioligands has been measured following amphetamine and other dopamine enhancing drugs, whereas the opposite effect (i.e., increased tracer accumulation) has been induced by drugs that decrease dopamine concentration (15)(16)(17). In baboons, decreased specific uptake of positron emission to...

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.

Previous studies have utilized single-photon emission computed tomography (SPECT) to demonstrate decreased [123I]beta-CIT striatal uptake in idiopathic Parkinson disease (PD) patients. The present study extends this work by examining SPECT outcome measures in a larger group of PD patients with varying disease severity. Twenty-eight L-dopa-responsive PD patients (Hoehn-Yahr stages 1-4) and 27 healthy controls had SPECT scans at 18 to 24 hours after injection of [123I]beta-CIT. Specific to nondisplaceable striatal uptake ratios (designated V3") were correlated with Hoehn-Yahr stage and Unified Parkinson's Disease Rating Scale (UPDRS) subscores. Linear discriminant function analyses utilizing striatal uptakes, putamen-to-caudate ratios, and ipsilateral-contralateral asymmetry indices were performed. Decreased striatal tracer uptake (V3") was correlated with total UPDRS score for both contralateral and ipsilateral striatum. Putamen uptake was relatively more reduced than caudate with mean putamen:caudate ratios of 0.50 +/- 0.17 and 0.82 +/- 0.09 for PD patients and controls, respectively. Ipsilateral:contralateral asymmetry was significantly greater in PD patients than controls. Discriminant function analysis utilizing V3" for ipsilateral and contralateral caudate and putamen correctly classified all 55 cases. These data demonstrate marked differences in [123I]beta-CIT SPECT measures in healthy controls and PD patients. The significant correlation of SPECT measures with motor severity suggests [123I]beta-CIT may be a useful marker of disease severity in PD.

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.