Brain metabolism

3.6.1 Radiopharmaceutical:

• 2-[¹⁸F]fluoro-2-deoxy-D-glucose, also known as:
  • [¹⁸F]fluorodeoxyglucose
  • [¹⁸F]FDG
  • FDG

3.6.2 Uptake mechanism / biology of the tracer

Glucose enters the neuron–astrocyte functional unit where it is phosphorylated by a hexokinase, which is the first pivotal step of that metabolic pathway. Active energy production takes place at the synaptic terminals via the tricarboxylic acid pathway, requiring oxygen and leading to high ATP availability (aerobic glycolysis). For these reasons, glucose metabolism has been shown to be closely coupled to neuronal function. [¹⁸F]FDG is a glucose analogue. Transport into cells is mediated by the glucose transporters (GLUT) expressed on the cell membrane. Once inside the cell, [¹⁸F]FDG is phosphorylated by the enzyme hexokinase and trapped. Glucose and, thus, [¹⁸F]FDG uptake distribution in the brain is mainly driven by basal neuronal activity and represents general neuronal integrity. FDG has thus the unique ability to estimate the local cerebral metabolic rate of glucose consumption (CMRglc), thus providing information on the distribution of neuronal death and synapse dysfunction in vivo. For a tissue unit, reduced [¹⁸F]FDG uptake essentially stands for either a reduction in number of synapses or a reduced synaptic metabolic activity. Although the specific molecular mechanisms of neuronal activity that are coupled to energy metabolism have not been exactly identified, it seems that much of the glucose metabolism measured by PET is coupled to glutamate-driven astrocytic glucose uptake. [¹⁸F]FDG -PET has a very low temporal resolution as radiolabelled glucose brain uptake takes about 20 min. During this time, any condition that affects the “psychosensorial resting” of the subject may significantly alter the results of scan.

3.6.3 Indications

• Mild Cognitive impairment (MCI) and dementia disorders. Early diagnosis and differential diagnosis of dementing disorders, such as Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). There is increasing use of [¹⁸F]FDG PET in the mild cognitive impairment, to help diagnose the underlying neurodegenerative aetiology.
• Parkinsonian Syndromes: differentiation between Parkinson’s disease (PD) and atypical parkinsonian syndromes, such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS/CBD). It is found to be superior to [¹²³I]IBZM SPECT for the differential diagnosis of parkinsonism.
• Epilepsy: interictal acquisition in the preoperative evaluation of adults and children with refractory epilepsy to identify epileptogenic zone (particularly in patients with a non-localising or nonconcordant video-electroencephalography monitoring and MRI result)
• Autoimmune Encephalitis: to support the preliminary clinical diagnosis of probable autoimmune encephalitis especially in case of negative or inconclusive MRI findings. The inclusion of a further whole-body scan in the same session could be considered given the paraneoplastic underlying aetiology of many cases autoimmune encephalitis.

3.6.4 Contra-indications

• There are no absolute contraindications to the administration of [¹⁸F]FDG
• In case of pregnancy, the benefits of undergoing an [¹⁸F]FDG PET scan should be balanced against the potential harm to the foetus. It is not recommended to interrupt breast feeding [3].
• Inability to cooperate or lack of compliance to the procedure.

3.6.5 Clinical performances

Dementia disorders: based on a large body of evidence on its diagnostic sensitivity for the identification of AD, in 2004 FDG PET imaging was approved by the Centers for Medicare and Medicaid Services (CMS, USA) as a routine examination tool for early and differential diagnosis of AD. Despite a huge amount of literature, available studies show very large range of values for Sensitivity and Specificity due to heterogeneity of the included patients (converter/non-converter, inclusion of amnestic or non-amnestic MCI etc.) and to the different methods used to read the images (visual versus semi-quantitative reading with different software). FDG PET has in particular demonstrated impact in patients with mild cognitive impairment or dementia in case of atypical presentation or course. A diagnostic change around 60% of the patients (with increased prescription of cholinesterase inhibitors) has been demonstrated in 94 patients with atypical/unclear MCI or dementia in a memory clinic setting [77]. Finally, for the differential diagnosis between AD and FTLD despite study heterogeneity, several studies demonstrated an accuracy ranging between 87-89.2% (similar to the accuracy obtained by amyloid PET) [78]. Details utility of [¹⁸F]FDG-PET to support the diagnosis of dementing neurodegenerative disorders have been recently provided within the EANM and European Academy of Neurology (EAN) Recommendations for the Use of Brain 18F-fluorodeoxyglucose Positron Emission Tomography in Neurodegenerative Cognitive Impairment and Dementia [79].

Differential Diagnosis of Parkinsonian Syndromes: [¹⁸F]FDG PET was found to be superior to [¹²³I]IBZM SPECT for the differential diagnosis of neurodegenerative parkinsonisms [80]. In seventy-eight patients, the area under the receiver operating characteristic curve for discrimination between atypical parkinonisms (APS) and Lewy body diseases (PD/DBL) was significantly larger for [¹⁸F]FDG -PET (0.94) than for [¹²³I]IBZM SPECT (0.74; p=0.0006). Sensitivity/specificity of FDG PET for diagnosing APS was 86%/91%, respectively. Sensitivity/specificity of [¹⁸F]FDG PET in identifying APS subgroups was 77%/97% for MSA, 74%/95% for PSP, and 75%/92% for CBD.

Epilepsy: It is recommended that paediatric epilepsy specialist units have access to interictal PET (especially in absence of ictal SPECT) [81]. [¹⁸F]FDG PET is considered most valuable for so-called “MRI negative” patients or in cases of nonspecific abnormalities. Co-registration with MRI and semi-quantitative analysis are recommended [82].

Autoimmune Encephalitis (AE): In the criteria for the diagnosis of autoimmune encephalitis published in 2016, a new approach has been proposed for the identification of “possible AE”. This approach is based on features and time-course of clinical presentation and on widely available tools such as MRI, CSF, or EEG [83]. In this position paper, [¹⁸F]FDG -PET was defined as a suitable tool for fulfilling the MRI positivity criterion in patients with limbic AE and, although it was acknowledged as having a potentially greater sensitivity (especially in patients with normal appearing MRI), its inclusion in the flowchart was less clearly defined. Indeed, to ascertain the prognostic value of [¹⁸F]FDG -PET and its role in driving therapy, larger studies are still needed on age-matched, untreated patients with the same Ab status, who undergo imaging at a similar time after the onset of their symptoms. This would enable a systematic correlation between MRI and [¹⁸F]FDG -PET findings and would help to clarify a number of unsolved clinical and technical issues.

3.6.6 Activities to administer

The suggested activities to administer for adults range from 150-250 MBq.

In paediatric nuclear medicine, the activities should be modified according to the EANM paediatric dosage card. The minimum recommended activity is 14 MBq.

3.6.7 Dosimetry

The effective dose per administered activity is 19 µSv/MBq [3]. The range of the effective doses for the suggested activities is: 2.9-4.8 mSv.

Caveat

“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but  it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."

3.6.8 Interpretation criteria/major pitfalls

The images should be carefully checked for:

• movement artefacts
• attenuation artefacts
• misalignment of the head

The physician should be aware of the variations in normal glucose brain metabolism, especially age dependent changes as well as medication related changes.
Preferably use standardized threshold settings and scaling methods to avoid unnecessary variation and for optimal personal reference building.
Additional quantification is recommended. Be aware of the specific limitations of the quantification software being used. The conclusion should never be based upon the quantification results alone.
Dementia disorders: Visual assessment requires a high level of expertise: normal distribution of brain glucose metabolism is not homogeneous across the whole brain and abnormal patterns characteristics of the various neurodegenerative diseases might partially overlap. The abnormalities observed in the most frequent degenerative disorders are listed here:

	AD	DLB	bvFTD	PSP	CBD	MSA-P	MSA-C
Frontal cortex	normal/ low	normal/ low	low	low	asymmetric	normal	normal
Temporal cortex	low	low	normal /low	normal	normal	normal	normal
Parietal	low	low	normal /low	normal /low	asymmetric	normal	normal
Occipital	normal	low	normal	normal	normal	normal	normal
Basal ganglia- thalamus	normal	normal /increased	normal	normal	asymmetric	low	normal
Midbrain	normal	normal	normal	low	normal	normal	normal
Cerebellum	normal	normal	normal	normal	normal	normal	low

The support of automated tools for the assessment of glucose metabolism distribution is important. Different tools exist, all based on a spatial normalization of the individual subject image to a reference database, an intensity normalization to the global counts or to the counts in a reference region (cerebellum or pons, most frequently), and on the evaluation of the deviation of the individual image from the distribution observed in normal subjects. Limited standardization of the relative information provided by different tools and of the various reference databases exists.

Epilepsy: The rapid changes occurring in neuronal activity and thus in glucose metabolism during the ictal state cannot be studied with the [¹⁸F]FDG PET scan as it takes around 30 min for the tracer to be taken up by the brain and reach a steady state. Thus, [¹⁸F]FDG PET is only performed as inter-ictal examination. An inter-ictal [¹⁸F]FDG PET may be particularly useful and more practical when the aim is to define epileptogenic region lateralization. EEG monitoring at the time of the FDG PET scan need to be performed to exclude the presence of clinical or subclinical seizures that may occur during the FDG uptake time, and that need to be taken into account when interpreting the PET findings. The epileptogenic region typically appears as an area of reduced tracer uptake in interictal [¹⁸F]FDG PET/CT. The area of interictal hypometabolism of [¹⁸F]FDG -PET is more often larger than the epileptogenic focus, probably expressing the abnormal function of closer areas involved by the first ictal spread. However, the mechanisms underlying the hypometabolism in epileptogenic cortex have not been clearly elucidated. Regardless of underlying cause of hypometabolism around the epileptogenic region, this evidence suggests that PET cannot be reliably used to precisely determine the surgical margin. Visual analysis is the first step of evaluation of images but coregistration with MRI as well as semiquantitative approaches have demonstrated to potentially increase the sensitivity to the epileptogenic focus. In particular, it has been suggested that the use of voxel-based whole-brain statistical approaches can improve the accuracy of [¹⁸F]FDG-PET in patients with extra-temporal lobe epilepsy.

Autoimmune Encephalitis: Pattern of MTL hypermetabolism has been initially identified as the most frequent finding in patients with AE. However more recent studies on larger samples of patients than the previously published case series and a systematic review of the literature, seem to suggest that hypermetabolism might not be the most common metabolic alteration in AE as hypometabolism can also frequently occur, and both hypo- and hypermetabolism may be apparent beyond the boundaries of the MTL [84]. Moreover, it has been suggested that some specific metabolic patterns correlate with the presence of specific Ab, such as a cerebral posterior hypometabolism in anti-NMDAR encephalitis, and a mesiotemporal hypermetabolism (associated with hyperintensities and swollen structures on MRI T2) in encephalitis with LGI1 and onconeural Ab.

3.6.9 Patient preparation

Patients should fast for at least 4-6 h. Nevertheless, in brain tumours, hyperglycaemia does not need to be corrected.
Drugs that may affect cerebral glucose metabolism should be avoided. They should be discontinued on the day of the PET examination, clinical situation permitting. Diabetic patients should not have their medication altered.

Before scanning:

• Check blood glucose level prior to [¹⁸F]FDG administration.
• Administer [¹⁸F]FDG in a quiet room with diminished lights and preferably at least 10 min after placement of the intravenous access.
• The patient must lie still for at least 30 min after the [¹⁸F]FDG injection, speaking, reading or any other activities are not allowed.
• If sedation is necessary, it should be given at least 30 min after [¹⁸F]FDG injection.
• Continuous monitoring of patients before and during scanning is necessary. For pre- operative evaluation of epilepsy, EEG monitoring is required. This should start prior to [¹⁸F]FDG administration and continue for at least 30 min post injection.
• Patients should void their urinary bladder just before scanning.

3.6.10 Methods

Standard 3D brain acquisition 30-45 min p.i., for a duration of 10-20 min, are recommended. The detailed recommendations regarding the brain [18F]FDG PET study are available in the EANM procedure guidelines for PET brain imaging using [18F]FDG, version 2 [60].