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Quantitative measurements of resting cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) show large between-subject and regional variability, but the relationships between CBF and CMRO2 measurements regionally and globally are not fully established. Here, we investigated the between-subject and regional associations between CBF and CMRO2 measures with independent and quantitative PET techniques. We included resting CBF and CMRO2 measurements from 50 healthy volunteers (aged 22–81yr), and calculated the regional and global values of oxygen delivery (DO2) and oxygen extraction fraction (OEF). Linear mixed-model analysis showed that CBF and CMRO2 measurements were closely associated regionally, but no significant between-subject association could be demonstrated, even when adjusting for arterial PCO2 and hemoglobin concentration. The analysis also showed regional differences of OEF, reflecting variable relationship between DO2 and CMRO2, resulting in lower estimates of OEF in thalami, brainstem, and mesial temporal cortices and higher estimates of OEF in occipital cortex. In the present study, we demonstrated no between-subject association of quantitative measurements of CBF and CMRO2 in healthy subjects. Thus, quantitative measurements of CBF did not reflect the underlying between-subject variability of oxygen metabolism measures, mainly because of large interindividual OEF variability not accounted for by PCO2 and hemoglobin concentration. NEW & NOTEWORTHY Using quantitative PET-measurements in healthy human subjects, we confirmed a regional association of CBF and CMRO2, but did not find an association of these values across subjects. This suggests that subjects have an individual coupling between perfusion and metabolism and shows that absolute perfusion measurements does not serve as a surrogate measure of individual

Evidence suggests that synapses are affected first in Parkinson’s disease (PD). Here, we tested the claim that pathological accumulation of α-synuclein, and subsequent synaptic disruption, occur in absence of dopaminergic neuron loss in PD. We determined early synaptic changes in rats that overexpress human α-synuclein by local injection of viral-vectors in midbrain. We aimed to achieve α-synuclein levels sufficient to induce terminal pathology without significant loss of nigral neurons. We tested synaptic disruption in vivo by analyzing motor defects and binding of a positron emission tomography (PET) radioligand to the vesicular monoamine transporter 2, (VMAT2), [11C]dihydrotetrabenazine (DTBZ). Animals overexpressing α-synuclein had progressive motor impairment and, 12 weeks post-surgery, showed asymmetric in vivo striatal DTBZ binding. The PET images matched ligand binding in post-mortem tissue, and histological markers of dopaminergic integrity. Histology confirmed the absence of nigral cell death with concomitant significant loss of striatal terminals. Progressive aggregation of proteinase-K resistant and Ser129-phosphorylated α-synuclein was observed in dopaminergic terminals, in dystrophic swellings that resembled axonal spheroids and contained mitochondria and vesicular proteins. In conclusion, pathological α-synuclein in nigro-striatal axonal terminals leads to early axonal pathology, synaptic disruption, dysfunction of dopaminergic neurotransmission, motor impairment, and measurable change of VMAT2 in the absence of cell loss.

There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral metabolic rate for glucose (CMRglc) in AD, and GLP-1 may serve to raise transporter numbers. We hypothesized that the GLP-1 analog liraglutide would prevent the decline of CMRglc in AD by raising blood-brain glucose transfer, depending on the duration of disease. We randomized 38 patients with AD to treatment with liraglutide (n = 18) or placebo (n = 20) for 6 months, and determined the blood-brain glucose transfer capacity (Tmax) in the two groups and a healthy age matched control group (n = 6). In both AD groups at baseline, T max estimates correlated inversely with the duration of AD, as did the estimates of CMRglc that in turn were positively correlated with cognition. The GLP-1 analog treatment, compared to placebo, highly significantly raised the T max estimates of cerebral cortex from 0.72 to 1.1 umol/g/min, equal to T max estimates in healthy volunteers. The result is consistent with the claim that GLP-1 analog treatment restores glucose transport at the BBB.

In animal models, the incretin hormone GLP-1 affects Alzheimer's disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMRglc) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [11C]PIB (PIB), CMRglc with [18F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P ≥ 0.38). In placebo treated patients CMRglc declined in all regions, significantly so by the following means in precuneus (P = 0.009, 3.2 μmol/hg/min, 95% CI: 5.45; 0.92), and in parietal (P = 0.04, 2.1 μmol/hg/min, 95% CI: 4.21; 0.081), temporal (P = 0.046, 1.54 μmol/hg/min, 95% CI: 3.05; 0.030), and occipital (P = 0.009, 2.10 μmol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum (P = 0.04, 1.54 μmol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMRglc after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMRglc that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the Aβ load or cognition measures, for which the study was underpowered.

Acute nicotine administration stimulates [14C]deoxyglucose trapping in thalamus and other regions of rat brain, but acute effects of nicotine and smoking on energy metabolism have rarely been investigated in human brain by positron emission tomography (PET). We obtained quantitative PET measurements of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) in 12 smokers who had refrained from smoking overnight, and in a historical group of nonsmokers, testing the prediction that overnight abstinence results in widespread, coupled reductions of CBF and CMRO2. At the end of the abstention period, global grey-matter CBF and CMRO2 were both reduced by 17% relative to nonsmokers. At 15 minutes after renewed smoking, global CBF had increased insignificantly, while global CMRO2 had increased by 11%. Regional analysis showed that CMRO2 had increased in the left putamen and thalamus, and in right posterior cortical regions at this time. At 60 and 105 minutes after smoking resumption, CBF had increased by 8% and CMRO2 had increased by 11-12%. Thus, we find substantial and global impairment of CBF/CMRO2 in abstaining smokers, and acute restoration by resumption of smoking. The reduced CBF and CMRO2 during acute abstention may mediate the cognitive changes described in chronic smokers.

Acute nicotine administration stimulates [14C]deoxyglucose trapping in thalamus and other regions of rat brain, but acute effects of nicotine and smoking on energy metabolism have rarely been investigated in human brain by positron emission tomography (PET). We obtained quantitative PET measurements of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) in 12 smokers who had refrained from smoking overnight, and in a historical group of nonsmokers, testing the prediction that overnight abstinence results in widespread, coupled reductions of CBF and CMRO2. At the end of the abstention period, global grey-matter CBF and CMRO2 were both reduced by 17% relative to nonsmokers. At 15 minutes after renewed smoking, global CBF had increased insignificantly, while global CMRO2 had increased by 11%. Regional analysis showed that CMRO2 had increased in the left putamen and thalamus, and in right posterior cortical regions at this time. At 60 and 105 minutes after smoking resumption, CBF had increased by 8% and CMRO2 had increased by 11–12%. Thus, we find substantial and global impairment of CBF/CMRO2 in abstaining smokers, and acute restoration by resumption of smoking. The reduced CBF and CMRO2 during acute abstention may mediate the cognitive changes described in chronic smokers.

In hyperglycemia, glucagon-like peptide-1 (GLP-1) lowers brain glucose concentration together with increased net blood-brain clearance and brain metabolism, but it is not known whether this effect depends on the prevailing plasma glucose (PG) concentration. In hypoglycemia, glucose depletion potentially impairs brain function. Here, we test the hypothesis that GLP-1 exacerbates the effect of hypoglycemia. To test the hypothesis, we determined glucose transport and consumption rates in seven healthy men in a randomized, double-blinded placebo-controlled cross-over experimental design. The acute effect of GLP-1 on glucose transfer in the brain was measured by positron emission tomography (PET) during a hypoglycemic clamp (3 mM plasma glucose) with (18)F-fluoro-2-deoxy-glucose (FDG) as tracer of glucose. In addition, we jointly analyzed cerebrometabolic effects of GLP-1 from the present hypoglycemia study and our previous hyperglycemia study to estimate the Michaelis-Menten constants of glucose transport and metabolism. The GLP-1 treatment lowered the vascular volume of brain tissue. Loading data from hypo- to hyperglycemia into the Michaelis-Menten equation, we found increased maximum phosphorylation velocity (V max) in the gray matter regions of cerebral cortex, thalamus, and cerebellum, as well as increased blood-brain glucose transport capacity (T max) in gray matter, white matter, cortex, thalamus, and cerebellum. In hypoglycemia, GLP-1 had no effects on net glucose metabolism, brain glucose concentration, or blood-brain glucose transport. Neither hexokinase nor transporter affinities varied significantly with treatment in any region. We conclude that GLP-1 changes blood-brain glucose transfer and brain glucose metabolic rates in a PG concentration-dependent manner. One consequence is that hypoglycemia eliminates these effects of GLP-1 on brain glucose homeostasis.

Rates of cerebral blood flow (CBF) and glucose consumption (CMR(glc)) rise in cerebral cortex during continuous stimulation, while the oxygen-glucose index (OGI) declines as an index of mismatched coupling of oxygen consumption (cerebral metabolic rate of oxygen-CMRO(2)) to CBF and CMR(glc). To test whether the mismatch reflects a specific role of aerobic glycolysis during functional brain activation, we determined CBF and CMRO(2) with positron emission tomography (PET) when 12 healthy volunteers executed finger-to-thumb apposition of the right hand. Movements began 1, 10, or 20¿minutes before administration of the radiotracers. In primary and supplementary motor cortices and cerebellum, CBF had increased at 1¿minute of exercise and remained elevated for the duration of the 20-minute session. In contrast, the CMRO(2) numerically had increased insignificantly in left M1 and supplementary motor area at 1¿minute, but had declined significantly at 10¿minutes, returning to baseline at 20¿minutes. As measures of CMR(glc) are impossible during short-term activations, we used measurements of CBF as indices of CMR(glc). The decline of CMRO(2) at 10¿minutes paralleled a calculated decrease of OGI at this time. The implied generation of lactate in the tissue suggested an important hypothetical role of the metabolite as regulator of CBF during activation.

This study aimed to test the hypothesis that sacral nerve stimulation affects afferent vagal projections to the central nervous system associated with frontal cortex activation in patients with fecal incontinence.